Genitourinary Cancer

Real-world survival outcomes for cancer patients on immune checkpoint inhibitors (ICIs) are inferior to outcomes reported in patients on clinical trials of ICIs, according to research published in JCO Clinical Cancer Informatics.

However, the research also suggests that real-world patients who receive ICIs achieve longer survival than patients on standard-of-care medications.

“Patients receiving ICIs in real-world practice may differ from those enrolled in trials in a variety of ways, including age, race, performance status, and comorbidity burden,” said study author Jerry S.H. Lee, PhD, of the University of Southern California, Los Angeles.

Dr. Lee noted that only 3%-4% of cancer patients participate in clinical trials. In fact, more than half of patients with melanoma and nearly three-quarters of those with non–small cell lung cancer (NSCLC) do not meet criteria for eligibility in clinical trials, he said.

To examine the discrepancies between real-world practice and clinical trials and to better understand which patients receive ICIs in clinical practice, Dr. Lee and colleagues conducted a retrospective analysis using electronic health record data from Veterans Administration (VA) facilities nationwide.

The researchers identified 11,888 cancer patients who were treated with ICIs. The cohort included patients who are underrepresented in pivotal clinical trials, including older, non-White, and/or higher disease-burdened patients.

The majority of patients were treated for NSCLC (51.1%), followed by melanoma (14.4%), renal cell carcinoma (RCC; 8.1%), squamous cell carcinoma of the head and neck (6.8%), urothelial cancer (6.4%), hepatocellular carcinoma (4.5%), and other less common cancer types (8.8%).
 

Overall survival by indication

In general, median overall survival (OS) in the VA cohort was inferior to median OS reported in clinical trials. However, patients treated with first-line nivolumab for melanoma and second-line pembrolizumab or nivolumab for NSCLC had similar OS in the real-world and trial data.

The researchers did not report exact OS numbers from clinical trials. However, they did report the exact numbers from the VA cohort and show OS differences between the VA cohort and clinical trials graphically.

Among patients in the VA cohort, the median OS was:

• 25.5 months in melanoma patients on first-line nivolumab
• 16.3 months in RCC patients receiving nivolumab in the second line or higher
• 14 months in RCC patients on first-line ipilimumab and nivolumab
• 10.6 months in NSCLC patients on first-line pembrolizumab
• 9.9 months in NSCLC patients receiving pembrolizumab or nivolumab in the second line or higher
• 9.1 months in NSCLC patients on first-line pembrolizumab and platinum-based chemotherapy
• 6.7 months in urothelial cancer patients receiving ICIs in the second line or higher.

A number of factors may have contributed to the shorter OS observed in the VA cohort, according to the researchers. The VA cohort is predominantly male, is older, and has a higher degree of comorbidity, compared with patients in clinical trials.

In addition, no data are available to determine the cause for discontinuation of therapy, and VA patients may have received ICIs after failing multiple lines of previous therapy, while clinical trials may limit patients to only one or two previous lines of therapy.

After stratifying VA patients by frailty status, the OS among non-frail patients was more similar to the OS reported in clinical trials.

“Real-world outcomes from the VA were more similar when adjusted for frailty, which shows the importance of patient diversity in clinical trials,” Dr. Lee said. He added that the definition of frailty among VA patients included potential injury during combat and therefore differs from a generic frailty definition.
 

ICIs vs. standard care

The researchers also found that VA patients treated with ICIs had longer OS, compared with a cohort of VA patients receiving standard-of-care therapies.

The median OS was as follows:

• In melanoma patients on first-line treatment – 39.29 months with nivolumab and 5.75 months with chemotherapy (P < .001).
• In RCC patients on first-line treatment – 14.01 months with ipilimumab plus nivolumab and 8.63 months with targeted therapy (P = .051).
• In RCC patients on second-line or greater treatment – 12.43 months with nivolumab and 8.09 months with everolimus (P < .001).
• In NSCLC patients on first-line therapy – 8.88 months with pembrolizumab and 6.38 months with a platinum doublet (P < .001).
• In NSCLC patients on first-line combination therapy – 10.59 months with pembrolizumab plus platinum chemotherapy and 6.38 months with a platinum doublet (P < .001).
• In NSCLC patients on second-line or greater therapy – 10.06 months with pembrolizumab or nivolumab and 6.41 months with docetaxel (P < .001).
• In urothelial cancer patients on second-line or greater therapy – 7.66 months with an ICI and 6.31 months with chemotherapy (P = .043).
   

Help for treatment decisions

“The real-world survival outcomes not only indicate the breadth of indications but also represent patients who tend not to be eligible for immunotherapy trials, based on their health status,” Dr. Lee said. “We hope this dataset of national-level experience provides practicing oncologists evidence to help patients and family members in the process of decision-making about therapy.”

Real-world data can also inform oncologists who face decisions on whether to prescribe or withhold ICIs and patients who face the financial burden of paying for ICIs, he said.

This dataset will be continually updated. The researchers have already added another 10,000 VA patients who have received immunotherapies in the year since the trial began.

“In a longitudinal way, we plan to examine what causes differences in outcomes and continue to find ways to extend care to veterans with a balance of high quality of life,” Dr. Lee said.

“Patients who participate in clinical trials are, on average, younger and healthier than the general population,” said Bora Youn, PhD, a senior biostatistician at Biogen in Cambridge, Mass., who was not involved in this study.

“In the case of immunotherapies, those with poor performance status and autoimmune conditions are often excluded from trials,” Dr. Youn added. “In the real world, these patients can also receive treatments, and clinicians often need to extrapolate the results from clinical trials. It is therefore important to collect real-world data to understand the effectiveness and safety of these therapies in patients with limited evidence.”

Dr. Youn led a real-world study, published in Cancer, of 1,256 Medicare recipients who were diagnosed with NSCLC and received ICI therapy.

“We found that factors associated with poor prognosis in general, such as squamous histology and failure of aggressive prior treatment, are also predictive of decreased survival among those who initiated immunotherapies. Yet, OS of older patients was relatively comparable to those observed in clinical trials,” Dr. Youn said.

“Understanding the real-world effectiveness of these treatments will help improve the evidence base, especially for those underrepresented in clinical trials. These studies can also help identify patients who are most likely to benefit from immunotherapies,” Dr. Youn added.

This study was supported by the VA Office of Research and Development Cooperative Studies Program. Dr. Lee and Dr. Youn disclosed no conflicts of interest.

SOURCE: Jennifer La et al. JCO Clinical Cancer Informatics. 2020:4:918-28.

Real-world survival outcomes for cancer patients on immune checkpoint inhibitors (ICIs) are inferior to outcomes reported in patients on clinical trials of ICIs, according to research published in JCO Clinical Cancer Informatics.

However, the research also suggests that real-world patients who receive ICIs achieve longer survival than patients on standard-of-care medications.

“Patients receiving ICIs in real-world practice may differ from those enrolled in trials in a variety of ways, including age, race, performance status, and comorbidity burden,” said study author Jerry S.H. Lee, PhD, of the University of Southern California, Los Angeles.

Dr. Lee noted that only 3%-4% of cancer patients participate in clinical trials. In fact, more than half of patients with melanoma and nearly three-quarters of those with non–small cell lung cancer (NSCLC) do not meet criteria for eligibility in clinical trials, he said.

To examine the discrepancies between real-world practice and clinical trials and to better understand which patients receive ICIs in clinical practice, Dr. Lee and colleagues conducted a retrospective analysis using electronic health record data from Veterans Administration (VA) facilities nationwide.

The researchers identified 11,888 cancer patients who were treated with ICIs. The cohort included patients who are underrepresented in pivotal clinical trials, including older, non-White, and/or higher disease-burdened patients.

The majority of patients were treated for NSCLC (51.1%), followed by melanoma (14.4%), renal cell carcinoma (RCC; 8.1%), squamous cell carcinoma of the head and neck (6.8%), urothelial cancer (6.4%), hepatocellular carcinoma (4.5%), and other less common cancer types (8.8%).
 

Overall survival by indication

In general, median overall survival (OS) in the VA cohort was inferior to median OS reported in clinical trials. However, patients treated with first-line nivolumab for melanoma and second-line pembrolizumab or nivolumab for NSCLC had similar OS in the real-world and trial data.

The researchers did not report exact OS numbers from clinical trials. However, they did report the exact numbers from the VA cohort and show OS differences between the VA cohort and clinical trials graphically.

Among patients in the VA cohort, the median OS was:

• 25.5 months in melanoma patients on first-line nivolumab
• 16.3 months in RCC patients receiving nivolumab in the second line or higher
• 14 months in RCC patients on first-line ipilimumab and nivolumab
• 10.6 months in NSCLC patients on first-line pembrolizumab
• 9.9 months in NSCLC patients receiving pembrolizumab or nivolumab in the second line or higher
• 9.1 months in NSCLC patients on first-line pembrolizumab and platinum-based chemotherapy
• 6.7 months in urothelial cancer patients receiving ICIs in the second line or higher.

A number of factors may have contributed to the shorter OS observed in the VA cohort, according to the researchers. The VA cohort is predominantly male, is older, and has a higher degree of comorbidity, compared with patients in clinical trials.

In addition, no data are available to determine the cause for discontinuation of therapy, and VA patients may have received ICIs after failing multiple lines of previous therapy, while clinical trials may limit patients to only one or two previous lines of therapy.

After stratifying VA patients by frailty status, the OS among non-frail patients was more similar to the OS reported in clinical trials.

“Real-world outcomes from the VA were more similar when adjusted for frailty, which shows the importance of patient diversity in clinical trials,” Dr. Lee said. He added that the definition of frailty among VA patients included potential injury during combat and therefore differs from a generic frailty definition.
 

ICIs vs. standard care

The researchers also found that VA patients treated with ICIs had longer OS, compared with a cohort of VA patients receiving standard-of-care therapies.

The median OS was as follows:

• In melanoma patients on first-line treatment – 39.29 months with nivolumab and 5.75 months with chemotherapy (P < .001).
• In RCC patients on first-line treatment – 14.01 months with ipilimumab plus nivolumab and 8.63 months with targeted therapy (P = .051).
• In RCC patients on second-line or greater treatment – 12.43 months with nivolumab and 8.09 months with everolimus (P < .001).
• In NSCLC patients on first-line therapy – 8.88 months with pembrolizumab and 6.38 months with a platinum doublet (P < .001).
• In NSCLC patients on first-line combination therapy – 10.59 months with pembrolizumab plus platinum chemotherapy and 6.38 months with a platinum doublet (P < .001).
• In NSCLC patients on second-line or greater therapy – 10.06 months with pembrolizumab or nivolumab and 6.41 months with docetaxel (P < .001).
• In urothelial cancer patients on second-line or greater therapy – 7.66 months with an ICI and 6.31 months with chemotherapy (P = .043).
   

Help for treatment decisions

“The real-world survival outcomes not only indicate the breadth of indications but also represent patients who tend not to be eligible for immunotherapy trials, based on their health status,” Dr. Lee said. “We hope this dataset of national-level experience provides practicing oncologists evidence to help patients and family members in the process of decision-making about therapy.”

Real-world data can also inform oncologists who face decisions on whether to prescribe or withhold ICIs and patients who face the financial burden of paying for ICIs, he said.

This dataset will be continually updated. The researchers have already added another 10,000 VA patients who have received immunotherapies in the year since the trial began.

“In a longitudinal way, we plan to examine what causes differences in outcomes and continue to find ways to extend care to veterans with a balance of high quality of life,” Dr. Lee said.

“Patients who participate in clinical trials are, on average, younger and healthier than the general population,” said Bora Youn, PhD, a senior biostatistician at Biogen in Cambridge, Mass., who was not involved in this study.

“In the case of immunotherapies, those with poor performance status and autoimmune conditions are often excluded from trials,” Dr. Youn added. “In the real world, these patients can also receive treatments, and clinicians often need to extrapolate the results from clinical trials. It is therefore important to collect real-world data to understand the effectiveness and safety of these therapies in patients with limited evidence.”

Dr. Youn led a real-world study, published in Cancer, of 1,256 Medicare recipients who were diagnosed with NSCLC and received ICI therapy.

“We found that factors associated with poor prognosis in general, such as squamous histology and failure of aggressive prior treatment, are also predictive of decreased survival among those who initiated immunotherapies. Yet, OS of older patients was relatively comparable to those observed in clinical trials,” Dr. Youn said.

“Understanding the real-world effectiveness of these treatments will help improve the evidence base, especially for those underrepresented in clinical trials. These studies can also help identify patients who are most likely to benefit from immunotherapies,” Dr. Youn added.

This study was supported by the VA Office of Research and Development Cooperative Studies Program. Dr. Lee and Dr. Youn disclosed no conflicts of interest.

SOURCE: Jennifer La et al. JCO Clinical Cancer Informatics. 2020:4:918-28.

Real-world survival outcomes for cancer patients on immune checkpoint inhibitors (ICIs) are inferior to outcomes reported in patients on clinical trials of ICIs, according to research published in JCO Clinical Cancer Informatics.

However, the research also suggests that real-world patients who receive ICIs achieve longer survival than patients on standard-of-care medications.

“Patients receiving ICIs in real-world practice may differ from those enrolled in trials in a variety of ways, including age, race, performance status, and comorbidity burden,” said study author Jerry S.H. Lee, PhD, of the University of Southern California, Los Angeles.

Dr. Lee noted that only 3%-4% of cancer patients participate in clinical trials. In fact, more than half of patients with melanoma and nearly three-quarters of those with non–small cell lung cancer (NSCLC) do not meet criteria for eligibility in clinical trials, he said.

To examine the discrepancies between real-world practice and clinical trials and to better understand which patients receive ICIs in clinical practice, Dr. Lee and colleagues conducted a retrospective analysis using electronic health record data from Veterans Administration (VA) facilities nationwide.

The researchers identified 11,888 cancer patients who were treated with ICIs. The cohort included patients who are underrepresented in pivotal clinical trials, including older, non-White, and/or higher disease-burdened patients.

The majority of patients were treated for NSCLC (51.1%), followed by melanoma (14.4%), renal cell carcinoma (RCC; 8.1%), squamous cell carcinoma of the head and neck (6.8%), urothelial cancer (6.4%), hepatocellular carcinoma (4.5%), and other less common cancer types (8.8%).
 

Overall survival by indication

In general, median overall survival (OS) in the VA cohort was inferior to median OS reported in clinical trials. However, patients treated with first-line nivolumab for melanoma and second-line pembrolizumab or nivolumab for NSCLC had similar OS in the real-world and trial data.

The researchers did not report exact OS numbers from clinical trials. However, they did report the exact numbers from the VA cohort and show OS differences between the VA cohort and clinical trials graphically.

Among patients in the VA cohort, the median OS was:

• 25.5 months in melanoma patients on first-line nivolumab
• 16.3 months in RCC patients receiving nivolumab in the second line or higher
• 14 months in RCC patients on first-line ipilimumab and nivolumab
• 10.6 months in NSCLC patients on first-line pembrolizumab
• 9.9 months in NSCLC patients receiving pembrolizumab or nivolumab in the second line or higher
• 9.1 months in NSCLC patients on first-line pembrolizumab and platinum-based chemotherapy
• 6.7 months in urothelial cancer patients receiving ICIs in the second line or higher.

A number of factors may have contributed to the shorter OS observed in the VA cohort, according to the researchers. The VA cohort is predominantly male, is older, and has a higher degree of comorbidity, compared with patients in clinical trials.

In addition, no data are available to determine the cause for discontinuation of therapy, and VA patients may have received ICIs after failing multiple lines of previous therapy, while clinical trials may limit patients to only one or two previous lines of therapy.

After stratifying VA patients by frailty status, the OS among non-frail patients was more similar to the OS reported in clinical trials.

“Real-world outcomes from the VA were more similar when adjusted for frailty, which shows the importance of patient diversity in clinical trials,” Dr. Lee said. He added that the definition of frailty among VA patients included potential injury during combat and therefore differs from a generic frailty definition.
 

ICIs vs. standard care

The researchers also found that VA patients treated with ICIs had longer OS, compared with a cohort of VA patients receiving standard-of-care therapies.

The median OS was as follows:

• In melanoma patients on first-line treatment – 39.29 months with nivolumab and 5.75 months with chemotherapy (P < .001).
• In RCC patients on first-line treatment – 14.01 months with ipilimumab plus nivolumab and 8.63 months with targeted therapy (P = .051).
• In RCC patients on second-line or greater treatment – 12.43 months with nivolumab and 8.09 months with everolimus (P < .001).
• In NSCLC patients on first-line therapy – 8.88 months with pembrolizumab and 6.38 months with a platinum doublet (P < .001).
• In NSCLC patients on first-line combination therapy – 10.59 months with pembrolizumab plus platinum chemotherapy and 6.38 months with a platinum doublet (P < .001).
• In NSCLC patients on second-line or greater therapy – 10.06 months with pembrolizumab or nivolumab and 6.41 months with docetaxel (P < .001).
• In urothelial cancer patients on second-line or greater therapy – 7.66 months with an ICI and 6.31 months with chemotherapy (P = .043).
   

Help for treatment decisions

“The real-world survival outcomes not only indicate the breadth of indications but also represent patients who tend not to be eligible for immunotherapy trials, based on their health status,” Dr. Lee said. “We hope this dataset of national-level experience provides practicing oncologists evidence to help patients and family members in the process of decision-making about therapy.”

Real-world data can also inform oncologists who face decisions on whether to prescribe or withhold ICIs and patients who face the financial burden of paying for ICIs, he said.

This dataset will be continually updated. The researchers have already added another 10,000 VA patients who have received immunotherapies in the year since the trial began.

“In a longitudinal way, we plan to examine what causes differences in outcomes and continue to find ways to extend care to veterans with a balance of high quality of life,” Dr. Lee said.

“Patients who participate in clinical trials are, on average, younger and healthier than the general population,” said Bora Youn, PhD, a senior biostatistician at Biogen in Cambridge, Mass., who was not involved in this study.

“In the case of immunotherapies, those with poor performance status and autoimmune conditions are often excluded from trials,” Dr. Youn added. “In the real world, these patients can also receive treatments, and clinicians often need to extrapolate the results from clinical trials. It is therefore important to collect real-world data to understand the effectiveness and safety of these therapies in patients with limited evidence.”

Dr. Youn led a real-world study, published in Cancer, of 1,256 Medicare recipients who were diagnosed with NSCLC and received ICI therapy.

“We found that factors associated with poor prognosis in general, such as squamous histology and failure of aggressive prior treatment, are also predictive of decreased survival among those who initiated immunotherapies. Yet, OS of older patients was relatively comparable to those observed in clinical trials,” Dr. Youn said.

“Understanding the real-world effectiveness of these treatments will help improve the evidence base, especially for those underrepresented in clinical trials. These studies can also help identify patients who are most likely to benefit from immunotherapies,” Dr. Youn added.

This study was supported by the VA Office of Research and Development Cooperative Studies Program. Dr. Lee and Dr. Youn disclosed no conflicts of interest.

SOURCE: Jennifer La et al. JCO Clinical Cancer Informatics. 2020:4:918-28.

Integrating PET imaging into postprostatectomy radiation therapy (RT) decisions and planning can improve prostate cancer outcomes, first results of the EMPIRE-1 trial suggest.

The findings were reported in a plenary session at the American Society for Radiation Oncology Annual Meeting 2020.

“Quite frankly, this is an area where we are shooting in the dark with conventional imaging, and that’s where we think molecular imaging has a potential role,” noted coprincipal investigator Ashesh B. Jani, MD, of the Winship Cancer Institute of Emory University, Atlanta.

“We hypothesized that radiotherapy outcomes can be improved upon by PET by excluding patients with extrapelvic disease and also by improving treatment field decisions and target definition,” Dr. Jani added.

Patients with prostate cancer were eligible for EMPIRE-1 if they had undergone prostatectomy and had a detectable prostate-specific antigen (PSA) level but negative findings on conventional imaging (a bone scan plus abdominopelvic CT and/or MRI).

A total of 165 patients were randomized to RT guided by the conventional imaging alone or combined with PET imaging using the radiotracer fluciclovine (18F). Treatment decisions in the latter group were strictly based on where uptake was seen.
 

Study results

The trial’s primary endpoint was treatment failure, defined as a PSA level exceeding 0.2 ng/mL from nadir followed by another rise, a continued PSA rise despite RT, progression on imaging or digital rectal exam, or initiation of systemic therapy.

“Most imaging studies tend to focus on diagnostic accuracy, pathologic correlation, and decision changes. It’s a very high bar for an imaging study to influence failure rates,” Dr. Jani pointed out.

Adding 18F-PET to conventional imaging altered the treatment decision for 35.4% of patients in that group (P < .001). It also significantly altered a range of volumetric and dosimetric parameters.

At a median follow-up of 2.48 years, the 3-year rate of failure-free survival was 63.0% with conventional imaging alone and 75.5% with the addition of 18F-PET (P = .003). The corresponding 4-year rate was 51.2% and 75.5%, respectively (P < .001).

In multivariate analysis, the conventional imaging group had double the risk of failure events relative to the PET group (hazard ratio, 2.04; P = .033).

Provider-reported data showed no significant difference between imaging groups in maximum acute or late genitourinary toxicity and gastrointestinal toxicity. An analysis of patient-reported toxicity data is pending.

“Randomized trials of imaging tests with a primary cancer control endpoint are important but uncommonly done,” Dr. Jani commented. “This is the first such trial of PET over conventional imaging in the postprostatectomy radiotherapy setting.”

“Inclusion of fluciclovine resulted in a significant improvement in failure rate at 3 years. This warrants further investigation,” he maintained.

To that end, the investigators have launched the EMPIRE-2 trial, which is comparing RT guided by 18F-PET with PET using another radiotracer that is not yet approved by the Food and Drug Administration, gallium-68 prostate-specific membrane antigen.
 

Findings in context

“There are several remarkable aspects of the EMPIRE-1 trial worth noting,” said invited discussant Neha Vapiwala, MD, of the University of Pennsylvania, Philadelphia.

She commended the trial’s randomization, given a bias that more imaging is better, and the diversity of its participants that better reflects the general population of prostate cancer patients.

“The study procedures appear to be well tolerated despite a net overall increase in the radiation volume treated in the patients who underwent PET, although we do still await patient-reported toxicity,” Dr. Vapiwala noted. “Finally, a high bar was set, with a clinically meaningful primary endpoint for an imaging study.

“This study ultimately demonstrated that, in the PET arm, better selection with PET was able to result in better patient outcomes,” she maintained.

At the same time, Dr. Vapiwala recommended caution when reducing or withholding definitive local therapy based on PET results, as occurred in 14 patients.

“We must always be able to see the forest from the trees, and when evaluating our patients with PET scans, what we see and what we don’t see is just one piece of the puzzle. Existing level 1 evidence and oncologic principles must still apply,” she said. “While PET can help paint a more complete picture, it should not define the picture itself.”

The study was supported by the National Institutes of Health. Dr. Jani disclosed advisory board service for Blue Earth Diagnostics. Dr. Vapiwala disclosed no relevant conflicts of interest.

SOURCE: Jani A et al. ASTRO 2020, Abstract LBA1.

Integrating PET imaging into postprostatectomy radiation therapy (RT) decisions and planning can improve prostate cancer outcomes, first results of the EMPIRE-1 trial suggest.

The findings were reported in a plenary session at the American Society for Radiation Oncology Annual Meeting 2020.

“Quite frankly, this is an area where we are shooting in the dark with conventional imaging, and that’s where we think molecular imaging has a potential role,” noted coprincipal investigator Ashesh B. Jani, MD, of the Winship Cancer Institute of Emory University, Atlanta.

“We hypothesized that radiotherapy outcomes can be improved upon by PET by excluding patients with extrapelvic disease and also by improving treatment field decisions and target definition,” Dr. Jani added.

Patients with prostate cancer were eligible for EMPIRE-1 if they had undergone prostatectomy and had a detectable prostate-specific antigen (PSA) level but negative findings on conventional imaging (a bone scan plus abdominopelvic CT and/or MRI).

A total of 165 patients were randomized to RT guided by the conventional imaging alone or combined with PET imaging using the radiotracer fluciclovine (18F). Treatment decisions in the latter group were strictly based on where uptake was seen.
 

Study results

The trial’s primary endpoint was treatment failure, defined as a PSA level exceeding 0.2 ng/mL from nadir followed by another rise, a continued PSA rise despite RT, progression on imaging or digital rectal exam, or initiation of systemic therapy.

“Most imaging studies tend to focus on diagnostic accuracy, pathologic correlation, and decision changes. It’s a very high bar for an imaging study to influence failure rates,” Dr. Jani pointed out.

Adding 18F-PET to conventional imaging altered the treatment decision for 35.4% of patients in that group (P < .001). It also significantly altered a range of volumetric and dosimetric parameters.

At a median follow-up of 2.48 years, the 3-year rate of failure-free survival was 63.0% with conventional imaging alone and 75.5% with the addition of 18F-PET (P = .003). The corresponding 4-year rate was 51.2% and 75.5%, respectively (P < .001).

In multivariate analysis, the conventional imaging group had double the risk of failure events relative to the PET group (hazard ratio, 2.04; P = .033).

Provider-reported data showed no significant difference between imaging groups in maximum acute or late genitourinary toxicity and gastrointestinal toxicity. An analysis of patient-reported toxicity data is pending.

“Randomized trials of imaging tests with a primary cancer control endpoint are important but uncommonly done,” Dr. Jani commented. “This is the first such trial of PET over conventional imaging in the postprostatectomy radiotherapy setting.”

“Inclusion of fluciclovine resulted in a significant improvement in failure rate at 3 years. This warrants further investigation,” he maintained.

To that end, the investigators have launched the EMPIRE-2 trial, which is comparing RT guided by 18F-PET with PET using another radiotracer that is not yet approved by the Food and Drug Administration, gallium-68 prostate-specific membrane antigen.
 

Findings in context

“There are several remarkable aspects of the EMPIRE-1 trial worth noting,” said invited discussant Neha Vapiwala, MD, of the University of Pennsylvania, Philadelphia.

She commended the trial’s randomization, given a bias that more imaging is better, and the diversity of its participants that better reflects the general population of prostate cancer patients.

“The study procedures appear to be well tolerated despite a net overall increase in the radiation volume treated in the patients who underwent PET, although we do still await patient-reported toxicity,” Dr. Vapiwala noted. “Finally, a high bar was set, with a clinically meaningful primary endpoint for an imaging study.

“This study ultimately demonstrated that, in the PET arm, better selection with PET was able to result in better patient outcomes,” she maintained.

At the same time, Dr. Vapiwala recommended caution when reducing or withholding definitive local therapy based on PET results, as occurred in 14 patients.

“We must always be able to see the forest from the trees, and when evaluating our patients with PET scans, what we see and what we don’t see is just one piece of the puzzle. Existing level 1 evidence and oncologic principles must still apply,” she said. “While PET can help paint a more complete picture, it should not define the picture itself.”

The study was supported by the National Institutes of Health. Dr. Jani disclosed advisory board service for Blue Earth Diagnostics. Dr. Vapiwala disclosed no relevant conflicts of interest.

SOURCE: Jani A et al. ASTRO 2020, Abstract LBA1.

Integrating PET imaging into postprostatectomy radiation therapy (RT) decisions and planning can improve prostate cancer outcomes, first results of the EMPIRE-1 trial suggest.

The findings were reported in a plenary session at the American Society for Radiation Oncology Annual Meeting 2020.

“Quite frankly, this is an area where we are shooting in the dark with conventional imaging, and that’s where we think molecular imaging has a potential role,” noted coprincipal investigator Ashesh B. Jani, MD, of the Winship Cancer Institute of Emory University, Atlanta.

“We hypothesized that radiotherapy outcomes can be improved upon by PET by excluding patients with extrapelvic disease and also by improving treatment field decisions and target definition,” Dr. Jani added.

Patients with prostate cancer were eligible for EMPIRE-1 if they had undergone prostatectomy and had a detectable prostate-specific antigen (PSA) level but negative findings on conventional imaging (a bone scan plus abdominopelvic CT and/or MRI).

A total of 165 patients were randomized to RT guided by the conventional imaging alone or combined with PET imaging using the radiotracer fluciclovine (18F). Treatment decisions in the latter group were strictly based on where uptake was seen.
 

Study results

The trial’s primary endpoint was treatment failure, defined as a PSA level exceeding 0.2 ng/mL from nadir followed by another rise, a continued PSA rise despite RT, progression on imaging or digital rectal exam, or initiation of systemic therapy.

“Most imaging studies tend to focus on diagnostic accuracy, pathologic correlation, and decision changes. It’s a very high bar for an imaging study to influence failure rates,” Dr. Jani pointed out.

Adding 18F-PET to conventional imaging altered the treatment decision for 35.4% of patients in that group (P < .001). It also significantly altered a range of volumetric and dosimetric parameters.

At a median follow-up of 2.48 years, the 3-year rate of failure-free survival was 63.0% with conventional imaging alone and 75.5% with the addition of 18F-PET (P = .003). The corresponding 4-year rate was 51.2% and 75.5%, respectively (P < .001).

In multivariate analysis, the conventional imaging group had double the risk of failure events relative to the PET group (hazard ratio, 2.04; P = .033).

Provider-reported data showed no significant difference between imaging groups in maximum acute or late genitourinary toxicity and gastrointestinal toxicity. An analysis of patient-reported toxicity data is pending.

“Randomized trials of imaging tests with a primary cancer control endpoint are important but uncommonly done,” Dr. Jani commented. “This is the first such trial of PET over conventional imaging in the postprostatectomy radiotherapy setting.”

“Inclusion of fluciclovine resulted in a significant improvement in failure rate at 3 years. This warrants further investigation,” he maintained.

To that end, the investigators have launched the EMPIRE-2 trial, which is comparing RT guided by 18F-PET with PET using another radiotracer that is not yet approved by the Food and Drug Administration, gallium-68 prostate-specific membrane antigen.
 

Findings in context

“There are several remarkable aspects of the EMPIRE-1 trial worth noting,” said invited discussant Neha Vapiwala, MD, of the University of Pennsylvania, Philadelphia.

She commended the trial’s randomization, given a bias that more imaging is better, and the diversity of its participants that better reflects the general population of prostate cancer patients.

“The study procedures appear to be well tolerated despite a net overall increase in the radiation volume treated in the patients who underwent PET, although we do still await patient-reported toxicity,” Dr. Vapiwala noted. “Finally, a high bar was set, with a clinically meaningful primary endpoint for an imaging study.

“This study ultimately demonstrated that, in the PET arm, better selection with PET was able to result in better patient outcomes,” she maintained.

At the same time, Dr. Vapiwala recommended caution when reducing or withholding definitive local therapy based on PET results, as occurred in 14 patients.

“We must always be able to see the forest from the trees, and when evaluating our patients with PET scans, what we see and what we don’t see is just one piece of the puzzle. Existing level 1 evidence and oncologic principles must still apply,” she said. “While PET can help paint a more complete picture, it should not define the picture itself.”

The study was supported by the National Institutes of Health. Dr. Jani disclosed advisory board service for Blue Earth Diagnostics. Dr. Vapiwala disclosed no relevant conflicts of interest.

SOURCE: Jani A et al. ASTRO 2020, Abstract LBA1.

Stereotactic radiosurgery (SRS) should replace whole-brain radiotherapy (WBRT) as the new standard of care for patients with four or more brain metastases, say researchers who report results from a randomized trial conducted in patients with four to 15 brain metastases

“SRS was associated with reduced risk of neurocognitive deterioration compared to WBRT, as demonstrated by a constellation of neurocognitive tests, individually or by composite scores,” said lead author Jing Li, MD, PhD, associate professor of radiation oncology and codirector of the Brain Metastasis Clinic at the University of Texas MD Anderson Cancer Center, Houston.

She was speaking at the American Society for Radiation Oncology (ASTRO) 2020 Annual Meeting, which was held online this year because of the COVID pandemic.

“The results from this phase 3 randomized trial strongly support the use of SRS in patients with four to 15 brain metastases to better preserve cognitive function and to minimize interruption of systemic therapy, without compromising overall survival,” said Li.

SRS is already the standard of care for patients with one to three brain metastases. Two previous phase 3 randomized trials showed that SRS was better at preserving cognitive function without compromising overall survival in comparison to WBRT.

However, there has been some controversy over the use of SRS for patients with multiple brain metastases, commented study discussant Sue S. Yom, MD, PhD, a professor in the Departments of Radiation Oncology and Otolaryngology–Head and Neck Surgery, University of California, San Francisco.

This study has shown, “in a practice-changing manner, that giving SRS can improve the quality of life of patients with metastatic disease,” she said.

Up to 30% of cancer patients develop brain metastases. Historically, these have been associated with poor overall survival, in the range of 1 to 4 months.
 

Reduces cognitive decline

The new trial involved 72 patients with four to 15 untreated, nonmelanoma brain metastases (up to 20 lesions were allowed at the time of treatment); the median number of brain metastases was eight. Most (83%) of the trial participants were White, nearly half were aged 60 years or older, and 58% were women.

Patients were randomly assigned to receive either SRS (15–24 Gy per Radiation Therapy Oncology Group protocol 9005) or WBRT (30 Gy in 10 fractions). On the basis of previous research, 62% of patients in the WBRT arm were also given memantine, a dementia drug that can help preserve cognitive function.

All participants completed neurocognitive testing, including testing of learning, memory, attention span, executive function, verbal fluency, processing speed, and motor dexterity, at enrollment and longitudinally.

The primary endpoints were Hopkins Verbal Learning Test – Revised Total Recall (HVLT-R TR) score and local control at 4 months. Secondary endpoints included overall survival, distant brain failure, toxicity, and time to initiation of systemic therapy.

In the primary endpoint analysis, at 4 months, the HVLT-R TR standardized z-score increased by +0.21 (standard error [SE], 0.27) for patients who received SRS, but it declined by –0.74 (SE, 0.36) for WBRT-treated patients (P = .041). On the basis of Clinical Trial Battery Composite score, neurocognitive function of patients in the SRS arm improved on average +0.23 (SE, 0.14) but declined an average –0.73 (SE, 0.35) in the WBRT arm (P = .008).

Li pointed out that there was also a “clinically meaningful and statistically significant benefit” with SRS at 1 month (P = .033) and 6 months (P = .012).

A total of 69 patients (35 for SRS and 34 for WBRT) were evaluable for overall survival, which was similar between the groups (SRS median, 7.8 months; WBRT median, 8.9 months; P = .59). Treatment with SRS resulted in better local control rates (95% at 4 months with SRS and 86.7% with WBRT; P = .09), but the median time to distant brain failure was shorter (10.5 months for WBRT and 6.3 months for SRS; P = .37).

In her discussion of the study, Yom noted that overall survival time was similar in the two arms and that, numerically, it may have even been a little longer in the SRS group. “While it is true that they had more relapses in untreated portions of the brain, they lived as long or longer than those who received WBRT and had better cognitive function,” she noted

Yom also noted that of particular importance was the finding that SRS was associated with shorter interruptions of systemic therapy (time to systemic therapy: SRS, 1.7 weeks; WBRT, 4.1 weeks; P = .001). Patients with metastatic disease usually have cancer in locations other than the brain. They may be receiving some type of systemic therapy, which is interrupted with WBRT, Li commented.

Toxicities of grade 3 or higher were observed in four patients in the WBRT arm and two in the SRS arm. Radiographic evidence of radiation necrosis, a side effect associated with SRS, was observed in 17% patients in the SRS arm of the trial (4% of all treated lesions).

The trial was halted early owing to the publication of another phase 3 trial (NRG Oncology CC 001), which provided level 1 evidence for replacing standard WBRT with hippocampal-avoidance WBRT. Despite the early trial termination, Li concluded that these results “strongly support the use of SRS in patients with four to 15 brain metastases to better preserve cognitive function and to minimize interruption of systemic therapy, without compromising overall survival.”

Li has received research funding from BMS and Medtronic and honorarium from Novocure and Monteris.

This article first appeared on Medscape.com.

Stereotactic radiosurgery (SRS) should replace whole-brain radiotherapy (WBRT) as the new standard of care for patients with four or more brain metastases, say researchers who report results from a randomized trial conducted in patients with four to 15 brain metastases

“SRS was associated with reduced risk of neurocognitive deterioration compared to WBRT, as demonstrated by a constellation of neurocognitive tests, individually or by composite scores,” said lead author Jing Li, MD, PhD, associate professor of radiation oncology and codirector of the Brain Metastasis Clinic at the University of Texas MD Anderson Cancer Center, Houston.

She was speaking at the American Society for Radiation Oncology (ASTRO) 2020 Annual Meeting, which was held online this year because of the COVID pandemic.

“The results from this phase 3 randomized trial strongly support the use of SRS in patients with four to 15 brain metastases to better preserve cognitive function and to minimize interruption of systemic therapy, without compromising overall survival,” said Li.

SRS is already the standard of care for patients with one to three brain metastases. Two previous phase 3 randomized trials showed that SRS was better at preserving cognitive function without compromising overall survival in comparison to WBRT.

However, there has been some controversy over the use of SRS for patients with multiple brain metastases, commented study discussant Sue S. Yom, MD, PhD, a professor in the Departments of Radiation Oncology and Otolaryngology–Head and Neck Surgery, University of California, San Francisco.

This study has shown, “in a practice-changing manner, that giving SRS can improve the quality of life of patients with metastatic disease,” she said.

Up to 30% of cancer patients develop brain metastases. Historically, these have been associated with poor overall survival, in the range of 1 to 4 months.
 

Reduces cognitive decline

The new trial involved 72 patients with four to 15 untreated, nonmelanoma brain metastases (up to 20 lesions were allowed at the time of treatment); the median number of brain metastases was eight. Most (83%) of the trial participants were White, nearly half were aged 60 years or older, and 58% were women.

Patients were randomly assigned to receive either SRS (15–24 Gy per Radiation Therapy Oncology Group protocol 9005) or WBRT (30 Gy in 10 fractions). On the basis of previous research, 62% of patients in the WBRT arm were also given memantine, a dementia drug that can help preserve cognitive function.

All participants completed neurocognitive testing, including testing of learning, memory, attention span, executive function, verbal fluency, processing speed, and motor dexterity, at enrollment and longitudinally.

The primary endpoints were Hopkins Verbal Learning Test – Revised Total Recall (HVLT-R TR) score and local control at 4 months. Secondary endpoints included overall survival, distant brain failure, toxicity, and time to initiation of systemic therapy.

In the primary endpoint analysis, at 4 months, the HVLT-R TR standardized z-score increased by +0.21 (standard error [SE], 0.27) for patients who received SRS, but it declined by –0.74 (SE, 0.36) for WBRT-treated patients (P = .041). On the basis of Clinical Trial Battery Composite score, neurocognitive function of patients in the SRS arm improved on average +0.23 (SE, 0.14) but declined an average –0.73 (SE, 0.35) in the WBRT arm (P = .008).

Li pointed out that there was also a “clinically meaningful and statistically significant benefit” with SRS at 1 month (P = .033) and 6 months (P = .012).

A total of 69 patients (35 for SRS and 34 for WBRT) were evaluable for overall survival, which was similar between the groups (SRS median, 7.8 months; WBRT median, 8.9 months; P = .59). Treatment with SRS resulted in better local control rates (95% at 4 months with SRS and 86.7% with WBRT; P = .09), but the median time to distant brain failure was shorter (10.5 months for WBRT and 6.3 months for SRS; P = .37).

In her discussion of the study, Yom noted that overall survival time was similar in the two arms and that, numerically, it may have even been a little longer in the SRS group. “While it is true that they had more relapses in untreated portions of the brain, they lived as long or longer than those who received WBRT and had better cognitive function,” she noted

Yom also noted that of particular importance was the finding that SRS was associated with shorter interruptions of systemic therapy (time to systemic therapy: SRS, 1.7 weeks; WBRT, 4.1 weeks; P = .001). Patients with metastatic disease usually have cancer in locations other than the brain. They may be receiving some type of systemic therapy, which is interrupted with WBRT, Li commented.

Toxicities of grade 3 or higher were observed in four patients in the WBRT arm and two in the SRS arm. Radiographic evidence of radiation necrosis, a side effect associated with SRS, was observed in 17% patients in the SRS arm of the trial (4% of all treated lesions).

The trial was halted early owing to the publication of another phase 3 trial (NRG Oncology CC 001), which provided level 1 evidence for replacing standard WBRT with hippocampal-avoidance WBRT. Despite the early trial termination, Li concluded that these results “strongly support the use of SRS in patients with four to 15 brain metastases to better preserve cognitive function and to minimize interruption of systemic therapy, without compromising overall survival.”

Li has received research funding from BMS and Medtronic and honorarium from Novocure and Monteris.

This article first appeared on Medscape.com.

Stereotactic radiosurgery (SRS) should replace whole-brain radiotherapy (WBRT) as the new standard of care for patients with four or more brain metastases, say researchers who report results from a randomized trial conducted in patients with four to 15 brain metastases

“SRS was associated with reduced risk of neurocognitive deterioration compared to WBRT, as demonstrated by a constellation of neurocognitive tests, individually or by composite scores,” said lead author Jing Li, MD, PhD, associate professor of radiation oncology and codirector of the Brain Metastasis Clinic at the University of Texas MD Anderson Cancer Center, Houston.

She was speaking at the American Society for Radiation Oncology (ASTRO) 2020 Annual Meeting, which was held online this year because of the COVID pandemic.

“The results from this phase 3 randomized trial strongly support the use of SRS in patients with four to 15 brain metastases to better preserve cognitive function and to minimize interruption of systemic therapy, without compromising overall survival,” said Li.

SRS is already the standard of care for patients with one to three brain metastases. Two previous phase 3 randomized trials showed that SRS was better at preserving cognitive function without compromising overall survival in comparison to WBRT.

However, there has been some controversy over the use of SRS for patients with multiple brain metastases, commented study discussant Sue S. Yom, MD, PhD, a professor in the Departments of Radiation Oncology and Otolaryngology–Head and Neck Surgery, University of California, San Francisco.

This study has shown, “in a practice-changing manner, that giving SRS can improve the quality of life of patients with metastatic disease,” she said.

Up to 30% of cancer patients develop brain metastases. Historically, these have been associated with poor overall survival, in the range of 1 to 4 months.
 

Reduces cognitive decline

The new trial involved 72 patients with four to 15 untreated, nonmelanoma brain metastases (up to 20 lesions were allowed at the time of treatment); the median number of brain metastases was eight. Most (83%) of the trial participants were White, nearly half were aged 60 years or older, and 58% were women.

Patients were randomly assigned to receive either SRS (15–24 Gy per Radiation Therapy Oncology Group protocol 9005) or WBRT (30 Gy in 10 fractions). On the basis of previous research, 62% of patients in the WBRT arm were also given memantine, a dementia drug that can help preserve cognitive function.

All participants completed neurocognitive testing, including testing of learning, memory, attention span, executive function, verbal fluency, processing speed, and motor dexterity, at enrollment and longitudinally.

The primary endpoints were Hopkins Verbal Learning Test – Revised Total Recall (HVLT-R TR) score and local control at 4 months. Secondary endpoints included overall survival, distant brain failure, toxicity, and time to initiation of systemic therapy.

In the primary endpoint analysis, at 4 months, the HVLT-R TR standardized z-score increased by +0.21 (standard error [SE], 0.27) for patients who received SRS, but it declined by –0.74 (SE, 0.36) for WBRT-treated patients (P = .041). On the basis of Clinical Trial Battery Composite score, neurocognitive function of patients in the SRS arm improved on average +0.23 (SE, 0.14) but declined an average –0.73 (SE, 0.35) in the WBRT arm (P = .008).

Li pointed out that there was also a “clinically meaningful and statistically significant benefit” with SRS at 1 month (P = .033) and 6 months (P = .012).

A total of 69 patients (35 for SRS and 34 for WBRT) were evaluable for overall survival, which was similar between the groups (SRS median, 7.8 months; WBRT median, 8.9 months; P = .59). Treatment with SRS resulted in better local control rates (95% at 4 months with SRS and 86.7% with WBRT; P = .09), but the median time to distant brain failure was shorter (10.5 months for WBRT and 6.3 months for SRS; P = .37).

In her discussion of the study, Yom noted that overall survival time was similar in the two arms and that, numerically, it may have even been a little longer in the SRS group. “While it is true that they had more relapses in untreated portions of the brain, they lived as long or longer than those who received WBRT and had better cognitive function,” she noted

Yom also noted that of particular importance was the finding that SRS was associated with shorter interruptions of systemic therapy (time to systemic therapy: SRS, 1.7 weeks; WBRT, 4.1 weeks; P = .001). Patients with metastatic disease usually have cancer in locations other than the brain. They may be receiving some type of systemic therapy, which is interrupted with WBRT, Li commented.

Toxicities of grade 3 or higher were observed in four patients in the WBRT arm and two in the SRS arm. Radiographic evidence of radiation necrosis, a side effect associated with SRS, was observed in 17% patients in the SRS arm of the trial (4% of all treated lesions).

The trial was halted early owing to the publication of another phase 3 trial (NRG Oncology CC 001), which provided level 1 evidence for replacing standard WBRT with hippocampal-avoidance WBRT. Despite the early trial termination, Li concluded that these results “strongly support the use of SRS in patients with four to 15 brain metastases to better preserve cognitive function and to minimize interruption of systemic therapy, without compromising overall survival.”

Li has received research funding from BMS and Medtronic and honorarium from Novocure and Monteris.

This article first appeared on Medscape.com.

Sexual dysfunction is a common treatment-related problem observed across numerous cancer diagnoses, and a new survey finds that 87% of cancer survivors have had such problems.

However, most of them also reported that their oncologist had not formally discussed the topic, and female patients were particularly unlikely to be asked about sexual dysfunction.

“The main takeaway from our study is that sexual side effects following treatment are very common,” said lead author James Taylor, MD, MPH, chief resident in radiation oncology at the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, Pennsylvania.

“Nearly 9 in 10 patients reported some change after cancer treatment that negatively affected their sexual health,” he said.

Taylor was speaking at the American Society for Radiation Oncology (ASTRO) Annual Meeting, held virtually this year because of the pandemic.

“Negative effects on sexual health after cancer treatment are unfortunately very common,” he said. “This is not just patients treated with radiation but this includes chemotherapy, hormonal therapy, surgery, and other treatment modalities.”

Potential issues include physical complications such as erectile dysfunction with prostate cancer treatment or vaginal dryness with gynecological cancer treatment. One recent study found that one-third of men who had undergone treatment for prostate cancer reported that a subsequent lack of sexual function has had the greatest impact on their quality of life. Another study reported that nearly all patients with breast cancer taking endocrine therapy experience a high degree of sexual dysfunction, including vulvovaginal dryness and severe dyspareunia.
 

Not discussed, not warned

Taylor and colleagues developed a questionnaire with input from radiation oncologists, medical oncologists, and surgeons, which consisted of more than 25 questions and was specifically targeted at cancer survivors.

A total of 405 adults completed the electronic survey about their experiences with sexual side effects after cancer treatment (391 responses were eligible for analysis). Most of the respondents were women (81%), and the most common cancer types were breast (67%), prostate (16%), and endometrial (6%). Treatments included chemotherapy (78%), radiation therapy (54%), and hormone therapy (47%).

“The questionnaires were distributed at Thomas Jefferson and throughout social media,” said Taylor. “The responses from social media are important because it shows a broad representation of patients who are treated in multiple clinics across the United States.”

Most of the survivors who responded (n = 337, 87%) stated cancer treatment had impacted sexual function or desire, with 53.8% reporting body image distortion, 73.4% with dyspareunia, and 42.3% unable to achieve orgasm.

Only about one-quarter (27.9%) said they had been formally asked about their sexual health by their clinician.

“Only about 40% said that they have been preemptively warned that their sexual health may be affected by treatment,” said Taylor.

Women were far less likely to be asked about their sexual health by their provider. The survey showed that male respondents were twice as likely to say they had been asked about sexual health and counseled about the potential toxicity (53% vs 22%; P < .001), and a substantially higher percentage of men reported receiving a formal assessment tool such as a survey (32% vs 5%; P = .001) compared with female respondents.

Taylor noted that the survey demonstrated several things. “One is that sexual toxicity is exceedingly common, and number two, it identified a gender disparity,” he said. “But number 3, and I think that this is an important aspect of our study, is that the majority of respondents felt that they would like a standard questionnaire to initiate and guide a discussion on sexual health with their provider.”

The reason that aspect is very important, he emphasized, is that “we know metrics and questionnaires already exist, so this gives us an actionable intervention that we can distribute and help mitigate some of these disparities.”
 

Importance of being holistic

The results of the survey “highlight the importance of being holistic in our approach to patient survivorship,” commented Karen Winkfield, MD, PhD, associate professor of radiation oncology at Wake Forest University, Winston-Salem, North Carolina, and executive director of the Meharry-Vanderbilt Alliance, Nashville, Tennessee.

“We need to ask patients about all parts of their well-being, including sexual health,” Winkfield said. “Body dysmorphism can impact anyone, but especially patients who have had surgery or radiation,” she said, while chemotherapy can impact energy and libido and have other toxicities that impact sexual health.

“I encourage all oncologists to ask patients about their sexual health, and a standardized form that can be used across all sites will make this much easier,” Winkfield commented. “We owe it to our patients to treat them holistically.”

The authors have reported no relevant financial relationships.

This article first appeared on Medscape.com.

Sexual dysfunction is a common treatment-related problem observed across numerous cancer diagnoses, and a new survey finds that 87% of cancer survivors have had such problems.

However, most of them also reported that their oncologist had not formally discussed the topic, and female patients were particularly unlikely to be asked about sexual dysfunction.

“The main takeaway from our study is that sexual side effects following treatment are very common,” said lead author James Taylor, MD, MPH, chief resident in radiation oncology at the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, Pennsylvania.

“Nearly 9 in 10 patients reported some change after cancer treatment that negatively affected their sexual health,” he said.

Taylor was speaking at the American Society for Radiation Oncology (ASTRO) Annual Meeting, held virtually this year because of the pandemic.

“Negative effects on sexual health after cancer treatment are unfortunately very common,” he said. “This is not just patients treated with radiation but this includes chemotherapy, hormonal therapy, surgery, and other treatment modalities.”

Potential issues include physical complications such as erectile dysfunction with prostate cancer treatment or vaginal dryness with gynecological cancer treatment. One recent study found that one-third of men who had undergone treatment for prostate cancer reported that a subsequent lack of sexual function has had the greatest impact on their quality of life. Another study reported that nearly all patients with breast cancer taking endocrine therapy experience a high degree of sexual dysfunction, including vulvovaginal dryness and severe dyspareunia.
 

Not discussed, not warned

Taylor and colleagues developed a questionnaire with input from radiation oncologists, medical oncologists, and surgeons, which consisted of more than 25 questions and was specifically targeted at cancer survivors.

A total of 405 adults completed the electronic survey about their experiences with sexual side effects after cancer treatment (391 responses were eligible for analysis). Most of the respondents were women (81%), and the most common cancer types were breast (67%), prostate (16%), and endometrial (6%). Treatments included chemotherapy (78%), radiation therapy (54%), and hormone therapy (47%).

“The questionnaires were distributed at Thomas Jefferson and throughout social media,” said Taylor. “The responses from social media are important because it shows a broad representation of patients who are treated in multiple clinics across the United States.”

Most of the survivors who responded (n = 337, 87%) stated cancer treatment had impacted sexual function or desire, with 53.8% reporting body image distortion, 73.4% with dyspareunia, and 42.3% unable to achieve orgasm.

Only about one-quarter (27.9%) said they had been formally asked about their sexual health by their clinician.

“Only about 40% said that they have been preemptively warned that their sexual health may be affected by treatment,” said Taylor.

Women were far less likely to be asked about their sexual health by their provider. The survey showed that male respondents were twice as likely to say they had been asked about sexual health and counseled about the potential toxicity (53% vs 22%; P < .001), and a substantially higher percentage of men reported receiving a formal assessment tool such as a survey (32% vs 5%; P = .001) compared with female respondents.

Taylor noted that the survey demonstrated several things. “One is that sexual toxicity is exceedingly common, and number two, it identified a gender disparity,” he said. “But number 3, and I think that this is an important aspect of our study, is that the majority of respondents felt that they would like a standard questionnaire to initiate and guide a discussion on sexual health with their provider.”

The reason that aspect is very important, he emphasized, is that “we know metrics and questionnaires already exist, so this gives us an actionable intervention that we can distribute and help mitigate some of these disparities.”
 

Importance of being holistic

The results of the survey “highlight the importance of being holistic in our approach to patient survivorship,” commented Karen Winkfield, MD, PhD, associate professor of radiation oncology at Wake Forest University, Winston-Salem, North Carolina, and executive director of the Meharry-Vanderbilt Alliance, Nashville, Tennessee.

“We need to ask patients about all parts of their well-being, including sexual health,” Winkfield said. “Body dysmorphism can impact anyone, but especially patients who have had surgery or radiation,” she said, while chemotherapy can impact energy and libido and have other toxicities that impact sexual health.

“I encourage all oncologists to ask patients about their sexual health, and a standardized form that can be used across all sites will make this much easier,” Winkfield commented. “We owe it to our patients to treat them holistically.”

The authors have reported no relevant financial relationships.

This article first appeared on Medscape.com.

Sexual dysfunction is a common treatment-related problem observed across numerous cancer diagnoses, and a new survey finds that 87% of cancer survivors have had such problems.

However, most of them also reported that their oncologist had not formally discussed the topic, and female patients were particularly unlikely to be asked about sexual dysfunction.

“The main takeaway from our study is that sexual side effects following treatment are very common,” said lead author James Taylor, MD, MPH, chief resident in radiation oncology at the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, Pennsylvania.

“Nearly 9 in 10 patients reported some change after cancer treatment that negatively affected their sexual health,” he said.

Taylor was speaking at the American Society for Radiation Oncology (ASTRO) Annual Meeting, held virtually this year because of the pandemic.

“Negative effects on sexual health after cancer treatment are unfortunately very common,” he said. “This is not just patients treated with radiation but this includes chemotherapy, hormonal therapy, surgery, and other treatment modalities.”

Potential issues include physical complications such as erectile dysfunction with prostate cancer treatment or vaginal dryness with gynecological cancer treatment. One recent study found that one-third of men who had undergone treatment for prostate cancer reported that a subsequent lack of sexual function has had the greatest impact on their quality of life. Another study reported that nearly all patients with breast cancer taking endocrine therapy experience a high degree of sexual dysfunction, including vulvovaginal dryness and severe dyspareunia.
 

Not discussed, not warned

Taylor and colleagues developed a questionnaire with input from radiation oncologists, medical oncologists, and surgeons, which consisted of more than 25 questions and was specifically targeted at cancer survivors.

A total of 405 adults completed the electronic survey about their experiences with sexual side effects after cancer treatment (391 responses were eligible for analysis). Most of the respondents were women (81%), and the most common cancer types were breast (67%), prostate (16%), and endometrial (6%). Treatments included chemotherapy (78%), radiation therapy (54%), and hormone therapy (47%).

“The questionnaires were distributed at Thomas Jefferson and throughout social media,” said Taylor. “The responses from social media are important because it shows a broad representation of patients who are treated in multiple clinics across the United States.”

Most of the survivors who responded (n = 337, 87%) stated cancer treatment had impacted sexual function or desire, with 53.8% reporting body image distortion, 73.4% with dyspareunia, and 42.3% unable to achieve orgasm.

Only about one-quarter (27.9%) said they had been formally asked about their sexual health by their clinician.

“Only about 40% said that they have been preemptively warned that their sexual health may be affected by treatment,” said Taylor.

Women were far less likely to be asked about their sexual health by their provider. The survey showed that male respondents were twice as likely to say they had been asked about sexual health and counseled about the potential toxicity (53% vs 22%; P < .001), and a substantially higher percentage of men reported receiving a formal assessment tool such as a survey (32% vs 5%; P = .001) compared with female respondents.

Taylor noted that the survey demonstrated several things. “One is that sexual toxicity is exceedingly common, and number two, it identified a gender disparity,” he said. “But number 3, and I think that this is an important aspect of our study, is that the majority of respondents felt that they would like a standard questionnaire to initiate and guide a discussion on sexual health with their provider.”

The reason that aspect is very important, he emphasized, is that “we know metrics and questionnaires already exist, so this gives us an actionable intervention that we can distribute and help mitigate some of these disparities.”
 

Importance of being holistic

The results of the survey “highlight the importance of being holistic in our approach to patient survivorship,” commented Karen Winkfield, MD, PhD, associate professor of radiation oncology at Wake Forest University, Winston-Salem, North Carolina, and executive director of the Meharry-Vanderbilt Alliance, Nashville, Tennessee.

“We need to ask patients about all parts of their well-being, including sexual health,” Winkfield said. “Body dysmorphism can impact anyone, but especially patients who have had surgery or radiation,” she said, while chemotherapy can impact energy and libido and have other toxicities that impact sexual health.

“I encourage all oncologists to ask patients about their sexual health, and a standardized form that can be used across all sites will make this much easier,” Winkfield commented. “We owe it to our patients to treat them holistically.”

The authors have reported no relevant financial relationships.

This article first appeared on Medscape.com.

Stereotactic body radiotherapy (SBRT) for lung oligometastases nets similar safety and efficacy whether it is delivered in multiple fractions or just one fraction. This was among key findings of a randomized, phase 2 trial reported at the American Society for Radiation Oncology Annual Meeting 2020.

“Most patients [with lung metastases] are treated with lifelong anticancer drug therapy only, with little prospect for long-term cancer control,” investigator Shankar Siva, MBBS, PhD, of Peter MacCallum Cancer Centre in Melbourne, said in a news briefing.

“However, some patients may have limited spread to the lungs and may be suitable for either surgery, which is an invasive approach, or SBRT, which is a noninvasive approach, with the aim to prolong long-term cancer control,” he added.
 

Patients and treatment

Dr. Siva and colleagues enrolled in their phase 2 trial (SAFRON II/TROG 13.01) 90 patients from 13 centers in Australia and New Zealand.

All patients had one to three lung metastases (from nonhematologic malignancies) that measured up to 5 cm in diameter and were located in the periphery.

The most common primaries were colorectal cancer (47%), lung cancer (11%), and kidney cancer (10%). The trial required that all primary and extrathoracic disease had been definitively treated.

The patients were randomized evenly to lung SBRT delivered with a single-fraction regimen (28 Gy in one fraction) or a multifraction regimen (48 Gy in four fractions) that netted the same biological equivalent dose.
 

Safety and efficacy

The two treatment groups did not differ significantly with respect to any-grade toxicities at 1 year, with the exception of higher rates of esophagitis and radiation dermatitis in the multifraction group, Dr. Siva reported.

The rate of grade 3 or worse toxicity at 1 year – the trial’s primary endpoint – was 5% with the single fraction and 3% with multiple fractions, with overlapping 80% confidence intervals, meeting the prespecified endpoint for acceptable toxicity.

The single-fraction group had two grade 3 events that resolved with intervention and no grade 4-5 events. The multifraction group had a single grade 5 event (fatal pneumonitis in a patient with underlying interstitial lung disease) and no grade 3-4 events.

The single-fraction and multifraction groups were also similar at 1 year on rates of freedom from local failure (93% and 95%, respectively), disease-free survival (59% and 60%, respectively), and overall survival (95% and 93%, respectively), with overlapping 95% CIs for each outcome.

Analyses of quality of life and cost-effectiveness are ongoing.
 

Applying the results: Useful in a pandemic?

“Single-session SBRT is safe, convenient, and noninvasive, and appears to be effective, to date, for lung secondaries. This approach may be considered as a one-stop, knockout type of approach for patients who have one to three metastases to the lung,” Dr. Siva proposed.

“These findings may have implications for treatment selection in a resource-constrained environment, such as the current global pandemic, when trying to reduce footfall or thoroughfare within a radiotherapy department, and it’s quite a convenient approach for patients,” he added.
 

“Stereotactic radiation has an obvious advantage over conventional radiation in several ways and may have a special advantage in the midst of the COVID-19 pandemic to reduce exposure to patients and our hospital personnel,” agreed news briefing moderator Sue S. Yom, MD, PhD, of the University of California, San Francisco.

However, use of stereotactic techniques remains controversial because they require technical precision and additional resources for planning and quality assurance, and they are often more expensive than conventional radiation therapy, she noted. Therefore, there must be evidence to justify their use in a palliative or metastatic setting.

The current trial is noteworthy for pushing the SBRT efficiency envelope, according to Dr. Yom.

“These findings are going to be confirmed by the study team with further follow-up at 3 years,” she pointed out. “If the findings of this study are maintained, it shows that patients with up to three metastatic tumors in the lung can have their treatment given in an extremely efficient manner over one session, which saves them time and hospital resources, and could be very significant to patients’ quality of life.”

The trial is sponsored by the Trans-Tasman Radiation Oncology Group and the Australasian Lung Cancer Trials Group. Dr. Siva disclosed relationships with Varian Industries, Merck, AstraZeneca, Bayer Pharmaceuticals, Bristol Meyers Squibb, and Reflexion. Dr. Yom disclosed no relevant conflicts.

SOURCE: Siva S et al. ASTRO 2020, Abstract 5.

Stereotactic body radiotherapy (SBRT) for lung oligometastases nets similar safety and efficacy whether it is delivered in multiple fractions or just one fraction. This was among key findings of a randomized, phase 2 trial reported at the American Society for Radiation Oncology Annual Meeting 2020.

“Most patients [with lung metastases] are treated with lifelong anticancer drug therapy only, with little prospect for long-term cancer control,” investigator Shankar Siva, MBBS, PhD, of Peter MacCallum Cancer Centre in Melbourne, said in a news briefing.

“However, some patients may have limited spread to the lungs and may be suitable for either surgery, which is an invasive approach, or SBRT, which is a noninvasive approach, with the aim to prolong long-term cancer control,” he added.
 

Patients and treatment

Dr. Siva and colleagues enrolled in their phase 2 trial (SAFRON II/TROG 13.01) 90 patients from 13 centers in Australia and New Zealand.

All patients had one to three lung metastases (from nonhematologic malignancies) that measured up to 5 cm in diameter and were located in the periphery.

The most common primaries were colorectal cancer (47%), lung cancer (11%), and kidney cancer (10%). The trial required that all primary and extrathoracic disease had been definitively treated.

The patients were randomized evenly to lung SBRT delivered with a single-fraction regimen (28 Gy in one fraction) or a multifraction regimen (48 Gy in four fractions) that netted the same biological equivalent dose.
 

Safety and efficacy

The two treatment groups did not differ significantly with respect to any-grade toxicities at 1 year, with the exception of higher rates of esophagitis and radiation dermatitis in the multifraction group, Dr. Siva reported.

The rate of grade 3 or worse toxicity at 1 year – the trial’s primary endpoint – was 5% with the single fraction and 3% with multiple fractions, with overlapping 80% confidence intervals, meeting the prespecified endpoint for acceptable toxicity.

The single-fraction group had two grade 3 events that resolved with intervention and no grade 4-5 events. The multifraction group had a single grade 5 event (fatal pneumonitis in a patient with underlying interstitial lung disease) and no grade 3-4 events.

The single-fraction and multifraction groups were also similar at 1 year on rates of freedom from local failure (93% and 95%, respectively), disease-free survival (59% and 60%, respectively), and overall survival (95% and 93%, respectively), with overlapping 95% CIs for each outcome.

Analyses of quality of life and cost-effectiveness are ongoing.
 

Applying the results: Useful in a pandemic?

“Single-session SBRT is safe, convenient, and noninvasive, and appears to be effective, to date, for lung secondaries. This approach may be considered as a one-stop, knockout type of approach for patients who have one to three metastases to the lung,” Dr. Siva proposed.

“These findings may have implications for treatment selection in a resource-constrained environment, such as the current global pandemic, when trying to reduce footfall or thoroughfare within a radiotherapy department, and it’s quite a convenient approach for patients,” he added.
 

“Stereotactic radiation has an obvious advantage over conventional radiation in several ways and may have a special advantage in the midst of the COVID-19 pandemic to reduce exposure to patients and our hospital personnel,” agreed news briefing moderator Sue S. Yom, MD, PhD, of the University of California, San Francisco.

However, use of stereotactic techniques remains controversial because they require technical precision and additional resources for planning and quality assurance, and they are often more expensive than conventional radiation therapy, she noted. Therefore, there must be evidence to justify their use in a palliative or metastatic setting.

The current trial is noteworthy for pushing the SBRT efficiency envelope, according to Dr. Yom.

“These findings are going to be confirmed by the study team with further follow-up at 3 years,” she pointed out. “If the findings of this study are maintained, it shows that patients with up to three metastatic tumors in the lung can have their treatment given in an extremely efficient manner over one session, which saves them time and hospital resources, and could be very significant to patients’ quality of life.”

The trial is sponsored by the Trans-Tasman Radiation Oncology Group and the Australasian Lung Cancer Trials Group. Dr. Siva disclosed relationships with Varian Industries, Merck, AstraZeneca, Bayer Pharmaceuticals, Bristol Meyers Squibb, and Reflexion. Dr. Yom disclosed no relevant conflicts.

SOURCE: Siva S et al. ASTRO 2020, Abstract 5.

Stereotactic body radiotherapy (SBRT) for lung oligometastases nets similar safety and efficacy whether it is delivered in multiple fractions or just one fraction. This was among key findings of a randomized, phase 2 trial reported at the American Society for Radiation Oncology Annual Meeting 2020.

“Most patients [with lung metastases] are treated with lifelong anticancer drug therapy only, with little prospect for long-term cancer control,” investigator Shankar Siva, MBBS, PhD, of Peter MacCallum Cancer Centre in Melbourne, said in a news briefing.

“However, some patients may have limited spread to the lungs and may be suitable for either surgery, which is an invasive approach, or SBRT, which is a noninvasive approach, with the aim to prolong long-term cancer control,” he added.
 

Patients and treatment

Dr. Siva and colleagues enrolled in their phase 2 trial (SAFRON II/TROG 13.01) 90 patients from 13 centers in Australia and New Zealand.

All patients had one to three lung metastases (from nonhematologic malignancies) that measured up to 5 cm in diameter and were located in the periphery.

The most common primaries were colorectal cancer (47%), lung cancer (11%), and kidney cancer (10%). The trial required that all primary and extrathoracic disease had been definitively treated.

The patients were randomized evenly to lung SBRT delivered with a single-fraction regimen (28 Gy in one fraction) or a multifraction regimen (48 Gy in four fractions) that netted the same biological equivalent dose.
 

Safety and efficacy

The two treatment groups did not differ significantly with respect to any-grade toxicities at 1 year, with the exception of higher rates of esophagitis and radiation dermatitis in the multifraction group, Dr. Siva reported.

The rate of grade 3 or worse toxicity at 1 year – the trial’s primary endpoint – was 5% with the single fraction and 3% with multiple fractions, with overlapping 80% confidence intervals, meeting the prespecified endpoint for acceptable toxicity.

The single-fraction group had two grade 3 events that resolved with intervention and no grade 4-5 events. The multifraction group had a single grade 5 event (fatal pneumonitis in a patient with underlying interstitial lung disease) and no grade 3-4 events.

The single-fraction and multifraction groups were also similar at 1 year on rates of freedom from local failure (93% and 95%, respectively), disease-free survival (59% and 60%, respectively), and overall survival (95% and 93%, respectively), with overlapping 95% CIs for each outcome.

Analyses of quality of life and cost-effectiveness are ongoing.
 

Applying the results: Useful in a pandemic?

“Single-session SBRT is safe, convenient, and noninvasive, and appears to be effective, to date, for lung secondaries. This approach may be considered as a one-stop, knockout type of approach for patients who have one to three metastases to the lung,” Dr. Siva proposed.

“These findings may have implications for treatment selection in a resource-constrained environment, such as the current global pandemic, when trying to reduce footfall or thoroughfare within a radiotherapy department, and it’s quite a convenient approach for patients,” he added.
 

“Stereotactic radiation has an obvious advantage over conventional radiation in several ways and may have a special advantage in the midst of the COVID-19 pandemic to reduce exposure to patients and our hospital personnel,” agreed news briefing moderator Sue S. Yom, MD, PhD, of the University of California, San Francisco.

However, use of stereotactic techniques remains controversial because they require technical precision and additional resources for planning and quality assurance, and they are often more expensive than conventional radiation therapy, she noted. Therefore, there must be evidence to justify their use in a palliative or metastatic setting.

The current trial is noteworthy for pushing the SBRT efficiency envelope, according to Dr. Yom.

“These findings are going to be confirmed by the study team with further follow-up at 3 years,” she pointed out. “If the findings of this study are maintained, it shows that patients with up to three metastatic tumors in the lung can have their treatment given in an extremely efficient manner over one session, which saves them time and hospital resources, and could be very significant to patients’ quality of life.”

The trial is sponsored by the Trans-Tasman Radiation Oncology Group and the Australasian Lung Cancer Trials Group. Dr. Siva disclosed relationships with Varian Industries, Merck, AstraZeneca, Bayer Pharmaceuticals, Bristol Meyers Squibb, and Reflexion. Dr. Yom disclosed no relevant conflicts.

SOURCE: Siva S et al. ASTRO 2020, Abstract 5.

A national effort to perform genotype drug matching across cancer types shows the value of next-generation sequencing and provides a roadmap for future precision oncology trials, according to experts.

Massachusetts General Hospital

The effort is the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial. For this study, researchers performed next-generation sequencing on tumor biopsy specimens to identify therapeutically actionable molecular alterations in patients with “underexplored” cancer types.

The trial included 5,954 patients with cancers that had progressed on standard treatments or rare cancers for which there is no standard treatment. If actionable alterations were found in these patients, they could receive new drugs in development that showed promise in other clinical trials or drugs that were approved by the Food and Drug Administration to treat at least one cancer type.

Data newly reported in the Journal of Clinical Oncology showed that 37.6% of patients had alterations that could be matched to targeted drugs, and 17.8% of patients were assigned to targeted treatment. Multiple actionable tumor mutations were seen in 11.9% of specimens, and resistance-conferring mutations were seen in 71.3% of specimens.

“The bottom line from this report is that next-generation sequencing is an efficient way to identify both approved and promising investigational therapies. For this reason, it should be considered standard of care for patients with advanced cancers,” said study chair Keith T. Flaherty, MD, director of the Henri and Belinda Termeer Center for Targeted Therapy at Massachusetts General Hospital Cancer Center in Boston.

“This study sets the benchmark for the ‘actionability’ of next-generation sequencing,” Dr. Flaherty added. “We expect this number [of actionable alterations] will continue to rise steadily as further advances are made in the development of therapies that target some of the genetic alterations for which we could not offer treatment options in NCI-MATCH.”
 

Relapsed/refractory vs. primary tumors

The NCI-MATCH researchers focused on the most commonly found genetic alterations and performed biopsies at study entry to provide the most accurate picture of the genetic landscape of relapsed/refractory cancer patients. That makes this cohort distinct from The Cancer Genome Atlas (TCGA), a database of patients with mostly untreated primary tumors, and other published cohorts that include genetic analysis of primary tumors and biopsies from the time of initial metastatic recurrence.

The researchers compared the tumor gene makeup of NCI-MATCH and TCGA patients with seven cancer types – breast, bile duct, cervix, colorectal, lung, pancreas, and prostate.

ECOG-ACRIN Cancer Research Group

“Perhaps the biggest surprise was the relatively minimal change in the genetic alterations found in these relapsed/refractory patients, compared to primary tumors,” Dr. Flaherty said. “These findings suggest that it is very reasonable to perform next-generation sequencing at the time of initial metastatic cancer diagnosis and to rely on those findings for the purposes of considering FDA-approved therapies and clinical trial participation.”
 

Multiple alterations and resistance

The complex genetics of cancers has led researchers to explore combinations of targeted and other therapies to address multiple defects at the same time.

“Not surprisingly, the most common collision of multiple genetic alterations within the same tumor was in the commonly altered tumor suppressor genes: TP53, APC, and PTEN,” Dr. Flaherty said.

“An increasing body of evidence supports a role for loss-of-function alterations in these genes to confer resistance to many targeted therapies,” he added. “While we don’t have targeted therapies yet established to directly counter this form of therapeutic resistance, we hypothesize that various types of combination therapy may be able to indirectly undercut resistance and enhance the benefit of many targeted therapies.”

The NCI-MATCH researchers will continue to mine this large dataset to better understand the many small, genetically defined cancer subpopulations.

“We will continue to report the outcome of the individual treatment subprotocols, and combining this genetic analysis with those outcomes will likely inform the next clinical trials,” Dr. Flaherty said.
 

Actionable mutations make a difference

Precision oncology experts agree that NCI-MATCH results are impressive and add a fuller appreciation that actionable mutations make a clinical difference.

“This is a powerful, extremely well-designed study, a tour de force of collaborative science,” said Stephen Gruber, MD, PhD, director of the Center for Precision Medicine at City of Hope National Medical Center in Duarte, Calif.

“The future holds even more promise,” he added. “Our ability to interrogate the genomic landscape of cancer is improving rapidly. Tumor testing helps get the right drug to the right tumor faster than a guidelines-based approach from historical data of combination chemotherapy. This is a likely game changer for the way oncologists will practice in the future, especially as we learn more results of subset trials. The NCI-MATCH researchers have taken a laser-focused look at the current data, but we now know we can look far more comprehensively at genomic profiles of tumors.”

From the viewpoint of the practicing oncologist, co-occurring resistance mutations make a difference in defining what combinations are likely and, more importantly, less likely to be effective. “When we see two mutations and one is likely to confer resistance, we can make a choice to avoid a drug that is not likely to work,” Dr. Gruber said.

“The NCI-MATCH trial allows both approved and investigational agents, which expands the possibility of matching patients to newer agents. This is especially relevant if there are no FDA-approved drugs yet for some molecular aberrations,” said Lillian L. Siu, MD, a senior medical oncologist at the Princess Margaret Cancer Centre in Toronto. “This trial enables such evaluations under the auspice of a clinical trial to provide important knowledge.”

Both experts agree that in-depth biological interrogations of cancer will move the field of precision oncology forward. Dr. Gruber said that “studies have not yet fully addressed the power of germline genetic testing of DNA. Inherited susceptibility will drive therapeutic choices – for example, PARP inhibitors that access homologous recombination deficiency for breast, ovarian, and prostate cancer. We will learn more about treatment choices for those cancers.”

Dr. Siu added: “I truly believe that liquid biopsies [circulating tumor DNA] will help us perform target-drug matching in a less invasive way. We need to explore beyond the genome to look at the transcriptome, proteome, epigenome, and immunome, among others. It is likely that multiomic predictors are going to be able to identify more therapeutic options compared to single genomic predictors.”

Dr. Flaherty noted that all tumor samples from patients assigned to treatment are being subjected to whole-exome sequencing to further the discovery of the genetic features of responsive and nonresponsive tumors.

NCI-MATCH was funded by the National Cancer Institute. Dr. Flaherty disclosed relationships with Clovis Oncology, Loxo, X4 Pharma, and many other companies. His coauthors disclosed many conflicts as well. Dr. Gruber is cofounder of Brogent International. Dr. Siu disclosed relationships with Agios, Treadwell Therapeutics, Merck, Pfizer, and many other companies.

SOURCE: Flaherty KT et al. J Clin Oncol. 2020 Oct 13. doi: 10.1200/JCO.19.03010.

A national effort to perform genotype drug matching across cancer types shows the value of next-generation sequencing and provides a roadmap for future precision oncology trials, according to experts.

Massachusetts General Hospital

The effort is the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial. For this study, researchers performed next-generation sequencing on tumor biopsy specimens to identify therapeutically actionable molecular alterations in patients with “underexplored” cancer types.

The trial included 5,954 patients with cancers that had progressed on standard treatments or rare cancers for which there is no standard treatment. If actionable alterations were found in these patients, they could receive new drugs in development that showed promise in other clinical trials or drugs that were approved by the Food and Drug Administration to treat at least one cancer type.

Data newly reported in the Journal of Clinical Oncology showed that 37.6% of patients had alterations that could be matched to targeted drugs, and 17.8% of patients were assigned to targeted treatment. Multiple actionable tumor mutations were seen in 11.9% of specimens, and resistance-conferring mutations were seen in 71.3% of specimens.

“The bottom line from this report is that next-generation sequencing is an efficient way to identify both approved and promising investigational therapies. For this reason, it should be considered standard of care for patients with advanced cancers,” said study chair Keith T. Flaherty, MD, director of the Henri and Belinda Termeer Center for Targeted Therapy at Massachusetts General Hospital Cancer Center in Boston.

“This study sets the benchmark for the ‘actionability’ of next-generation sequencing,” Dr. Flaherty added. “We expect this number [of actionable alterations] will continue to rise steadily as further advances are made in the development of therapies that target some of the genetic alterations for which we could not offer treatment options in NCI-MATCH.”
 

Relapsed/refractory vs. primary tumors

The NCI-MATCH researchers focused on the most commonly found genetic alterations and performed biopsies at study entry to provide the most accurate picture of the genetic landscape of relapsed/refractory cancer patients. That makes this cohort distinct from The Cancer Genome Atlas (TCGA), a database of patients with mostly untreated primary tumors, and other published cohorts that include genetic analysis of primary tumors and biopsies from the time of initial metastatic recurrence.

The researchers compared the tumor gene makeup of NCI-MATCH and TCGA patients with seven cancer types – breast, bile duct, cervix, colorectal, lung, pancreas, and prostate.

ECOG-ACRIN Cancer Research Group

“Perhaps the biggest surprise was the relatively minimal change in the genetic alterations found in these relapsed/refractory patients, compared to primary tumors,” Dr. Flaherty said. “These findings suggest that it is very reasonable to perform next-generation sequencing at the time of initial metastatic cancer diagnosis and to rely on those findings for the purposes of considering FDA-approved therapies and clinical trial participation.”
 

Multiple alterations and resistance

The complex genetics of cancers has led researchers to explore combinations of targeted and other therapies to address multiple defects at the same time.

“Not surprisingly, the most common collision of multiple genetic alterations within the same tumor was in the commonly altered tumor suppressor genes: TP53, APC, and PTEN,” Dr. Flaherty said.

“An increasing body of evidence supports a role for loss-of-function alterations in these genes to confer resistance to many targeted therapies,” he added. “While we don’t have targeted therapies yet established to directly counter this form of therapeutic resistance, we hypothesize that various types of combination therapy may be able to indirectly undercut resistance and enhance the benefit of many targeted therapies.”

The NCI-MATCH researchers will continue to mine this large dataset to better understand the many small, genetically defined cancer subpopulations.

“We will continue to report the outcome of the individual treatment subprotocols, and combining this genetic analysis with those outcomes will likely inform the next clinical trials,” Dr. Flaherty said.
 

Actionable mutations make a difference

Precision oncology experts agree that NCI-MATCH results are impressive and add a fuller appreciation that actionable mutations make a clinical difference.

“This is a powerful, extremely well-designed study, a tour de force of collaborative science,” said Stephen Gruber, MD, PhD, director of the Center for Precision Medicine at City of Hope National Medical Center in Duarte, Calif.

“The future holds even more promise,” he added. “Our ability to interrogate the genomic landscape of cancer is improving rapidly. Tumor testing helps get the right drug to the right tumor faster than a guidelines-based approach from historical data of combination chemotherapy. This is a likely game changer for the way oncologists will practice in the future, especially as we learn more results of subset trials. The NCI-MATCH researchers have taken a laser-focused look at the current data, but we now know we can look far more comprehensively at genomic profiles of tumors.”

From the viewpoint of the practicing oncologist, co-occurring resistance mutations make a difference in defining what combinations are likely and, more importantly, less likely to be effective. “When we see two mutations and one is likely to confer resistance, we can make a choice to avoid a drug that is not likely to work,” Dr. Gruber said.

“The NCI-MATCH trial allows both approved and investigational agents, which expands the possibility of matching patients to newer agents. This is especially relevant if there are no FDA-approved drugs yet for some molecular aberrations,” said Lillian L. Siu, MD, a senior medical oncologist at the Princess Margaret Cancer Centre in Toronto. “This trial enables such evaluations under the auspice of a clinical trial to provide important knowledge.”

Both experts agree that in-depth biological interrogations of cancer will move the field of precision oncology forward. Dr. Gruber said that “studies have not yet fully addressed the power of germline genetic testing of DNA. Inherited susceptibility will drive therapeutic choices – for example, PARP inhibitors that access homologous recombination deficiency for breast, ovarian, and prostate cancer. We will learn more about treatment choices for those cancers.”

Dr. Siu added: “I truly believe that liquid biopsies [circulating tumor DNA] will help us perform target-drug matching in a less invasive way. We need to explore beyond the genome to look at the transcriptome, proteome, epigenome, and immunome, among others. It is likely that multiomic predictors are going to be able to identify more therapeutic options compared to single genomic predictors.”

Dr. Flaherty noted that all tumor samples from patients assigned to treatment are being subjected to whole-exome sequencing to further the discovery of the genetic features of responsive and nonresponsive tumors.

NCI-MATCH was funded by the National Cancer Institute. Dr. Flaherty disclosed relationships with Clovis Oncology, Loxo, X4 Pharma, and many other companies. His coauthors disclosed many conflicts as well. Dr. Gruber is cofounder of Brogent International. Dr. Siu disclosed relationships with Agios, Treadwell Therapeutics, Merck, Pfizer, and many other companies.

SOURCE: Flaherty KT et al. J Clin Oncol. 2020 Oct 13. doi: 10.1200/JCO.19.03010.

A national effort to perform genotype drug matching across cancer types shows the value of next-generation sequencing and provides a roadmap for future precision oncology trials, according to experts.

Massachusetts General Hospital

The effort is the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial. For this study, researchers performed next-generation sequencing on tumor biopsy specimens to identify therapeutically actionable molecular alterations in patients with “underexplored” cancer types.

The trial included 5,954 patients with cancers that had progressed on standard treatments or rare cancers for which there is no standard treatment. If actionable alterations were found in these patients, they could receive new drugs in development that showed promise in other clinical trials or drugs that were approved by the Food and Drug Administration to treat at least one cancer type.

Data newly reported in the Journal of Clinical Oncology showed that 37.6% of patients had alterations that could be matched to targeted drugs, and 17.8% of patients were assigned to targeted treatment. Multiple actionable tumor mutations were seen in 11.9% of specimens, and resistance-conferring mutations were seen in 71.3% of specimens.

“The bottom line from this report is that next-generation sequencing is an efficient way to identify both approved and promising investigational therapies. For this reason, it should be considered standard of care for patients with advanced cancers,” said study chair Keith T. Flaherty, MD, director of the Henri and Belinda Termeer Center for Targeted Therapy at Massachusetts General Hospital Cancer Center in Boston.

“This study sets the benchmark for the ‘actionability’ of next-generation sequencing,” Dr. Flaherty added. “We expect this number [of actionable alterations] will continue to rise steadily as further advances are made in the development of therapies that target some of the genetic alterations for which we could not offer treatment options in NCI-MATCH.”
 

Relapsed/refractory vs. primary tumors

The NCI-MATCH researchers focused on the most commonly found genetic alterations and performed biopsies at study entry to provide the most accurate picture of the genetic landscape of relapsed/refractory cancer patients. That makes this cohort distinct from The Cancer Genome Atlas (TCGA), a database of patients with mostly untreated primary tumors, and other published cohorts that include genetic analysis of primary tumors and biopsies from the time of initial metastatic recurrence.

The researchers compared the tumor gene makeup of NCI-MATCH and TCGA patients with seven cancer types – breast, bile duct, cervix, colorectal, lung, pancreas, and prostate.

ECOG-ACRIN Cancer Research Group

“Perhaps the biggest surprise was the relatively minimal change in the genetic alterations found in these relapsed/refractory patients, compared to primary tumors,” Dr. Flaherty said. “These findings suggest that it is very reasonable to perform next-generation sequencing at the time of initial metastatic cancer diagnosis and to rely on those findings for the purposes of considering FDA-approved therapies and clinical trial participation.”
 

Multiple alterations and resistance

The complex genetics of cancers has led researchers to explore combinations of targeted and other therapies to address multiple defects at the same time.

“Not surprisingly, the most common collision of multiple genetic alterations within the same tumor was in the commonly altered tumor suppressor genes: TP53, APC, and PTEN,” Dr. Flaherty said.

“An increasing body of evidence supports a role for loss-of-function alterations in these genes to confer resistance to many targeted therapies,” he added. “While we don’t have targeted therapies yet established to directly counter this form of therapeutic resistance, we hypothesize that various types of combination therapy may be able to indirectly undercut resistance and enhance the benefit of many targeted therapies.”

The NCI-MATCH researchers will continue to mine this large dataset to better understand the many small, genetically defined cancer subpopulations.

“We will continue to report the outcome of the individual treatment subprotocols, and combining this genetic analysis with those outcomes will likely inform the next clinical trials,” Dr. Flaherty said.
 

Actionable mutations make a difference

Precision oncology experts agree that NCI-MATCH results are impressive and add a fuller appreciation that actionable mutations make a clinical difference.

“This is a powerful, extremely well-designed study, a tour de force of collaborative science,” said Stephen Gruber, MD, PhD, director of the Center for Precision Medicine at City of Hope National Medical Center in Duarte, Calif.

“The future holds even more promise,” he added. “Our ability to interrogate the genomic landscape of cancer is improving rapidly. Tumor testing helps get the right drug to the right tumor faster than a guidelines-based approach from historical data of combination chemotherapy. This is a likely game changer for the way oncologists will practice in the future, especially as we learn more results of subset trials. The NCI-MATCH researchers have taken a laser-focused look at the current data, but we now know we can look far more comprehensively at genomic profiles of tumors.”

From the viewpoint of the practicing oncologist, co-occurring resistance mutations make a difference in defining what combinations are likely and, more importantly, less likely to be effective. “When we see two mutations and one is likely to confer resistance, we can make a choice to avoid a drug that is not likely to work,” Dr. Gruber said.

“The NCI-MATCH trial allows both approved and investigational agents, which expands the possibility of matching patients to newer agents. This is especially relevant if there are no FDA-approved drugs yet for some molecular aberrations,” said Lillian L. Siu, MD, a senior medical oncologist at the Princess Margaret Cancer Centre in Toronto. “This trial enables such evaluations under the auspice of a clinical trial to provide important knowledge.”

Both experts agree that in-depth biological interrogations of cancer will move the field of precision oncology forward. Dr. Gruber said that “studies have not yet fully addressed the power of germline genetic testing of DNA. Inherited susceptibility will drive therapeutic choices – for example, PARP inhibitors that access homologous recombination deficiency for breast, ovarian, and prostate cancer. We will learn more about treatment choices for those cancers.”

Dr. Siu added: “I truly believe that liquid biopsies [circulating tumor DNA] will help us perform target-drug matching in a less invasive way. We need to explore beyond the genome to look at the transcriptome, proteome, epigenome, and immunome, among others. It is likely that multiomic predictors are going to be able to identify more therapeutic options compared to single genomic predictors.”

Dr. Flaherty noted that all tumor samples from patients assigned to treatment are being subjected to whole-exome sequencing to further the discovery of the genetic features of responsive and nonresponsive tumors.

NCI-MATCH was funded by the National Cancer Institute. Dr. Flaherty disclosed relationships with Clovis Oncology, Loxo, X4 Pharma, and many other companies. His coauthors disclosed many conflicts as well. Dr. Gruber is cofounder of Brogent International. Dr. Siu disclosed relationships with Agios, Treadwell Therapeutics, Merck, Pfizer, and many other companies.

SOURCE: Flaherty KT et al. J Clin Oncol. 2020 Oct 13. doi: 10.1200/JCO.19.03010.

It’s not ready for the clinic, but new research suggests that angiotensin receptor II blockers (ARBs) widely used to treat hypertension may improve responses to cancer immunotherapy agents targeted against the programmed death-1/ligand-1 (PD-1/PD-L1) pathway.

That conclusion comes from an observational study of 597 patients with more than 3 dozen different cancer types treated in clinical trials at the US National Institutes of Health. Investigators found that both objective response rates and 3-year overall survival (OS) rates were significantly higher for patients treated with a PD-1/PD-L1 inhibitor who were on ARBs, compared with patients who weren’t taking the antihypertensive agents.

An association was also seen between higher ORR and OS rates for patients taking ACE inhibitors, but it was not statistically significant, reported Julius Strauss, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Md.

All study patients received PD-1/PD-L1 inhibitors, and the ORR for patients treated with ARBs was 33.8%, compared with 19.5% for those treated with ACE inhibitors, and 17% for those who took neither drug. The respective complete response (CR) rates were 11.3%, 3.7%, and 3.1%.

Strauss discussed the data during an online briefing prior to his presentation of the findings during the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, which is taking place virtually.

Several early studies have suggested that angiotensin II, in addition to its effect on blood pressure, can also affect cancer growth by leading to downstream production of two proteins: vascular endothelial growth factor (VEGF) and transforming growth factor–beta (TGF-beta), he explained.

“Both of these [proteins] have been linked to cancer growth and cancer resistance to immune system attack,” Strauss observed.

He also discussed the mechanics of possible effects. Angiotensin II increases VEGF and TGF-beta through binding to the AT1 receptor, but has the opposite effect when it binds to the AT2 receptor, resulting in a decrease in both of the growth factors, he added.

ACE inhibitors prevent the conversion of angiotensin I to angiotensin II, with the result being that the drugs indirectly block both the AT1 and AT2 receptors.

In contrast, ARBs block only the AT1 receptor and leave the AT2 counter-regulatory receptor alone, said Strauss.
 

More data, including on overall survival

Strauss and colleagues examined whether ACE inhibitors and/or ARBs could have an effect on the response to PD-1/PD-L1 immune checkpoint inhibitors delivered with or without other immunotherapies, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors, or targeted agents such as tyrosine kinase inhibitors (TKIs).

They pooled data on 597 patients receiving PD-1/PD-L1 inhibitors in clinical trials for various cancers, including 71 receiving concomitant ARBs, 82 receiving an ACE inhibitor, and 444 who were not receiving either class of antihypertensives.

The above-mentioned improvement in ORR with ARBs compared with patients not receiving the drug was statistically significant (P = .001), as was the improvement in CR rates (P = .002). In contrast, neither ORR nor CR were significantly better with patients on ACE inhibitors compared with patients not taking these drugs.

In multiple regression analysis controlling for age, gender, body mass index (BMI), tumor type, and additional therapies given, the superior ORR and CR rates with ARBs remained (P = .039 and .002, respectively), while there continued to be no significant additional benefit with ACE inhibitors.

The median overall survival was 35.2 months for patients on ARBs, 26.2 months for those on ACE inhibitors, and 18.8 months for patients on neither drug. The respective 3-year OS rates were 48.1%, 37.2%, and 31.5%, with the difference between the ARB and no-drug groups being significant (P = .0078).

In regression analysis controlling for the factors mentioned before, the OS advantage with ARBs but not ACE inhibitors remained significant (P = .006 for ARBs, and .078 for ACE inhibitors).

Strauss emphasized that further study is needed to determine if AT1 blockade can improve outcomes when combined anti-PD-1/PD-L1-based therapy.

It might be reasonable for patients who are taking ACE inhibitors to control blood pressure and are also receiving immunotherapy with a PD-1/PD-L1 inhibitor to be switched to an ARB if it is deemed safe and if further research bears it out, said Strauss in response to a question from Medscape Medical News.
 

Hypothesis-generating study

Meeting cochair Emiliano Calvo, MD, PhD, from Hospital de Madrid Norte Sanchinarro in Madrid, who attended the media briefing but was not involved in the study, commented that hypothesis-generating research using drugs already on the market for other indications adds important value to cancer therapy.

James Gulley, MD, PhD, from the Center for Cancer Research at the NCI, also a meeting cochair, agreed with Calvo.

“Thinking about utilizing the data that already exists to really get hypothesis-generating questions, it also opens up the possibility for real-world data, real-world evidence from these big datasets from [electronic medical records] that we could really interrogate and understand what we might see and get these hypothesis-generating findings that we could then prospectively evaluate,” Gulley said.

The research was funded by the National Cancer Institute. Strauss and Gulley are National Cancer Institute employees. Calvo disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

It’s not ready for the clinic, but new research suggests that angiotensin receptor II blockers (ARBs) widely used to treat hypertension may improve responses to cancer immunotherapy agents targeted against the programmed death-1/ligand-1 (PD-1/PD-L1) pathway.

That conclusion comes from an observational study of 597 patients with more than 3 dozen different cancer types treated in clinical trials at the US National Institutes of Health. Investigators found that both objective response rates and 3-year overall survival (OS) rates were significantly higher for patients treated with a PD-1/PD-L1 inhibitor who were on ARBs, compared with patients who weren’t taking the antihypertensive agents.

An association was also seen between higher ORR and OS rates for patients taking ACE inhibitors, but it was not statistically significant, reported Julius Strauss, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Md.

All study patients received PD-1/PD-L1 inhibitors, and the ORR for patients treated with ARBs was 33.8%, compared with 19.5% for those treated with ACE inhibitors, and 17% for those who took neither drug. The respective complete response (CR) rates were 11.3%, 3.7%, and 3.1%.

Strauss discussed the data during an online briefing prior to his presentation of the findings during the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, which is taking place virtually.

Several early studies have suggested that angiotensin II, in addition to its effect on blood pressure, can also affect cancer growth by leading to downstream production of two proteins: vascular endothelial growth factor (VEGF) and transforming growth factor–beta (TGF-beta), he explained.

“Both of these [proteins] have been linked to cancer growth and cancer resistance to immune system attack,” Strauss observed.

He also discussed the mechanics of possible effects. Angiotensin II increases VEGF and TGF-beta through binding to the AT1 receptor, but has the opposite effect when it binds to the AT2 receptor, resulting in a decrease in both of the growth factors, he added.

ACE inhibitors prevent the conversion of angiotensin I to angiotensin II, with the result being that the drugs indirectly block both the AT1 and AT2 receptors.

In contrast, ARBs block only the AT1 receptor and leave the AT2 counter-regulatory receptor alone, said Strauss.
 

More data, including on overall survival

Strauss and colleagues examined whether ACE inhibitors and/or ARBs could have an effect on the response to PD-1/PD-L1 immune checkpoint inhibitors delivered with or without other immunotherapies, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors, or targeted agents such as tyrosine kinase inhibitors (TKIs).

They pooled data on 597 patients receiving PD-1/PD-L1 inhibitors in clinical trials for various cancers, including 71 receiving concomitant ARBs, 82 receiving an ACE inhibitor, and 444 who were not receiving either class of antihypertensives.

The above-mentioned improvement in ORR with ARBs compared with patients not receiving the drug was statistically significant (P = .001), as was the improvement in CR rates (P = .002). In contrast, neither ORR nor CR were significantly better with patients on ACE inhibitors compared with patients not taking these drugs.

In multiple regression analysis controlling for age, gender, body mass index (BMI), tumor type, and additional therapies given, the superior ORR and CR rates with ARBs remained (P = .039 and .002, respectively), while there continued to be no significant additional benefit with ACE inhibitors.

The median overall survival was 35.2 months for patients on ARBs, 26.2 months for those on ACE inhibitors, and 18.8 months for patients on neither drug. The respective 3-year OS rates were 48.1%, 37.2%, and 31.5%, with the difference between the ARB and no-drug groups being significant (P = .0078).

In regression analysis controlling for the factors mentioned before, the OS advantage with ARBs but not ACE inhibitors remained significant (P = .006 for ARBs, and .078 for ACE inhibitors).

Strauss emphasized that further study is needed to determine if AT1 blockade can improve outcomes when combined anti-PD-1/PD-L1-based therapy.

It might be reasonable for patients who are taking ACE inhibitors to control blood pressure and are also receiving immunotherapy with a PD-1/PD-L1 inhibitor to be switched to an ARB if it is deemed safe and if further research bears it out, said Strauss in response to a question from Medscape Medical News.
 

Hypothesis-generating study

Meeting cochair Emiliano Calvo, MD, PhD, from Hospital de Madrid Norte Sanchinarro in Madrid, who attended the media briefing but was not involved in the study, commented that hypothesis-generating research using drugs already on the market for other indications adds important value to cancer therapy.

James Gulley, MD, PhD, from the Center for Cancer Research at the NCI, also a meeting cochair, agreed with Calvo.

“Thinking about utilizing the data that already exists to really get hypothesis-generating questions, it also opens up the possibility for real-world data, real-world evidence from these big datasets from [electronic medical records] that we could really interrogate and understand what we might see and get these hypothesis-generating findings that we could then prospectively evaluate,” Gulley said.

The research was funded by the National Cancer Institute. Strauss and Gulley are National Cancer Institute employees. Calvo disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

It’s not ready for the clinic, but new research suggests that angiotensin receptor II blockers (ARBs) widely used to treat hypertension may improve responses to cancer immunotherapy agents targeted against the programmed death-1/ligand-1 (PD-1/PD-L1) pathway.

That conclusion comes from an observational study of 597 patients with more than 3 dozen different cancer types treated in clinical trials at the US National Institutes of Health. Investigators found that both objective response rates and 3-year overall survival (OS) rates were significantly higher for patients treated with a PD-1/PD-L1 inhibitor who were on ARBs, compared with patients who weren’t taking the antihypertensive agents.

An association was also seen between higher ORR and OS rates for patients taking ACE inhibitors, but it was not statistically significant, reported Julius Strauss, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Md.

All study patients received PD-1/PD-L1 inhibitors, and the ORR for patients treated with ARBs was 33.8%, compared with 19.5% for those treated with ACE inhibitors, and 17% for those who took neither drug. The respective complete response (CR) rates were 11.3%, 3.7%, and 3.1%.

Strauss discussed the data during an online briefing prior to his presentation of the findings during the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, which is taking place virtually.

Several early studies have suggested that angiotensin II, in addition to its effect on blood pressure, can also affect cancer growth by leading to downstream production of two proteins: vascular endothelial growth factor (VEGF) and transforming growth factor–beta (TGF-beta), he explained.

“Both of these [proteins] have been linked to cancer growth and cancer resistance to immune system attack,” Strauss observed.

He also discussed the mechanics of possible effects. Angiotensin II increases VEGF and TGF-beta through binding to the AT1 receptor, but has the opposite effect when it binds to the AT2 receptor, resulting in a decrease in both of the growth factors, he added.

ACE inhibitors prevent the conversion of angiotensin I to angiotensin II, with the result being that the drugs indirectly block both the AT1 and AT2 receptors.

In contrast, ARBs block only the AT1 receptor and leave the AT2 counter-regulatory receptor alone, said Strauss.
 

More data, including on overall survival

Strauss and colleagues examined whether ACE inhibitors and/or ARBs could have an effect on the response to PD-1/PD-L1 immune checkpoint inhibitors delivered with or without other immunotherapies, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors, or targeted agents such as tyrosine kinase inhibitors (TKIs).

They pooled data on 597 patients receiving PD-1/PD-L1 inhibitors in clinical trials for various cancers, including 71 receiving concomitant ARBs, 82 receiving an ACE inhibitor, and 444 who were not receiving either class of antihypertensives.

The above-mentioned improvement in ORR with ARBs compared with patients not receiving the drug was statistically significant (P = .001), as was the improvement in CR rates (P = .002). In contrast, neither ORR nor CR were significantly better with patients on ACE inhibitors compared with patients not taking these drugs.

In multiple regression analysis controlling for age, gender, body mass index (BMI), tumor type, and additional therapies given, the superior ORR and CR rates with ARBs remained (P = .039 and .002, respectively), while there continued to be no significant additional benefit with ACE inhibitors.

The median overall survival was 35.2 months for patients on ARBs, 26.2 months for those on ACE inhibitors, and 18.8 months for patients on neither drug. The respective 3-year OS rates were 48.1%, 37.2%, and 31.5%, with the difference between the ARB and no-drug groups being significant (P = .0078).

In regression analysis controlling for the factors mentioned before, the OS advantage with ARBs but not ACE inhibitors remained significant (P = .006 for ARBs, and .078 for ACE inhibitors).

Strauss emphasized that further study is needed to determine if AT1 blockade can improve outcomes when combined anti-PD-1/PD-L1-based therapy.

It might be reasonable for patients who are taking ACE inhibitors to control blood pressure and are also receiving immunotherapy with a PD-1/PD-L1 inhibitor to be switched to an ARB if it is deemed safe and if further research bears it out, said Strauss in response to a question from Medscape Medical News.
 

Hypothesis-generating study

Meeting cochair Emiliano Calvo, MD, PhD, from Hospital de Madrid Norte Sanchinarro in Madrid, who attended the media briefing but was not involved in the study, commented that hypothesis-generating research using drugs already on the market for other indications adds important value to cancer therapy.

James Gulley, MD, PhD, from the Center for Cancer Research at the NCI, also a meeting cochair, agreed with Calvo.

“Thinking about utilizing the data that already exists to really get hypothesis-generating questions, it also opens up the possibility for real-world data, real-world evidence from these big datasets from [electronic medical records] that we could really interrogate and understand what we might see and get these hypothesis-generating findings that we could then prospectively evaluate,” Gulley said.

The research was funded by the National Cancer Institute. Strauss and Gulley are National Cancer Institute employees. Calvo disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

A novel urine-based assay improved detection of urothelial carcinoma when compared with conventional urine cytology in a prospective, observational study.

The study authors developed a low-coverage whole-genome sequencing technique, called “Urine Exfoliated Cells Copy Number Aberration Detector” (UroCAD), to detect copy number variants in urine-exfoliated cells.

The team then tested whether UroCAD could detect urothelial carcinomas in a single-blinded trial.

Shuxiong Zeng, MD, PhD, of Naval Medical University, Shanghai, China, and colleagues described this work in Clinical Cancer Research.
 

Study details and results

The researchers first tested UroCAD on urine samples from a discovery cohort of 190 patients – 126 with urothelial carcinoma and 64 noncancer controls. In this group, UroCAD detected urothelial carcinoma with a sensitivity of 82.5% and a specificity of 96.9%.

The researchers also analyzed samples from a validation cohort of 95 patients – 56 with urothelial carcinoma and 39 noncancer controls.

In this cohort, UroCAD had significantly higher sensitivity than urine cytology (80.4% and 33.9%, respectively; P < .001) but similar specificity (94.9% and 100%, respectively; P = .49) for the detection of urothelial carcinoma.

Among seven patients with pTa tumors, UroCAD had a sensitivity of 71.4%, while urine cytology had a sensitivity of 0%.

UroCAD’s sensitivity was greater for high-grade than low-grade urothelial carcinomas (86.7% and 60.0%, respectively). The assay was also more sensitive for larger tumors, with sensitivities of 66.7% for tumors measuring 1 cm or less, 72% for tumors between 1 cm and 3 cm, and 95.5% for tumors larger than 3 cm.

“The relatively lower sensitivity of UroCAD for the detection of lower-grade or smaller tumors is not unexpected, as these tumors are less likely to have abundant chromosomal alterations,” study author Chuan-Liang Xu, MD, PhD, of the Changhai Hospital in Shanghai, explained in a press release. “Ultimately, we believe that our assay could help to reduce the frequency of cystoscopy examination but not to replace it.”

The researchers noted that UroCAD positivity was associated with microscopic epithelial cells in cancer patients, and this suggests that insufficient exfoliative cells “might be the major technique limitation.”
 

Conclusions and next steps

“In summary, UroCAD could be a highly specific, robust, and noninvasive urothelial carcinoma diagnostic method with improved sensitivity and similar specificity as compared with cytology tests,” the researchers concluded.

“Within the next 5 years, we can see UroCAD in a variety of commercial formats available to the global markets, including the USA,” Dr. Xu commented in an interview. “We see UroCAD as a disruptive technology in diagnosing and monitoring patients with urothelial carcinoma.

“In America, given the COVID-19 pandemic, we also envision UroCAD becoming commercially available in the form of a mailed, at-home collection kit for high-risk patients, which may also be purchased off the shelf at commercial pharmacies,” Dr. Xu added. “We hope UroCAD will make a positive clinical impact to the urology field.”

In a follow-up trial (NCT04432909), researchers are evaluating the utility of UroCAD in the surveillance of urothelial carcinoma.

The current research was supported by various funding sources in China. The authors reported having no conflicts of interest.

SOURCE: Zeng S et al. Clin Cancer Res. 2020 Oct 9. doi: 10.1158/1078-0432.CCR-20-0401.

A novel urine-based assay improved detection of urothelial carcinoma when compared with conventional urine cytology in a prospective, observational study.

The study authors developed a low-coverage whole-genome sequencing technique, called “Urine Exfoliated Cells Copy Number Aberration Detector” (UroCAD), to detect copy number variants in urine-exfoliated cells.

The team then tested whether UroCAD could detect urothelial carcinomas in a single-blinded trial.

Shuxiong Zeng, MD, PhD, of Naval Medical University, Shanghai, China, and colleagues described this work in Clinical Cancer Research.
 

Study details and results

The researchers first tested UroCAD on urine samples from a discovery cohort of 190 patients – 126 with urothelial carcinoma and 64 noncancer controls. In this group, UroCAD detected urothelial carcinoma with a sensitivity of 82.5% and a specificity of 96.9%.

The researchers also analyzed samples from a validation cohort of 95 patients – 56 with urothelial carcinoma and 39 noncancer controls.

In this cohort, UroCAD had significantly higher sensitivity than urine cytology (80.4% and 33.9%, respectively; P < .001) but similar specificity (94.9% and 100%, respectively; P = .49) for the detection of urothelial carcinoma.

Among seven patients with pTa tumors, UroCAD had a sensitivity of 71.4%, while urine cytology had a sensitivity of 0%.

UroCAD’s sensitivity was greater for high-grade than low-grade urothelial carcinomas (86.7% and 60.0%, respectively). The assay was also more sensitive for larger tumors, with sensitivities of 66.7% for tumors measuring 1 cm or less, 72% for tumors between 1 cm and 3 cm, and 95.5% for tumors larger than 3 cm.

“The relatively lower sensitivity of UroCAD for the detection of lower-grade or smaller tumors is not unexpected, as these tumors are less likely to have abundant chromosomal alterations,” study author Chuan-Liang Xu, MD, PhD, of the Changhai Hospital in Shanghai, explained in a press release. “Ultimately, we believe that our assay could help to reduce the frequency of cystoscopy examination but not to replace it.”

The researchers noted that UroCAD positivity was associated with microscopic epithelial cells in cancer patients, and this suggests that insufficient exfoliative cells “might be the major technique limitation.”
 

Conclusions and next steps

“In summary, UroCAD could be a highly specific, robust, and noninvasive urothelial carcinoma diagnostic method with improved sensitivity and similar specificity as compared with cytology tests,” the researchers concluded.

“Within the next 5 years, we can see UroCAD in a variety of commercial formats available to the global markets, including the USA,” Dr. Xu commented in an interview. “We see UroCAD as a disruptive technology in diagnosing and monitoring patients with urothelial carcinoma.

“In America, given the COVID-19 pandemic, we also envision UroCAD becoming commercially available in the form of a mailed, at-home collection kit for high-risk patients, which may also be purchased off the shelf at commercial pharmacies,” Dr. Xu added. “We hope UroCAD will make a positive clinical impact to the urology field.”

In a follow-up trial (NCT04432909), researchers are evaluating the utility of UroCAD in the surveillance of urothelial carcinoma.

The current research was supported by various funding sources in China. The authors reported having no conflicts of interest.

SOURCE: Zeng S et al. Clin Cancer Res. 2020 Oct 9. doi: 10.1158/1078-0432.CCR-20-0401.

A novel urine-based assay improved detection of urothelial carcinoma when compared with conventional urine cytology in a prospective, observational study.

The study authors developed a low-coverage whole-genome sequencing technique, called “Urine Exfoliated Cells Copy Number Aberration Detector” (UroCAD), to detect copy number variants in urine-exfoliated cells.

The team then tested whether UroCAD could detect urothelial carcinomas in a single-blinded trial.

Shuxiong Zeng, MD, PhD, of Naval Medical University, Shanghai, China, and colleagues described this work in Clinical Cancer Research.
 

Study details and results

The researchers first tested UroCAD on urine samples from a discovery cohort of 190 patients – 126 with urothelial carcinoma and 64 noncancer controls. In this group, UroCAD detected urothelial carcinoma with a sensitivity of 82.5% and a specificity of 96.9%.

The researchers also analyzed samples from a validation cohort of 95 patients – 56 with urothelial carcinoma and 39 noncancer controls.

In this cohort, UroCAD had significantly higher sensitivity than urine cytology (80.4% and 33.9%, respectively; P < .001) but similar specificity (94.9% and 100%, respectively; P = .49) for the detection of urothelial carcinoma.

Among seven patients with pTa tumors, UroCAD had a sensitivity of 71.4%, while urine cytology had a sensitivity of 0%.

UroCAD’s sensitivity was greater for high-grade than low-grade urothelial carcinomas (86.7% and 60.0%, respectively). The assay was also more sensitive for larger tumors, with sensitivities of 66.7% for tumors measuring 1 cm or less, 72% for tumors between 1 cm and 3 cm, and 95.5% for tumors larger than 3 cm.

“The relatively lower sensitivity of UroCAD for the detection of lower-grade or smaller tumors is not unexpected, as these tumors are less likely to have abundant chromosomal alterations,” study author Chuan-Liang Xu, MD, PhD, of the Changhai Hospital in Shanghai, explained in a press release. “Ultimately, we believe that our assay could help to reduce the frequency of cystoscopy examination but not to replace it.”

The researchers noted that UroCAD positivity was associated with microscopic epithelial cells in cancer patients, and this suggests that insufficient exfoliative cells “might be the major technique limitation.”
 

Conclusions and next steps

“In summary, UroCAD could be a highly specific, robust, and noninvasive urothelial carcinoma diagnostic method with improved sensitivity and similar specificity as compared with cytology tests,” the researchers concluded.

“Within the next 5 years, we can see UroCAD in a variety of commercial formats available to the global markets, including the USA,” Dr. Xu commented in an interview. “We see UroCAD as a disruptive technology in diagnosing and monitoring patients with urothelial carcinoma.

“In America, given the COVID-19 pandemic, we also envision UroCAD becoming commercially available in the form of a mailed, at-home collection kit for high-risk patients, which may also be purchased off the shelf at commercial pharmacies,” Dr. Xu added. “We hope UroCAD will make a positive clinical impact to the urology field.”

In a follow-up trial (NCT04432909), researchers are evaluating the utility of UroCAD in the surveillance of urothelial carcinoma.

The current research was supported by various funding sources in China. The authors reported having no conflicts of interest.

SOURCE: Zeng S et al. Clin Cancer Res. 2020 Oct 9. doi: 10.1158/1078-0432.CCR-20-0401.

Canceled appointments, postponed surgeries, and delayed cancer diagnoses – all are a recipe for exhaustion for oncologists around the world, struggling to reach and treat their patients during the pandemic. Physicians and their teams felt the pain as COVID-19 took its initial march around the globe.

“We saw the distress of people with cancer who could no longer get to anyone on the phone. Their medical visit was usually canceled. Their radiotherapy session was postponed or modified, and chemotherapy postponed,” says Axel Kahn, MD, chairman of the board of directors of La Ligue Nationale Contre le Cancer (National League Against Cancer). “In the vast majority of cases, cancer treatment can be postponed or readjusted, without affecting the patient’s chances of survival, but there has been a lot of anxiety because the patients do not know that.”

The stay-at-home factor was one that played out across many months during the first wave.

“I believe that the ‘stay-home’ message that we transmitted was rigorously followed by patients who should have come to the emergency room much earlier and who, therefore, were admitted with a much more deteriorated general condition than in non-COVID-19 times,” says Benjamín Domingo Arrué, MD, from the department of medical oncology at Hospital Universitari i Politècnic La Fe in Valencia, Spain.

And in Brazil, some of the impact from the initial hit of COVID-19 on oncology is only now being felt, according to Laura Testa, MD, head of breast medical oncology, Instituto do Câncer do Estado de São Paulo.

“We are starting to see a lot of cancer cases that didn’t show up at the beginning of the pandemic, but now they are arriving to us already in advanced stages,” she said. “These patients need hospital care. If the situation worsens and goes back to what we saw at the peak of the curve, I fear the public system won’t be able to treat properly the oncology patients that need hospital care and the patients with cancer who also have COVID-19.”

But even as health care worker fatigue and concerns linger, oncologists say that what they have learned in the last 6 months has helped them prepare as COVID-19 cases increase and a second global wave kicks up.
 

Lessons from the first wave

In the United States, COVID-19 hit different regions at different times and to different degrees. One of the areas hit first was Seattle.

“We jumped on top of this, we were evidence based, we put things in place very, very quickly,” said Julie Gralow, MD, professor at the University of Washington and the Fred Hutchinson Cancer Research Center, both in Seattle.

“We did a really good job keeping COVID out of our cancer centers,” Dr. Gralow said. “We learned how to be super safe, and to keep symptomatic people out of the building, and to limit the extra people they could bring with them. It’s all about the number of contacts you have.”

The story was different, though, for oncologists in several other countries, and sometimes it varied immensely within each nation.

“We treated fewer patients with cancer during the first wave,” says Dirk Arnold, MD, medical director of the Asklepios Tumor Center Hamburg (Germany), in an interview. “In part, this was because staff were quarantined and because we had a completely different infrastructure in all of the hospitals. But also fewer patients with cancer came to the clinic at all. A lot of resources were directed toward COVID-19.” 

In Spain, telemedicine helped keep up with visits, but other areas felt the effect of COVID-19 patient loads.

“At least in the oncology department of our center, we have practically maintained 100% of visits, mostly by telephone,” says Dr. Arrué, “but the reality is that our country has not yet been prepared for telemedicine.”

Laura Mezquita, MD, of the department of medical oncology at Hospital Clinic de Barcelona, describes a more dramatic situation: “We have seen how some of our patients, especially with metastatic disease, have been dismissed for intensive care and life-support treatments, as well as specific treatments against COVID-19 (tocilizumab, remdesivir, etc.) due to the general health collapse of the former wave,” she said. She adds that specific oncologic populations, such as those with thoracic tumors, have been more affected.
 

Distress among oncologists 

Many oncologists are still feeling stressed and fatigued after the first wave, just as a second string of outbreaks is on its way. 

A survey presented at last month’s ESMO 2020 Congress found that, in July-August, moral distress was reported by one-third of the oncologists who responded, and more than half reported a feeling of exhaustion. 

“The tiredness and team exhaustion is noticeable,” said Dr. Arnold. “We recently had a task force discussion about what will happen when we have a second wave and how the department and our services will adapt. It was clear that those who were at the very front in the first wave had only a limited desire to do that again in the second wave.”

Another concern: COVID-19’s effect on staffing levels. 

“We have a population of young caregivers who are affected by the COVID-19 disease with an absenteeism rate that is quite unprecedented,” said Sophie Beaupère, general delegate of Unicancer since January.

She said that, in general, the absenteeism rate in the cancer centers averages 5%-6%, depending on the year. But that rate is now skyrocketing.
 

Stop-start cycle for surgery

As caregivers quarantined around the world, more than 10% of patients with cancer had treatment canceled or delayed during the first wave of the pandemic, according to another survey from ESMO, involving 109 oncologists from 18 countries.

Difficulties were reported for surgeries by 34% of the centers, but also difficulties with delivering chemotherapy (22% of centers), radiotherapy (13.7%), and therapy with checkpoint inhibitors (9.1%), monoclonal antibodies (9%), and oral targeted therapy (3.7%).

Stopping surgery is a real concern in France, noted Dr. Kahn, the National League Against Cancer chair. He says that in regions that were badly hit by COVID-19, “it was not possible to have access to the operating room for people who absolutely needed surgery; for example, patients with lung cancer that was still operable. Most of the recovery rooms were mobilized for resuscitation.”

There may be some solutions, suggested Thierry Breton, director general of the National Institute of Cancer in France. “We are getting prepared, with the health ministry, for a possible increase in hospital tension, which would lead to a situation where we would have to reschedule operations. Nationally, regionally, and locally, we are seeing how we can resume and prioritize surgeries that have not been done.”
 

Delays in cancer diagnosis

While COVID-19 affected treatment, many oncologists say the major impact of the first wave was a delay in diagnosing cancer. Some of this was a result of the suspension of cancer screening programs, but there was also fear among the general public about visiting clinics and hospitals during a pandemic.

“We didn’t do so well with cancer during the first wave here in the U.K.,” said Karol Sikora, PhD, MBBChir, professor of cancer medicine and founding dean at the University of Buckingham Medical School, London. “Cancer diagnostic pathways virtually stalled partly because patients didn’t seek help, but getting scans and biopsies was also very difficult. Even patients referred urgently under the ‘2-weeks-wait’ rule were turned down.” 

In France, “the delay in diagnosis is indisputable,” said Dr. Kahn. “About 50% of the cancer diagnoses one would expect during this period were missed.” 

“I am worried that there remains a major traffic jam that has not been caught up with, and, in the meantime, the health crisis is worsening,” he added.  

In Seattle, Dr. Gralow said the first COVID-19 wave had little impact on treatment for breast cancer, but it was in screening for breast cancer “where things really got messed up.”

“Even though we’ve been fully ramped up again,” she said, concerns remain. To ensure that screening mammography is maintained, “we have spaced out the visits to keep our waiting rooms less populated, with a longer time between using the machine so we can clean it. To do this, we have extended operating hours and are now opening on Saturday.

“So we’re actually at 100% of our capacity, but I’m really nervous, though, that a lot of people put off their screening mammogram and aren’t going to come in and get it.

“Not only did people get the message to stay home and not do nonessential things, but I think a lot of people lost their health insurance when they lost their jobs,” she said, and without health insurance, they are not covered for cancer screening.
 

Looking ahead, with a plan

Many oncologists agree that access to care can and must be improved – and there were some positive moves.

“Some regimens changed during the first months of the pandemic, and I don’t see them going back to the way they were anytime soon,” said Dr. Testa. “The changes/adaptations that were made to minimize the chance of SARS-CoV-2 infection are still in place and will go on for a while. In this context, telemedicine helped a lot. The pandemic forced the stakeholders to step up and put it in place in March. And now it’s here to stay.”

The experience gained in the last several months has driven preparation for the next wave.

“We are not going to see the disorganization that we saw during the first wave,” said Florence Joly, MD, PhD, head of medical oncology at the Centre François Baclesse in Caen, France. “The difference between now and earlier this year is that COVID diagnostic tests are available. That was one of the problems in the first wave. We had no way to diagnose.”

On the East Coast of the United States, medical oncologist Charu Aggarwal, MD, MPH, is also optimistic: “I think we’re at a place where we can manage.”

“I believe if there was going to be a new wave of COVID-19 cases we would be: better psychologically prepared and better organized,” said Dr. Aggarwal, assistant professor of medicine in the hematology-oncology division at the University of Pennsylvania, Philadelphia. “We already have experience with all of the tools, we have telemedicine available, we have screening protocols available, we have testing, we are already universally masking, everyone’s hand-washing, so I do think that means we would be okay.” 

Dr. Arnold agreed that “we are much better prepared than for the first wave, but … we have immense tasks in the area of patient management, the digitization of patient care, the clear allocation of resources when there is a second or third wave. In many areas of preparation, I believe, unfortunately, we are not as well positioned as we had actually hoped.” 

The first wave of COVID hit cancer services in the United Kingdom particularly hard: One modeling study suggested that delays in cancer referrals will lead to thousands of additional deaths and tens of thousands of life-years lost.

“Cancer services are working at near normal levels now, but they are still fragile and could be severely compromised again if the NHS [National Health Service] gets flooded by COVID patients,” said Dr. Sikora.

The second wave may be different. “Although the number of infections has increased, the hospitalizations have only risen a little. Let’s see what happens,” he said in an interview. Since then, however, infections have continued to rise, and there has been an increase in hospitalizations. New social distancing measures in the United Kingdom were put into place on Oct. 12, with the aim of protecting the NHS from overload.

Dr. Arrué describes it this way: “The reality is that the ‘second wave’ has left behind the initial grief and shock that both patients and health professionals experienced when faced with something that, until now, we had only seen in the movies.” The second wave has led to new restrictions – including a partial lockdown since the beginning of October.

Dr. Aggarwal says her department recently had a conference with Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, about the impact of COVID-19 on oncology.

“I asked him what advice he’d give oncologists, and he said to go back to as much screening as you were doing previously as quickly as possible. That’s what must be relayed to our oncologists in the community – and also to primary care physicians – because they are often the ones who are ordering and championing the screening efforts.”

This article was originated by Aude Lecrubier, Medscape French edition, and developed by Zosia Chustecka, Medscape Oncology. With additional reporting by Kate Johnson, freelance medical journalist, Claudia Gottschling for Medscape Germany, Leoleli Schwartz for Medscape em português, Tim Locke for Medscape United Kingdom, and Carla Nieto Martínez, freelance medical journalist for Medscape Spanish edition. 

This article first appeared on Medscape.com.

Canceled appointments, postponed surgeries, and delayed cancer diagnoses – all are a recipe for exhaustion for oncologists around the world, struggling to reach and treat their patients during the pandemic. Physicians and their teams felt the pain as COVID-19 took its initial march around the globe.

“We saw the distress of people with cancer who could no longer get to anyone on the phone. Their medical visit was usually canceled. Their radiotherapy session was postponed or modified, and chemotherapy postponed,” says Axel Kahn, MD, chairman of the board of directors of La Ligue Nationale Contre le Cancer (National League Against Cancer). “In the vast majority of cases, cancer treatment can be postponed or readjusted, without affecting the patient’s chances of survival, but there has been a lot of anxiety because the patients do not know that.”

The stay-at-home factor was one that played out across many months during the first wave.

“I believe that the ‘stay-home’ message that we transmitted was rigorously followed by patients who should have come to the emergency room much earlier and who, therefore, were admitted with a much more deteriorated general condition than in non-COVID-19 times,” says Benjamín Domingo Arrué, MD, from the department of medical oncology at Hospital Universitari i Politècnic La Fe in Valencia, Spain.

And in Brazil, some of the impact from the initial hit of COVID-19 on oncology is only now being felt, according to Laura Testa, MD, head of breast medical oncology, Instituto do Câncer do Estado de São Paulo.

“We are starting to see a lot of cancer cases that didn’t show up at the beginning of the pandemic, but now they are arriving to us already in advanced stages,” she said. “These patients need hospital care. If the situation worsens and goes back to what we saw at the peak of the curve, I fear the public system won’t be able to treat properly the oncology patients that need hospital care and the patients with cancer who also have COVID-19.”

But even as health care worker fatigue and concerns linger, oncologists say that what they have learned in the last 6 months has helped them prepare as COVID-19 cases increase and a second global wave kicks up.
 

Lessons from the first wave

In the United States, COVID-19 hit different regions at different times and to different degrees. One of the areas hit first was Seattle.

“We jumped on top of this, we were evidence based, we put things in place very, very quickly,” said Julie Gralow, MD, professor at the University of Washington and the Fred Hutchinson Cancer Research Center, both in Seattle.

“We did a really good job keeping COVID out of our cancer centers,” Dr. Gralow said. “We learned how to be super safe, and to keep symptomatic people out of the building, and to limit the extra people they could bring with them. It’s all about the number of contacts you have.”

The story was different, though, for oncologists in several other countries, and sometimes it varied immensely within each nation.

“We treated fewer patients with cancer during the first wave,” says Dirk Arnold, MD, medical director of the Asklepios Tumor Center Hamburg (Germany), in an interview. “In part, this was because staff were quarantined and because we had a completely different infrastructure in all of the hospitals. But also fewer patients with cancer came to the clinic at all. A lot of resources were directed toward COVID-19.” 

In Spain, telemedicine helped keep up with visits, but other areas felt the effect of COVID-19 patient loads.

“At least in the oncology department of our center, we have practically maintained 100% of visits, mostly by telephone,” says Dr. Arrué, “but the reality is that our country has not yet been prepared for telemedicine.”

Laura Mezquita, MD, of the department of medical oncology at Hospital Clinic de Barcelona, describes a more dramatic situation: “We have seen how some of our patients, especially with metastatic disease, have been dismissed for intensive care and life-support treatments, as well as specific treatments against COVID-19 (tocilizumab, remdesivir, etc.) due to the general health collapse of the former wave,” she said. She adds that specific oncologic populations, such as those with thoracic tumors, have been more affected.
 

Distress among oncologists 

Many oncologists are still feeling stressed and fatigued after the first wave, just as a second string of outbreaks is on its way. 

A survey presented at last month’s ESMO 2020 Congress found that, in July-August, moral distress was reported by one-third of the oncologists who responded, and more than half reported a feeling of exhaustion. 

“The tiredness and team exhaustion is noticeable,” said Dr. Arnold. “We recently had a task force discussion about what will happen when we have a second wave and how the department and our services will adapt. It was clear that those who were at the very front in the first wave had only a limited desire to do that again in the second wave.”

Another concern: COVID-19’s effect on staffing levels. 

“We have a population of young caregivers who are affected by the COVID-19 disease with an absenteeism rate that is quite unprecedented,” said Sophie Beaupère, general delegate of Unicancer since January.

She said that, in general, the absenteeism rate in the cancer centers averages 5%-6%, depending on the year. But that rate is now skyrocketing.
 

Stop-start cycle for surgery

As caregivers quarantined around the world, more than 10% of patients with cancer had treatment canceled or delayed during the first wave of the pandemic, according to another survey from ESMO, involving 109 oncologists from 18 countries.

Difficulties were reported for surgeries by 34% of the centers, but also difficulties with delivering chemotherapy (22% of centers), radiotherapy (13.7%), and therapy with checkpoint inhibitors (9.1%), monoclonal antibodies (9%), and oral targeted therapy (3.7%).

Stopping surgery is a real concern in France, noted Dr. Kahn, the National League Against Cancer chair. He says that in regions that were badly hit by COVID-19, “it was not possible to have access to the operating room for people who absolutely needed surgery; for example, patients with lung cancer that was still operable. Most of the recovery rooms were mobilized for resuscitation.”

There may be some solutions, suggested Thierry Breton, director general of the National Institute of Cancer in France. “We are getting prepared, with the health ministry, for a possible increase in hospital tension, which would lead to a situation where we would have to reschedule operations. Nationally, regionally, and locally, we are seeing how we can resume and prioritize surgeries that have not been done.”
 

Delays in cancer diagnosis

While COVID-19 affected treatment, many oncologists say the major impact of the first wave was a delay in diagnosing cancer. Some of this was a result of the suspension of cancer screening programs, but there was also fear among the general public about visiting clinics and hospitals during a pandemic.

“We didn’t do so well with cancer during the first wave here in the U.K.,” said Karol Sikora, PhD, MBBChir, professor of cancer medicine and founding dean at the University of Buckingham Medical School, London. “Cancer diagnostic pathways virtually stalled partly because patients didn’t seek help, but getting scans and biopsies was also very difficult. Even patients referred urgently under the ‘2-weeks-wait’ rule were turned down.” 

In France, “the delay in diagnosis is indisputable,” said Dr. Kahn. “About 50% of the cancer diagnoses one would expect during this period were missed.” 

“I am worried that there remains a major traffic jam that has not been caught up with, and, in the meantime, the health crisis is worsening,” he added.  

In Seattle, Dr. Gralow said the first COVID-19 wave had little impact on treatment for breast cancer, but it was in screening for breast cancer “where things really got messed up.”

“Even though we’ve been fully ramped up again,” she said, concerns remain. To ensure that screening mammography is maintained, “we have spaced out the visits to keep our waiting rooms less populated, with a longer time between using the machine so we can clean it. To do this, we have extended operating hours and are now opening on Saturday.

“So we’re actually at 100% of our capacity, but I’m really nervous, though, that a lot of people put off their screening mammogram and aren’t going to come in and get it.

“Not only did people get the message to stay home and not do nonessential things, but I think a lot of people lost their health insurance when they lost their jobs,” she said, and without health insurance, they are not covered for cancer screening.
 

Looking ahead, with a plan

Many oncologists agree that access to care can and must be improved – and there were some positive moves.

“Some regimens changed during the first months of the pandemic, and I don’t see them going back to the way they were anytime soon,” said Dr. Testa. “The changes/adaptations that were made to minimize the chance of SARS-CoV-2 infection are still in place and will go on for a while. In this context, telemedicine helped a lot. The pandemic forced the stakeholders to step up and put it in place in March. And now it’s here to stay.”

The experience gained in the last several months has driven preparation for the next wave.

“We are not going to see the disorganization that we saw during the first wave,” said Florence Joly, MD, PhD, head of medical oncology at the Centre François Baclesse in Caen, France. “The difference between now and earlier this year is that COVID diagnostic tests are available. That was one of the problems in the first wave. We had no way to diagnose.”

On the East Coast of the United States, medical oncologist Charu Aggarwal, MD, MPH, is also optimistic: “I think we’re at a place where we can manage.”

“I believe if there was going to be a new wave of COVID-19 cases we would be: better psychologically prepared and better organized,” said Dr. Aggarwal, assistant professor of medicine in the hematology-oncology division at the University of Pennsylvania, Philadelphia. “We already have experience with all of the tools, we have telemedicine available, we have screening protocols available, we have testing, we are already universally masking, everyone’s hand-washing, so I do think that means we would be okay.” 

Dr. Arnold agreed that “we are much better prepared than for the first wave, but … we have immense tasks in the area of patient management, the digitization of patient care, the clear allocation of resources when there is a second or third wave. In many areas of preparation, I believe, unfortunately, we are not as well positioned as we had actually hoped.” 

The first wave of COVID hit cancer services in the United Kingdom particularly hard: One modeling study suggested that delays in cancer referrals will lead to thousands of additional deaths and tens of thousands of life-years lost.

“Cancer services are working at near normal levels now, but they are still fragile and could be severely compromised again if the NHS [National Health Service] gets flooded by COVID patients,” said Dr. Sikora.

The second wave may be different. “Although the number of infections has increased, the hospitalizations have only risen a little. Let’s see what happens,” he said in an interview. Since then, however, infections have continued to rise, and there has been an increase in hospitalizations. New social distancing measures in the United Kingdom were put into place on Oct. 12, with the aim of protecting the NHS from overload.

Dr. Arrué describes it this way: “The reality is that the ‘second wave’ has left behind the initial grief and shock that both patients and health professionals experienced when faced with something that, until now, we had only seen in the movies.” The second wave has led to new restrictions – including a partial lockdown since the beginning of October.

Dr. Aggarwal says her department recently had a conference with Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, about the impact of COVID-19 on oncology.

“I asked him what advice he’d give oncologists, and he said to go back to as much screening as you were doing previously as quickly as possible. That’s what must be relayed to our oncologists in the community – and also to primary care physicians – because they are often the ones who are ordering and championing the screening efforts.”

This article was originated by Aude Lecrubier, Medscape French edition, and developed by Zosia Chustecka, Medscape Oncology. With additional reporting by Kate Johnson, freelance medical journalist, Claudia Gottschling for Medscape Germany, Leoleli Schwartz for Medscape em português, Tim Locke for Medscape United Kingdom, and Carla Nieto Martínez, freelance medical journalist for Medscape Spanish edition. 

This article first appeared on Medscape.com.

Canceled appointments, postponed surgeries, and delayed cancer diagnoses – all are a recipe for exhaustion for oncologists around the world, struggling to reach and treat their patients during the pandemic. Physicians and their teams felt the pain as COVID-19 took its initial march around the globe.

“We saw the distress of people with cancer who could no longer get to anyone on the phone. Their medical visit was usually canceled. Their radiotherapy session was postponed or modified, and chemotherapy postponed,” says Axel Kahn, MD, chairman of the board of directors of La Ligue Nationale Contre le Cancer (National League Against Cancer). “In the vast majority of cases, cancer treatment can be postponed or readjusted, without affecting the patient’s chances of survival, but there has been a lot of anxiety because the patients do not know that.”

The stay-at-home factor was one that played out across many months during the first wave.

“I believe that the ‘stay-home’ message that we transmitted was rigorously followed by patients who should have come to the emergency room much earlier and who, therefore, were admitted with a much more deteriorated general condition than in non-COVID-19 times,” says Benjamín Domingo Arrué, MD, from the department of medical oncology at Hospital Universitari i Politècnic La Fe in Valencia, Spain.

And in Brazil, some of the impact from the initial hit of COVID-19 on oncology is only now being felt, according to Laura Testa, MD, head of breast medical oncology, Instituto do Câncer do Estado de São Paulo.

“We are starting to see a lot of cancer cases that didn’t show up at the beginning of the pandemic, but now they are arriving to us already in advanced stages,” she said. “These patients need hospital care. If the situation worsens and goes back to what we saw at the peak of the curve, I fear the public system won’t be able to treat properly the oncology patients that need hospital care and the patients with cancer who also have COVID-19.”

But even as health care worker fatigue and concerns linger, oncologists say that what they have learned in the last 6 months has helped them prepare as COVID-19 cases increase and a second global wave kicks up.
 

Lessons from the first wave

In the United States, COVID-19 hit different regions at different times and to different degrees. One of the areas hit first was Seattle.

“We jumped on top of this, we were evidence based, we put things in place very, very quickly,” said Julie Gralow, MD, professor at the University of Washington and the Fred Hutchinson Cancer Research Center, both in Seattle.

“We did a really good job keeping COVID out of our cancer centers,” Dr. Gralow said. “We learned how to be super safe, and to keep symptomatic people out of the building, and to limit the extra people they could bring with them. It’s all about the number of contacts you have.”

The story was different, though, for oncologists in several other countries, and sometimes it varied immensely within each nation.

“We treated fewer patients with cancer during the first wave,” says Dirk Arnold, MD, medical director of the Asklepios Tumor Center Hamburg (Germany), in an interview. “In part, this was because staff were quarantined and because we had a completely different infrastructure in all of the hospitals. But also fewer patients with cancer came to the clinic at all. A lot of resources were directed toward COVID-19.” 

In Spain, telemedicine helped keep up with visits, but other areas felt the effect of COVID-19 patient loads.

“At least in the oncology department of our center, we have practically maintained 100% of visits, mostly by telephone,” says Dr. Arrué, “but the reality is that our country has not yet been prepared for telemedicine.”

Laura Mezquita, MD, of the department of medical oncology at Hospital Clinic de Barcelona, describes a more dramatic situation: “We have seen how some of our patients, especially with metastatic disease, have been dismissed for intensive care and life-support treatments, as well as specific treatments against COVID-19 (tocilizumab, remdesivir, etc.) due to the general health collapse of the former wave,” she said. She adds that specific oncologic populations, such as those with thoracic tumors, have been more affected.
 

Distress among oncologists 

Many oncologists are still feeling stressed and fatigued after the first wave, just as a second string of outbreaks is on its way. 

A survey presented at last month’s ESMO 2020 Congress found that, in July-August, moral distress was reported by one-third of the oncologists who responded, and more than half reported a feeling of exhaustion. 

“The tiredness and team exhaustion is noticeable,” said Dr. Arnold. “We recently had a task force discussion about what will happen when we have a second wave and how the department and our services will adapt. It was clear that those who were at the very front in the first wave had only a limited desire to do that again in the second wave.”

Another concern: COVID-19’s effect on staffing levels. 

“We have a population of young caregivers who are affected by the COVID-19 disease with an absenteeism rate that is quite unprecedented,” said Sophie Beaupère, general delegate of Unicancer since January.

She said that, in general, the absenteeism rate in the cancer centers averages 5%-6%, depending on the year. But that rate is now skyrocketing.
 

Stop-start cycle for surgery

As caregivers quarantined around the world, more than 10% of patients with cancer had treatment canceled or delayed during the first wave of the pandemic, according to another survey from ESMO, involving 109 oncologists from 18 countries.

Difficulties were reported for surgeries by 34% of the centers, but also difficulties with delivering chemotherapy (22% of centers), radiotherapy (13.7%), and therapy with checkpoint inhibitors (9.1%), monoclonal antibodies (9%), and oral targeted therapy (3.7%).

Stopping surgery is a real concern in France, noted Dr. Kahn, the National League Against Cancer chair. He says that in regions that were badly hit by COVID-19, “it was not possible to have access to the operating room for people who absolutely needed surgery; for example, patients with lung cancer that was still operable. Most of the recovery rooms were mobilized for resuscitation.”

There may be some solutions, suggested Thierry Breton, director general of the National Institute of Cancer in France. “We are getting prepared, with the health ministry, for a possible increase in hospital tension, which would lead to a situation where we would have to reschedule operations. Nationally, regionally, and locally, we are seeing how we can resume and prioritize surgeries that have not been done.”
 

Delays in cancer diagnosis

While COVID-19 affected treatment, many oncologists say the major impact of the first wave was a delay in diagnosing cancer. Some of this was a result of the suspension of cancer screening programs, but there was also fear among the general public about visiting clinics and hospitals during a pandemic.

“We didn’t do so well with cancer during the first wave here in the U.K.,” said Karol Sikora, PhD, MBBChir, professor of cancer medicine and founding dean at the University of Buckingham Medical School, London. “Cancer diagnostic pathways virtually stalled partly because patients didn’t seek help, but getting scans and biopsies was also very difficult. Even patients referred urgently under the ‘2-weeks-wait’ rule were turned down.” 

In France, “the delay in diagnosis is indisputable,” said Dr. Kahn. “About 50% of the cancer diagnoses one would expect during this period were missed.” 

“I am worried that there remains a major traffic jam that has not been caught up with, and, in the meantime, the health crisis is worsening,” he added.  

In Seattle, Dr. Gralow said the first COVID-19 wave had little impact on treatment for breast cancer, but it was in screening for breast cancer “where things really got messed up.”

“Even though we’ve been fully ramped up again,” she said, concerns remain. To ensure that screening mammography is maintained, “we have spaced out the visits to keep our waiting rooms less populated, with a longer time between using the machine so we can clean it. To do this, we have extended operating hours and are now opening on Saturday.

“So we’re actually at 100% of our capacity, but I’m really nervous, though, that a lot of people put off their screening mammogram and aren’t going to come in and get it.

“Not only did people get the message to stay home and not do nonessential things, but I think a lot of people lost their health insurance when they lost their jobs,” she said, and without health insurance, they are not covered for cancer screening.
 

Looking ahead, with a plan

Many oncologists agree that access to care can and must be improved – and there were some positive moves.

“Some regimens changed during the first months of the pandemic, and I don’t see them going back to the way they were anytime soon,” said Dr. Testa. “The changes/adaptations that were made to minimize the chance of SARS-CoV-2 infection are still in place and will go on for a while. In this context, telemedicine helped a lot. The pandemic forced the stakeholders to step up and put it in place in March. And now it’s here to stay.”

The experience gained in the last several months has driven preparation for the next wave.

“We are not going to see the disorganization that we saw during the first wave,” said Florence Joly, MD, PhD, head of medical oncology at the Centre François Baclesse in Caen, France. “The difference between now and earlier this year is that COVID diagnostic tests are available. That was one of the problems in the first wave. We had no way to diagnose.”

On the East Coast of the United States, medical oncologist Charu Aggarwal, MD, MPH, is also optimistic: “I think we’re at a place where we can manage.”

“I believe if there was going to be a new wave of COVID-19 cases we would be: better psychologically prepared and better organized,” said Dr. Aggarwal, assistant professor of medicine in the hematology-oncology division at the University of Pennsylvania, Philadelphia. “We already have experience with all of the tools, we have telemedicine available, we have screening protocols available, we have testing, we are already universally masking, everyone’s hand-washing, so I do think that means we would be okay.” 

Dr. Arnold agreed that “we are much better prepared than for the first wave, but … we have immense tasks in the area of patient management, the digitization of patient care, the clear allocation of resources when there is a second or third wave. In many areas of preparation, I believe, unfortunately, we are not as well positioned as we had actually hoped.” 

The first wave of COVID hit cancer services in the United Kingdom particularly hard: One modeling study suggested that delays in cancer referrals will lead to thousands of additional deaths and tens of thousands of life-years lost.

“Cancer services are working at near normal levels now, but they are still fragile and could be severely compromised again if the NHS [National Health Service] gets flooded by COVID patients,” said Dr. Sikora.

The second wave may be different. “Although the number of infections has increased, the hospitalizations have only risen a little. Let’s see what happens,” he said in an interview. Since then, however, infections have continued to rise, and there has been an increase in hospitalizations. New social distancing measures in the United Kingdom were put into place on Oct. 12, with the aim of protecting the NHS from overload.

Dr. Arrué describes it this way: “The reality is that the ‘second wave’ has left behind the initial grief and shock that both patients and health professionals experienced when faced with something that, until now, we had only seen in the movies.” The second wave has led to new restrictions – including a partial lockdown since the beginning of October.

Dr. Aggarwal says her department recently had a conference with Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, about the impact of COVID-19 on oncology.

“I asked him what advice he’d give oncologists, and he said to go back to as much screening as you were doing previously as quickly as possible. That’s what must be relayed to our oncologists in the community – and also to primary care physicians – because they are often the ones who are ordering and championing the screening efforts.”

This article was originated by Aude Lecrubier, Medscape French edition, and developed by Zosia Chustecka, Medscape Oncology. With additional reporting by Kate Johnson, freelance medical journalist, Claudia Gottschling for Medscape Germany, Leoleli Schwartz for Medscape em português, Tim Locke for Medscape United Kingdom, and Carla Nieto Martínez, freelance medical journalist for Medscape Spanish edition. 

This article first appeared on Medscape.com.

The investigational agent MK-6482 demonstrated durable efficacy and a favorable safety profile in a phase 2 trial of patients with Von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) and nonrenal lesions, according to a presentation at the European Society for Medical Oncology Virtual Congress 2020.

MK-6482 is an oral inhibitor of hypoxia inducible factor-(HIF) 2-alpha. The drug previously showed favorable safety and antitumor activity in advanced RCC, Ramaprasad Srinivasan, MD, PhD, of the National Cancer Institute, Bethesda, Md., said when presenting data from the phase 2 trial.

Dr. Srinivasan noted that, in VHL disease, RCC occurs in 25%-60% of individuals and is a key cause of morbidity and shortened life expectancy despite aggressive treatment. HIF-2-alpha accumulation activates genes that drive tumor growth in VHL-associated RCC.

The primary objective of Dr. Srinivasan’s phase 2 study was to evaluate the efficacy of the HIF-2-alpha inhibitor MK-6482 (at 120 mg daily) for the treatment of VHL-associated RCC.

The study included 61 treatment-naive patients with VHL diagnoses based on germline mutations. All subjects had RCC and additional non-RCC lesions, including pancreatic (100%), central nervous system (CNS) hemangioblastoma (70.5%), and retinal lesions (26.2%).

The patients’ median age at baseline was 41 years (range, 19-66), and 52.5% were men. Most (82%) had an European Cooperative Oncology Group performance status of 0.
 

Efficacy and safety

At a median follow-up of 68.7 weeks, 56 patients were receiving ongoing treatment.

By independent central review, the overall response rate in target RCC lesions was 36.1% (all partial responses), with unconfirmed partial responses in 11.5% and stable disease in 62.3%. There was no progression in target lesions. Decreases in target lesion size were observed in 91.8% of patients.

The median time to response was 31.1 weeks (range, 11.9-62.3 weeks), and the median duration of response was not reached (range, 11.9-62.3 weeks). The 1-year progression-free survival rate was 98.3%.

“Promising clinical activity was observed with MK-6482 in treatment-naive patients with VHL-associated RCC,” Dr. Srinivasan said. He added that efficacy was durable in both RCC and non-renal lesions.

Complete responses were observed in 6.6% (4/61) of pancreatic lesions and 11.6% (5/43) of CNS hemangioblastomas. Partial response and stable disease rates in pancreatic lesions were 57.4% and 34.4%, respectively. Partial response and stable disease rates in CNS hemangioblastomas were 18.6% and 65.1%, respectively.

In the 16 patients with retinal lesions, 68.8% saw an improvement and 25% had stable disease. No progression was reported.

“MK-6482 was well tolerated and has a favorable safety profile,” Dr. Srinivasan noted.

Most patients (98.4%) had treatment-related adverse events (AEs), with anemia being the most common. Grade 3 AEs included anemia (6.6%), fatigue (4.9%), dyspnea (1.6%), and hypoxia (1.6%). One patient (1.6%) discontinued treatment because of grade 1 dizziness. There was one grade 4 AE and one fatal AE, but both were considered unrelated to study treatment.
 

Remaining questions and next steps

The challenge in managing VHL-associated RCC tumors is finding a balance between the risk of cancer dissemination and renal morbidity, said study discussant Cristina Suárez, MD, PhD, of Hospital Universitari Vall d’Hebron in Barcelona.

“There is no standard of care systemic treatment, and recruitment for clinical trials is challenging,” Dr. Suárez added.

While response rates in RCC lesions with MK-6482 were generally in line with the experience reported for sunitinib and pazopanib, response rates were particularly favorable with MK-6482 in pancreatic lesions and CNS hemangioblastomas, Dr. Suárez said.

“These are the best response rates reported in non-RCC lesions,” she noted.

However, Dr. Suárez said, important questions remain. Specifically, how long should patients continue on treatment, and will lesion rebound occur after treatment discontinuation?

Larger multicenter trials are needed, Dr. Suárez said, pointing out that the current study is the largest to date of systemic therapy for patients with VHL disease.

The study was funded by Merck Sharp & Dohme Corp. Dr. Srinivasan disclosed funding from Merck and Calithera Biosciences. Dr. Suárez disclosed relationships with Astellas, AstraZeneca, Bayer, and many other companies.

SOURCE: Srinivasan R et al. ESMO 2020. Abstract LBA26.

The investigational agent MK-6482 demonstrated durable efficacy and a favorable safety profile in a phase 2 trial of patients with Von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) and nonrenal lesions, according to a presentation at the European Society for Medical Oncology Virtual Congress 2020.

MK-6482 is an oral inhibitor of hypoxia inducible factor-(HIF) 2-alpha. The drug previously showed favorable safety and antitumor activity in advanced RCC, Ramaprasad Srinivasan, MD, PhD, of the National Cancer Institute, Bethesda, Md., said when presenting data from the phase 2 trial.

Dr. Srinivasan noted that, in VHL disease, RCC occurs in 25%-60% of individuals and is a key cause of morbidity and shortened life expectancy despite aggressive treatment. HIF-2-alpha accumulation activates genes that drive tumor growth in VHL-associated RCC.

The primary objective of Dr. Srinivasan’s phase 2 study was to evaluate the efficacy of the HIF-2-alpha inhibitor MK-6482 (at 120 mg daily) for the treatment of VHL-associated RCC.

The study included 61 treatment-naive patients with VHL diagnoses based on germline mutations. All subjects had RCC and additional non-RCC lesions, including pancreatic (100%), central nervous system (CNS) hemangioblastoma (70.5%), and retinal lesions (26.2%).

The patients’ median age at baseline was 41 years (range, 19-66), and 52.5% were men. Most (82%) had an European Cooperative Oncology Group performance status of 0.
 

Efficacy and safety

At a median follow-up of 68.7 weeks, 56 patients were receiving ongoing treatment.

By independent central review, the overall response rate in target RCC lesions was 36.1% (all partial responses), with unconfirmed partial responses in 11.5% and stable disease in 62.3%. There was no progression in target lesions. Decreases in target lesion size were observed in 91.8% of patients.

The median time to response was 31.1 weeks (range, 11.9-62.3 weeks), and the median duration of response was not reached (range, 11.9-62.3 weeks). The 1-year progression-free survival rate was 98.3%.

“Promising clinical activity was observed with MK-6482 in treatment-naive patients with VHL-associated RCC,” Dr. Srinivasan said. He added that efficacy was durable in both RCC and non-renal lesions.

Complete responses were observed in 6.6% (4/61) of pancreatic lesions and 11.6% (5/43) of CNS hemangioblastomas. Partial response and stable disease rates in pancreatic lesions were 57.4% and 34.4%, respectively. Partial response and stable disease rates in CNS hemangioblastomas were 18.6% and 65.1%, respectively.

In the 16 patients with retinal lesions, 68.8% saw an improvement and 25% had stable disease. No progression was reported.

“MK-6482 was well tolerated and has a favorable safety profile,” Dr. Srinivasan noted.

Most patients (98.4%) had treatment-related adverse events (AEs), with anemia being the most common. Grade 3 AEs included anemia (6.6%), fatigue (4.9%), dyspnea (1.6%), and hypoxia (1.6%). One patient (1.6%) discontinued treatment because of grade 1 dizziness. There was one grade 4 AE and one fatal AE, but both were considered unrelated to study treatment.
 

Remaining questions and next steps

The challenge in managing VHL-associated RCC tumors is finding a balance between the risk of cancer dissemination and renal morbidity, said study discussant Cristina Suárez, MD, PhD, of Hospital Universitari Vall d’Hebron in Barcelona.

“There is no standard of care systemic treatment, and recruitment for clinical trials is challenging,” Dr. Suárez added.

While response rates in RCC lesions with MK-6482 were generally in line with the experience reported for sunitinib and pazopanib, response rates were particularly favorable with MK-6482 in pancreatic lesions and CNS hemangioblastomas, Dr. Suárez said.

“These are the best response rates reported in non-RCC lesions,” she noted.

However, Dr. Suárez said, important questions remain. Specifically, how long should patients continue on treatment, and will lesion rebound occur after treatment discontinuation?

Larger multicenter trials are needed, Dr. Suárez said, pointing out that the current study is the largest to date of systemic therapy for patients with VHL disease.

The study was funded by Merck Sharp & Dohme Corp. Dr. Srinivasan disclosed funding from Merck and Calithera Biosciences. Dr. Suárez disclosed relationships with Astellas, AstraZeneca, Bayer, and many other companies.

SOURCE: Srinivasan R et al. ESMO 2020. Abstract LBA26.

The investigational agent MK-6482 demonstrated durable efficacy and a favorable safety profile in a phase 2 trial of patients with Von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) and nonrenal lesions, according to a presentation at the European Society for Medical Oncology Virtual Congress 2020.

MK-6482 is an oral inhibitor of hypoxia inducible factor-(HIF) 2-alpha. The drug previously showed favorable safety and antitumor activity in advanced RCC, Ramaprasad Srinivasan, MD, PhD, of the National Cancer Institute, Bethesda, Md., said when presenting data from the phase 2 trial.

Dr. Srinivasan noted that, in VHL disease, RCC occurs in 25%-60% of individuals and is a key cause of morbidity and shortened life expectancy despite aggressive treatment. HIF-2-alpha accumulation activates genes that drive tumor growth in VHL-associated RCC.

The primary objective of Dr. Srinivasan’s phase 2 study was to evaluate the efficacy of the HIF-2-alpha inhibitor MK-6482 (at 120 mg daily) for the treatment of VHL-associated RCC.

The study included 61 treatment-naive patients with VHL diagnoses based on germline mutations. All subjects had RCC and additional non-RCC lesions, including pancreatic (100%), central nervous system (CNS) hemangioblastoma (70.5%), and retinal lesions (26.2%).

The patients’ median age at baseline was 41 years (range, 19-66), and 52.5% were men. Most (82%) had an European Cooperative Oncology Group performance status of 0.
 

Efficacy and safety

At a median follow-up of 68.7 weeks, 56 patients were receiving ongoing treatment.

By independent central review, the overall response rate in target RCC lesions was 36.1% (all partial responses), with unconfirmed partial responses in 11.5% and stable disease in 62.3%. There was no progression in target lesions. Decreases in target lesion size were observed in 91.8% of patients.

The median time to response was 31.1 weeks (range, 11.9-62.3 weeks), and the median duration of response was not reached (range, 11.9-62.3 weeks). The 1-year progression-free survival rate was 98.3%.

“Promising clinical activity was observed with MK-6482 in treatment-naive patients with VHL-associated RCC,” Dr. Srinivasan said. He added that efficacy was durable in both RCC and non-renal lesions.

Complete responses were observed in 6.6% (4/61) of pancreatic lesions and 11.6% (5/43) of CNS hemangioblastomas. Partial response and stable disease rates in pancreatic lesions were 57.4% and 34.4%, respectively. Partial response and stable disease rates in CNS hemangioblastomas were 18.6% and 65.1%, respectively.

In the 16 patients with retinal lesions, 68.8% saw an improvement and 25% had stable disease. No progression was reported.

“MK-6482 was well tolerated and has a favorable safety profile,” Dr. Srinivasan noted.

Most patients (98.4%) had treatment-related adverse events (AEs), with anemia being the most common. Grade 3 AEs included anemia (6.6%), fatigue (4.9%), dyspnea (1.6%), and hypoxia (1.6%). One patient (1.6%) discontinued treatment because of grade 1 dizziness. There was one grade 4 AE and one fatal AE, but both were considered unrelated to study treatment.
 

Remaining questions and next steps

The challenge in managing VHL-associated RCC tumors is finding a balance between the risk of cancer dissemination and renal morbidity, said study discussant Cristina Suárez, MD, PhD, of Hospital Universitari Vall d’Hebron in Barcelona.

“There is no standard of care systemic treatment, and recruitment for clinical trials is challenging,” Dr. Suárez added.

While response rates in RCC lesions with MK-6482 were generally in line with the experience reported for sunitinib and pazopanib, response rates were particularly favorable with MK-6482 in pancreatic lesions and CNS hemangioblastomas, Dr. Suárez said.

“These are the best response rates reported in non-RCC lesions,” she noted.

However, Dr. Suárez said, important questions remain. Specifically, how long should patients continue on treatment, and will lesion rebound occur after treatment discontinuation?

Larger multicenter trials are needed, Dr. Suárez said, pointing out that the current study is the largest to date of systemic therapy for patients with VHL disease.

The study was funded by Merck Sharp & Dohme Corp. Dr. Srinivasan disclosed funding from Merck and Calithera Biosciences. Dr. Suárez disclosed relationships with Astellas, AstraZeneca, Bayer, and many other companies.

SOURCE: Srinivasan R et al. ESMO 2020. Abstract LBA26.