Drug Therapy

From Western Michigan University, Homer Stryker MD School of Medicine, Kalamazoo, MI (Dr. Vaillant and Dr. Kavanaugh), Ferris State University, Grand Rapids, MI (Dr. Mersfelder), and Bronson Methodist Hospital, Kalamazoo, MI (Dr. Maynard).

Abstract

• Background: Procalcitonin has emerged as an important marker of sepsis and lung infections of bacterial origin. The role of procalcitonin in guiding antibiotic stewardship in lower respiratory tract infections and sepsis has been extensively studied, and use of this biomarker has been shown to decrease antibiotic usage in clinical trials. We sought to evaluate the impact of a pharmacist-driven initiative regarding discontinuation of antibiotics utilizing procalcitonin levels at a community teaching hospital.
• Methods: We retrospectively gathered baseline data on adult patients admitted to a community teaching hospital who were 18 years of age and older, under the care of an inpatient service, and had a single procalcitonin level < 0.25 mcg/L obtained during admission. We then prospectively identified an intervention group of similar patients using a web-based, real-time clinical surveillance system. When a low procalcitonin level was identified in the intervention group, the participating clinical pharmacists screened for antibiotic use and the indication(s), determined whether the antibiotic could be discontinued based on the low procalcitonin level and the absence of another indication for antibiotics, and, when appropriate, contacted the patient’s health care provider via telephone to discuss possible antibiotic discontinuation. The total antibiotic treatment duration was compared between the baseline and intervention groups.
• Results: A total of 172 patients were included in this study (86 in each group). The duration of antibiotic use was not significantly different between the baseline (3.14 ± 4.04 days) and the intervention (3.34 ± 2.8 days) groups (P = 0.1083). Other patient demographics did not influence antibiotic duration.
• Conclusion: Our study did not demonstrate a difference in total antibiotic treatment duration with the utilization of procalcitonin and an oral communication intervention made by a clinical pharmacist at a community-based teaching hospital. Outside of clinical trials, and in the absence of an algorithmic approach, procalcitonin has not consistently been shown to aid in the diagnosis and treatment of infectious diseases. It is important to have a comprehensive antimicrobial stewardship program to reduce antibiotic use and effectively use laboratory values.

Keywords: antibiotic use; bacterial infection; biomarkers; procalcitonin.

Procalcitonin is the precursor of the hormone calcitonin, which is normally produced in the parafollicular cells of the thyroid gland under physiological conditions.¹ However, procalcitonin is also released in response to a proinflammatory stimulus, especially that of bacterial origin.¹ The source of the procalcitonin surge seen during proinflammatory states is not the parafollicular cells of the thyroid, but rather the neuroendocrine cells of the lung and intestine.¹ Stimulants of procalcitonin in these scenarios include bacterial endotoxin, tumor necrosis factor, and interleukin-6.^1,2 Due to these observations, procalcitonin has emerged as an important marker of sepsis and lung infections of bacterial origin.³

The role of procalcitonin in guiding antibiotic stewardship in lower respiratory tract infections and sepsis has been extensively studied.^4,5 Various randomized controlled trials have shown that antibiotic stewardship guided by procalcitonin levels resulted in lower rates of antibiotic initiation and shorter duration of antibiotic use.^4-6 Similar results were obtained in prospective studies evaluating its role in patients with chronic obstructive pulmonary disease and sepsis.^7,8 Based on these data, protocol-driven procalcitonin-guided antibiotic stewardship appears beneficial.

Many of these studies employed rigorous protocols. Studies of procalcitonin use in a so-called real-world setting, in which the provider can order and use procalcitonin levels without the use of protocols, are limited. The objective of our study was to evaluate the impact of a pharmacist-driven initiative on discontinuing antibiotics, if indicated, utilizing single procalcitonin measurement results of < 0.25 mcg/L at a community teaching hospital.

Methods

Our study utilized a 2-phase approach. The first phase was a retrospective chart review to establish baseline data regarding adult inpatients with a low procalcitonin level; these patients were randomly selected over a 1-year period (2017). Patients were included if they were 18 years of age or older, under the care of an inpatient service, and had a single procalcitonin level < 0.25 mcg/L obtained during their admission. Patients admitted to the intensive care unit were excluded. In the second phase, we prospectively identified similar patients admitted between January and March 2018 using a web-based, real-time clinical surveillance system. When patients with low procalcitonin levels were identified, 2 participating clinical pharmacists screened for antibiotic use and indication. If it was determined that the antibiotic could be discontinued as a result of the low procalcitonin level and no additional indication for antibiotics was present, the pharmacist contacted the patient’s health care provider via telephone to discuss possible antibiotic discontinuation. Data collected before and after the intervention included total antibiotic treatment duration, white blood cell count, maximum temperature, age, and procalcitonin level.

A sample size of 86 was calculated to provide an alpha of 0.05 and a power of 0.8. A nonparametric Wilcoxon 2-sample test was used to test for a difference in duration of antibiotic treatment between the baseline and intervention groups. A nonparametric test was used due to right-skewed data. All patients were included in the group analysis, regardless of antibiotic use, as the procalcitonin level may have been used in the decision to initiate antibiotics, and this is more representative of a real-world application of the test. This allowed for detection of a significant decrease of 2 days in antibiotic duration post intervention, with a 10% margin to compensate for potential missing data. Data from 86 patients obtained prior to the pharmacist intervention acted as a control comparison group. Statistical analysis was performed using SAS 9.4.

Results

A total of 172 patients were included in this study: 86 patients prior to the intervention, and 86 after implementation. Baseline demographics, laboratory values, vitals, and principal diagnoses for both groups are shown in Table 1 and Table 2. The most common indications for procalcitonin measurement were pneumonia (45.9%), chronic obstructive pulmonary disease (15.7%), and sepsis (14.5%). The remaining diagnoses were encephalopathy, fever and leukocytosis, skin and soft tissue infection, urinary tract infection or pyelonephritis, bone and joint infection, meningitis, intra-abdominal infection, and asthma exacerbation.

Antibiotic therapy was initiated in 68% of the patients overall, 59% in the baseline group and 76% in the intervention group. The duration of antibiotic use was not significantly different between the baseline (3.14 ± 4.04 days) and intervention (3.34 ± 2.8 days) groups (P = 0.1083). Furthermore, antibiotic treatment duration did not vary significantly with patient age, white blood cell count, maximum temperature, or procalcitonin level in either group. Although there was no difference in total antibiotic treatment duration, a post-hoc analysis revealed a 0.6-day decrease in the interval between the date of procalcitonin measurement and the stop date of antibiotics in the intervention group. The average time from admission to obtaining a procalcitonin level was 3 days in the baseline group and 2 days in the intervention group.

Discussion

Our study did not demonstrate a difference in total antibiotic treatment duration with procalcitonin measurement and an oral communication intervention made by a clinical pharmacist at a community teaching hospital with a well-established antimicrobial stewardship program. This may be due to several factors. First, the providers did not receive ongoing education regarding the appropriate use or interpretation of procalcitonin. The procalcitonin result in the electronic health record references the risk for progression to severe sepsis and/or septic shock, but does not indicate how to use procalcitonin as an aid in antibiotic decision-making. However, a recent study in patients with lower respiratory tract infections treated by providers who had been educated on the use of procalcitonin failed to find a reduction in total antibiotic use.⁹ Second, our study included hospital-wide use of procalcitonin, and was not limited to infections for which procalcitonin use has the strongest evidence (eg, upper respiratory tract infections, pneumonia, sepsis). Thus, providers may have been less likely to use protocolized guidelines. Last, we did not limit the data on antibiotic duration to patients with a procalcitonin level obtained within a defined time frame from antibiotic initiation or time of admission, and some patients had procalcitonin levels measured several days into their hospital stay. While this is likely to have skewed the data in favor of longer antibiotic treatment courses, it also represents a more realistic way in which this laboratory test is being used. Our post-hoc finding of earlier discontinuation of antibiotics after procalcitonin measurement suggests that our intervention may have influenced the decision to discontinue antibiotics. Such an effect may be augmented if procalcitonin is measured earlier in a hospital admission.

Previous studies have also failed to show that the use of procalcitonin decreased duration of antibiotics.^9,10 In the aforementioned study regarding real-world outcomes in patients with lower respiratory tract infections, antibiotic duration was not reduced, despite provider education.⁹ A large observational study that evaluated real-world outcomes in intensive care unit patients did not find decreased antibiotic use or improved outcomes with procalcitonin use.¹⁰ With these large studies evaluating the 2 most common infectious diseases for which procalcitonin has previously been found to have clinical benefit, it is important for institutions to re-evaluate how procalcitonin is being utilized by providers. Furthermore, institutions should explore ways to optimize procalcitonin use and decrease unnecessary health care costs. Notably, the current community-acquired pneumonia guidelines recommend against routine use of procalcitonin.¹¹

Conclusion

Outside of clinical trials, and in the absence of an algorithmic approach, procalcitonin has not consistently been shown to aid in the diagnosis or treatment of infectious diseases. It is important to have a comprehensive antimicrobial stewardship program that includes an algorithmic protocol to promote appropriate laboratory testing and reduce total antibiotic use. In addition to improved communication with providers, other interventions need to be investigated to effectively use this biomarker or limit its use.

Acknowledgment: The authors thank the Western Michigan University Department of Epidemiology and Biostatistics for their assistance in preparing this article.

Corresponding author: James Vaillant, MD, Western Michigan University, Homer Stryker MD School of Medicine, 1000 Oakland Drive, Kalamazoo, MI, 49008; [email protected].

Financial disclosures: None.

From Western Michigan University, Homer Stryker MD School of Medicine, Kalamazoo, MI (Dr. Vaillant and Dr. Kavanaugh), Ferris State University, Grand Rapids, MI (Dr. Mersfelder), and Bronson Methodist Hospital, Kalamazoo, MI (Dr. Maynard).

Abstract

• Background: Procalcitonin has emerged as an important marker of sepsis and lung infections of bacterial origin. The role of procalcitonin in guiding antibiotic stewardship in lower respiratory tract infections and sepsis has been extensively studied, and use of this biomarker has been shown to decrease antibiotic usage in clinical trials. We sought to evaluate the impact of a pharmacist-driven initiative regarding discontinuation of antibiotics utilizing procalcitonin levels at a community teaching hospital.
• Methods: We retrospectively gathered baseline data on adult patients admitted to a community teaching hospital who were 18 years of age and older, under the care of an inpatient service, and had a single procalcitonin level < 0.25 mcg/L obtained during admission. We then prospectively identified an intervention group of similar patients using a web-based, real-time clinical surveillance system. When a low procalcitonin level was identified in the intervention group, the participating clinical pharmacists screened for antibiotic use and the indication(s), determined whether the antibiotic could be discontinued based on the low procalcitonin level and the absence of another indication for antibiotics, and, when appropriate, contacted the patient’s health care provider via telephone to discuss possible antibiotic discontinuation. The total antibiotic treatment duration was compared between the baseline and intervention groups.
• Results: A total of 172 patients were included in this study (86 in each group). The duration of antibiotic use was not significantly different between the baseline (3.14 ± 4.04 days) and the intervention (3.34 ± 2.8 days) groups (P = 0.1083). Other patient demographics did not influence antibiotic duration.
• Conclusion: Our study did not demonstrate a difference in total antibiotic treatment duration with the utilization of procalcitonin and an oral communication intervention made by a clinical pharmacist at a community-based teaching hospital. Outside of clinical trials, and in the absence of an algorithmic approach, procalcitonin has not consistently been shown to aid in the diagnosis and treatment of infectious diseases. It is important to have a comprehensive antimicrobial stewardship program to reduce antibiotic use and effectively use laboratory values.

Keywords: antibiotic use; bacterial infection; biomarkers; procalcitonin.

Procalcitonin is the precursor of the hormone calcitonin, which is normally produced in the parafollicular cells of the thyroid gland under physiological conditions.¹ However, procalcitonin is also released in response to a proinflammatory stimulus, especially that of bacterial origin.¹ The source of the procalcitonin surge seen during proinflammatory states is not the parafollicular cells of the thyroid, but rather the neuroendocrine cells of the lung and intestine.¹ Stimulants of procalcitonin in these scenarios include bacterial endotoxin, tumor necrosis factor, and interleukin-6.^1,2 Due to these observations, procalcitonin has emerged as an important marker of sepsis and lung infections of bacterial origin.³

The role of procalcitonin in guiding antibiotic stewardship in lower respiratory tract infections and sepsis has been extensively studied.^4,5 Various randomized controlled trials have shown that antibiotic stewardship guided by procalcitonin levels resulted in lower rates of antibiotic initiation and shorter duration of antibiotic use.^4-6 Similar results were obtained in prospective studies evaluating its role in patients with chronic obstructive pulmonary disease and sepsis.^7,8 Based on these data, protocol-driven procalcitonin-guided antibiotic stewardship appears beneficial.

Many of these studies employed rigorous protocols. Studies of procalcitonin use in a so-called real-world setting, in which the provider can order and use procalcitonin levels without the use of protocols, are limited. The objective of our study was to evaluate the impact of a pharmacist-driven initiative on discontinuing antibiotics, if indicated, utilizing single procalcitonin measurement results of < 0.25 mcg/L at a community teaching hospital.

Methods

Our study utilized a 2-phase approach. The first phase was a retrospective chart review to establish baseline data regarding adult inpatients with a low procalcitonin level; these patients were randomly selected over a 1-year period (2017). Patients were included if they were 18 years of age or older, under the care of an inpatient service, and had a single procalcitonin level < 0.25 mcg/L obtained during their admission. Patients admitted to the intensive care unit were excluded. In the second phase, we prospectively identified similar patients admitted between January and March 2018 using a web-based, real-time clinical surveillance system. When patients with low procalcitonin levels were identified, 2 participating clinical pharmacists screened for antibiotic use and indication. If it was determined that the antibiotic could be discontinued as a result of the low procalcitonin level and no additional indication for antibiotics was present, the pharmacist contacted the patient’s health care provider via telephone to discuss possible antibiotic discontinuation. Data collected before and after the intervention included total antibiotic treatment duration, white blood cell count, maximum temperature, age, and procalcitonin level.

A sample size of 86 was calculated to provide an alpha of 0.05 and a power of 0.8. A nonparametric Wilcoxon 2-sample test was used to test for a difference in duration of antibiotic treatment between the baseline and intervention groups. A nonparametric test was used due to right-skewed data. All patients were included in the group analysis, regardless of antibiotic use, as the procalcitonin level may have been used in the decision to initiate antibiotics, and this is more representative of a real-world application of the test. This allowed for detection of a significant decrease of 2 days in antibiotic duration post intervention, with a 10% margin to compensate for potential missing data. Data from 86 patients obtained prior to the pharmacist intervention acted as a control comparison group. Statistical analysis was performed using SAS 9.4.

Results

A total of 172 patients were included in this study: 86 patients prior to the intervention, and 86 after implementation. Baseline demographics, laboratory values, vitals, and principal diagnoses for both groups are shown in Table 1 and Table 2. The most common indications for procalcitonin measurement were pneumonia (45.9%), chronic obstructive pulmonary disease (15.7%), and sepsis (14.5%). The remaining diagnoses were encephalopathy, fever and leukocytosis, skin and soft tissue infection, urinary tract infection or pyelonephritis, bone and joint infection, meningitis, intra-abdominal infection, and asthma exacerbation.

Antibiotic therapy was initiated in 68% of the patients overall, 59% in the baseline group and 76% in the intervention group. The duration of antibiotic use was not significantly different between the baseline (3.14 ± 4.04 days) and intervention (3.34 ± 2.8 days) groups (P = 0.1083). Furthermore, antibiotic treatment duration did not vary significantly with patient age, white blood cell count, maximum temperature, or procalcitonin level in either group. Although there was no difference in total antibiotic treatment duration, a post-hoc analysis revealed a 0.6-day decrease in the interval between the date of procalcitonin measurement and the stop date of antibiotics in the intervention group. The average time from admission to obtaining a procalcitonin level was 3 days in the baseline group and 2 days in the intervention group.

Discussion

Our study did not demonstrate a difference in total antibiotic treatment duration with procalcitonin measurement and an oral communication intervention made by a clinical pharmacist at a community teaching hospital with a well-established antimicrobial stewardship program. This may be due to several factors. First, the providers did not receive ongoing education regarding the appropriate use or interpretation of procalcitonin. The procalcitonin result in the electronic health record references the risk for progression to severe sepsis and/or septic shock, but does not indicate how to use procalcitonin as an aid in antibiotic decision-making. However, a recent study in patients with lower respiratory tract infections treated by providers who had been educated on the use of procalcitonin failed to find a reduction in total antibiotic use.⁹ Second, our study included hospital-wide use of procalcitonin, and was not limited to infections for which procalcitonin use has the strongest evidence (eg, upper respiratory tract infections, pneumonia, sepsis). Thus, providers may have been less likely to use protocolized guidelines. Last, we did not limit the data on antibiotic duration to patients with a procalcitonin level obtained within a defined time frame from antibiotic initiation or time of admission, and some patients had procalcitonin levels measured several days into their hospital stay. While this is likely to have skewed the data in favor of longer antibiotic treatment courses, it also represents a more realistic way in which this laboratory test is being used. Our post-hoc finding of earlier discontinuation of antibiotics after procalcitonin measurement suggests that our intervention may have influenced the decision to discontinue antibiotics. Such an effect may be augmented if procalcitonin is measured earlier in a hospital admission.

Previous studies have also failed to show that the use of procalcitonin decreased duration of antibiotics.^9,10 In the aforementioned study regarding real-world outcomes in patients with lower respiratory tract infections, antibiotic duration was not reduced, despite provider education.⁹ A large observational study that evaluated real-world outcomes in intensive care unit patients did not find decreased antibiotic use or improved outcomes with procalcitonin use.¹⁰ With these large studies evaluating the 2 most common infectious diseases for which procalcitonin has previously been found to have clinical benefit, it is important for institutions to re-evaluate how procalcitonin is being utilized by providers. Furthermore, institutions should explore ways to optimize procalcitonin use and decrease unnecessary health care costs. Notably, the current community-acquired pneumonia guidelines recommend against routine use of procalcitonin.¹¹

Conclusion

Outside of clinical trials, and in the absence of an algorithmic approach, procalcitonin has not consistently been shown to aid in the diagnosis or treatment of infectious diseases. It is important to have a comprehensive antimicrobial stewardship program that includes an algorithmic protocol to promote appropriate laboratory testing and reduce total antibiotic use. In addition to improved communication with providers, other interventions need to be investigated to effectively use this biomarker or limit its use.

Acknowledgment: The authors thank the Western Michigan University Department of Epidemiology and Biostatistics for their assistance in preparing this article.

Corresponding author: James Vaillant, MD, Western Michigan University, Homer Stryker MD School of Medicine, 1000 Oakland Drive, Kalamazoo, MI, 49008; [email protected].

Financial disclosures: None.

From Western Michigan University, Homer Stryker MD School of Medicine, Kalamazoo, MI (Dr. Vaillant and Dr. Kavanaugh), Ferris State University, Grand Rapids, MI (Dr. Mersfelder), and Bronson Methodist Hospital, Kalamazoo, MI (Dr. Maynard).

Abstract

• Background: Procalcitonin has emerged as an important marker of sepsis and lung infections of bacterial origin. The role of procalcitonin in guiding antibiotic stewardship in lower respiratory tract infections and sepsis has been extensively studied, and use of this biomarker has been shown to decrease antibiotic usage in clinical trials. We sought to evaluate the impact of a pharmacist-driven initiative regarding discontinuation of antibiotics utilizing procalcitonin levels at a community teaching hospital.
• Methods: We retrospectively gathered baseline data on adult patients admitted to a community teaching hospital who were 18 years of age and older, under the care of an inpatient service, and had a single procalcitonin level < 0.25 mcg/L obtained during admission. We then prospectively identified an intervention group of similar patients using a web-based, real-time clinical surveillance system. When a low procalcitonin level was identified in the intervention group, the participating clinical pharmacists screened for antibiotic use and the indication(s), determined whether the antibiotic could be discontinued based on the low procalcitonin level and the absence of another indication for antibiotics, and, when appropriate, contacted the patient’s health care provider via telephone to discuss possible antibiotic discontinuation. The total antibiotic treatment duration was compared between the baseline and intervention groups.
• Results: A total of 172 patients were included in this study (86 in each group). The duration of antibiotic use was not significantly different between the baseline (3.14 ± 4.04 days) and the intervention (3.34 ± 2.8 days) groups (P = 0.1083). Other patient demographics did not influence antibiotic duration.
• Conclusion: Our study did not demonstrate a difference in total antibiotic treatment duration with the utilization of procalcitonin and an oral communication intervention made by a clinical pharmacist at a community-based teaching hospital. Outside of clinical trials, and in the absence of an algorithmic approach, procalcitonin has not consistently been shown to aid in the diagnosis and treatment of infectious diseases. It is important to have a comprehensive antimicrobial stewardship program to reduce antibiotic use and effectively use laboratory values.

Keywords: antibiotic use; bacterial infection; biomarkers; procalcitonin.

Procalcitonin is the precursor of the hormone calcitonin, which is normally produced in the parafollicular cells of the thyroid gland under physiological conditions.¹ However, procalcitonin is also released in response to a proinflammatory stimulus, especially that of bacterial origin.¹ The source of the procalcitonin surge seen during proinflammatory states is not the parafollicular cells of the thyroid, but rather the neuroendocrine cells of the lung and intestine.¹ Stimulants of procalcitonin in these scenarios include bacterial endotoxin, tumor necrosis factor, and interleukin-6.^1,2 Due to these observations, procalcitonin has emerged as an important marker of sepsis and lung infections of bacterial origin.³

The role of procalcitonin in guiding antibiotic stewardship in lower respiratory tract infections and sepsis has been extensively studied.^4,5 Various randomized controlled trials have shown that antibiotic stewardship guided by procalcitonin levels resulted in lower rates of antibiotic initiation and shorter duration of antibiotic use.^4-6 Similar results were obtained in prospective studies evaluating its role in patients with chronic obstructive pulmonary disease and sepsis.^7,8 Based on these data, protocol-driven procalcitonin-guided antibiotic stewardship appears beneficial.

Many of these studies employed rigorous protocols. Studies of procalcitonin use in a so-called real-world setting, in which the provider can order and use procalcitonin levels without the use of protocols, are limited. The objective of our study was to evaluate the impact of a pharmacist-driven initiative on discontinuing antibiotics, if indicated, utilizing single procalcitonin measurement results of < 0.25 mcg/L at a community teaching hospital.

Methods

Our study utilized a 2-phase approach. The first phase was a retrospective chart review to establish baseline data regarding adult inpatients with a low procalcitonin level; these patients were randomly selected over a 1-year period (2017). Patients were included if they were 18 years of age or older, under the care of an inpatient service, and had a single procalcitonin level < 0.25 mcg/L obtained during their admission. Patients admitted to the intensive care unit were excluded. In the second phase, we prospectively identified similar patients admitted between January and March 2018 using a web-based, real-time clinical surveillance system. When patients with low procalcitonin levels were identified, 2 participating clinical pharmacists screened for antibiotic use and indication. If it was determined that the antibiotic could be discontinued as a result of the low procalcitonin level and no additional indication for antibiotics was present, the pharmacist contacted the patient’s health care provider via telephone to discuss possible antibiotic discontinuation. Data collected before and after the intervention included total antibiotic treatment duration, white blood cell count, maximum temperature, age, and procalcitonin level.

A sample size of 86 was calculated to provide an alpha of 0.05 and a power of 0.8. A nonparametric Wilcoxon 2-sample test was used to test for a difference in duration of antibiotic treatment between the baseline and intervention groups. A nonparametric test was used due to right-skewed data. All patients were included in the group analysis, regardless of antibiotic use, as the procalcitonin level may have been used in the decision to initiate antibiotics, and this is more representative of a real-world application of the test. This allowed for detection of a significant decrease of 2 days in antibiotic duration post intervention, with a 10% margin to compensate for potential missing data. Data from 86 patients obtained prior to the pharmacist intervention acted as a control comparison group. Statistical analysis was performed using SAS 9.4.

Results

A total of 172 patients were included in this study: 86 patients prior to the intervention, and 86 after implementation. Baseline demographics, laboratory values, vitals, and principal diagnoses for both groups are shown in Table 1 and Table 2. The most common indications for procalcitonin measurement were pneumonia (45.9%), chronic obstructive pulmonary disease (15.7%), and sepsis (14.5%). The remaining diagnoses were encephalopathy, fever and leukocytosis, skin and soft tissue infection, urinary tract infection or pyelonephritis, bone and joint infection, meningitis, intra-abdominal infection, and asthma exacerbation.

Antibiotic therapy was initiated in 68% of the patients overall, 59% in the baseline group and 76% in the intervention group. The duration of antibiotic use was not significantly different between the baseline (3.14 ± 4.04 days) and intervention (3.34 ± 2.8 days) groups (P = 0.1083). Furthermore, antibiotic treatment duration did not vary significantly with patient age, white blood cell count, maximum temperature, or procalcitonin level in either group. Although there was no difference in total antibiotic treatment duration, a post-hoc analysis revealed a 0.6-day decrease in the interval between the date of procalcitonin measurement and the stop date of antibiotics in the intervention group. The average time from admission to obtaining a procalcitonin level was 3 days in the baseline group and 2 days in the intervention group.

Discussion

Our study did not demonstrate a difference in total antibiotic treatment duration with procalcitonin measurement and an oral communication intervention made by a clinical pharmacist at a community teaching hospital with a well-established antimicrobial stewardship program. This may be due to several factors. First, the providers did not receive ongoing education regarding the appropriate use or interpretation of procalcitonin. The procalcitonin result in the electronic health record references the risk for progression to severe sepsis and/or septic shock, but does not indicate how to use procalcitonin as an aid in antibiotic decision-making. However, a recent study in patients with lower respiratory tract infections treated by providers who had been educated on the use of procalcitonin failed to find a reduction in total antibiotic use.⁹ Second, our study included hospital-wide use of procalcitonin, and was not limited to infections for which procalcitonin use has the strongest evidence (eg, upper respiratory tract infections, pneumonia, sepsis). Thus, providers may have been less likely to use protocolized guidelines. Last, we did not limit the data on antibiotic duration to patients with a procalcitonin level obtained within a defined time frame from antibiotic initiation or time of admission, and some patients had procalcitonin levels measured several days into their hospital stay. While this is likely to have skewed the data in favor of longer antibiotic treatment courses, it also represents a more realistic way in which this laboratory test is being used. Our post-hoc finding of earlier discontinuation of antibiotics after procalcitonin measurement suggests that our intervention may have influenced the decision to discontinue antibiotics. Such an effect may be augmented if procalcitonin is measured earlier in a hospital admission.

Previous studies have also failed to show that the use of procalcitonin decreased duration of antibiotics.^9,10 In the aforementioned study regarding real-world outcomes in patients with lower respiratory tract infections, antibiotic duration was not reduced, despite provider education.⁹ A large observational study that evaluated real-world outcomes in intensive care unit patients did not find decreased antibiotic use or improved outcomes with procalcitonin use.¹⁰ With these large studies evaluating the 2 most common infectious diseases for which procalcitonin has previously been found to have clinical benefit, it is important for institutions to re-evaluate how procalcitonin is being utilized by providers. Furthermore, institutions should explore ways to optimize procalcitonin use and decrease unnecessary health care costs. Notably, the current community-acquired pneumonia guidelines recommend against routine use of procalcitonin.¹¹

Conclusion

Outside of clinical trials, and in the absence of an algorithmic approach, procalcitonin has not consistently been shown to aid in the diagnosis or treatment of infectious diseases. It is important to have a comprehensive antimicrobial stewardship program that includes an algorithmic protocol to promote appropriate laboratory testing and reduce total antibiotic use. In addition to improved communication with providers, other interventions need to be investigated to effectively use this biomarker or limit its use.

Acknowledgment: The authors thank the Western Michigan University Department of Epidemiology and Biostatistics for their assistance in preparing this article.

Corresponding author: James Vaillant, MD, Western Michigan University, Homer Stryker MD School of Medicine, 1000 Oakland Drive, Kalamazoo, MI, 49008; [email protected].

Financial disclosures: None.

Study Overview

Objective. To assess the efficacy, safety, and clinical benefit of remdesivir in hospitalized adults with confirmed pneumonia due to severe SARS-CoV-2 infection.

Design. Randomized, investigator-initiated, placebo-controlled, double-blind, multicenter trial.

Setting and participants. The trial took place between February 6, 2020 and March 12, 2020, at 10 hospitals in Wuhan, China. Study participants included adult patients (aged ≥ 18 years) admitted to hospital who tested positive for SARS-CoV-2 by reverse transcription polymerase chain reaction assay and had the following clinical characteristics: radiographic evidence of pneumonia; hypoxia with oxygen saturation ≤ 94% on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen ≤ 300 mm Hg; and symptom onset to enrollment ≤ 12 days. Some of the exclusion criteria for participation in the study were pregnancy or breast feeding, liver cirrhosis, abnormal liver enzymes ≥ 5 times the upper limit of normal, severe renal impairment or receipt of renal replacement therapy, plan for transfer to a non-study hospital, and enrollment in a trial for COVID-19 within the previous month.

Intervention. Participants were randomized in a 2:1 ratio to the remdesivir group or the placebo group and were administered either intravenous infusions of remdesivir (200 mg on day 1 followed by 100 mg daily on days 2-10) or the same volume of placebo for 10 days. Clinical and safety data assessed included laboratory testing, electrocardiogram, and medication adverse effects. Testing of oropharyngeal and nasopharyngeal swab samples, anal swab samples, sputum, and stool was performed for viral RNA detection and quantification on days 1, 3, 5, 7, 10, 14, 21, and 28.

Main outcome measures. The primary endpoint of this study was time to clinical improvement within 28 days after randomization. Clinical improvement was defined as a 2-point reduction in participants’ admission status on a 6-point ordinal scale (1 = discharged or clinical recovery, 6 = death) or live discharge from hospital, whichever came first. Secondary outcomes included all-cause mortality at day 28 and duration of hospital admission, oxygen support, and invasive mechanical ventilation. Virological measures and safety outcomes ascertained included treatment-emergent adverse events, serious adverse events, and premature discontinuation of remdesivir.

The sample size estimate for the original study design was a total of 453 patients (302 in the remdesivir group and 151 in the placebo group). This sample size would provide 80% power, assuming a hazard ratio (HR) of 1.4 comparing remdesivir to placebo, and corresponding to a change in time to clinical improvement of 6 days. The analysis of primary outcome was performed on an intention-to-treat basis. Time to clinical improvement within 28 days was assessed with Kaplan-Meier plots.

Main results. A total of 255 patients were screened, of whom 237 were enrolled and randomized to remdesivir (158) or placebo (79) group. Of the participants in the remdesivir group, 155 started study treatment and 150 completed treatment per protocol. For the participants in the placebo group, 78 started study treatment and 76 completed treatment per-protocol. Study enrollment was terminated after March 12, 2020, before attaining the prespecified sample size, because no additional patients met study eligibility criteria due to various public health measures implemented in Wuhan. The median age of participants was 65 years (IQR, 56-71), the majority were men (56% in remdesivir group vs 65% in placebo group), and the most common comorbidities included hypertension, diabetes, and coronary artery disease. Median time from symptom onset to study enrollment was 10 days (IQR, 9-12). The time to clinical improvement between treatments (21 days for remdesivir group vs 23 days for placebo group) was not significantly different (HR, 1.23; 95% confidence interval [CI], 0.87-1.75). In addition, in participants who received treatment within 10 days of symptom onset, those who were administered remdesivir had a nonsignificant (HR, 1.52; 95% CI, 0.95-2.43) but faster time (18 days) to clinical improvement, compared to those administered placebo (23 days). Moreover, treatment with remdesivir versus placebo did not lead to differences in secondary outcomes (eg, 28-day mortality and duration of hospital stay, oxygen support, and invasive mechanical ventilation), changes in viral load over time, or adverse events between the groups.

Conclusion. This study found that, compared with placebo, intravenous remdesivir did not significantly improve the time to clinical improvement, mortality, or time to clearance of SARS-CoV-2 in hospitalized adults with severe COVID-19. A numeric reduction in time to clinical improvement with early remdesivir treatment (ie, within 10 days of symptom onset) that approached statistical significance was observed in this underpowered study.

Commentary

Within a few short months since its emergence. SARS-CoV-2 infection has caused a global pandemic, posing a dire threat to public health due to its adverse effects on morbidity (eg, respiratory failure, thromboembolic diseases, multiorgan failure) and mortality. To date, no pharmacologic treatment has been shown to effectively improve clinical outcomes in patients with COVID-19. Multiple ongoing clinical trials are being conducted globally to determine potential therapeutic treatments for severe COVID-19. The first clinical trials of hydroxychloroquine and lopinavir-ritonavir, agents traditionally used for other indications, such as malaria and HIV, did not show a clear benefit in COVID-19.^1,2 Remdesivir, a nucleoside analogue prodrug, is a broad-spectrum antiviral agent that was previously used for treatment of Ebola and has been shown to have inhibitory effects on pathogenic coronaviruses. The study reported by Wang and colleagues was the first randomized controlled trial (RCT) aimed at evaluating whether remdesivir improves outcomes in patients with severe COVID-19. Thus, the worsening COVID-19 pandemic, coupled with the absence of a curative treatment, underscore the urgency of this trial.

The study was grounded on observational data from several recent case reports and case series centering on the potential efficacy of remdesivir in treating COVID-19.³ The study itself was designed well (ie, randomized, placebo-controlled, double-blind, multicenter) and carefully implemented (ie, high protocol adherence to treatments, no loss to follow-up). The principal limitation of this study was its inability to reach the estimated statistical power of study. Due to successful epidemic control in Wuhan, which led to marked reductions in hospital admission of patients with COVID-19, and implementation of stringent termination criteria per the study protocol, only 237 participants were enrolled, instead of the 453, as specified by the sample estimate. This corresponded to a reduction of statistical power from 80% to 58%. Due to this limitation, the study was underpowered, rendering its findings inconclusive.

Despite this limitation, the study found that those treated with remdesivir within 10 days of symptom onset had a numerically faster time (although not statistically significant) to clinical improvement. This leads to an interesting question: whether remdesivir administration early in COVID-19 course could improve clinical outcomes, a question that warrants further investigation by an adequately powered trial. Also, data from this study provided evidence that intravenous remdesivir administration is likely safe in adults during the treatment period, although the long-term drug effects, as well as the safety profile in pediatric patients, remain unknown at this time.

While the study reported by Wang and colleagues was underpowered and is thus inconclusive, several other ongoing RCTs are evaluating the potential clinical benefit of remdesivir treatment in patients hospitalized with COVID-19. On the date of online publication of this report in The Lancet, the National Institutes of Health (NIH) published a news release summarizing preliminary findings from the Adaptive COVID-19 Treatment Trial (ACTT), which showed positive effects of remdesivir on clinical recovery from advanced COVID-19.⁴ The ACTT, the first RCT launched in the United States to evaluate experimental treatment for COVID-19, included 1063 hospitalized participants with advanced COVID-19 and lung involvement. Participants who were administered remdesivir had a 31% faster time to recovery compared to those in the placebo group (median time to recovery, 11 days vs 15 days, respectively; P < 0.001), and had near statistically significant improved survival (mortality rate, 8.0% vs 11.6%, respectively; P = 0.059). In response to these findings, the US Food and Drug Administration (FDA) issued an emergency use authorization for remdesivir on May 1, 2020, for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.⁵ While the findings noted from the NIH news release are very encouraging and provide the first evidence of a potentially beneficial antiviral treatment for severe COVID-19 in humans, the scientific community awaits the peer-reviewed publication of the ACTT to better assess the safety and effectiveness of remdesivir therapy and determine the trial’s implications in the management of COVID-19.

The discovery of an effective pharmacologic intervention for COVID-19 is of utmost urgency. While the present study was unable to answer the question of whether remdesivir is effective in improving clinical outcomes in patients with severe COVID-19, other ongoing or completed (ie, ACTT) studies will likely address this knowledge gap in the coming months. The FDA’s emergency use authorization for remdesivir provides a glimpse into this possibility.

–Katerina Oikonomou, MD, Brookdale Department of Geriatrics & Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY

–Fred Ko, MD

Study Overview

Objective. To assess the efficacy, safety, and clinical benefit of remdesivir in hospitalized adults with confirmed pneumonia due to severe SARS-CoV-2 infection.

Design. Randomized, investigator-initiated, placebo-controlled, double-blind, multicenter trial.

Setting and participants. The trial took place between February 6, 2020 and March 12, 2020, at 10 hospitals in Wuhan, China. Study participants included adult patients (aged ≥ 18 years) admitted to hospital who tested positive for SARS-CoV-2 by reverse transcription polymerase chain reaction assay and had the following clinical characteristics: radiographic evidence of pneumonia; hypoxia with oxygen saturation ≤ 94% on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen ≤ 300 mm Hg; and symptom onset to enrollment ≤ 12 days. Some of the exclusion criteria for participation in the study were pregnancy or breast feeding, liver cirrhosis, abnormal liver enzymes ≥ 5 times the upper limit of normal, severe renal impairment or receipt of renal replacement therapy, plan for transfer to a non-study hospital, and enrollment in a trial for COVID-19 within the previous month.

Intervention. Participants were randomized in a 2:1 ratio to the remdesivir group or the placebo group and were administered either intravenous infusions of remdesivir (200 mg on day 1 followed by 100 mg daily on days 2-10) or the same volume of placebo for 10 days. Clinical and safety data assessed included laboratory testing, electrocardiogram, and medication adverse effects. Testing of oropharyngeal and nasopharyngeal swab samples, anal swab samples, sputum, and stool was performed for viral RNA detection and quantification on days 1, 3, 5, 7, 10, 14, 21, and 28.

Main outcome measures. The primary endpoint of this study was time to clinical improvement within 28 days after randomization. Clinical improvement was defined as a 2-point reduction in participants’ admission status on a 6-point ordinal scale (1 = discharged or clinical recovery, 6 = death) or live discharge from hospital, whichever came first. Secondary outcomes included all-cause mortality at day 28 and duration of hospital admission, oxygen support, and invasive mechanical ventilation. Virological measures and safety outcomes ascertained included treatment-emergent adverse events, serious adverse events, and premature discontinuation of remdesivir.

The sample size estimate for the original study design was a total of 453 patients (302 in the remdesivir group and 151 in the placebo group). This sample size would provide 80% power, assuming a hazard ratio (HR) of 1.4 comparing remdesivir to placebo, and corresponding to a change in time to clinical improvement of 6 days. The analysis of primary outcome was performed on an intention-to-treat basis. Time to clinical improvement within 28 days was assessed with Kaplan-Meier plots.

Main results. A total of 255 patients were screened, of whom 237 were enrolled and randomized to remdesivir (158) or placebo (79) group. Of the participants in the remdesivir group, 155 started study treatment and 150 completed treatment per protocol. For the participants in the placebo group, 78 started study treatment and 76 completed treatment per-protocol. Study enrollment was terminated after March 12, 2020, before attaining the prespecified sample size, because no additional patients met study eligibility criteria due to various public health measures implemented in Wuhan. The median age of participants was 65 years (IQR, 56-71), the majority were men (56% in remdesivir group vs 65% in placebo group), and the most common comorbidities included hypertension, diabetes, and coronary artery disease. Median time from symptom onset to study enrollment was 10 days (IQR, 9-12). The time to clinical improvement between treatments (21 days for remdesivir group vs 23 days for placebo group) was not significantly different (HR, 1.23; 95% confidence interval [CI], 0.87-1.75). In addition, in participants who received treatment within 10 days of symptom onset, those who were administered remdesivir had a nonsignificant (HR, 1.52; 95% CI, 0.95-2.43) but faster time (18 days) to clinical improvement, compared to those administered placebo (23 days). Moreover, treatment with remdesivir versus placebo did not lead to differences in secondary outcomes (eg, 28-day mortality and duration of hospital stay, oxygen support, and invasive mechanical ventilation), changes in viral load over time, or adverse events between the groups.

Conclusion. This study found that, compared with placebo, intravenous remdesivir did not significantly improve the time to clinical improvement, mortality, or time to clearance of SARS-CoV-2 in hospitalized adults with severe COVID-19. A numeric reduction in time to clinical improvement with early remdesivir treatment (ie, within 10 days of symptom onset) that approached statistical significance was observed in this underpowered study.

Commentary

Within a few short months since its emergence. SARS-CoV-2 infection has caused a global pandemic, posing a dire threat to public health due to its adverse effects on morbidity (eg, respiratory failure, thromboembolic diseases, multiorgan failure) and mortality. To date, no pharmacologic treatment has been shown to effectively improve clinical outcomes in patients with COVID-19. Multiple ongoing clinical trials are being conducted globally to determine potential therapeutic treatments for severe COVID-19. The first clinical trials of hydroxychloroquine and lopinavir-ritonavir, agents traditionally used for other indications, such as malaria and HIV, did not show a clear benefit in COVID-19.^1,2 Remdesivir, a nucleoside analogue prodrug, is a broad-spectrum antiviral agent that was previously used for treatment of Ebola and has been shown to have inhibitory effects on pathogenic coronaviruses. The study reported by Wang and colleagues was the first randomized controlled trial (RCT) aimed at evaluating whether remdesivir improves outcomes in patients with severe COVID-19. Thus, the worsening COVID-19 pandemic, coupled with the absence of a curative treatment, underscore the urgency of this trial.

The study was grounded on observational data from several recent case reports and case series centering on the potential efficacy of remdesivir in treating COVID-19.³ The study itself was designed well (ie, randomized, placebo-controlled, double-blind, multicenter) and carefully implemented (ie, high protocol adherence to treatments, no loss to follow-up). The principal limitation of this study was its inability to reach the estimated statistical power of study. Due to successful epidemic control in Wuhan, which led to marked reductions in hospital admission of patients with COVID-19, and implementation of stringent termination criteria per the study protocol, only 237 participants were enrolled, instead of the 453, as specified by the sample estimate. This corresponded to a reduction of statistical power from 80% to 58%. Due to this limitation, the study was underpowered, rendering its findings inconclusive.

Despite this limitation, the study found that those treated with remdesivir within 10 days of symptom onset had a numerically faster time (although not statistically significant) to clinical improvement. This leads to an interesting question: whether remdesivir administration early in COVID-19 course could improve clinical outcomes, a question that warrants further investigation by an adequately powered trial. Also, data from this study provided evidence that intravenous remdesivir administration is likely safe in adults during the treatment period, although the long-term drug effects, as well as the safety profile in pediatric patients, remain unknown at this time.

While the study reported by Wang and colleagues was underpowered and is thus inconclusive, several other ongoing RCTs are evaluating the potential clinical benefit of remdesivir treatment in patients hospitalized with COVID-19. On the date of online publication of this report in The Lancet, the National Institutes of Health (NIH) published a news release summarizing preliminary findings from the Adaptive COVID-19 Treatment Trial (ACTT), which showed positive effects of remdesivir on clinical recovery from advanced COVID-19.⁴ The ACTT, the first RCT launched in the United States to evaluate experimental treatment for COVID-19, included 1063 hospitalized participants with advanced COVID-19 and lung involvement. Participants who were administered remdesivir had a 31% faster time to recovery compared to those in the placebo group (median time to recovery, 11 days vs 15 days, respectively; P < 0.001), and had near statistically significant improved survival (mortality rate, 8.0% vs 11.6%, respectively; P = 0.059). In response to these findings, the US Food and Drug Administration (FDA) issued an emergency use authorization for remdesivir on May 1, 2020, for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.⁵ While the findings noted from the NIH news release are very encouraging and provide the first evidence of a potentially beneficial antiviral treatment for severe COVID-19 in humans, the scientific community awaits the peer-reviewed publication of the ACTT to better assess the safety and effectiveness of remdesivir therapy and determine the trial’s implications in the management of COVID-19.

The discovery of an effective pharmacologic intervention for COVID-19 is of utmost urgency. While the present study was unable to answer the question of whether remdesivir is effective in improving clinical outcomes in patients with severe COVID-19, other ongoing or completed (ie, ACTT) studies will likely address this knowledge gap in the coming months. The FDA’s emergency use authorization for remdesivir provides a glimpse into this possibility.

–Katerina Oikonomou, MD, Brookdale Department of Geriatrics & Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY

–Fred Ko, MD

Study Overview

Objective. To assess the efficacy, safety, and clinical benefit of remdesivir in hospitalized adults with confirmed pneumonia due to severe SARS-CoV-2 infection.

Design. Randomized, investigator-initiated, placebo-controlled, double-blind, multicenter trial.

Setting and participants. The trial took place between February 6, 2020 and March 12, 2020, at 10 hospitals in Wuhan, China. Study participants included adult patients (aged ≥ 18 years) admitted to hospital who tested positive for SARS-CoV-2 by reverse transcription polymerase chain reaction assay and had the following clinical characteristics: radiographic evidence of pneumonia; hypoxia with oxygen saturation ≤ 94% on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen ≤ 300 mm Hg; and symptom onset to enrollment ≤ 12 days. Some of the exclusion criteria for participation in the study were pregnancy or breast feeding, liver cirrhosis, abnormal liver enzymes ≥ 5 times the upper limit of normal, severe renal impairment or receipt of renal replacement therapy, plan for transfer to a non-study hospital, and enrollment in a trial for COVID-19 within the previous month.

Intervention. Participants were randomized in a 2:1 ratio to the remdesivir group or the placebo group and were administered either intravenous infusions of remdesivir (200 mg on day 1 followed by 100 mg daily on days 2-10) or the same volume of placebo for 10 days. Clinical and safety data assessed included laboratory testing, electrocardiogram, and medication adverse effects. Testing of oropharyngeal and nasopharyngeal swab samples, anal swab samples, sputum, and stool was performed for viral RNA detection and quantification on days 1, 3, 5, 7, 10, 14, 21, and 28.

Main outcome measures. The primary endpoint of this study was time to clinical improvement within 28 days after randomization. Clinical improvement was defined as a 2-point reduction in participants’ admission status on a 6-point ordinal scale (1 = discharged or clinical recovery, 6 = death) or live discharge from hospital, whichever came first. Secondary outcomes included all-cause mortality at day 28 and duration of hospital admission, oxygen support, and invasive mechanical ventilation. Virological measures and safety outcomes ascertained included treatment-emergent adverse events, serious adverse events, and premature discontinuation of remdesivir.

The sample size estimate for the original study design was a total of 453 patients (302 in the remdesivir group and 151 in the placebo group). This sample size would provide 80% power, assuming a hazard ratio (HR) of 1.4 comparing remdesivir to placebo, and corresponding to a change in time to clinical improvement of 6 days. The analysis of primary outcome was performed on an intention-to-treat basis. Time to clinical improvement within 28 days was assessed with Kaplan-Meier plots.

Main results. A total of 255 patients were screened, of whom 237 were enrolled and randomized to remdesivir (158) or placebo (79) group. Of the participants in the remdesivir group, 155 started study treatment and 150 completed treatment per protocol. For the participants in the placebo group, 78 started study treatment and 76 completed treatment per-protocol. Study enrollment was terminated after March 12, 2020, before attaining the prespecified sample size, because no additional patients met study eligibility criteria due to various public health measures implemented in Wuhan. The median age of participants was 65 years (IQR, 56-71), the majority were men (56% in remdesivir group vs 65% in placebo group), and the most common comorbidities included hypertension, diabetes, and coronary artery disease. Median time from symptom onset to study enrollment was 10 days (IQR, 9-12). The time to clinical improvement between treatments (21 days for remdesivir group vs 23 days for placebo group) was not significantly different (HR, 1.23; 95% confidence interval [CI], 0.87-1.75). In addition, in participants who received treatment within 10 days of symptom onset, those who were administered remdesivir had a nonsignificant (HR, 1.52; 95% CI, 0.95-2.43) but faster time (18 days) to clinical improvement, compared to those administered placebo (23 days). Moreover, treatment with remdesivir versus placebo did not lead to differences in secondary outcomes (eg, 28-day mortality and duration of hospital stay, oxygen support, and invasive mechanical ventilation), changes in viral load over time, or adverse events between the groups.

Conclusion. This study found that, compared with placebo, intravenous remdesivir did not significantly improve the time to clinical improvement, mortality, or time to clearance of SARS-CoV-2 in hospitalized adults with severe COVID-19. A numeric reduction in time to clinical improvement with early remdesivir treatment (ie, within 10 days of symptom onset) that approached statistical significance was observed in this underpowered study.

Commentary

Within a few short months since its emergence. SARS-CoV-2 infection has caused a global pandemic, posing a dire threat to public health due to its adverse effects on morbidity (eg, respiratory failure, thromboembolic diseases, multiorgan failure) and mortality. To date, no pharmacologic treatment has been shown to effectively improve clinical outcomes in patients with COVID-19. Multiple ongoing clinical trials are being conducted globally to determine potential therapeutic treatments for severe COVID-19. The first clinical trials of hydroxychloroquine and lopinavir-ritonavir, agents traditionally used for other indications, such as malaria and HIV, did not show a clear benefit in COVID-19.^1,2 Remdesivir, a nucleoside analogue prodrug, is a broad-spectrum antiviral agent that was previously used for treatment of Ebola and has been shown to have inhibitory effects on pathogenic coronaviruses. The study reported by Wang and colleagues was the first randomized controlled trial (RCT) aimed at evaluating whether remdesivir improves outcomes in patients with severe COVID-19. Thus, the worsening COVID-19 pandemic, coupled with the absence of a curative treatment, underscore the urgency of this trial.

The study was grounded on observational data from several recent case reports and case series centering on the potential efficacy of remdesivir in treating COVID-19.³ The study itself was designed well (ie, randomized, placebo-controlled, double-blind, multicenter) and carefully implemented (ie, high protocol adherence to treatments, no loss to follow-up). The principal limitation of this study was its inability to reach the estimated statistical power of study. Due to successful epidemic control in Wuhan, which led to marked reductions in hospital admission of patients with COVID-19, and implementation of stringent termination criteria per the study protocol, only 237 participants were enrolled, instead of the 453, as specified by the sample estimate. This corresponded to a reduction of statistical power from 80% to 58%. Due to this limitation, the study was underpowered, rendering its findings inconclusive.

Despite this limitation, the study found that those treated with remdesivir within 10 days of symptom onset had a numerically faster time (although not statistically significant) to clinical improvement. This leads to an interesting question: whether remdesivir administration early in COVID-19 course could improve clinical outcomes, a question that warrants further investigation by an adequately powered trial. Also, data from this study provided evidence that intravenous remdesivir administration is likely safe in adults during the treatment period, although the long-term drug effects, as well as the safety profile in pediatric patients, remain unknown at this time.

While the study reported by Wang and colleagues was underpowered and is thus inconclusive, several other ongoing RCTs are evaluating the potential clinical benefit of remdesivir treatment in patients hospitalized with COVID-19. On the date of online publication of this report in The Lancet, the National Institutes of Health (NIH) published a news release summarizing preliminary findings from the Adaptive COVID-19 Treatment Trial (ACTT), which showed positive effects of remdesivir on clinical recovery from advanced COVID-19.⁴ The ACTT, the first RCT launched in the United States to evaluate experimental treatment for COVID-19, included 1063 hospitalized participants with advanced COVID-19 and lung involvement. Participants who were administered remdesivir had a 31% faster time to recovery compared to those in the placebo group (median time to recovery, 11 days vs 15 days, respectively; P < 0.001), and had near statistically significant improved survival (mortality rate, 8.0% vs 11.6%, respectively; P = 0.059). In response to these findings, the US Food and Drug Administration (FDA) issued an emergency use authorization for remdesivir on May 1, 2020, for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.⁵ While the findings noted from the NIH news release are very encouraging and provide the first evidence of a potentially beneficial antiviral treatment for severe COVID-19 in humans, the scientific community awaits the peer-reviewed publication of the ACTT to better assess the safety and effectiveness of remdesivir therapy and determine the trial’s implications in the management of COVID-19.

The discovery of an effective pharmacologic intervention for COVID-19 is of utmost urgency. While the present study was unable to answer the question of whether remdesivir is effective in improving clinical outcomes in patients with severe COVID-19, other ongoing or completed (ie, ACTT) studies will likely address this knowledge gap in the coming months. The FDA’s emergency use authorization for remdesivir provides a glimpse into this possibility.

–Katerina Oikonomou, MD, Brookdale Department of Geriatrics & Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY

–Fred Ko, MD

Ustekinumab or a tumor necrosis factor inhibitor (TNFi) are better used alone than with methotrexate in the treatment of psoriatic arthritis suggest the results of PsABio (A Study on Assessment of STELARA and Tumor Necrosis Factor Alpha Inhibitor Therapies in Participants With Psoriatic Arthritis), a large, ongoing, prospective observational study.

The percentages of patients achieving multiple psoriatic arthritis disease activity outcome measures at 6 months were higher if biologic monotherapy was used rather than a biologic in combination with methotrexate.

For example, minimal disease activity (MDA) was achieved by 27.5% of patients taking ustekinumab as monotherapy and by 32.1% of those taking a TNFi alone. When methotrexate was used in combination, the respective percentages of patients achieving MDA were 23.7% and 27.8%.

A similar pattern was seen for very-low disease activity (VLDA), with 9.8% of patients in the ustekinumab monotherapy arm and 12% of those in the TNFi monotherapy arm achieving this target, compared with 5.7% and 5.4% when these drugs were combined with methotrexate.

MDA is defined as meeting five or more cutoffs for seven domains of disease activity, and VLDA for all seven: 0-1 tender joints, 0-1 swollen joints, Psoriasis Area Severity Index 1 or less or body surface area involved 3% or less, 0-1 tender entheseal points, Health Assessment Questionnaire score of 0.5 or less, patient global disease activity visual analog scale score of 20 or lower, and patient pain visual analog scale score of 15 or lower.

Other outcome measures used that showed no advantage of adding methotrexate to these biologics were the Clinical Disease Activity in Psoriatic Arthritis low disease activity and remission scores, the patient acceptable symptoms rate of the 12-item Psoriatic Arthritis Impact of Disease Questionnaire, and improvement in skin involvement.

“Patients were no more likely to achieve lower disease activity or a remission target having received methotrexate than they did just on the biologic drug on its own,” Stefan Siebert, MBBCh, PhD, one of the PsABio investigators, said in an interview.

Dr. Siebert, who is clinical senior lecturer in inflammation and rheumatology at the University of Glasgow (Scotland), was scheduled to present the findings at the British Society for Rheumatology annual conference. The meeting was canceled because of the ongoing COVID-19 crisis. Abstracts and ePosters from the meeting have since been released in a supplement to Rheumatology and via the BSR’s conference app.
 

First data for ustekinumab

“There certainly doesn’t appear to be any added benefit from using methotrexate on a group level in patients getting ustekinumab and TNF inhibitors,” Dr. Siebert said. “We’ve looked at everything,” he emphasized, and “none of the single domains or composite measures were improved by the addition of methotrexate. I think we knew that for TNF inhibitors, but the key thing is we’ve never known that for ustekinumab, and this is the first study to show that.”

Indeed, the findings match up with those from the SEAM-PsA (Etanercept and Methotrexate in Subjects with Psoriatic Arthritis) study in which patients who were treated with the TNFi etanercept as monotherapy did much better than those given the TNFi in combination with methotrexate or methotrexate alone. While not a randomized trial, PsABio now shows that the same is true for ustekinumab.

Obviously, there are some clear differences between a clinical trial and an observational study such as PsABio. For one thing, there was no randomization and patients taking methotrexate were presumably doing so for good reason, Dr. Siebert said. Secondly, there was no methotrexate-only arm.

PsABio recruited patients who were starting treatment with either ustekinumab or a new TNFi as first-, second-, or third-line biologic disease-modifying antirheumatic therapy (DMARD). “These are all people starting on a biologic, so they’ve already got severe disease and have failed methotrexate on some level. So everything we’ve done is biologic without methotrexate or biologic with methotrexate,” Dr. Siebert explained. Patients may not have been taking methotrexate for a variety of reasons, such as inefficacy or side effects, so PsABio “doesn’t tell us anything about methotrexate on its own.”

Time to rethink ingrained methotrexate use

The rationale for using methotrexate in combination with biologics in psoriatic arthritis comes from its long-standing use in rheumatoid arthritis. Much of what is advocated in guidelines comes from experience in RA, Dr. Siebert said.

“In rheumatoid arthritis, we know that the TNF inhibitors work much better if you use methotrexate, that’s a given,” he noted. “We’ve been trained that you have to have methotrexate to have a biologic. However, PsABio, together with other studies, show that you don’t have to, and you should have a good reason to add methotrexate.”

Individual patients may still benefit from methotrexate use, but the decision to treat all patients the same is not supported by the current evidence. “It’s good that it shows that, actually, once you get someone on a decent biologic, it’s working: It’s doing what it ‘says on the tin’ for a lot of patients. I really think that is the key message, here, that you don’t have to; this reassures clinicians and actually makes them think ‘should this patient be on methotrexate?’ ” Dr. Siebert said.

The PsABio study was funded by Janssen. Dr. Siebert has acted as a consultant to and received research funding from Janssen, UCB, Pfizer, Boehringer Ingelheim, Novartis, and Celgene. He has also acted as a consultant for AbbVie and received research support from Bristol-Myers Squibb.

SOURCE: Siebert S et al. Rheumatology. 2020;59(Suppl 2). doi: 10.1093/rheumatology/keaa110.023, Abstract O24.

Ustekinumab or a tumor necrosis factor inhibitor (TNFi) are better used alone than with methotrexate in the treatment of psoriatic arthritis suggest the results of PsABio (A Study on Assessment of STELARA and Tumor Necrosis Factor Alpha Inhibitor Therapies in Participants With Psoriatic Arthritis), a large, ongoing, prospective observational study.

The percentages of patients achieving multiple psoriatic arthritis disease activity outcome measures at 6 months were higher if biologic monotherapy was used rather than a biologic in combination with methotrexate.

For example, minimal disease activity (MDA) was achieved by 27.5% of patients taking ustekinumab as monotherapy and by 32.1% of those taking a TNFi alone. When methotrexate was used in combination, the respective percentages of patients achieving MDA were 23.7% and 27.8%.

A similar pattern was seen for very-low disease activity (VLDA), with 9.8% of patients in the ustekinumab monotherapy arm and 12% of those in the TNFi monotherapy arm achieving this target, compared with 5.7% and 5.4% when these drugs were combined with methotrexate.

MDA is defined as meeting five or more cutoffs for seven domains of disease activity, and VLDA for all seven: 0-1 tender joints, 0-1 swollen joints, Psoriasis Area Severity Index 1 or less or body surface area involved 3% or less, 0-1 tender entheseal points, Health Assessment Questionnaire score of 0.5 or less, patient global disease activity visual analog scale score of 20 or lower, and patient pain visual analog scale score of 15 or lower.

Other outcome measures used that showed no advantage of adding methotrexate to these biologics were the Clinical Disease Activity in Psoriatic Arthritis low disease activity and remission scores, the patient acceptable symptoms rate of the 12-item Psoriatic Arthritis Impact of Disease Questionnaire, and improvement in skin involvement.

“Patients were no more likely to achieve lower disease activity or a remission target having received methotrexate than they did just on the biologic drug on its own,” Stefan Siebert, MBBCh, PhD, one of the PsABio investigators, said in an interview.

Dr. Siebert, who is clinical senior lecturer in inflammation and rheumatology at the University of Glasgow (Scotland), was scheduled to present the findings at the British Society for Rheumatology annual conference. The meeting was canceled because of the ongoing COVID-19 crisis. Abstracts and ePosters from the meeting have since been released in a supplement to Rheumatology and via the BSR’s conference app.
 

First data for ustekinumab

“There certainly doesn’t appear to be any added benefit from using methotrexate on a group level in patients getting ustekinumab and TNF inhibitors,” Dr. Siebert said. “We’ve looked at everything,” he emphasized, and “none of the single domains or composite measures were improved by the addition of methotrexate. I think we knew that for TNF inhibitors, but the key thing is we’ve never known that for ustekinumab, and this is the first study to show that.”

Indeed, the findings match up with those from the SEAM-PsA (Etanercept and Methotrexate in Subjects with Psoriatic Arthritis) study in which patients who were treated with the TNFi etanercept as monotherapy did much better than those given the TNFi in combination with methotrexate or methotrexate alone. While not a randomized trial, PsABio now shows that the same is true for ustekinumab.

Obviously, there are some clear differences between a clinical trial and an observational study such as PsABio. For one thing, there was no randomization and patients taking methotrexate were presumably doing so for good reason, Dr. Siebert said. Secondly, there was no methotrexate-only arm.

PsABio recruited patients who were starting treatment with either ustekinumab or a new TNFi as first-, second-, or third-line biologic disease-modifying antirheumatic therapy (DMARD). “These are all people starting on a biologic, so they’ve already got severe disease and have failed methotrexate on some level. So everything we’ve done is biologic without methotrexate or biologic with methotrexate,” Dr. Siebert explained. Patients may not have been taking methotrexate for a variety of reasons, such as inefficacy or side effects, so PsABio “doesn’t tell us anything about methotrexate on its own.”

Time to rethink ingrained methotrexate use

The rationale for using methotrexate in combination with biologics in psoriatic arthritis comes from its long-standing use in rheumatoid arthritis. Much of what is advocated in guidelines comes from experience in RA, Dr. Siebert said.

“In rheumatoid arthritis, we know that the TNF inhibitors work much better if you use methotrexate, that’s a given,” he noted. “We’ve been trained that you have to have methotrexate to have a biologic. However, PsABio, together with other studies, show that you don’t have to, and you should have a good reason to add methotrexate.”

Individual patients may still benefit from methotrexate use, but the decision to treat all patients the same is not supported by the current evidence. “It’s good that it shows that, actually, once you get someone on a decent biologic, it’s working: It’s doing what it ‘says on the tin’ for a lot of patients. I really think that is the key message, here, that you don’t have to; this reassures clinicians and actually makes them think ‘should this patient be on methotrexate?’ ” Dr. Siebert said.

The PsABio study was funded by Janssen. Dr. Siebert has acted as a consultant to and received research funding from Janssen, UCB, Pfizer, Boehringer Ingelheim, Novartis, and Celgene. He has also acted as a consultant for AbbVie and received research support from Bristol-Myers Squibb.

SOURCE: Siebert S et al. Rheumatology. 2020;59(Suppl 2). doi: 10.1093/rheumatology/keaa110.023, Abstract O24.

Ustekinumab or a tumor necrosis factor inhibitor (TNFi) are better used alone than with methotrexate in the treatment of psoriatic arthritis suggest the results of PsABio (A Study on Assessment of STELARA and Tumor Necrosis Factor Alpha Inhibitor Therapies in Participants With Psoriatic Arthritis), a large, ongoing, prospective observational study.

The percentages of patients achieving multiple psoriatic arthritis disease activity outcome measures at 6 months were higher if biologic monotherapy was used rather than a biologic in combination with methotrexate.

For example, minimal disease activity (MDA) was achieved by 27.5% of patients taking ustekinumab as monotherapy and by 32.1% of those taking a TNFi alone. When methotrexate was used in combination, the respective percentages of patients achieving MDA were 23.7% and 27.8%.

A similar pattern was seen for very-low disease activity (VLDA), with 9.8% of patients in the ustekinumab monotherapy arm and 12% of those in the TNFi monotherapy arm achieving this target, compared with 5.7% and 5.4% when these drugs were combined with methotrexate.

MDA is defined as meeting five or more cutoffs for seven domains of disease activity, and VLDA for all seven: 0-1 tender joints, 0-1 swollen joints, Psoriasis Area Severity Index 1 or less or body surface area involved 3% or less, 0-1 tender entheseal points, Health Assessment Questionnaire score of 0.5 or less, patient global disease activity visual analog scale score of 20 or lower, and patient pain visual analog scale score of 15 or lower.

Other outcome measures used that showed no advantage of adding methotrexate to these biologics were the Clinical Disease Activity in Psoriatic Arthritis low disease activity and remission scores, the patient acceptable symptoms rate of the 12-item Psoriatic Arthritis Impact of Disease Questionnaire, and improvement in skin involvement.

“Patients were no more likely to achieve lower disease activity or a remission target having received methotrexate than they did just on the biologic drug on its own,” Stefan Siebert, MBBCh, PhD, one of the PsABio investigators, said in an interview.

Dr. Siebert, who is clinical senior lecturer in inflammation and rheumatology at the University of Glasgow (Scotland), was scheduled to present the findings at the British Society for Rheumatology annual conference. The meeting was canceled because of the ongoing COVID-19 crisis. Abstracts and ePosters from the meeting have since been released in a supplement to Rheumatology and via the BSR’s conference app.
 

First data for ustekinumab

“There certainly doesn’t appear to be any added benefit from using methotrexate on a group level in patients getting ustekinumab and TNF inhibitors,” Dr. Siebert said. “We’ve looked at everything,” he emphasized, and “none of the single domains or composite measures were improved by the addition of methotrexate. I think we knew that for TNF inhibitors, but the key thing is we’ve never known that for ustekinumab, and this is the first study to show that.”

Indeed, the findings match up with those from the SEAM-PsA (Etanercept and Methotrexate in Subjects with Psoriatic Arthritis) study in which patients who were treated with the TNFi etanercept as monotherapy did much better than those given the TNFi in combination with methotrexate or methotrexate alone. While not a randomized trial, PsABio now shows that the same is true for ustekinumab.

Obviously, there are some clear differences between a clinical trial and an observational study such as PsABio. For one thing, there was no randomization and patients taking methotrexate were presumably doing so for good reason, Dr. Siebert said. Secondly, there was no methotrexate-only arm.

PsABio recruited patients who were starting treatment with either ustekinumab or a new TNFi as first-, second-, or third-line biologic disease-modifying antirheumatic therapy (DMARD). “These are all people starting on a biologic, so they’ve already got severe disease and have failed methotrexate on some level. So everything we’ve done is biologic without methotrexate or biologic with methotrexate,” Dr. Siebert explained. Patients may not have been taking methotrexate for a variety of reasons, such as inefficacy or side effects, so PsABio “doesn’t tell us anything about methotrexate on its own.”

Time to rethink ingrained methotrexate use

The rationale for using methotrexate in combination with biologics in psoriatic arthritis comes from its long-standing use in rheumatoid arthritis. Much of what is advocated in guidelines comes from experience in RA, Dr. Siebert said.

“In rheumatoid arthritis, we know that the TNF inhibitors work much better if you use methotrexate, that’s a given,” he noted. “We’ve been trained that you have to have methotrexate to have a biologic. However, PsABio, together with other studies, show that you don’t have to, and you should have a good reason to add methotrexate.”

Individual patients may still benefit from methotrexate use, but the decision to treat all patients the same is not supported by the current evidence. “It’s good that it shows that, actually, once you get someone on a decent biologic, it’s working: It’s doing what it ‘says on the tin’ for a lot of patients. I really think that is the key message, here, that you don’t have to; this reassures clinicians and actually makes them think ‘should this patient be on methotrexate?’ ” Dr. Siebert said.

The PsABio study was funded by Janssen. Dr. Siebert has acted as a consultant to and received research funding from Janssen, UCB, Pfizer, Boehringer Ingelheim, Novartis, and Celgene. He has also acted as a consultant for AbbVie and received research support from Bristol-Myers Squibb.

SOURCE: Siebert S et al. Rheumatology. 2020;59(Suppl 2). doi: 10.1093/rheumatology/keaa110.023, Abstract O24.

The Food and Drug Administration has approved ixekizumab for treatment of moderate to severe plaque psoriasis in patients aged 6-17 years, according to an announcement from Lilly.

Patients need to be candidates for systemic therapy or phototherapy and have no known hypersensitivity to the biologic.

The safety, tolerability, and efficacy of the interleukin-17a antagonist were demonstrated in a phase 3 study that included 171 patients aged 6-17 years with moderate to severe plaque psoriasis. At 12 weeks, 89% those on ixekizumab achieved a 75% improvement on Psoriasis Area and Severity Index score, compared with 25% of those on placebo, and 81% achieved a static Physician’s Global Assessment of clear or almost clear, compared with 11% of those on placebo, according to the Lilly statement.

The safety profile seen with ixekizumab (Taltz) among the pediatric patients with plaque psoriasis is consistent with what has been observed among adult patients, although there were higher rates of conjunctivitis, influenza, and urticaria among the pediatric patients, the statement noted. The biologic may increase the risk of infection, and patients should be evaluated for tuberculosis, hypersensitivity, and inflammatory bowel disease. It is also recommended that routine immunizations be completed before initiating treatment.

Ixekizumab was initially approved for treating adults with moderate to severe plaque psoriasis in 2016, followed by approvals for treatment of adults with active psoriatic arthritis in 2017, and for adults with ankylosing spondylitis in August 2019.

The biologic therapies – etanercept, a tumor necrosis factor blocker, and ustekinumab (Stelara), an IL-12/23 antagonist – were previously approved by the FDA for pediatric psoriasis, in children ages 4 years and older and 12 years and older, respectively.

Updated prescribing information for ixekizumab can be found on the Lilly website.

[email protected]

The Food and Drug Administration has approved ixekizumab for treatment of moderate to severe plaque psoriasis in patients aged 6-17 years, according to an announcement from Lilly.

Patients need to be candidates for systemic therapy or phototherapy and have no known hypersensitivity to the biologic.

The safety, tolerability, and efficacy of the interleukin-17a antagonist were demonstrated in a phase 3 study that included 171 patients aged 6-17 years with moderate to severe plaque psoriasis. At 12 weeks, 89% those on ixekizumab achieved a 75% improvement on Psoriasis Area and Severity Index score, compared with 25% of those on placebo, and 81% achieved a static Physician’s Global Assessment of clear or almost clear, compared with 11% of those on placebo, according to the Lilly statement.

The safety profile seen with ixekizumab (Taltz) among the pediatric patients with plaque psoriasis is consistent with what has been observed among adult patients, although there were higher rates of conjunctivitis, influenza, and urticaria among the pediatric patients, the statement noted. The biologic may increase the risk of infection, and patients should be evaluated for tuberculosis, hypersensitivity, and inflammatory bowel disease. It is also recommended that routine immunizations be completed before initiating treatment.

Ixekizumab was initially approved for treating adults with moderate to severe plaque psoriasis in 2016, followed by approvals for treatment of adults with active psoriatic arthritis in 2017, and for adults with ankylosing spondylitis in August 2019.

The biologic therapies – etanercept, a tumor necrosis factor blocker, and ustekinumab (Stelara), an IL-12/23 antagonist – were previously approved by the FDA for pediatric psoriasis, in children ages 4 years and older and 12 years and older, respectively.

Updated prescribing information for ixekizumab can be found on the Lilly website.

[email protected]

The Food and Drug Administration has approved ixekizumab for treatment of moderate to severe plaque psoriasis in patients aged 6-17 years, according to an announcement from Lilly.

Patients need to be candidates for systemic therapy or phototherapy and have no known hypersensitivity to the biologic.

The safety, tolerability, and efficacy of the interleukin-17a antagonist were demonstrated in a phase 3 study that included 171 patients aged 6-17 years with moderate to severe plaque psoriasis. At 12 weeks, 89% those on ixekizumab achieved a 75% improvement on Psoriasis Area and Severity Index score, compared with 25% of those on placebo, and 81% achieved a static Physician’s Global Assessment of clear or almost clear, compared with 11% of those on placebo, according to the Lilly statement.

The safety profile seen with ixekizumab (Taltz) among the pediatric patients with plaque psoriasis is consistent with what has been observed among adult patients, although there were higher rates of conjunctivitis, influenza, and urticaria among the pediatric patients, the statement noted. The biologic may increase the risk of infection, and patients should be evaluated for tuberculosis, hypersensitivity, and inflammatory bowel disease. It is also recommended that routine immunizations be completed before initiating treatment.

Ixekizumab was initially approved for treating adults with moderate to severe plaque psoriasis in 2016, followed by approvals for treatment of adults with active psoriatic arthritis in 2017, and for adults with ankylosing spondylitis in August 2019.

The biologic therapies – etanercept, a tumor necrosis factor blocker, and ustekinumab (Stelara), an IL-12/23 antagonist – were previously approved by the FDA for pediatric psoriasis, in children ages 4 years and older and 12 years and older, respectively.

Updated prescribing information for ixekizumab can be found on the Lilly website.

[email protected]

AstraZeneca has announced that the phase 3 DAPA-CKD trial for dapagliflozin (Farxiga) in patients with chronic kidney disease has been halted early because of overwhelming efficacy of the drug, at the recommendation of an independent data monitoring committee.

DAPA-CKD is an international, multicenter, randomized, double-blinded trial in 4,245 patients with stage 2-4 chronic kidney disease. Patients received either 10 mg of the dapagliflozin once-daily or a placebo. The primary composite endpoint is worsening of renal function, defined as a composite of an estimated glomerular filtration rate decline of at least 50%, onset of end-stage kidney disease, and death from cardiovascular or renal cause.

The decision to stop the trial came after a routine assessment of efficacy and safety that showed dapagliflozin’s benefits significantly earlier than expected. AstraZeneca will initiate closure of the study, and results will be published and submitted for presentation at a forthcoming medical meeting.

Dapagliflozin is a sodium-glucose transporter 2 inhibitor currently indicated for the treatment type 2 diabetes patients with inadequately controlled type 2 diabetes and for reduction of the risk of hospitalization for heart failure. In August 2019, the drug was granted Fast Track status by the Food and Drug Administration for the treatment of chronic kidney disease. In January 2020, the agency also granted Fast Track status for the reduction of risk of cardiovascular death or worsening of heart failure in adult patients, regardless of diabetes status, with heart failure with reduced ejection fraction.

“Chronic kidney disease patients have limited treatment options, particularly those without type-2 diabetes. We are very pleased the data monitoring committee concluded that patients experienced overwhelming benefit. Farxiga has the potential to change the management of chronic kidney disease for patients around the world,” Mene Pangalos, executive vice president of BioPharmaceuticals R&D, said in the press release.

[email protected]

AstraZeneca has announced that the phase 3 DAPA-CKD trial for dapagliflozin (Farxiga) in patients with chronic kidney disease has been halted early because of overwhelming efficacy of the drug, at the recommendation of an independent data monitoring committee.

DAPA-CKD is an international, multicenter, randomized, double-blinded trial in 4,245 patients with stage 2-4 chronic kidney disease. Patients received either 10 mg of the dapagliflozin once-daily or a placebo. The primary composite endpoint is worsening of renal function, defined as a composite of an estimated glomerular filtration rate decline of at least 50%, onset of end-stage kidney disease, and death from cardiovascular or renal cause.

The decision to stop the trial came after a routine assessment of efficacy and safety that showed dapagliflozin’s benefits significantly earlier than expected. AstraZeneca will initiate closure of the study, and results will be published and submitted for presentation at a forthcoming medical meeting.

Dapagliflozin is a sodium-glucose transporter 2 inhibitor currently indicated for the treatment type 2 diabetes patients with inadequately controlled type 2 diabetes and for reduction of the risk of hospitalization for heart failure. In August 2019, the drug was granted Fast Track status by the Food and Drug Administration for the treatment of chronic kidney disease. In January 2020, the agency also granted Fast Track status for the reduction of risk of cardiovascular death or worsening of heart failure in adult patients, regardless of diabetes status, with heart failure with reduced ejection fraction.

“Chronic kidney disease patients have limited treatment options, particularly those without type-2 diabetes. We are very pleased the data monitoring committee concluded that patients experienced overwhelming benefit. Farxiga has the potential to change the management of chronic kidney disease for patients around the world,” Mene Pangalos, executive vice president of BioPharmaceuticals R&D, said in the press release.

[email protected]

AstraZeneca has announced that the phase 3 DAPA-CKD trial for dapagliflozin (Farxiga) in patients with chronic kidney disease has been halted early because of overwhelming efficacy of the drug, at the recommendation of an independent data monitoring committee.

DAPA-CKD is an international, multicenter, randomized, double-blinded trial in 4,245 patients with stage 2-4 chronic kidney disease. Patients received either 10 mg of the dapagliflozin once-daily or a placebo. The primary composite endpoint is worsening of renal function, defined as a composite of an estimated glomerular filtration rate decline of at least 50%, onset of end-stage kidney disease, and death from cardiovascular or renal cause.

The decision to stop the trial came after a routine assessment of efficacy and safety that showed dapagliflozin’s benefits significantly earlier than expected. AstraZeneca will initiate closure of the study, and results will be published and submitted for presentation at a forthcoming medical meeting.

Dapagliflozin is a sodium-glucose transporter 2 inhibitor currently indicated for the treatment type 2 diabetes patients with inadequately controlled type 2 diabetes and for reduction of the risk of hospitalization for heart failure. In August 2019, the drug was granted Fast Track status by the Food and Drug Administration for the treatment of chronic kidney disease. In January 2020, the agency also granted Fast Track status for the reduction of risk of cardiovascular death or worsening of heart failure in adult patients, regardless of diabetes status, with heart failure with reduced ejection fraction.

“Chronic kidney disease patients have limited treatment options, particularly those without type-2 diabetes. We are very pleased the data monitoring committee concluded that patients experienced overwhelming benefit. Farxiga has the potential to change the management of chronic kidney disease for patients around the world,” Mene Pangalos, executive vice president of BioPharmaceuticals R&D, said in the press release.

[email protected]

From the University of Alabama at Birmingham, Division of Hematology Oncology, Birmingham, AL, and the University of South Alabama, Division of Hematology Oncology, Mobile, AL. Dr. Paluri and Dr. Hatic contributed equally to this article.

Abstract

• Objective: To review systemic treatment options for patients with locally advanced unresectable hepatocellular carcinoma (HCC).
• Methods: Review of the literature.
• Results: The paradigm of what constitutes first-line treatment for advanced HCC is shifting. Until recently, many patients with advanced HCC were treated with repeated locoregional therapies, such as transartertial embolization (TACE). However, retrospective studies suggest that continuing TACE after refractoriness or failure may not be beneficial and may delay subsequent treatments because of deterioration of liver function or declines in performance status. With recent approvals of several systemic therapy options, including immunotherapy, it is vital to conduct a risk-benefit assessment prior to repeating TACE after failure, so that patients are not denied the use of available systemic therapeutic options due to declined performance status or organ function from these procedures. The optimal timing and the sequence of systemic and locoregional therapy must be carefully evaluated by a multidisciplinary team.
• Conclusion: Randomized clinical trials to improve patient selection and determine the proper sequence of treatments are needed. Given the heterogeneity of HCC, molecular profiling of the tumor to differentiate responders from nonresponders may elucidate potential biomarkers to effectively guide treatment recommendations.

Keywords: liver cancer; molecular therapy; immunotherapy.

Hepatocellular carcinoma (HCC) represents 90% of primary liver malignancies. It is the fifth most common malignancy in males and the ninth most common in females worldwide.¹ In contrast to other major cancers (colon, breast, prostate), the incidence of and mortality from HCC has increased over the past decade, following a brief decline between 1999 and 2004.² The epidemiology and incidence of HCC is closely linked to chronic liver disease and conditions predisposing to liver cirrhosis. Worldwide, hepatitis B virus infection is the leading cause of liver cirrhosis and, hence, HCC. In the United States, 50% of HCC cases are linked to hepatitis C virus (HCV) infection. Diabetes mellitus and alcoholic and nonalcoholic steatohepatitis are the other major etiologies of HCC. Indeed, the metabolic syndrome, independent of other factors, is associated with a 2-fold increase in the risk of HCC.³

Although most cases of HCC are predated by liver cirrhosis, in about 20% of patients HCC occurs without liver cirrhosis.⁴ Similar to other malignancies, surgery in the form of resection (for isolated lesions in the context of good liver function) or liver transplant (for low-volume disease with mildly impaired liver function) provides the best chance of a cure. Locoregional therapies involving hepatic artery–directed therapy are offered for patients with more advanced disease that is limited to the liver, while systemic therapy is offered for advanced unresectable disease that involves portal vein invasion, lymph nodes, and distant metastasis. The Barcelona Clinic Liver Cancer (BCLC) staging system is the most widely used for staging and treatment in HCC. It not only considers the size of the tumor, but also incorporates the degree of liver dysfunction and the patient’s functional status.^5,6

Molecular Pathogenesis

Similar to other malignancies, a multistep process of carcinogenesis, with accumulation of genomic alterations at the molecular and cellular levels, is recognized in HCC. In about 80% of cases, repeated and chronic injury, inflammation, and repair lead to a distortion of normal liver architecture and development of cirrhotic nodules. Exome sequencing of HCC tissues has identified risk factor–specific mutational signatures, including those related to the tumor microenvironment, and defined the extensive landscape of altered genes and pathways in HCC (eg, angiogenic and MET pathways).⁷ In the Schulze et al study, the frequency of alterations that could be targeted by available Food and Drug Administration (FDA)–approved drugs comprised either amplifications or mutations of FLTs (6%), FGF3 or 4 or 19 (4%), PDGFRs (3%), VEGFA (1%), HGF (3%), MTOR (2%), EGFR (1%), FGFRs (1%), and MET (1%).⁷ Epigenetic modification of growth-factor expression, particularly insulin-like growth factor 2 and transforming growth factor alpha, and structural alterations that lead to loss of heterozygosity are early events that cause hepatocyte proliferation and progression of dysplastic nodules.^8,9 Advances in whole-exome sequencing have identified TERT promoter mutations, leading to activation of telomerase, as an early event in HCC pathogenesis. Other commonly altered genes include CTNNB1 (B-Catenin) and TP53. As a group, alterations in the MAP kinase pathway genes occur in about 40% of HCC cases.

Actionable oncogenic driver alterations are not as common as tumor suppressor pathway alterations in HCC, making targeted drug development challenging.^10,11 The FGFR (fibroblast growth factor receptor) pathway, which plays a critical role in carcinogenesis-related cell growth, survival, neo-angiogenesis, and acquired resistance to other cancer treatments, is being explored as a treatment target.¹² The molecular characterization of HCC may help with identifying new biomarkers and present opportunities for developing therapeutic targets.

CASE PRESENTATION

A 61-year-old man with a history of chronic hepatitis C and hypertension presents to his primary care physician due to right upper quadrant pain. Laboratory evaluation shows transaminases elevated 2 times the upper limit of normal. This leads to an ultrasound and follow-up magnetic resonance imaging. Imaging shows diffuse cirrhotic changes, with a 6-cm, well-circumscribed lesion within the left lobe of the liver that shows rapid arterial enhancement with venous washout. These vascular characteristics are consistent with HCC. In addition, 2 satellite lesions in the left lobe and sonographic evidence of invasion into the portal vein are present. Periportal lymph nodes are pathologically enlarged.

The physical examination is unremarkable, except for mild tenderness over the right upper quadrant of the abdomen. Serum bilirubin, albumin, platelets, and international normalized ratio are normal, and alpha fetoprotein (AFP) is elevated at 1769 ng/mL. The patient’s family history is unremarkable for any major illness or cancer. Computed tomography scan of the chest and pelvis shows no evidence of other lesions. His liver disease is classified as Child–Pugh A. Due to locally advanced presentation, the tumor is deemed to be nontransplantable and unresectable, and is staged as BCLC-C. The patient continues to work and his performance status is ECOG (Eastern Cooperative Oncology Group) 0. He is referred to the liver tumor clinic for further evaluation and management. The tumor board consensus is to initiate systemic treatment.

What systemic treatment would you recommend for this patient with locally advanced unresectable HCC with nodal metastasis?

First-Line Therapeutic Options

Systemic treatment of HCC is challenging because of the underlying liver cirrhosis and hepatic dysfunction present in most patients. Overall prognosis is therefore dependent on the disease biology and burden and on the degree of hepatic dysfunction. These factors must be considered in patients with advanced disease who present for systemic therapy. As such, patients with BCLC class D HCC with poor performance status and impaired liver function are better off with best supportive care and hospice services (Figure). Table 1 and Table 2 outline the landmark trials that led to the approval of agents for advanced HCC treatment.

Sorafenib

In the patient with BCLC class C HCC who has preserved liver function (traditionally based on a Child–Pugh score of ≤ 6 and a decent functional status [ECOG performance status 1-2]), sorafenib is the first FDA-approved first-line treatment. Sorafenib is a small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) kinase signaling, in addition to many other tyrosine kinase pathways (including the platelet-derived growth factor and Raf-Ras pathways). Evidence for the clinical benefit of sorafenib comes from the SHARP trial.¹³ This was a multinational, but primarily European, randomized phase 3 study that compared sorafenib to best supportive care for advanced HCC in patients with a Child–Pugh score ≤ 6A and a robust performance status (ECOG 0 and 1). Overall survival (OS) with placebo and sorafenib was 7.9 months and 10.7 months, respectively. There was no difference in time to radiologic progression, and the progression-free survival (PFS) at 4 months was 62% with sorafenib and 42% with placebo. Patients with HCV-associated HCC appeared to derive a more substantial benefit from sorafenib.¹⁴ In a smaller randomized study of sorafenib in Asian patients with predominantly hepatitis B–associated HCC, OS in the sorafenib and best supportive care arms was lower than that reported in the SHARP study (6.5 months vs 4.2 months), although OS still was longer in the sorafenib group.¹⁵

Significant adverse events reported with sorafenib include fatigue (30%), hand and foot syndrome (30%), diarrhea (15%), and mucositis (10%). Major proportions of patients in the clinical setting have not tolerated the standard dose of 400 mg twice daily. Dose-adjusted administration of sorafenib has been advocated in patients with more impaired liver function (Child–Pugh class 7B) and bilirubin of 1.5 to 3 times the upper limit of normal, although it is unclear whether these patients are deriving any benefit from sorafenib.¹⁶ At this time, in a patient with preserved liver function, starting with 400 mg twice daily, followed by dose reduction based on toxicity, remains standard.

Lenvatinib

After multiple attempts to develop newer first-line treatments for HCC, lenvatinib, another small-molecule multikinase inhibitor of VEGFR signaling, was approved by the FDA in August 2018. Approval was based on a noninferiority study of lenvatinib versus sorafenib in patients with unresectable, treatment-naïve HCC who had preserved liver function and excellent performance status.¹⁷ Lenvatinib was noninferior to sorafenib, with an OS of 13.6 months versus 12.3 months for sorafenib. Lenvatinib was associated with an improved response rate (24% vs 9%), increased time to disease progression, and longer PFS (7.3 months vs 3.6 months). Patients with a performance status of 0 and 1 were allowed in this trial. Lenvatinib is associated with a more favorable adverse effect profile and is desirable in patients in whom tumor shrinkage is important. Compared to those treated with sorafenib, patients treated with lenvatinib reported a somewhat higher incidence of higher-grade hypertension (42% vs 30%), loss of appetite (34% vs 27%), and weight loss (31%), but lower rates of diarrhea (39% vs 46%) and skin toxicity (27% vs 52%).

Following the sorafenib approval, clinical studies of several other agents did not meet their primary endpoint and failed to show improvement in clinical outcomes compared to sorafenib. However, over the past years the treatment landscape for advanced HCC has been changed with the approval of several agents in the second line. The overall response rate (ORR) has become the new theme for management of advanced disease. With multiple therapeutic options available, optimal sequencing now plays a critical role, especially for transitioning from locoregional to systemic therapy. Five drugs are now indicated for second-line treatment of patients who progressed on or were intolerant to sorafenib: regorafenib, cabozantinib, ramucirumab, nivolumab, and pembrolizumab.

Regorafenib

Regorafenib was evaluated in the advanced HCC setting in a single-arm, phase 2 trial involving 36 patients with Child–Pugh class A liver disease who had progressed on prior sorafenib.¹⁸ Patients received regorafenib 160 mg orally once daily for 3 weeks on/1 week off cycles. Disease control was achieved in 72% of patients, with stable disease in 25 patients (69%). Based on these results, regorafenib was further evaluated in the multicenter, phase 3, 2:1 randomized, double-blind, placebo-controlled RESORCE study, which enrolled 573 patients.¹⁹ Due to the overlapping safety profiles of sorafenib and regorafenib, the inclusion criteria required patients to have tolerated a sorafenib dose of at least 400 mg daily for 20 of the past 28 days of treatment prior to enrollment. The primary endpoint of the study, OS, was met (median OS of 10.6 months in regorafenib arm versus 7.8 months in placebo arm; hazard ratio [HR], 0.63; P < 0.0001). Serious adverse events occurred in 44% of the patients who received regorafenib; the most common were hypertension (15%), hand-foot-skin reaction (HFSR, 13%), fatigue (9%), bleeding events (6%), and diarrhea (3%). Seven (2%) deaths in the regorafenib group were attributable to this drug. HFSR due to regorafenib was found to be associated with better survival outcomes.²⁰ In the selected subpopulation for the study, treatment with the sequence of sorafenib followed by regorafenib resulted in a median OS of 26 months.²¹

Cabozantinib

CELESTIAL was a phase 3, double-blind study that assessed the efficacy of cabozantinib versus placebo in patients with advanced HCC who had received prior sorafenib.²² In this study, 707 patients with Child–Pugh class A liver disease who progressed on at least 1 prior systemic therapy were randomized in a 2:1 ratio to treatment with cabozantinib at 60 mg daily or placebo. Patients treated with cabozantinib had a longer OS (10.2 months vs 8.0 months), resulting in a 24% reduction in the risk of death (HR, 0.76), and a longer median PFS (5.2 months versus 1.9 months). The disease control rate was higher with cabozantinib (64% vs 33%) as well. The incidence of high‐grade adverse events in the cabozantinib group was twice that of the placebo group. Common adverse events reported with cabozantinib included HFSR (17%), hypertension (16%), increased aspartate aminotransferase (12%), fatigue (10%), and diarrhea (10%). 

Ramucirumab

REACH was a phase 3 study exploring the efficacy of ramucirumab that did not meet its primary endpoint; however, the subgroup analysis in AFP-high patients showed an OS improvement with ramucirumab.²³ This led to the phase 3 REACH-2 trial, a multicenter, randomized, double-blind biomarker study in patients with advanced HCC who either progressed on or were intolerant to sorafenib and had an AFP level ≥ 400 ng/mL.²⁴ Patients were randomized to ramucirumab 8 mg/kg every 2 weeks or placebo. The study met its primary endpoint, showing improved OS (8.5 months vs 7.3 months; P = 0.0059). The most common treatment-related adverse events in the ramucirumab group were ascites (5%), hypertension (12%), asthenia (5%), malignant neoplasm progression (6%), increased aspartate aminotransferase concentration (5%), and thrombocytopenia.

Immunotherapy

HCC is considered an inflammation-induced cancer, which renders immunotherapeutic strategies more appealing. The PD-L1/PD-1 pathway is the critical immune checkpoint mechanism and is an important target for treatment. HCC uses a complex, overlapping set of mechanisms to evade cancer-specific immunity and to suppress the immune system. Initial efforts to develop immunotherapies for HCC focused on anti-PD-1 and anti-PD-L1 antibodies. CheckMate 040 evaluated nivolumab in 262 sorafenib-naïve and -treated patients with advanced HCC (98% with Child–Pugh scores of 5 or 6), with a median follow-up of 12.9 months.²⁵ In sorafenib-naïve patients (n = 80), the ORR was 23%, and the disease control rate was 63%. In sorafenib-treated patients (n = 182), the ORR was 18%. Response was not associated with PD-L1 expression. Durable objective responses, a manageable safety profile, and promising efficacy led the FDA to grant accelerated approval of nivolumab for the treatment of patients with HCC who have been previously treated with sorafenib. Based on this, the phase 3 randomized CheckMate-459 trial evaluated the efficacy of nivolumab versus sorafenib in the first-line. Median OS and ORR were better with nivolumab (16.4 months vs 14.7 months; HR 0.85; P = 0.752; and 15% [with 5 complete responses] vs 7%), as was the safety profile (22% vs 49% reporting grade 3 and 4 adverse events). ²⁶

The KEYNOTE-224 study²⁷ evaluated pembrolizumab in 104 patients with previously treated advanced HCC. This study showed an ORR of 17%, with 1 complete response and 17 partial responses. One-third of the patients had progressive disease, while 46 had stable disease. Among those who responded, 56% maintained a durable response for more than 1 year. Subsequently, in KEYNOTE 240, pembrolizumab showed an improvement in OS (13.9 months vs 10.6 months; HR, 0.78; P = 0.0238) and PFS (3.0 months versus 2.8 months; HR, 0.78; P = 0.0186) compared with placebo.²⁸ The ORR for pembrolizumab was 16.9% (95% confidence interval [CI], 12.7%-21.8%) versus 2.2% (95% CI, 0.5%-6.4%; P = 0.00001) for placebo. Mean duration of response was 13.8 months.

In the IMbrave150 trial, atezolizumab/bevacizumab combination, compared to sorafenib, had better OS (not estimable vs 13.2 months; P = 0.0006), PFS (6.8 months vs 4.5 months, P < 0.0001), and ORR (33% vs 13%, P < 0.0001), but grade 3-4 events were similar.²⁹ This combination has potential for first-line approval. The COSMIC–312 study is comparing the combination of cabozantinib and atezolizumab to sorafenib monotherapy and cabozantinib monotherapy in advanced HCC.

Resistance to immunotherapy can be extrinsic, associated with activation mechanisms of T-cells, or intrinsic, related to immune recognition, gene expression, and cell-signaling pathways.³⁰ Tumor-immune heterogeneity and antigen presentation contribute to complex resistance mechanisms.^31,32 Although clinical outcomes have improved with immune checkpoint inhibitors, the response rate is low and responses are inconsistent, likely due to an immunosuppressive tumor microenvironment.³³ Therefore, several novel combinations of checkpoint inhibitors and targeted drugs are being evaluated to bypass some of the resistance mechanisms (Table 3).

Chemotherapy

Multiple combinations of cytotoxic regimens have been evaluated, but efficacy has been modest, suggesting the limited role for traditional chemotherapy in the systemic management of advanced HCC. Response rates to chemotherapy are low and responses are not durable. Gemcitabine- and doxorubicin-based treatment and FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) are some regimens that have been studied, with a median OS of less than 1 year for these regimens.^34-36 FOLFOX had a higher response rate (8.15% vs 2.67%; P = 0.02) and longer median OS (6.40 months versus 4.97 months; HR, 0.80; 95% CI, 0.63-1.02; P = 0.07) than doxorubicin.³⁴ With the gemcitabine/oxaliplatin combination, ORR was 18%, with stable disease in 58% of patients, and median PFS and OS were 6.3 months and 11.5 months, respectively.³⁵ In a study that compared doxorubicin and PIAF (cisplatin/interferon a-2b/doxorubicin/5-fluorouracil), median OS was 6.83 months and 8.67 months, respectively (P = 0.83). The hazard ratio for death from any cause in the PIAF group compared with the doxorubicin group was 0.97 (95% CI, 0.71-1.32). PIAF had a higher ORR (20.9%; 95% CI, 12.5%-29.2%) than doxorubicin (10.5%; 95% CI, 3.9%-16.9%).

The phase 3 ALLIANCE study evaluated the combination of sorafenib and doxorubicin in treatment-naïve HCC patients with Child–Pugh class A liver disease, and did not demonstrate superiority with the addition of cytotoxic chemotherapy.³⁷ Indeed, the combination of chemotherapy with sorafenib appears harmful in terms of lower OS (9.3 months vs 10.6 months; HR, 1.06; 95% CI, 0.8-1.4) and worse toxicity. Patients treated with the combination experienced more hematologic (37.8% vs 8.1%) and nonhematologic adverse events (63.6% vs 61.5%).

Locoregional Therapy

The role of locoregional therapy in advanced HCC remains the subject of intense debate. Patients with BCLC stage C HCC with metastatic disease and those with lymph node involvement are candidates for systemic therapy. The optimal candidate for locoregional therapy is the patient with localized intermediate-stage disease, particularly hepatic artery–delivered therapeutic interventions. However, the presence of a solitary large tumor or portal vein involvement constitutes gray areas regarding which therapy to deliver directly to the tumor via the hepatic artery, and increasingly stereotactic body radiation therapy is being offered.

Transarterial Chemoembolization

Transarterial chemoembolization (TACE), with or without chemotherapy, is the most widely adopted locoregional therapy in the management of HCC. TACE exploits the differential vascular supply to the HCC and normal liver parenchyma. Normal liver receives only one-fourth of its blood supply from the hepatic artery (three-fourths from the portal vein), whereas HCC is mainly supplied by the hepatic artery. A survival benefit for TACE compared to best supportive care is widely acknowledged for intermediate-stage HCC, and transarterial embolization (TAE) with gelatin sponge or microspheres is noninferior to TACE.^38,39 Overall safety profile and efficacy inform therapy selection in advanced HCC, although the evidence for TACE in advanced HCC is less robust. Although single-institution experiences suggest survival numbers similar to and even superior to sorafenib,^40,41 there is a scarcity of large randomized clinical trial data to back this up. Based on this, patients with advanced HCC should only be offered liver-directed therapy within a clinical trial or on a case-by-case basis under multidisciplinary tumor board consensus.

A serious adverse effect of TACE is post-embolization syndrome, which occurs in about 30% of patients and may be associated with poor prognosis.⁴² The syndrome consists of right upper quadrant abdominal pain, malaise, and worsening nausea/vomiting following the embolization procedure. Laboratory abnormalities and other complications may persist for up to 30 days after the procedure. This is a concern, because post-embolization syndrome may affect the ability to deliver systemic therapy.

Transarterial Radioembolization

In the past few years, there has been an uptick in the utilization of transarterial radioembolization (TARE), which instead of delivering glass beads, as done in TAE, or chemotherapy-infused beads, as done in TACE, delivers the radioisotope Y-90 to the tumor via the hepatic artery. TARE is able to administer larger doses of radiation to the tumor while avoiding normal liver tissue, as compared to external-beam radiation. There has been no head-to-head comparison of these different intra-arterial therapy approaches, but TARE with Y-90 has been shown to be safe in patients with portal vein thrombosis. A recent multicenter retrospective study of TARE demonstrated a median OS of 8.8 to 10.8 months in patients with BCLC C HCC,⁴³ and in a large randomized study of Y-90 compared to sorafenib in advanced and previously treated intermediate HCC, there was no difference in median OS between the treatment modalities (8 months for selective internal radiotherapy, 9 months for sorafenib; P = 0.18). Treatment with Y-90 was better tolerated.⁴⁴ A major impediment to the adoption of TARE is the time it takes to order, plan, and deliver Y-90 to patients. Radio-embolization-induced liver disease, similar to post-embolization syndrome, is characterized by jaundice and ascites, which may occur 4 to 8 weeks postprocedure and is more common in patients with HCC who do not have cirrhosis. Compared to TACE, TARE may offer a better adverse effect profile, with improvement in quality of life.

Combination of Systemic and Locoregional Therapy

Even in carefully selected patients with intermediate- and advanced-stage HCC, locoregional therapy is not curative. Tumor embolization may promote more angiogenesis, and hence tumor progression, by causing hypoxia and upregulation of hypoxia-inducible factor.⁴⁵ This upregulation of angiogenesis as a resistance mechanism to tumor embolization provides a rationale for combining systemic therapy (typically based on abrogating angiogenesis) with TACE/TAE. Most of the experience has been with sorafenib in intermediate-stage disease, and the results have been disappointing. The administration of sorafenib after at least a partial response with TACE did not provide additional benefit in terms of time to progression.⁴⁶ Similarly, in the SPACE trial, concurrent therapy with TACE-doxorubicin-eluting beads and sorafenib compared to TACE-doxorubicin-eluting beads and placebo yielded similar time to progression numbers for both treatment modalities.⁴⁷ While the data have been disappointing in intermediate-stage disease, as described earlier, registry data suggest that patients with advanced-stage disease may benefit from this approach.⁴⁸

In the phase 2 TACTICS trial, 156 patients with unresectable HCC were randomized to receive TACE alone or sorafenib plus TACE, with a novel endpoint, time to untreatable progression (TTUP) and/or progression to TACE refractoriness.⁴⁹ Treatment with sorafenib following TACE was continued until TTUP, decline in liver function to Child–Pugh class C, or the development of vascular invasion or extrahepatic spread. Development of new lesions while on sorafenib was not considered as progressive disease as long as the lesions were amenable to TACE. In this study, PFS was longer with sorafenib-TACE compared to TACE alone (26.7 months vs 20.6 months; P = 0.02). However, the TTUP endpoint needs further validation, and we are still awaiting the survival outcomes of this study. At this time, there are insufficient data to recommend the combination of liver-directed locoregional therapy and sorafenib or other systemic therapy options outside of a clinical trial setting.

Current Treatment Approach for Advanced HCC (BCLC-C)

Although progress is being made in the development of effective therapies, advanced HCC is generally incurable. These patients experience significant symptom burden throughout the course of the disease. Therefore, the optimal treatment plan must focus on improving or maintaining quality of life, in addition to overall efficacy. It is important to actively involve patients in treatment decisions for an individualized treatment plan, and to discuss the best strategy for incorporating current advances in targeted and immunotherapies. The paradigm of what constitutes first-line treatment for advanced HCC is shifting due to the recent systemic therapy approvals. Prior to the availability of these therapies, many patients with advanced HCC were treated with repeated locoregional therapies. For instance, TACE was often used to treat unresectable HCC multiple times beyond progression. There was no consensus on the definition of TACE failure, and hence it was used in broader, unselected populations. Retrospective studies suggest that continuing TACE after refractoriness or failure may not be beneficial, and may delay subsequent treatments because of deterioration of liver function or declines in performance status. With recent approvals of several systemic therapy options, including immunotherapy, it is vital to conduct a risk-benefit assessment prior to repeating TACE after failure, so that patients are not denied the use of available systemic therapeutic options due to declined performance status or organ function from these procedures. The optimal timing and the sequence of systemic and locoregional therapy must be carefully evaluated by a multidisciplinary team.

CASE CONCLUSION

An important part of evaluating a new patient with HCC is to determine whether they are a candidate for curative therapies, such as transplant or surgical resection. These are no longer an option for patients with intermediate disease. For patients with advanced disease characteristics, such as vascular invasion or systemic metastasis, the evidence supports using systemic therapy with sorafenib or lenvatinib. Lenvatinib, with a better tolerance profile and response rate, is the treatment of choice for the patient described in the case scenario. Lenvatinib is also indicated for first-line treatment of advanced HCC, and is useful in very aggressive tumors, such as those with an AFP level exceeding 200 ng/mL.

Future Directions

The emerging role of novel systemic therapeutics, including immunotherapy, has drastically changed the treatment landscape for hepatocellular cancers, with 6 new drugs for treating advanced hepatocellular cancers approved recently. While these systemic drugs have improved survival in advanced HCC in the past decade, patient selection and treatment sequencing remain a challenge, due to a lack of biomarkers capable of predicting antitumor responses. In addition, there is an unmet need for treatment options for patients with Child–Pugh class B7 and C liver disease and poor performance status.

The goal of future management should be to achieve personalized care aimed at improved safety and efficacy by targeting multiple cancer pathways in the HCC cascade with combination treatments. Randomized clinical trials to improve patient selection and determine the proper sequence of treatments are needed. Given the heterogeneity of HCC, molecular profiling of the tumor to differentiate responders from nonresponders may elucidate potential biomarkers to effectively guide treatment recommendations.

From the University of Alabama at Birmingham, Division of Hematology Oncology, Birmingham, AL, and the University of South Alabama, Division of Hematology Oncology, Mobile, AL. Dr. Paluri and Dr. Hatic contributed equally to this article.

Abstract

• Objective: To review systemic treatment options for patients with locally advanced unresectable hepatocellular carcinoma (HCC).
• Methods: Review of the literature.
• Results: The paradigm of what constitutes first-line treatment for advanced HCC is shifting. Until recently, many patients with advanced HCC were treated with repeated locoregional therapies, such as transartertial embolization (TACE). However, retrospective studies suggest that continuing TACE after refractoriness or failure may not be beneficial and may delay subsequent treatments because of deterioration of liver function or declines in performance status. With recent approvals of several systemic therapy options, including immunotherapy, it is vital to conduct a risk-benefit assessment prior to repeating TACE after failure, so that patients are not denied the use of available systemic therapeutic options due to declined performance status or organ function from these procedures. The optimal timing and the sequence of systemic and locoregional therapy must be carefully evaluated by a multidisciplinary team.
• Conclusion: Randomized clinical trials to improve patient selection and determine the proper sequence of treatments are needed. Given the heterogeneity of HCC, molecular profiling of the tumor to differentiate responders from nonresponders may elucidate potential biomarkers to effectively guide treatment recommendations.

Keywords: liver cancer; molecular therapy; immunotherapy.

Hepatocellular carcinoma (HCC) represents 90% of primary liver malignancies. It is the fifth most common malignancy in males and the ninth most common in females worldwide.¹ In contrast to other major cancers (colon, breast, prostate), the incidence of and mortality from HCC has increased over the past decade, following a brief decline between 1999 and 2004.² The epidemiology and incidence of HCC is closely linked to chronic liver disease and conditions predisposing to liver cirrhosis. Worldwide, hepatitis B virus infection is the leading cause of liver cirrhosis and, hence, HCC. In the United States, 50% of HCC cases are linked to hepatitis C virus (HCV) infection. Diabetes mellitus and alcoholic and nonalcoholic steatohepatitis are the other major etiologies of HCC. Indeed, the metabolic syndrome, independent of other factors, is associated with a 2-fold increase in the risk of HCC.³

Although most cases of HCC are predated by liver cirrhosis, in about 20% of patients HCC occurs without liver cirrhosis.⁴ Similar to other malignancies, surgery in the form of resection (for isolated lesions in the context of good liver function) or liver transplant (for low-volume disease with mildly impaired liver function) provides the best chance of a cure. Locoregional therapies involving hepatic artery–directed therapy are offered for patients with more advanced disease that is limited to the liver, while systemic therapy is offered for advanced unresectable disease that involves portal vein invasion, lymph nodes, and distant metastasis. The Barcelona Clinic Liver Cancer (BCLC) staging system is the most widely used for staging and treatment in HCC. It not only considers the size of the tumor, but also incorporates the degree of liver dysfunction and the patient’s functional status.^5,6

Molecular Pathogenesis

Similar to other malignancies, a multistep process of carcinogenesis, with accumulation of genomic alterations at the molecular and cellular levels, is recognized in HCC. In about 80% of cases, repeated and chronic injury, inflammation, and repair lead to a distortion of normal liver architecture and development of cirrhotic nodules. Exome sequencing of HCC tissues has identified risk factor–specific mutational signatures, including those related to the tumor microenvironment, and defined the extensive landscape of altered genes and pathways in HCC (eg, angiogenic and MET pathways).⁷ In the Schulze et al study, the frequency of alterations that could be targeted by available Food and Drug Administration (FDA)–approved drugs comprised either amplifications or mutations of FLTs (6%), FGF3 or 4 or 19 (4%), PDGFRs (3%), VEGFA (1%), HGF (3%), MTOR (2%), EGFR (1%), FGFRs (1%), and MET (1%).⁷ Epigenetic modification of growth-factor expression, particularly insulin-like growth factor 2 and transforming growth factor alpha, and structural alterations that lead to loss of heterozygosity are early events that cause hepatocyte proliferation and progression of dysplastic nodules.^8,9 Advances in whole-exome sequencing have identified TERT promoter mutations, leading to activation of telomerase, as an early event in HCC pathogenesis. Other commonly altered genes include CTNNB1 (B-Catenin) and TP53. As a group, alterations in the MAP kinase pathway genes occur in about 40% of HCC cases.

Actionable oncogenic driver alterations are not as common as tumor suppressor pathway alterations in HCC, making targeted drug development challenging.^10,11 The FGFR (fibroblast growth factor receptor) pathway, which plays a critical role in carcinogenesis-related cell growth, survival, neo-angiogenesis, and acquired resistance to other cancer treatments, is being explored as a treatment target.¹² The molecular characterization of HCC may help with identifying new biomarkers and present opportunities for developing therapeutic targets.

CASE PRESENTATION

A 61-year-old man with a history of chronic hepatitis C and hypertension presents to his primary care physician due to right upper quadrant pain. Laboratory evaluation shows transaminases elevated 2 times the upper limit of normal. This leads to an ultrasound and follow-up magnetic resonance imaging. Imaging shows diffuse cirrhotic changes, with a 6-cm, well-circumscribed lesion within the left lobe of the liver that shows rapid arterial enhancement with venous washout. These vascular characteristics are consistent with HCC. In addition, 2 satellite lesions in the left lobe and sonographic evidence of invasion into the portal vein are present. Periportal lymph nodes are pathologically enlarged.

The physical examination is unremarkable, except for mild tenderness over the right upper quadrant of the abdomen. Serum bilirubin, albumin, platelets, and international normalized ratio are normal, and alpha fetoprotein (AFP) is elevated at 1769 ng/mL. The patient’s family history is unremarkable for any major illness or cancer. Computed tomography scan of the chest and pelvis shows no evidence of other lesions. His liver disease is classified as Child–Pugh A. Due to locally advanced presentation, the tumor is deemed to be nontransplantable and unresectable, and is staged as BCLC-C. The patient continues to work and his performance status is ECOG (Eastern Cooperative Oncology Group) 0. He is referred to the liver tumor clinic for further evaluation and management. The tumor board consensus is to initiate systemic treatment.

What systemic treatment would you recommend for this patient with locally advanced unresectable HCC with nodal metastasis?

First-Line Therapeutic Options

Systemic treatment of HCC is challenging because of the underlying liver cirrhosis and hepatic dysfunction present in most patients. Overall prognosis is therefore dependent on the disease biology and burden and on the degree of hepatic dysfunction. These factors must be considered in patients with advanced disease who present for systemic therapy. As such, patients with BCLC class D HCC with poor performance status and impaired liver function are better off with best supportive care and hospice services (Figure). Table 1 and Table 2 outline the landmark trials that led to the approval of agents for advanced HCC treatment.

Sorafenib

In the patient with BCLC class C HCC who has preserved liver function (traditionally based on a Child–Pugh score of ≤ 6 and a decent functional status [ECOG performance status 1-2]), sorafenib is the first FDA-approved first-line treatment. Sorafenib is a small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) kinase signaling, in addition to many other tyrosine kinase pathways (including the platelet-derived growth factor and Raf-Ras pathways). Evidence for the clinical benefit of sorafenib comes from the SHARP trial.¹³ This was a multinational, but primarily European, randomized phase 3 study that compared sorafenib to best supportive care for advanced HCC in patients with a Child–Pugh score ≤ 6A and a robust performance status (ECOG 0 and 1). Overall survival (OS) with placebo and sorafenib was 7.9 months and 10.7 months, respectively. There was no difference in time to radiologic progression, and the progression-free survival (PFS) at 4 months was 62% with sorafenib and 42% with placebo. Patients with HCV-associated HCC appeared to derive a more substantial benefit from sorafenib.¹⁴ In a smaller randomized study of sorafenib in Asian patients with predominantly hepatitis B–associated HCC, OS in the sorafenib and best supportive care arms was lower than that reported in the SHARP study (6.5 months vs 4.2 months), although OS still was longer in the sorafenib group.¹⁵

Significant adverse events reported with sorafenib include fatigue (30%), hand and foot syndrome (30%), diarrhea (15%), and mucositis (10%). Major proportions of patients in the clinical setting have not tolerated the standard dose of 400 mg twice daily. Dose-adjusted administration of sorafenib has been advocated in patients with more impaired liver function (Child–Pugh class 7B) and bilirubin of 1.5 to 3 times the upper limit of normal, although it is unclear whether these patients are deriving any benefit from sorafenib.¹⁶ At this time, in a patient with preserved liver function, starting with 400 mg twice daily, followed by dose reduction based on toxicity, remains standard.

Lenvatinib

After multiple attempts to develop newer first-line treatments for HCC, lenvatinib, another small-molecule multikinase inhibitor of VEGFR signaling, was approved by the FDA in August 2018. Approval was based on a noninferiority study of lenvatinib versus sorafenib in patients with unresectable, treatment-naïve HCC who had preserved liver function and excellent performance status.¹⁷ Lenvatinib was noninferior to sorafenib, with an OS of 13.6 months versus 12.3 months for sorafenib. Lenvatinib was associated with an improved response rate (24% vs 9%), increased time to disease progression, and longer PFS (7.3 months vs 3.6 months). Patients with a performance status of 0 and 1 were allowed in this trial. Lenvatinib is associated with a more favorable adverse effect profile and is desirable in patients in whom tumor shrinkage is important. Compared to those treated with sorafenib, patients treated with lenvatinib reported a somewhat higher incidence of higher-grade hypertension (42% vs 30%), loss of appetite (34% vs 27%), and weight loss (31%), but lower rates of diarrhea (39% vs 46%) and skin toxicity (27% vs 52%).

Following the sorafenib approval, clinical studies of several other agents did not meet their primary endpoint and failed to show improvement in clinical outcomes compared to sorafenib. However, over the past years the treatment landscape for advanced HCC has been changed with the approval of several agents in the second line. The overall response rate (ORR) has become the new theme for management of advanced disease. With multiple therapeutic options available, optimal sequencing now plays a critical role, especially for transitioning from locoregional to systemic therapy. Five drugs are now indicated for second-line treatment of patients who progressed on or were intolerant to sorafenib: regorafenib, cabozantinib, ramucirumab, nivolumab, and pembrolizumab.

Regorafenib

Regorafenib was evaluated in the advanced HCC setting in a single-arm, phase 2 trial involving 36 patients with Child–Pugh class A liver disease who had progressed on prior sorafenib.¹⁸ Patients received regorafenib 160 mg orally once daily for 3 weeks on/1 week off cycles. Disease control was achieved in 72% of patients, with stable disease in 25 patients (69%). Based on these results, regorafenib was further evaluated in the multicenter, phase 3, 2:1 randomized, double-blind, placebo-controlled RESORCE study, which enrolled 573 patients.¹⁹ Due to the overlapping safety profiles of sorafenib and regorafenib, the inclusion criteria required patients to have tolerated a sorafenib dose of at least 400 mg daily for 20 of the past 28 days of treatment prior to enrollment. The primary endpoint of the study, OS, was met (median OS of 10.6 months in regorafenib arm versus 7.8 months in placebo arm; hazard ratio [HR], 0.63; P < 0.0001). Serious adverse events occurred in 44% of the patients who received regorafenib; the most common were hypertension (15%), hand-foot-skin reaction (HFSR, 13%), fatigue (9%), bleeding events (6%), and diarrhea (3%). Seven (2%) deaths in the regorafenib group were attributable to this drug. HFSR due to regorafenib was found to be associated with better survival outcomes.²⁰ In the selected subpopulation for the study, treatment with the sequence of sorafenib followed by regorafenib resulted in a median OS of 26 months.²¹

Cabozantinib

CELESTIAL was a phase 3, double-blind study that assessed the efficacy of cabozantinib versus placebo in patients with advanced HCC who had received prior sorafenib.²² In this study, 707 patients with Child–Pugh class A liver disease who progressed on at least 1 prior systemic therapy were randomized in a 2:1 ratio to treatment with cabozantinib at 60 mg daily or placebo. Patients treated with cabozantinib had a longer OS (10.2 months vs 8.0 months), resulting in a 24% reduction in the risk of death (HR, 0.76), and a longer median PFS (5.2 months versus 1.9 months). The disease control rate was higher with cabozantinib (64% vs 33%) as well. The incidence of high‐grade adverse events in the cabozantinib group was twice that of the placebo group. Common adverse events reported with cabozantinib included HFSR (17%), hypertension (16%), increased aspartate aminotransferase (12%), fatigue (10%), and diarrhea (10%). 

Ramucirumab

REACH was a phase 3 study exploring the efficacy of ramucirumab that did not meet its primary endpoint; however, the subgroup analysis in AFP-high patients showed an OS improvement with ramucirumab.²³ This led to the phase 3 REACH-2 trial, a multicenter, randomized, double-blind biomarker study in patients with advanced HCC who either progressed on or were intolerant to sorafenib and had an AFP level ≥ 400 ng/mL.²⁴ Patients were randomized to ramucirumab 8 mg/kg every 2 weeks or placebo. The study met its primary endpoint, showing improved OS (8.5 months vs 7.3 months; P = 0.0059). The most common treatment-related adverse events in the ramucirumab group were ascites (5%), hypertension (12%), asthenia (5%), malignant neoplasm progression (6%), increased aspartate aminotransferase concentration (5%), and thrombocytopenia.

Immunotherapy

HCC is considered an inflammation-induced cancer, which renders immunotherapeutic strategies more appealing. The PD-L1/PD-1 pathway is the critical immune checkpoint mechanism and is an important target for treatment. HCC uses a complex, overlapping set of mechanisms to evade cancer-specific immunity and to suppress the immune system. Initial efforts to develop immunotherapies for HCC focused on anti-PD-1 and anti-PD-L1 antibodies. CheckMate 040 evaluated nivolumab in 262 sorafenib-naïve and -treated patients with advanced HCC (98% with Child–Pugh scores of 5 or 6), with a median follow-up of 12.9 months.²⁵ In sorafenib-naïve patients (n = 80), the ORR was 23%, and the disease control rate was 63%. In sorafenib-treated patients (n = 182), the ORR was 18%. Response was not associated with PD-L1 expression. Durable objective responses, a manageable safety profile, and promising efficacy led the FDA to grant accelerated approval of nivolumab for the treatment of patients with HCC who have been previously treated with sorafenib. Based on this, the phase 3 randomized CheckMate-459 trial evaluated the efficacy of nivolumab versus sorafenib in the first-line. Median OS and ORR were better with nivolumab (16.4 months vs 14.7 months; HR 0.85; P = 0.752; and 15% [with 5 complete responses] vs 7%), as was the safety profile (22% vs 49% reporting grade 3 and 4 adverse events). ²⁶

The KEYNOTE-224 study²⁷ evaluated pembrolizumab in 104 patients with previously treated advanced HCC. This study showed an ORR of 17%, with 1 complete response and 17 partial responses. One-third of the patients had progressive disease, while 46 had stable disease. Among those who responded, 56% maintained a durable response for more than 1 year. Subsequently, in KEYNOTE 240, pembrolizumab showed an improvement in OS (13.9 months vs 10.6 months; HR, 0.78; P = 0.0238) and PFS (3.0 months versus 2.8 months; HR, 0.78; P = 0.0186) compared with placebo.²⁸ The ORR for pembrolizumab was 16.9% (95% confidence interval [CI], 12.7%-21.8%) versus 2.2% (95% CI, 0.5%-6.4%; P = 0.00001) for placebo. Mean duration of response was 13.8 months.

In the IMbrave150 trial, atezolizumab/bevacizumab combination, compared to sorafenib, had better OS (not estimable vs 13.2 months; P = 0.0006), PFS (6.8 months vs 4.5 months, P < 0.0001), and ORR (33% vs 13%, P < 0.0001), but grade 3-4 events were similar.²⁹ This combination has potential for first-line approval. The COSMIC–312 study is comparing the combination of cabozantinib and atezolizumab to sorafenib monotherapy and cabozantinib monotherapy in advanced HCC.

Resistance to immunotherapy can be extrinsic, associated with activation mechanisms of T-cells, or intrinsic, related to immune recognition, gene expression, and cell-signaling pathways.³⁰ Tumor-immune heterogeneity and antigen presentation contribute to complex resistance mechanisms.^31,32 Although clinical outcomes have improved with immune checkpoint inhibitors, the response rate is low and responses are inconsistent, likely due to an immunosuppressive tumor microenvironment.³³ Therefore, several novel combinations of checkpoint inhibitors and targeted drugs are being evaluated to bypass some of the resistance mechanisms (Table 3).

Chemotherapy

Multiple combinations of cytotoxic regimens have been evaluated, but efficacy has been modest, suggesting the limited role for traditional chemotherapy in the systemic management of advanced HCC. Response rates to chemotherapy are low and responses are not durable. Gemcitabine- and doxorubicin-based treatment and FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) are some regimens that have been studied, with a median OS of less than 1 year for these regimens.^34-36 FOLFOX had a higher response rate (8.15% vs 2.67%; P = 0.02) and longer median OS (6.40 months versus 4.97 months; HR, 0.80; 95% CI, 0.63-1.02; P = 0.07) than doxorubicin.³⁴ With the gemcitabine/oxaliplatin combination, ORR was 18%, with stable disease in 58% of patients, and median PFS and OS were 6.3 months and 11.5 months, respectively.³⁵ In a study that compared doxorubicin and PIAF (cisplatin/interferon a-2b/doxorubicin/5-fluorouracil), median OS was 6.83 months and 8.67 months, respectively (P = 0.83). The hazard ratio for death from any cause in the PIAF group compared with the doxorubicin group was 0.97 (95% CI, 0.71-1.32). PIAF had a higher ORR (20.9%; 95% CI, 12.5%-29.2%) than doxorubicin (10.5%; 95% CI, 3.9%-16.9%).

The phase 3 ALLIANCE study evaluated the combination of sorafenib and doxorubicin in treatment-naïve HCC patients with Child–Pugh class A liver disease, and did not demonstrate superiority with the addition of cytotoxic chemotherapy.³⁷ Indeed, the combination of chemotherapy with sorafenib appears harmful in terms of lower OS (9.3 months vs 10.6 months; HR, 1.06; 95% CI, 0.8-1.4) and worse toxicity. Patients treated with the combination experienced more hematologic (37.8% vs 8.1%) and nonhematologic adverse events (63.6% vs 61.5%).

Locoregional Therapy

The role of locoregional therapy in advanced HCC remains the subject of intense debate. Patients with BCLC stage C HCC with metastatic disease and those with lymph node involvement are candidates for systemic therapy. The optimal candidate for locoregional therapy is the patient with localized intermediate-stage disease, particularly hepatic artery–delivered therapeutic interventions. However, the presence of a solitary large tumor or portal vein involvement constitutes gray areas regarding which therapy to deliver directly to the tumor via the hepatic artery, and increasingly stereotactic body radiation therapy is being offered.

Transarterial Chemoembolization

Transarterial chemoembolization (TACE), with or without chemotherapy, is the most widely adopted locoregional therapy in the management of HCC. TACE exploits the differential vascular supply to the HCC and normal liver parenchyma. Normal liver receives only one-fourth of its blood supply from the hepatic artery (three-fourths from the portal vein), whereas HCC is mainly supplied by the hepatic artery. A survival benefit for TACE compared to best supportive care is widely acknowledged for intermediate-stage HCC, and transarterial embolization (TAE) with gelatin sponge or microspheres is noninferior to TACE.^38,39 Overall safety profile and efficacy inform therapy selection in advanced HCC, although the evidence for TACE in advanced HCC is less robust. Although single-institution experiences suggest survival numbers similar to and even superior to sorafenib,^40,41 there is a scarcity of large randomized clinical trial data to back this up. Based on this, patients with advanced HCC should only be offered liver-directed therapy within a clinical trial or on a case-by-case basis under multidisciplinary tumor board consensus.

A serious adverse effect of TACE is post-embolization syndrome, which occurs in about 30% of patients and may be associated with poor prognosis.⁴² The syndrome consists of right upper quadrant abdominal pain, malaise, and worsening nausea/vomiting following the embolization procedure. Laboratory abnormalities and other complications may persist for up to 30 days after the procedure. This is a concern, because post-embolization syndrome may affect the ability to deliver systemic therapy.

Transarterial Radioembolization

In the past few years, there has been an uptick in the utilization of transarterial radioembolization (TARE), which instead of delivering glass beads, as done in TAE, or chemotherapy-infused beads, as done in TACE, delivers the radioisotope Y-90 to the tumor via the hepatic artery. TARE is able to administer larger doses of radiation to the tumor while avoiding normal liver tissue, as compared to external-beam radiation. There has been no head-to-head comparison of these different intra-arterial therapy approaches, but TARE with Y-90 has been shown to be safe in patients with portal vein thrombosis. A recent multicenter retrospective study of TARE demonstrated a median OS of 8.8 to 10.8 months in patients with BCLC C HCC,⁴³ and in a large randomized study of Y-90 compared to sorafenib in advanced and previously treated intermediate HCC, there was no difference in median OS between the treatment modalities (8 months for selective internal radiotherapy, 9 months for sorafenib; P = 0.18). Treatment with Y-90 was better tolerated.⁴⁴ A major impediment to the adoption of TARE is the time it takes to order, plan, and deliver Y-90 to patients. Radio-embolization-induced liver disease, similar to post-embolization syndrome, is characterized by jaundice and ascites, which may occur 4 to 8 weeks postprocedure and is more common in patients with HCC who do not have cirrhosis. Compared to TACE, TARE may offer a better adverse effect profile, with improvement in quality of life.

Combination of Systemic and Locoregional Therapy

Even in carefully selected patients with intermediate- and advanced-stage HCC, locoregional therapy is not curative. Tumor embolization may promote more angiogenesis, and hence tumor progression, by causing hypoxia and upregulation of hypoxia-inducible factor.⁴⁵ This upregulation of angiogenesis as a resistance mechanism to tumor embolization provides a rationale for combining systemic therapy (typically based on abrogating angiogenesis) with TACE/TAE. Most of the experience has been with sorafenib in intermediate-stage disease, and the results have been disappointing. The administration of sorafenib after at least a partial response with TACE did not provide additional benefit in terms of time to progression.⁴⁶ Similarly, in the SPACE trial, concurrent therapy with TACE-doxorubicin-eluting beads and sorafenib compared to TACE-doxorubicin-eluting beads and placebo yielded similar time to progression numbers for both treatment modalities.⁴⁷ While the data have been disappointing in intermediate-stage disease, as described earlier, registry data suggest that patients with advanced-stage disease may benefit from this approach.⁴⁸

In the phase 2 TACTICS trial, 156 patients with unresectable HCC were randomized to receive TACE alone or sorafenib plus TACE, with a novel endpoint, time to untreatable progression (TTUP) and/or progression to TACE refractoriness.⁴⁹ Treatment with sorafenib following TACE was continued until TTUP, decline in liver function to Child–Pugh class C, or the development of vascular invasion or extrahepatic spread. Development of new lesions while on sorafenib was not considered as progressive disease as long as the lesions were amenable to TACE. In this study, PFS was longer with sorafenib-TACE compared to TACE alone (26.7 months vs 20.6 months; P = 0.02). However, the TTUP endpoint needs further validation, and we are still awaiting the survival outcomes of this study. At this time, there are insufficient data to recommend the combination of liver-directed locoregional therapy and sorafenib or other systemic therapy options outside of a clinical trial setting.

Current Treatment Approach for Advanced HCC (BCLC-C)

Although progress is being made in the development of effective therapies, advanced HCC is generally incurable. These patients experience significant symptom burden throughout the course of the disease. Therefore, the optimal treatment plan must focus on improving or maintaining quality of life, in addition to overall efficacy. It is important to actively involve patients in treatment decisions for an individualized treatment plan, and to discuss the best strategy for incorporating current advances in targeted and immunotherapies. The paradigm of what constitutes first-line treatment for advanced HCC is shifting due to the recent systemic therapy approvals. Prior to the availability of these therapies, many patients with advanced HCC were treated with repeated locoregional therapies. For instance, TACE was often used to treat unresectable HCC multiple times beyond progression. There was no consensus on the definition of TACE failure, and hence it was used in broader, unselected populations. Retrospective studies suggest that continuing TACE after refractoriness or failure may not be beneficial, and may delay subsequent treatments because of deterioration of liver function or declines in performance status. With recent approvals of several systemic therapy options, including immunotherapy, it is vital to conduct a risk-benefit assessment prior to repeating TACE after failure, so that patients are not denied the use of available systemic therapeutic options due to declined performance status or organ function from these procedures. The optimal timing and the sequence of systemic and locoregional therapy must be carefully evaluated by a multidisciplinary team.

CASE CONCLUSION

An important part of evaluating a new patient with HCC is to determine whether they are a candidate for curative therapies, such as transplant or surgical resection. These are no longer an option for patients with intermediate disease. For patients with advanced disease characteristics, such as vascular invasion or systemic metastasis, the evidence supports using systemic therapy with sorafenib or lenvatinib. Lenvatinib, with a better tolerance profile and response rate, is the treatment of choice for the patient described in the case scenario. Lenvatinib is also indicated for first-line treatment of advanced HCC, and is useful in very aggressive tumors, such as those with an AFP level exceeding 200 ng/mL.

Future Directions

The emerging role of novel systemic therapeutics, including immunotherapy, has drastically changed the treatment landscape for hepatocellular cancers, with 6 new drugs for treating advanced hepatocellular cancers approved recently. While these systemic drugs have improved survival in advanced HCC in the past decade, patient selection and treatment sequencing remain a challenge, due to a lack of biomarkers capable of predicting antitumor responses. In addition, there is an unmet need for treatment options for patients with Child–Pugh class B7 and C liver disease and poor performance status.

The goal of future management should be to achieve personalized care aimed at improved safety and efficacy by targeting multiple cancer pathways in the HCC cascade with combination treatments. Randomized clinical trials to improve patient selection and determine the proper sequence of treatments are needed. Given the heterogeneity of HCC, molecular profiling of the tumor to differentiate responders from nonresponders may elucidate potential biomarkers to effectively guide treatment recommendations.

From the University of Alabama at Birmingham, Division of Hematology Oncology, Birmingham, AL, and the University of South Alabama, Division of Hematology Oncology, Mobile, AL. Dr. Paluri and Dr. Hatic contributed equally to this article.

Abstract

• Objective: To review systemic treatment options for patients with locally advanced unresectable hepatocellular carcinoma (HCC).
• Methods: Review of the literature.
• Results: The paradigm of what constitutes first-line treatment for advanced HCC is shifting. Until recently, many patients with advanced HCC were treated with repeated locoregional therapies, such as transartertial embolization (TACE). However, retrospective studies suggest that continuing TACE after refractoriness or failure may not be beneficial and may delay subsequent treatments because of deterioration of liver function or declines in performance status. With recent approvals of several systemic therapy options, including immunotherapy, it is vital to conduct a risk-benefit assessment prior to repeating TACE after failure, so that patients are not denied the use of available systemic therapeutic options due to declined performance status or organ function from these procedures. The optimal timing and the sequence of systemic and locoregional therapy must be carefully evaluated by a multidisciplinary team.
• Conclusion: Randomized clinical trials to improve patient selection and determine the proper sequence of treatments are needed. Given the heterogeneity of HCC, molecular profiling of the tumor to differentiate responders from nonresponders may elucidate potential biomarkers to effectively guide treatment recommendations.

Keywords: liver cancer; molecular therapy; immunotherapy.

Hepatocellular carcinoma (HCC) represents 90% of primary liver malignancies. It is the fifth most common malignancy in males and the ninth most common in females worldwide.¹ In contrast to other major cancers (colon, breast, prostate), the incidence of and mortality from HCC has increased over the past decade, following a brief decline between 1999 and 2004.² The epidemiology and incidence of HCC is closely linked to chronic liver disease and conditions predisposing to liver cirrhosis. Worldwide, hepatitis B virus infection is the leading cause of liver cirrhosis and, hence, HCC. In the United States, 50% of HCC cases are linked to hepatitis C virus (HCV) infection. Diabetes mellitus and alcoholic and nonalcoholic steatohepatitis are the other major etiologies of HCC. Indeed, the metabolic syndrome, independent of other factors, is associated with a 2-fold increase in the risk of HCC.³

Although most cases of HCC are predated by liver cirrhosis, in about 20% of patients HCC occurs without liver cirrhosis.⁴ Similar to other malignancies, surgery in the form of resection (for isolated lesions in the context of good liver function) or liver transplant (for low-volume disease with mildly impaired liver function) provides the best chance of a cure. Locoregional therapies involving hepatic artery–directed therapy are offered for patients with more advanced disease that is limited to the liver, while systemic therapy is offered for advanced unresectable disease that involves portal vein invasion, lymph nodes, and distant metastasis. The Barcelona Clinic Liver Cancer (BCLC) staging system is the most widely used for staging and treatment in HCC. It not only considers the size of the tumor, but also incorporates the degree of liver dysfunction and the patient’s functional status.^5,6

Molecular Pathogenesis

Similar to other malignancies, a multistep process of carcinogenesis, with accumulation of genomic alterations at the molecular and cellular levels, is recognized in HCC. In about 80% of cases, repeated and chronic injury, inflammation, and repair lead to a distortion of normal liver architecture and development of cirrhotic nodules. Exome sequencing of HCC tissues has identified risk factor–specific mutational signatures, including those related to the tumor microenvironment, and defined the extensive landscape of altered genes and pathways in HCC (eg, angiogenic and MET pathways).⁷ In the Schulze et al study, the frequency of alterations that could be targeted by available Food and Drug Administration (FDA)–approved drugs comprised either amplifications or mutations of FLTs (6%), FGF3 or 4 or 19 (4%), PDGFRs (3%), VEGFA (1%), HGF (3%), MTOR (2%), EGFR (1%), FGFRs (1%), and MET (1%).⁷ Epigenetic modification of growth-factor expression, particularly insulin-like growth factor 2 and transforming growth factor alpha, and structural alterations that lead to loss of heterozygosity are early events that cause hepatocyte proliferation and progression of dysplastic nodules.^8,9 Advances in whole-exome sequencing have identified TERT promoter mutations, leading to activation of telomerase, as an early event in HCC pathogenesis. Other commonly altered genes include CTNNB1 (B-Catenin) and TP53. As a group, alterations in the MAP kinase pathway genes occur in about 40% of HCC cases.

Actionable oncogenic driver alterations are not as common as tumor suppressor pathway alterations in HCC, making targeted drug development challenging.^10,11 The FGFR (fibroblast growth factor receptor) pathway, which plays a critical role in carcinogenesis-related cell growth, survival, neo-angiogenesis, and acquired resistance to other cancer treatments, is being explored as a treatment target.¹² The molecular characterization of HCC may help with identifying new biomarkers and present opportunities for developing therapeutic targets.

CASE PRESENTATION

A 61-year-old man with a history of chronic hepatitis C and hypertension presents to his primary care physician due to right upper quadrant pain. Laboratory evaluation shows transaminases elevated 2 times the upper limit of normal. This leads to an ultrasound and follow-up magnetic resonance imaging. Imaging shows diffuse cirrhotic changes, with a 6-cm, well-circumscribed lesion within the left lobe of the liver that shows rapid arterial enhancement with venous washout. These vascular characteristics are consistent with HCC. In addition, 2 satellite lesions in the left lobe and sonographic evidence of invasion into the portal vein are present. Periportal lymph nodes are pathologically enlarged.

The physical examination is unremarkable, except for mild tenderness over the right upper quadrant of the abdomen. Serum bilirubin, albumin, platelets, and international normalized ratio are normal, and alpha fetoprotein (AFP) is elevated at 1769 ng/mL. The patient’s family history is unremarkable for any major illness or cancer. Computed tomography scan of the chest and pelvis shows no evidence of other lesions. His liver disease is classified as Child–Pugh A. Due to locally advanced presentation, the tumor is deemed to be nontransplantable and unresectable, and is staged as BCLC-C. The patient continues to work and his performance status is ECOG (Eastern Cooperative Oncology Group) 0. He is referred to the liver tumor clinic for further evaluation and management. The tumor board consensus is to initiate systemic treatment.

What systemic treatment would you recommend for this patient with locally advanced unresectable HCC with nodal metastasis?

First-Line Therapeutic Options

Systemic treatment of HCC is challenging because of the underlying liver cirrhosis and hepatic dysfunction present in most patients. Overall prognosis is therefore dependent on the disease biology and burden and on the degree of hepatic dysfunction. These factors must be considered in patients with advanced disease who present for systemic therapy. As such, patients with BCLC class D HCC with poor performance status and impaired liver function are better off with best supportive care and hospice services (Figure). Table 1 and Table 2 outline the landmark trials that led to the approval of agents for advanced HCC treatment.

Sorafenib

In the patient with BCLC class C HCC who has preserved liver function (traditionally based on a Child–Pugh score of ≤ 6 and a decent functional status [ECOG performance status 1-2]), sorafenib is the first FDA-approved first-line treatment. Sorafenib is a small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) kinase signaling, in addition to many other tyrosine kinase pathways (including the platelet-derived growth factor and Raf-Ras pathways). Evidence for the clinical benefit of sorafenib comes from the SHARP trial.¹³ This was a multinational, but primarily European, randomized phase 3 study that compared sorafenib to best supportive care for advanced HCC in patients with a Child–Pugh score ≤ 6A and a robust performance status (ECOG 0 and 1). Overall survival (OS) with placebo and sorafenib was 7.9 months and 10.7 months, respectively. There was no difference in time to radiologic progression, and the progression-free survival (PFS) at 4 months was 62% with sorafenib and 42% with placebo. Patients with HCV-associated HCC appeared to derive a more substantial benefit from sorafenib.¹⁴ In a smaller randomized study of sorafenib in Asian patients with predominantly hepatitis B–associated HCC, OS in the sorafenib and best supportive care arms was lower than that reported in the SHARP study (6.5 months vs 4.2 months), although OS still was longer in the sorafenib group.¹⁵

Significant adverse events reported with sorafenib include fatigue (30%), hand and foot syndrome (30%), diarrhea (15%), and mucositis (10%). Major proportions of patients in the clinical setting have not tolerated the standard dose of 400 mg twice daily. Dose-adjusted administration of sorafenib has been advocated in patients with more impaired liver function (Child–Pugh class 7B) and bilirubin of 1.5 to 3 times the upper limit of normal, although it is unclear whether these patients are deriving any benefit from sorafenib.¹⁶ At this time, in a patient with preserved liver function, starting with 400 mg twice daily, followed by dose reduction based on toxicity, remains standard.

Lenvatinib

After multiple attempts to develop newer first-line treatments for HCC, lenvatinib, another small-molecule multikinase inhibitor of VEGFR signaling, was approved by the FDA in August 2018. Approval was based on a noninferiority study of lenvatinib versus sorafenib in patients with unresectable, treatment-naïve HCC who had preserved liver function and excellent performance status.¹⁷ Lenvatinib was noninferior to sorafenib, with an OS of 13.6 months versus 12.3 months for sorafenib. Lenvatinib was associated with an improved response rate (24% vs 9%), increased time to disease progression, and longer PFS (7.3 months vs 3.6 months). Patients with a performance status of 0 and 1 were allowed in this trial. Lenvatinib is associated with a more favorable adverse effect profile and is desirable in patients in whom tumor shrinkage is important. Compared to those treated with sorafenib, patients treated with lenvatinib reported a somewhat higher incidence of higher-grade hypertension (42% vs 30%), loss of appetite (34% vs 27%), and weight loss (31%), but lower rates of diarrhea (39% vs 46%) and skin toxicity (27% vs 52%).

Following the sorafenib approval, clinical studies of several other agents did not meet their primary endpoint and failed to show improvement in clinical outcomes compared to sorafenib. However, over the past years the treatment landscape for advanced HCC has been changed with the approval of several agents in the second line. The overall response rate (ORR) has become the new theme for management of advanced disease. With multiple therapeutic options available, optimal sequencing now plays a critical role, especially for transitioning from locoregional to systemic therapy. Five drugs are now indicated for second-line treatment of patients who progressed on or were intolerant to sorafenib: regorafenib, cabozantinib, ramucirumab, nivolumab, and pembrolizumab.

Regorafenib

Regorafenib was evaluated in the advanced HCC setting in a single-arm, phase 2 trial involving 36 patients with Child–Pugh class A liver disease who had progressed on prior sorafenib.¹⁸ Patients received regorafenib 160 mg orally once daily for 3 weeks on/1 week off cycles. Disease control was achieved in 72% of patients, with stable disease in 25 patients (69%). Based on these results, regorafenib was further evaluated in the multicenter, phase 3, 2:1 randomized, double-blind, placebo-controlled RESORCE study, which enrolled 573 patients.¹⁹ Due to the overlapping safety profiles of sorafenib and regorafenib, the inclusion criteria required patients to have tolerated a sorafenib dose of at least 400 mg daily for 20 of the past 28 days of treatment prior to enrollment. The primary endpoint of the study, OS, was met (median OS of 10.6 months in regorafenib arm versus 7.8 months in placebo arm; hazard ratio [HR], 0.63; P < 0.0001). Serious adverse events occurred in 44% of the patients who received regorafenib; the most common were hypertension (15%), hand-foot-skin reaction (HFSR, 13%), fatigue (9%), bleeding events (6%), and diarrhea (3%). Seven (2%) deaths in the regorafenib group were attributable to this drug. HFSR due to regorafenib was found to be associated with better survival outcomes.²⁰ In the selected subpopulation for the study, treatment with the sequence of sorafenib followed by regorafenib resulted in a median OS of 26 months.²¹

Cabozantinib

CELESTIAL was a phase 3, double-blind study that assessed the efficacy of cabozantinib versus placebo in patients with advanced HCC who had received prior sorafenib.²² In this study, 707 patients with Child–Pugh class A liver disease who progressed on at least 1 prior systemic therapy were randomized in a 2:1 ratio to treatment with cabozantinib at 60 mg daily or placebo. Patients treated with cabozantinib had a longer OS (10.2 months vs 8.0 months), resulting in a 24% reduction in the risk of death (HR, 0.76), and a longer median PFS (5.2 months versus 1.9 months). The disease control rate was higher with cabozantinib (64% vs 33%) as well. The incidence of high‐grade adverse events in the cabozantinib group was twice that of the placebo group. Common adverse events reported with cabozantinib included HFSR (17%), hypertension (16%), increased aspartate aminotransferase (12%), fatigue (10%), and diarrhea (10%). 

Ramucirumab

REACH was a phase 3 study exploring the efficacy of ramucirumab that did not meet its primary endpoint; however, the subgroup analysis in AFP-high patients showed an OS improvement with ramucirumab.²³ This led to the phase 3 REACH-2 trial, a multicenter, randomized, double-blind biomarker study in patients with advanced HCC who either progressed on or were intolerant to sorafenib and had an AFP level ≥ 400 ng/mL.²⁴ Patients were randomized to ramucirumab 8 mg/kg every 2 weeks or placebo. The study met its primary endpoint, showing improved OS (8.5 months vs 7.3 months; P = 0.0059). The most common treatment-related adverse events in the ramucirumab group were ascites (5%), hypertension (12%), asthenia (5%), malignant neoplasm progression (6%), increased aspartate aminotransferase concentration (5%), and thrombocytopenia.

Immunotherapy

HCC is considered an inflammation-induced cancer, which renders immunotherapeutic strategies more appealing. The PD-L1/PD-1 pathway is the critical immune checkpoint mechanism and is an important target for treatment. HCC uses a complex, overlapping set of mechanisms to evade cancer-specific immunity and to suppress the immune system. Initial efforts to develop immunotherapies for HCC focused on anti-PD-1 and anti-PD-L1 antibodies. CheckMate 040 evaluated nivolumab in 262 sorafenib-naïve and -treated patients with advanced HCC (98% with Child–Pugh scores of 5 or 6), with a median follow-up of 12.9 months.²⁵ In sorafenib-naïve patients (n = 80), the ORR was 23%, and the disease control rate was 63%. In sorafenib-treated patients (n = 182), the ORR was 18%. Response was not associated with PD-L1 expression. Durable objective responses, a manageable safety profile, and promising efficacy led the FDA to grant accelerated approval of nivolumab for the treatment of patients with HCC who have been previously treated with sorafenib. Based on this, the phase 3 randomized CheckMate-459 trial evaluated the efficacy of nivolumab versus sorafenib in the first-line. Median OS and ORR were better with nivolumab (16.4 months vs 14.7 months; HR 0.85; P = 0.752; and 15% [with 5 complete responses] vs 7%), as was the safety profile (22% vs 49% reporting grade 3 and 4 adverse events). ²⁶

The KEYNOTE-224 study²⁷ evaluated pembrolizumab in 104 patients with previously treated advanced HCC. This study showed an ORR of 17%, with 1 complete response and 17 partial responses. One-third of the patients had progressive disease, while 46 had stable disease. Among those who responded, 56% maintained a durable response for more than 1 year. Subsequently, in KEYNOTE 240, pembrolizumab showed an improvement in OS (13.9 months vs 10.6 months; HR, 0.78; P = 0.0238) and PFS (3.0 months versus 2.8 months; HR, 0.78; P = 0.0186) compared with placebo.²⁸ The ORR for pembrolizumab was 16.9% (95% confidence interval [CI], 12.7%-21.8%) versus 2.2% (95% CI, 0.5%-6.4%; P = 0.00001) for placebo. Mean duration of response was 13.8 months.

In the IMbrave150 trial, atezolizumab/bevacizumab combination, compared to sorafenib, had better OS (not estimable vs 13.2 months; P = 0.0006), PFS (6.8 months vs 4.5 months, P < 0.0001), and ORR (33% vs 13%, P < 0.0001), but grade 3-4 events were similar.²⁹ This combination has potential for first-line approval. The COSMIC–312 study is comparing the combination of cabozantinib and atezolizumab to sorafenib monotherapy and cabozantinib monotherapy in advanced HCC.

Resistance to immunotherapy can be extrinsic, associated with activation mechanisms of T-cells, or intrinsic, related to immune recognition, gene expression, and cell-signaling pathways.³⁰ Tumor-immune heterogeneity and antigen presentation contribute to complex resistance mechanisms.^31,32 Although clinical outcomes have improved with immune checkpoint inhibitors, the response rate is low and responses are inconsistent, likely due to an immunosuppressive tumor microenvironment.³³ Therefore, several novel combinations of checkpoint inhibitors and targeted drugs are being evaluated to bypass some of the resistance mechanisms (Table 3).

Chemotherapy

Multiple combinations of cytotoxic regimens have been evaluated, but efficacy has been modest, suggesting the limited role for traditional chemotherapy in the systemic management of advanced HCC. Response rates to chemotherapy are low and responses are not durable. Gemcitabine- and doxorubicin-based treatment and FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) are some regimens that have been studied, with a median OS of less than 1 year for these regimens.^34-36 FOLFOX had a higher response rate (8.15% vs 2.67%; P = 0.02) and longer median OS (6.40 months versus 4.97 months; HR, 0.80; 95% CI, 0.63-1.02; P = 0.07) than doxorubicin.³⁴ With the gemcitabine/oxaliplatin combination, ORR was 18%, with stable disease in 58% of patients, and median PFS and OS were 6.3 months and 11.5 months, respectively.³⁵ In a study that compared doxorubicin and PIAF (cisplatin/interferon a-2b/doxorubicin/5-fluorouracil), median OS was 6.83 months and 8.67 months, respectively (P = 0.83). The hazard ratio for death from any cause in the PIAF group compared with the doxorubicin group was 0.97 (95% CI, 0.71-1.32). PIAF had a higher ORR (20.9%; 95% CI, 12.5%-29.2%) than doxorubicin (10.5%; 95% CI, 3.9%-16.9%).

The phase 3 ALLIANCE study evaluated the combination of sorafenib and doxorubicin in treatment-naïve HCC patients with Child–Pugh class A liver disease, and did not demonstrate superiority with the addition of cytotoxic chemotherapy.³⁷ Indeed, the combination of chemotherapy with sorafenib appears harmful in terms of lower OS (9.3 months vs 10.6 months; HR, 1.06; 95% CI, 0.8-1.4) and worse toxicity. Patients treated with the combination experienced more hematologic (37.8% vs 8.1%) and nonhematologic adverse events (63.6% vs 61.5%).

Locoregional Therapy

The role of locoregional therapy in advanced HCC remains the subject of intense debate. Patients with BCLC stage C HCC with metastatic disease and those with lymph node involvement are candidates for systemic therapy. The optimal candidate for locoregional therapy is the patient with localized intermediate-stage disease, particularly hepatic artery–delivered therapeutic interventions. However, the presence of a solitary large tumor or portal vein involvement constitutes gray areas regarding which therapy to deliver directly to the tumor via the hepatic artery, and increasingly stereotactic body radiation therapy is being offered.

Transarterial Chemoembolization

Transarterial chemoembolization (TACE), with or without chemotherapy, is the most widely adopted locoregional therapy in the management of HCC. TACE exploits the differential vascular supply to the HCC and normal liver parenchyma. Normal liver receives only one-fourth of its blood supply from the hepatic artery (three-fourths from the portal vein), whereas HCC is mainly supplied by the hepatic artery. A survival benefit for TACE compared to best supportive care is widely acknowledged for intermediate-stage HCC, and transarterial embolization (TAE) with gelatin sponge or microspheres is noninferior to TACE.^38,39 Overall safety profile and efficacy inform therapy selection in advanced HCC, although the evidence for TACE in advanced HCC is less robust. Although single-institution experiences suggest survival numbers similar to and even superior to sorafenib,^40,41 there is a scarcity of large randomized clinical trial data to back this up. Based on this, patients with advanced HCC should only be offered liver-directed therapy within a clinical trial or on a case-by-case basis under multidisciplinary tumor board consensus.

A serious adverse effect of TACE is post-embolization syndrome, which occurs in about 30% of patients and may be associated with poor prognosis.⁴² The syndrome consists of right upper quadrant abdominal pain, malaise, and worsening nausea/vomiting following the embolization procedure. Laboratory abnormalities and other complications may persist for up to 30 days after the procedure. This is a concern, because post-embolization syndrome may affect the ability to deliver systemic therapy.

Transarterial Radioembolization

In the past few years, there has been an uptick in the utilization of transarterial radioembolization (TARE), which instead of delivering glass beads, as done in TAE, or chemotherapy-infused beads, as done in TACE, delivers the radioisotope Y-90 to the tumor via the hepatic artery. TARE is able to administer larger doses of radiation to the tumor while avoiding normal liver tissue, as compared to external-beam radiation. There has been no head-to-head comparison of these different intra-arterial therapy approaches, but TARE with Y-90 has been shown to be safe in patients with portal vein thrombosis. A recent multicenter retrospective study of TARE demonstrated a median OS of 8.8 to 10.8 months in patients with BCLC C HCC,⁴³ and in a large randomized study of Y-90 compared to sorafenib in advanced and previously treated intermediate HCC, there was no difference in median OS between the treatment modalities (8 months for selective internal radiotherapy, 9 months for sorafenib; P = 0.18). Treatment with Y-90 was better tolerated.⁴⁴ A major impediment to the adoption of TARE is the time it takes to order, plan, and deliver Y-90 to patients. Radio-embolization-induced liver disease, similar to post-embolization syndrome, is characterized by jaundice and ascites, which may occur 4 to 8 weeks postprocedure and is more common in patients with HCC who do not have cirrhosis. Compared to TACE, TARE may offer a better adverse effect profile, with improvement in quality of life.

Combination of Systemic and Locoregional Therapy

Even in carefully selected patients with intermediate- and advanced-stage HCC, locoregional therapy is not curative. Tumor embolization may promote more angiogenesis, and hence tumor progression, by causing hypoxia and upregulation of hypoxia-inducible factor.⁴⁵ This upregulation of angiogenesis as a resistance mechanism to tumor embolization provides a rationale for combining systemic therapy (typically based on abrogating angiogenesis) with TACE/TAE. Most of the experience has been with sorafenib in intermediate-stage disease, and the results have been disappointing. The administration of sorafenib after at least a partial response with TACE did not provide additional benefit in terms of time to progression.⁴⁶ Similarly, in the SPACE trial, concurrent therapy with TACE-doxorubicin-eluting beads and sorafenib compared to TACE-doxorubicin-eluting beads and placebo yielded similar time to progression numbers for both treatment modalities.⁴⁷ While the data have been disappointing in intermediate-stage disease, as described earlier, registry data suggest that patients with advanced-stage disease may benefit from this approach.⁴⁸

In the phase 2 TACTICS trial, 156 patients with unresectable HCC were randomized to receive TACE alone or sorafenib plus TACE, with a novel endpoint, time to untreatable progression (TTUP) and/or progression to TACE refractoriness.⁴⁹ Treatment with sorafenib following TACE was continued until TTUP, decline in liver function to Child–Pugh class C, or the development of vascular invasion or extrahepatic spread. Development of new lesions while on sorafenib was not considered as progressive disease as long as the lesions were amenable to TACE. In this study, PFS was longer with sorafenib-TACE compared to TACE alone (26.7 months vs 20.6 months; P = 0.02). However, the TTUP endpoint needs further validation, and we are still awaiting the survival outcomes of this study. At this time, there are insufficient data to recommend the combination of liver-directed locoregional therapy and sorafenib or other systemic therapy options outside of a clinical trial setting.

Current Treatment Approach for Advanced HCC (BCLC-C)

Although progress is being made in the development of effective therapies, advanced HCC is generally incurable. These patients experience significant symptom burden throughout the course of the disease. Therefore, the optimal treatment plan must focus on improving or maintaining quality of life, in addition to overall efficacy. It is important to actively involve patients in treatment decisions for an individualized treatment plan, and to discuss the best strategy for incorporating current advances in targeted and immunotherapies. The paradigm of what constitutes first-line treatment for advanced HCC is shifting due to the recent systemic therapy approvals. Prior to the availability of these therapies, many patients with advanced HCC were treated with repeated locoregional therapies. For instance, TACE was often used to treat unresectable HCC multiple times beyond progression. There was no consensus on the definition of TACE failure, and hence it was used in broader, unselected populations. Retrospective studies suggest that continuing TACE after refractoriness or failure may not be beneficial, and may delay subsequent treatments because of deterioration of liver function or declines in performance status. With recent approvals of several systemic therapy options, including immunotherapy, it is vital to conduct a risk-benefit assessment prior to repeating TACE after failure, so that patients are not denied the use of available systemic therapeutic options due to declined performance status or organ function from these procedures. The optimal timing and the sequence of systemic and locoregional therapy must be carefully evaluated by a multidisciplinary team.

CASE CONCLUSION

An important part of evaluating a new patient with HCC is to determine whether they are a candidate for curative therapies, such as transplant or surgical resection. These are no longer an option for patients with intermediate disease. For patients with advanced disease characteristics, such as vascular invasion or systemic metastasis, the evidence supports using systemic therapy with sorafenib or lenvatinib. Lenvatinib, with a better tolerance profile and response rate, is the treatment of choice for the patient described in the case scenario. Lenvatinib is also indicated for first-line treatment of advanced HCC, and is useful in very aggressive tumors, such as those with an AFP level exceeding 200 ng/mL.

Future Directions

The emerging role of novel systemic therapeutics, including immunotherapy, has drastically changed the treatment landscape for hepatocellular cancers, with 6 new drugs for treating advanced hepatocellular cancers approved recently. While these systemic drugs have improved survival in advanced HCC in the past decade, patient selection and treatment sequencing remain a challenge, due to a lack of biomarkers capable of predicting antitumor responses. In addition, there is an unmet need for treatment options for patients with Child–Pugh class B7 and C liver disease and poor performance status.

The goal of future management should be to achieve personalized care aimed at improved safety and efficacy by targeting multiple cancer pathways in the HCC cascade with combination treatments. Randomized clinical trials to improve patient selection and determine the proper sequence of treatments are needed. Given the heterogeneity of HCC, molecular profiling of the tumor to differentiate responders from nonresponders may elucidate potential biomarkers to effectively guide treatment recommendations.

Study Overview

Objective. To examine the effect of clinical geriatric assessments and collaborative medication review by geriatricians and family physicians on quality of life and other patient outcomes in home-dwelling older adults with polypharmacy.

Design. The study was a single-blind, cluster randomized clinical trial enrolling home-dwelling adults aged 70 years and older who were taking 7 or more medications. Family physicians in Norway were recruited to participate in the trial with their patients. Randomization was at the family physician level to avoid contamination between intervention and control groups.

Setting and participants. The study was conducted in Akershus and Oslo, Norway. Family physicians were recruited to participate in the trial with their patients. A total of 84 family physicians were recruited, of which 70 were included in the trial and randomized to intervention versus control; 14 were excluded because they had no eligible patients. The cluster size of each family physician was limited to 5 patients per physician to avoid large variation in cluster sizes. Patients were eligible for enrollment if they were home-dwelling, aged 70 years or older, and were taking 7 or more systemic medications regularly and had medications administered by the home nursing service. Patients were excluded if they were expected to die or be institutionalized within 6 months, or if they were discouraged from participation by their family physician. A total of 174 patients were recruited, with 87 patients in each group (34 family physicians were in the control group and 36 in the intervention group).

Intervention. The intervention included a geriatric assessment performed by a physician trained in geriatric medicine and supervised by a senior consultant. The geriatric assessment consisted of review of medical history; systematic screening for current problems; clinical examination; supplementary tests, if indicated; and review of each medication being used. The review of medication included the indication for each medication, dosage, adverse effects, and interactions. The geriatric assessment consultation took 1 hour to complete, on average. After the geriatric assessment, the family physician and the geriatrician met to discuss each medication and to establish a collaborative plan for adjustments and follow-up; this meeting was approximately 15 minutes in duration. Lastly, clinical follow-up with the older adult was conducted by the geriatrician or the family physician, as agreed upon in the plan, with most follow-up conducted by the family physician. Participants randomized to the control group received usual care without any intervention.

Main outcome measures. Outcomes were assessed at 16-week and 24-week follow-up. The main study outcome measure was health-related quality of life (HRQoL), as measured by the 15D instrument, at 16 weeks. The quality-of-life measure included the following aspects, each rated on an ordinal scale of 5 levels: mobility, vision, hearing, breathing, sleeping, eating, speech, elimination, usual activities, mental function, discomfort or symptoms, depression, distress, vitality, and sexual activity. The index scale including all aspects is in the range of 0 to 1, with a higher score indicating better quality of life. A predetermined change of 0.015 or more is considered clinically important, and a positive change of 0.035 indicates much better HRQoL. Other outcomes included: appropriateness of medications measured by the Medication Appropriateness Index and the Assessment of Underutilization; physical function (short Physical Performance battery); gait speed; grip strength; cognitive functioning; physical and cognitive disability (Functional Independence Measure); caregiver burden (Relative Stress Scale); physical measures, including orthostatic blood pressure, falls, and weight; hospital admissions; use of home nursing service; incidence of institutionalization; and mortality.

Main results. The study included 174 patients with an average age of 83.3 years (SD, 7.3); 67.8% were women. Of those who were randomized to the intervention and control groups, 158 (90.8%) completed the trial. The average number of regularly used medications was 10.1 (SD, 2.7) in the intervention group and 9.5 (SD, 2.6) in the control group. At week 16 of follow-up, patients in the intervention group had an improved HRQoL score measured by the 15D instrument; the difference between the intervention group and control groups was 0.045 (95% confidence interval [CI], 0.004 -0.086; P = 0.03). Medication appropriateness was better in the intervention group, as compared with the control group at both 16 weeks and 24 weeks. Nearly all (99%) patients in the intervention group experienced medication changes, which included withdrawal of medications, dosage adjustment, or new drug regimens. There was a trend towards a higher rate of hospitalization during follow-up in the intervention group (adjusted risk ratio, 2.03; 95% CI, 0.98-4.24; P = 0.06). Other secondary outcomes were not substantially different between the intervention and control groups.

Conclusion. The study demonstrated that a clinical geriatric assessment and collaborative medication review by geriatrician and family physician led to improved HRQoL and improved medication use.

The use of multiple medications in older adults is common, with almost 20% of older adults over age 65 taking 10 or more medications.¹ Polypharmacy in older adults is associated with lower adherence rates and increases the potential for interactions between medications.² Age-related changes, such as changes in absorption, metabolism, and excretion, affect pharmacokinetics of medications and potentiate adverse drug reactions, requiring adjustments in use and dosing to optimize safety and outcomes. Recognizing the potential effects of medications in older adults, evidence-based guidelines, such as the Beers criteria³ and START/STOPP criteria,⁴ have been developed to identify potentially inappropriate medications in older adults and to improve prescribing. Randomized trials using the START/STOPP criteria have demonstrated improved medication appropriateness, reduced polypharmacy, and reduced adverse drug reactions.⁵ Although this study did not use a criteria-based approach for improving medication use, it demonstrated that in a population of older adults with polypharmacy, medication review with geriatricians can lead to improved HRQoL while improving medication appropriateness. The collaborative approach between the family physician and geriatrician, rather than a consultative approach with recommendations from a geriatrician, may have contributed to increased uptake of medication changes. Such an approach may be a reasonable strategy to improve medication use in older adults.

A limitation of the study is that the improvement in HRQoL could have been the result of medication changes, but could also have been due to other changes in the plan of care that resulted from the geriatric assessment. As noted by the authors, the increase in hospital admissions, though not statistically significant, could have resulted from the medication modifications; however, it was also noted that the geriatric assessments could have identified severe illnesses that required hospitalization, as the timeline from geriatric assessment to hospitalization suggested was the case. Thus, the increase in hospitalization resulting from timely identification of severe illness was more likely a benefit than an adverse effect; however, further studies should be done to elucidate this.

Applications for Clinical Practice

Older adults with multiple chronic conditions and complex medication regimens are at risk for poor health outcomes, and a purposeful medication review to improve medication use, leading to the removal of unnecessary and potentially harmful medications, adjustment of dosages, and initiation of appropriate medications, may yield health benefits, such as improved HRQoL. The present study utilized an approach that could be scalable, which is important given the limited number of clinicians with geriatrics expertise. For health systems with geriatrics clinical expertise, it may be reasonable to consider adopting a similar collaborative approach in order to improve care for older adults most at risk. Further reports on how patients and family physicians perceive this intervention will enhance our understanding of whether it could be implemented widely.

–William W. Hung, MD, MPH

Study Overview

Objective. To examine the effect of clinical geriatric assessments and collaborative medication review by geriatricians and family physicians on quality of life and other patient outcomes in home-dwelling older adults with polypharmacy.

Design. The study was a single-blind, cluster randomized clinical trial enrolling home-dwelling adults aged 70 years and older who were taking 7 or more medications. Family physicians in Norway were recruited to participate in the trial with their patients. Randomization was at the family physician level to avoid contamination between intervention and control groups.

Setting and participants. The study was conducted in Akershus and Oslo, Norway. Family physicians were recruited to participate in the trial with their patients. A total of 84 family physicians were recruited, of which 70 were included in the trial and randomized to intervention versus control; 14 were excluded because they had no eligible patients. The cluster size of each family physician was limited to 5 patients per physician to avoid large variation in cluster sizes. Patients were eligible for enrollment if they were home-dwelling, aged 70 years or older, and were taking 7 or more systemic medications regularly and had medications administered by the home nursing service. Patients were excluded if they were expected to die or be institutionalized within 6 months, or if they were discouraged from participation by their family physician. A total of 174 patients were recruited, with 87 patients in each group (34 family physicians were in the control group and 36 in the intervention group).

Intervention. The intervention included a geriatric assessment performed by a physician trained in geriatric medicine and supervised by a senior consultant. The geriatric assessment consisted of review of medical history; systematic screening for current problems; clinical examination; supplementary tests, if indicated; and review of each medication being used. The review of medication included the indication for each medication, dosage, adverse effects, and interactions. The geriatric assessment consultation took 1 hour to complete, on average. After the geriatric assessment, the family physician and the geriatrician met to discuss each medication and to establish a collaborative plan for adjustments and follow-up; this meeting was approximately 15 minutes in duration. Lastly, clinical follow-up with the older adult was conducted by the geriatrician or the family physician, as agreed upon in the plan, with most follow-up conducted by the family physician. Participants randomized to the control group received usual care without any intervention.

Main outcome measures. Outcomes were assessed at 16-week and 24-week follow-up. The main study outcome measure was health-related quality of life (HRQoL), as measured by the 15D instrument, at 16 weeks. The quality-of-life measure included the following aspects, each rated on an ordinal scale of 5 levels: mobility, vision, hearing, breathing, sleeping, eating, speech, elimination, usual activities, mental function, discomfort or symptoms, depression, distress, vitality, and sexual activity. The index scale including all aspects is in the range of 0 to 1, with a higher score indicating better quality of life. A predetermined change of 0.015 or more is considered clinically important, and a positive change of 0.035 indicates much better HRQoL. Other outcomes included: appropriateness of medications measured by the Medication Appropriateness Index and the Assessment of Underutilization; physical function (short Physical Performance battery); gait speed; grip strength; cognitive functioning; physical and cognitive disability (Functional Independence Measure); caregiver burden (Relative Stress Scale); physical measures, including orthostatic blood pressure, falls, and weight; hospital admissions; use of home nursing service; incidence of institutionalization; and mortality.

Main results. The study included 174 patients with an average age of 83.3 years (SD, 7.3); 67.8% were women. Of those who were randomized to the intervention and control groups, 158 (90.8%) completed the trial. The average number of regularly used medications was 10.1 (SD, 2.7) in the intervention group and 9.5 (SD, 2.6) in the control group. At week 16 of follow-up, patients in the intervention group had an improved HRQoL score measured by the 15D instrument; the difference between the intervention group and control groups was 0.045 (95% confidence interval [CI], 0.004 -0.086; P = 0.03). Medication appropriateness was better in the intervention group, as compared with the control group at both 16 weeks and 24 weeks. Nearly all (99%) patients in the intervention group experienced medication changes, which included withdrawal of medications, dosage adjustment, or new drug regimens. There was a trend towards a higher rate of hospitalization during follow-up in the intervention group (adjusted risk ratio, 2.03; 95% CI, 0.98-4.24; P = 0.06). Other secondary outcomes were not substantially different between the intervention and control groups.

Conclusion. The study demonstrated that a clinical geriatric assessment and collaborative medication review by geriatrician and family physician led to improved HRQoL and improved medication use.

The use of multiple medications in older adults is common, with almost 20% of older adults over age 65 taking 10 or more medications.¹ Polypharmacy in older adults is associated with lower adherence rates and increases the potential for interactions between medications.² Age-related changes, such as changes in absorption, metabolism, and excretion, affect pharmacokinetics of medications and potentiate adverse drug reactions, requiring adjustments in use and dosing to optimize safety and outcomes. Recognizing the potential effects of medications in older adults, evidence-based guidelines, such as the Beers criteria³ and START/STOPP criteria,⁴ have been developed to identify potentially inappropriate medications in older adults and to improve prescribing. Randomized trials using the START/STOPP criteria have demonstrated improved medication appropriateness, reduced polypharmacy, and reduced adverse drug reactions.⁵ Although this study did not use a criteria-based approach for improving medication use, it demonstrated that in a population of older adults with polypharmacy, medication review with geriatricians can lead to improved HRQoL while improving medication appropriateness. The collaborative approach between the family physician and geriatrician, rather than a consultative approach with recommendations from a geriatrician, may have contributed to increased uptake of medication changes. Such an approach may be a reasonable strategy to improve medication use in older adults.

A limitation of the study is that the improvement in HRQoL could have been the result of medication changes, but could also have been due to other changes in the plan of care that resulted from the geriatric assessment. As noted by the authors, the increase in hospital admissions, though not statistically significant, could have resulted from the medication modifications; however, it was also noted that the geriatric assessments could have identified severe illnesses that required hospitalization, as the timeline from geriatric assessment to hospitalization suggested was the case. Thus, the increase in hospitalization resulting from timely identification of severe illness was more likely a benefit than an adverse effect; however, further studies should be done to elucidate this.

Applications for Clinical Practice

Older adults with multiple chronic conditions and complex medication regimens are at risk for poor health outcomes, and a purposeful medication review to improve medication use, leading to the removal of unnecessary and potentially harmful medications, adjustment of dosages, and initiation of appropriate medications, may yield health benefits, such as improved HRQoL. The present study utilized an approach that could be scalable, which is important given the limited number of clinicians with geriatrics expertise. For health systems with geriatrics clinical expertise, it may be reasonable to consider adopting a similar collaborative approach in order to improve care for older adults most at risk. Further reports on how patients and family physicians perceive this intervention will enhance our understanding of whether it could be implemented widely.

–William W. Hung, MD, MPH

Study Overview

Objective. To examine the effect of clinical geriatric assessments and collaborative medication review by geriatricians and family physicians on quality of life and other patient outcomes in home-dwelling older adults with polypharmacy.

Design. The study was a single-blind, cluster randomized clinical trial enrolling home-dwelling adults aged 70 years and older who were taking 7 or more medications. Family physicians in Norway were recruited to participate in the trial with their patients. Randomization was at the family physician level to avoid contamination between intervention and control groups.

Setting and participants. The study was conducted in Akershus and Oslo, Norway. Family physicians were recruited to participate in the trial with their patients. A total of 84 family physicians were recruited, of which 70 were included in the trial and randomized to intervention versus control; 14 were excluded because they had no eligible patients. The cluster size of each family physician was limited to 5 patients per physician to avoid large variation in cluster sizes. Patients were eligible for enrollment if they were home-dwelling, aged 70 years or older, and were taking 7 or more systemic medications regularly and had medications administered by the home nursing service. Patients were excluded if they were expected to die or be institutionalized within 6 months, or if they were discouraged from participation by their family physician. A total of 174 patients were recruited, with 87 patients in each group (34 family physicians were in the control group and 36 in the intervention group).

Intervention. The intervention included a geriatric assessment performed by a physician trained in geriatric medicine and supervised by a senior consultant. The geriatric assessment consisted of review of medical history; systematic screening for current problems; clinical examination; supplementary tests, if indicated; and review of each medication being used. The review of medication included the indication for each medication, dosage, adverse effects, and interactions. The geriatric assessment consultation took 1 hour to complete, on average. After the geriatric assessment, the family physician and the geriatrician met to discuss each medication and to establish a collaborative plan for adjustments and follow-up; this meeting was approximately 15 minutes in duration. Lastly, clinical follow-up with the older adult was conducted by the geriatrician or the family physician, as agreed upon in the plan, with most follow-up conducted by the family physician. Participants randomized to the control group received usual care without any intervention.

Main outcome measures. Outcomes were assessed at 16-week and 24-week follow-up. The main study outcome measure was health-related quality of life (HRQoL), as measured by the 15D instrument, at 16 weeks. The quality-of-life measure included the following aspects, each rated on an ordinal scale of 5 levels: mobility, vision, hearing, breathing, sleeping, eating, speech, elimination, usual activities, mental function, discomfort or symptoms, depression, distress, vitality, and sexual activity. The index scale including all aspects is in the range of 0 to 1, with a higher score indicating better quality of life. A predetermined change of 0.015 or more is considered clinically important, and a positive change of 0.035 indicates much better HRQoL. Other outcomes included: appropriateness of medications measured by the Medication Appropriateness Index and the Assessment of Underutilization; physical function (short Physical Performance battery); gait speed; grip strength; cognitive functioning; physical and cognitive disability (Functional Independence Measure); caregiver burden (Relative Stress Scale); physical measures, including orthostatic blood pressure, falls, and weight; hospital admissions; use of home nursing service; incidence of institutionalization; and mortality.

Main results. The study included 174 patients with an average age of 83.3 years (SD, 7.3); 67.8% were women. Of those who were randomized to the intervention and control groups, 158 (90.8%) completed the trial. The average number of regularly used medications was 10.1 (SD, 2.7) in the intervention group and 9.5 (SD, 2.6) in the control group. At week 16 of follow-up, patients in the intervention group had an improved HRQoL score measured by the 15D instrument; the difference between the intervention group and control groups was 0.045 (95% confidence interval [CI], 0.004 -0.086; P = 0.03). Medication appropriateness was better in the intervention group, as compared with the control group at both 16 weeks and 24 weeks. Nearly all (99%) patients in the intervention group experienced medication changes, which included withdrawal of medications, dosage adjustment, or new drug regimens. There was a trend towards a higher rate of hospitalization during follow-up in the intervention group (adjusted risk ratio, 2.03; 95% CI, 0.98-4.24; P = 0.06). Other secondary outcomes were not substantially different between the intervention and control groups.

Conclusion. The study demonstrated that a clinical geriatric assessment and collaborative medication review by geriatrician and family physician led to improved HRQoL and improved medication use.

The use of multiple medications in older adults is common, with almost 20% of older adults over age 65 taking 10 or more medications.¹ Polypharmacy in older adults is associated with lower adherence rates and increases the potential for interactions between medications.² Age-related changes, such as changes in absorption, metabolism, and excretion, affect pharmacokinetics of medications and potentiate adverse drug reactions, requiring adjustments in use and dosing to optimize safety and outcomes. Recognizing the potential effects of medications in older adults, evidence-based guidelines, such as the Beers criteria³ and START/STOPP criteria,⁴ have been developed to identify potentially inappropriate medications in older adults and to improve prescribing. Randomized trials using the START/STOPP criteria have demonstrated improved medication appropriateness, reduced polypharmacy, and reduced adverse drug reactions.⁵ Although this study did not use a criteria-based approach for improving medication use, it demonstrated that in a population of older adults with polypharmacy, medication review with geriatricians can lead to improved HRQoL while improving medication appropriateness. The collaborative approach between the family physician and geriatrician, rather than a consultative approach with recommendations from a geriatrician, may have contributed to increased uptake of medication changes. Such an approach may be a reasonable strategy to improve medication use in older adults.

A limitation of the study is that the improvement in HRQoL could have been the result of medication changes, but could also have been due to other changes in the plan of care that resulted from the geriatric assessment. As noted by the authors, the increase in hospital admissions, though not statistically significant, could have resulted from the medication modifications; however, it was also noted that the geriatric assessments could have identified severe illnesses that required hospitalization, as the timeline from geriatric assessment to hospitalization suggested was the case. Thus, the increase in hospitalization resulting from timely identification of severe illness was more likely a benefit than an adverse effect; however, further studies should be done to elucidate this.

Applications for Clinical Practice

Older adults with multiple chronic conditions and complex medication regimens are at risk for poor health outcomes, and a purposeful medication review to improve medication use, leading to the removal of unnecessary and potentially harmful medications, adjustment of dosages, and initiation of appropriate medications, may yield health benefits, such as improved HRQoL. The present study utilized an approach that could be scalable, which is important given the limited number of clinicians with geriatrics expertise. For health systems with geriatrics clinical expertise, it may be reasonable to consider adopting a similar collaborative approach in order to improve care for older adults most at risk. Further reports on how patients and family physicians perceive this intervention will enhance our understanding of whether it could be implemented widely.

–William W. Hung, MD, MPH

Study Overview

Objective. To evaluate the efficacy and safety of pembrolizumab in combination with neoadjuvant chemotherapy followed by adjuvant pembrolizumab in early-stage triple-negative breast cancer.

Design. International, multicenter, randomized, double-blind, phase 3 trial.

Intervention. Patients were randomly assigned in a 2:1 fashion to receive either pembrolizumab or placebo. Patients received 4 cycles of neoadjuvant pembrolizumab or placebo once every 3 weeks, in addition to weekly paclitaxel 80 mg/m² plus carboplatin AUC5 once every 3 weeks. This was followed by 4 cycles of pembrolizumab or placebo plus doxorubicin 60 mg/m² or epirubicin 90 mg/m² plus cyclophosphamide 600 mg/m² once every 3 weeks. Patients then underwent definitive surgery 3 to 6 weeks after completion of neoadjuvant therapy. In the adjuvant setting, patients received pembrolizumab or placebo once every 3 weeks for up to 9 cycles. Adjuvant capecitabine was not allowed.

Setting and participants. A total of 1174 patients underwent randomization: 784 patients in the pembrolizumab/chemotherapy group and 390 patients in the placebo/chemotherapy group. Eligible patients had newly diagnosed, centrally confirmed triple-negative breast cancer (nonmetastatic: T1c, N1-2 or T2-4, N0-2). Patients were eligible regardless of PD-L1 status, and those with inflammatory breast cancer and multifocal primaries were eligible.

Main outcome measures. The primary endpoints of this study were pathologic complete response (pCR) rate (defined as ypT0/ypTis, ypN0) at the time of surgery and event-free survival (EFS) in the intention-to-treat population. Secondary endpoints included pCR in all patients, pCR among patients with PD-L1–positive tumors, EFS among patients with PD-L1–positive tumors, and overall survival among all patients and those with PD-L1–positive tumors. PD-L1 expression was assessed using the PD-L1 IHC 22C3 pharmDx assay (Agilent, Santa Clara, CA). Expression was characterized according to the combined positive score, with a score of 1% or greater being considered positive.

Results. The baseline characteristics were well balanced between the treatment arms. At the time of the second interim analysis, the median duration of follow-up was 15.5 months. The pCR rate among the first 602 patients who were randomized was 64.8% in the pembrolizumab/chemotherapy group and 51.2% in the placebo group (P < 0.001; 95% confidence interval, 5.4-21.8). The pCR rate in the PD-L1–positive population was 68.9% in the pembrolizumab/chemotherapy group, as compared to 54.9% in the placebo group. In the PD-L1–negative population, the pCR rate was 45.3% in the pembrolizumab/chemotherapy group, as compared to 30.3% in the placebo group. At the time of analysis, 104 events had occurred, and the estimated percentage of patients at 18 months who were alive without disease progression was 91% in the pembrolizumab group and 85% in the placebo group. The median was not reached in either group.

Grade 3 or higher adverse events in the neoadjuvant phase were seen in 76.8% and 72.2% of patients in the pembrolizumab and placebo arms, respectively. Serious treatment-related adverse events occurred in 32% of patients in the pembrolizumab group compared to 19% in the placebo group. Febrile neutropenia and anemia were the most common. Discontinuation of the trial drug due to adverse events occurred in 23% of patients in the pembrolizumab arm and in 12% in the placebo arm. The majority of treatment-related adverse events occurred in the neoadjuvant phase. In the adjuvant phase, treatment-related adverse events occurred in 48% and 43% of patients in the pembrolizumab and placebo groups, respectively.

Conclusion. The combination of neoadjuvant chemotherapy and pembrolizumab in patients with newly diagnosed, early-stage, triple-negative breast cancer yielded a higher percentage of patients achieving a pCR as compared with chemotherapy plus placebo.

Commentary

The current study adds to the growing body of literature outlining the efficacy of immune checkpoint inhibition in triple-negative breast cancer. The previously published IMpassion130 trial showed that the addition of the PD-L1 antibody atezolizumab to nab-paclitaxel improved progression-free survival in patients with PD-L1–positive (1% or greater), metastatic triple-negative breast cancer.¹ Similarly, in the phase 2 I-SPY2 trial, the addition of pembrolizumab to standard neoadjuvant chemotherapy led to a near tripling of the pCR rates in triple-negative breast cancer.² While the current study demonstrated improved pCR rates with pembrolizumab, no difference in EFS has yet been demonstrated; however, longer-term follow-up will be required. There certainly are numerous studies documenting an association between pCR and improved disease-free survival and possibly overall survival. Cortazar and colleagues performed a pooled analysis of 12 international trials, which demonstrated an association between pCR and improved EFS (hazard ratio [HR], 0.24) and overall survival (HR, 0.16) in patients with triple-negative breast cancer.³ The results of the current study will require longer-term follow-up to confirm such an association.

The current study appears to have demonstrated a benefit with the addition of pembrolizumab across treatment subgroups, particularly in the PD-L1–positive and PD-L1–negative populations. While this differs from the findings of the IMpassion130 trial, it is quite difficult to draw definitive conclusions because the 2 trials studied different antibodies, and thus used a different assay to define PD-L1 positivity. Notable differences exist in determination of PD-L1 status across assays, and it is important for providers to use the appropriate assay for each antibody. These differences highlight the need for more informative biomarkers to predict a benefit from immune checkpoint inhibition.

It is also noteworthy that the control arm in the current trial was a platinum-based regimen. Platinum-based neoadjuvant regimens previously have been shown to induce higher pCR rates in triple-negative breast cancer; however, the incorporation of carboplatin as standard of care remains a topic of debate.⁴ Nevertheless, a similar trial evaluating the efficacy of atezolizumab combined with platinum-based neoadjuvant chemotherapy in triple-negative breast cancer, NSABP B-59 (NCT03281954), is underway, with the control arm also incorporating carboplatin. The results of this study will also help validate the role of checkpoint inhibitors in the neoadjuvant setting in triple-negative breast cancer. Of note, this trial did not allow for the use of adjuvant capecitabine, which has been previously shown in the CREATE-X trial to prolong survival in this population.⁵ How the use of adjuvant capecitabine would impact these results is completely unknown.⁶ The incidence of grade 3 or higher toxicities in the current trial appeared to be similar in both groups. There did appear to be a higher incidence of infusion reactions and skin reactions in the pembrolizumab groups. Immune-related adverse events were consistent with prior pembrolizumab data.

Applications for Clinical Practice

KEYNOTE-522 adds to the growing evidence suggesting that incorporation of immune checkpoint inhibitors into neoadjuvant therapy in patients with triple-negative breast cancer can improve pCR rates; however, its use as a standard of care will require longer-term follow-up to ensure the noted findings translate into improvement in EFS and, ultimately, overall survival.

– Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy and safety of pembrolizumab in combination with neoadjuvant chemotherapy followed by adjuvant pembrolizumab in early-stage triple-negative breast cancer.

Design. International, multicenter, randomized, double-blind, phase 3 trial.

Intervention. Patients were randomly assigned in a 2:1 fashion to receive either pembrolizumab or placebo. Patients received 4 cycles of neoadjuvant pembrolizumab or placebo once every 3 weeks, in addition to weekly paclitaxel 80 mg/m² plus carboplatin AUC5 once every 3 weeks. This was followed by 4 cycles of pembrolizumab or placebo plus doxorubicin 60 mg/m² or epirubicin 90 mg/m² plus cyclophosphamide 600 mg/m² once every 3 weeks. Patients then underwent definitive surgery 3 to 6 weeks after completion of neoadjuvant therapy. In the adjuvant setting, patients received pembrolizumab or placebo once every 3 weeks for up to 9 cycles. Adjuvant capecitabine was not allowed.

Setting and participants. A total of 1174 patients underwent randomization: 784 patients in the pembrolizumab/chemotherapy group and 390 patients in the placebo/chemotherapy group. Eligible patients had newly diagnosed, centrally confirmed triple-negative breast cancer (nonmetastatic: T1c, N1-2 or T2-4, N0-2). Patients were eligible regardless of PD-L1 status, and those with inflammatory breast cancer and multifocal primaries were eligible.

Main outcome measures. The primary endpoints of this study were pathologic complete response (pCR) rate (defined as ypT0/ypTis, ypN0) at the time of surgery and event-free survival (EFS) in the intention-to-treat population. Secondary endpoints included pCR in all patients, pCR among patients with PD-L1–positive tumors, EFS among patients with PD-L1–positive tumors, and overall survival among all patients and those with PD-L1–positive tumors. PD-L1 expression was assessed using the PD-L1 IHC 22C3 pharmDx assay (Agilent, Santa Clara, CA). Expression was characterized according to the combined positive score, with a score of 1% or greater being considered positive.

Results. The baseline characteristics were well balanced between the treatment arms. At the time of the second interim analysis, the median duration of follow-up was 15.5 months. The pCR rate among the first 602 patients who were randomized was 64.8% in the pembrolizumab/chemotherapy group and 51.2% in the placebo group (P < 0.001; 95% confidence interval, 5.4-21.8). The pCR rate in the PD-L1–positive population was 68.9% in the pembrolizumab/chemotherapy group, as compared to 54.9% in the placebo group. In the PD-L1–negative population, the pCR rate was 45.3% in the pembrolizumab/chemotherapy group, as compared to 30.3% in the placebo group. At the time of analysis, 104 events had occurred, and the estimated percentage of patients at 18 months who were alive without disease progression was 91% in the pembrolizumab group and 85% in the placebo group. The median was not reached in either group.

Grade 3 or higher adverse events in the neoadjuvant phase were seen in 76.8% and 72.2% of patients in the pembrolizumab and placebo arms, respectively. Serious treatment-related adverse events occurred in 32% of patients in the pembrolizumab group compared to 19% in the placebo group. Febrile neutropenia and anemia were the most common. Discontinuation of the trial drug due to adverse events occurred in 23% of patients in the pembrolizumab arm and in 12% in the placebo arm. The majority of treatment-related adverse events occurred in the neoadjuvant phase. In the adjuvant phase, treatment-related adverse events occurred in 48% and 43% of patients in the pembrolizumab and placebo groups, respectively.

Conclusion. The combination of neoadjuvant chemotherapy and pembrolizumab in patients with newly diagnosed, early-stage, triple-negative breast cancer yielded a higher percentage of patients achieving a pCR as compared with chemotherapy plus placebo.

Commentary

The current study adds to the growing body of literature outlining the efficacy of immune checkpoint inhibition in triple-negative breast cancer. The previously published IMpassion130 trial showed that the addition of the PD-L1 antibody atezolizumab to nab-paclitaxel improved progression-free survival in patients with PD-L1–positive (1% or greater), metastatic triple-negative breast cancer.¹ Similarly, in the phase 2 I-SPY2 trial, the addition of pembrolizumab to standard neoadjuvant chemotherapy led to a near tripling of the pCR rates in triple-negative breast cancer.² While the current study demonstrated improved pCR rates with pembrolizumab, no difference in EFS has yet been demonstrated; however, longer-term follow-up will be required. There certainly are numerous studies documenting an association between pCR and improved disease-free survival and possibly overall survival. Cortazar and colleagues performed a pooled analysis of 12 international trials, which demonstrated an association between pCR and improved EFS (hazard ratio [HR], 0.24) and overall survival (HR, 0.16) in patients with triple-negative breast cancer.³ The results of the current study will require longer-term follow-up to confirm such an association.

The current study appears to have demonstrated a benefit with the addition of pembrolizumab across treatment subgroups, particularly in the PD-L1–positive and PD-L1–negative populations. While this differs from the findings of the IMpassion130 trial, it is quite difficult to draw definitive conclusions because the 2 trials studied different antibodies, and thus used a different assay to define PD-L1 positivity. Notable differences exist in determination of PD-L1 status across assays, and it is important for providers to use the appropriate assay for each antibody. These differences highlight the need for more informative biomarkers to predict a benefit from immune checkpoint inhibition.

It is also noteworthy that the control arm in the current trial was a platinum-based regimen. Platinum-based neoadjuvant regimens previously have been shown to induce higher pCR rates in triple-negative breast cancer; however, the incorporation of carboplatin as standard of care remains a topic of debate.⁴ Nevertheless, a similar trial evaluating the efficacy of atezolizumab combined with platinum-based neoadjuvant chemotherapy in triple-negative breast cancer, NSABP B-59 (NCT03281954), is underway, with the control arm also incorporating carboplatin. The results of this study will also help validate the role of checkpoint inhibitors in the neoadjuvant setting in triple-negative breast cancer. Of note, this trial did not allow for the use of adjuvant capecitabine, which has been previously shown in the CREATE-X trial to prolong survival in this population.⁵ How the use of adjuvant capecitabine would impact these results is completely unknown.⁶ The incidence of grade 3 or higher toxicities in the current trial appeared to be similar in both groups. There did appear to be a higher incidence of infusion reactions and skin reactions in the pembrolizumab groups. Immune-related adverse events were consistent with prior pembrolizumab data.

Applications for Clinical Practice

KEYNOTE-522 adds to the growing evidence suggesting that incorporation of immune checkpoint inhibitors into neoadjuvant therapy in patients with triple-negative breast cancer can improve pCR rates; however, its use as a standard of care will require longer-term follow-up to ensure the noted findings translate into improvement in EFS and, ultimately, overall survival.

– Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy and safety of pembrolizumab in combination with neoadjuvant chemotherapy followed by adjuvant pembrolizumab in early-stage triple-negative breast cancer.

Design. International, multicenter, randomized, double-blind, phase 3 trial.

Intervention. Patients were randomly assigned in a 2:1 fashion to receive either pembrolizumab or placebo. Patients received 4 cycles of neoadjuvant pembrolizumab or placebo once every 3 weeks, in addition to weekly paclitaxel 80 mg/m² plus carboplatin AUC5 once every 3 weeks. This was followed by 4 cycles of pembrolizumab or placebo plus doxorubicin 60 mg/m² or epirubicin 90 mg/m² plus cyclophosphamide 600 mg/m² once every 3 weeks. Patients then underwent definitive surgery 3 to 6 weeks after completion of neoadjuvant therapy. In the adjuvant setting, patients received pembrolizumab or placebo once every 3 weeks for up to 9 cycles. Adjuvant capecitabine was not allowed.

Setting and participants. A total of 1174 patients underwent randomization: 784 patients in the pembrolizumab/chemotherapy group and 390 patients in the placebo/chemotherapy group. Eligible patients had newly diagnosed, centrally confirmed triple-negative breast cancer (nonmetastatic: T1c, N1-2 or T2-4, N0-2). Patients were eligible regardless of PD-L1 status, and those with inflammatory breast cancer and multifocal primaries were eligible.

Main outcome measures. The primary endpoints of this study were pathologic complete response (pCR) rate (defined as ypT0/ypTis, ypN0) at the time of surgery and event-free survival (EFS) in the intention-to-treat population. Secondary endpoints included pCR in all patients, pCR among patients with PD-L1–positive tumors, EFS among patients with PD-L1–positive tumors, and overall survival among all patients and those with PD-L1–positive tumors. PD-L1 expression was assessed using the PD-L1 IHC 22C3 pharmDx assay (Agilent, Santa Clara, CA). Expression was characterized according to the combined positive score, with a score of 1% or greater being considered positive.

Results. The baseline characteristics were well balanced between the treatment arms. At the time of the second interim analysis, the median duration of follow-up was 15.5 months. The pCR rate among the first 602 patients who were randomized was 64.8% in the pembrolizumab/chemotherapy group and 51.2% in the placebo group (P < 0.001; 95% confidence interval, 5.4-21.8). The pCR rate in the PD-L1–positive population was 68.9% in the pembrolizumab/chemotherapy group, as compared to 54.9% in the placebo group. In the PD-L1–negative population, the pCR rate was 45.3% in the pembrolizumab/chemotherapy group, as compared to 30.3% in the placebo group. At the time of analysis, 104 events had occurred, and the estimated percentage of patients at 18 months who were alive without disease progression was 91% in the pembrolizumab group and 85% in the placebo group. The median was not reached in either group.

Grade 3 or higher adverse events in the neoadjuvant phase were seen in 76.8% and 72.2% of patients in the pembrolizumab and placebo arms, respectively. Serious treatment-related adverse events occurred in 32% of patients in the pembrolizumab group compared to 19% in the placebo group. Febrile neutropenia and anemia were the most common. Discontinuation of the trial drug due to adverse events occurred in 23% of patients in the pembrolizumab arm and in 12% in the placebo arm. The majority of treatment-related adverse events occurred in the neoadjuvant phase. In the adjuvant phase, treatment-related adverse events occurred in 48% and 43% of patients in the pembrolizumab and placebo groups, respectively.

Conclusion. The combination of neoadjuvant chemotherapy and pembrolizumab in patients with newly diagnosed, early-stage, triple-negative breast cancer yielded a higher percentage of patients achieving a pCR as compared with chemotherapy plus placebo.

Commentary

The current study adds to the growing body of literature outlining the efficacy of immune checkpoint inhibition in triple-negative breast cancer. The previously published IMpassion130 trial showed that the addition of the PD-L1 antibody atezolizumab to nab-paclitaxel improved progression-free survival in patients with PD-L1–positive (1% or greater), metastatic triple-negative breast cancer.¹ Similarly, in the phase 2 I-SPY2 trial, the addition of pembrolizumab to standard neoadjuvant chemotherapy led to a near tripling of the pCR rates in triple-negative breast cancer.² While the current study demonstrated improved pCR rates with pembrolizumab, no difference in EFS has yet been demonstrated; however, longer-term follow-up will be required. There certainly are numerous studies documenting an association between pCR and improved disease-free survival and possibly overall survival. Cortazar and colleagues performed a pooled analysis of 12 international trials, which demonstrated an association between pCR and improved EFS (hazard ratio [HR], 0.24) and overall survival (HR, 0.16) in patients with triple-negative breast cancer.³ The results of the current study will require longer-term follow-up to confirm such an association.

The current study appears to have demonstrated a benefit with the addition of pembrolizumab across treatment subgroups, particularly in the PD-L1–positive and PD-L1–negative populations. While this differs from the findings of the IMpassion130 trial, it is quite difficult to draw definitive conclusions because the 2 trials studied different antibodies, and thus used a different assay to define PD-L1 positivity. Notable differences exist in determination of PD-L1 status across assays, and it is important for providers to use the appropriate assay for each antibody. These differences highlight the need for more informative biomarkers to predict a benefit from immune checkpoint inhibition.

It is also noteworthy that the control arm in the current trial was a platinum-based regimen. Platinum-based neoadjuvant regimens previously have been shown to induce higher pCR rates in triple-negative breast cancer; however, the incorporation of carboplatin as standard of care remains a topic of debate.⁴ Nevertheless, a similar trial evaluating the efficacy of atezolizumab combined with platinum-based neoadjuvant chemotherapy in triple-negative breast cancer, NSABP B-59 (NCT03281954), is underway, with the control arm also incorporating carboplatin. The results of this study will also help validate the role of checkpoint inhibitors in the neoadjuvant setting in triple-negative breast cancer. Of note, this trial did not allow for the use of adjuvant capecitabine, which has been previously shown in the CREATE-X trial to prolong survival in this population.⁵ How the use of adjuvant capecitabine would impact these results is completely unknown.⁶ The incidence of grade 3 or higher toxicities in the current trial appeared to be similar in both groups. There did appear to be a higher incidence of infusion reactions and skin reactions in the pembrolizumab groups. Immune-related adverse events were consistent with prior pembrolizumab data.

Applications for Clinical Practice

KEYNOTE-522 adds to the growing evidence suggesting that incorporation of immune checkpoint inhibitors into neoadjuvant therapy in patients with triple-negative breast cancer can improve pCR rates; however, its use as a standard of care will require longer-term follow-up to ensure the noted findings translate into improvement in EFS and, ultimately, overall survival.

– Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of cabazitaxel compared to androgen-signaling–targeted inhibitors (ASTIs) in patients with metastatic castration-resistant prostate cancer who have received docetaxel and have progressed within 12 months of treatment with either abiraterone or enzalutamide.

Design. The CARD trial was an international, randomized, open-label phase 3 trial conducted across 13 European countries.

Setting and participants. Eligible patients were 18 years of age or older; had metastatic castration-resistant prostate cancer previously treated with docetaxel; and had disease progression during 12 months of treatment with abiraterone or enzalutamide. All patients had histologically proven prostate cancer, castrate levels of serum testosterone, and disease progression, defined by at least 2 new bone lesions or rising prostate-specific antigen (PSA) level. A total of 255 patients underwent randomization between November 2015 and November 2018, with 129 assigned to receive cabazitaxel and 126 patients assigned to receive an ASTI, 58 of whom received abiraterone and 66 of whom received enzalutamide. Patients who had received an ASTI in the setting of castrate-sensitive metastatic prostate cancer were included.

Intervention. Patients were randomized in a 1:1 fashion to receive either cabazitaxel or abiraterone or enzalutamide. Patients receiving cabazitaxel 25 mg/m² intravenously every 3 weeks also received oral prednisone daily and primary prophylactic granulocyte-colony stimulating factor. Patients assigned to receive an ASTI received abiraterone 1000 mg orally daily with prednisone 5 mg twice daily or enzalutamide 160 mg daily. Patients in the ASTI group who had progressed on abiraterone were assigned to enzalutamide, and alternatively, those on enzalutamide were assigned to abiraterone. Patients were treated until 1 of the following occurred: imaging-based disease progression, unacceptable toxicity, or advancing to an alternative therapy.

Main outcome measures. The primary endpoint was imaging-based progression-free survival, which was defined as the time from randomization until objective tumor progression, progression of bone lesions, or death. The secondary endpoints were overall survival, progression-free survival, PSA response, tumor and pain responses, a new symptomatic skeletal event, and safety.

Results. The median follow-up was 9.2 months. Imaging-based disease progression or death from any cause occurred in 95 (73.6%) participants in the cabazitaxel group, as compared to 101 (80.2%) who were assigned to receive an ASTI. The median imaging-based progression-free survival was 8.0 months in the cabazitaxel group and 3.7 months in the abiraterone/enzalutamide group. The median duration of treatment was longer in those receiving cabazitaxel (22 vs 12.5 weeks). The primary reason for treatment discontinuation was disease progression (in 43.7% of patients receiving cabazitaxel and 71% receiving an ASTI) or an adverse event (19.8% and 8.9%, respectively).

The trial’s secondary endpoints demonstrated improved outcomes in the cabazitaxel group compared to the abiraterone/enzalutamide group. There were 70 deaths (54.2%) in the cabazitaxel group and 83 (65.9%) in the ASTI group. Both the median overall survival (13.6 months in the cabazitaxel group and 11 months in the ASTI group) and the median progression-free survival (4.4 months and 2.7 months, respectively) were improved in those who received cabazitaxel. There was a 50% or greater reduction in the PSA level from baseline in 35.7% of the cabazitaxel group and 13.5% of the ASTI group.

Regarding the safety of the agents, the incidence of adverse events was similar in each group (38.9% in the cabazitaxel group and 38.7% in the ASTI group). Treatment discontinuation occurred more frequently in the cabazitaxel group (19.8%) compared to the ASTI group (8.9%). Adverse events of grade 3 or higher occurred more frequently with cabazitaxel; these were asthenia (4% vs 2.4%), diarrhea (3.2% vs 0), peripheral neuropathy (3.2% vs 0 patients), and febrile neutropenia (3.2% vs 0 patients).

Conclusion. Patients who had disease progression within 12 months on an ASTI and had previously been treated for metastatic castration-resistant prostate cancer with docetaxel had longer imaging-based progression-free survival and overall survival when treated with cabazitaxel compared to those treated with an alternative ASTI. Other clinical outcomes, including overall survival and progression-free survival, were also improved in the cabazitaxel group.

Commentary

Four ASTIs are approved for therapy in men with advanced prostate cancer. The next line of therapy following progression on an ASTI, whether to consider second-line androgen targeted inhibitors or proceed to taxane-based chemotherapy, has been unclear. The current CARD trial sought to answer this question and provides evidence that cabazitaxel is the next line of therapy for these patients. The trial’s primary endpoint, imaging-based disease progression, was reported in 73.6% of those who received cabazitaxel and in 80.2% of those who received abiraterone or enzalutamide. Patients treated with cabazitaxel had a longer imaging-based progression-free survival (8.0 months vs 3.7 months) and a longer duration of treatment (22 vs 12.5 weeks).

Because there is clinical evidence of cross-resistance between different ASTIs, the value of sequential therapy has been unclear. Emergence of androgen-receptor splice variant 7 (AR-V7) mutational status in circulating tumor cells is associated with poor outcomes with secondary androgen-signaling inhibitor therapy, and may be an indicator of resistance to subsequent androgen-signaling inhibitors.^1,2 In the PROPHECY trial, the response rates to subsequent androgen targeted therapy in patients with AR-V7 mutations ranged from 30% to 40%.³ Understanding how AR-V7 mutational status may impact such outcomes will certainly help define whether a subgroup exists in whom use of second-line androgen signaling inhibitors may be considered.

The patients enrolled in the current study appear to represent a subgroup of patients with biologically aggressive disease or with inherent resistance to ASTIs. The patients included in this study progressed within 1 year of androgen targeted therapy, which is representative of a more aggressive population of patients who may be hormone insensitive and derive more benefit from chemotherapy. Initial androgen deprivation therapy was given for 13.7 and 12.6 months to the cabazitaxel and enzalutamide/abiraterone arms, respectively, prior to developing castrate-resistant prostate cancer. Patients enrolled in this study also previously received docetaxel, deselecting those who are taxane-resistant and therefore may be less likely to respond to additional taxane-based therapy. Detection of AR-V7 splice variant expression in circulating tumor cells, consideration of biomarker data, and sensitivity to taxanes may help guide decisions regarding the use of sequential androgen-targeted agents; however, there has been no clear data to guide such an approach. It is also important to consider that, because this is a European study, the approved dose given in this trial was 25 mg/m². The PROSELICA trial previously demonstrated noninferiority of 20 mg/m² compared with 25 mg/m², with fewer adverse events, which is the dose now utilized in the United States.⁴

The adverse events of grade 3 or greater occurring in the cabazitaxel group should be discussed with patients, including fatigue, diarrhea, peripheral neuropathy, and febrile neutropenia.

The data from the CARD trial provide guidance regarding therapy sequencing in those with advanced prostate cancer after progression on first-line androgen targeted inhibitors and docetaxel; however, further work is needed to understand the universal application of this data in this cohort.

Applications in Clinical Practice

Patients with metastatic castration-resistant prostate cancer who have received docetaxel and progressed on an androgen-signaling inhibitor within 12 months should be considered for cabazitaxel over an alternative androgen-signaling inhibitor. This decision should be based on several factors, including AR-V7 mutational status, duration of androgen deprivation therapy, and hormone and taxane sensitivity in the past. Future studies are likely to incorporate genomic biomarkers rather than clinical criteria alone to make treatment decisions.

–Britni Souther, DO, and Daniel Isaac, DO, MS, Michigan State University, East Lansing, MI

Study Overview

Objective. To evaluate the efficacy of cabazitaxel compared to androgen-signaling–targeted inhibitors (ASTIs) in patients with metastatic castration-resistant prostate cancer who have received docetaxel and have progressed within 12 months of treatment with either abiraterone or enzalutamide.

Design. The CARD trial was an international, randomized, open-label phase 3 trial conducted across 13 European countries.

Setting and participants. Eligible patients were 18 years of age or older; had metastatic castration-resistant prostate cancer previously treated with docetaxel; and had disease progression during 12 months of treatment with abiraterone or enzalutamide. All patients had histologically proven prostate cancer, castrate levels of serum testosterone, and disease progression, defined by at least 2 new bone lesions or rising prostate-specific antigen (PSA) level. A total of 255 patients underwent randomization between November 2015 and November 2018, with 129 assigned to receive cabazitaxel and 126 patients assigned to receive an ASTI, 58 of whom received abiraterone and 66 of whom received enzalutamide. Patients who had received an ASTI in the setting of castrate-sensitive metastatic prostate cancer were included.

Intervention. Patients were randomized in a 1:1 fashion to receive either cabazitaxel or abiraterone or enzalutamide. Patients receiving cabazitaxel 25 mg/m² intravenously every 3 weeks also received oral prednisone daily and primary prophylactic granulocyte-colony stimulating factor. Patients assigned to receive an ASTI received abiraterone 1000 mg orally daily with prednisone 5 mg twice daily or enzalutamide 160 mg daily. Patients in the ASTI group who had progressed on abiraterone were assigned to enzalutamide, and alternatively, those on enzalutamide were assigned to abiraterone. Patients were treated until 1 of the following occurred: imaging-based disease progression, unacceptable toxicity, or advancing to an alternative therapy.

Main outcome measures. The primary endpoint was imaging-based progression-free survival, which was defined as the time from randomization until objective tumor progression, progression of bone lesions, or death. The secondary endpoints were overall survival, progression-free survival, PSA response, tumor and pain responses, a new symptomatic skeletal event, and safety.

Results. The median follow-up was 9.2 months. Imaging-based disease progression or death from any cause occurred in 95 (73.6%) participants in the cabazitaxel group, as compared to 101 (80.2%) who were assigned to receive an ASTI. The median imaging-based progression-free survival was 8.0 months in the cabazitaxel group and 3.7 months in the abiraterone/enzalutamide group. The median duration of treatment was longer in those receiving cabazitaxel (22 vs 12.5 weeks). The primary reason for treatment discontinuation was disease progression (in 43.7% of patients receiving cabazitaxel and 71% receiving an ASTI) or an adverse event (19.8% and 8.9%, respectively).

The trial’s secondary endpoints demonstrated improved outcomes in the cabazitaxel group compared to the abiraterone/enzalutamide group. There were 70 deaths (54.2%) in the cabazitaxel group and 83 (65.9%) in the ASTI group. Both the median overall survival (13.6 months in the cabazitaxel group and 11 months in the ASTI group) and the median progression-free survival (4.4 months and 2.7 months, respectively) were improved in those who received cabazitaxel. There was a 50% or greater reduction in the PSA level from baseline in 35.7% of the cabazitaxel group and 13.5% of the ASTI group.

Regarding the safety of the agents, the incidence of adverse events was similar in each group (38.9% in the cabazitaxel group and 38.7% in the ASTI group). Treatment discontinuation occurred more frequently in the cabazitaxel group (19.8%) compared to the ASTI group (8.9%). Adverse events of grade 3 or higher occurred more frequently with cabazitaxel; these were asthenia (4% vs 2.4%), diarrhea (3.2% vs 0), peripheral neuropathy (3.2% vs 0 patients), and febrile neutropenia (3.2% vs 0 patients).

Conclusion. Patients who had disease progression within 12 months on an ASTI and had previously been treated for metastatic castration-resistant prostate cancer with docetaxel had longer imaging-based progression-free survival and overall survival when treated with cabazitaxel compared to those treated with an alternative ASTI. Other clinical outcomes, including overall survival and progression-free survival, were also improved in the cabazitaxel group.

Commentary

Four ASTIs are approved for therapy in men with advanced prostate cancer. The next line of therapy following progression on an ASTI, whether to consider second-line androgen targeted inhibitors or proceed to taxane-based chemotherapy, has been unclear. The current CARD trial sought to answer this question and provides evidence that cabazitaxel is the next line of therapy for these patients. The trial’s primary endpoint, imaging-based disease progression, was reported in 73.6% of those who received cabazitaxel and in 80.2% of those who received abiraterone or enzalutamide. Patients treated with cabazitaxel had a longer imaging-based progression-free survival (8.0 months vs 3.7 months) and a longer duration of treatment (22 vs 12.5 weeks).

Because there is clinical evidence of cross-resistance between different ASTIs, the value of sequential therapy has been unclear. Emergence of androgen-receptor splice variant 7 (AR-V7) mutational status in circulating tumor cells is associated with poor outcomes with secondary androgen-signaling inhibitor therapy, and may be an indicator of resistance to subsequent androgen-signaling inhibitors.^1,2 In the PROPHECY trial, the response rates to subsequent androgen targeted therapy in patients with AR-V7 mutations ranged from 30% to 40%.³ Understanding how AR-V7 mutational status may impact such outcomes will certainly help define whether a subgroup exists in whom use of second-line androgen signaling inhibitors may be considered.

The patients enrolled in the current study appear to represent a subgroup of patients with biologically aggressive disease or with inherent resistance to ASTIs. The patients included in this study progressed within 1 year of androgen targeted therapy, which is representative of a more aggressive population of patients who may be hormone insensitive and derive more benefit from chemotherapy. Initial androgen deprivation therapy was given for 13.7 and 12.6 months to the cabazitaxel and enzalutamide/abiraterone arms, respectively, prior to developing castrate-resistant prostate cancer. Patients enrolled in this study also previously received docetaxel, deselecting those who are taxane-resistant and therefore may be less likely to respond to additional taxane-based therapy. Detection of AR-V7 splice variant expression in circulating tumor cells, consideration of biomarker data, and sensitivity to taxanes may help guide decisions regarding the use of sequential androgen-targeted agents; however, there has been no clear data to guide such an approach. It is also important to consider that, because this is a European study, the approved dose given in this trial was 25 mg/m². The PROSELICA trial previously demonstrated noninferiority of 20 mg/m² compared with 25 mg/m², with fewer adverse events, which is the dose now utilized in the United States.⁴

The adverse events of grade 3 or greater occurring in the cabazitaxel group should be discussed with patients, including fatigue, diarrhea, peripheral neuropathy, and febrile neutropenia.

The data from the CARD trial provide guidance regarding therapy sequencing in those with advanced prostate cancer after progression on first-line androgen targeted inhibitors and docetaxel; however, further work is needed to understand the universal application of this data in this cohort.

Applications in Clinical Practice

Patients with metastatic castration-resistant prostate cancer who have received docetaxel and progressed on an androgen-signaling inhibitor within 12 months should be considered for cabazitaxel over an alternative androgen-signaling inhibitor. This decision should be based on several factors, including AR-V7 mutational status, duration of androgen deprivation therapy, and hormone and taxane sensitivity in the past. Future studies are likely to incorporate genomic biomarkers rather than clinical criteria alone to make treatment decisions.

–Britni Souther, DO, and Daniel Isaac, DO, MS, Michigan State University, East Lansing, MI

Study Overview

Objective. To evaluate the efficacy of cabazitaxel compared to androgen-signaling–targeted inhibitors (ASTIs) in patients with metastatic castration-resistant prostate cancer who have received docetaxel and have progressed within 12 months of treatment with either abiraterone or enzalutamide.

Design. The CARD trial was an international, randomized, open-label phase 3 trial conducted across 13 European countries.

Setting and participants. Eligible patients were 18 years of age or older; had metastatic castration-resistant prostate cancer previously treated with docetaxel; and had disease progression during 12 months of treatment with abiraterone or enzalutamide. All patients had histologically proven prostate cancer, castrate levels of serum testosterone, and disease progression, defined by at least 2 new bone lesions or rising prostate-specific antigen (PSA) level. A total of 255 patients underwent randomization between November 2015 and November 2018, with 129 assigned to receive cabazitaxel and 126 patients assigned to receive an ASTI, 58 of whom received abiraterone and 66 of whom received enzalutamide. Patients who had received an ASTI in the setting of castrate-sensitive metastatic prostate cancer were included.

Intervention. Patients were randomized in a 1:1 fashion to receive either cabazitaxel or abiraterone or enzalutamide. Patients receiving cabazitaxel 25 mg/m² intravenously every 3 weeks also received oral prednisone daily and primary prophylactic granulocyte-colony stimulating factor. Patients assigned to receive an ASTI received abiraterone 1000 mg orally daily with prednisone 5 mg twice daily or enzalutamide 160 mg daily. Patients in the ASTI group who had progressed on abiraterone were assigned to enzalutamide, and alternatively, those on enzalutamide were assigned to abiraterone. Patients were treated until 1 of the following occurred: imaging-based disease progression, unacceptable toxicity, or advancing to an alternative therapy.

Main outcome measures. The primary endpoint was imaging-based progression-free survival, which was defined as the time from randomization until objective tumor progression, progression of bone lesions, or death. The secondary endpoints were overall survival, progression-free survival, PSA response, tumor and pain responses, a new symptomatic skeletal event, and safety.

Results. The median follow-up was 9.2 months. Imaging-based disease progression or death from any cause occurred in 95 (73.6%) participants in the cabazitaxel group, as compared to 101 (80.2%) who were assigned to receive an ASTI. The median imaging-based progression-free survival was 8.0 months in the cabazitaxel group and 3.7 months in the abiraterone/enzalutamide group. The median duration of treatment was longer in those receiving cabazitaxel (22 vs 12.5 weeks). The primary reason for treatment discontinuation was disease progression (in 43.7% of patients receiving cabazitaxel and 71% receiving an ASTI) or an adverse event (19.8% and 8.9%, respectively).

The trial’s secondary endpoints demonstrated improved outcomes in the cabazitaxel group compared to the abiraterone/enzalutamide group. There were 70 deaths (54.2%) in the cabazitaxel group and 83 (65.9%) in the ASTI group. Both the median overall survival (13.6 months in the cabazitaxel group and 11 months in the ASTI group) and the median progression-free survival (4.4 months and 2.7 months, respectively) were improved in those who received cabazitaxel. There was a 50% or greater reduction in the PSA level from baseline in 35.7% of the cabazitaxel group and 13.5% of the ASTI group.

Regarding the safety of the agents, the incidence of adverse events was similar in each group (38.9% in the cabazitaxel group and 38.7% in the ASTI group). Treatment discontinuation occurred more frequently in the cabazitaxel group (19.8%) compared to the ASTI group (8.9%). Adverse events of grade 3 or higher occurred more frequently with cabazitaxel; these were asthenia (4% vs 2.4%), diarrhea (3.2% vs 0), peripheral neuropathy (3.2% vs 0 patients), and febrile neutropenia (3.2% vs 0 patients).

Conclusion. Patients who had disease progression within 12 months on an ASTI and had previously been treated for metastatic castration-resistant prostate cancer with docetaxel had longer imaging-based progression-free survival and overall survival when treated with cabazitaxel compared to those treated with an alternative ASTI. Other clinical outcomes, including overall survival and progression-free survival, were also improved in the cabazitaxel group.

Commentary

Four ASTIs are approved for therapy in men with advanced prostate cancer. The next line of therapy following progression on an ASTI, whether to consider second-line androgen targeted inhibitors or proceed to taxane-based chemotherapy, has been unclear. The current CARD trial sought to answer this question and provides evidence that cabazitaxel is the next line of therapy for these patients. The trial’s primary endpoint, imaging-based disease progression, was reported in 73.6% of those who received cabazitaxel and in 80.2% of those who received abiraterone or enzalutamide. Patients treated with cabazitaxel had a longer imaging-based progression-free survival (8.0 months vs 3.7 months) and a longer duration of treatment (22 vs 12.5 weeks).

Because there is clinical evidence of cross-resistance between different ASTIs, the value of sequential therapy has been unclear. Emergence of androgen-receptor splice variant 7 (AR-V7) mutational status in circulating tumor cells is associated with poor outcomes with secondary androgen-signaling inhibitor therapy, and may be an indicator of resistance to subsequent androgen-signaling inhibitors.^1,2 In the PROPHECY trial, the response rates to subsequent androgen targeted therapy in patients with AR-V7 mutations ranged from 30% to 40%.³ Understanding how AR-V7 mutational status may impact such outcomes will certainly help define whether a subgroup exists in whom use of second-line androgen signaling inhibitors may be considered.

The patients enrolled in the current study appear to represent a subgroup of patients with biologically aggressive disease or with inherent resistance to ASTIs. The patients included in this study progressed within 1 year of androgen targeted therapy, which is representative of a more aggressive population of patients who may be hormone insensitive and derive more benefit from chemotherapy. Initial androgen deprivation therapy was given for 13.7 and 12.6 months to the cabazitaxel and enzalutamide/abiraterone arms, respectively, prior to developing castrate-resistant prostate cancer. Patients enrolled in this study also previously received docetaxel, deselecting those who are taxane-resistant and therefore may be less likely to respond to additional taxane-based therapy. Detection of AR-V7 splice variant expression in circulating tumor cells, consideration of biomarker data, and sensitivity to taxanes may help guide decisions regarding the use of sequential androgen-targeted agents; however, there has been no clear data to guide such an approach. It is also important to consider that, because this is a European study, the approved dose given in this trial was 25 mg/m². The PROSELICA trial previously demonstrated noninferiority of 20 mg/m² compared with 25 mg/m², with fewer adverse events, which is the dose now utilized in the United States.⁴

The adverse events of grade 3 or greater occurring in the cabazitaxel group should be discussed with patients, including fatigue, diarrhea, peripheral neuropathy, and febrile neutropenia.

The data from the CARD trial provide guidance regarding therapy sequencing in those with advanced prostate cancer after progression on first-line androgen targeted inhibitors and docetaxel; however, further work is needed to understand the universal application of this data in this cohort.

Applications in Clinical Practice

Patients with metastatic castration-resistant prostate cancer who have received docetaxel and progressed on an androgen-signaling inhibitor within 12 months should be considered for cabazitaxel over an alternative androgen-signaling inhibitor. This decision should be based on several factors, including AR-V7 mutational status, duration of androgen deprivation therapy, and hormone and taxane sensitivity in the past. Future studies are likely to incorporate genomic biomarkers rather than clinical criteria alone to make treatment decisions.

–Britni Souther, DO, and Daniel Isaac, DO, MS, Michigan State University, East Lansing, MI

LAHAINA, HAWAII – Novel topical medications are in the works that will address the longstanding unmet need for a Food and Drug Administration–approved noncorticosteroid topical for use in pediatric atopic dermatitis, Lawrence F. Eichenfield, MD, reported at the SDEF Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

Bruce Jancin/MDedge News

These new agents will be embraced by clinicians for use in delicate skin areas, as well as in the common clinical scenario involving steroid-averse parents, predicted Dr. Eichenfield, professor of dermatology and pediatrics at the University of California, San Diego, and chief of pediatric and adolescent dermatology at Rady Children’s Hospital.

First up is crisaborole (Eucrisa), which is approved for atopic dermatitis (AD) in children aged two years and older and has been under review at the Food and Drug Administration for use in infantile AD. (On March 24, several weeks after the meeting, the FDA approved crisaborole down to aged three months for treatment of mild to moderate AD). Agents earlier in the developmental pipeline include two topical Janus kinase (JAK) inhibitors, ruxolitinib and delgocitinib, as well as tapinarof.

Crisaborole: This phosphodiesterase 4 inhibitor is FDA approved down to 2 years of age. In the phase 4, open-label CrisADe CARE 1 study, crisaborole was studied in 137 children ages 3 months to under 24 months. CrisADe CARE 1, presented at the 2019 annual conference of the Pediatric Dermatology Research Alliance (PeDRA), showed close to a 60% reduction from baseline in Eczema Area and Severity Index (EASI) scores after 28 days of twice-daily therapy in the youngsters, 61% of who had moderate AD, the rest mild disease.

Tolerability and safety were reassuring in the phase 4 study. Although about 3% of subjects each experienced application site pain, discomfort, or erythema, the rate of study discontinuation was impressively low at 2.9%, Dr. Eichenfield observed.

Delgocitinib: Japanese investigators have reported positive results in a phase 2 study of delgocitinib ointment in 98 children and adolescents aged 2-15 years, with AD. After 4 weeks of twice-daily treatment, modified EASI scores improved by a mean of 54% with delgocitinib 0.25% and by 62% with 0.5%, compared with less than a 5% improvement with the vehicle control (J Allergy Clin Immunol. 2019 Dec;144[6]:1575-83). The ointment formulation is being developed specifically for the Japanese market.

Studies of an alternative formulation of the JAK inhibitor as a cream rather than ointment, intended for the U.S. and European markets, are in the early stages, conducted by Leo Pharma. Delgocitinib cream, under study in adults and children down to age 2 years with AD, is also under study for chronic hand dermatitis, a program Dr. Eichenfield is enthusiastic about.

“Hand eczema is something you’re going to hear a lot about in the next 2 years. In the U.S., we have no drug approved specifically for hand eczema. And we actually see a lot of hand eczema in pediatric and adolescent patients. I’d say 75%-80% of the ones I see also have atopic dermatitis,” he said.

Ruxolitinib: Incyte, which is developing the topical JAK inhibitor, recently announced positive results in the first of four phase 3 randomized trials, this one conducted in AD patients aged 12 years and older. The efficacy appears to be comparable to that of topical steroids. Studies in younger children are also planned. Ruxolitinib cream is in advanced clinical trials for treatment of vitiligo.

Tapinarof: This topical aryl hydrocarbon receptor agonist downregulates Th17 cytokines, an attribute desirable for treatment of psoriasis. But it also downregulates Th2 cytokines and improves the damaged skin barrier characteristic of AD via upregulation of the filaggrin and involucrin genes in keratinocytes. In a phase 2b, double-blind clinical trial conducted in 247 adults and adolescents with moderate to severe AD, 12 weeks of once-daily tapinarof 1% enabled 51% of patients to achieve a 75% or greater improvement in EASI scores, compared with 18% in controls on vehicle (J Am Acad Dermatol. 2019 Jan;80[1]:89-98.e3).

Dermavant, which is developing the drug, plans to seek an initial indication for treatment of psoriasis, where a phase 3 study is underway, before pursuing regulatory approval in AD.

Dr. Eichenfield disclosed serving as a consultant or investigator for various pharmaceutical companies, including Pfizer, and Dermavant.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

This article was updated 3/27/20.

LAHAINA, HAWAII – Novel topical medications are in the works that will address the longstanding unmet need for a Food and Drug Administration–approved noncorticosteroid topical for use in pediatric atopic dermatitis, Lawrence F. Eichenfield, MD, reported at the SDEF Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

Bruce Jancin/MDedge News

These new agents will be embraced by clinicians for use in delicate skin areas, as well as in the common clinical scenario involving steroid-averse parents, predicted Dr. Eichenfield, professor of dermatology and pediatrics at the University of California, San Diego, and chief of pediatric and adolescent dermatology at Rady Children’s Hospital.

First up is crisaborole (Eucrisa), which is approved for atopic dermatitis (AD) in children aged two years and older and has been under review at the Food and Drug Administration for use in infantile AD. (On March 24, several weeks after the meeting, the FDA approved crisaborole down to aged three months for treatment of mild to moderate AD). Agents earlier in the developmental pipeline include two topical Janus kinase (JAK) inhibitors, ruxolitinib and delgocitinib, as well as tapinarof.

Crisaborole: This phosphodiesterase 4 inhibitor is FDA approved down to 2 years of age. In the phase 4, open-label CrisADe CARE 1 study, crisaborole was studied in 137 children ages 3 months to under 24 months. CrisADe CARE 1, presented at the 2019 annual conference of the Pediatric Dermatology Research Alliance (PeDRA), showed close to a 60% reduction from baseline in Eczema Area and Severity Index (EASI) scores after 28 days of twice-daily therapy in the youngsters, 61% of who had moderate AD, the rest mild disease.

Tolerability and safety were reassuring in the phase 4 study. Although about 3% of subjects each experienced application site pain, discomfort, or erythema, the rate of study discontinuation was impressively low at 2.9%, Dr. Eichenfield observed.

Delgocitinib: Japanese investigators have reported positive results in a phase 2 study of delgocitinib ointment in 98 children and adolescents aged 2-15 years, with AD. After 4 weeks of twice-daily treatment, modified EASI scores improved by a mean of 54% with delgocitinib 0.25% and by 62% with 0.5%, compared with less than a 5% improvement with the vehicle control (J Allergy Clin Immunol. 2019 Dec;144[6]:1575-83). The ointment formulation is being developed specifically for the Japanese market.

Studies of an alternative formulation of the JAK inhibitor as a cream rather than ointment, intended for the U.S. and European markets, are in the early stages, conducted by Leo Pharma. Delgocitinib cream, under study in adults and children down to age 2 years with AD, is also under study for chronic hand dermatitis, a program Dr. Eichenfield is enthusiastic about.

“Hand eczema is something you’re going to hear a lot about in the next 2 years. In the U.S., we have no drug approved specifically for hand eczema. And we actually see a lot of hand eczema in pediatric and adolescent patients. I’d say 75%-80% of the ones I see also have atopic dermatitis,” he said.

Ruxolitinib: Incyte, which is developing the topical JAK inhibitor, recently announced positive results in the first of four phase 3 randomized trials, this one conducted in AD patients aged 12 years and older. The efficacy appears to be comparable to that of topical steroids. Studies in younger children are also planned. Ruxolitinib cream is in advanced clinical trials for treatment of vitiligo.

Tapinarof: This topical aryl hydrocarbon receptor agonist downregulates Th17 cytokines, an attribute desirable for treatment of psoriasis. But it also downregulates Th2 cytokines and improves the damaged skin barrier characteristic of AD via upregulation of the filaggrin and involucrin genes in keratinocytes. In a phase 2b, double-blind clinical trial conducted in 247 adults and adolescents with moderate to severe AD, 12 weeks of once-daily tapinarof 1% enabled 51% of patients to achieve a 75% or greater improvement in EASI scores, compared with 18% in controls on vehicle (J Am Acad Dermatol. 2019 Jan;80[1]:89-98.e3).

Dermavant, which is developing the drug, plans to seek an initial indication for treatment of psoriasis, where a phase 3 study is underway, before pursuing regulatory approval in AD.

Dr. Eichenfield disclosed serving as a consultant or investigator for various pharmaceutical companies, including Pfizer, and Dermavant.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

This article was updated 3/27/20.

LAHAINA, HAWAII – Novel topical medications are in the works that will address the longstanding unmet need for a Food and Drug Administration–approved noncorticosteroid topical for use in pediatric atopic dermatitis, Lawrence F. Eichenfield, MD, reported at the SDEF Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

Bruce Jancin/MDedge News

These new agents will be embraced by clinicians for use in delicate skin areas, as well as in the common clinical scenario involving steroid-averse parents, predicted Dr. Eichenfield, professor of dermatology and pediatrics at the University of California, San Diego, and chief of pediatric and adolescent dermatology at Rady Children’s Hospital.

First up is crisaborole (Eucrisa), which is approved for atopic dermatitis (AD) in children aged two years and older and has been under review at the Food and Drug Administration for use in infantile AD. (On March 24, several weeks after the meeting, the FDA approved crisaborole down to aged three months for treatment of mild to moderate AD). Agents earlier in the developmental pipeline include two topical Janus kinase (JAK) inhibitors, ruxolitinib and delgocitinib, as well as tapinarof.

Crisaborole: This phosphodiesterase 4 inhibitor is FDA approved down to 2 years of age. In the phase 4, open-label CrisADe CARE 1 study, crisaborole was studied in 137 children ages 3 months to under 24 months. CrisADe CARE 1, presented at the 2019 annual conference of the Pediatric Dermatology Research Alliance (PeDRA), showed close to a 60% reduction from baseline in Eczema Area and Severity Index (EASI) scores after 28 days of twice-daily therapy in the youngsters, 61% of who had moderate AD, the rest mild disease.

Tolerability and safety were reassuring in the phase 4 study. Although about 3% of subjects each experienced application site pain, discomfort, or erythema, the rate of study discontinuation was impressively low at 2.9%, Dr. Eichenfield observed.

Delgocitinib: Japanese investigators have reported positive results in a phase 2 study of delgocitinib ointment in 98 children and adolescents aged 2-15 years, with AD. After 4 weeks of twice-daily treatment, modified EASI scores improved by a mean of 54% with delgocitinib 0.25% and by 62% with 0.5%, compared with less than a 5% improvement with the vehicle control (J Allergy Clin Immunol. 2019 Dec;144[6]:1575-83). The ointment formulation is being developed specifically for the Japanese market.

Studies of an alternative formulation of the JAK inhibitor as a cream rather than ointment, intended for the U.S. and European markets, are in the early stages, conducted by Leo Pharma. Delgocitinib cream, under study in adults and children down to age 2 years with AD, is also under study for chronic hand dermatitis, a program Dr. Eichenfield is enthusiastic about.

“Hand eczema is something you’re going to hear a lot about in the next 2 years. In the U.S., we have no drug approved specifically for hand eczema. And we actually see a lot of hand eczema in pediatric and adolescent patients. I’d say 75%-80% of the ones I see also have atopic dermatitis,” he said.

Ruxolitinib: Incyte, which is developing the topical JAK inhibitor, recently announced positive results in the first of four phase 3 randomized trials, this one conducted in AD patients aged 12 years and older. The efficacy appears to be comparable to that of topical steroids. Studies in younger children are also planned. Ruxolitinib cream is in advanced clinical trials for treatment of vitiligo.

Tapinarof: This topical aryl hydrocarbon receptor agonist downregulates Th17 cytokines, an attribute desirable for treatment of psoriasis. But it also downregulates Th2 cytokines and improves the damaged skin barrier characteristic of AD via upregulation of the filaggrin and involucrin genes in keratinocytes. In a phase 2b, double-blind clinical trial conducted in 247 adults and adolescents with moderate to severe AD, 12 weeks of once-daily tapinarof 1% enabled 51% of patients to achieve a 75% or greater improvement in EASI scores, compared with 18% in controls on vehicle (J Am Acad Dermatol. 2019 Jan;80[1]:89-98.e3).

Dermavant, which is developing the drug, plans to seek an initial indication for treatment of psoriasis, where a phase 3 study is underway, before pursuing regulatory approval in AD.

Dr. Eichenfield disclosed serving as a consultant or investigator for various pharmaceutical companies, including Pfizer, and Dermavant.

SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

[email protected]

This article was updated 3/27/20.