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Combo shows promise for checkpoint inhibitor-refractory urothelial carcinoma
NATIONAL HARBOR, MD. – Sitravatinib may “restore or enhance” the activity of anti-PD-1 therapy in patients with checkpoint inhibitor–refractory urothelial carcinoma, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.
Clinical activity was observed with combination sitravatinib and nivolumab in patients with urothelial carcinoma who had disease progression on or after an immune checkpoint inhibitor and were previously treated with platinum-based chemotherapy.
“Up until a few years ago, the only therapies we had [for urothelial carcinoma] were cytotoxic, platinum-based chemotherapies,” said Pavlos Msaouel, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston.
“Thankfully, since 2016, immune checkpoint therapy has become part of our toolbox. But even with single-agent, approved immune checkpoint therapies, anti-PD-1/anti-PD-L1, the response rates are still low, around 20%, and durable responses are only seen in a subset of patients. So we have to do better, if possible, potentially by combining immune checkpoint therapies with other immunotherapies such as sitravatinib.”
Dr. Msaouel explained that sitravatinib inhibits a spectrum of related receptor tyrosine kinases, including TAM family receptors (TYRO3, Axl, and Mer), split family receptors (VEGFR2/PDGFR and c-KIT), and c-Met. Researchers are investigating sitravatinib in combination with nivolumab in a phase 2 trial of patients with urothelial carcinoma (NCT03606174). Dr. Msaouel presented results from one cohort on this trial – 33 patients who had previously received platinum-based chemotherapy and a PD-1/PD-L1 inhibitor.
At baseline, the patients’ median age was 68 years (range, 47-83 years), and 70% were male. Patients had metastatic (n = 30) or locally advanced (n = 3) disease. They had received a median of two (range, one to four) prior systemic therapies.
For this study, patients received oral sitravatinib at 120 mg daily and intravenous nivolumab at 240 mg every 2 weeks or 480 mg every 4 weeks on continuous 28-day cycles. Tumor assessments were performed every 8 weeks.
Results
Of the 22 patients evaluable for efficacy, 1 patient achieved a complete response, 5 had a partial response, 15 had stable disease, and 1 progressed. Eight patients had tumor regression greater than 30%.
Treatment duration exceeded 26 weeks in six patients. Nine patients, including four responders, were still on study at the data cutoff in mid-October.
“This ongoing trial continues to show promising clinical activity, including tumor regression and prolonged duration on treatment,” Dr. Msaouel said.
He added that combination sitravatinib and nivolumab has “an acceptable side effect profile, with manageable adverse events.”
Common treatment-related adverse events, in all 33 patients, were fatigue (58%), diarrhea (48%), decreased appetite (33%), dysphonia (33%), nausea (33%), and alanine aminotransferase increase (21%).
Grade 3 treatment-related adverse events included fatigue (12%), hypertension (12%), diarrhea (9%), lipase increase (9%), decreased appetite (3%), and palmar-plantar erythrodysesthesia syndrome (3%). There were no grade 4 or 5 treatment-related events.
Mirati Therapeutics sponsored the trial. Dr. Msaouel disclosed relationships with Mirati, Bristol-Myers Squibb, Exelixis, Pfizer, and Takeda.
SOURCE: Msaouel P et al. SITC 2019. Abstract O23.
NATIONAL HARBOR, MD. – Sitravatinib may “restore or enhance” the activity of anti-PD-1 therapy in patients with checkpoint inhibitor–refractory urothelial carcinoma, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.
Clinical activity was observed with combination sitravatinib and nivolumab in patients with urothelial carcinoma who had disease progression on or after an immune checkpoint inhibitor and were previously treated with platinum-based chemotherapy.
“Up until a few years ago, the only therapies we had [for urothelial carcinoma] were cytotoxic, platinum-based chemotherapies,” said Pavlos Msaouel, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston.
“Thankfully, since 2016, immune checkpoint therapy has become part of our toolbox. But even with single-agent, approved immune checkpoint therapies, anti-PD-1/anti-PD-L1, the response rates are still low, around 20%, and durable responses are only seen in a subset of patients. So we have to do better, if possible, potentially by combining immune checkpoint therapies with other immunotherapies such as sitravatinib.”
Dr. Msaouel explained that sitravatinib inhibits a spectrum of related receptor tyrosine kinases, including TAM family receptors (TYRO3, Axl, and Mer), split family receptors (VEGFR2/PDGFR and c-KIT), and c-Met. Researchers are investigating sitravatinib in combination with nivolumab in a phase 2 trial of patients with urothelial carcinoma (NCT03606174). Dr. Msaouel presented results from one cohort on this trial – 33 patients who had previously received platinum-based chemotherapy and a PD-1/PD-L1 inhibitor.
At baseline, the patients’ median age was 68 years (range, 47-83 years), and 70% were male. Patients had metastatic (n = 30) or locally advanced (n = 3) disease. They had received a median of two (range, one to four) prior systemic therapies.
For this study, patients received oral sitravatinib at 120 mg daily and intravenous nivolumab at 240 mg every 2 weeks or 480 mg every 4 weeks on continuous 28-day cycles. Tumor assessments were performed every 8 weeks.
Results
Of the 22 patients evaluable for efficacy, 1 patient achieved a complete response, 5 had a partial response, 15 had stable disease, and 1 progressed. Eight patients had tumor regression greater than 30%.
Treatment duration exceeded 26 weeks in six patients. Nine patients, including four responders, were still on study at the data cutoff in mid-October.
“This ongoing trial continues to show promising clinical activity, including tumor regression and prolonged duration on treatment,” Dr. Msaouel said.
He added that combination sitravatinib and nivolumab has “an acceptable side effect profile, with manageable adverse events.”
Common treatment-related adverse events, in all 33 patients, were fatigue (58%), diarrhea (48%), decreased appetite (33%), dysphonia (33%), nausea (33%), and alanine aminotransferase increase (21%).
Grade 3 treatment-related adverse events included fatigue (12%), hypertension (12%), diarrhea (9%), lipase increase (9%), decreased appetite (3%), and palmar-plantar erythrodysesthesia syndrome (3%). There were no grade 4 or 5 treatment-related events.
Mirati Therapeutics sponsored the trial. Dr. Msaouel disclosed relationships with Mirati, Bristol-Myers Squibb, Exelixis, Pfizer, and Takeda.
SOURCE: Msaouel P et al. SITC 2019. Abstract O23.
NATIONAL HARBOR, MD. – Sitravatinib may “restore or enhance” the activity of anti-PD-1 therapy in patients with checkpoint inhibitor–refractory urothelial carcinoma, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.
Clinical activity was observed with combination sitravatinib and nivolumab in patients with urothelial carcinoma who had disease progression on or after an immune checkpoint inhibitor and were previously treated with platinum-based chemotherapy.
“Up until a few years ago, the only therapies we had [for urothelial carcinoma] were cytotoxic, platinum-based chemotherapies,” said Pavlos Msaouel, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston.
“Thankfully, since 2016, immune checkpoint therapy has become part of our toolbox. But even with single-agent, approved immune checkpoint therapies, anti-PD-1/anti-PD-L1, the response rates are still low, around 20%, and durable responses are only seen in a subset of patients. So we have to do better, if possible, potentially by combining immune checkpoint therapies with other immunotherapies such as sitravatinib.”
Dr. Msaouel explained that sitravatinib inhibits a spectrum of related receptor tyrosine kinases, including TAM family receptors (TYRO3, Axl, and Mer), split family receptors (VEGFR2/PDGFR and c-KIT), and c-Met. Researchers are investigating sitravatinib in combination with nivolumab in a phase 2 trial of patients with urothelial carcinoma (NCT03606174). Dr. Msaouel presented results from one cohort on this trial – 33 patients who had previously received platinum-based chemotherapy and a PD-1/PD-L1 inhibitor.
At baseline, the patients’ median age was 68 years (range, 47-83 years), and 70% were male. Patients had metastatic (n = 30) or locally advanced (n = 3) disease. They had received a median of two (range, one to four) prior systemic therapies.
For this study, patients received oral sitravatinib at 120 mg daily and intravenous nivolumab at 240 mg every 2 weeks or 480 mg every 4 weeks on continuous 28-day cycles. Tumor assessments were performed every 8 weeks.
Results
Of the 22 patients evaluable for efficacy, 1 patient achieved a complete response, 5 had a partial response, 15 had stable disease, and 1 progressed. Eight patients had tumor regression greater than 30%.
Treatment duration exceeded 26 weeks in six patients. Nine patients, including four responders, were still on study at the data cutoff in mid-October.
“This ongoing trial continues to show promising clinical activity, including tumor regression and prolonged duration on treatment,” Dr. Msaouel said.
He added that combination sitravatinib and nivolumab has “an acceptable side effect profile, with manageable adverse events.”
Common treatment-related adverse events, in all 33 patients, were fatigue (58%), diarrhea (48%), decreased appetite (33%), dysphonia (33%), nausea (33%), and alanine aminotransferase increase (21%).
Grade 3 treatment-related adverse events included fatigue (12%), hypertension (12%), diarrhea (9%), lipase increase (9%), decreased appetite (3%), and palmar-plantar erythrodysesthesia syndrome (3%). There were no grade 4 or 5 treatment-related events.
Mirati Therapeutics sponsored the trial. Dr. Msaouel disclosed relationships with Mirati, Bristol-Myers Squibb, Exelixis, Pfizer, and Takeda.
SOURCE: Msaouel P et al. SITC 2019. Abstract O23.
REPORTING FROM SITC 2019
Short-course DAA therapy may prevent hepatitis transmission in transplant patients
BOSTON – A short course of results of a recent study show.
The regimen, given right before transplantation and for 7 days afterward, reduced the cost of direct-acting antiviral (DAA) therapy and allowed patients to complete hepatitis C virus (HCV) therapy before hospital discharge, according to authors of the study, which was presented at the annual meeting of the American Association for the Study of Liver Diseases.
If confirmed in subsequent studies, this regimen could become the standard of care for donor-positive, recipient-negative transplantation, said lead study author Jordan J. Feld, MD, R. Phelan Chair in translational liver disease research at the University of Toronto and research director at the Toronto Centre for Liver Disease.
“Transplant recipients are understandably nervous about accepting organs from people with HCV infection,” said Dr. Feld in a press release. “This very short therapy allows them to leave hospital free of HCV, which is a huge benefit. Not only is it cheaper and likely safer, but the patients really prefer not having to worry about HCV with all of the other challenges after a transplant.”
Results of this study come at a time when the proportion of overdose death organ donors is on the rise, from just 1% in 2000 to 15% in 2016, according to Dr. Feld. Overdose deaths account for the largest percentage of HCV-infected donors, most of whom are young and often otherwise healthy, he added.
Recipients of HCV-infected organs can be cured after transplant as a number of studies have previously shown. However, preventing transmission would be better than cure, Dr. Feld said, in part because of issues with drug-drug interactions, potential for relapse, and issues with procuring the drugs after transplant.
Accordingly, Dr. Feld and colleagues sought to evaluate “preemptive” treatment with DAA therapy combined with ezetimibe, which they said has been shown to inhibit HCV entry blockers. The recipients, who were listed for heart, lung, kidney, or kidney-pancreas transplant, were given glecaprevir/pibrentasvir plus ezetimibe starting 6-12 hours prior to transplantation, and then daily for 7 days.
The median age was 36 years for the 16 donors reported, and 61 years for the 25 recipients. Most recipients (12 patients) had a lung transplant, while 8 had a heart transplant, 4 had a kidney transplant, and 1 had a kidney-pancreas transplant.
There were no virologic failures, according to the investigators, with sustained virologic response (SVR) after 6 weeks in 7 patients, and SVR after 12 weeks in the remaining 18. Three recipients did have detectable HCV RNA, though all cleared and had SVR at 6 weeks in one case, and SVR at 12 weeks in the other two, according to the investigators’ report.
Of 22 serious adverse events noted in the study, 1 was considered treatment related, according to the report, and there were 2 deaths among lung transplant patients, caused by sepsis in 1 case to sepsis and subarachnoid hemorrhage in another.
It’s not clear whether ezetimibe is needed in this short-duration regimen, but in any case, it is well tolerated and inexpensive, and so there is “minimal downside” to include it, Dr. Feld and coinvestigators wrote in their report.
Dr. Feld reported disclosures related to Abbvie, Abbott, Enanta Pharmaceuticals, Gilead, Janssen, Merck, and Roche.
SOURCE: Feld JJ et al. The Liver Meeting 2019, Abstract 38.
BOSTON – A short course of results of a recent study show.
The regimen, given right before transplantation and for 7 days afterward, reduced the cost of direct-acting antiviral (DAA) therapy and allowed patients to complete hepatitis C virus (HCV) therapy before hospital discharge, according to authors of the study, which was presented at the annual meeting of the American Association for the Study of Liver Diseases.
If confirmed in subsequent studies, this regimen could become the standard of care for donor-positive, recipient-negative transplantation, said lead study author Jordan J. Feld, MD, R. Phelan Chair in translational liver disease research at the University of Toronto and research director at the Toronto Centre for Liver Disease.
“Transplant recipients are understandably nervous about accepting organs from people with HCV infection,” said Dr. Feld in a press release. “This very short therapy allows them to leave hospital free of HCV, which is a huge benefit. Not only is it cheaper and likely safer, but the patients really prefer not having to worry about HCV with all of the other challenges after a transplant.”
Results of this study come at a time when the proportion of overdose death organ donors is on the rise, from just 1% in 2000 to 15% in 2016, according to Dr. Feld. Overdose deaths account for the largest percentage of HCV-infected donors, most of whom are young and often otherwise healthy, he added.
Recipients of HCV-infected organs can be cured after transplant as a number of studies have previously shown. However, preventing transmission would be better than cure, Dr. Feld said, in part because of issues with drug-drug interactions, potential for relapse, and issues with procuring the drugs after transplant.
Accordingly, Dr. Feld and colleagues sought to evaluate “preemptive” treatment with DAA therapy combined with ezetimibe, which they said has been shown to inhibit HCV entry blockers. The recipients, who were listed for heart, lung, kidney, or kidney-pancreas transplant, were given glecaprevir/pibrentasvir plus ezetimibe starting 6-12 hours prior to transplantation, and then daily for 7 days.
The median age was 36 years for the 16 donors reported, and 61 years for the 25 recipients. Most recipients (12 patients) had a lung transplant, while 8 had a heart transplant, 4 had a kidney transplant, and 1 had a kidney-pancreas transplant.
There were no virologic failures, according to the investigators, with sustained virologic response (SVR) after 6 weeks in 7 patients, and SVR after 12 weeks in the remaining 18. Three recipients did have detectable HCV RNA, though all cleared and had SVR at 6 weeks in one case, and SVR at 12 weeks in the other two, according to the investigators’ report.
Of 22 serious adverse events noted in the study, 1 was considered treatment related, according to the report, and there were 2 deaths among lung transplant patients, caused by sepsis in 1 case to sepsis and subarachnoid hemorrhage in another.
It’s not clear whether ezetimibe is needed in this short-duration regimen, but in any case, it is well tolerated and inexpensive, and so there is “minimal downside” to include it, Dr. Feld and coinvestigators wrote in their report.
Dr. Feld reported disclosures related to Abbvie, Abbott, Enanta Pharmaceuticals, Gilead, Janssen, Merck, and Roche.
SOURCE: Feld JJ et al. The Liver Meeting 2019, Abstract 38.
BOSTON – A short course of results of a recent study show.
The regimen, given right before transplantation and for 7 days afterward, reduced the cost of direct-acting antiviral (DAA) therapy and allowed patients to complete hepatitis C virus (HCV) therapy before hospital discharge, according to authors of the study, which was presented at the annual meeting of the American Association for the Study of Liver Diseases.
If confirmed in subsequent studies, this regimen could become the standard of care for donor-positive, recipient-negative transplantation, said lead study author Jordan J. Feld, MD, R. Phelan Chair in translational liver disease research at the University of Toronto and research director at the Toronto Centre for Liver Disease.
“Transplant recipients are understandably nervous about accepting organs from people with HCV infection,” said Dr. Feld in a press release. “This very short therapy allows them to leave hospital free of HCV, which is a huge benefit. Not only is it cheaper and likely safer, but the patients really prefer not having to worry about HCV with all of the other challenges after a transplant.”
Results of this study come at a time when the proportion of overdose death organ donors is on the rise, from just 1% in 2000 to 15% in 2016, according to Dr. Feld. Overdose deaths account for the largest percentage of HCV-infected donors, most of whom are young and often otherwise healthy, he added.
Recipients of HCV-infected organs can be cured after transplant as a number of studies have previously shown. However, preventing transmission would be better than cure, Dr. Feld said, in part because of issues with drug-drug interactions, potential for relapse, and issues with procuring the drugs after transplant.
Accordingly, Dr. Feld and colleagues sought to evaluate “preemptive” treatment with DAA therapy combined with ezetimibe, which they said has been shown to inhibit HCV entry blockers. The recipients, who were listed for heart, lung, kidney, or kidney-pancreas transplant, were given glecaprevir/pibrentasvir plus ezetimibe starting 6-12 hours prior to transplantation, and then daily for 7 days.
The median age was 36 years for the 16 donors reported, and 61 years for the 25 recipients. Most recipients (12 patients) had a lung transplant, while 8 had a heart transplant, 4 had a kidney transplant, and 1 had a kidney-pancreas transplant.
There were no virologic failures, according to the investigators, with sustained virologic response (SVR) after 6 weeks in 7 patients, and SVR after 12 weeks in the remaining 18. Three recipients did have detectable HCV RNA, though all cleared and had SVR at 6 weeks in one case, and SVR at 12 weeks in the other two, according to the investigators’ report.
Of 22 serious adverse events noted in the study, 1 was considered treatment related, according to the report, and there were 2 deaths among lung transplant patients, caused by sepsis in 1 case to sepsis and subarachnoid hemorrhage in another.
It’s not clear whether ezetimibe is needed in this short-duration regimen, but in any case, it is well tolerated and inexpensive, and so there is “minimal downside” to include it, Dr. Feld and coinvestigators wrote in their report.
Dr. Feld reported disclosures related to Abbvie, Abbott, Enanta Pharmaceuticals, Gilead, Janssen, Merck, and Roche.
SOURCE: Feld JJ et al. The Liver Meeting 2019, Abstract 38.
REPORTING FROM THE LIVER MEETING 2019
Expert shares tips for TNF-alpha inhibitor use in special populations
LAS VEGAS – Francisco A. Kerdel, BSc, MBBS, said at the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar.
Dr. Kerdel, professor and vice chair of the department of dermatology at Florida International University, Miami, noted that, while tumor necrosis factor (TNF)–alpha inhibitors are category B drugs, inadequate data exist regarding lactation and exposure throughout pregnancy. “Rates of malformations and spontaneous abortions with therapy are similar to those in the general population, higher concentrations of infliximab and adalimumab have been found in infant and cord blood, compared with certolizumab pegol,” an anti-TNF biologic, he said.
In a prospective, postmarketing, multicenter pharmacokinetic study, researchers found a lack of placental transfer of certolizumab pegol during pregnancy (Ann Rheum Dis. 2018;77:228-33). Specifically, certolizumab levels were below the lower limit of quantification (less than 0.032 mcg/mL) in 13 of 14 infant samples at birth and in all infant samples at weeks 4 and 8. Only one infant had a minimal certolizumab level at birth (infant/mother ratio of 0.0009). No antibodies were detected at any time point during the study. Safety data in mothers were in line with the known safety profile of certolizumab and pregnancy profile of these underlying diseases. Adverse events experienced by the infants did not show any patterns or clusters of events suggesting a specific safety signal in children.
In a separate postmarketing pharmacokinetic study, investigators evaluated the transfer of certolizumab into breast milk (Ann Rheum Dis. 2017;76:1890-6). They found that the average daily infant dose of certolizumab was minimal. Specifically, the highest concentration of certolizumab in breast milk (0.0758 mcg/mL) was less than 1% of the expected mean plasma trough concentration of a therapeutic dose.
How do TNF-alpha inhibitors fare in the pediatric population? In a retrospective study of 390 children with psoriasis treated at 20 centers in the United States, Canada, and Europe, researchers evaluated the safety of systemic agents (JAMA Dermatol. 2017;153[11]:1147-57). Most (69%) were prescribed methotrexate, followed by biologics, acitretin, cyclosporine, and fumaric acid. Drug discontinuation (because of adverse events), which is sometimes used as an efficacy parameter, occurred in 12% of those who were on methotrexate, compared with 3% of those on biologics, 67% of those on acitretin, and 68% of those on fumaric acid.
At the other end of the age spectrum, biologic therapy is generally effective and well tolerated in elderly patients. “Sometimes, they may be more effective than other traditional drugs,” Dr. Kerdel said. “We’re a little bit concerned about immunosenescence, which can increase the risk for severe infections and malignancies. And, 90% of elderly patients with psoriasis may have comorbidities that need to be taken into account when treating psoriasis.”
Other factors come into play when choosing the right anti-TNF agent, including weight. While clinical trials show efficacy across weight groups, infliximab has weight-based dosing, “which may make it a better choice,” Dr. Kerdel said. “Patients taking etanercept may need a biweekly dose.”
Treatment flexibility also comes into play. For example, stopping therapy because of an infection or surgery may be problematic in drugs with a long half-life. Then there’s the issue of patient preference. “Some people don’t want to be injected frequently,” he said. “Some people don’t want to be injected at all and may require a simpler dosing regimen.”
Optimizing anti-TNF-alpha treatment starts with recognizing that there is a loss of response over time, Dr. Kerdel said, “or there may not be a response at all.” Contributing factors may include immunogenicity, suboptimal dosing, and poor patient adherence. In order to optimize treatment, clinicians can try switching agents or combination therapy, and explore continuous versus intermittent dosing.
“We really don’t have good data on the best protocol for switching treatment after failure of an anti-TNF-alpha agent,” he added. In cases of primary and secondary treatment failure, there is no consensus or guidelines on which second-line agent to use, nor good data on which measures to use.
No evidence-based guidelines are available for screening and monitoring patients receiving biologic therapy for psoriasis, either. “Evidence is strongest [grade B] for tuberculosis screening in patients treated with biologic agents,” Dr. Kerdel said. “Among known hepatitis B virus carriers, consider monitoring liver function tests and viral load [grade C]. High-grade evidence is lacking to support other routine testing. Physicians should use clinical judgment when screening and monitoring patients.”
He concluded his presentation by noting that there are a number of biosimilar agents available or in the pipeline for infliximab, adalimumab, and etanercept. This raises a number of questions for current and future consideration. For one, “will biosimilars show the same long-term efficacy and safety as the innovator products?” he asked. “Real-world, postmarketing, and registry data are needed. Will biosimilar agents offer significant cost benefits? Will biosimilar labeling be adequately transparent? Will we find biomarkers to help us target biologic agents to specific patients and subtypes of psoriasis?”
Dr. Kerdel reported that he is a member of the speaker’s bureau for AbbVie, Amgen, Celgene, Janssen, Novartis, Lilly, Leo, Ortho, and Novartis. He has also received grant/research support from AbbVie, Amgen, AstraZeneca, Celgene, Janssen, Leo, Lilly, Menlo Therapeutics, Novartis, Pfizer, and XBiotech.
SDEF and this news organization are owned by the same parent company.
LAS VEGAS – Francisco A. Kerdel, BSc, MBBS, said at the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar.
Dr. Kerdel, professor and vice chair of the department of dermatology at Florida International University, Miami, noted that, while tumor necrosis factor (TNF)–alpha inhibitors are category B drugs, inadequate data exist regarding lactation and exposure throughout pregnancy. “Rates of malformations and spontaneous abortions with therapy are similar to those in the general population, higher concentrations of infliximab and adalimumab have been found in infant and cord blood, compared with certolizumab pegol,” an anti-TNF biologic, he said.
In a prospective, postmarketing, multicenter pharmacokinetic study, researchers found a lack of placental transfer of certolizumab pegol during pregnancy (Ann Rheum Dis. 2018;77:228-33). Specifically, certolizumab levels were below the lower limit of quantification (less than 0.032 mcg/mL) in 13 of 14 infant samples at birth and in all infant samples at weeks 4 and 8. Only one infant had a minimal certolizumab level at birth (infant/mother ratio of 0.0009). No antibodies were detected at any time point during the study. Safety data in mothers were in line with the known safety profile of certolizumab and pregnancy profile of these underlying diseases. Adverse events experienced by the infants did not show any patterns or clusters of events suggesting a specific safety signal in children.
In a separate postmarketing pharmacokinetic study, investigators evaluated the transfer of certolizumab into breast milk (Ann Rheum Dis. 2017;76:1890-6). They found that the average daily infant dose of certolizumab was minimal. Specifically, the highest concentration of certolizumab in breast milk (0.0758 mcg/mL) was less than 1% of the expected mean plasma trough concentration of a therapeutic dose.
How do TNF-alpha inhibitors fare in the pediatric population? In a retrospective study of 390 children with psoriasis treated at 20 centers in the United States, Canada, and Europe, researchers evaluated the safety of systemic agents (JAMA Dermatol. 2017;153[11]:1147-57). Most (69%) were prescribed methotrexate, followed by biologics, acitretin, cyclosporine, and fumaric acid. Drug discontinuation (because of adverse events), which is sometimes used as an efficacy parameter, occurred in 12% of those who were on methotrexate, compared with 3% of those on biologics, 67% of those on acitretin, and 68% of those on fumaric acid.
At the other end of the age spectrum, biologic therapy is generally effective and well tolerated in elderly patients. “Sometimes, they may be more effective than other traditional drugs,” Dr. Kerdel said. “We’re a little bit concerned about immunosenescence, which can increase the risk for severe infections and malignancies. And, 90% of elderly patients with psoriasis may have comorbidities that need to be taken into account when treating psoriasis.”
Other factors come into play when choosing the right anti-TNF agent, including weight. While clinical trials show efficacy across weight groups, infliximab has weight-based dosing, “which may make it a better choice,” Dr. Kerdel said. “Patients taking etanercept may need a biweekly dose.”
Treatment flexibility also comes into play. For example, stopping therapy because of an infection or surgery may be problematic in drugs with a long half-life. Then there’s the issue of patient preference. “Some people don’t want to be injected frequently,” he said. “Some people don’t want to be injected at all and may require a simpler dosing regimen.”
Optimizing anti-TNF-alpha treatment starts with recognizing that there is a loss of response over time, Dr. Kerdel said, “or there may not be a response at all.” Contributing factors may include immunogenicity, suboptimal dosing, and poor patient adherence. In order to optimize treatment, clinicians can try switching agents or combination therapy, and explore continuous versus intermittent dosing.
“We really don’t have good data on the best protocol for switching treatment after failure of an anti-TNF-alpha agent,” he added. In cases of primary and secondary treatment failure, there is no consensus or guidelines on which second-line agent to use, nor good data on which measures to use.
No evidence-based guidelines are available for screening and monitoring patients receiving biologic therapy for psoriasis, either. “Evidence is strongest [grade B] for tuberculosis screening in patients treated with biologic agents,” Dr. Kerdel said. “Among known hepatitis B virus carriers, consider monitoring liver function tests and viral load [grade C]. High-grade evidence is lacking to support other routine testing. Physicians should use clinical judgment when screening and monitoring patients.”
He concluded his presentation by noting that there are a number of biosimilar agents available or in the pipeline for infliximab, adalimumab, and etanercept. This raises a number of questions for current and future consideration. For one, “will biosimilars show the same long-term efficacy and safety as the innovator products?” he asked. “Real-world, postmarketing, and registry data are needed. Will biosimilar agents offer significant cost benefits? Will biosimilar labeling be adequately transparent? Will we find biomarkers to help us target biologic agents to specific patients and subtypes of psoriasis?”
Dr. Kerdel reported that he is a member of the speaker’s bureau for AbbVie, Amgen, Celgene, Janssen, Novartis, Lilly, Leo, Ortho, and Novartis. He has also received grant/research support from AbbVie, Amgen, AstraZeneca, Celgene, Janssen, Leo, Lilly, Menlo Therapeutics, Novartis, Pfizer, and XBiotech.
SDEF and this news organization are owned by the same parent company.
LAS VEGAS – Francisco A. Kerdel, BSc, MBBS, said at the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar.
Dr. Kerdel, professor and vice chair of the department of dermatology at Florida International University, Miami, noted that, while tumor necrosis factor (TNF)–alpha inhibitors are category B drugs, inadequate data exist regarding lactation and exposure throughout pregnancy. “Rates of malformations and spontaneous abortions with therapy are similar to those in the general population, higher concentrations of infliximab and adalimumab have been found in infant and cord blood, compared with certolizumab pegol,” an anti-TNF biologic, he said.
In a prospective, postmarketing, multicenter pharmacokinetic study, researchers found a lack of placental transfer of certolizumab pegol during pregnancy (Ann Rheum Dis. 2018;77:228-33). Specifically, certolizumab levels were below the lower limit of quantification (less than 0.032 mcg/mL) in 13 of 14 infant samples at birth and in all infant samples at weeks 4 and 8. Only one infant had a minimal certolizumab level at birth (infant/mother ratio of 0.0009). No antibodies were detected at any time point during the study. Safety data in mothers were in line with the known safety profile of certolizumab and pregnancy profile of these underlying diseases. Adverse events experienced by the infants did not show any patterns or clusters of events suggesting a specific safety signal in children.
In a separate postmarketing pharmacokinetic study, investigators evaluated the transfer of certolizumab into breast milk (Ann Rheum Dis. 2017;76:1890-6). They found that the average daily infant dose of certolizumab was minimal. Specifically, the highest concentration of certolizumab in breast milk (0.0758 mcg/mL) was less than 1% of the expected mean plasma trough concentration of a therapeutic dose.
How do TNF-alpha inhibitors fare in the pediatric population? In a retrospective study of 390 children with psoriasis treated at 20 centers in the United States, Canada, and Europe, researchers evaluated the safety of systemic agents (JAMA Dermatol. 2017;153[11]:1147-57). Most (69%) were prescribed methotrexate, followed by biologics, acitretin, cyclosporine, and fumaric acid. Drug discontinuation (because of adverse events), which is sometimes used as an efficacy parameter, occurred in 12% of those who were on methotrexate, compared with 3% of those on biologics, 67% of those on acitretin, and 68% of those on fumaric acid.
At the other end of the age spectrum, biologic therapy is generally effective and well tolerated in elderly patients. “Sometimes, they may be more effective than other traditional drugs,” Dr. Kerdel said. “We’re a little bit concerned about immunosenescence, which can increase the risk for severe infections and malignancies. And, 90% of elderly patients with psoriasis may have comorbidities that need to be taken into account when treating psoriasis.”
Other factors come into play when choosing the right anti-TNF agent, including weight. While clinical trials show efficacy across weight groups, infliximab has weight-based dosing, “which may make it a better choice,” Dr. Kerdel said. “Patients taking etanercept may need a biweekly dose.”
Treatment flexibility also comes into play. For example, stopping therapy because of an infection or surgery may be problematic in drugs with a long half-life. Then there’s the issue of patient preference. “Some people don’t want to be injected frequently,” he said. “Some people don’t want to be injected at all and may require a simpler dosing regimen.”
Optimizing anti-TNF-alpha treatment starts with recognizing that there is a loss of response over time, Dr. Kerdel said, “or there may not be a response at all.” Contributing factors may include immunogenicity, suboptimal dosing, and poor patient adherence. In order to optimize treatment, clinicians can try switching agents or combination therapy, and explore continuous versus intermittent dosing.
“We really don’t have good data on the best protocol for switching treatment after failure of an anti-TNF-alpha agent,” he added. In cases of primary and secondary treatment failure, there is no consensus or guidelines on which second-line agent to use, nor good data on which measures to use.
No evidence-based guidelines are available for screening and monitoring patients receiving biologic therapy for psoriasis, either. “Evidence is strongest [grade B] for tuberculosis screening in patients treated with biologic agents,” Dr. Kerdel said. “Among known hepatitis B virus carriers, consider monitoring liver function tests and viral load [grade C]. High-grade evidence is lacking to support other routine testing. Physicians should use clinical judgment when screening and monitoring patients.”
He concluded his presentation by noting that there are a number of biosimilar agents available or in the pipeline for infliximab, adalimumab, and etanercept. This raises a number of questions for current and future consideration. For one, “will biosimilars show the same long-term efficacy and safety as the innovator products?” he asked. “Real-world, postmarketing, and registry data are needed. Will biosimilar agents offer significant cost benefits? Will biosimilar labeling be adequately transparent? Will we find biomarkers to help us target biologic agents to specific patients and subtypes of psoriasis?”
Dr. Kerdel reported that he is a member of the speaker’s bureau for AbbVie, Amgen, Celgene, Janssen, Novartis, Lilly, Leo, Ortho, and Novartis. He has also received grant/research support from AbbVie, Amgen, AstraZeneca, Celgene, Janssen, Leo, Lilly, Menlo Therapeutics, Novartis, Pfizer, and XBiotech.
SDEF and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM THE SDEF LAS VEGAS DERMATOLOGY SEMINAR
Cancer pain management inadequate in opioid-saturated areas
Patients with cancer who live in regions with high levels of opioid misuse may be undertreated for pain, according to investigators who studied opioid prescription patterns and cancer incidence in rural southwest Virginia.
Among 4,324 patients with cancer, only 22.16% were prescribed a Controlled Schedule II (C-II) prescription opioid medication at least 3 times in 1 year, from prescribers likely to be treating cancer pain. More than 60% of patients never received a C-II opioid prescription, reported Virginia T. LeBaron, PhD, of the University of Virginia School of Nursing in Charlottesville, and colleagues.
“A clearer view of geographic patterns and predictors of both POM [prescription opioid medication] prescribing and potential harms can inform targeted interventions and policy initiatives that achieve a balanced approach to POMs – ensuring access for patients in need while reducing risk to both patients and communities. Our research makes an important contribution by exploring how the current ‘opioid epidemic’ relates to rural patients with cancer,” they wrote. Their report is in Journal of Oncology Practice.
The investigators studied the confluence of disproportionately high cancer mortality rates and opioid fatality rates in rural southwest Virginia, in the heart of Appalachia.
They conducted a longitudinal, exploratory secondary analysis of data from the Commonwealth of Virginia All Payer Claims database to look at opioid prescribing patterns and explore whether concerns about opioid misuse could result in undertreatment of pain in cancer patients.
They looked at prescribing patterns at the patient, provider, and insurance claim levels, predictors of opioid prescription frequency, opioid-related harms and patterns related to opioid prescribing, cancer incidence, and fatalities.
They identified 4,324 patients with cancer, 958 of whom (22.16%) received a C-II opioid at least three times in any study year. The majority of patients were in the 45-64 age range, and approximately 88% were diagnosed with solid malignancies, with breast cancer and lung cancer being the most frequent diagnoses.
As noted, more than 60% of patients never received a C-II prescription.
“The large percentages of cancer patients never prescribed a C-II are concerning for a number of reasons, especially when we consider the results per year,” the investigators wrote. “First, the ‘no C-II’ patients remain over 80% of the total sample, each year, even after accounting for the upscheduling (from C-III to C-II) of commonly-prescribed hydrocodone products in 2014. Second, anecdotal data and emerging empirical evidence demonstrate that patients with legitimate pain needs, including patients with cancer, experience significant difficulty accessing POMs.”
They noted that regulations regarding opioid prescriptions have become increasingly strict since the end date of their analysis in 2015, suggesting that the number of patients with cancer who are not receiving C-II opioids today may be even higher.
They also pointed to evidence of prescription practices suggesting suboptimal pain management or potential patient harm, such as frequent prescription of opioid-acetaminophen combinations that are dose-limited due to acetaminophen toxicity; coprescription of opioids and benzodiazepines, which is not recommended under current prescribing guidelines; and infrequent use of deterrent formulations of C-II opioids such as crush-resistant tablets.
The study was supported by the University of Virginia Cancer Center, Cancer Control & Population Health Division and the Virginia Tobacco Region Revitalization Commission. The authors reported having no disclaimers or conflicts of interest.
SOURCE: LeBaron VT et al. J Oncol Pract. 2019 Nov. 4. doi: 10.1200/JOP.19.00149.
Patients with cancer who live in regions with high levels of opioid misuse may be undertreated for pain, according to investigators who studied opioid prescription patterns and cancer incidence in rural southwest Virginia.
Among 4,324 patients with cancer, only 22.16% were prescribed a Controlled Schedule II (C-II) prescription opioid medication at least 3 times in 1 year, from prescribers likely to be treating cancer pain. More than 60% of patients never received a C-II opioid prescription, reported Virginia T. LeBaron, PhD, of the University of Virginia School of Nursing in Charlottesville, and colleagues.
“A clearer view of geographic patterns and predictors of both POM [prescription opioid medication] prescribing and potential harms can inform targeted interventions and policy initiatives that achieve a balanced approach to POMs – ensuring access for patients in need while reducing risk to both patients and communities. Our research makes an important contribution by exploring how the current ‘opioid epidemic’ relates to rural patients with cancer,” they wrote. Their report is in Journal of Oncology Practice.
The investigators studied the confluence of disproportionately high cancer mortality rates and opioid fatality rates in rural southwest Virginia, in the heart of Appalachia.
They conducted a longitudinal, exploratory secondary analysis of data from the Commonwealth of Virginia All Payer Claims database to look at opioid prescribing patterns and explore whether concerns about opioid misuse could result in undertreatment of pain in cancer patients.
They looked at prescribing patterns at the patient, provider, and insurance claim levels, predictors of opioid prescription frequency, opioid-related harms and patterns related to opioid prescribing, cancer incidence, and fatalities.
They identified 4,324 patients with cancer, 958 of whom (22.16%) received a C-II opioid at least three times in any study year. The majority of patients were in the 45-64 age range, and approximately 88% were diagnosed with solid malignancies, with breast cancer and lung cancer being the most frequent diagnoses.
As noted, more than 60% of patients never received a C-II prescription.
“The large percentages of cancer patients never prescribed a C-II are concerning for a number of reasons, especially when we consider the results per year,” the investigators wrote. “First, the ‘no C-II’ patients remain over 80% of the total sample, each year, even after accounting for the upscheduling (from C-III to C-II) of commonly-prescribed hydrocodone products in 2014. Second, anecdotal data and emerging empirical evidence demonstrate that patients with legitimate pain needs, including patients with cancer, experience significant difficulty accessing POMs.”
They noted that regulations regarding opioid prescriptions have become increasingly strict since the end date of their analysis in 2015, suggesting that the number of patients with cancer who are not receiving C-II opioids today may be even higher.
They also pointed to evidence of prescription practices suggesting suboptimal pain management or potential patient harm, such as frequent prescription of opioid-acetaminophen combinations that are dose-limited due to acetaminophen toxicity; coprescription of opioids and benzodiazepines, which is not recommended under current prescribing guidelines; and infrequent use of deterrent formulations of C-II opioids such as crush-resistant tablets.
The study was supported by the University of Virginia Cancer Center, Cancer Control & Population Health Division and the Virginia Tobacco Region Revitalization Commission. The authors reported having no disclaimers or conflicts of interest.
SOURCE: LeBaron VT et al. J Oncol Pract. 2019 Nov. 4. doi: 10.1200/JOP.19.00149.
Patients with cancer who live in regions with high levels of opioid misuse may be undertreated for pain, according to investigators who studied opioid prescription patterns and cancer incidence in rural southwest Virginia.
Among 4,324 patients with cancer, only 22.16% were prescribed a Controlled Schedule II (C-II) prescription opioid medication at least 3 times in 1 year, from prescribers likely to be treating cancer pain. More than 60% of patients never received a C-II opioid prescription, reported Virginia T. LeBaron, PhD, of the University of Virginia School of Nursing in Charlottesville, and colleagues.
“A clearer view of geographic patterns and predictors of both POM [prescription opioid medication] prescribing and potential harms can inform targeted interventions and policy initiatives that achieve a balanced approach to POMs – ensuring access for patients in need while reducing risk to both patients and communities. Our research makes an important contribution by exploring how the current ‘opioid epidemic’ relates to rural patients with cancer,” they wrote. Their report is in Journal of Oncology Practice.
The investigators studied the confluence of disproportionately high cancer mortality rates and opioid fatality rates in rural southwest Virginia, in the heart of Appalachia.
They conducted a longitudinal, exploratory secondary analysis of data from the Commonwealth of Virginia All Payer Claims database to look at opioid prescribing patterns and explore whether concerns about opioid misuse could result in undertreatment of pain in cancer patients.
They looked at prescribing patterns at the patient, provider, and insurance claim levels, predictors of opioid prescription frequency, opioid-related harms and patterns related to opioid prescribing, cancer incidence, and fatalities.
They identified 4,324 patients with cancer, 958 of whom (22.16%) received a C-II opioid at least three times in any study year. The majority of patients were in the 45-64 age range, and approximately 88% were diagnosed with solid malignancies, with breast cancer and lung cancer being the most frequent diagnoses.
As noted, more than 60% of patients never received a C-II prescription.
“The large percentages of cancer patients never prescribed a C-II are concerning for a number of reasons, especially when we consider the results per year,” the investigators wrote. “First, the ‘no C-II’ patients remain over 80% of the total sample, each year, even after accounting for the upscheduling (from C-III to C-II) of commonly-prescribed hydrocodone products in 2014. Second, anecdotal data and emerging empirical evidence demonstrate that patients with legitimate pain needs, including patients with cancer, experience significant difficulty accessing POMs.”
They noted that regulations regarding opioid prescriptions have become increasingly strict since the end date of their analysis in 2015, suggesting that the number of patients with cancer who are not receiving C-II opioids today may be even higher.
They also pointed to evidence of prescription practices suggesting suboptimal pain management or potential patient harm, such as frequent prescription of opioid-acetaminophen combinations that are dose-limited due to acetaminophen toxicity; coprescription of opioids and benzodiazepines, which is not recommended under current prescribing guidelines; and infrequent use of deterrent formulations of C-II opioids such as crush-resistant tablets.
The study was supported by the University of Virginia Cancer Center, Cancer Control & Population Health Division and the Virginia Tobacco Region Revitalization Commission. The authors reported having no disclaimers or conflicts of interest.
SOURCE: LeBaron VT et al. J Oncol Pract. 2019 Nov. 4. doi: 10.1200/JOP.19.00149.
FROM JOURNAL OF ONCOLOGY PRACTICE
Glecaprevir/pibrentasvir highly effective in HCV genotype 3, among others
BOSTON – Specifically in patients with hepatitis C virus (HCV) genotype 3 infection and compensated cirrhosis, glecaprevir/pibrentasvir (Mavyret) was safe and had high efficacy in a phase 3 clinical trial, echoing an earlier report describing clinical results for the fixed-dose combination in multiple other genotypes.
Treatment with glecaprevir/pibrentasvir was safe and produced high rates of sustained virologic response 12 weeks after treatment (SVR12) for the genotype 3 patients and compensated cirrhosis in the recent results from the EXPEDITION-8 study, which will be presented at the annual meeting of the American Association for the Study of Liver Diseases.
In a previous report from EXPEDITION-8, investigators said that the treatment was well tolerated and effective in patients with HCV genotypes 1, 2, 4, 5, and 6.
“The availability of an 8-week, pangenotypic regimen for all treatment-naive HCV-infected patients regardless of cirrhosis status may simplify the HCV care pathway, furthering progress towards HCV elimination,” said investigator Robert S. Brown Jr., MD, MPH, and coinvestigators in a late-breaking abstract of the latest study results.
The nonrandomized, multicenter, phase 3b study included 343 adults with HCV genotypes 1-6 who received glecaprevir 300 mg and pibrentasvir 120 mg once daily for 8 weeks. A total of 63% of patients were male, 83% were white; 18% had HCV genotype 3, while the majority (67%) had HCV genotype 1.
For the genotype 3 patients, SVR12 rates were 95.2% in the intention-to-treat population, and 98.4% in the per-protocol population, Dr. Brown and coauthors said in their report on the study. For genotype 1, 2, 4, 5, and 6 patients, the intention-to-treat and per-protocol SVR12 rates were 98.2% and 100%.
Taken together, the SVR12 rates for all genotypes were 97.7% and 99.7%, respectively, for the intention-to-treat and per-protocol populations, according to the investigators.
There were no virologic failures on treatment, and one patients with genotype 3 relapsed in week 4 posttreatment, while one genotype 1 patient discontinued treatment though not because of adverse events, they said.
Most adverse events were grade 1 in severity, and included fatigue, pruritus, headache, and nausea. There were no liver-related toxicities, and no serious adverse events that were related to the study treatment, according to the investigators.
Glecaprevir/pibrentasvir is indicated for patients aged 12 years and older with treatment-naive HCV genotype 1-6 infection without cirrhosis or with compensated cirrhosis, and in patients with HCV genotype 1 infection previously treated with an HCV NS5A inhibitor or an NS3/4A protease inhibitor.
Dr. Brown reported disclosures related to pharmaceutical companies including AbbVie, which markets Mavyret.
SOURCE: Brown RS et al. The Liver Meeting 2019. Abstract LP9.
BOSTON – Specifically in patients with hepatitis C virus (HCV) genotype 3 infection and compensated cirrhosis, glecaprevir/pibrentasvir (Mavyret) was safe and had high efficacy in a phase 3 clinical trial, echoing an earlier report describing clinical results for the fixed-dose combination in multiple other genotypes.
Treatment with glecaprevir/pibrentasvir was safe and produced high rates of sustained virologic response 12 weeks after treatment (SVR12) for the genotype 3 patients and compensated cirrhosis in the recent results from the EXPEDITION-8 study, which will be presented at the annual meeting of the American Association for the Study of Liver Diseases.
In a previous report from EXPEDITION-8, investigators said that the treatment was well tolerated and effective in patients with HCV genotypes 1, 2, 4, 5, and 6.
“The availability of an 8-week, pangenotypic regimen for all treatment-naive HCV-infected patients regardless of cirrhosis status may simplify the HCV care pathway, furthering progress towards HCV elimination,” said investigator Robert S. Brown Jr., MD, MPH, and coinvestigators in a late-breaking abstract of the latest study results.
The nonrandomized, multicenter, phase 3b study included 343 adults with HCV genotypes 1-6 who received glecaprevir 300 mg and pibrentasvir 120 mg once daily for 8 weeks. A total of 63% of patients were male, 83% were white; 18% had HCV genotype 3, while the majority (67%) had HCV genotype 1.
For the genotype 3 patients, SVR12 rates were 95.2% in the intention-to-treat population, and 98.4% in the per-protocol population, Dr. Brown and coauthors said in their report on the study. For genotype 1, 2, 4, 5, and 6 patients, the intention-to-treat and per-protocol SVR12 rates were 98.2% and 100%.
Taken together, the SVR12 rates for all genotypes were 97.7% and 99.7%, respectively, for the intention-to-treat and per-protocol populations, according to the investigators.
There were no virologic failures on treatment, and one patients with genotype 3 relapsed in week 4 posttreatment, while one genotype 1 patient discontinued treatment though not because of adverse events, they said.
Most adverse events were grade 1 in severity, and included fatigue, pruritus, headache, and nausea. There were no liver-related toxicities, and no serious adverse events that were related to the study treatment, according to the investigators.
Glecaprevir/pibrentasvir is indicated for patients aged 12 years and older with treatment-naive HCV genotype 1-6 infection without cirrhosis or with compensated cirrhosis, and in patients with HCV genotype 1 infection previously treated with an HCV NS5A inhibitor or an NS3/4A protease inhibitor.
Dr. Brown reported disclosures related to pharmaceutical companies including AbbVie, which markets Mavyret.
SOURCE: Brown RS et al. The Liver Meeting 2019. Abstract LP9.
BOSTON – Specifically in patients with hepatitis C virus (HCV) genotype 3 infection and compensated cirrhosis, glecaprevir/pibrentasvir (Mavyret) was safe and had high efficacy in a phase 3 clinical trial, echoing an earlier report describing clinical results for the fixed-dose combination in multiple other genotypes.
Treatment with glecaprevir/pibrentasvir was safe and produced high rates of sustained virologic response 12 weeks after treatment (SVR12) for the genotype 3 patients and compensated cirrhosis in the recent results from the EXPEDITION-8 study, which will be presented at the annual meeting of the American Association for the Study of Liver Diseases.
In a previous report from EXPEDITION-8, investigators said that the treatment was well tolerated and effective in patients with HCV genotypes 1, 2, 4, 5, and 6.
“The availability of an 8-week, pangenotypic regimen for all treatment-naive HCV-infected patients regardless of cirrhosis status may simplify the HCV care pathway, furthering progress towards HCV elimination,” said investigator Robert S. Brown Jr., MD, MPH, and coinvestigators in a late-breaking abstract of the latest study results.
The nonrandomized, multicenter, phase 3b study included 343 adults with HCV genotypes 1-6 who received glecaprevir 300 mg and pibrentasvir 120 mg once daily for 8 weeks. A total of 63% of patients were male, 83% were white; 18% had HCV genotype 3, while the majority (67%) had HCV genotype 1.
For the genotype 3 patients, SVR12 rates were 95.2% in the intention-to-treat population, and 98.4% in the per-protocol population, Dr. Brown and coauthors said in their report on the study. For genotype 1, 2, 4, 5, and 6 patients, the intention-to-treat and per-protocol SVR12 rates were 98.2% and 100%.
Taken together, the SVR12 rates for all genotypes were 97.7% and 99.7%, respectively, for the intention-to-treat and per-protocol populations, according to the investigators.
There were no virologic failures on treatment, and one patients with genotype 3 relapsed in week 4 posttreatment, while one genotype 1 patient discontinued treatment though not because of adverse events, they said.
Most adverse events were grade 1 in severity, and included fatigue, pruritus, headache, and nausea. There were no liver-related toxicities, and no serious adverse events that were related to the study treatment, according to the investigators.
Glecaprevir/pibrentasvir is indicated for patients aged 12 years and older with treatment-naive HCV genotype 1-6 infection without cirrhosis or with compensated cirrhosis, and in patients with HCV genotype 1 infection previously treated with an HCV NS5A inhibitor or an NS3/4A protease inhibitor.
Dr. Brown reported disclosures related to pharmaceutical companies including AbbVie, which markets Mavyret.
SOURCE: Brown RS et al. The Liver Meeting 2019. Abstract LP9.
REPORTING FROM THE LIVER MEETING 2019
Key clinical point: In patients with hepatitis C virus (HCV) genotype 3 infection and compensated cirrhosis, glecaprevir/pibrentasvir was safe and had high efficacy, echoing an earlier result for the fixed-dose combination in genotypes 1, 2, and 4-6.
Major finding: For the genotype 3 patients, the rate of sustained virologic response 12 weeks after treatment (SVR12) was 95.2% in the intention-to-treat population, and 98.4% in the per-protocol population.
Study details: Further results from EXPEDITION-8, a single-arm phase 3b study including 343 adult patients with HCV genotypes 1-6.
Disclosures: Dr. Brown reported disclosures related to AbbVie, Gilead, Intercept, Dova, Shionogi, Merck, and Bristol-Myers Squibb.
Source: Brown RS et al. The Liver Meeting 2019. Abstract LP9.
Hepatitis C vaccine alters viral trajectory, but fails in chronic infection protection
BOSTON – A prime-boost hepatitis C virus (HCV) vaccine regimen did not protect against chronic infection, but it did evoke immune responses and differences in viral trajectory, according to investigators in what is believed to be the first randomized, placebo-controlled efficacy trial in this setting.
There were no apparent safety concerns with the vaccine according to investigators, led by Kimberly Page, PhD, MPH, of the University of New Mexico, Albuquerque.
“A safe and effective vaccine to prevent chronic hepatitis C virus infection is essential to reduce transmission,” Dr. Page and coauthors said in a late-breaking abstract of the study results, which will be presented at the annual meeting of the American Association for the Study of Liver Diseases.
The phase 1/2 trial described by Dr. Page and colleagues included 455 adults at risk of HCV infection because of injection drug use. They were randomized to vaccine, which consisted of a recombinant chimpanzee adenovirus-3 vectored vaccine prime plus a recombinant Modified Vaccinia virus Ankara boost, or to two doses of placebo at days 0 and 56 of the study.
There was no difference in chronic HCV infection at 6 months, the primary endpoint of the study. There were 14 chronically infected participants in the vaccine group, as well as 14 in the placebo group, for an overall incidence of infection of 13.0/100 person-years, Dr. Page and coauthors reported in the abstract.
However, there were significant differences in HCV RNA geometric mean peak at 1 month, which was 193,795 IU/L in the vaccine group and 1,078,092 IU/L in the placebo group, according to investigators. Similarly, geometric mean fold rise after infection was 0.2 in the vaccine group and 13.5 in the placebo group.
A total of 78% of vaccinated individuals had T-cell responses to at least one vaccine antigen pool, investigators said, adding that the vaccine was safe, well tolerated, and not associated with any serious adverse events.
Dr. Page had no disclosures related to the abstract.
SOURCE: Page K et al. The Liver Meeting 2019. Abstract LP17.
BOSTON – A prime-boost hepatitis C virus (HCV) vaccine regimen did not protect against chronic infection, but it did evoke immune responses and differences in viral trajectory, according to investigators in what is believed to be the first randomized, placebo-controlled efficacy trial in this setting.
There were no apparent safety concerns with the vaccine according to investigators, led by Kimberly Page, PhD, MPH, of the University of New Mexico, Albuquerque.
“A safe and effective vaccine to prevent chronic hepatitis C virus infection is essential to reduce transmission,” Dr. Page and coauthors said in a late-breaking abstract of the study results, which will be presented at the annual meeting of the American Association for the Study of Liver Diseases.
The phase 1/2 trial described by Dr. Page and colleagues included 455 adults at risk of HCV infection because of injection drug use. They were randomized to vaccine, which consisted of a recombinant chimpanzee adenovirus-3 vectored vaccine prime plus a recombinant Modified Vaccinia virus Ankara boost, or to two doses of placebo at days 0 and 56 of the study.
There was no difference in chronic HCV infection at 6 months, the primary endpoint of the study. There were 14 chronically infected participants in the vaccine group, as well as 14 in the placebo group, for an overall incidence of infection of 13.0/100 person-years, Dr. Page and coauthors reported in the abstract.
However, there were significant differences in HCV RNA geometric mean peak at 1 month, which was 193,795 IU/L in the vaccine group and 1,078,092 IU/L in the placebo group, according to investigators. Similarly, geometric mean fold rise after infection was 0.2 in the vaccine group and 13.5 in the placebo group.
A total of 78% of vaccinated individuals had T-cell responses to at least one vaccine antigen pool, investigators said, adding that the vaccine was safe, well tolerated, and not associated with any serious adverse events.
Dr. Page had no disclosures related to the abstract.
SOURCE: Page K et al. The Liver Meeting 2019. Abstract LP17.
BOSTON – A prime-boost hepatitis C virus (HCV) vaccine regimen did not protect against chronic infection, but it did evoke immune responses and differences in viral trajectory, according to investigators in what is believed to be the first randomized, placebo-controlled efficacy trial in this setting.
There were no apparent safety concerns with the vaccine according to investigators, led by Kimberly Page, PhD, MPH, of the University of New Mexico, Albuquerque.
“A safe and effective vaccine to prevent chronic hepatitis C virus infection is essential to reduce transmission,” Dr. Page and coauthors said in a late-breaking abstract of the study results, which will be presented at the annual meeting of the American Association for the Study of Liver Diseases.
The phase 1/2 trial described by Dr. Page and colleagues included 455 adults at risk of HCV infection because of injection drug use. They were randomized to vaccine, which consisted of a recombinant chimpanzee adenovirus-3 vectored vaccine prime plus a recombinant Modified Vaccinia virus Ankara boost, or to two doses of placebo at days 0 and 56 of the study.
There was no difference in chronic HCV infection at 6 months, the primary endpoint of the study. There were 14 chronically infected participants in the vaccine group, as well as 14 in the placebo group, for an overall incidence of infection of 13.0/100 person-years, Dr. Page and coauthors reported in the abstract.
However, there were significant differences in HCV RNA geometric mean peak at 1 month, which was 193,795 IU/L in the vaccine group and 1,078,092 IU/L in the placebo group, according to investigators. Similarly, geometric mean fold rise after infection was 0.2 in the vaccine group and 13.5 in the placebo group.
A total of 78% of vaccinated individuals had T-cell responses to at least one vaccine antigen pool, investigators said, adding that the vaccine was safe, well tolerated, and not associated with any serious adverse events.
Dr. Page had no disclosures related to the abstract.
SOURCE: Page K et al. The Liver Meeting 2019. Abstract LP17.
REPORTING FROM THE LIVER MEETING 2019
Key clinical point: A prime-boost HCV vaccine altered viral trajectory but did not protect against chronic infection.
Major finding: At 6 months after vaccination, there were 14 chronically infected participants in the vaccine group, and 14 in the placebo group.
Study details: A randomized, placebo controlled phase 1/2 trial including 455 adults at risk of HCV infection.
Disclosures: The first author reported no disclosures.
Source: Page K et al. The Liver Meeting 2019. Abstract LP17.
Dupilumab effective in early- and late-onset asthma
NEW ORLEANS – A new analysis suggests
Dupilumab may be more effective in reducing severe asthma exacerbations in patients with late-onset asthma, but the drug’s effect on lung function appeared the same regardless of asthma onset. Nicola Hanania, MD, of Baylor College of Medicine in Houston presented these results at the annual meeting of the American College of Chest Physicians.
Dr. Hanania and colleagues conducted a subanalysis of the LIBERTY ASTHMA QUEST study (NCT02414854). Previous data from this study showed that patients with uncontrolled, moderate to severe asthma who received dupilumab had fewer exacerbations and better lung function than did patients who received placebo (N Engl J Med. 2018;378:2486-96).
In their subanalysis, Dr. Hanania and his colleagues evaluated the efficacy of dupilumab, given at 200 mg or 300 mg every 2 weeks, in patients with early-onset asthma (at 40 years of age or younger) and late-onset asthma (at 41 years or older). The analysis included 919 patients with early-onset asthma who received dupilumab and 450 early-onset patients who received placebo. There were 345 patients with late-onset asthma who received dupilumab and 188 late-onset patients who received placebo.
Exacerbations
Dupilumab significantly reduced the adjusted annualized severe exacerbation rates during the 52-week treatment period. Significant reductions occurred in both early- and late-onset patients, though reductions were greater in the late-onset group.
In early-onset patients, dupilumab reduced severe exacerbations by 38% when given at 200 mg and by 37% when given at 300 mg (P less than .001 vs. placebo). In late-onset patients, dupilumab reduced exacerbations by 64% and 69%, respectively (P less than .001 vs. placebo).
Dr. Hanania said it isn’t clear why late-onset patients appear to derive more benefit with regard to exacerbations. It may be because these patients have more comorbidities or because they aren’t using their inhalers correctly. The researchers are investigating these possibilities.
Dr. Hanania went on to note that reductions in exacerbation rates were greatest in patients with elevated blood eosinophils (150 cells/mcL or greater) or fractional exhaled nitric oxide (FeNO; 25 ppb or greater).
In patients with early-onset asthma and elevated eosinophils, dupilumab reduced severe exacerbations by 50% when given at 200 mg and by 55% when given at 300 mg (P less than .001 vs. placebo). In late-onset patients with elevated eosinophils, dupilumab reduced exacerbations by 65% and 73%, respectively (P less than .001 vs. placebo).
In patients with early-onset asthma and elevated FeNO, dupilumab reduced severe exacerbations by 56% when given at 200 mg and by 52% when given at 300 mg (P less than .001 vs. placebo). In late-onset patients with elevated FeNO, dupilumab reduced exacerbations by 79% and 71%, respectively (P less than .001 vs. placebo).
Lung function
Dupilumab also improved prebronchodilator forced expiratory volume in 1 second (pre-BD FEV1), compared with placebo, with similar results in early- and late-onset patients.
In early-onset patients, the P values were less than .001 for both doses of dupilumab at weeks 12 and 52. In late-onset patients, the P values were less than .001 for the 300-mg dose at week 12 and the 200-mg dose at week 52, less than .01 for the 200-mg dose at week 12, and less than .05 for the 300-mg dose at week 52.
The effects of dupilumab on pre-BD FEV1 were greatest in patients with elevated eosinophils or FeNO. At week 12, the P value was less than .001 for both doses of dupilumab in early-onset patients with elevated eosinophils or FeNO. The P value was less than .01 for both doses in late-onset patients with elevated eosinophils. And the P value was less than .001 for both doses in late-onset patients with elevated FeNO.
This research was sponsored by Sanofi and Regeneron. Dr. Hanania disclosed relationships with Genentech, Novartis, AstraZeneca, Boehringer Ingelheim, GSK, Regeneron, and Sanofi.
SOURCE: Hanania N et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.870.
NEW ORLEANS – A new analysis suggests
Dupilumab may be more effective in reducing severe asthma exacerbations in patients with late-onset asthma, but the drug’s effect on lung function appeared the same regardless of asthma onset. Nicola Hanania, MD, of Baylor College of Medicine in Houston presented these results at the annual meeting of the American College of Chest Physicians.
Dr. Hanania and colleagues conducted a subanalysis of the LIBERTY ASTHMA QUEST study (NCT02414854). Previous data from this study showed that patients with uncontrolled, moderate to severe asthma who received dupilumab had fewer exacerbations and better lung function than did patients who received placebo (N Engl J Med. 2018;378:2486-96).
In their subanalysis, Dr. Hanania and his colleagues evaluated the efficacy of dupilumab, given at 200 mg or 300 mg every 2 weeks, in patients with early-onset asthma (at 40 years of age or younger) and late-onset asthma (at 41 years or older). The analysis included 919 patients with early-onset asthma who received dupilumab and 450 early-onset patients who received placebo. There were 345 patients with late-onset asthma who received dupilumab and 188 late-onset patients who received placebo.
Exacerbations
Dupilumab significantly reduced the adjusted annualized severe exacerbation rates during the 52-week treatment period. Significant reductions occurred in both early- and late-onset patients, though reductions were greater in the late-onset group.
In early-onset patients, dupilumab reduced severe exacerbations by 38% when given at 200 mg and by 37% when given at 300 mg (P less than .001 vs. placebo). In late-onset patients, dupilumab reduced exacerbations by 64% and 69%, respectively (P less than .001 vs. placebo).
Dr. Hanania said it isn’t clear why late-onset patients appear to derive more benefit with regard to exacerbations. It may be because these patients have more comorbidities or because they aren’t using their inhalers correctly. The researchers are investigating these possibilities.
Dr. Hanania went on to note that reductions in exacerbation rates were greatest in patients with elevated blood eosinophils (150 cells/mcL or greater) or fractional exhaled nitric oxide (FeNO; 25 ppb or greater).
In patients with early-onset asthma and elevated eosinophils, dupilumab reduced severe exacerbations by 50% when given at 200 mg and by 55% when given at 300 mg (P less than .001 vs. placebo). In late-onset patients with elevated eosinophils, dupilumab reduced exacerbations by 65% and 73%, respectively (P less than .001 vs. placebo).
In patients with early-onset asthma and elevated FeNO, dupilumab reduced severe exacerbations by 56% when given at 200 mg and by 52% when given at 300 mg (P less than .001 vs. placebo). In late-onset patients with elevated FeNO, dupilumab reduced exacerbations by 79% and 71%, respectively (P less than .001 vs. placebo).
Lung function
Dupilumab also improved prebronchodilator forced expiratory volume in 1 second (pre-BD FEV1), compared with placebo, with similar results in early- and late-onset patients.
In early-onset patients, the P values were less than .001 for both doses of dupilumab at weeks 12 and 52. In late-onset patients, the P values were less than .001 for the 300-mg dose at week 12 and the 200-mg dose at week 52, less than .01 for the 200-mg dose at week 12, and less than .05 for the 300-mg dose at week 52.
The effects of dupilumab on pre-BD FEV1 were greatest in patients with elevated eosinophils or FeNO. At week 12, the P value was less than .001 for both doses of dupilumab in early-onset patients with elevated eosinophils or FeNO. The P value was less than .01 for both doses in late-onset patients with elevated eosinophils. And the P value was less than .001 for both doses in late-onset patients with elevated FeNO.
This research was sponsored by Sanofi and Regeneron. Dr. Hanania disclosed relationships with Genentech, Novartis, AstraZeneca, Boehringer Ingelheim, GSK, Regeneron, and Sanofi.
SOURCE: Hanania N et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.870.
NEW ORLEANS – A new analysis suggests
Dupilumab may be more effective in reducing severe asthma exacerbations in patients with late-onset asthma, but the drug’s effect on lung function appeared the same regardless of asthma onset. Nicola Hanania, MD, of Baylor College of Medicine in Houston presented these results at the annual meeting of the American College of Chest Physicians.
Dr. Hanania and colleagues conducted a subanalysis of the LIBERTY ASTHMA QUEST study (NCT02414854). Previous data from this study showed that patients with uncontrolled, moderate to severe asthma who received dupilumab had fewer exacerbations and better lung function than did patients who received placebo (N Engl J Med. 2018;378:2486-96).
In their subanalysis, Dr. Hanania and his colleagues evaluated the efficacy of dupilumab, given at 200 mg or 300 mg every 2 weeks, in patients with early-onset asthma (at 40 years of age or younger) and late-onset asthma (at 41 years or older). The analysis included 919 patients with early-onset asthma who received dupilumab and 450 early-onset patients who received placebo. There were 345 patients with late-onset asthma who received dupilumab and 188 late-onset patients who received placebo.
Exacerbations
Dupilumab significantly reduced the adjusted annualized severe exacerbation rates during the 52-week treatment period. Significant reductions occurred in both early- and late-onset patients, though reductions were greater in the late-onset group.
In early-onset patients, dupilumab reduced severe exacerbations by 38% when given at 200 mg and by 37% when given at 300 mg (P less than .001 vs. placebo). In late-onset patients, dupilumab reduced exacerbations by 64% and 69%, respectively (P less than .001 vs. placebo).
Dr. Hanania said it isn’t clear why late-onset patients appear to derive more benefit with regard to exacerbations. It may be because these patients have more comorbidities or because they aren’t using their inhalers correctly. The researchers are investigating these possibilities.
Dr. Hanania went on to note that reductions in exacerbation rates were greatest in patients with elevated blood eosinophils (150 cells/mcL or greater) or fractional exhaled nitric oxide (FeNO; 25 ppb or greater).
In patients with early-onset asthma and elevated eosinophils, dupilumab reduced severe exacerbations by 50% when given at 200 mg and by 55% when given at 300 mg (P less than .001 vs. placebo). In late-onset patients with elevated eosinophils, dupilumab reduced exacerbations by 65% and 73%, respectively (P less than .001 vs. placebo).
In patients with early-onset asthma and elevated FeNO, dupilumab reduced severe exacerbations by 56% when given at 200 mg and by 52% when given at 300 mg (P less than .001 vs. placebo). In late-onset patients with elevated FeNO, dupilumab reduced exacerbations by 79% and 71%, respectively (P less than .001 vs. placebo).
Lung function
Dupilumab also improved prebronchodilator forced expiratory volume in 1 second (pre-BD FEV1), compared with placebo, with similar results in early- and late-onset patients.
In early-onset patients, the P values were less than .001 for both doses of dupilumab at weeks 12 and 52. In late-onset patients, the P values were less than .001 for the 300-mg dose at week 12 and the 200-mg dose at week 52, less than .01 for the 200-mg dose at week 12, and less than .05 for the 300-mg dose at week 52.
The effects of dupilumab on pre-BD FEV1 were greatest in patients with elevated eosinophils or FeNO. At week 12, the P value was less than .001 for both doses of dupilumab in early-onset patients with elevated eosinophils or FeNO. The P value was less than .01 for both doses in late-onset patients with elevated eosinophils. And the P value was less than .001 for both doses in late-onset patients with elevated FeNO.
This research was sponsored by Sanofi and Regeneron. Dr. Hanania disclosed relationships with Genentech, Novartis, AstraZeneca, Boehringer Ingelheim, GSK, Regeneron, and Sanofi.
SOURCE: Hanania N et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.870.
REPORTING FROM CHEST 2019
Better overall survival with nivolumab vs. chemo for advanced ESCC
BARCELONA – Nivolumab was associated with improved overall survival and a favorable safety profile, compared with chemotherapy, in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC) in the open-label phase 3 ATTRACTION-3 study.
The overall survival (OS) benefit was observed regardless of tumor programmed death-ligand 1 (PD-L1) expression, Byoung Chul Cho, MD, reported at the European Society for Medical Oncology Congress.
The findings were reported online simultaneously in The Lancet Oncology.
Median OS at a minimum follow-up of 17.6 months was 10.9 vs. 8.4 months in 210 patients randomized to receive treatment with the PD-1 inhibitor nivolumab and 209 who received chemotherapy, respectively (hazard ratio, 0.77), said Dr. Cho of Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
“Notably, there was a 13% and 10% improvement in overall survival rates at 12 months (47% vs. 34%) and 18 months (31% vs. 21%), respectively,” he said, also noting that the HRs for death favored nivolumab vs. chemotherapy across multiple prespecified subgroups, including those based on tumor PD-L1 expression (HRs, 0.69 and 0.84 for PD-L1 of 1% or greater and less than 1%, respectively).
No meaningful difference was seen in progression-free survival between the nivolumab and chemotherapy groups (12% vs. 7%; HR, 1.08), or in objective response rates (19% vs. 22%), he said.
“However, responses were substantially more durable with nivolumab, compared to chemotherapy; duration of response was 6.9 months with nivolumab vs. 3.9 months in the chemotherapy arm,” he said. “Notably, 21% of patients in the nivolumab arm were still in response, compared to only 6% in the chemotherapy arm.”
Patients enrolled in the open label study had unresectable advanced or recurrent ESCC refractory or intolerant to one prior fluoropyrimidine/platinum-based therapy. They were randomized 1:1 to receive 240 mg of nivolumab every 2 weeks or investigators’ choice of paclitaxel or docetaxel.
Fewer treatment-related adverse events (TRAEs) were reported with nivolumab, Dr. Cho said.
Any grade TRAEs occurred in 66% vs. 95% of patients in the groups, respectively, and grade 3-4 TRAEs occurred in 18% vs. 63%. The majority of select TRAEs – defined as those with potential immunologic etiology, including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin effects – were grade 1 or 2, and the only difference between the nivolumab and chemotherapy groups with respect to those was in endocrine effects, which affected 11% vs. less than 1% of patients, respectively.
Grade 3/4 select TRAEs occurred in less than 2% of patients, Dr. Cho noted.
An exploratory analysis further showed significant overall improvement in health-related quality of life with nivolumab through week 42 on treatment, he added.
The findings are of note, because metastatic esophageal cancer has a 5-year relative survival rate of less than 8%, and ESCC accounts for about 90% of cases worldwide, he said, adding that current second-line chemotherapy options for ESCC offer poor long-term survival and are associated with toxicity.
Nivolumab, which showed promising antitumor activity and manageable toxicity for advanced ESCC in patients who were refractory to or intolerant of standard chemotherapies in the phase 2 ATTRACTION-1 study, is the first immune checkpoint inhibitor to demonstrate a statistically significant, clinically meaningful improvement in OS vs. chemotherapy in this setting, he said.
The findings of this final analysis of ATTRACTION-3, which shows a 23% reduction in the risk of death, a 2.5-month improvement in median OS, benefit across PD-L1 subgroups, and a favorable safety profile, suggest that nivolumab represents a new standard second-line treatment option for patients with advanced ESCC, he concluded.
ATTRACTION-3 was funded by Ono Pharmaceutical Co., in collaboration with Bristol-Myers Squibb. Dr. Cho reported relationships with Bristol-Myers Squibb, Ono Pharmaceutical, and others. He also reported stock ownership and/or patents with TheraCanVac and Champions Oncology.
SOURCE: Cho B et al. ESMO 2019, Abstract LBA11.
BARCELONA – Nivolumab was associated with improved overall survival and a favorable safety profile, compared with chemotherapy, in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC) in the open-label phase 3 ATTRACTION-3 study.
The overall survival (OS) benefit was observed regardless of tumor programmed death-ligand 1 (PD-L1) expression, Byoung Chul Cho, MD, reported at the European Society for Medical Oncology Congress.
The findings were reported online simultaneously in The Lancet Oncology.
Median OS at a minimum follow-up of 17.6 months was 10.9 vs. 8.4 months in 210 patients randomized to receive treatment with the PD-1 inhibitor nivolumab and 209 who received chemotherapy, respectively (hazard ratio, 0.77), said Dr. Cho of Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
“Notably, there was a 13% and 10% improvement in overall survival rates at 12 months (47% vs. 34%) and 18 months (31% vs. 21%), respectively,” he said, also noting that the HRs for death favored nivolumab vs. chemotherapy across multiple prespecified subgroups, including those based on tumor PD-L1 expression (HRs, 0.69 and 0.84 for PD-L1 of 1% or greater and less than 1%, respectively).
No meaningful difference was seen in progression-free survival between the nivolumab and chemotherapy groups (12% vs. 7%; HR, 1.08), or in objective response rates (19% vs. 22%), he said.
“However, responses were substantially more durable with nivolumab, compared to chemotherapy; duration of response was 6.9 months with nivolumab vs. 3.9 months in the chemotherapy arm,” he said. “Notably, 21% of patients in the nivolumab arm were still in response, compared to only 6% in the chemotherapy arm.”
Patients enrolled in the open label study had unresectable advanced or recurrent ESCC refractory or intolerant to one prior fluoropyrimidine/platinum-based therapy. They were randomized 1:1 to receive 240 mg of nivolumab every 2 weeks or investigators’ choice of paclitaxel or docetaxel.
Fewer treatment-related adverse events (TRAEs) were reported with nivolumab, Dr. Cho said.
Any grade TRAEs occurred in 66% vs. 95% of patients in the groups, respectively, and grade 3-4 TRAEs occurred in 18% vs. 63%. The majority of select TRAEs – defined as those with potential immunologic etiology, including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin effects – were grade 1 or 2, and the only difference between the nivolumab and chemotherapy groups with respect to those was in endocrine effects, which affected 11% vs. less than 1% of patients, respectively.
Grade 3/4 select TRAEs occurred in less than 2% of patients, Dr. Cho noted.
An exploratory analysis further showed significant overall improvement in health-related quality of life with nivolumab through week 42 on treatment, he added.
The findings are of note, because metastatic esophageal cancer has a 5-year relative survival rate of less than 8%, and ESCC accounts for about 90% of cases worldwide, he said, adding that current second-line chemotherapy options for ESCC offer poor long-term survival and are associated with toxicity.
Nivolumab, which showed promising antitumor activity and manageable toxicity for advanced ESCC in patients who were refractory to or intolerant of standard chemotherapies in the phase 2 ATTRACTION-1 study, is the first immune checkpoint inhibitor to demonstrate a statistically significant, clinically meaningful improvement in OS vs. chemotherapy in this setting, he said.
The findings of this final analysis of ATTRACTION-3, which shows a 23% reduction in the risk of death, a 2.5-month improvement in median OS, benefit across PD-L1 subgroups, and a favorable safety profile, suggest that nivolumab represents a new standard second-line treatment option for patients with advanced ESCC, he concluded.
ATTRACTION-3 was funded by Ono Pharmaceutical Co., in collaboration with Bristol-Myers Squibb. Dr. Cho reported relationships with Bristol-Myers Squibb, Ono Pharmaceutical, and others. He also reported stock ownership and/or patents with TheraCanVac and Champions Oncology.
SOURCE: Cho B et al. ESMO 2019, Abstract LBA11.
BARCELONA – Nivolumab was associated with improved overall survival and a favorable safety profile, compared with chemotherapy, in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC) in the open-label phase 3 ATTRACTION-3 study.
The overall survival (OS) benefit was observed regardless of tumor programmed death-ligand 1 (PD-L1) expression, Byoung Chul Cho, MD, reported at the European Society for Medical Oncology Congress.
The findings were reported online simultaneously in The Lancet Oncology.
Median OS at a minimum follow-up of 17.6 months was 10.9 vs. 8.4 months in 210 patients randomized to receive treatment with the PD-1 inhibitor nivolumab and 209 who received chemotherapy, respectively (hazard ratio, 0.77), said Dr. Cho of Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
“Notably, there was a 13% and 10% improvement in overall survival rates at 12 months (47% vs. 34%) and 18 months (31% vs. 21%), respectively,” he said, also noting that the HRs for death favored nivolumab vs. chemotherapy across multiple prespecified subgroups, including those based on tumor PD-L1 expression (HRs, 0.69 and 0.84 for PD-L1 of 1% or greater and less than 1%, respectively).
No meaningful difference was seen in progression-free survival between the nivolumab and chemotherapy groups (12% vs. 7%; HR, 1.08), or in objective response rates (19% vs. 22%), he said.
“However, responses were substantially more durable with nivolumab, compared to chemotherapy; duration of response was 6.9 months with nivolumab vs. 3.9 months in the chemotherapy arm,” he said. “Notably, 21% of patients in the nivolumab arm were still in response, compared to only 6% in the chemotherapy arm.”
Patients enrolled in the open label study had unresectable advanced or recurrent ESCC refractory or intolerant to one prior fluoropyrimidine/platinum-based therapy. They were randomized 1:1 to receive 240 mg of nivolumab every 2 weeks or investigators’ choice of paclitaxel or docetaxel.
Fewer treatment-related adverse events (TRAEs) were reported with nivolumab, Dr. Cho said.
Any grade TRAEs occurred in 66% vs. 95% of patients in the groups, respectively, and grade 3-4 TRAEs occurred in 18% vs. 63%. The majority of select TRAEs – defined as those with potential immunologic etiology, including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin effects – were grade 1 or 2, and the only difference between the nivolumab and chemotherapy groups with respect to those was in endocrine effects, which affected 11% vs. less than 1% of patients, respectively.
Grade 3/4 select TRAEs occurred in less than 2% of patients, Dr. Cho noted.
An exploratory analysis further showed significant overall improvement in health-related quality of life with nivolumab through week 42 on treatment, he added.
The findings are of note, because metastatic esophageal cancer has a 5-year relative survival rate of less than 8%, and ESCC accounts for about 90% of cases worldwide, he said, adding that current second-line chemotherapy options for ESCC offer poor long-term survival and are associated with toxicity.
Nivolumab, which showed promising antitumor activity and manageable toxicity for advanced ESCC in patients who were refractory to or intolerant of standard chemotherapies in the phase 2 ATTRACTION-1 study, is the first immune checkpoint inhibitor to demonstrate a statistically significant, clinically meaningful improvement in OS vs. chemotherapy in this setting, he said.
The findings of this final analysis of ATTRACTION-3, which shows a 23% reduction in the risk of death, a 2.5-month improvement in median OS, benefit across PD-L1 subgroups, and a favorable safety profile, suggest that nivolumab represents a new standard second-line treatment option for patients with advanced ESCC, he concluded.
ATTRACTION-3 was funded by Ono Pharmaceutical Co., in collaboration with Bristol-Myers Squibb. Dr. Cho reported relationships with Bristol-Myers Squibb, Ono Pharmaceutical, and others. He also reported stock ownership and/or patents with TheraCanVac and Champions Oncology.
SOURCE: Cho B et al. ESMO 2019, Abstract LBA11.
REPORTING FROM ESMO 2019
Key clinical point: Nivolumab was associated with improved OS vs. chemotherapy, in previously treated advanced ESCC.
Major finding: Median OS was 10.9 vs. 8.4 months with nivolumab vs. chemotherapy, respectively (hazard ratio, 0.77).
Study details: A randomized, open-label, phase 3 study of 419 patients.
Disclosures: ATTRACTION-3 was funded by Ono Pharmaceutical Co., in collaboration with Bristol-Myers Squibb. Dr. Cho reported relationships with Bristol-Myers Squibb, Ono Pharmaceutical, and others. He reported stock ownership and/or patents with TheraCanVac and Champions Oncology.
Source: Cho B et al. ESMO 2019, Abstract LBA11.
More evidence that statins reduce HCC risk
SAN ANTONIO – The evidence that statin therapy reduces the risk of developing hepatocellular carcinoma, while not rising to the highest-level 1A strata, is nonetheless sufficiently persuasive at this point that consideration should be given to prescribing a statin in all patients with risk factors for the malignancy, regardless of their cardiovascular risk profile, Muhammad Talal Sarmini, MD, asserted at the annual meeting of the American College of Gastroenterology.
This includes individuals with hepatitis B or C virus infection as well as those with cirrhosis. The jury is still out as to whether nonalcoholic steatohepatitis is a risk factor for hepatocellular carcinoma (HCC), observed Dr. Sarmini of the Cleveland Clinic.
He presented a new meta-analysis, which concluded that patients on statin therapy had a 43% lower risk of new-onset HCC than persons not taking a statin. This meta-analysis – the largest ever addressing the issue – included 20 studies totaling more than 2.6 million patients and 24,341 cases of new-onset HCC. There were 11 retrospective case-control studies, 6 cohort studies, and 3 randomized trials. Five studies were from the United States, nine from Asia, and six were European.
In subgroup analyses aimed at assessing the consistency of the study results across various domains, there was a 45% reduction in the risk of HCC in association with statin therapy in the three studies of patients with hepatitis B virus, and significant reductions as well in Asia, Europe, and the United States when those participants were evaluated separately. The reduction was significant in both the case-control and cohort studies, but not when the three randomized, controlled trials (RCTs) were analyzed collectively. However, Dr. Sarmini shrugged off the neutral RCT results.
“It’s worth noting that the RCTs reported data from patients who were on statins with 4-5 years of follow-up. They were not at high risk for HCC. Given the nature of the disease and the relatively short period of follow-up, these studies only reported 81 cases of HCC. So they were very limited,” he said.
Audience members were eager to learn if Dr. Sarmini had found a differential preventive effect for lipophilic statins, such as atorvastatin or simvastatin, versus hydrophilic statins. He replied that, unfortunately, the published study results don’t allow for such an analysis. However, a large, propensity-matched cohort study published too recently for inclusion in his meta-analysis shed light on this matter. This Swedish national registry study included 16,668 propensity score–matched adults with chronic hepatitis B or C infection, of whom 6,554 initiated lipophilic statin therapy, 1,780 began treatment with a hydrophilic statin, and the rest were statin nonusers. The lipophilic statin users had an adjusted 44% reduction in 10-year HCC risk, compared with nonusers, while hydrophilic statins weren’t associated with a significant preventive effect (Ann Intern Med. 2019 Sep 3;171[5]:318-27).
Dr. Sarmini said that the meta-analysis results, together with the Swedish registry findings, highlight the need for additional well-designed cohort studies and RCTs of statins in populations at high risk for HCC in order to verify the existence of an HCC preventive effect and pinpoint which statins are effective at what dosages.
HCC is the fourth-leading cause of cancer-related mortality globally, accounting for 800,000 deaths annually. And the incidence is rising on a year-by-year basis.
Dr. Sarmini reported having no financial conflicts regarding his study, which was conducted free of commercial support.
SAN ANTONIO – The evidence that statin therapy reduces the risk of developing hepatocellular carcinoma, while not rising to the highest-level 1A strata, is nonetheless sufficiently persuasive at this point that consideration should be given to prescribing a statin in all patients with risk factors for the malignancy, regardless of their cardiovascular risk profile, Muhammad Talal Sarmini, MD, asserted at the annual meeting of the American College of Gastroenterology.
This includes individuals with hepatitis B or C virus infection as well as those with cirrhosis. The jury is still out as to whether nonalcoholic steatohepatitis is a risk factor for hepatocellular carcinoma (HCC), observed Dr. Sarmini of the Cleveland Clinic.
He presented a new meta-analysis, which concluded that patients on statin therapy had a 43% lower risk of new-onset HCC than persons not taking a statin. This meta-analysis – the largest ever addressing the issue – included 20 studies totaling more than 2.6 million patients and 24,341 cases of new-onset HCC. There were 11 retrospective case-control studies, 6 cohort studies, and 3 randomized trials. Five studies were from the United States, nine from Asia, and six were European.
In subgroup analyses aimed at assessing the consistency of the study results across various domains, there was a 45% reduction in the risk of HCC in association with statin therapy in the three studies of patients with hepatitis B virus, and significant reductions as well in Asia, Europe, and the United States when those participants were evaluated separately. The reduction was significant in both the case-control and cohort studies, but not when the three randomized, controlled trials (RCTs) were analyzed collectively. However, Dr. Sarmini shrugged off the neutral RCT results.
“It’s worth noting that the RCTs reported data from patients who were on statins with 4-5 years of follow-up. They were not at high risk for HCC. Given the nature of the disease and the relatively short period of follow-up, these studies only reported 81 cases of HCC. So they were very limited,” he said.
Audience members were eager to learn if Dr. Sarmini had found a differential preventive effect for lipophilic statins, such as atorvastatin or simvastatin, versus hydrophilic statins. He replied that, unfortunately, the published study results don’t allow for such an analysis. However, a large, propensity-matched cohort study published too recently for inclusion in his meta-analysis shed light on this matter. This Swedish national registry study included 16,668 propensity score–matched adults with chronic hepatitis B or C infection, of whom 6,554 initiated lipophilic statin therapy, 1,780 began treatment with a hydrophilic statin, and the rest were statin nonusers. The lipophilic statin users had an adjusted 44% reduction in 10-year HCC risk, compared with nonusers, while hydrophilic statins weren’t associated with a significant preventive effect (Ann Intern Med. 2019 Sep 3;171[5]:318-27).
Dr. Sarmini said that the meta-analysis results, together with the Swedish registry findings, highlight the need for additional well-designed cohort studies and RCTs of statins in populations at high risk for HCC in order to verify the existence of an HCC preventive effect and pinpoint which statins are effective at what dosages.
HCC is the fourth-leading cause of cancer-related mortality globally, accounting for 800,000 deaths annually. And the incidence is rising on a year-by-year basis.
Dr. Sarmini reported having no financial conflicts regarding his study, which was conducted free of commercial support.
SAN ANTONIO – The evidence that statin therapy reduces the risk of developing hepatocellular carcinoma, while not rising to the highest-level 1A strata, is nonetheless sufficiently persuasive at this point that consideration should be given to prescribing a statin in all patients with risk factors for the malignancy, regardless of their cardiovascular risk profile, Muhammad Talal Sarmini, MD, asserted at the annual meeting of the American College of Gastroenterology.
This includes individuals with hepatitis B or C virus infection as well as those with cirrhosis. The jury is still out as to whether nonalcoholic steatohepatitis is a risk factor for hepatocellular carcinoma (HCC), observed Dr. Sarmini of the Cleveland Clinic.
He presented a new meta-analysis, which concluded that patients on statin therapy had a 43% lower risk of new-onset HCC than persons not taking a statin. This meta-analysis – the largest ever addressing the issue – included 20 studies totaling more than 2.6 million patients and 24,341 cases of new-onset HCC. There were 11 retrospective case-control studies, 6 cohort studies, and 3 randomized trials. Five studies were from the United States, nine from Asia, and six were European.
In subgroup analyses aimed at assessing the consistency of the study results across various domains, there was a 45% reduction in the risk of HCC in association with statin therapy in the three studies of patients with hepatitis B virus, and significant reductions as well in Asia, Europe, and the United States when those participants were evaluated separately. The reduction was significant in both the case-control and cohort studies, but not when the three randomized, controlled trials (RCTs) were analyzed collectively. However, Dr. Sarmini shrugged off the neutral RCT results.
“It’s worth noting that the RCTs reported data from patients who were on statins with 4-5 years of follow-up. They were not at high risk for HCC. Given the nature of the disease and the relatively short period of follow-up, these studies only reported 81 cases of HCC. So they were very limited,” he said.
Audience members were eager to learn if Dr. Sarmini had found a differential preventive effect for lipophilic statins, such as atorvastatin or simvastatin, versus hydrophilic statins. He replied that, unfortunately, the published study results don’t allow for such an analysis. However, a large, propensity-matched cohort study published too recently for inclusion in his meta-analysis shed light on this matter. This Swedish national registry study included 16,668 propensity score–matched adults with chronic hepatitis B or C infection, of whom 6,554 initiated lipophilic statin therapy, 1,780 began treatment with a hydrophilic statin, and the rest were statin nonusers. The lipophilic statin users had an adjusted 44% reduction in 10-year HCC risk, compared with nonusers, while hydrophilic statins weren’t associated with a significant preventive effect (Ann Intern Med. 2019 Sep 3;171[5]:318-27).
Dr. Sarmini said that the meta-analysis results, together with the Swedish registry findings, highlight the need for additional well-designed cohort studies and RCTs of statins in populations at high risk for HCC in order to verify the existence of an HCC preventive effect and pinpoint which statins are effective at what dosages.
HCC is the fourth-leading cause of cancer-related mortality globally, accounting for 800,000 deaths annually. And the incidence is rising on a year-by-year basis.
Dr. Sarmini reported having no financial conflicts regarding his study, which was conducted free of commercial support.
REPORTING FROM ACG 2019
Probiotics with Lactobacillus reduce loss in spine BMD for postmenopausal women
, according to recent research published in The Lancet Rheumatology.
“The menopausal and early postmenopausal lumbar spine bone loss is substantial in women, and by using a prevention therapy with bacteria naturally occurring in the human gut microbiota we observed a close to complete protection against lumbar spine bone loss in healthy postmenopausal women,” Per-Anders Jansson, MD, chief physician at the University of Gothenburg (Sweden), and colleagues wrote in their study.
Dr. Jansson and colleagues performed a double-blind trial at four centers in Sweden in which 249 postmenopausal women were randomized during April-November 2016 to receive probiotics consisting of three Lactobacillus strains or placebo once per day for 12 months. Participants were healthy women, neither underweight nor overweight, and were postmenopausal, which was defined as being 2-12 years or less from last menstruation. The Lactobacillus strains, L. paracasei 8700:2 (DSM 13434), L. plantarum Heal 9 (DSM 15312), and L. plantarum Heal 19 (DSM 15313), were equally represented in a capsule at a dose of 1 x 1010 colony-forming unit per capsule. The researchers measured the lumbar spine bone mineral density (LS-BMD) at baseline and at 12 months, and also evaluated the safety profile of participants in both the probiotic and placebo groups.
Overall, 234 participants (94%) had data available for analysis at the end of the study. There was a significant reduction in LS-BMD loss for participants who received the probiotic treatment, compared with women in the control group (mean difference, 0.71%; 95% confidence interval, 0.06%-1.35%), while there was a significant loss in LS-BMD for participants in the placebo group (percentage change, –0.72%; 95% CI, –1.22% to –0.22%) compared with loss in the probiotic group (percentage change, –0.01%; 95% CI, –0.50% to 0.48%). Using analysis of covariance, the researchers found the probiotic group had reduced LS-BMD loss after adjustment for factors such as study site, age at baseline, BMD at baseline, and number of years from menopause (mean difference, 7.44 mg/cm2; 95% CI, 0.38 to 14.50).
In a subgroup analysis of women above and below the median time since menopause at baseline (6 years), participants in the probiotic group who were below the median time saw a significant protective effect of Lactobacillus treatment (mean difference, 1.08%; 95% CI, 0.20%-1.96%), compared with women above the median time (mean difference, 0.31%; 95% CI, –0.62% to 1.23%).
Researchers also examined the effects of probiotic treatment on total hip and femoral neck BMD as secondary endpoints. Lactobacillus treatment did not appear to affect total hip (–1.01%; 95% CI, –1.65% to –0.37%) or trochanter BMD (–1.13%; 95% CI, –2.27% to 0.20%), but femoral neck BMD was reduced in the probiotic group (–1.34%; 95% CI, –2.09% to –0.58%), compared with the placebo group (–0.88%; 95% CI, –1.64% to –0.13%).
Limitations of the study included examining only one dose of Lactobacillus treatment and no analysis of the effect of short-chain fatty acids on LS-BMD. The researchers noted that “recent studies have shown that short-chain fatty acids, which are generated by fermentation of complex carbohydrates by the gut microbiota, are important regulators of both bone formation and resorption.”
The researchers also acknowledged that the LS-BMD effect size for the probiotic treatment over the 12 months was a lower magnitude, compared with first-line treatments for osteoporosis in postmenopausal women using bisphosphonates. “Further long-term studies should be done to evaluate if the bone-protective effect becomes more pronounced with prolonged treatment with the Lactobacillus strains used in the present study,” they said.
In a related editorial, Shivani Sahni, PhD, of Harvard Medical School, Boston, and Connie M. Weaver, PhD, of Purdue University, West Lafayette, Ind., reiterated that the effect size of probiotics is “of far less magnitude” than such treatments as bisphosphonates and expressed concern about the reduction of femoral neck BMD in the probiotic group, which was not explained in the study (Lancet Rheumatol. 2019 Nov;1[3]:e135-e137. doi: 10.1016/S2665-9913(19)30073-6). There is a need to learn the optimum dose of probiotics as well as which Lactobacillus strains should be used in future studies, as the strains chosen by Jansson et al. were based on results in mice.
In the meantime, patients might be better off choosing dietary interventions with proven bone protection and no documented negative effects on the hip, such as prebiotics like soluble corn fiber and dried prunes, in tandem with drug therapies, Dr. Sahni and Dr. Weaver said.
“Although Jansson and colleagues’ results are important, more work is needed before such probiotics are ready for consumers,” they concluded.
This study was funded by Probi, which employs two of the study’s authors. Three authors reported being coinventors of a patent involving the effects of probiotics in osteoporosis treatment, and one author is listed as an inventor on a pending patent application on probiotic compositions and uses. Dr. Sahni reported receiving grants from Dairy Management. Dr. Weaver reported no relevant conflicts of interest.
SOURCE: Jansson P-A et al. Lancet Rheumatol. 2019 Nov;1(3):e154-e162. doi: 10.1016/S2665-9913(19)30068-2
, according to recent research published in The Lancet Rheumatology.
“The menopausal and early postmenopausal lumbar spine bone loss is substantial in women, and by using a prevention therapy with bacteria naturally occurring in the human gut microbiota we observed a close to complete protection against lumbar spine bone loss in healthy postmenopausal women,” Per-Anders Jansson, MD, chief physician at the University of Gothenburg (Sweden), and colleagues wrote in their study.
Dr. Jansson and colleagues performed a double-blind trial at four centers in Sweden in which 249 postmenopausal women were randomized during April-November 2016 to receive probiotics consisting of three Lactobacillus strains or placebo once per day for 12 months. Participants were healthy women, neither underweight nor overweight, and were postmenopausal, which was defined as being 2-12 years or less from last menstruation. The Lactobacillus strains, L. paracasei 8700:2 (DSM 13434), L. plantarum Heal 9 (DSM 15312), and L. plantarum Heal 19 (DSM 15313), were equally represented in a capsule at a dose of 1 x 1010 colony-forming unit per capsule. The researchers measured the lumbar spine bone mineral density (LS-BMD) at baseline and at 12 months, and also evaluated the safety profile of participants in both the probiotic and placebo groups.
Overall, 234 participants (94%) had data available for analysis at the end of the study. There was a significant reduction in LS-BMD loss for participants who received the probiotic treatment, compared with women in the control group (mean difference, 0.71%; 95% confidence interval, 0.06%-1.35%), while there was a significant loss in LS-BMD for participants in the placebo group (percentage change, –0.72%; 95% CI, –1.22% to –0.22%) compared with loss in the probiotic group (percentage change, –0.01%; 95% CI, –0.50% to 0.48%). Using analysis of covariance, the researchers found the probiotic group had reduced LS-BMD loss after adjustment for factors such as study site, age at baseline, BMD at baseline, and number of years from menopause (mean difference, 7.44 mg/cm2; 95% CI, 0.38 to 14.50).
In a subgroup analysis of women above and below the median time since menopause at baseline (6 years), participants in the probiotic group who were below the median time saw a significant protective effect of Lactobacillus treatment (mean difference, 1.08%; 95% CI, 0.20%-1.96%), compared with women above the median time (mean difference, 0.31%; 95% CI, –0.62% to 1.23%).
Researchers also examined the effects of probiotic treatment on total hip and femoral neck BMD as secondary endpoints. Lactobacillus treatment did not appear to affect total hip (–1.01%; 95% CI, –1.65% to –0.37%) or trochanter BMD (–1.13%; 95% CI, –2.27% to 0.20%), but femoral neck BMD was reduced in the probiotic group (–1.34%; 95% CI, –2.09% to –0.58%), compared with the placebo group (–0.88%; 95% CI, –1.64% to –0.13%).
Limitations of the study included examining only one dose of Lactobacillus treatment and no analysis of the effect of short-chain fatty acids on LS-BMD. The researchers noted that “recent studies have shown that short-chain fatty acids, which are generated by fermentation of complex carbohydrates by the gut microbiota, are important regulators of both bone formation and resorption.”
The researchers also acknowledged that the LS-BMD effect size for the probiotic treatment over the 12 months was a lower magnitude, compared with first-line treatments for osteoporosis in postmenopausal women using bisphosphonates. “Further long-term studies should be done to evaluate if the bone-protective effect becomes more pronounced with prolonged treatment with the Lactobacillus strains used in the present study,” they said.
In a related editorial, Shivani Sahni, PhD, of Harvard Medical School, Boston, and Connie M. Weaver, PhD, of Purdue University, West Lafayette, Ind., reiterated that the effect size of probiotics is “of far less magnitude” than such treatments as bisphosphonates and expressed concern about the reduction of femoral neck BMD in the probiotic group, which was not explained in the study (Lancet Rheumatol. 2019 Nov;1[3]:e135-e137. doi: 10.1016/S2665-9913(19)30073-6). There is a need to learn the optimum dose of probiotics as well as which Lactobacillus strains should be used in future studies, as the strains chosen by Jansson et al. were based on results in mice.
In the meantime, patients might be better off choosing dietary interventions with proven bone protection and no documented negative effects on the hip, such as prebiotics like soluble corn fiber and dried prunes, in tandem with drug therapies, Dr. Sahni and Dr. Weaver said.
“Although Jansson and colleagues’ results are important, more work is needed before such probiotics are ready for consumers,” they concluded.
This study was funded by Probi, which employs two of the study’s authors. Three authors reported being coinventors of a patent involving the effects of probiotics in osteoporosis treatment, and one author is listed as an inventor on a pending patent application on probiotic compositions and uses. Dr. Sahni reported receiving grants from Dairy Management. Dr. Weaver reported no relevant conflicts of interest.
SOURCE: Jansson P-A et al. Lancet Rheumatol. 2019 Nov;1(3):e154-e162. doi: 10.1016/S2665-9913(19)30068-2
, according to recent research published in The Lancet Rheumatology.
“The menopausal and early postmenopausal lumbar spine bone loss is substantial in women, and by using a prevention therapy with bacteria naturally occurring in the human gut microbiota we observed a close to complete protection against lumbar spine bone loss in healthy postmenopausal women,” Per-Anders Jansson, MD, chief physician at the University of Gothenburg (Sweden), and colleagues wrote in their study.
Dr. Jansson and colleagues performed a double-blind trial at four centers in Sweden in which 249 postmenopausal women were randomized during April-November 2016 to receive probiotics consisting of three Lactobacillus strains or placebo once per day for 12 months. Participants were healthy women, neither underweight nor overweight, and were postmenopausal, which was defined as being 2-12 years or less from last menstruation. The Lactobacillus strains, L. paracasei 8700:2 (DSM 13434), L. plantarum Heal 9 (DSM 15312), and L. plantarum Heal 19 (DSM 15313), were equally represented in a capsule at a dose of 1 x 1010 colony-forming unit per capsule. The researchers measured the lumbar spine bone mineral density (LS-BMD) at baseline and at 12 months, and also evaluated the safety profile of participants in both the probiotic and placebo groups.
Overall, 234 participants (94%) had data available for analysis at the end of the study. There was a significant reduction in LS-BMD loss for participants who received the probiotic treatment, compared with women in the control group (mean difference, 0.71%; 95% confidence interval, 0.06%-1.35%), while there was a significant loss in LS-BMD for participants in the placebo group (percentage change, –0.72%; 95% CI, –1.22% to –0.22%) compared with loss in the probiotic group (percentage change, –0.01%; 95% CI, –0.50% to 0.48%). Using analysis of covariance, the researchers found the probiotic group had reduced LS-BMD loss after adjustment for factors such as study site, age at baseline, BMD at baseline, and number of years from menopause (mean difference, 7.44 mg/cm2; 95% CI, 0.38 to 14.50).
In a subgroup analysis of women above and below the median time since menopause at baseline (6 years), participants in the probiotic group who were below the median time saw a significant protective effect of Lactobacillus treatment (mean difference, 1.08%; 95% CI, 0.20%-1.96%), compared with women above the median time (mean difference, 0.31%; 95% CI, –0.62% to 1.23%).
Researchers also examined the effects of probiotic treatment on total hip and femoral neck BMD as secondary endpoints. Lactobacillus treatment did not appear to affect total hip (–1.01%; 95% CI, –1.65% to –0.37%) or trochanter BMD (–1.13%; 95% CI, –2.27% to 0.20%), but femoral neck BMD was reduced in the probiotic group (–1.34%; 95% CI, –2.09% to –0.58%), compared with the placebo group (–0.88%; 95% CI, –1.64% to –0.13%).
Limitations of the study included examining only one dose of Lactobacillus treatment and no analysis of the effect of short-chain fatty acids on LS-BMD. The researchers noted that “recent studies have shown that short-chain fatty acids, which are generated by fermentation of complex carbohydrates by the gut microbiota, are important regulators of both bone formation and resorption.”
The researchers also acknowledged that the LS-BMD effect size for the probiotic treatment over the 12 months was a lower magnitude, compared with first-line treatments for osteoporosis in postmenopausal women using bisphosphonates. “Further long-term studies should be done to evaluate if the bone-protective effect becomes more pronounced with prolonged treatment with the Lactobacillus strains used in the present study,” they said.
In a related editorial, Shivani Sahni, PhD, of Harvard Medical School, Boston, and Connie M. Weaver, PhD, of Purdue University, West Lafayette, Ind., reiterated that the effect size of probiotics is “of far less magnitude” than such treatments as bisphosphonates and expressed concern about the reduction of femoral neck BMD in the probiotic group, which was not explained in the study (Lancet Rheumatol. 2019 Nov;1[3]:e135-e137. doi: 10.1016/S2665-9913(19)30073-6). There is a need to learn the optimum dose of probiotics as well as which Lactobacillus strains should be used in future studies, as the strains chosen by Jansson et al. were based on results in mice.
In the meantime, patients might be better off choosing dietary interventions with proven bone protection and no documented negative effects on the hip, such as prebiotics like soluble corn fiber and dried prunes, in tandem with drug therapies, Dr. Sahni and Dr. Weaver said.
“Although Jansson and colleagues’ results are important, more work is needed before such probiotics are ready for consumers,” they concluded.
This study was funded by Probi, which employs two of the study’s authors. Three authors reported being coinventors of a patent involving the effects of probiotics in osteoporosis treatment, and one author is listed as an inventor on a pending patent application on probiotic compositions and uses. Dr. Sahni reported receiving grants from Dairy Management. Dr. Weaver reported no relevant conflicts of interest.
SOURCE: Jansson P-A et al. Lancet Rheumatol. 2019 Nov;1(3):e154-e162. doi: 10.1016/S2665-9913(19)30068-2
FROM THE LANCET RHEUMATOLOGY