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Sharon Worcester is an award-winning medical journalist for MDedge News. She has been with the company since 1996, first as the Southeast Bureau Chief (1996-2009) when the company was known as International Medical News Group, then as a freelance writer (2010-2015) before returning as a reporter in 2015. She previously worked as a daily newspaper reporter covering health and local government. Sharon currently reports primarily on oncology and hematology. She has a BA from Eckerd College and an MA in Mass Communication/Print Journalism from the University of Florida. Connect with her via LinkedIn and follow her on twitter @SW_MedReporter.
Study: No increased mortality with ACA-prompted readmission declines
Concerns that efforts to reduce 30-day hospital readmission rates under the Affordable Care Act’s Hospital Readmission Reduction Program might lead to unintended increases in mortality rates appear to be unfounded, according to a review of more than 6.7 million hospitalizations for heart failure, acute myocardial infarction, or pneumonia between 2008 and 2014.
In fact, reductions in 30-day readmission rates among Medicare fee-for-service beneficiaries are weakly but significantly correlated with reductions in hospital 30-day mortality rates after discharge, according to Kumar Dharmarajan, MD, of Yale New Haven (Conn.) Health, and colleagues (JAMA 2017 Jul 18;318[3]:270-8. doi: 10.1001/jama.2017.8444).
From 2008 to 2014, the RARRs declined in aggregate across hospitals (–0.053% for heart failure, –0.044% for acute MI, and –0.033% for pneumonia).
“In contrast, monthly aggregate trends across hospitals in 30-day risk-adjusted mortality rates after discharge varied by admitting condition” the investigators said.
For heart failure, acute MI, and pneumonia, there was an increase of 0.008%, a decrease of 0.003%, and an increase of 0.001%, respectively, they said. However, paired monthly trends in 30-day RARRs and 30-day RAMRs after discharge “identified concomitant reduction in readmission and mortality rates within hospitals.”
Correlation coefficients of the paired monthly trends for heart failure, acute MI, and pneumonia in 2008-2014 were 0.066, 0.067, and 0.108, respectively.
“Paired trends in hospital 30-day risk-adjusted readmission rates and both 90-day risk-adjusted mortality rates after discharge and 90-day risk-adjusted mortality rates after the admission date also identified concomitant reductions in readmission and mortality rates within hospitals,” the authors wrote.
The findings “do not support increasing postdischarge mortality related to reducing hospital readmissions,” they concluded.
The authors work under contract with the Centers for Medicare & Medicaid Services to develop and maintain performance measures. Dr. Dharmarajan reported serving as a consultant and scientific advisory board member for Clover Health at the time this research was performed. He is supported by grants from the National Institute on Aging and the American Federation for Aging Research, and the Yale Claude D. Pepper Older Americans Independence Center.
The findings by Dharmarajan and colleagues are “certainly good news,” Karen E. Joynt Maddox, MD, wrote in an editorial.
The study provides support for strategies that hospitals are using to reduce readmissions, and also underscores the importance of evaluating unintended consequences of policy changes such as the Affordable Care Act’s Hospital Readmissions Reduction Program (HRRP), she said (JAMA. 2017 Jul 18;318[3]:243-4).
The study did not address the possibility that attention to reducing readmissions has taken priority over reducing mortality, which could have the unintended consequence of slowing improvements in mortality, she noted, suggesting that for this and other reasons it may be “time to reexamine and reengineer the HRRP to avoid unintended consequences and to ensure that its incentives are fully aligned with the ultimate goal of improving the health outcomes of patients.
“Only with full knowledge of the advantages and disadvantages of a particular policy decision can policy makers and advocates work to craft statutes and rules that maximize benefits while minimizing harms,” she wrote.
Dr. Joynt Maddox is with Brigham and Women’s Hospital, Boston. She is supported by a grant from the National Heart, Lung, and Blood Institute.
The findings by Dharmarajan and colleagues are “certainly good news,” Karen E. Joynt Maddox, MD, wrote in an editorial.
The study provides support for strategies that hospitals are using to reduce readmissions, and also underscores the importance of evaluating unintended consequences of policy changes such as the Affordable Care Act’s Hospital Readmissions Reduction Program (HRRP), she said (JAMA. 2017 Jul 18;318[3]:243-4).
The study did not address the possibility that attention to reducing readmissions has taken priority over reducing mortality, which could have the unintended consequence of slowing improvements in mortality, she noted, suggesting that for this and other reasons it may be “time to reexamine and reengineer the HRRP to avoid unintended consequences and to ensure that its incentives are fully aligned with the ultimate goal of improving the health outcomes of patients.
“Only with full knowledge of the advantages and disadvantages of a particular policy decision can policy makers and advocates work to craft statutes and rules that maximize benefits while minimizing harms,” she wrote.
Dr. Joynt Maddox is with Brigham and Women’s Hospital, Boston. She is supported by a grant from the National Heart, Lung, and Blood Institute.
The findings by Dharmarajan and colleagues are “certainly good news,” Karen E. Joynt Maddox, MD, wrote in an editorial.
The study provides support for strategies that hospitals are using to reduce readmissions, and also underscores the importance of evaluating unintended consequences of policy changes such as the Affordable Care Act’s Hospital Readmissions Reduction Program (HRRP), she said (JAMA. 2017 Jul 18;318[3]:243-4).
The study did not address the possibility that attention to reducing readmissions has taken priority over reducing mortality, which could have the unintended consequence of slowing improvements in mortality, she noted, suggesting that for this and other reasons it may be “time to reexamine and reengineer the HRRP to avoid unintended consequences and to ensure that its incentives are fully aligned with the ultimate goal of improving the health outcomes of patients.
“Only with full knowledge of the advantages and disadvantages of a particular policy decision can policy makers and advocates work to craft statutes and rules that maximize benefits while minimizing harms,” she wrote.
Dr. Joynt Maddox is with Brigham and Women’s Hospital, Boston. She is supported by a grant from the National Heart, Lung, and Blood Institute.
Concerns that efforts to reduce 30-day hospital readmission rates under the Affordable Care Act’s Hospital Readmission Reduction Program might lead to unintended increases in mortality rates appear to be unfounded, according to a review of more than 6.7 million hospitalizations for heart failure, acute myocardial infarction, or pneumonia between 2008 and 2014.
In fact, reductions in 30-day readmission rates among Medicare fee-for-service beneficiaries are weakly but significantly correlated with reductions in hospital 30-day mortality rates after discharge, according to Kumar Dharmarajan, MD, of Yale New Haven (Conn.) Health, and colleagues (JAMA 2017 Jul 18;318[3]:270-8. doi: 10.1001/jama.2017.8444).
From 2008 to 2014, the RARRs declined in aggregate across hospitals (–0.053% for heart failure, –0.044% for acute MI, and –0.033% for pneumonia).
“In contrast, monthly aggregate trends across hospitals in 30-day risk-adjusted mortality rates after discharge varied by admitting condition” the investigators said.
For heart failure, acute MI, and pneumonia, there was an increase of 0.008%, a decrease of 0.003%, and an increase of 0.001%, respectively, they said. However, paired monthly trends in 30-day RARRs and 30-day RAMRs after discharge “identified concomitant reduction in readmission and mortality rates within hospitals.”
Correlation coefficients of the paired monthly trends for heart failure, acute MI, and pneumonia in 2008-2014 were 0.066, 0.067, and 0.108, respectively.
“Paired trends in hospital 30-day risk-adjusted readmission rates and both 90-day risk-adjusted mortality rates after discharge and 90-day risk-adjusted mortality rates after the admission date also identified concomitant reductions in readmission and mortality rates within hospitals,” the authors wrote.
The findings “do not support increasing postdischarge mortality related to reducing hospital readmissions,” they concluded.
The authors work under contract with the Centers for Medicare & Medicaid Services to develop and maintain performance measures. Dr. Dharmarajan reported serving as a consultant and scientific advisory board member for Clover Health at the time this research was performed. He is supported by grants from the National Institute on Aging and the American Federation for Aging Research, and the Yale Claude D. Pepper Older Americans Independence Center.
Concerns that efforts to reduce 30-day hospital readmission rates under the Affordable Care Act’s Hospital Readmission Reduction Program might lead to unintended increases in mortality rates appear to be unfounded, according to a review of more than 6.7 million hospitalizations for heart failure, acute myocardial infarction, or pneumonia between 2008 and 2014.
In fact, reductions in 30-day readmission rates among Medicare fee-for-service beneficiaries are weakly but significantly correlated with reductions in hospital 30-day mortality rates after discharge, according to Kumar Dharmarajan, MD, of Yale New Haven (Conn.) Health, and colleagues (JAMA 2017 Jul 18;318[3]:270-8. doi: 10.1001/jama.2017.8444).
From 2008 to 2014, the RARRs declined in aggregate across hospitals (–0.053% for heart failure, –0.044% for acute MI, and –0.033% for pneumonia).
“In contrast, monthly aggregate trends across hospitals in 30-day risk-adjusted mortality rates after discharge varied by admitting condition” the investigators said.
For heart failure, acute MI, and pneumonia, there was an increase of 0.008%, a decrease of 0.003%, and an increase of 0.001%, respectively, they said. However, paired monthly trends in 30-day RARRs and 30-day RAMRs after discharge “identified concomitant reduction in readmission and mortality rates within hospitals.”
Correlation coefficients of the paired monthly trends for heart failure, acute MI, and pneumonia in 2008-2014 were 0.066, 0.067, and 0.108, respectively.
“Paired trends in hospital 30-day risk-adjusted readmission rates and both 90-day risk-adjusted mortality rates after discharge and 90-day risk-adjusted mortality rates after the admission date also identified concomitant reductions in readmission and mortality rates within hospitals,” the authors wrote.
The findings “do not support increasing postdischarge mortality related to reducing hospital readmissions,” they concluded.
The authors work under contract with the Centers for Medicare & Medicaid Services to develop and maintain performance measures. Dr. Dharmarajan reported serving as a consultant and scientific advisory board member for Clover Health at the time this research was performed. He is supported by grants from the National Institute on Aging and the American Federation for Aging Research, and the Yale Claude D. Pepper Older Americans Independence Center.
FROM JAMA
Key clinical point:
Major finding: Correlation coefficients of the paired monthly trends for heart failure, acute myocardial infarction, and pneumonia in 2008-2014 were 0.066, 0.067, and 0.108, respectively.
Data source: A retrospective review of more than 6.7 million hospitalized Medicare fee-for-service beneficiaries.
Disclosures: The authors work under contract with the Centers for Medicare & Medicaid Services to develop and maintain performance measures. Dr. Dharmarajan reported serving as a consultant and scientific advisory board member for Clover Health at the time this research was performed. He is supported by grants from the National Institute on Aging and the American Federation for Aging Research, and the Yale Claude D. Pepper Older Americans Independence Center.
Report: Opioid epidemic fight must increase substantially and immediately
A concerted, multiagency, multipronged counterattack is needed to break the opioid epidemic’s grip on the nation, according to a new report from the National Academies of Sciences, Engineering, and Medicine.
The report, commissioned by the Food and Drug Administration to strengthen its own 2016 Opioids Action Plan, presents a national strategy for addressing this “urgent public health priority.”
“The ongoing opioid crisis lies at the intersection of two substantial public health challenges – reducing the burden of suffering from pain and containing the rising toll of the harms that can result from the use of opioid medications,” according to a summary of the report, “Pain Management and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use.”
The National Academies’ Committee on Pain Management and Regulatory Strategies to Address Prescription Opioid Abuse spent more than a year studying the matter and developing the report. Among its recommendations is a call for investment in research to better understand pain and opioid use disorder.
“We have a specific lack of knowledge about how pain and opiate use disorder [OUD] interact – that is, why patients in pain might be more or less at risk for the development of opiate use disorder when exposed to either illicit or prescription medication,” committee member David Clark, MD, professor of anesthesia, perioperative pain medicine, and pain at Stanford (Calif.) University, said during a webinar on the report.
“This leads up to one of our first recommendations, which is to invest in research to better understand pain and opiate use disorder,” Dr. Clark said. “We want to emphasize that we need to improve our understanding of the neurobiology of pain,” which will, hopefully, provide a better foundation for the development of nonopioid treatments.
The committee also recommended that the FDA:
- Incorporate public health considerations into opioid-related regulatory decisions.
- Require additional studies along with the collection and analysis of data needed to thoroughly assess broad public health considerations.
- Ensure that public health considerations are adequately incorporated into clinical development.
- Increase transparency of regulatory decisions for opioids in light of the proposed systems approach.
“The committee believes a commitment to transparency is critical to maintain balance between preserving access to opioids when needed and mitigating opioid-related harms and to maintain public trust,” the report’s authors said. “The committee also believes aggressive use of the FDA’s currently available authorities, such as Risk Evaluation and Mitigation Strategies (REMS), safety labeling changes, and risk communications is critical to supporting the safe and effective use of opioids.”
The committee also recommended strengthening the postapproval oversight of opioids.
A full review of currently marketed and approved opioids was also recommended, as was the application of public health consideration to opioid scheduling decisions.
“The particular characteristics of opioids, we believe, require a certain amount of what we term ‘opioid exceptionalism’ from the regulator in terms of trying to consider the larger societal effects of approval and use of opioid medication,” committee member Aaron S. Kesselheim, MD, JD, of Harvard Medical School, Boston, said during the webinar. “We believe that this public health approach is both reasonable for the FDA, given the fact that it is primarily a public health agency, and can be implemented at all different levels of the development process.”
Strategies recommended by the committee for the FDA, state agencies, health professionals, and relevant private organizations, such as through public-private partnerships, include:
- Restricting the supply of opioids, with careful attention to risks and benefits of interventions aimed at reducing the supply in the community. Recommendation: Improve access to drug take-back programs.
- Improving prescribing practices. Recommendations: Establish comprehensive pain education materials and curricula for health care providers; facilitate reimbursement for comprehensive pain management; and improve the use of prescription drug monitoring program data for surveillance and intervention.
- Reducing demand. Recommendations: Evaluate the impact on patient and public education about opioids on promoting safe and effective pain management; expand treatment for opioid use disorder; improve education regarding treatment of OUD for health care providers; and remove barriers to coverage of approved medication for OUD treatment.
- Reducing harm. Recommendations: Leverage prescribers and pharmacists to help address opioid use disorder; and improve access to naloxone and safe injection equipment.
According to the report, containing the opioid epidemic and ameliorating its harmful effects on society through the development of these strategies will require “years of sustained and coordinated effort.”
Indeed, things will get worse before they get better, the committee predicted.
“Trends indicate that premature deaths associated with the use of opioids are likely to climb and that opioid overdose and other opioid-related harm will dramatically reduce quality of life for many people for years to come,” the report’s authors noted. “Access to evidence-based treatment for OUD and efforts to prevent overdose deaths and other harms should therefore be increased substantially and immediately as a public health priority.”
A concerted, multiagency, multipronged counterattack is needed to break the opioid epidemic’s grip on the nation, according to a new report from the National Academies of Sciences, Engineering, and Medicine.
The report, commissioned by the Food and Drug Administration to strengthen its own 2016 Opioids Action Plan, presents a national strategy for addressing this “urgent public health priority.”
“The ongoing opioid crisis lies at the intersection of two substantial public health challenges – reducing the burden of suffering from pain and containing the rising toll of the harms that can result from the use of opioid medications,” according to a summary of the report, “Pain Management and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use.”
The National Academies’ Committee on Pain Management and Regulatory Strategies to Address Prescription Opioid Abuse spent more than a year studying the matter and developing the report. Among its recommendations is a call for investment in research to better understand pain and opioid use disorder.
“We have a specific lack of knowledge about how pain and opiate use disorder [OUD] interact – that is, why patients in pain might be more or less at risk for the development of opiate use disorder when exposed to either illicit or prescription medication,” committee member David Clark, MD, professor of anesthesia, perioperative pain medicine, and pain at Stanford (Calif.) University, said during a webinar on the report.
“This leads up to one of our first recommendations, which is to invest in research to better understand pain and opiate use disorder,” Dr. Clark said. “We want to emphasize that we need to improve our understanding of the neurobiology of pain,” which will, hopefully, provide a better foundation for the development of nonopioid treatments.
The committee also recommended that the FDA:
- Incorporate public health considerations into opioid-related regulatory decisions.
- Require additional studies along with the collection and analysis of data needed to thoroughly assess broad public health considerations.
- Ensure that public health considerations are adequately incorporated into clinical development.
- Increase transparency of regulatory decisions for opioids in light of the proposed systems approach.
“The committee believes a commitment to transparency is critical to maintain balance between preserving access to opioids when needed and mitigating opioid-related harms and to maintain public trust,” the report’s authors said. “The committee also believes aggressive use of the FDA’s currently available authorities, such as Risk Evaluation and Mitigation Strategies (REMS), safety labeling changes, and risk communications is critical to supporting the safe and effective use of opioids.”
The committee also recommended strengthening the postapproval oversight of opioids.
A full review of currently marketed and approved opioids was also recommended, as was the application of public health consideration to opioid scheduling decisions.
“The particular characteristics of opioids, we believe, require a certain amount of what we term ‘opioid exceptionalism’ from the regulator in terms of trying to consider the larger societal effects of approval and use of opioid medication,” committee member Aaron S. Kesselheim, MD, JD, of Harvard Medical School, Boston, said during the webinar. “We believe that this public health approach is both reasonable for the FDA, given the fact that it is primarily a public health agency, and can be implemented at all different levels of the development process.”
Strategies recommended by the committee for the FDA, state agencies, health professionals, and relevant private organizations, such as through public-private partnerships, include:
- Restricting the supply of opioids, with careful attention to risks and benefits of interventions aimed at reducing the supply in the community. Recommendation: Improve access to drug take-back programs.
- Improving prescribing practices. Recommendations: Establish comprehensive pain education materials and curricula for health care providers; facilitate reimbursement for comprehensive pain management; and improve the use of prescription drug monitoring program data for surveillance and intervention.
- Reducing demand. Recommendations: Evaluate the impact on patient and public education about opioids on promoting safe and effective pain management; expand treatment for opioid use disorder; improve education regarding treatment of OUD for health care providers; and remove barriers to coverage of approved medication for OUD treatment.
- Reducing harm. Recommendations: Leverage prescribers and pharmacists to help address opioid use disorder; and improve access to naloxone and safe injection equipment.
According to the report, containing the opioid epidemic and ameliorating its harmful effects on society through the development of these strategies will require “years of sustained and coordinated effort.”
Indeed, things will get worse before they get better, the committee predicted.
“Trends indicate that premature deaths associated with the use of opioids are likely to climb and that opioid overdose and other opioid-related harm will dramatically reduce quality of life for many people for years to come,” the report’s authors noted. “Access to evidence-based treatment for OUD and efforts to prevent overdose deaths and other harms should therefore be increased substantially and immediately as a public health priority.”
A concerted, multiagency, multipronged counterattack is needed to break the opioid epidemic’s grip on the nation, according to a new report from the National Academies of Sciences, Engineering, and Medicine.
The report, commissioned by the Food and Drug Administration to strengthen its own 2016 Opioids Action Plan, presents a national strategy for addressing this “urgent public health priority.”
“The ongoing opioid crisis lies at the intersection of two substantial public health challenges – reducing the burden of suffering from pain and containing the rising toll of the harms that can result from the use of opioid medications,” according to a summary of the report, “Pain Management and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use.”
The National Academies’ Committee on Pain Management and Regulatory Strategies to Address Prescription Opioid Abuse spent more than a year studying the matter and developing the report. Among its recommendations is a call for investment in research to better understand pain and opioid use disorder.
“We have a specific lack of knowledge about how pain and opiate use disorder [OUD] interact – that is, why patients in pain might be more or less at risk for the development of opiate use disorder when exposed to either illicit or prescription medication,” committee member David Clark, MD, professor of anesthesia, perioperative pain medicine, and pain at Stanford (Calif.) University, said during a webinar on the report.
“This leads up to one of our first recommendations, which is to invest in research to better understand pain and opiate use disorder,” Dr. Clark said. “We want to emphasize that we need to improve our understanding of the neurobiology of pain,” which will, hopefully, provide a better foundation for the development of nonopioid treatments.
The committee also recommended that the FDA:
- Incorporate public health considerations into opioid-related regulatory decisions.
- Require additional studies along with the collection and analysis of data needed to thoroughly assess broad public health considerations.
- Ensure that public health considerations are adequately incorporated into clinical development.
- Increase transparency of regulatory decisions for opioids in light of the proposed systems approach.
“The committee believes a commitment to transparency is critical to maintain balance between preserving access to opioids when needed and mitigating opioid-related harms and to maintain public trust,” the report’s authors said. “The committee also believes aggressive use of the FDA’s currently available authorities, such as Risk Evaluation and Mitigation Strategies (REMS), safety labeling changes, and risk communications is critical to supporting the safe and effective use of opioids.”
The committee also recommended strengthening the postapproval oversight of opioids.
A full review of currently marketed and approved opioids was also recommended, as was the application of public health consideration to opioid scheduling decisions.
“The particular characteristics of opioids, we believe, require a certain amount of what we term ‘opioid exceptionalism’ from the regulator in terms of trying to consider the larger societal effects of approval and use of opioid medication,” committee member Aaron S. Kesselheim, MD, JD, of Harvard Medical School, Boston, said during the webinar. “We believe that this public health approach is both reasonable for the FDA, given the fact that it is primarily a public health agency, and can be implemented at all different levels of the development process.”
Strategies recommended by the committee for the FDA, state agencies, health professionals, and relevant private organizations, such as through public-private partnerships, include:
- Restricting the supply of opioids, with careful attention to risks and benefits of interventions aimed at reducing the supply in the community. Recommendation: Improve access to drug take-back programs.
- Improving prescribing practices. Recommendations: Establish comprehensive pain education materials and curricula for health care providers; facilitate reimbursement for comprehensive pain management; and improve the use of prescription drug monitoring program data for surveillance and intervention.
- Reducing demand. Recommendations: Evaluate the impact on patient and public education about opioids on promoting safe and effective pain management; expand treatment for opioid use disorder; improve education regarding treatment of OUD for health care providers; and remove barriers to coverage of approved medication for OUD treatment.
- Reducing harm. Recommendations: Leverage prescribers and pharmacists to help address opioid use disorder; and improve access to naloxone and safe injection equipment.
According to the report, containing the opioid epidemic and ameliorating its harmful effects on society through the development of these strategies will require “years of sustained and coordinated effort.”
Indeed, things will get worse before they get better, the committee predicted.
“Trends indicate that premature deaths associated with the use of opioids are likely to climb and that opioid overdose and other opioid-related harm will dramatically reduce quality of life for many people for years to come,” the report’s authors noted. “Access to evidence-based treatment for OUD and efforts to prevent overdose deaths and other harms should therefore be increased substantially and immediately as a public health priority.”
First-line obinutuzumab monotherapy in CLL linked to good response, reduced toxicity
NEW YORK – Obinutuzumab monotherapy was effective for the first-line treatment of chronic lymphocytic leukemia in a small study of patients with a high rate of unmutated immunoglobulin heavy-chain variable region (IGHV) genes.
The overall response rate to obinutuzumab, a type 2 anti-CD20 humanized monoclonal antibody, was 100% in 20 previously untreated patients. Median progression-free survival was 30 months, and no deaths occurred at a median of 23 months follow-up, Nathan D. Gay, MD, reported in a poster at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL).
The good results imply that initial monotherapy may be an alternative approach that limits the toxicity associated with the recommended combination of chlorambucil and obinutuzumab.
At the time of analysis, 3 of the 20 patients (15%) had relapsed, and the mean time to next line therapy was 29 months,” Dr. Gay of Oregon Health & Science University, Portland and his colleagues wrote. Minimal residual disease (MRD) analysis completed in 16 patients showed that 5 (31%) were MRD-negative 6 months after the completion of therapy.
Study participants were adults with a median age of 62.5 years and a median cumulative illness rating scale score of 6.5 on the 0-56 scale. Most (80%) had unmutated IGHV and none harbored 17p deletion. All met iwCLL diagnostic criteria for CLL based on peripheral blood counts and flow cytometry,
All but one patient received 6 cycles of intravenous obinutuzumab given at 100 mg on day 1, 900 mg on day 2, 1000 mg on days 8 and 15 of the first cycle, and 1000 mg on day 1 for cycles 2-6.
The remaining patient discontinued treatment after two cycles because of grade 4 neutropenia.
Obinutuzumab is approved for use in combination with oral chlorambucil in patients with previously untreated CLL. The approval was based on the CLL11 study, which demonstrated improved overall response, complete response rate, and peripheral blood MRD negativity rates with obinutuzumab plus chlorambucil, vs. rituximab plus chlorambucil, the authors said. Based on those findings, obinutuzumab plus chlorambucil is considered a standard of care option in treatment-naive CLL lacking del(17p)/TP53 mutation in patients who are not candidates for first-line therapy with fludarabine, cyclophosphamide, and rituximab (FCR).
However, while chlorambucil is generally well tolerated, it has limited efficacy and is associated with overall grade 3-4 toxicity of about 44%. Obinutuzumab has significant single-agent activity in previously untreated CLL and was shown in a recent phase 2 dose-response study to be associated with an overall response rate of 49%-67% and complete response rates of 5%-20%, but data on the efficacy of first line obinutuzumab monotherapy using standard dosing outside of a clinical trial are lacking, they said.
The current study represents an analysis of all patients treated with first line obinutuzumab monotherapy at Oregon Health & Science University.
In the current study, the most common side effects were infusion reactions and cytopenias. Grade 3 or higher neutropenia, anemia, and thrombocytopenia occurred in 32%, 11%, and 32% of patients, respectively, and one patient developed a grade 3 infection.
“In our cohort of patients with untreated CLL, we found first line obinutuzumab monotherapy to be very effective and well tolerated,” they wrote, noting that this was true despite a high rate of unmutated IGHV. “These data, using first-line obinutuzumab monotherapy, compare favorably with combination therapy with chlorambucil.
“Omitting chlorambucil from this combination in favor of initial obinutuzumab monotherapy may eliminate the short- and long-term toxicity associated with the use of chemotherapy,” they concluded.
The authors reported having no disclosures.
NEW YORK – Obinutuzumab monotherapy was effective for the first-line treatment of chronic lymphocytic leukemia in a small study of patients with a high rate of unmutated immunoglobulin heavy-chain variable region (IGHV) genes.
The overall response rate to obinutuzumab, a type 2 anti-CD20 humanized monoclonal antibody, was 100% in 20 previously untreated patients. Median progression-free survival was 30 months, and no deaths occurred at a median of 23 months follow-up, Nathan D. Gay, MD, reported in a poster at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL).
The good results imply that initial monotherapy may be an alternative approach that limits the toxicity associated with the recommended combination of chlorambucil and obinutuzumab.
At the time of analysis, 3 of the 20 patients (15%) had relapsed, and the mean time to next line therapy was 29 months,” Dr. Gay of Oregon Health & Science University, Portland and his colleagues wrote. Minimal residual disease (MRD) analysis completed in 16 patients showed that 5 (31%) were MRD-negative 6 months after the completion of therapy.
Study participants were adults with a median age of 62.5 years and a median cumulative illness rating scale score of 6.5 on the 0-56 scale. Most (80%) had unmutated IGHV and none harbored 17p deletion. All met iwCLL diagnostic criteria for CLL based on peripheral blood counts and flow cytometry,
All but one patient received 6 cycles of intravenous obinutuzumab given at 100 mg on day 1, 900 mg on day 2, 1000 mg on days 8 and 15 of the first cycle, and 1000 mg on day 1 for cycles 2-6.
The remaining patient discontinued treatment after two cycles because of grade 4 neutropenia.
Obinutuzumab is approved for use in combination with oral chlorambucil in patients with previously untreated CLL. The approval was based on the CLL11 study, which demonstrated improved overall response, complete response rate, and peripheral blood MRD negativity rates with obinutuzumab plus chlorambucil, vs. rituximab plus chlorambucil, the authors said. Based on those findings, obinutuzumab plus chlorambucil is considered a standard of care option in treatment-naive CLL lacking del(17p)/TP53 mutation in patients who are not candidates for first-line therapy with fludarabine, cyclophosphamide, and rituximab (FCR).
However, while chlorambucil is generally well tolerated, it has limited efficacy and is associated with overall grade 3-4 toxicity of about 44%. Obinutuzumab has significant single-agent activity in previously untreated CLL and was shown in a recent phase 2 dose-response study to be associated with an overall response rate of 49%-67% and complete response rates of 5%-20%, but data on the efficacy of first line obinutuzumab monotherapy using standard dosing outside of a clinical trial are lacking, they said.
The current study represents an analysis of all patients treated with first line obinutuzumab monotherapy at Oregon Health & Science University.
In the current study, the most common side effects were infusion reactions and cytopenias. Grade 3 or higher neutropenia, anemia, and thrombocytopenia occurred in 32%, 11%, and 32% of patients, respectively, and one patient developed a grade 3 infection.
“In our cohort of patients with untreated CLL, we found first line obinutuzumab monotherapy to be very effective and well tolerated,” they wrote, noting that this was true despite a high rate of unmutated IGHV. “These data, using first-line obinutuzumab monotherapy, compare favorably with combination therapy with chlorambucil.
“Omitting chlorambucil from this combination in favor of initial obinutuzumab monotherapy may eliminate the short- and long-term toxicity associated with the use of chemotherapy,” they concluded.
The authors reported having no disclosures.
NEW YORK – Obinutuzumab monotherapy was effective for the first-line treatment of chronic lymphocytic leukemia in a small study of patients with a high rate of unmutated immunoglobulin heavy-chain variable region (IGHV) genes.
The overall response rate to obinutuzumab, a type 2 anti-CD20 humanized monoclonal antibody, was 100% in 20 previously untreated patients. Median progression-free survival was 30 months, and no deaths occurred at a median of 23 months follow-up, Nathan D. Gay, MD, reported in a poster at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL).
The good results imply that initial monotherapy may be an alternative approach that limits the toxicity associated with the recommended combination of chlorambucil and obinutuzumab.
At the time of analysis, 3 of the 20 patients (15%) had relapsed, and the mean time to next line therapy was 29 months,” Dr. Gay of Oregon Health & Science University, Portland and his colleagues wrote. Minimal residual disease (MRD) analysis completed in 16 patients showed that 5 (31%) were MRD-negative 6 months after the completion of therapy.
Study participants were adults with a median age of 62.5 years and a median cumulative illness rating scale score of 6.5 on the 0-56 scale. Most (80%) had unmutated IGHV and none harbored 17p deletion. All met iwCLL diagnostic criteria for CLL based on peripheral blood counts and flow cytometry,
All but one patient received 6 cycles of intravenous obinutuzumab given at 100 mg on day 1, 900 mg on day 2, 1000 mg on days 8 and 15 of the first cycle, and 1000 mg on day 1 for cycles 2-6.
The remaining patient discontinued treatment after two cycles because of grade 4 neutropenia.
Obinutuzumab is approved for use in combination with oral chlorambucil in patients with previously untreated CLL. The approval was based on the CLL11 study, which demonstrated improved overall response, complete response rate, and peripheral blood MRD negativity rates with obinutuzumab plus chlorambucil, vs. rituximab plus chlorambucil, the authors said. Based on those findings, obinutuzumab plus chlorambucil is considered a standard of care option in treatment-naive CLL lacking del(17p)/TP53 mutation in patients who are not candidates for first-line therapy with fludarabine, cyclophosphamide, and rituximab (FCR).
However, while chlorambucil is generally well tolerated, it has limited efficacy and is associated with overall grade 3-4 toxicity of about 44%. Obinutuzumab has significant single-agent activity in previously untreated CLL and was shown in a recent phase 2 dose-response study to be associated with an overall response rate of 49%-67% and complete response rates of 5%-20%, but data on the efficacy of first line obinutuzumab monotherapy using standard dosing outside of a clinical trial are lacking, they said.
The current study represents an analysis of all patients treated with first line obinutuzumab monotherapy at Oregon Health & Science University.
In the current study, the most common side effects were infusion reactions and cytopenias. Grade 3 or higher neutropenia, anemia, and thrombocytopenia occurred in 32%, 11%, and 32% of patients, respectively, and one patient developed a grade 3 infection.
“In our cohort of patients with untreated CLL, we found first line obinutuzumab monotherapy to be very effective and well tolerated,” they wrote, noting that this was true despite a high rate of unmutated IGHV. “These data, using first-line obinutuzumab monotherapy, compare favorably with combination therapy with chlorambucil.
“Omitting chlorambucil from this combination in favor of initial obinutuzumab monotherapy may eliminate the short- and long-term toxicity associated with the use of chemotherapy,” they concluded.
The authors reported having no disclosures.
AT THE iwCLL MEETING
Key clinical point:
Major finding: Overall response rate, 100%; median progression-free survival, 30 months.
Data source: A study of 20 patients treated with obinutuzumab monotherapy.
Disclosures: The authors reported having no disclosures.
NF-kB inhibitor IT-901 shows promise in Richter syndrome
NEW YORK – The novel NF-kB inhibitor IT-901 appears active against Richter syndrome, according to in vitro analyses of primary leukemic cells and in vivo analyses in patient-derived xenograft models.
The findings suggest that NF-kB inhibition should be considered as a therapeutic strategy for Richter syndrome patients, Tiziana Vaisitti, PhD, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
Several factors have been shown to be associated with the development of Richter syndrome (RS), including somatic and germline genetic characteristics, biologic and clinical features, and certain CLL therapies. Recent studies have identified a critical role of mutations in specific genes, such as CKN2A, TP53, and NOTCH1 in the transformation of CLL to RS, which ultimately results in the aberrant activation of selected pathways – including NF-kB, Dr. Vaisitti of the University of Turin and the Italian Institute for Genomic Medicine, Turin, Italy explained.
In an ongoing study on the effects of IT-901 in CLL, she and her colleagues showed that “this compound was able to interfere with NF-kB transcriptional activity.”
That effect is followed by rapid and marked reduction in “the oxidative phosphorylation capacity of CLL cells, determined also by the transcriptional regulation of genes that control this process.”
“Moreover, this compound induces a significant increase and release of mitochondrial reactive oxygen species,” she said, adding: “The final result of this cascade of events is that IT-901 is able to rapidly induce apoptosis selectively in primary CLL cells, independently of the clinical subgroup of patients we are considering, and with very little toxicity on normal lymphocytes.”
The experimental data indicated that IT-901 is effective not only on the leukemic side, but it also acts on the stromal bystander component of the disease, mainly on nurse-like cells, by modulating the expression of molecules critical for CLL survival, she said.
Those findings were reported at the 2016 American Society of Hematology annual meeting (Blood. 2016;128:304).
For the current analyses, she and her colleagues tested the effects of IT-901 in RS, which affects up to 10% of patients with CLL, and for which there is an unmet therapeutic need. They looked at the mechanisms of action of the compound in leukemic cells both in vitro and in vivo.
In line with previous data, NF-kB was “constitutively highly active in RS cells freshly isolated from patients,” she reported.
Exposure to IT-901 at a 5 microM dose for 6 hours significantly decreased binding of p50 and p65 to DNA, and western blotting analyses on nuclear extracts indicated impaired translocation of those subunits in the nucleus, and compromised expression of the whole NF-kB complex, she said.
IT-901 also induced apoptosis in primary RS cells in a dose- and time-dependent manner; significant efficacy was seen after 24 hours of treatment, with more than half of the cells dead.
These results were then confirmed in an RS cell line established in the lab from a patient-derived xenograft (PDX) model, and even in the presence of a protective stromal layer IT-901 was able to induce apoptosis, she said.
The effects of IT-901 treatment were then analyzed in vivo using 3 different PDX models established from primary cells of RS patients and characterized by different molecular and genetic features. RS cells obtained from the PDX-tumor mass, were subcutaneously injected in severely immune-compromised mice and left to engraft until a palpable mass was present. IT-901 was then administered at a dose of 15 mg/kg, every day for 2 weeks, with a 2 day break after 5 days of administration.
Tumor size was significantly reduced, and as was demonstrated in vitro, immune-histochemical analyses of the tumor mass showed diminished expression and localization of the p65 subunit into the nucleus of tumor cells and increased cleavage of Caspase-3 in the treated mice as compared with vehicle-treated mice.
The findings provide proof-of-principle that IT-901 is effective in RS cells, diminishing NF-kB transcriptional activity and expression, and finally inducing apoptosis, Dr. Vaisitti said.
Dr. Vaisitti has received research funding from Immune Target.
NEW YORK – The novel NF-kB inhibitor IT-901 appears active against Richter syndrome, according to in vitro analyses of primary leukemic cells and in vivo analyses in patient-derived xenograft models.
The findings suggest that NF-kB inhibition should be considered as a therapeutic strategy for Richter syndrome patients, Tiziana Vaisitti, PhD, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
Several factors have been shown to be associated with the development of Richter syndrome (RS), including somatic and germline genetic characteristics, biologic and clinical features, and certain CLL therapies. Recent studies have identified a critical role of mutations in specific genes, such as CKN2A, TP53, and NOTCH1 in the transformation of CLL to RS, which ultimately results in the aberrant activation of selected pathways – including NF-kB, Dr. Vaisitti of the University of Turin and the Italian Institute for Genomic Medicine, Turin, Italy explained.
In an ongoing study on the effects of IT-901 in CLL, she and her colleagues showed that “this compound was able to interfere with NF-kB transcriptional activity.”
That effect is followed by rapid and marked reduction in “the oxidative phosphorylation capacity of CLL cells, determined also by the transcriptional regulation of genes that control this process.”
“Moreover, this compound induces a significant increase and release of mitochondrial reactive oxygen species,” she said, adding: “The final result of this cascade of events is that IT-901 is able to rapidly induce apoptosis selectively in primary CLL cells, independently of the clinical subgroup of patients we are considering, and with very little toxicity on normal lymphocytes.”
The experimental data indicated that IT-901 is effective not only on the leukemic side, but it also acts on the stromal bystander component of the disease, mainly on nurse-like cells, by modulating the expression of molecules critical for CLL survival, she said.
Those findings were reported at the 2016 American Society of Hematology annual meeting (Blood. 2016;128:304).
For the current analyses, she and her colleagues tested the effects of IT-901 in RS, which affects up to 10% of patients with CLL, and for which there is an unmet therapeutic need. They looked at the mechanisms of action of the compound in leukemic cells both in vitro and in vivo.
In line with previous data, NF-kB was “constitutively highly active in RS cells freshly isolated from patients,” she reported.
Exposure to IT-901 at a 5 microM dose for 6 hours significantly decreased binding of p50 and p65 to DNA, and western blotting analyses on nuclear extracts indicated impaired translocation of those subunits in the nucleus, and compromised expression of the whole NF-kB complex, she said.
IT-901 also induced apoptosis in primary RS cells in a dose- and time-dependent manner; significant efficacy was seen after 24 hours of treatment, with more than half of the cells dead.
These results were then confirmed in an RS cell line established in the lab from a patient-derived xenograft (PDX) model, and even in the presence of a protective stromal layer IT-901 was able to induce apoptosis, she said.
The effects of IT-901 treatment were then analyzed in vivo using 3 different PDX models established from primary cells of RS patients and characterized by different molecular and genetic features. RS cells obtained from the PDX-tumor mass, were subcutaneously injected in severely immune-compromised mice and left to engraft until a palpable mass was present. IT-901 was then administered at a dose of 15 mg/kg, every day for 2 weeks, with a 2 day break after 5 days of administration.
Tumor size was significantly reduced, and as was demonstrated in vitro, immune-histochemical analyses of the tumor mass showed diminished expression and localization of the p65 subunit into the nucleus of tumor cells and increased cleavage of Caspase-3 in the treated mice as compared with vehicle-treated mice.
The findings provide proof-of-principle that IT-901 is effective in RS cells, diminishing NF-kB transcriptional activity and expression, and finally inducing apoptosis, Dr. Vaisitti said.
Dr. Vaisitti has received research funding from Immune Target.
NEW YORK – The novel NF-kB inhibitor IT-901 appears active against Richter syndrome, according to in vitro analyses of primary leukemic cells and in vivo analyses in patient-derived xenograft models.
The findings suggest that NF-kB inhibition should be considered as a therapeutic strategy for Richter syndrome patients, Tiziana Vaisitti, PhD, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
Several factors have been shown to be associated with the development of Richter syndrome (RS), including somatic and germline genetic characteristics, biologic and clinical features, and certain CLL therapies. Recent studies have identified a critical role of mutations in specific genes, such as CKN2A, TP53, and NOTCH1 in the transformation of CLL to RS, which ultimately results in the aberrant activation of selected pathways – including NF-kB, Dr. Vaisitti of the University of Turin and the Italian Institute for Genomic Medicine, Turin, Italy explained.
In an ongoing study on the effects of IT-901 in CLL, she and her colleagues showed that “this compound was able to interfere with NF-kB transcriptional activity.”
That effect is followed by rapid and marked reduction in “the oxidative phosphorylation capacity of CLL cells, determined also by the transcriptional regulation of genes that control this process.”
“Moreover, this compound induces a significant increase and release of mitochondrial reactive oxygen species,” she said, adding: “The final result of this cascade of events is that IT-901 is able to rapidly induce apoptosis selectively in primary CLL cells, independently of the clinical subgroup of patients we are considering, and with very little toxicity on normal lymphocytes.”
The experimental data indicated that IT-901 is effective not only on the leukemic side, but it also acts on the stromal bystander component of the disease, mainly on nurse-like cells, by modulating the expression of molecules critical for CLL survival, she said.
Those findings were reported at the 2016 American Society of Hematology annual meeting (Blood. 2016;128:304).
For the current analyses, she and her colleagues tested the effects of IT-901 in RS, which affects up to 10% of patients with CLL, and for which there is an unmet therapeutic need. They looked at the mechanisms of action of the compound in leukemic cells both in vitro and in vivo.
In line with previous data, NF-kB was “constitutively highly active in RS cells freshly isolated from patients,” she reported.
Exposure to IT-901 at a 5 microM dose for 6 hours significantly decreased binding of p50 and p65 to DNA, and western blotting analyses on nuclear extracts indicated impaired translocation of those subunits in the nucleus, and compromised expression of the whole NF-kB complex, she said.
IT-901 also induced apoptosis in primary RS cells in a dose- and time-dependent manner; significant efficacy was seen after 24 hours of treatment, with more than half of the cells dead.
These results were then confirmed in an RS cell line established in the lab from a patient-derived xenograft (PDX) model, and even in the presence of a protective stromal layer IT-901 was able to induce apoptosis, she said.
The effects of IT-901 treatment were then analyzed in vivo using 3 different PDX models established from primary cells of RS patients and characterized by different molecular and genetic features. RS cells obtained from the PDX-tumor mass, were subcutaneously injected in severely immune-compromised mice and left to engraft until a palpable mass was present. IT-901 was then administered at a dose of 15 mg/kg, every day for 2 weeks, with a 2 day break after 5 days of administration.
Tumor size was significantly reduced, and as was demonstrated in vitro, immune-histochemical analyses of the tumor mass showed diminished expression and localization of the p65 subunit into the nucleus of tumor cells and increased cleavage of Caspase-3 in the treated mice as compared with vehicle-treated mice.
The findings provide proof-of-principle that IT-901 is effective in RS cells, diminishing NF-kB transcriptional activity and expression, and finally inducing apoptosis, Dr. Vaisitti said.
Dr. Vaisitti has received research funding from Immune Target.
AT THE iwCLL MEETING
Key clinical point:
Major finding: IT-901 induced apoptosis in primary RS cells in a dose- and time-dependent manner; significant efficacy was seen after 24 hours of treatment, with more than half of the cells dead.
Data source: In vitro and in vivo analyses.
Disclosures: Dr. Vaisitti has received research funding from Immune Target.
Telomere length predicts FCR response in CLL patients
NEW YORK – Telomere length reliably predicts response to fludarabine-cyclophosphamide-rituximab (FCR) treatment in patients with chronic lymphocytic leukemia, according to an analysis of 278 samples from the ARCTIC and ADMIRE clinical trials of FCR in previously untreated CLL.
The findings were particularly pronounced in the immunoglobulin heavy-chain variable region gene (IGHV)–mutated patients and suggest a role for telomere measurement as a predictive tool in risk-adapted clinical trials, Kevin Norris reported in a poster at the annual International Workshop on Chronic Lymphocytic Leukemia.
Short telomere length was associated with quicker time to progression (median of 3.9 years vs. 5.5 years; hazard ratio[HR], 2.04) and reduced overall survival (OS) (median of 5.5 years vs. OS not reached; HR, 2.1), compared with long telomere length. IGHV-mutated patients with short telomeres were more than five times more likely to relapse (median progression-free survival 2.97 vs. PFS not reached; HR, 5.1), and more than four times more likely to die than were patients with long telomere length (median OS, 4.15 years vs. OS not reached; HR, 4.16), said Mr. Norris, a research associate at Cardiff (Wales) University.
The association between telomere length and FCR response was less pronounced among IGHV-unmutated patients, but those with short telomeres in this group still had an inferior response and shorter survival, compared with those with long telomeres (HR, 1.6 and 1.6, respectively), he noted.
Mr. Norris also noted that in contrast to the telomere length findings, CD38 expression and b2-microglobulin were not predictive of time to progression or OS.
“In multivariate analysis, telomere length was the dominant covariable for both PFS (HR, 2.58) and OS (HR, 2.84); when telomere length was entered into the model no other variable retained independent prognostic significance,” he and his colleagues wrote.
Telomere length in this analysis was assessed by use of the high throughput single telomere length analysis (HT-STELA) assay.
It has recently been shown that a proportion of IGHV-mutated CLL patients treated with FCR can achieve long-term remissions. The current findings demonstrate that these patients can be accurately identified by measuring telomere length, the investigators said, noting that they saw a similar pattern in patients in the UK CLL4 trial who were treated with fludarabine and cyclophosphamide
“Our results demonstrate that telomere length is the major determinant of response and survival following treatment with FCR,” they wrote. “IGHV-mutated patients with longer telomeres have a high probability of achieving a long-term remission following treatment with FCR (greater than 81% survival after 5 years). Equally, IGHV-mutated patients with short dysfunctional telomeres show a markedly inferior response to FCR and should be considered for alternative treatment options in the frontline setting.”
Patient material for this study was obtained from the UK CLL Trials Biobank, University of Liverpool, which is funded by Bloodwise. The authors reported having no other disclosures.
NEW YORK – Telomere length reliably predicts response to fludarabine-cyclophosphamide-rituximab (FCR) treatment in patients with chronic lymphocytic leukemia, according to an analysis of 278 samples from the ARCTIC and ADMIRE clinical trials of FCR in previously untreated CLL.
The findings were particularly pronounced in the immunoglobulin heavy-chain variable region gene (IGHV)–mutated patients and suggest a role for telomere measurement as a predictive tool in risk-adapted clinical trials, Kevin Norris reported in a poster at the annual International Workshop on Chronic Lymphocytic Leukemia.
Short telomere length was associated with quicker time to progression (median of 3.9 years vs. 5.5 years; hazard ratio[HR], 2.04) and reduced overall survival (OS) (median of 5.5 years vs. OS not reached; HR, 2.1), compared with long telomere length. IGHV-mutated patients with short telomeres were more than five times more likely to relapse (median progression-free survival 2.97 vs. PFS not reached; HR, 5.1), and more than four times more likely to die than were patients with long telomere length (median OS, 4.15 years vs. OS not reached; HR, 4.16), said Mr. Norris, a research associate at Cardiff (Wales) University.
The association between telomere length and FCR response was less pronounced among IGHV-unmutated patients, but those with short telomeres in this group still had an inferior response and shorter survival, compared with those with long telomeres (HR, 1.6 and 1.6, respectively), he noted.
Mr. Norris also noted that in contrast to the telomere length findings, CD38 expression and b2-microglobulin were not predictive of time to progression or OS.
“In multivariate analysis, telomere length was the dominant covariable for both PFS (HR, 2.58) and OS (HR, 2.84); when telomere length was entered into the model no other variable retained independent prognostic significance,” he and his colleagues wrote.
Telomere length in this analysis was assessed by use of the high throughput single telomere length analysis (HT-STELA) assay.
It has recently been shown that a proportion of IGHV-mutated CLL patients treated with FCR can achieve long-term remissions. The current findings demonstrate that these patients can be accurately identified by measuring telomere length, the investigators said, noting that they saw a similar pattern in patients in the UK CLL4 trial who were treated with fludarabine and cyclophosphamide
“Our results demonstrate that telomere length is the major determinant of response and survival following treatment with FCR,” they wrote. “IGHV-mutated patients with longer telomeres have a high probability of achieving a long-term remission following treatment with FCR (greater than 81% survival after 5 years). Equally, IGHV-mutated patients with short dysfunctional telomeres show a markedly inferior response to FCR and should be considered for alternative treatment options in the frontline setting.”
Patient material for this study was obtained from the UK CLL Trials Biobank, University of Liverpool, which is funded by Bloodwise. The authors reported having no other disclosures.
NEW YORK – Telomere length reliably predicts response to fludarabine-cyclophosphamide-rituximab (FCR) treatment in patients with chronic lymphocytic leukemia, according to an analysis of 278 samples from the ARCTIC and ADMIRE clinical trials of FCR in previously untreated CLL.
The findings were particularly pronounced in the immunoglobulin heavy-chain variable region gene (IGHV)–mutated patients and suggest a role for telomere measurement as a predictive tool in risk-adapted clinical trials, Kevin Norris reported in a poster at the annual International Workshop on Chronic Lymphocytic Leukemia.
Short telomere length was associated with quicker time to progression (median of 3.9 years vs. 5.5 years; hazard ratio[HR], 2.04) and reduced overall survival (OS) (median of 5.5 years vs. OS not reached; HR, 2.1), compared with long telomere length. IGHV-mutated patients with short telomeres were more than five times more likely to relapse (median progression-free survival 2.97 vs. PFS not reached; HR, 5.1), and more than four times more likely to die than were patients with long telomere length (median OS, 4.15 years vs. OS not reached; HR, 4.16), said Mr. Norris, a research associate at Cardiff (Wales) University.
The association between telomere length and FCR response was less pronounced among IGHV-unmutated patients, but those with short telomeres in this group still had an inferior response and shorter survival, compared with those with long telomeres (HR, 1.6 and 1.6, respectively), he noted.
Mr. Norris also noted that in contrast to the telomere length findings, CD38 expression and b2-microglobulin were not predictive of time to progression or OS.
“In multivariate analysis, telomere length was the dominant covariable for both PFS (HR, 2.58) and OS (HR, 2.84); when telomere length was entered into the model no other variable retained independent prognostic significance,” he and his colleagues wrote.
Telomere length in this analysis was assessed by use of the high throughput single telomere length analysis (HT-STELA) assay.
It has recently been shown that a proportion of IGHV-mutated CLL patients treated with FCR can achieve long-term remissions. The current findings demonstrate that these patients can be accurately identified by measuring telomere length, the investigators said, noting that they saw a similar pattern in patients in the UK CLL4 trial who were treated with fludarabine and cyclophosphamide
“Our results demonstrate that telomere length is the major determinant of response and survival following treatment with FCR,” they wrote. “IGHV-mutated patients with longer telomeres have a high probability of achieving a long-term remission following treatment with FCR (greater than 81% survival after 5 years). Equally, IGHV-mutated patients with short dysfunctional telomeres show a markedly inferior response to FCR and should be considered for alternative treatment options in the frontline setting.”
Patient material for this study was obtained from the UK CLL Trials Biobank, University of Liverpool, which is funded by Bloodwise. The authors reported having no other disclosures.
AT THE iwCLL MEETING
Key clinical point:
Major finding: Short vs. long telomere length was associated with quicker time to progression and reduced overall survival (hazard ratios, 2.04 and 2.1, respectively).
Data source: An analysis of 278 samples from the ARCTIC and ADMIRE trials.
Disclosures: Patient material for this study was obtained from the UK CLL Trials Biobank, University of Liverpool, which is funded by Bloodwise. The authors reported having no other disclosures.
SOLE trial: Intermittent letrozole may provide benefit for some breast cancer patients
CHICAGO – Five years of extended intermittent letrozole provided no overall improvement in disease-free survival (DFS) when compared with continuous treatment with the aromatase inhibitor among postmenopausal women who received 4-6 years of endocrine therapy for hormone receptor–positive, lymph node–positive early breast cancer in the randomized phase III Study of Letrozole Extension (SOLE).
However, the similarities in DFS and adverse events incidence in the intermittent and continuous treatment groups – and improvements in a number of quality of life measures with intermittent treatment – suggest that temporary treatment breaks are acceptable in those who could benefit from them, Marco Colleoni, MD, reported at the annual meeting of the American Society of Clinical Oncology.
The DFS among 2,425 women who received 5 years of intermittent letrozole after completing 4-6 years of adjuvant endocrine therapy was 85.8%, compared with 87.5% among 2,426 women who received 5 years of continuous letrozole after adjuvant therapy (hazard ratio, 1.08) said Dr. Colleoni of the European Institute of Oncology, Milan, Italy.
Similar outcomes were observed for breast cancer–free interval (HR, 0.98), distant recurrence-free interval (HR, 0.88), and overall survival (HR, 0.85), he said.
Of note, trends toward greater improvement on both the primary and secondary endpoints were seen with continuous therapy among those who received prior selective estrogen receptor modulator (SERM) vs. aromatase inhibitor (AI) therapy, but the differences did not reach statistical significance, he said.
Adjuvant extended endocrine therapy with letrozole has been recommended after initial tamoxifen for postmenopausal women with hormone receptor–positive (HR+) breast cancer, but the magnitude of the beneficial effect of extended letrozole in women who previously received an aromatase inhibitor has been limited, Dr. Colleoni said.
“Therefore, based on available data, the use of an AI for 10 years should be discussed on an individualized basis,” he said.
However, there is rationale for the intermittent use of letrozole as a therapeutic option to prolong sensitivity to endocrine therapies,” he noted.
“Breast cancer cells, in fact, can develop resistance following antihormonal therapy. In particular, cells that are maintained estrogen-free for years start to grow spontaneously. It has been shown ... that minimal concentrations of estrogen, similar to those achievable through interruption of treatment with aromatase inhibitors, can produce a cytocidal effect on cells that are deprived of estrogen,” he explained. “Moreover, in breast cancer cells transplanted into animal models, a response to a 6-week withdrawal of letrozole was observed when the treatment was started again.”
Thus, the SOLE study was designed to look at the value of extended adjuvant therapy in patients with HR+ breast cancer, the role of intermittent administration of letrozole in patients previously treated with AIs, the impact of intermittent vs. continuous administration on the side effect profile and quality of life and adherence to intermittent administration, he said.
Study participants were women with a median age of 60 years who were enrolled from 240 centers in 22 countries between November 2007 and July 2012. They had HR+ invasive breast cancer, any HER2 status, and disease confined to the breast and axillary lymph nodes. All had received SERM, AI, or combination SERM and AI treatment for 4-6 years but must have discontinued that therapy within 1 year prior to randomization.
Women in the intermittent treatment group were treated for the first 9 months of years 1-4 and for 12 months in year 5. Those in the continuous treatment group received 2.5 mg of letrozole daily for 5 years.
The adverse events were as expected, with 36.2% and 34.5% of patients in the intermittent and continuous treatment groups experiencing grade 3 or 5 events, respectively, and were similar, Dr. Colleoni said.
Treatment was discontinued for DFS events in 8% of patients and for other reasons in 24% of patients. Treatment was completed by 39% of patients and currently is ongoing in 29%, he said.
“When we designed the SOLE study, we were worried about ... the treatment gap. We’re delighted to observe that more than 90% of the patients regularly resumed [treatment] after interruption, ... reassuring [us of] the feasibility of a treatment gap during extended adjuvant letrozole,” he said.
Additionally, a quality of life substudy of 955 patients from the SOLE trial, who were assessed at baseline and at 6, 12, 18, and 24 months, showed a consistent pattern favoring intermittent therapy on patient-reported quality of life measures. Specifically, there was significantly less worsening from baseline with respect to vaginal problems, musculoskeletal pain, sleep disturbance, physical wellbeing, and mood at 12 months in the intermittent vs. continuous letrozole group and significantly greater improvement in hot flashes at 24 months in the intermittent vs. continuous group, he said.
“The results ... provide clinically relevant information on intermittent administration of extended letrozole for patients who could benefit from temporary treatment breaks,” he concluded, noting that translational studies are ongoing, such as measurement of estradiol levels during treatment gaps.
The SOLE trial was supported by Novartis. Dr. Colleoni reported receiving honoraria from Novartis, and serving as a consultant or advisor for AstraZeneca, Celldex, OBI Pharma, Pfizer, Pierre Fabre, and Puma Biotechnology.
CHICAGO – Five years of extended intermittent letrozole provided no overall improvement in disease-free survival (DFS) when compared with continuous treatment with the aromatase inhibitor among postmenopausal women who received 4-6 years of endocrine therapy for hormone receptor–positive, lymph node–positive early breast cancer in the randomized phase III Study of Letrozole Extension (SOLE).
However, the similarities in DFS and adverse events incidence in the intermittent and continuous treatment groups – and improvements in a number of quality of life measures with intermittent treatment – suggest that temporary treatment breaks are acceptable in those who could benefit from them, Marco Colleoni, MD, reported at the annual meeting of the American Society of Clinical Oncology.
The DFS among 2,425 women who received 5 years of intermittent letrozole after completing 4-6 years of adjuvant endocrine therapy was 85.8%, compared with 87.5% among 2,426 women who received 5 years of continuous letrozole after adjuvant therapy (hazard ratio, 1.08) said Dr. Colleoni of the European Institute of Oncology, Milan, Italy.
Similar outcomes were observed for breast cancer–free interval (HR, 0.98), distant recurrence-free interval (HR, 0.88), and overall survival (HR, 0.85), he said.
Of note, trends toward greater improvement on both the primary and secondary endpoints were seen with continuous therapy among those who received prior selective estrogen receptor modulator (SERM) vs. aromatase inhibitor (AI) therapy, but the differences did not reach statistical significance, he said.
Adjuvant extended endocrine therapy with letrozole has been recommended after initial tamoxifen for postmenopausal women with hormone receptor–positive (HR+) breast cancer, but the magnitude of the beneficial effect of extended letrozole in women who previously received an aromatase inhibitor has been limited, Dr. Colleoni said.
“Therefore, based on available data, the use of an AI for 10 years should be discussed on an individualized basis,” he said.
However, there is rationale for the intermittent use of letrozole as a therapeutic option to prolong sensitivity to endocrine therapies,” he noted.
“Breast cancer cells, in fact, can develop resistance following antihormonal therapy. In particular, cells that are maintained estrogen-free for years start to grow spontaneously. It has been shown ... that minimal concentrations of estrogen, similar to those achievable through interruption of treatment with aromatase inhibitors, can produce a cytocidal effect on cells that are deprived of estrogen,” he explained. “Moreover, in breast cancer cells transplanted into animal models, a response to a 6-week withdrawal of letrozole was observed when the treatment was started again.”
Thus, the SOLE study was designed to look at the value of extended adjuvant therapy in patients with HR+ breast cancer, the role of intermittent administration of letrozole in patients previously treated with AIs, the impact of intermittent vs. continuous administration on the side effect profile and quality of life and adherence to intermittent administration, he said.
Study participants were women with a median age of 60 years who were enrolled from 240 centers in 22 countries between November 2007 and July 2012. They had HR+ invasive breast cancer, any HER2 status, and disease confined to the breast and axillary lymph nodes. All had received SERM, AI, or combination SERM and AI treatment for 4-6 years but must have discontinued that therapy within 1 year prior to randomization.
Women in the intermittent treatment group were treated for the first 9 months of years 1-4 and for 12 months in year 5. Those in the continuous treatment group received 2.5 mg of letrozole daily for 5 years.
The adverse events were as expected, with 36.2% and 34.5% of patients in the intermittent and continuous treatment groups experiencing grade 3 or 5 events, respectively, and were similar, Dr. Colleoni said.
Treatment was discontinued for DFS events in 8% of patients and for other reasons in 24% of patients. Treatment was completed by 39% of patients and currently is ongoing in 29%, he said.
“When we designed the SOLE study, we were worried about ... the treatment gap. We’re delighted to observe that more than 90% of the patients regularly resumed [treatment] after interruption, ... reassuring [us of] the feasibility of a treatment gap during extended adjuvant letrozole,” he said.
Additionally, a quality of life substudy of 955 patients from the SOLE trial, who were assessed at baseline and at 6, 12, 18, and 24 months, showed a consistent pattern favoring intermittent therapy on patient-reported quality of life measures. Specifically, there was significantly less worsening from baseline with respect to vaginal problems, musculoskeletal pain, sleep disturbance, physical wellbeing, and mood at 12 months in the intermittent vs. continuous letrozole group and significantly greater improvement in hot flashes at 24 months in the intermittent vs. continuous group, he said.
“The results ... provide clinically relevant information on intermittent administration of extended letrozole for patients who could benefit from temporary treatment breaks,” he concluded, noting that translational studies are ongoing, such as measurement of estradiol levels during treatment gaps.
The SOLE trial was supported by Novartis. Dr. Colleoni reported receiving honoraria from Novartis, and serving as a consultant or advisor for AstraZeneca, Celldex, OBI Pharma, Pfizer, Pierre Fabre, and Puma Biotechnology.
CHICAGO – Five years of extended intermittent letrozole provided no overall improvement in disease-free survival (DFS) when compared with continuous treatment with the aromatase inhibitor among postmenopausal women who received 4-6 years of endocrine therapy for hormone receptor–positive, lymph node–positive early breast cancer in the randomized phase III Study of Letrozole Extension (SOLE).
However, the similarities in DFS and adverse events incidence in the intermittent and continuous treatment groups – and improvements in a number of quality of life measures with intermittent treatment – suggest that temporary treatment breaks are acceptable in those who could benefit from them, Marco Colleoni, MD, reported at the annual meeting of the American Society of Clinical Oncology.
The DFS among 2,425 women who received 5 years of intermittent letrozole after completing 4-6 years of adjuvant endocrine therapy was 85.8%, compared with 87.5% among 2,426 women who received 5 years of continuous letrozole after adjuvant therapy (hazard ratio, 1.08) said Dr. Colleoni of the European Institute of Oncology, Milan, Italy.
Similar outcomes were observed for breast cancer–free interval (HR, 0.98), distant recurrence-free interval (HR, 0.88), and overall survival (HR, 0.85), he said.
Of note, trends toward greater improvement on both the primary and secondary endpoints were seen with continuous therapy among those who received prior selective estrogen receptor modulator (SERM) vs. aromatase inhibitor (AI) therapy, but the differences did not reach statistical significance, he said.
Adjuvant extended endocrine therapy with letrozole has been recommended after initial tamoxifen for postmenopausal women with hormone receptor–positive (HR+) breast cancer, but the magnitude of the beneficial effect of extended letrozole in women who previously received an aromatase inhibitor has been limited, Dr. Colleoni said.
“Therefore, based on available data, the use of an AI for 10 years should be discussed on an individualized basis,” he said.
However, there is rationale for the intermittent use of letrozole as a therapeutic option to prolong sensitivity to endocrine therapies,” he noted.
“Breast cancer cells, in fact, can develop resistance following antihormonal therapy. In particular, cells that are maintained estrogen-free for years start to grow spontaneously. It has been shown ... that minimal concentrations of estrogen, similar to those achievable through interruption of treatment with aromatase inhibitors, can produce a cytocidal effect on cells that are deprived of estrogen,” he explained. “Moreover, in breast cancer cells transplanted into animal models, a response to a 6-week withdrawal of letrozole was observed when the treatment was started again.”
Thus, the SOLE study was designed to look at the value of extended adjuvant therapy in patients with HR+ breast cancer, the role of intermittent administration of letrozole in patients previously treated with AIs, the impact of intermittent vs. continuous administration on the side effect profile and quality of life and adherence to intermittent administration, he said.
Study participants were women with a median age of 60 years who were enrolled from 240 centers in 22 countries between November 2007 and July 2012. They had HR+ invasive breast cancer, any HER2 status, and disease confined to the breast and axillary lymph nodes. All had received SERM, AI, or combination SERM and AI treatment for 4-6 years but must have discontinued that therapy within 1 year prior to randomization.
Women in the intermittent treatment group were treated for the first 9 months of years 1-4 and for 12 months in year 5. Those in the continuous treatment group received 2.5 mg of letrozole daily for 5 years.
The adverse events were as expected, with 36.2% and 34.5% of patients in the intermittent and continuous treatment groups experiencing grade 3 or 5 events, respectively, and were similar, Dr. Colleoni said.
Treatment was discontinued for DFS events in 8% of patients and for other reasons in 24% of patients. Treatment was completed by 39% of patients and currently is ongoing in 29%, he said.
“When we designed the SOLE study, we were worried about ... the treatment gap. We’re delighted to observe that more than 90% of the patients regularly resumed [treatment] after interruption, ... reassuring [us of] the feasibility of a treatment gap during extended adjuvant letrozole,” he said.
Additionally, a quality of life substudy of 955 patients from the SOLE trial, who were assessed at baseline and at 6, 12, 18, and 24 months, showed a consistent pattern favoring intermittent therapy on patient-reported quality of life measures. Specifically, there was significantly less worsening from baseline with respect to vaginal problems, musculoskeletal pain, sleep disturbance, physical wellbeing, and mood at 12 months in the intermittent vs. continuous letrozole group and significantly greater improvement in hot flashes at 24 months in the intermittent vs. continuous group, he said.
“The results ... provide clinically relevant information on intermittent administration of extended letrozole for patients who could benefit from temporary treatment breaks,” he concluded, noting that translational studies are ongoing, such as measurement of estradiol levels during treatment gaps.
The SOLE trial was supported by Novartis. Dr. Colleoni reported receiving honoraria from Novartis, and serving as a consultant or advisor for AstraZeneca, Celldex, OBI Pharma, Pfizer, Pierre Fabre, and Puma Biotechnology.
AT ASCO 2017
Key clinical point:
Major finding: Disease-free survival was 85.8% and 87.5% with intermittent and continuous letrozole, respectively (hazard ratio, 1.08).
Data source: The phase III SOLE study of 4,851 women.
Disclosures: The SOLE trial was supported by Novartis. Dr. Colleoni reported receiving honoraria from Novartis and serving as a consultant or advisor for AstraZeneca, Celldex, OBI Pharma, Pfizer, Pierre Fabre, and Puma Biotechnology.
ALTTO follow-up: Dual HER2 blockade may benefit HER2+/HR- tumors
CHICAGO – HER2-positive/HR-negative breast tumors may have a different biology than HER2+/HR+ tumors and may derive more benefit from dual HER2 blockade, according to 5-year results from the phase III ALTTO trial comparing 1 year of adjuvant anti-HER2 therapy with lapatinib and trastuzumab alone, sequentially, or in combination in patients with HER2-positive early breast cancer.
The hazard ratios for this preplanned updated analysis at a median of 6.9 years of follow-up (when all patients had reached 5 years of follow-up) are similar to those from the primary analysis reported at the 2014 ASCO annual meeting and published in the Journal of Clinical Oncology in 2015 (J Clin Oncol. 2015;34:1034-42) at a median clinical follow-up of 4.5 years, Alvaro Moreno-Aspitia, MD, reported at the annual meeting of the American Society of Clinical Oncology.
In the current analysis, the rate of disease-free survival was 85% with combined lapatinib and trastuzumab (L+T), 84% for sequential trastuzumab and lapatinib (T–L), and 82% with T (hazard ratio for disease-free survival was 0.86 for L+T vs. T and 0.93 for T–L vs. T alone,) said Dr. Moreno-Aspitia of Mayo Clinic, Jacksonville, Fla.
“So, at this time, as noted in the primary analysis, there’s no benefit on the primary endpoint in regard to dual HER2 blockade as provided in this clinical trial,” he said.
There also were no significant differences seen in disease-free survival based on chemotherapy timing, he said.
Notably, disease-free survival was similar across treatment groups among patients with HER2+/HR+ tumors (85% for L+T, 85% to T–L, and 83% for T; HRs, 0.91 and 0.90 vs. T, respectively), but, among those with HER2+/HR– tumors, the 6-year disease-free survival difference for L+T (84%) vs. T (80%) was slightly greater (HR, 0.80).
“This is a hypothesis generating observation that also holds that possibly these patients with hormone receptor–negative tumors may derive benefit from dual HER2 blockade,” Dr. Moreno-Aspitia said, noting that this has also been observed in several other trials.
The 6-year overall survival in ALTTO was 93%, 92%, and 91% for L+T, T–L, and T, respectively (HRs for overall survival, 0.86 for L+T vs. T and 0.88 for T–L).
“At this time, there is absolutely no [overall survival] benefit on dual HER2 blockade over single agent trastuzumab. However, it is very rewarding to see that over 90% of the patients who participated in this trial are alive at this longer-term follow-up,” he said.
As for cardiac events, the numbers remained low as in the primary ALTTO analysis, and no new safety signals had emerged.
ALTTO study subjects were 8,381 patients randomized from 946 sites in 44 countries between June 2007 and July 2011. Those in the L+T group received both agents together for 52 weeks; those in the sequential treatment group received T for 12 weeks followed by a 6-week wash-out period, followed by lapatinib for 34 weeks; and those in the trastuzumab arm (the control arm) and the lapatinib arm each received treatment for 52 weeks. In 2011 the lapatinib arm was closed because of futility, and results for that arm are not included in this analysis.
Long-term follow up of participants continues, a large number of correlative studies are ongoing, and final results will be reported when all patients have been followed for at least 10 years, Dr. Moreno-Aspitia said.
The ALTTO trial was sponsored by GlaxoSmithKline and Novartis. Dr. Moreno-Aspitia reported having no disclosures.
CHICAGO – HER2-positive/HR-negative breast tumors may have a different biology than HER2+/HR+ tumors and may derive more benefit from dual HER2 blockade, according to 5-year results from the phase III ALTTO trial comparing 1 year of adjuvant anti-HER2 therapy with lapatinib and trastuzumab alone, sequentially, or in combination in patients with HER2-positive early breast cancer.
The hazard ratios for this preplanned updated analysis at a median of 6.9 years of follow-up (when all patients had reached 5 years of follow-up) are similar to those from the primary analysis reported at the 2014 ASCO annual meeting and published in the Journal of Clinical Oncology in 2015 (J Clin Oncol. 2015;34:1034-42) at a median clinical follow-up of 4.5 years, Alvaro Moreno-Aspitia, MD, reported at the annual meeting of the American Society of Clinical Oncology.
In the current analysis, the rate of disease-free survival was 85% with combined lapatinib and trastuzumab (L+T), 84% for sequential trastuzumab and lapatinib (T–L), and 82% with T (hazard ratio for disease-free survival was 0.86 for L+T vs. T and 0.93 for T–L vs. T alone,) said Dr. Moreno-Aspitia of Mayo Clinic, Jacksonville, Fla.
“So, at this time, as noted in the primary analysis, there’s no benefit on the primary endpoint in regard to dual HER2 blockade as provided in this clinical trial,” he said.
There also were no significant differences seen in disease-free survival based on chemotherapy timing, he said.
Notably, disease-free survival was similar across treatment groups among patients with HER2+/HR+ tumors (85% for L+T, 85% to T–L, and 83% for T; HRs, 0.91 and 0.90 vs. T, respectively), but, among those with HER2+/HR– tumors, the 6-year disease-free survival difference for L+T (84%) vs. T (80%) was slightly greater (HR, 0.80).
“This is a hypothesis generating observation that also holds that possibly these patients with hormone receptor–negative tumors may derive benefit from dual HER2 blockade,” Dr. Moreno-Aspitia said, noting that this has also been observed in several other trials.
The 6-year overall survival in ALTTO was 93%, 92%, and 91% for L+T, T–L, and T, respectively (HRs for overall survival, 0.86 for L+T vs. T and 0.88 for T–L).
“At this time, there is absolutely no [overall survival] benefit on dual HER2 blockade over single agent trastuzumab. However, it is very rewarding to see that over 90% of the patients who participated in this trial are alive at this longer-term follow-up,” he said.
As for cardiac events, the numbers remained low as in the primary ALTTO analysis, and no new safety signals had emerged.
ALTTO study subjects were 8,381 patients randomized from 946 sites in 44 countries between June 2007 and July 2011. Those in the L+T group received both agents together for 52 weeks; those in the sequential treatment group received T for 12 weeks followed by a 6-week wash-out period, followed by lapatinib for 34 weeks; and those in the trastuzumab arm (the control arm) and the lapatinib arm each received treatment for 52 weeks. In 2011 the lapatinib arm was closed because of futility, and results for that arm are not included in this analysis.
Long-term follow up of participants continues, a large number of correlative studies are ongoing, and final results will be reported when all patients have been followed for at least 10 years, Dr. Moreno-Aspitia said.
The ALTTO trial was sponsored by GlaxoSmithKline and Novartis. Dr. Moreno-Aspitia reported having no disclosures.
CHICAGO – HER2-positive/HR-negative breast tumors may have a different biology than HER2+/HR+ tumors and may derive more benefit from dual HER2 blockade, according to 5-year results from the phase III ALTTO trial comparing 1 year of adjuvant anti-HER2 therapy with lapatinib and trastuzumab alone, sequentially, or in combination in patients with HER2-positive early breast cancer.
The hazard ratios for this preplanned updated analysis at a median of 6.9 years of follow-up (when all patients had reached 5 years of follow-up) are similar to those from the primary analysis reported at the 2014 ASCO annual meeting and published in the Journal of Clinical Oncology in 2015 (J Clin Oncol. 2015;34:1034-42) at a median clinical follow-up of 4.5 years, Alvaro Moreno-Aspitia, MD, reported at the annual meeting of the American Society of Clinical Oncology.
In the current analysis, the rate of disease-free survival was 85% with combined lapatinib and trastuzumab (L+T), 84% for sequential trastuzumab and lapatinib (T–L), and 82% with T (hazard ratio for disease-free survival was 0.86 for L+T vs. T and 0.93 for T–L vs. T alone,) said Dr. Moreno-Aspitia of Mayo Clinic, Jacksonville, Fla.
“So, at this time, as noted in the primary analysis, there’s no benefit on the primary endpoint in regard to dual HER2 blockade as provided in this clinical trial,” he said.
There also were no significant differences seen in disease-free survival based on chemotherapy timing, he said.
Notably, disease-free survival was similar across treatment groups among patients with HER2+/HR+ tumors (85% for L+T, 85% to T–L, and 83% for T; HRs, 0.91 and 0.90 vs. T, respectively), but, among those with HER2+/HR– tumors, the 6-year disease-free survival difference for L+T (84%) vs. T (80%) was slightly greater (HR, 0.80).
“This is a hypothesis generating observation that also holds that possibly these patients with hormone receptor–negative tumors may derive benefit from dual HER2 blockade,” Dr. Moreno-Aspitia said, noting that this has also been observed in several other trials.
The 6-year overall survival in ALTTO was 93%, 92%, and 91% for L+T, T–L, and T, respectively (HRs for overall survival, 0.86 for L+T vs. T and 0.88 for T–L).
“At this time, there is absolutely no [overall survival] benefit on dual HER2 blockade over single agent trastuzumab. However, it is very rewarding to see that over 90% of the patients who participated in this trial are alive at this longer-term follow-up,” he said.
As for cardiac events, the numbers remained low as in the primary ALTTO analysis, and no new safety signals had emerged.
ALTTO study subjects were 8,381 patients randomized from 946 sites in 44 countries between June 2007 and July 2011. Those in the L+T group received both agents together for 52 weeks; those in the sequential treatment group received T for 12 weeks followed by a 6-week wash-out period, followed by lapatinib for 34 weeks; and those in the trastuzumab arm (the control arm) and the lapatinib arm each received treatment for 52 weeks. In 2011 the lapatinib arm was closed because of futility, and results for that arm are not included in this analysis.
Long-term follow up of participants continues, a large number of correlative studies are ongoing, and final results will be reported when all patients have been followed for at least 10 years, Dr. Moreno-Aspitia said.
The ALTTO trial was sponsored by GlaxoSmithKline and Novartis. Dr. Moreno-Aspitia reported having no disclosures.
AT ASCO 2017
Key clinical point:
Major finding: DFS differed slightly between lapatinib plus trastuzumab and trastuzumab alone (84% vs. 80%; HR, 0.80) among those with HER2+/HR-negative tumors but not among those with HER2+/HR+ tumors.
Data source: The phase III ALTTO trial of 8,381 patients.
Disclosures: The ALTTO trial was sponsored by GlaxoSmithKline and Novartis. Dr. Moreno-Aspitia reported having no disclosures.
FDA advisory committee supports new CV liraglutide indication
A Food and Drug Administration advisory committee voted 17-2 in support of a supplemental new drug application for liraglutide (Victoza) injections to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease.
Novo Nordisk, the maker of the glucagon-like peptide-1 (GLP-1) analogue, proposed the additional indication for liraglutide as an adjunct to standard treatment of cardiovascular risk factors in such patients based solely on the results of the randomized, placebo-controlled postmarketing LEADER trial.
If this additional indication for liraglutide is approved by the FDA, the drug would join the antidiabetic drug empagliflozin (Jardiance) in having a second indication for the reduction of the risk of cardiovascular death. The supplemental new drug application for Jardiance was approved by the FDA in December 2016 – also based on the results of a single trial (the EMPA-REG outcomes trial). Of note, the American Diabetes Association in its 2017 Standards of Medical Care has already called for consideration of both liraglutide and empagliflozin to reduce the risk of cardiovascular death in patients with type 2 diabetes and documented cardiovascular disease.
Liraglutide is currently approved for blood glucose lowering in adults with type 2 diabetes and is marketed as Saxenda for the treatment of overweight and obese adults with at least one weight-related comorbidity. It was shown in the LEADER trial to be associated with a significant 13% lower risk vs. placebo for a composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke in patients with type 2 diabetes.
All 19 voting members of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) agreed that the LEADER results confirm there is no excess cardiovascular risk associated with liraglutide in patients with type 2 diabetes, but, on the question of whether the results provide “the substantial evidence required to establish that liraglutide 1.8 mg reduces cardiovascular risk in patients with type 2 diabetes mellitus and established cardiovascular disease,” almost all voting members expressed concerns about subgroup analyses showing reduced benefit among U.S. patients, compared with those from other countries.
“I think probably the most influential finding for me was the overall cardiovascular mortality finding, followed by the consistency of the results,” said biostatistics expert James D. Neaton, PhD, of the University of Minnesota, Minneapolis. He added that the indication should focus on patients at high cardiovascular event risk, as the LEADER population was a very high risk group.
Similarly, temporary voting member Marvin A. Konstam, MD, of Tufts University, Boston, said “the primary trial results are very robust and substantiated.
“And I think the cardiovascular mortality is the biggest contributor to that, which is obviously a very important finding,” he said, also stressing that the indication should focus on patients with established cardiovascular disease.
“I am concerned about the U.S. population, but at the end of the day, it’s a subgroup, and I just can’t overrate that to diminish the overall finding,” he added.
Peter W.F. Wilson, MD, EMDAC chairperson, said he “wrestles with exactly who benefits the most because of overlapping of some of the groupings.
“But people who really have atherosclerotic cardiovascular disease ... are probably the people who will benefit the most, and I hope those are the people who will get it,” said Dr. Wilson, professor of medicine at Emory University, professor of public health at Rollins School of Public Health, and director of epidemiology and genomic medicine at the Atlanta VA Medical Center.
In explaining his “no” vote, Daniel Budnitz, MD, of the Centers for Disease Control and Prevention, Atlanta, said his was a tough decision, but that ultimately, since the U.S. population is the one the FDA is addressing with its labeling, the subgroup concerns weighed heavily.
“And I do worry about a slippery slope of using single-trial data for new indications, when there are questions and when you do have an interaction term for the U.S. vs. the rest of the world,” he said, adding that he would like to see either another international trial where the United States population does not differ from the rest of the world, or a U.S. trial.
Carmen J. Allegra, MD, of the University of Florida, Gainesville, also voted no, and said he, too, was concerned by the subgroup analysis.
“I was very much concerned and swayed by the subgroup analysis. The U.S. target population is a pretty darn important population for us to consider, and we saw a significant interaction with outcomes vs. the region by the FDA’s analysis,” he said. “I was really swayed by the fact that we really didn’t see evidence of superiority in the U.S. population.”
The LEADER trial, which was designed in accordance with FDA Guidance issued in 2008 to demonstrate that new antidiabetes drugs do not result in unacceptably increased cardiovascular risk, included 9,340 patients who were randomized to receive liraglutide or placebo as add-on to standard of care treatment and who were followed for a median of 3.8 years. Those randomized to receive liraglutide experienced significantly lower risk of the composite primary outcome (hazard ratio, 0.87), Notably, the effect was diminished among U.S. patients, compared with the overall benefit.
However, after hearing LEADER analyses from Novo Nordisk representatives and FDA representatives, and testimony from numerous individuals, including patients, physicians, and patient advocates who spoke overwhelmingly in favor of approval of the supplemental drug application, the committee recommended that approval.
“This was not a slam dunk. I think the subgroup analysis was interesting discussion, but in the end you have to take the data and the primary outcome measure as what you move on,” said temporary voting member David C. Robbins, MD, of the University of Kansas, Kansas City, adding that “the good is outweighing the bad on this.
“I’m glad to see diabetes management moving toward more than lowering blood sugar. It’s a good step in the right direction,” he said.
The FDA, which usually follows the recommendations of its advisory committees, will now consider the supplemental new drug application for liraglutide.
In a statement released after the vote, Todd Hobbs, MD, vice president and U.S. chief medical officer of Novo Nordisk, noted that cardiovascular disease remains the leading cause of death for people with type 2 diabetes. The discussion during the EMDAC meeting is “an important reminder that there is an unmet need to provide benefits beyond HbA1c control” in patients with type 2 diabetes.
EMDAC committee members were screened and found to be in compliance with federal ethics and conflict of interest laws; one (Dr. Konstam) was granted a waiver in accordance with rules allowing such waivers when the need for an individual’s service outweighs any potential financial conflicts of interest. Dr. Konstam reported financial relationships with competing firms.
A Food and Drug Administration advisory committee voted 17-2 in support of a supplemental new drug application for liraglutide (Victoza) injections to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease.
Novo Nordisk, the maker of the glucagon-like peptide-1 (GLP-1) analogue, proposed the additional indication for liraglutide as an adjunct to standard treatment of cardiovascular risk factors in such patients based solely on the results of the randomized, placebo-controlled postmarketing LEADER trial.
If this additional indication for liraglutide is approved by the FDA, the drug would join the antidiabetic drug empagliflozin (Jardiance) in having a second indication for the reduction of the risk of cardiovascular death. The supplemental new drug application for Jardiance was approved by the FDA in December 2016 – also based on the results of a single trial (the EMPA-REG outcomes trial). Of note, the American Diabetes Association in its 2017 Standards of Medical Care has already called for consideration of both liraglutide and empagliflozin to reduce the risk of cardiovascular death in patients with type 2 diabetes and documented cardiovascular disease.
Liraglutide is currently approved for blood glucose lowering in adults with type 2 diabetes and is marketed as Saxenda for the treatment of overweight and obese adults with at least one weight-related comorbidity. It was shown in the LEADER trial to be associated with a significant 13% lower risk vs. placebo for a composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke in patients with type 2 diabetes.
All 19 voting members of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) agreed that the LEADER results confirm there is no excess cardiovascular risk associated with liraglutide in patients with type 2 diabetes, but, on the question of whether the results provide “the substantial evidence required to establish that liraglutide 1.8 mg reduces cardiovascular risk in patients with type 2 diabetes mellitus and established cardiovascular disease,” almost all voting members expressed concerns about subgroup analyses showing reduced benefit among U.S. patients, compared with those from other countries.
“I think probably the most influential finding for me was the overall cardiovascular mortality finding, followed by the consistency of the results,” said biostatistics expert James D. Neaton, PhD, of the University of Minnesota, Minneapolis. He added that the indication should focus on patients at high cardiovascular event risk, as the LEADER population was a very high risk group.
Similarly, temporary voting member Marvin A. Konstam, MD, of Tufts University, Boston, said “the primary trial results are very robust and substantiated.
“And I think the cardiovascular mortality is the biggest contributor to that, which is obviously a very important finding,” he said, also stressing that the indication should focus on patients with established cardiovascular disease.
“I am concerned about the U.S. population, but at the end of the day, it’s a subgroup, and I just can’t overrate that to diminish the overall finding,” he added.
Peter W.F. Wilson, MD, EMDAC chairperson, said he “wrestles with exactly who benefits the most because of overlapping of some of the groupings.
“But people who really have atherosclerotic cardiovascular disease ... are probably the people who will benefit the most, and I hope those are the people who will get it,” said Dr. Wilson, professor of medicine at Emory University, professor of public health at Rollins School of Public Health, and director of epidemiology and genomic medicine at the Atlanta VA Medical Center.
In explaining his “no” vote, Daniel Budnitz, MD, of the Centers for Disease Control and Prevention, Atlanta, said his was a tough decision, but that ultimately, since the U.S. population is the one the FDA is addressing with its labeling, the subgroup concerns weighed heavily.
“And I do worry about a slippery slope of using single-trial data for new indications, when there are questions and when you do have an interaction term for the U.S. vs. the rest of the world,” he said, adding that he would like to see either another international trial where the United States population does not differ from the rest of the world, or a U.S. trial.
Carmen J. Allegra, MD, of the University of Florida, Gainesville, also voted no, and said he, too, was concerned by the subgroup analysis.
“I was very much concerned and swayed by the subgroup analysis. The U.S. target population is a pretty darn important population for us to consider, and we saw a significant interaction with outcomes vs. the region by the FDA’s analysis,” he said. “I was really swayed by the fact that we really didn’t see evidence of superiority in the U.S. population.”
The LEADER trial, which was designed in accordance with FDA Guidance issued in 2008 to demonstrate that new antidiabetes drugs do not result in unacceptably increased cardiovascular risk, included 9,340 patients who were randomized to receive liraglutide or placebo as add-on to standard of care treatment and who were followed for a median of 3.8 years. Those randomized to receive liraglutide experienced significantly lower risk of the composite primary outcome (hazard ratio, 0.87), Notably, the effect was diminished among U.S. patients, compared with the overall benefit.
However, after hearing LEADER analyses from Novo Nordisk representatives and FDA representatives, and testimony from numerous individuals, including patients, physicians, and patient advocates who spoke overwhelmingly in favor of approval of the supplemental drug application, the committee recommended that approval.
“This was not a slam dunk. I think the subgroup analysis was interesting discussion, but in the end you have to take the data and the primary outcome measure as what you move on,” said temporary voting member David C. Robbins, MD, of the University of Kansas, Kansas City, adding that “the good is outweighing the bad on this.
“I’m glad to see diabetes management moving toward more than lowering blood sugar. It’s a good step in the right direction,” he said.
The FDA, which usually follows the recommendations of its advisory committees, will now consider the supplemental new drug application for liraglutide.
In a statement released after the vote, Todd Hobbs, MD, vice president and U.S. chief medical officer of Novo Nordisk, noted that cardiovascular disease remains the leading cause of death for people with type 2 diabetes. The discussion during the EMDAC meeting is “an important reminder that there is an unmet need to provide benefits beyond HbA1c control” in patients with type 2 diabetes.
EMDAC committee members were screened and found to be in compliance with federal ethics and conflict of interest laws; one (Dr. Konstam) was granted a waiver in accordance with rules allowing such waivers when the need for an individual’s service outweighs any potential financial conflicts of interest. Dr. Konstam reported financial relationships with competing firms.
A Food and Drug Administration advisory committee voted 17-2 in support of a supplemental new drug application for liraglutide (Victoza) injections to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease.
Novo Nordisk, the maker of the glucagon-like peptide-1 (GLP-1) analogue, proposed the additional indication for liraglutide as an adjunct to standard treatment of cardiovascular risk factors in such patients based solely on the results of the randomized, placebo-controlled postmarketing LEADER trial.
If this additional indication for liraglutide is approved by the FDA, the drug would join the antidiabetic drug empagliflozin (Jardiance) in having a second indication for the reduction of the risk of cardiovascular death. The supplemental new drug application for Jardiance was approved by the FDA in December 2016 – also based on the results of a single trial (the EMPA-REG outcomes trial). Of note, the American Diabetes Association in its 2017 Standards of Medical Care has already called for consideration of both liraglutide and empagliflozin to reduce the risk of cardiovascular death in patients with type 2 diabetes and documented cardiovascular disease.
Liraglutide is currently approved for blood glucose lowering in adults with type 2 diabetes and is marketed as Saxenda for the treatment of overweight and obese adults with at least one weight-related comorbidity. It was shown in the LEADER trial to be associated with a significant 13% lower risk vs. placebo for a composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke in patients with type 2 diabetes.
All 19 voting members of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) agreed that the LEADER results confirm there is no excess cardiovascular risk associated with liraglutide in patients with type 2 diabetes, but, on the question of whether the results provide “the substantial evidence required to establish that liraglutide 1.8 mg reduces cardiovascular risk in patients with type 2 diabetes mellitus and established cardiovascular disease,” almost all voting members expressed concerns about subgroup analyses showing reduced benefit among U.S. patients, compared with those from other countries.
“I think probably the most influential finding for me was the overall cardiovascular mortality finding, followed by the consistency of the results,” said biostatistics expert James D. Neaton, PhD, of the University of Minnesota, Minneapolis. He added that the indication should focus on patients at high cardiovascular event risk, as the LEADER population was a very high risk group.
Similarly, temporary voting member Marvin A. Konstam, MD, of Tufts University, Boston, said “the primary trial results are very robust and substantiated.
“And I think the cardiovascular mortality is the biggest contributor to that, which is obviously a very important finding,” he said, also stressing that the indication should focus on patients with established cardiovascular disease.
“I am concerned about the U.S. population, but at the end of the day, it’s a subgroup, and I just can’t overrate that to diminish the overall finding,” he added.
Peter W.F. Wilson, MD, EMDAC chairperson, said he “wrestles with exactly who benefits the most because of overlapping of some of the groupings.
“But people who really have atherosclerotic cardiovascular disease ... are probably the people who will benefit the most, and I hope those are the people who will get it,” said Dr. Wilson, professor of medicine at Emory University, professor of public health at Rollins School of Public Health, and director of epidemiology and genomic medicine at the Atlanta VA Medical Center.
In explaining his “no” vote, Daniel Budnitz, MD, of the Centers for Disease Control and Prevention, Atlanta, said his was a tough decision, but that ultimately, since the U.S. population is the one the FDA is addressing with its labeling, the subgroup concerns weighed heavily.
“And I do worry about a slippery slope of using single-trial data for new indications, when there are questions and when you do have an interaction term for the U.S. vs. the rest of the world,” he said, adding that he would like to see either another international trial where the United States population does not differ from the rest of the world, or a U.S. trial.
Carmen J. Allegra, MD, of the University of Florida, Gainesville, also voted no, and said he, too, was concerned by the subgroup analysis.
“I was very much concerned and swayed by the subgroup analysis. The U.S. target population is a pretty darn important population for us to consider, and we saw a significant interaction with outcomes vs. the region by the FDA’s analysis,” he said. “I was really swayed by the fact that we really didn’t see evidence of superiority in the U.S. population.”
The LEADER trial, which was designed in accordance with FDA Guidance issued in 2008 to demonstrate that new antidiabetes drugs do not result in unacceptably increased cardiovascular risk, included 9,340 patients who were randomized to receive liraglutide or placebo as add-on to standard of care treatment and who were followed for a median of 3.8 years. Those randomized to receive liraglutide experienced significantly lower risk of the composite primary outcome (hazard ratio, 0.87), Notably, the effect was diminished among U.S. patients, compared with the overall benefit.
However, after hearing LEADER analyses from Novo Nordisk representatives and FDA representatives, and testimony from numerous individuals, including patients, physicians, and patient advocates who spoke overwhelmingly in favor of approval of the supplemental drug application, the committee recommended that approval.
“This was not a slam dunk. I think the subgroup analysis was interesting discussion, but in the end you have to take the data and the primary outcome measure as what you move on,” said temporary voting member David C. Robbins, MD, of the University of Kansas, Kansas City, adding that “the good is outweighing the bad on this.
“I’m glad to see diabetes management moving toward more than lowering blood sugar. It’s a good step in the right direction,” he said.
The FDA, which usually follows the recommendations of its advisory committees, will now consider the supplemental new drug application for liraglutide.
In a statement released after the vote, Todd Hobbs, MD, vice president and U.S. chief medical officer of Novo Nordisk, noted that cardiovascular disease remains the leading cause of death for people with type 2 diabetes. The discussion during the EMDAC meeting is “an important reminder that there is an unmet need to provide benefits beyond HbA1c control” in patients with type 2 diabetes.
EMDAC committee members were screened and found to be in compliance with federal ethics and conflict of interest laws; one (Dr. Konstam) was granted a waiver in accordance with rules allowing such waivers when the need for an individual’s service outweighs any potential financial conflicts of interest. Dr. Konstam reported financial relationships with competing firms.
Short-HER trial: DFS is similar, cardiac toxicity lower with short trastuzumab course
CHICAGO – Nine weeks of treatment with trastuzumab resulted in comparable disease-free and overall survival to that seen with the standard 12 months of trastuzumab – with about one-third of the rate of severe cardiac toxicity – in patients with HER2-positive early breast cancer in the Italian phase III multicenter Short-HER study.
The 5-year disease-free survival rate in 626 patients who received 9 weeks of trastuzumab was 87.5%, compared with 85.4% in 627 patients who received 1 year of trastuzumab therapy (hazard ratio, 1.15), Pier F. Conte, MD, reported at the annual meeting of the American Society of Clinical Oncology.
The upper limit of the 90% confidence interval (0.91-1.46) crossed the noninferiority margin set at 1.29 for this frequentist analysis, Dr. Conte of the University of Padova, Italy, said, noting that a subgroup analysis showed that patients with stage III disease and those with four or more positive lymph nodes – who together represented about 15% of the study population – had a disease-free survival advantage with longer treatment (HR, 2.30 and 2.25, respectively), and an interaction test was statistically significant.
However, a preplanned Bayesian analysis showed a 78% probability that the shorter treatment is not inferior to longer treatment for disease-free survival, he said.
The secondary endpoint of overall survival was also similar in the two groups (95.1% vs. 95.0%; HR, 1.06).
As for the secondary endpoint of cardiac events, the rate was 5.1% with shorter treatment vs. 14.4% with longer treatment. Grade 2 cardiac events occurred in 11.2% vs. 3.5% of patients in the treatment arms, respectively, and the grade 3 cardiac vents occurred in 2.7% vs. 1.1%, respectively. The rate of grade 4 events was 0.5% in both groups.
The overall difference between the groups with respect to cardiac events was highly statistically significant in favor of shorter treatment (HR, 0.32), Dr. Conte said.
Multiple studies have demonstrated the superiority of combining trastuzumab and adjuvant chemotherapy for HER2+ early breast cancer, and, following the release of some of those findings at the ASCO annual meeting in 2005, the agent was granted accelerated approval for this indication, Dr. Conte said.
“It was, however, clear that there were a number of reasons to believe that further investigation was appropriate on the optimal duration of trastuzumab duration,” he said, explaining that the same magnitude of benefit was reported by the small FinHER study with 9 weeks of trastuzumab and that clinical data suggest synergism of trastuzumab with chemotherapy.
“Finally, in the real world, there are patients at lower risk of relapse (more node-negative, more small tumors) and at higher risk of cardiac toxicity because of age or comorbidities,” he said. “So, the hypotheses behind the Short-HER [study] was that a shorter duration of trastuzumab administered concomitantly with chemotherapy might produce comparable efficacy with significantly lower toxicities and, of course, costs.”
Short-HER study subjects, who had a mean age of 55 years, had either HER2-positive, node-positive, or high-risk node-negative disease and were randomized to receive either the shorter treatment, including three courses of docetaxel given three times weekly plus trastuzumab given weekly for 9 doses, followed by three courses of 5-fluorouracil/epirubicin/cyclophosphamide, or standard 12-month treatment with four courses of anthracycline-based chemotherapy followed by four courses of docetaxel in combination with trastuzumab given three times weekly, followed by 14 additional courses of trastuzumab given three times weekly (for a total of 18 3-times-weekly doses). Radiation therapy was administered when indicated after chemotherapy, and hormonal therapy was started after completion of chemotherapy in patients with hormone-receptor–positive tumors.
Based on the frequentist analysis, noninferiority of the shorter treatment approach cannot be claimed, but, according to the preplanned Bayesian analysis, noninferiority is likely, Dr. Conte said.
“One year of trastuzumab is still standard. The Short-Her trial, however, reinforces the hypothesis that treatment deescalation retains efficacy with less toxicity. A shorter treatment might be an option for patients at low risk of relapse and/or higher risk of cardiac toxicity,” he said. “Moreover, these results might facilitate trastuzumab to patients in low/middle income countries.”
Individual patient meta-analysis with other trials testing different durations of trastuzumab administration is ongoing, he noted.
The Short-HER study was funded by the Italian Drug Agency, and drugs and insurance coverage were supplied by the National Health System. The study was sponsored by the University of Modena & Regio Emilia and the University of Padova. Dr. Conte has served on the speakers’ bureau for AstraZeneca, Lilly, Novartis, and Roche/Genentech and has received research funding and/or travel or other expenses from AstraZeneca, Celgene, and Novartis.
CHICAGO – Nine weeks of treatment with trastuzumab resulted in comparable disease-free and overall survival to that seen with the standard 12 months of trastuzumab – with about one-third of the rate of severe cardiac toxicity – in patients with HER2-positive early breast cancer in the Italian phase III multicenter Short-HER study.
The 5-year disease-free survival rate in 626 patients who received 9 weeks of trastuzumab was 87.5%, compared with 85.4% in 627 patients who received 1 year of trastuzumab therapy (hazard ratio, 1.15), Pier F. Conte, MD, reported at the annual meeting of the American Society of Clinical Oncology.
The upper limit of the 90% confidence interval (0.91-1.46) crossed the noninferiority margin set at 1.29 for this frequentist analysis, Dr. Conte of the University of Padova, Italy, said, noting that a subgroup analysis showed that patients with stage III disease and those with four or more positive lymph nodes – who together represented about 15% of the study population – had a disease-free survival advantage with longer treatment (HR, 2.30 and 2.25, respectively), and an interaction test was statistically significant.
However, a preplanned Bayesian analysis showed a 78% probability that the shorter treatment is not inferior to longer treatment for disease-free survival, he said.
The secondary endpoint of overall survival was also similar in the two groups (95.1% vs. 95.0%; HR, 1.06).
As for the secondary endpoint of cardiac events, the rate was 5.1% with shorter treatment vs. 14.4% with longer treatment. Grade 2 cardiac events occurred in 11.2% vs. 3.5% of patients in the treatment arms, respectively, and the grade 3 cardiac vents occurred in 2.7% vs. 1.1%, respectively. The rate of grade 4 events was 0.5% in both groups.
The overall difference between the groups with respect to cardiac events was highly statistically significant in favor of shorter treatment (HR, 0.32), Dr. Conte said.
Multiple studies have demonstrated the superiority of combining trastuzumab and adjuvant chemotherapy for HER2+ early breast cancer, and, following the release of some of those findings at the ASCO annual meeting in 2005, the agent was granted accelerated approval for this indication, Dr. Conte said.
“It was, however, clear that there were a number of reasons to believe that further investigation was appropriate on the optimal duration of trastuzumab duration,” he said, explaining that the same magnitude of benefit was reported by the small FinHER study with 9 weeks of trastuzumab and that clinical data suggest synergism of trastuzumab with chemotherapy.
“Finally, in the real world, there are patients at lower risk of relapse (more node-negative, more small tumors) and at higher risk of cardiac toxicity because of age or comorbidities,” he said. “So, the hypotheses behind the Short-HER [study] was that a shorter duration of trastuzumab administered concomitantly with chemotherapy might produce comparable efficacy with significantly lower toxicities and, of course, costs.”
Short-HER study subjects, who had a mean age of 55 years, had either HER2-positive, node-positive, or high-risk node-negative disease and were randomized to receive either the shorter treatment, including three courses of docetaxel given three times weekly plus trastuzumab given weekly for 9 doses, followed by three courses of 5-fluorouracil/epirubicin/cyclophosphamide, or standard 12-month treatment with four courses of anthracycline-based chemotherapy followed by four courses of docetaxel in combination with trastuzumab given three times weekly, followed by 14 additional courses of trastuzumab given three times weekly (for a total of 18 3-times-weekly doses). Radiation therapy was administered when indicated after chemotherapy, and hormonal therapy was started after completion of chemotherapy in patients with hormone-receptor–positive tumors.
Based on the frequentist analysis, noninferiority of the shorter treatment approach cannot be claimed, but, according to the preplanned Bayesian analysis, noninferiority is likely, Dr. Conte said.
“One year of trastuzumab is still standard. The Short-Her trial, however, reinforces the hypothesis that treatment deescalation retains efficacy with less toxicity. A shorter treatment might be an option for patients at low risk of relapse and/or higher risk of cardiac toxicity,” he said. “Moreover, these results might facilitate trastuzumab to patients in low/middle income countries.”
Individual patient meta-analysis with other trials testing different durations of trastuzumab administration is ongoing, he noted.
The Short-HER study was funded by the Italian Drug Agency, and drugs and insurance coverage were supplied by the National Health System. The study was sponsored by the University of Modena & Regio Emilia and the University of Padova. Dr. Conte has served on the speakers’ bureau for AstraZeneca, Lilly, Novartis, and Roche/Genentech and has received research funding and/or travel or other expenses from AstraZeneca, Celgene, and Novartis.
CHICAGO – Nine weeks of treatment with trastuzumab resulted in comparable disease-free and overall survival to that seen with the standard 12 months of trastuzumab – with about one-third of the rate of severe cardiac toxicity – in patients with HER2-positive early breast cancer in the Italian phase III multicenter Short-HER study.
The 5-year disease-free survival rate in 626 patients who received 9 weeks of trastuzumab was 87.5%, compared with 85.4% in 627 patients who received 1 year of trastuzumab therapy (hazard ratio, 1.15), Pier F. Conte, MD, reported at the annual meeting of the American Society of Clinical Oncology.
The upper limit of the 90% confidence interval (0.91-1.46) crossed the noninferiority margin set at 1.29 for this frequentist analysis, Dr. Conte of the University of Padova, Italy, said, noting that a subgroup analysis showed that patients with stage III disease and those with four or more positive lymph nodes – who together represented about 15% of the study population – had a disease-free survival advantage with longer treatment (HR, 2.30 and 2.25, respectively), and an interaction test was statistically significant.
However, a preplanned Bayesian analysis showed a 78% probability that the shorter treatment is not inferior to longer treatment for disease-free survival, he said.
The secondary endpoint of overall survival was also similar in the two groups (95.1% vs. 95.0%; HR, 1.06).
As for the secondary endpoint of cardiac events, the rate was 5.1% with shorter treatment vs. 14.4% with longer treatment. Grade 2 cardiac events occurred in 11.2% vs. 3.5% of patients in the treatment arms, respectively, and the grade 3 cardiac vents occurred in 2.7% vs. 1.1%, respectively. The rate of grade 4 events was 0.5% in both groups.
The overall difference between the groups with respect to cardiac events was highly statistically significant in favor of shorter treatment (HR, 0.32), Dr. Conte said.
Multiple studies have demonstrated the superiority of combining trastuzumab and adjuvant chemotherapy for HER2+ early breast cancer, and, following the release of some of those findings at the ASCO annual meeting in 2005, the agent was granted accelerated approval for this indication, Dr. Conte said.
“It was, however, clear that there were a number of reasons to believe that further investigation was appropriate on the optimal duration of trastuzumab duration,” he said, explaining that the same magnitude of benefit was reported by the small FinHER study with 9 weeks of trastuzumab and that clinical data suggest synergism of trastuzumab with chemotherapy.
“Finally, in the real world, there are patients at lower risk of relapse (more node-negative, more small tumors) and at higher risk of cardiac toxicity because of age or comorbidities,” he said. “So, the hypotheses behind the Short-HER [study] was that a shorter duration of trastuzumab administered concomitantly with chemotherapy might produce comparable efficacy with significantly lower toxicities and, of course, costs.”
Short-HER study subjects, who had a mean age of 55 years, had either HER2-positive, node-positive, or high-risk node-negative disease and were randomized to receive either the shorter treatment, including three courses of docetaxel given three times weekly plus trastuzumab given weekly for 9 doses, followed by three courses of 5-fluorouracil/epirubicin/cyclophosphamide, or standard 12-month treatment with four courses of anthracycline-based chemotherapy followed by four courses of docetaxel in combination with trastuzumab given three times weekly, followed by 14 additional courses of trastuzumab given three times weekly (for a total of 18 3-times-weekly doses). Radiation therapy was administered when indicated after chemotherapy, and hormonal therapy was started after completion of chemotherapy in patients with hormone-receptor–positive tumors.
Based on the frequentist analysis, noninferiority of the shorter treatment approach cannot be claimed, but, according to the preplanned Bayesian analysis, noninferiority is likely, Dr. Conte said.
“One year of trastuzumab is still standard. The Short-Her trial, however, reinforces the hypothesis that treatment deescalation retains efficacy with less toxicity. A shorter treatment might be an option for patients at low risk of relapse and/or higher risk of cardiac toxicity,” he said. “Moreover, these results might facilitate trastuzumab to patients in low/middle income countries.”
Individual patient meta-analysis with other trials testing different durations of trastuzumab administration is ongoing, he noted.
The Short-HER study was funded by the Italian Drug Agency, and drugs and insurance coverage were supplied by the National Health System. The study was sponsored by the University of Modena & Regio Emilia and the University of Padova. Dr. Conte has served on the speakers’ bureau for AstraZeneca, Lilly, Novartis, and Roche/Genentech and has received research funding and/or travel or other expenses from AstraZeneca, Celgene, and Novartis.
AT ASCO 2017
Key clinical point:
Major finding: The 5-year disease-free survival rates were 87.5% and 85.4% with 9 weeks, vs. 1 year, of trastuzumab (HR, 1.15).
Data source: The phase III Short-HER study of 1,253 patients.
Disclosures: The Short-HER study was funded by the Italian Drug Agency, and drugs and insurance coverage were supplied by the National Health System. The study was sponsored by the University of Modena & Regio Emilia and the University of Padova. Dr. Conte has served on the speakers’ bureau for AstraZeneca, Lilly, Novartis, and Roche/Genentech and has received research funding and/or travel or other expenses from AstraZeneca, Celgene, and Novartis.
PORTEC-3: Possible benefit with combined CT/RT in high-risk endometrial cancer
CHICAGO – Adjuvant chemotherapy given during and after pelvic radiotherapy in women with high-risk endometrial cancer provided no significant 5-year failure-free or overall survival benefit, compared with pelvic radiotherapy alone, in the randomized PORTEC-3 intergroup trial. It did, however, show a trend toward improved 5-year failure-free survival (FFS).
Further, study participants with stage III endometrial cancer experienced a statistically significant 11% improvement in FFS – defined as relapse or endometrial cancer-related death – at 5 years, Stephanie M. de Boer, MD, reported at the annual meeting of the American Society of Clinical Oncology.
The 5-year FFS rate in 330 women who received both chemotherapy and radiotherapy was 76%, vs. 69% in 330 women who received only radiotherapy (hazard ratio, 0.77). The respective 5-year overall survival rates were 82%, vs. 77% (HR, 0.79), said Dr. de Boer of Leiden University Medical Center, the Netherlands.
The differences did not reach statistical significance, but there was a “trend for better failure-free survival” beginning after 1 year and “a small suggestion for an overall survival benefit” after 3 years in patients treated with chemotherapy and radiotherapy, she said.
Among the 45% of study participants with stage III endometrial cancer, 5-year FFS and overall survival were significantly lower than in those with stage I-II disease (64% vs. 79% and 74% vs. 83%, respectively), but those with stage III disease experienced the greatest benefit with adjuvant chemotherapy.
“Five-year failure-free survival was 69% for those [with stage III disease] treated with radiotherapy and chemotherapy, vs. 58% for those treated with radiotherapy alone,” she said, noting that the hazard ratio was 0.66.
Five-year overall survival in the stage III patients was 79%, vs. 70% (HR, 0.69). Only the difference in FFS reached statistical significance, Dr. de Boer noted.
Study subjects were women with either Federation Internationale de Gynecologie et d’Obstetrique stage I grade 3 endometrial cancer with deep myometrial invasion and/or lymphovascular space invasion or with stage II or III disease or with serous/clear cell histology. They had a mean age of 62 years, good performance status, and no residual macroscopic tumor after surgery. They were randomly assigned to receive two cycles of cisplatin at 50 mg/m2 in week 1 and 4 of radiotherapy (48.6 Gy in 1.8 Gy fractions), followed by four cycles of carboplatin AUC5 and paclitaxel at 175 mg/m2 in 3-week intervals, or to receive radiotherapy alone.
Median follow-up was 60.2 months.
“The rationale of the PORTEC-3 trial was that 15% of endometrial cancer patients have high-risk disease features, and these patients are at increased risk of distant metastases and endometrial cancer–related death,” Dr. de Boer said.
Several trials have looked at intensified treatment in these patients and include some that have compared chemotherapy and radiation and that found no difference in progression-free survival or overall survival. A Radiation Therapy Oncology Group (RTOG) phase II trial of concurrent chemotherapy and radiotherapy, however, showed promising results and a feasible toxicity profile, she said.
A phase III Nordic Society of Gynecologic Oncology (SGO)/European Organization for Research and Treatment of Cancer (EORTC) trial suggested that sequential chemotherapy and radiotherapy was associated with improved progression-free survival.
“But, various chemotherapy schedules and sequences have been used in these trials, and no extensive quality of life analysis was done,” she noted.
In PORTEC-3, radiotherapy and two cycles of concurrent cisplatin followed by four cycles of carboplatin and paclitaxel showed some promise, and quality of life analyses showed no difference between groups at 1 and 2 years after randomization.
In fact, although the adverse events findings as reported in 2016 in Lancet Oncology showed that, during therapy and for the first 6 months after therapy, “significantly more and more severe toxicity” occurred in the chemotherapy and radiotherapy group, vs. the radiotherapy group alone, this effect was transient and not associated with long-term effects on quality of life.
“There was significant recovery without significant differences at 1 and 2 years after randomization,” Dr. de Boer said, adding that the toxicity translated to worse physical functioning and quality of life during and for 6 months after therapy but that no differences in quality of life, and only small differences in physical functioning, were seen at 1 and 2 years.
The residual effect on physical functioning may have been related to the tingling and numbness, which was the most important long-term side effect reported in the trial, she said, noting that 25% of patients in the chemotherapy and radiotherapy group reported tingling and numbness at 2 years, compared with 6% in the radiotherapy group.
Based on these findings, combined chemotherapy and radiotherapy cannot be recommended as standard for patients with stage I and II high-risk endometrial cancer, she said.
However, based on the 11% FFS benefit for stage III patients, “the combined chemotherapy and radiotherapy schedule is recommended to maximize failure-free survival,” she concluded, noting that interpretation of overall survival results may need longer follow-up.
Ritu Salani, MD, who was invited to discuss Dr. de Boer’s abstract, said the PORTEC-3 findings raise a number of questions for studies going forward, such as the role of therapy sequence.
“Radiation has always preceded chemotherapy, and I wonder if distant recurrences could actually be impacted if we do chemotherapy first, whether it’s a complete course or in a sandwich-approach style. I think these are questions that we need to continue to address,” said Dr. Salani of Ohio State University, Columbus.
Other questions posed by Dr. Salani focused on whether high risk early stage and advanced disease should be studied separately, whether maintenance therapy should be evaluated in this population, whether there was under-staging in PORTEC-3 as 42% of patients did not undergo lymphadenectomy, whether there is a role for sentinel node assessment, and whether residual disease status should be a surgical metric and if chemotherapy should be reserved for those with residual disease.
“I think we continue to have many treatment options, and I think our tumor board debates will continue. And I think PORTEC-3 will add to this discussion. But, at this point I think we’re left to individualize treatment and to continue to provide the best outcome for our patients while minimizing toxicity,” she concluded.
Dr. de Boer reported having no disclosures. Dr. Salani has received honoraria from Clovis Oncology and Lynparza and has served as a consultant or advisor for Genentech/Roche.
CHICAGO – Adjuvant chemotherapy given during and after pelvic radiotherapy in women with high-risk endometrial cancer provided no significant 5-year failure-free or overall survival benefit, compared with pelvic radiotherapy alone, in the randomized PORTEC-3 intergroup trial. It did, however, show a trend toward improved 5-year failure-free survival (FFS).
Further, study participants with stage III endometrial cancer experienced a statistically significant 11% improvement in FFS – defined as relapse or endometrial cancer-related death – at 5 years, Stephanie M. de Boer, MD, reported at the annual meeting of the American Society of Clinical Oncology.
The 5-year FFS rate in 330 women who received both chemotherapy and radiotherapy was 76%, vs. 69% in 330 women who received only radiotherapy (hazard ratio, 0.77). The respective 5-year overall survival rates were 82%, vs. 77% (HR, 0.79), said Dr. de Boer of Leiden University Medical Center, the Netherlands.
The differences did not reach statistical significance, but there was a “trend for better failure-free survival” beginning after 1 year and “a small suggestion for an overall survival benefit” after 3 years in patients treated with chemotherapy and radiotherapy, she said.
Among the 45% of study participants with stage III endometrial cancer, 5-year FFS and overall survival were significantly lower than in those with stage I-II disease (64% vs. 79% and 74% vs. 83%, respectively), but those with stage III disease experienced the greatest benefit with adjuvant chemotherapy.
“Five-year failure-free survival was 69% for those [with stage III disease] treated with radiotherapy and chemotherapy, vs. 58% for those treated with radiotherapy alone,” she said, noting that the hazard ratio was 0.66.
Five-year overall survival in the stage III patients was 79%, vs. 70% (HR, 0.69). Only the difference in FFS reached statistical significance, Dr. de Boer noted.
Study subjects were women with either Federation Internationale de Gynecologie et d’Obstetrique stage I grade 3 endometrial cancer with deep myometrial invasion and/or lymphovascular space invasion or with stage II or III disease or with serous/clear cell histology. They had a mean age of 62 years, good performance status, and no residual macroscopic tumor after surgery. They were randomly assigned to receive two cycles of cisplatin at 50 mg/m2 in week 1 and 4 of radiotherapy (48.6 Gy in 1.8 Gy fractions), followed by four cycles of carboplatin AUC5 and paclitaxel at 175 mg/m2 in 3-week intervals, or to receive radiotherapy alone.
Median follow-up was 60.2 months.
“The rationale of the PORTEC-3 trial was that 15% of endometrial cancer patients have high-risk disease features, and these patients are at increased risk of distant metastases and endometrial cancer–related death,” Dr. de Boer said.
Several trials have looked at intensified treatment in these patients and include some that have compared chemotherapy and radiation and that found no difference in progression-free survival or overall survival. A Radiation Therapy Oncology Group (RTOG) phase II trial of concurrent chemotherapy and radiotherapy, however, showed promising results and a feasible toxicity profile, she said.
A phase III Nordic Society of Gynecologic Oncology (SGO)/European Organization for Research and Treatment of Cancer (EORTC) trial suggested that sequential chemotherapy and radiotherapy was associated with improved progression-free survival.
“But, various chemotherapy schedules and sequences have been used in these trials, and no extensive quality of life analysis was done,” she noted.
In PORTEC-3, radiotherapy and two cycles of concurrent cisplatin followed by four cycles of carboplatin and paclitaxel showed some promise, and quality of life analyses showed no difference between groups at 1 and 2 years after randomization.
In fact, although the adverse events findings as reported in 2016 in Lancet Oncology showed that, during therapy and for the first 6 months after therapy, “significantly more and more severe toxicity” occurred in the chemotherapy and radiotherapy group, vs. the radiotherapy group alone, this effect was transient and not associated with long-term effects on quality of life.
“There was significant recovery without significant differences at 1 and 2 years after randomization,” Dr. de Boer said, adding that the toxicity translated to worse physical functioning and quality of life during and for 6 months after therapy but that no differences in quality of life, and only small differences in physical functioning, were seen at 1 and 2 years.
The residual effect on physical functioning may have been related to the tingling and numbness, which was the most important long-term side effect reported in the trial, she said, noting that 25% of patients in the chemotherapy and radiotherapy group reported tingling and numbness at 2 years, compared with 6% in the radiotherapy group.
Based on these findings, combined chemotherapy and radiotherapy cannot be recommended as standard for patients with stage I and II high-risk endometrial cancer, she said.
However, based on the 11% FFS benefit for stage III patients, “the combined chemotherapy and radiotherapy schedule is recommended to maximize failure-free survival,” she concluded, noting that interpretation of overall survival results may need longer follow-up.
Ritu Salani, MD, who was invited to discuss Dr. de Boer’s abstract, said the PORTEC-3 findings raise a number of questions for studies going forward, such as the role of therapy sequence.
“Radiation has always preceded chemotherapy, and I wonder if distant recurrences could actually be impacted if we do chemotherapy first, whether it’s a complete course or in a sandwich-approach style. I think these are questions that we need to continue to address,” said Dr. Salani of Ohio State University, Columbus.
Other questions posed by Dr. Salani focused on whether high risk early stage and advanced disease should be studied separately, whether maintenance therapy should be evaluated in this population, whether there was under-staging in PORTEC-3 as 42% of patients did not undergo lymphadenectomy, whether there is a role for sentinel node assessment, and whether residual disease status should be a surgical metric and if chemotherapy should be reserved for those with residual disease.
“I think we continue to have many treatment options, and I think our tumor board debates will continue. And I think PORTEC-3 will add to this discussion. But, at this point I think we’re left to individualize treatment and to continue to provide the best outcome for our patients while minimizing toxicity,” she concluded.
Dr. de Boer reported having no disclosures. Dr. Salani has received honoraria from Clovis Oncology and Lynparza and has served as a consultant or advisor for Genentech/Roche.
CHICAGO – Adjuvant chemotherapy given during and after pelvic radiotherapy in women with high-risk endometrial cancer provided no significant 5-year failure-free or overall survival benefit, compared with pelvic radiotherapy alone, in the randomized PORTEC-3 intergroup trial. It did, however, show a trend toward improved 5-year failure-free survival (FFS).
Further, study participants with stage III endometrial cancer experienced a statistically significant 11% improvement in FFS – defined as relapse or endometrial cancer-related death – at 5 years, Stephanie M. de Boer, MD, reported at the annual meeting of the American Society of Clinical Oncology.
The 5-year FFS rate in 330 women who received both chemotherapy and radiotherapy was 76%, vs. 69% in 330 women who received only radiotherapy (hazard ratio, 0.77). The respective 5-year overall survival rates were 82%, vs. 77% (HR, 0.79), said Dr. de Boer of Leiden University Medical Center, the Netherlands.
The differences did not reach statistical significance, but there was a “trend for better failure-free survival” beginning after 1 year and “a small suggestion for an overall survival benefit” after 3 years in patients treated with chemotherapy and radiotherapy, she said.
Among the 45% of study participants with stage III endometrial cancer, 5-year FFS and overall survival were significantly lower than in those with stage I-II disease (64% vs. 79% and 74% vs. 83%, respectively), but those with stage III disease experienced the greatest benefit with adjuvant chemotherapy.
“Five-year failure-free survival was 69% for those [with stage III disease] treated with radiotherapy and chemotherapy, vs. 58% for those treated with radiotherapy alone,” she said, noting that the hazard ratio was 0.66.
Five-year overall survival in the stage III patients was 79%, vs. 70% (HR, 0.69). Only the difference in FFS reached statistical significance, Dr. de Boer noted.
Study subjects were women with either Federation Internationale de Gynecologie et d’Obstetrique stage I grade 3 endometrial cancer with deep myometrial invasion and/or lymphovascular space invasion or with stage II or III disease or with serous/clear cell histology. They had a mean age of 62 years, good performance status, and no residual macroscopic tumor after surgery. They were randomly assigned to receive two cycles of cisplatin at 50 mg/m2 in week 1 and 4 of radiotherapy (48.6 Gy in 1.8 Gy fractions), followed by four cycles of carboplatin AUC5 and paclitaxel at 175 mg/m2 in 3-week intervals, or to receive radiotherapy alone.
Median follow-up was 60.2 months.
“The rationale of the PORTEC-3 trial was that 15% of endometrial cancer patients have high-risk disease features, and these patients are at increased risk of distant metastases and endometrial cancer–related death,” Dr. de Boer said.
Several trials have looked at intensified treatment in these patients and include some that have compared chemotherapy and radiation and that found no difference in progression-free survival or overall survival. A Radiation Therapy Oncology Group (RTOG) phase II trial of concurrent chemotherapy and radiotherapy, however, showed promising results and a feasible toxicity profile, she said.
A phase III Nordic Society of Gynecologic Oncology (SGO)/European Organization for Research and Treatment of Cancer (EORTC) trial suggested that sequential chemotherapy and radiotherapy was associated with improved progression-free survival.
“But, various chemotherapy schedules and sequences have been used in these trials, and no extensive quality of life analysis was done,” she noted.
In PORTEC-3, radiotherapy and two cycles of concurrent cisplatin followed by four cycles of carboplatin and paclitaxel showed some promise, and quality of life analyses showed no difference between groups at 1 and 2 years after randomization.
In fact, although the adverse events findings as reported in 2016 in Lancet Oncology showed that, during therapy and for the first 6 months after therapy, “significantly more and more severe toxicity” occurred in the chemotherapy and radiotherapy group, vs. the radiotherapy group alone, this effect was transient and not associated with long-term effects on quality of life.
“There was significant recovery without significant differences at 1 and 2 years after randomization,” Dr. de Boer said, adding that the toxicity translated to worse physical functioning and quality of life during and for 6 months after therapy but that no differences in quality of life, and only small differences in physical functioning, were seen at 1 and 2 years.
The residual effect on physical functioning may have been related to the tingling and numbness, which was the most important long-term side effect reported in the trial, she said, noting that 25% of patients in the chemotherapy and radiotherapy group reported tingling and numbness at 2 years, compared with 6% in the radiotherapy group.
Based on these findings, combined chemotherapy and radiotherapy cannot be recommended as standard for patients with stage I and II high-risk endometrial cancer, she said.
However, based on the 11% FFS benefit for stage III patients, “the combined chemotherapy and radiotherapy schedule is recommended to maximize failure-free survival,” she concluded, noting that interpretation of overall survival results may need longer follow-up.
Ritu Salani, MD, who was invited to discuss Dr. de Boer’s abstract, said the PORTEC-3 findings raise a number of questions for studies going forward, such as the role of therapy sequence.
“Radiation has always preceded chemotherapy, and I wonder if distant recurrences could actually be impacted if we do chemotherapy first, whether it’s a complete course or in a sandwich-approach style. I think these are questions that we need to continue to address,” said Dr. Salani of Ohio State University, Columbus.
Other questions posed by Dr. Salani focused on whether high risk early stage and advanced disease should be studied separately, whether maintenance therapy should be evaluated in this population, whether there was under-staging in PORTEC-3 as 42% of patients did not undergo lymphadenectomy, whether there is a role for sentinel node assessment, and whether residual disease status should be a surgical metric and if chemotherapy should be reserved for those with residual disease.
“I think we continue to have many treatment options, and I think our tumor board debates will continue. And I think PORTEC-3 will add to this discussion. But, at this point I think we’re left to individualize treatment and to continue to provide the best outcome for our patients while minimizing toxicity,” she concluded.
Dr. de Boer reported having no disclosures. Dr. Salani has received honoraria from Clovis Oncology and Lynparza and has served as a consultant or advisor for Genentech/Roche.
AT ASCO 2017
Key clinical point:
Major finding: The 5-year FFS rate in 330 women who received both chemotherapy and radiotherapy was 76%, vs. 69% in 330 women who received only radiotherapy (HR, 0.77).
Data source: The randomized PORTEC-3 trial of 660 patients.
Disclosures: Dr. de Boer reported having no disclosures. Dr. Salani has received honoraria from Clovis Oncology and Lynparza and has served as a consultant or advisor for Genentech/Roche.