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VcR-CVAD yields high responses, ‘excellent’ survival in MCL
Adding rituximab and bortezomib to a moderate-intensity chemotherapy regimen and following it up with maintenance rituximab produced high response rates and “excellent” survival outcomes for adults with previously untreated mantle cell lymphoma (MCL), investigators reported in long-term follow-up of a small study.
The objective response rate (ORR) among 30 patients with MCL treated with VcR-CVAD – bortezomib (Velcade), rituximab, and hyperCVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) followed by rituximab maintenance – was 90%, including a high proportion of complete responses (CR) or unconfirmed complete responses.
After a median follow-up of 7.8 years, the rates of 6-year progression-free and overall survival (PFS and OS) were 53% and 70%, respectively, with patients older and younger than 60 years having equally good outcomes, according to Julie E. Chang, MD, of the Wisconsin Institute of Medical Research in Madison, and her colleagues.
VcR-CVAD is a moderate-intensity regimen with a favorable toxicity profile that allowed tolerability even in an older population, the investigators noted. “An important lesson illustrated by VcR-CVAD is that long-term remissions are achievable in some patients without intensive inductions or consolidation,” they wrote in Clinical Lymphoma, Myeloma & Leukemia.
The investigators previously reported that after a median follow-up of 42 months, the 3-year PFS and OS were 63% and 86%, respectively, and that these outcomes were comparable to those reported with more intensive regimens (Br J Haematol. 2011 Oct;155[2]:190-7).
As noted, the ORR was 90%, including 77% CR/unconfirmed CR, 6-year PFS was 53%, and 6-year OS was 70%.
A univariate analysis showed a significant interaction between lactate dehydrogenase levels and age for PFS, and a trend, albeit not significant, toward an interaction with LDH levels and age for OS.
In multivariate analysis, worse Eastern Cooperative Oncology Group (ECOG) performance status at baseline showed a nonsignificant trend toward worse OS. In contrast, an increase of one in the number of extranodal disease sites was associated with better OS (relative risk 0.66, 95% confidence interval 0.01-0.66).
The investigators noted that the advent of new agents with activity against MCL and the use of prognostic information, such as minimal residual disease measurements, could help clinicians develop induction and maintenance strategies with better efficacy and lower toxicity than VcR-CVAD.
The study was supported by the National Institutes of Health, Millennium Pharmaceuticals, and the University of Wisconsin Forward Lymphoma Research Fund. Dr. Chang reported research funding from Genentech. One coauthor disclosed consulting work for Genentech and Millennium and research funding from Genentech.
hematologynews@frontlinemedcom.com
SOURCE: Chang J et al. Clin Lymphoma Myeloma Leuk. 2018 Jan;18(1):e61-e67. doi: 10.1016/j.clml.2017.10.006.
Adding rituximab and bortezomib to a moderate-intensity chemotherapy regimen and following it up with maintenance rituximab produced high response rates and “excellent” survival outcomes for adults with previously untreated mantle cell lymphoma (MCL), investigators reported in long-term follow-up of a small study.
The objective response rate (ORR) among 30 patients with MCL treated with VcR-CVAD – bortezomib (Velcade), rituximab, and hyperCVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) followed by rituximab maintenance – was 90%, including a high proportion of complete responses (CR) or unconfirmed complete responses.
After a median follow-up of 7.8 years, the rates of 6-year progression-free and overall survival (PFS and OS) were 53% and 70%, respectively, with patients older and younger than 60 years having equally good outcomes, according to Julie E. Chang, MD, of the Wisconsin Institute of Medical Research in Madison, and her colleagues.
VcR-CVAD is a moderate-intensity regimen with a favorable toxicity profile that allowed tolerability even in an older population, the investigators noted. “An important lesson illustrated by VcR-CVAD is that long-term remissions are achievable in some patients without intensive inductions or consolidation,” they wrote in Clinical Lymphoma, Myeloma & Leukemia.
The investigators previously reported that after a median follow-up of 42 months, the 3-year PFS and OS were 63% and 86%, respectively, and that these outcomes were comparable to those reported with more intensive regimens (Br J Haematol. 2011 Oct;155[2]:190-7).
As noted, the ORR was 90%, including 77% CR/unconfirmed CR, 6-year PFS was 53%, and 6-year OS was 70%.
A univariate analysis showed a significant interaction between lactate dehydrogenase levels and age for PFS, and a trend, albeit not significant, toward an interaction with LDH levels and age for OS.
In multivariate analysis, worse Eastern Cooperative Oncology Group (ECOG) performance status at baseline showed a nonsignificant trend toward worse OS. In contrast, an increase of one in the number of extranodal disease sites was associated with better OS (relative risk 0.66, 95% confidence interval 0.01-0.66).
The investigators noted that the advent of new agents with activity against MCL and the use of prognostic information, such as minimal residual disease measurements, could help clinicians develop induction and maintenance strategies with better efficacy and lower toxicity than VcR-CVAD.
The study was supported by the National Institutes of Health, Millennium Pharmaceuticals, and the University of Wisconsin Forward Lymphoma Research Fund. Dr. Chang reported research funding from Genentech. One coauthor disclosed consulting work for Genentech and Millennium and research funding from Genentech.
hematologynews@frontlinemedcom.com
SOURCE: Chang J et al. Clin Lymphoma Myeloma Leuk. 2018 Jan;18(1):e61-e67. doi: 10.1016/j.clml.2017.10.006.
Adding rituximab and bortezomib to a moderate-intensity chemotherapy regimen and following it up with maintenance rituximab produced high response rates and “excellent” survival outcomes for adults with previously untreated mantle cell lymphoma (MCL), investigators reported in long-term follow-up of a small study.
The objective response rate (ORR) among 30 patients with MCL treated with VcR-CVAD – bortezomib (Velcade), rituximab, and hyperCVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) followed by rituximab maintenance – was 90%, including a high proportion of complete responses (CR) or unconfirmed complete responses.
After a median follow-up of 7.8 years, the rates of 6-year progression-free and overall survival (PFS and OS) were 53% and 70%, respectively, with patients older and younger than 60 years having equally good outcomes, according to Julie E. Chang, MD, of the Wisconsin Institute of Medical Research in Madison, and her colleagues.
VcR-CVAD is a moderate-intensity regimen with a favorable toxicity profile that allowed tolerability even in an older population, the investigators noted. “An important lesson illustrated by VcR-CVAD is that long-term remissions are achievable in some patients without intensive inductions or consolidation,” they wrote in Clinical Lymphoma, Myeloma & Leukemia.
The investigators previously reported that after a median follow-up of 42 months, the 3-year PFS and OS were 63% and 86%, respectively, and that these outcomes were comparable to those reported with more intensive regimens (Br J Haematol. 2011 Oct;155[2]:190-7).
As noted, the ORR was 90%, including 77% CR/unconfirmed CR, 6-year PFS was 53%, and 6-year OS was 70%.
A univariate analysis showed a significant interaction between lactate dehydrogenase levels and age for PFS, and a trend, albeit not significant, toward an interaction with LDH levels and age for OS.
In multivariate analysis, worse Eastern Cooperative Oncology Group (ECOG) performance status at baseline showed a nonsignificant trend toward worse OS. In contrast, an increase of one in the number of extranodal disease sites was associated with better OS (relative risk 0.66, 95% confidence interval 0.01-0.66).
The investigators noted that the advent of new agents with activity against MCL and the use of prognostic information, such as minimal residual disease measurements, could help clinicians develop induction and maintenance strategies with better efficacy and lower toxicity than VcR-CVAD.
The study was supported by the National Institutes of Health, Millennium Pharmaceuticals, and the University of Wisconsin Forward Lymphoma Research Fund. Dr. Chang reported research funding from Genentech. One coauthor disclosed consulting work for Genentech and Millennium and research funding from Genentech.
hematologynews@frontlinemedcom.com
SOURCE: Chang J et al. Clin Lymphoma Myeloma Leuk. 2018 Jan;18(1):e61-e67. doi: 10.1016/j.clml.2017.10.006.
FROM CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA
Key clinical point:
Major finding: The objective response rate was 90%, including 77% complete or unconfirmed complete responses.
Study details: Open-label study of 30 patients with previously untreated MCL.
Disclosures: The study was supported by the National Institutes of Health, Millennium Pharmaceuticals, and the University of Wisconsin Forward Lymphoma Research Fund. Dr. Chang reported research funding from Genentech. A coauthor reported consulting work for Genentech and Millennium and research funding from Genentech.
Source: Chang J et al. Clin Lymphoma Myeloma Leuk. 2018 Jan;18(1):e61-e67. doi: 10.1016/j.clml.2017.10.006.
DNA sequencing could help identify relapse risk in treated AML
ATLANTA – Clinicians may be able to get a jump on identifying risk factors for relapse among adults with acute myeloid leukemia (AML) in first complete remission through the use of next-generation DNA sequencing, investigators reported.
Among 430 adults with AML with somatic driver mutations persistent in bone marrow during morphological complete remission (CR) following induction therapy, the presence of minimal residual disease (MRD) bearing specific disease-related mutations on next-generation sequencing (NGS) was significantly associated with both the cumulative incidence of relapse and with overall survival. Tim Grob, MD, of Erasmus University Medical Center in Rotterdam, the Netherlands, reported the findings during a late-breaking abstract session at the annual meeting of the American Society of Hematology.
By excluding three common AML mutations in genes commonly associated with clonal hematopoiesis – DNMT3A, TET2, and ASXL1 (collectively, DTA) – Dr. Grob and his colleagues at centers in the Netherlands, Belgium, and Switzerland were able to demonstrate that non-DTA mutations present in the marrow of patients in CR are highly predictive for relapse within 5 years and for worse overall survival.
They also showed that mutations associated with clonal hematopoiesis (the presence of small, preleukemic clones) in CR is not significantly associated with risk of relapse.
More than 80% of patients with AML are able to have a CR after induction therapy, but a significant proportion of patients will also experience relapse. Investigators have yet to nail down which leukemia-specific mutations that linger in patients with CR may be responsible for subsequent relapses, Dr. Grob said.
To get a better handle on which residual mutations may signal the need for extra vigilance or additional therapy in patients in CR after two cycles of induction therapy, the investigators used targeted next-generation (high-throughput) sequencing at the time of diagnosis and first CR in 430 patients enrolled in joint Dutch/Swiss clinical trials. The median patient age was 51.
The investigators screened marrow samples using a commercially available gene panel (Illumina) covering 54 genes that are commonly mutated in myeloid malignancies.
They divided the patients into a training cohort (283 patients) and a validation set (147) for confirmation of results.
About half of all patients in the training cohort (51.4%) had persistent mutations in bone marrow that occurred with highly variable variant allele frequencies. The most common mutations were in the DTA group with the most frequently mutated gene being DNMT3A (78.7% variant allele frequency), followed by TET2 (54.2%) and ASXL1 (51.6%).
Mutations in DTA genes in this cohort were not associated with the incidence of relapse at any variant allele frequency cut-off point used, which indicated that these mutations represented a stage of clonal hematopoiesis rather than early relapse signals.
However, among patients who had persistent DTA mutations, there was significant correlation with a risk for relapse when they also had persistence of any other non-DTA mutations. The cumulative 5-year incidence of relapse in patients with both persistent DTA and non-DTA mutations was 76.4%, compared with 39.4% for those without other, non-DTA mutations (P = .002).
Also in the training cohort, persistent non-DTA mutations (NGS MRD) were found to be highly associated with the risk of relapse with a subdistribution hazard ratio (SHR) of 1.85 (P = .001). In the validation set the effect was even stronger, with an SHR or 2.81 (P less than .001).
When data from the training and validation cohort were combined, the 5-year cumulative incidence of relapse was 58.3% for non-DTA mutation, vs. 33.9% (P less than .001).
NGS MRD was also predictive of overall survival, with a hazard ratio in the training cohort of 1.64 (P = .012) and an HR in the validation cohort of 3.08 (P less than .001).
In multivariable analysis of all 430 patients, adjusted for age, white blood cell count, 2017 European LeukemiaNet risk category, and number of induction cycles need to achieve CR, NGS MRD was an independent prognostic factor for both relapse (SHR 1.89, P less than .001) and overall survival (HR 1.64 P = .003).
When the investigators conducted a sensitivity analysis with time-dependent correction for allogeneic stem cell transplantation, they found that NGS MRD was still significantly prognostic for both relapse and survival.
The study was supported by the Dutch Cancer Society, the Haemato-Oncology Foundation for Adults in the Netherlands, the Swiss Group for Clinical Cancer Research, and The Netherlands Organization for Health Research and Development. Dr. Grob reported having no relevant disclosures.
SOURCE: Jongen-Lavrencic M et al. ASH 2017 Abstract LBA 5.
ATLANTA – Clinicians may be able to get a jump on identifying risk factors for relapse among adults with acute myeloid leukemia (AML) in first complete remission through the use of next-generation DNA sequencing, investigators reported.
Among 430 adults with AML with somatic driver mutations persistent in bone marrow during morphological complete remission (CR) following induction therapy, the presence of minimal residual disease (MRD) bearing specific disease-related mutations on next-generation sequencing (NGS) was significantly associated with both the cumulative incidence of relapse and with overall survival. Tim Grob, MD, of Erasmus University Medical Center in Rotterdam, the Netherlands, reported the findings during a late-breaking abstract session at the annual meeting of the American Society of Hematology.
By excluding three common AML mutations in genes commonly associated with clonal hematopoiesis – DNMT3A, TET2, and ASXL1 (collectively, DTA) – Dr. Grob and his colleagues at centers in the Netherlands, Belgium, and Switzerland were able to demonstrate that non-DTA mutations present in the marrow of patients in CR are highly predictive for relapse within 5 years and for worse overall survival.
They also showed that mutations associated with clonal hematopoiesis (the presence of small, preleukemic clones) in CR is not significantly associated with risk of relapse.
More than 80% of patients with AML are able to have a CR after induction therapy, but a significant proportion of patients will also experience relapse. Investigators have yet to nail down which leukemia-specific mutations that linger in patients with CR may be responsible for subsequent relapses, Dr. Grob said.
To get a better handle on which residual mutations may signal the need for extra vigilance or additional therapy in patients in CR after two cycles of induction therapy, the investigators used targeted next-generation (high-throughput) sequencing at the time of diagnosis and first CR in 430 patients enrolled in joint Dutch/Swiss clinical trials. The median patient age was 51.
The investigators screened marrow samples using a commercially available gene panel (Illumina) covering 54 genes that are commonly mutated in myeloid malignancies.
They divided the patients into a training cohort (283 patients) and a validation set (147) for confirmation of results.
About half of all patients in the training cohort (51.4%) had persistent mutations in bone marrow that occurred with highly variable variant allele frequencies. The most common mutations were in the DTA group with the most frequently mutated gene being DNMT3A (78.7% variant allele frequency), followed by TET2 (54.2%) and ASXL1 (51.6%).
Mutations in DTA genes in this cohort were not associated with the incidence of relapse at any variant allele frequency cut-off point used, which indicated that these mutations represented a stage of clonal hematopoiesis rather than early relapse signals.
However, among patients who had persistent DTA mutations, there was significant correlation with a risk for relapse when they also had persistence of any other non-DTA mutations. The cumulative 5-year incidence of relapse in patients with both persistent DTA and non-DTA mutations was 76.4%, compared with 39.4% for those without other, non-DTA mutations (P = .002).
Also in the training cohort, persistent non-DTA mutations (NGS MRD) were found to be highly associated with the risk of relapse with a subdistribution hazard ratio (SHR) of 1.85 (P = .001). In the validation set the effect was even stronger, with an SHR or 2.81 (P less than .001).
When data from the training and validation cohort were combined, the 5-year cumulative incidence of relapse was 58.3% for non-DTA mutation, vs. 33.9% (P less than .001).
NGS MRD was also predictive of overall survival, with a hazard ratio in the training cohort of 1.64 (P = .012) and an HR in the validation cohort of 3.08 (P less than .001).
In multivariable analysis of all 430 patients, adjusted for age, white blood cell count, 2017 European LeukemiaNet risk category, and number of induction cycles need to achieve CR, NGS MRD was an independent prognostic factor for both relapse (SHR 1.89, P less than .001) and overall survival (HR 1.64 P = .003).
When the investigators conducted a sensitivity analysis with time-dependent correction for allogeneic stem cell transplantation, they found that NGS MRD was still significantly prognostic for both relapse and survival.
The study was supported by the Dutch Cancer Society, the Haemato-Oncology Foundation for Adults in the Netherlands, the Swiss Group for Clinical Cancer Research, and The Netherlands Organization for Health Research and Development. Dr. Grob reported having no relevant disclosures.
SOURCE: Jongen-Lavrencic M et al. ASH 2017 Abstract LBA 5.
ATLANTA – Clinicians may be able to get a jump on identifying risk factors for relapse among adults with acute myeloid leukemia (AML) in first complete remission through the use of next-generation DNA sequencing, investigators reported.
Among 430 adults with AML with somatic driver mutations persistent in bone marrow during morphological complete remission (CR) following induction therapy, the presence of minimal residual disease (MRD) bearing specific disease-related mutations on next-generation sequencing (NGS) was significantly associated with both the cumulative incidence of relapse and with overall survival. Tim Grob, MD, of Erasmus University Medical Center in Rotterdam, the Netherlands, reported the findings during a late-breaking abstract session at the annual meeting of the American Society of Hematology.
By excluding three common AML mutations in genes commonly associated with clonal hematopoiesis – DNMT3A, TET2, and ASXL1 (collectively, DTA) – Dr. Grob and his colleagues at centers in the Netherlands, Belgium, and Switzerland were able to demonstrate that non-DTA mutations present in the marrow of patients in CR are highly predictive for relapse within 5 years and for worse overall survival.
They also showed that mutations associated with clonal hematopoiesis (the presence of small, preleukemic clones) in CR is not significantly associated with risk of relapse.
More than 80% of patients with AML are able to have a CR after induction therapy, but a significant proportion of patients will also experience relapse. Investigators have yet to nail down which leukemia-specific mutations that linger in patients with CR may be responsible for subsequent relapses, Dr. Grob said.
To get a better handle on which residual mutations may signal the need for extra vigilance or additional therapy in patients in CR after two cycles of induction therapy, the investigators used targeted next-generation (high-throughput) sequencing at the time of diagnosis and first CR in 430 patients enrolled in joint Dutch/Swiss clinical trials. The median patient age was 51.
The investigators screened marrow samples using a commercially available gene panel (Illumina) covering 54 genes that are commonly mutated in myeloid malignancies.
They divided the patients into a training cohort (283 patients) and a validation set (147) for confirmation of results.
About half of all patients in the training cohort (51.4%) had persistent mutations in bone marrow that occurred with highly variable variant allele frequencies. The most common mutations were in the DTA group with the most frequently mutated gene being DNMT3A (78.7% variant allele frequency), followed by TET2 (54.2%) and ASXL1 (51.6%).
Mutations in DTA genes in this cohort were not associated with the incidence of relapse at any variant allele frequency cut-off point used, which indicated that these mutations represented a stage of clonal hematopoiesis rather than early relapse signals.
However, among patients who had persistent DTA mutations, there was significant correlation with a risk for relapse when they also had persistence of any other non-DTA mutations. The cumulative 5-year incidence of relapse in patients with both persistent DTA and non-DTA mutations was 76.4%, compared with 39.4% for those without other, non-DTA mutations (P = .002).
Also in the training cohort, persistent non-DTA mutations (NGS MRD) were found to be highly associated with the risk of relapse with a subdistribution hazard ratio (SHR) of 1.85 (P = .001). In the validation set the effect was even stronger, with an SHR or 2.81 (P less than .001).
When data from the training and validation cohort were combined, the 5-year cumulative incidence of relapse was 58.3% for non-DTA mutation, vs. 33.9% (P less than .001).
NGS MRD was also predictive of overall survival, with a hazard ratio in the training cohort of 1.64 (P = .012) and an HR in the validation cohort of 3.08 (P less than .001).
In multivariable analysis of all 430 patients, adjusted for age, white blood cell count, 2017 European LeukemiaNet risk category, and number of induction cycles need to achieve CR, NGS MRD was an independent prognostic factor for both relapse (SHR 1.89, P less than .001) and overall survival (HR 1.64 P = .003).
When the investigators conducted a sensitivity analysis with time-dependent correction for allogeneic stem cell transplantation, they found that NGS MRD was still significantly prognostic for both relapse and survival.
The study was supported by the Dutch Cancer Society, the Haemato-Oncology Foundation for Adults in the Netherlands, the Swiss Group for Clinical Cancer Research, and The Netherlands Organization for Health Research and Development. Dr. Grob reported having no relevant disclosures.
SOURCE: Jongen-Lavrencic M et al. ASH 2017 Abstract LBA 5.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: The presence of any non-DTA mutation after CR was an independent prognostic factor for relapse (SHR 1.89) and overall survival (HR 1.64).
Study details: Prospective analysis of bone marrow samples from 430 patients with AML at diagnosis and in first complete remission.
Disclosures: The study was supported by the Dutch Cancer Society, the Haemato-Oncology Foundation for Adults in the Netherlands, the Swiss Group for Clinical Cancer Research, and The Netherlands Organization for Health Research and Development. Dr. Grob reported having no relevant disclosures.
Source: Jongen-Lavrencic M et al. ASH 2017 Abstract LBA 5.
Amyloid depleter/antibody duo reduces systemic amyloidosis severity
A one-two combination consisting of a drug to deplete amyloid fibrils from circulation and a monoclonal antibody to mop up residual amyloid protein appears to be safe and shows promising activity against systemic amyloidosis in an early clinical trial.
Pairing the investigational small molecule agent miridesap and the experimental monoclonal antibody dezamizumab resulted in clearance or reductions in amyloid deposits in the livers, spleens, and kidneys of adults with systemic amyloidosis, reported Prof. Sir Mark B. Pepys of University College, London, and his colleagues.
Systemic amyloidosis is caused by extracellular deposition of amyloid fibrils coated with serum amyloid P component (SAP), a normal plasma protein. Miridesap has been shown to deplete levels of circulating SAP, but fails to clear SAP lingering in amyloid deposits. Dezamizumab is a fully humanized immunoglobulin G1 antibody that is directed against SAP and provokes immune system clearance of residual protein.
The investigators enrolled 23 adults with systemic amyloidosis into an open-label, nonrandomized trial of safety, pharmacokinetics, and dose responses to up to three cycles of miridesap followed by dezamizumab. They used scintigraphy with radiolabeling to measure amyloid burden, equilibrium MRI to measure organ extracellular volume, and transient elastography to evaluate liver stiffness.
They found that a 2,000-mg dose of dezamizumab reduced amyloid load in the liver and/or spleen in five of seven patients, and that liver stiffness, a sensitive marker for hepatic amyloid load, initially increased in some patients, but then fell “substantially,” suggesting amyloid clearance and resolution of cellular infiltrates. Progressive dose-related clearance of amyloid in the liver was also associated with improvements in liver function tests.
In addition, 7 of 11 patients had reductions in renal amyloid burden, with the greatest benefit seen in patients treated with higher doses of the antibody.
The trial cohort also included six patients with clinical cardiac amyloidosis: three with monoclonal immunoglobulin light-chain amyloidosis (AL), and three with ATTR (transthyretin) amyloidosis. Although the investigators had excluded patients with cardiac amyloidosis in the first part of the study out of safety concerns, there were no new arrhythmias and no increases in cardiac troponin T or creatine kinase concentrations. One patient had a 17% reduction in left ventricular mass, suggesting a reduction in cardiac amyloid burden.
Patients tolerated the treatment, with self-limiting, early-onset rashes after higher antibody doses being the most frequent adverse event.
“However, the identified and potential risks of the intervention are considered manageable, and thus acceptable, in relation to the demonstrable clinical benefits of removing amyloid from vital organs,” the investigators wrote.
GlaxoSmithKline funded the study. Three of the coauthors are GSK employees and stockholders. Prof. Pepys is the inventor on patents for miridesap and miridesap plus anti-SAP antibody.
Source: Richards D et al. Sci. Transl. Med. 2018. doi: 10.1126/scitranslmed.aan3128.
A one-two combination consisting of a drug to deplete amyloid fibrils from circulation and a monoclonal antibody to mop up residual amyloid protein appears to be safe and shows promising activity against systemic amyloidosis in an early clinical trial.
Pairing the investigational small molecule agent miridesap and the experimental monoclonal antibody dezamizumab resulted in clearance or reductions in amyloid deposits in the livers, spleens, and kidneys of adults with systemic amyloidosis, reported Prof. Sir Mark B. Pepys of University College, London, and his colleagues.
Systemic amyloidosis is caused by extracellular deposition of amyloid fibrils coated with serum amyloid P component (SAP), a normal plasma protein. Miridesap has been shown to deplete levels of circulating SAP, but fails to clear SAP lingering in amyloid deposits. Dezamizumab is a fully humanized immunoglobulin G1 antibody that is directed against SAP and provokes immune system clearance of residual protein.
The investigators enrolled 23 adults with systemic amyloidosis into an open-label, nonrandomized trial of safety, pharmacokinetics, and dose responses to up to three cycles of miridesap followed by dezamizumab. They used scintigraphy with radiolabeling to measure amyloid burden, equilibrium MRI to measure organ extracellular volume, and transient elastography to evaluate liver stiffness.
They found that a 2,000-mg dose of dezamizumab reduced amyloid load in the liver and/or spleen in five of seven patients, and that liver stiffness, a sensitive marker for hepatic amyloid load, initially increased in some patients, but then fell “substantially,” suggesting amyloid clearance and resolution of cellular infiltrates. Progressive dose-related clearance of amyloid in the liver was also associated with improvements in liver function tests.
In addition, 7 of 11 patients had reductions in renal amyloid burden, with the greatest benefit seen in patients treated with higher doses of the antibody.
The trial cohort also included six patients with clinical cardiac amyloidosis: three with monoclonal immunoglobulin light-chain amyloidosis (AL), and three with ATTR (transthyretin) amyloidosis. Although the investigators had excluded patients with cardiac amyloidosis in the first part of the study out of safety concerns, there were no new arrhythmias and no increases in cardiac troponin T or creatine kinase concentrations. One patient had a 17% reduction in left ventricular mass, suggesting a reduction in cardiac amyloid burden.
Patients tolerated the treatment, with self-limiting, early-onset rashes after higher antibody doses being the most frequent adverse event.
“However, the identified and potential risks of the intervention are considered manageable, and thus acceptable, in relation to the demonstrable clinical benefits of removing amyloid from vital organs,” the investigators wrote.
GlaxoSmithKline funded the study. Three of the coauthors are GSK employees and stockholders. Prof. Pepys is the inventor on patents for miridesap and miridesap plus anti-SAP antibody.
Source: Richards D et al. Sci. Transl. Med. 2018. doi: 10.1126/scitranslmed.aan3128.
A one-two combination consisting of a drug to deplete amyloid fibrils from circulation and a monoclonal antibody to mop up residual amyloid protein appears to be safe and shows promising activity against systemic amyloidosis in an early clinical trial.
Pairing the investigational small molecule agent miridesap and the experimental monoclonal antibody dezamizumab resulted in clearance or reductions in amyloid deposits in the livers, spleens, and kidneys of adults with systemic amyloidosis, reported Prof. Sir Mark B. Pepys of University College, London, and his colleagues.
Systemic amyloidosis is caused by extracellular deposition of amyloid fibrils coated with serum amyloid P component (SAP), a normal plasma protein. Miridesap has been shown to deplete levels of circulating SAP, but fails to clear SAP lingering in amyloid deposits. Dezamizumab is a fully humanized immunoglobulin G1 antibody that is directed against SAP and provokes immune system clearance of residual protein.
The investigators enrolled 23 adults with systemic amyloidosis into an open-label, nonrandomized trial of safety, pharmacokinetics, and dose responses to up to three cycles of miridesap followed by dezamizumab. They used scintigraphy with radiolabeling to measure amyloid burden, equilibrium MRI to measure organ extracellular volume, and transient elastography to evaluate liver stiffness.
They found that a 2,000-mg dose of dezamizumab reduced amyloid load in the liver and/or spleen in five of seven patients, and that liver stiffness, a sensitive marker for hepatic amyloid load, initially increased in some patients, but then fell “substantially,” suggesting amyloid clearance and resolution of cellular infiltrates. Progressive dose-related clearance of amyloid in the liver was also associated with improvements in liver function tests.
In addition, 7 of 11 patients had reductions in renal amyloid burden, with the greatest benefit seen in patients treated with higher doses of the antibody.
The trial cohort also included six patients with clinical cardiac amyloidosis: three with monoclonal immunoglobulin light-chain amyloidosis (AL), and three with ATTR (transthyretin) amyloidosis. Although the investigators had excluded patients with cardiac amyloidosis in the first part of the study out of safety concerns, there were no new arrhythmias and no increases in cardiac troponin T or creatine kinase concentrations. One patient had a 17% reduction in left ventricular mass, suggesting a reduction in cardiac amyloid burden.
Patients tolerated the treatment, with self-limiting, early-onset rashes after higher antibody doses being the most frequent adverse event.
“However, the identified and potential risks of the intervention are considered manageable, and thus acceptable, in relation to the demonstrable clinical benefits of removing amyloid from vital organs,” the investigators wrote.
GlaxoSmithKline funded the study. Three of the coauthors are GSK employees and stockholders. Prof. Pepys is the inventor on patents for miridesap and miridesap plus anti-SAP antibody.
Source: Richards D et al. Sci. Transl. Med. 2018. doi: 10.1126/scitranslmed.aan3128.
FROM SCIENCE TRANSLATIONAL MEDICINE
Key clinical point: A combination of an amyloid-depleting agent and immunotherapeutic antibody appears effective and safe in patients with systemic amyloidosis.
Major finding: A 2,000-mg dose of dezamizumab reduced amyloid load in the liver and/or spleen in five of seven patients.
Data source: Open-label, nonrandomized clinical trial of 23 adults with various subtypes of systemic amyloidosis.
Disclosures: GlaxoSmithKline funded the study. Three of the coauthors are GSK employees and stockholders. Prof. Pepys is the inventor on patents for miridesap and miridesap plus anti-SAP antibody.
Source: Richards D et al. Sci. Transl. Med. 2018;10:eaan3128.
Sorafenib plus chemo prolongs event-free survival in AML
ATLANTA – Adding the targeted agent sorafenib (Nexavar) to standard induction and consolidation chemotherapy in adults with acute myeloid leukemia (AML) significantly extended event-free survival out to more than 6 years and improved relapse-free survival, updated results from the SORAML trial showed.
At a median follow-up of 78 months, median event-free survival (EFS) – the primary endpoint – was 26 months in the chemotherapy plus sorafenib arm, compared with 9 months for chemotherapy plus placebo; these results translate to a hazard ratio for progression or death with sorafenib of 0.68 (P = .011), reported Christoph Röllig, MD, MSc, of University Hospital Carl Gustav Carus in Dresden, Germany.
Sorafenib is a multikinase inhibitor that blocks several cellular pathways that may be involved in leukemogenesis and AML maintenance. To see whether it could improve outcomes over standard chemotherapy alone, the SORAML investigators enrolled 267 patients who were aged 60 years or younger and had good performance status with newly diagnosed AML, irrespective of FLT3 mutational status.
In this phase 2 trial, patients were randomly assigned in a double-blinded fashion to standard chemotherapy plus either oral sorafenib 400 mg twice daily or placebo on days 10 through 19 of induction cycles 1 and 2, from day 8 of each consolidation cycles, and as maintenance for 12 months.
Chemotherapy consisted of two cycles of induction therapy with daunorubicin (60 mg/m2 on days 3-5) plus cytarabine (100 mg/m2 on days 1-7), followed by three cycles of high-dose cytarabine-based consolidation therapy (3 g/m2 twice daily on days 1, 3, and 5).
Intermediate-risk patients with a sibling donor and all high-risk patients with matched donors were scheduled for allogeneic stem cell transplantation in first remission.
The planned final analysis of the trial, reported in 2015, showed that, after a median follow-up of 36 months, the median EFS with sorafenib was 21 months, compared with 9 months for placebo. This difference translated into 3-year EFS rates of 40% vs. 22%, respectively (HR, 0.64; P = .013).
The overall survival (OS) analysis trended in favor of sorafenib at 3 years, but the difference was not statistically significant.
At ASH 2017, Dr. Röllig presented longer-term follow-up data and reported treatments after relapse (intensive versus palliative), remission rates, and survival outcomes. The primary endpoint of EFS continued to favor the sorafenib arm at 6.5 years’ median follow-up.
A multivariate analysis controlling for age, risk category, mutational status, lactate dehydrogenase levels, and secondary or treatment-related AML showed that the benefit of sorafenib was even stronger, with a HR of 0.614 for EFS with sorafenib, compared with EFS with placebo (P = .006). The targeted agent was also superior in patients stratified by risk category and in patients with NPM1 and FLT3-ITD mutations.
Relapse-free survival after 6.5 years was also better in the sorafenib arm, at a median of 63 months, than it was in the placebo arm, in which the median relapse-free survival was only 23 months (HR, 0.64; P = .035).
Following relapse, 73% of patients in the sorafenib arm and 82% of those in the placebo arm were treated with curative intent. Treatments consisted largely of salvage stem cell transplant (SCT) in 93% of this subgroup in the sorafenib arm and in 95% of those in the placebo arm. In each arm, the majority of patients were treated with human leukocyte antigen–identical SCT.
Patients in the sorafenib arm were more likely to require a second allogeneic SCT, which may be attributable to the fact that most patients in this group received their first SCT during the second complete remission, Dr. Röllig said.
Median overall survival from relapse at 6.5 years’ median follow-up was 10 months for patients treated with sorafenib, compared with 27 months for placebo, but this difference did not reach statistical significance.
OS at 6.5 years’ median follow-up had not been reached in the sorafenib arm, compared with 83 months for the placebo arm, translating into 4-year OS rates of 62% and 55%, respectively. The hazard ratio was 0.819 favoring sorafenib, but it was not statistically significant (P = .282).
During a question-and-answer session following the presentation, Farhad Ravandi-Kashani, MD, of the University of Texas MD Anderson Cancer Center in Houston asked why more patients in the placebo arm than in the sorafenib arm were treated after relapse with curative intent and whether there was any crossover to sorafenib at the time of salvage therapy, which could have confounded the results.
“The reasons why they had slightly less curative treatments in the sorafenib arm I can’t explain. There are no indicators; it could just be chance,” Dr. Röllig said.
Of the 30 patients in the sorafenib arm who relapsed, 2 received sorafenib in salvage therapy, but this was a matter of chance given that the treatment assignment was blinded to both physician and patient, he added.
The study was sponsored by the Technical University of Dresden and funded by Bayer. Dr. Röllig reported research funding from Bayer and Janssen; he also reported off-label use of sorafenib.
SOURCE: Röllig C et al. ASH 2017 Abstract 721.
ATLANTA – Adding the targeted agent sorafenib (Nexavar) to standard induction and consolidation chemotherapy in adults with acute myeloid leukemia (AML) significantly extended event-free survival out to more than 6 years and improved relapse-free survival, updated results from the SORAML trial showed.
At a median follow-up of 78 months, median event-free survival (EFS) – the primary endpoint – was 26 months in the chemotherapy plus sorafenib arm, compared with 9 months for chemotherapy plus placebo; these results translate to a hazard ratio for progression or death with sorafenib of 0.68 (P = .011), reported Christoph Röllig, MD, MSc, of University Hospital Carl Gustav Carus in Dresden, Germany.
Sorafenib is a multikinase inhibitor that blocks several cellular pathways that may be involved in leukemogenesis and AML maintenance. To see whether it could improve outcomes over standard chemotherapy alone, the SORAML investigators enrolled 267 patients who were aged 60 years or younger and had good performance status with newly diagnosed AML, irrespective of FLT3 mutational status.
In this phase 2 trial, patients were randomly assigned in a double-blinded fashion to standard chemotherapy plus either oral sorafenib 400 mg twice daily or placebo on days 10 through 19 of induction cycles 1 and 2, from day 8 of each consolidation cycles, and as maintenance for 12 months.
Chemotherapy consisted of two cycles of induction therapy with daunorubicin (60 mg/m2 on days 3-5) plus cytarabine (100 mg/m2 on days 1-7), followed by three cycles of high-dose cytarabine-based consolidation therapy (3 g/m2 twice daily on days 1, 3, and 5).
Intermediate-risk patients with a sibling donor and all high-risk patients with matched donors were scheduled for allogeneic stem cell transplantation in first remission.
The planned final analysis of the trial, reported in 2015, showed that, after a median follow-up of 36 months, the median EFS with sorafenib was 21 months, compared with 9 months for placebo. This difference translated into 3-year EFS rates of 40% vs. 22%, respectively (HR, 0.64; P = .013).
The overall survival (OS) analysis trended in favor of sorafenib at 3 years, but the difference was not statistically significant.
At ASH 2017, Dr. Röllig presented longer-term follow-up data and reported treatments after relapse (intensive versus palliative), remission rates, and survival outcomes. The primary endpoint of EFS continued to favor the sorafenib arm at 6.5 years’ median follow-up.
A multivariate analysis controlling for age, risk category, mutational status, lactate dehydrogenase levels, and secondary or treatment-related AML showed that the benefit of sorafenib was even stronger, with a HR of 0.614 for EFS with sorafenib, compared with EFS with placebo (P = .006). The targeted agent was also superior in patients stratified by risk category and in patients with NPM1 and FLT3-ITD mutations.
Relapse-free survival after 6.5 years was also better in the sorafenib arm, at a median of 63 months, than it was in the placebo arm, in which the median relapse-free survival was only 23 months (HR, 0.64; P = .035).
Following relapse, 73% of patients in the sorafenib arm and 82% of those in the placebo arm were treated with curative intent. Treatments consisted largely of salvage stem cell transplant (SCT) in 93% of this subgroup in the sorafenib arm and in 95% of those in the placebo arm. In each arm, the majority of patients were treated with human leukocyte antigen–identical SCT.
Patients in the sorafenib arm were more likely to require a second allogeneic SCT, which may be attributable to the fact that most patients in this group received their first SCT during the second complete remission, Dr. Röllig said.
Median overall survival from relapse at 6.5 years’ median follow-up was 10 months for patients treated with sorafenib, compared with 27 months for placebo, but this difference did not reach statistical significance.
OS at 6.5 years’ median follow-up had not been reached in the sorafenib arm, compared with 83 months for the placebo arm, translating into 4-year OS rates of 62% and 55%, respectively. The hazard ratio was 0.819 favoring sorafenib, but it was not statistically significant (P = .282).
During a question-and-answer session following the presentation, Farhad Ravandi-Kashani, MD, of the University of Texas MD Anderson Cancer Center in Houston asked why more patients in the placebo arm than in the sorafenib arm were treated after relapse with curative intent and whether there was any crossover to sorafenib at the time of salvage therapy, which could have confounded the results.
“The reasons why they had slightly less curative treatments in the sorafenib arm I can’t explain. There are no indicators; it could just be chance,” Dr. Röllig said.
Of the 30 patients in the sorafenib arm who relapsed, 2 received sorafenib in salvage therapy, but this was a matter of chance given that the treatment assignment was blinded to both physician and patient, he added.
The study was sponsored by the Technical University of Dresden and funded by Bayer. Dr. Röllig reported research funding from Bayer and Janssen; he also reported off-label use of sorafenib.
SOURCE: Röllig C et al. ASH 2017 Abstract 721.
ATLANTA – Adding the targeted agent sorafenib (Nexavar) to standard induction and consolidation chemotherapy in adults with acute myeloid leukemia (AML) significantly extended event-free survival out to more than 6 years and improved relapse-free survival, updated results from the SORAML trial showed.
At a median follow-up of 78 months, median event-free survival (EFS) – the primary endpoint – was 26 months in the chemotherapy plus sorafenib arm, compared with 9 months for chemotherapy plus placebo; these results translate to a hazard ratio for progression or death with sorafenib of 0.68 (P = .011), reported Christoph Röllig, MD, MSc, of University Hospital Carl Gustav Carus in Dresden, Germany.
Sorafenib is a multikinase inhibitor that blocks several cellular pathways that may be involved in leukemogenesis and AML maintenance. To see whether it could improve outcomes over standard chemotherapy alone, the SORAML investigators enrolled 267 patients who were aged 60 years or younger and had good performance status with newly diagnosed AML, irrespective of FLT3 mutational status.
In this phase 2 trial, patients were randomly assigned in a double-blinded fashion to standard chemotherapy plus either oral sorafenib 400 mg twice daily or placebo on days 10 through 19 of induction cycles 1 and 2, from day 8 of each consolidation cycles, and as maintenance for 12 months.
Chemotherapy consisted of two cycles of induction therapy with daunorubicin (60 mg/m2 on days 3-5) plus cytarabine (100 mg/m2 on days 1-7), followed by three cycles of high-dose cytarabine-based consolidation therapy (3 g/m2 twice daily on days 1, 3, and 5).
Intermediate-risk patients with a sibling donor and all high-risk patients with matched donors were scheduled for allogeneic stem cell transplantation in first remission.
The planned final analysis of the trial, reported in 2015, showed that, after a median follow-up of 36 months, the median EFS with sorafenib was 21 months, compared with 9 months for placebo. This difference translated into 3-year EFS rates of 40% vs. 22%, respectively (HR, 0.64; P = .013).
The overall survival (OS) analysis trended in favor of sorafenib at 3 years, but the difference was not statistically significant.
At ASH 2017, Dr. Röllig presented longer-term follow-up data and reported treatments after relapse (intensive versus palliative), remission rates, and survival outcomes. The primary endpoint of EFS continued to favor the sorafenib arm at 6.5 years’ median follow-up.
A multivariate analysis controlling for age, risk category, mutational status, lactate dehydrogenase levels, and secondary or treatment-related AML showed that the benefit of sorafenib was even stronger, with a HR of 0.614 for EFS with sorafenib, compared with EFS with placebo (P = .006). The targeted agent was also superior in patients stratified by risk category and in patients with NPM1 and FLT3-ITD mutations.
Relapse-free survival after 6.5 years was also better in the sorafenib arm, at a median of 63 months, than it was in the placebo arm, in which the median relapse-free survival was only 23 months (HR, 0.64; P = .035).
Following relapse, 73% of patients in the sorafenib arm and 82% of those in the placebo arm were treated with curative intent. Treatments consisted largely of salvage stem cell transplant (SCT) in 93% of this subgroup in the sorafenib arm and in 95% of those in the placebo arm. In each arm, the majority of patients were treated with human leukocyte antigen–identical SCT.
Patients in the sorafenib arm were more likely to require a second allogeneic SCT, which may be attributable to the fact that most patients in this group received their first SCT during the second complete remission, Dr. Röllig said.
Median overall survival from relapse at 6.5 years’ median follow-up was 10 months for patients treated with sorafenib, compared with 27 months for placebo, but this difference did not reach statistical significance.
OS at 6.5 years’ median follow-up had not been reached in the sorafenib arm, compared with 83 months for the placebo arm, translating into 4-year OS rates of 62% and 55%, respectively. The hazard ratio was 0.819 favoring sorafenib, but it was not statistically significant (P = .282).
During a question-and-answer session following the presentation, Farhad Ravandi-Kashani, MD, of the University of Texas MD Anderson Cancer Center in Houston asked why more patients in the placebo arm than in the sorafenib arm were treated after relapse with curative intent and whether there was any crossover to sorafenib at the time of salvage therapy, which could have confounded the results.
“The reasons why they had slightly less curative treatments in the sorafenib arm I can’t explain. There are no indicators; it could just be chance,” Dr. Röllig said.
Of the 30 patients in the sorafenib arm who relapsed, 2 received sorafenib in salvage therapy, but this was a matter of chance given that the treatment assignment was blinded to both physician and patient, he added.
The study was sponsored by the Technical University of Dresden and funded by Bayer. Dr. Röllig reported research funding from Bayer and Janssen; he also reported off-label use of sorafenib.
SOURCE: Röllig C et al. ASH 2017 Abstract 721.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: At a median of 6.5 years, the hazard ratio for progression or death with sorafenib plus chemotherapy versus placebo plus chemotherapy was 0.68 (P = .011).
Data source: Randomized, double-blind, phase 2 trial comprising 267 patients with de novo AML.
Disclosures: The study was sponsored by the Technical University of Dresden and funded by Bayer. Dr. Röllig reported research funding from Bayer and from Janssen; he also reported off-label use of sorafenib.
Source: Röllig C et al. ASH 2017 Abstract 721.
Venetoclax/rituximab boosts PFS in relapsed/refractory CLL
ATLANTA – In patients with relapsed/refractory chronic lymphocytic leukemia (CLL), a combination of venetoclax (Venclexta) and rituximab was superior to bendamustine (Treanda) and rituximab for prolonging progression-free survival (PFS), with effects consistent across subgroups, regardless of mutational status, and a clinically meaningful improvement in overall survival.
An interim analysis from the phase 3 MURANO trial showed that after a median follow-up of 23.8 months, the median PFS for patients randomized to venetoclax/rituximab had not been reached, compared with 17 months for patients assigned to bendamustine/rituximab, reported John F. Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre at the University of Melbourne.
Relapsed/refractory CLL often has a suboptimal response to conventional chemotherapy because of adverse biological features that can accumulate in cells, he said.
The combination of bendamustine and rituximab has been associated with about 60% overall responses rates, a median PFS of approximately 15 months, and overall survival of nearly 3 years in patients with CLL, he noted.
The rationale for pairing venetoclax with rituximab in this population comes from evidence showing efficacy of the monoclonal antibody, an oral B-cell lymphoma–2 (BCL-2) inhibitor, as monotherapy in patients with relapsed/refractory CLL, including those with poor prognostic features such as the 17p deletion (del17p).
Dr. Seymour and his colleagues recently published results from a phase 1b trial of venetoclax/rituximab in patients with relapsed/refractory CLL. The combination was associated with a 51% complete response rate, and a 28% rate of negative marrow minimal residual disease (MRD) (Lancet Oncol. 2017 Feb;18[2]:230-40)
In the MURANO study (NCT02005471), the investigators evaluated whether time-limited therapy with venetoclax/rituximab could improve PFS over bendamustine/rituximab.
Patients 18 and older with CLL who had been treated with one to three prior lines of therapy, including at least one chemotherapy-containing regimen, were enrolled. Prior treatment with bendamustine was allowed only if patients had had a duration of response of at least 24 months.
After stratification by del17p status, responsiveness to prior therapy, and geographic region, 389 patients were randomly assigned to receive rituximab 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2 through 6, plus either bendamustine 70 mg/m2 on days 1 and 2 of each of six cycles, or venetoclax 400 mg orally once daily until disease progression, cessation for toxicity, or up to a maximum of 2 years starting from day 1 of cycle 1.
As noted,
The respective 1- and 2-year PFS rates with venetoclax were 91.2% and 82.8%, compared with 74.1% and 37.4% with bendamustine.
The venetoclax/rituximab combination was also significantly superior across all subgroups, regardless of the number of prior therapies, refractory vs. relapsed after most recent prior therapy, del17p status, TP53 mutational status, or baseline immunoglobulin heavy chain variable (IGHV) mutated or unmutated status
Response rates assessed by both investigators and independent reviewers were also better with venetoclax. The investigator-assessed overall response rate (ORR) was 93.3%, compared with 67.7% for bendamustine/rituximab, including 26.8% complete responses (CR), compared with 8.2%. Independent reviewers decreed an ORR of 92.3% for venentoclax, vs. 72.3% for bendamustine, including respective CR rates of 8.2% and 3.6%.
The investigators also found that the percentage of MRD negativity was higher with venetoclax/rituximab, with 62% of patients in this group being MRD negative at 9 months. This rate remained fairly constant at 12-, 15- and 18-month follow-ups (60%, 57%, and 60%, respectively).
In contrast, 13% of patients treated with bendamustine were MRD negative at 9 months, and the rates gradually declined over time to 10%, 9%, and 5%.
Investigators also saw a clinically meaningful improvement in overall survival with the venetoclax/rituximab duo, although survival data are still not mature in this ongoing trial. The median OS had not been reached in either group at the time of data cutoff.
Respective 1- and 2-year OS rates with venetoclax were 95.9% and 91.9%, and with bendamustine were 91.1% and 86.6%.
At the time of this interim analysis, the hazard ratio favoring venetoclax/rituximab was 0.48 (P = .0186).
Drug discontinuation was more frequent with venetoclax/rituximab (25% vs, 17%), with disease progression and adverse events without progression being the most frequent reasons for stopping in each arm.
Serious adverse events occurred in 46% of patients on venetoclax/rituximab and 43% on bendamustine/rituximab. A higher percentage of patients on venetoclax/rituximab had grade 3 or 4 adverse events (82% vs, 70%). Ten patients (5%) in the venetoclax/rituximab arm died, and 11 patients (6%) on bendamustine/rituximab died.
Events with a greater than 2% difference included more frequent neutropenia, tumor lysis syndrome, hyperglycemia and hypogammaglobulinema with venetoclax/rituximab, and more frequent anemia, thrombocytopenia, febrile neutropenia, pneumonia, infusion-related reactions, and hypotension with bendamustine/rituximab.
In the question-and-response portion following Dr. Seymour’s presentation, an audience member commented that the continuation of venetoclax/rituximab beyond the initial treatment cycles amounted to a maintenance strategy, and that patients in the experimental arm were in treatment longer, which likely influenced the results.
“You’re absolutely correct that the treatment duration differed, although, of course, the capacity to deliver more than six cycles of bendamustine/rituximab would have been problematic,” Dr. Seymour replied.
“There are some data that antibody treatment may prolong progression-free survival. However, when this study was designed in 2013 that data was certainly not available, and I believe currently even maintenance antibodies are not an accepted standard of treatment,” he added.
The MURANO trial was funded by AbbVie and Genentech. Dr. Seymour disclosed honoraria, speakers bureau, research funding, and advisory activities with AbbVie and other companies.
SOURCE: Seymour J et al. ASH 2017 LBA-2.
ATLANTA – In patients with relapsed/refractory chronic lymphocytic leukemia (CLL), a combination of venetoclax (Venclexta) and rituximab was superior to bendamustine (Treanda) and rituximab for prolonging progression-free survival (PFS), with effects consistent across subgroups, regardless of mutational status, and a clinically meaningful improvement in overall survival.
An interim analysis from the phase 3 MURANO trial showed that after a median follow-up of 23.8 months, the median PFS for patients randomized to venetoclax/rituximab had not been reached, compared with 17 months for patients assigned to bendamustine/rituximab, reported John F. Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre at the University of Melbourne.
Relapsed/refractory CLL often has a suboptimal response to conventional chemotherapy because of adverse biological features that can accumulate in cells, he said.
The combination of bendamustine and rituximab has been associated with about 60% overall responses rates, a median PFS of approximately 15 months, and overall survival of nearly 3 years in patients with CLL, he noted.
The rationale for pairing venetoclax with rituximab in this population comes from evidence showing efficacy of the monoclonal antibody, an oral B-cell lymphoma–2 (BCL-2) inhibitor, as monotherapy in patients with relapsed/refractory CLL, including those with poor prognostic features such as the 17p deletion (del17p).
Dr. Seymour and his colleagues recently published results from a phase 1b trial of venetoclax/rituximab in patients with relapsed/refractory CLL. The combination was associated with a 51% complete response rate, and a 28% rate of negative marrow minimal residual disease (MRD) (Lancet Oncol. 2017 Feb;18[2]:230-40)
In the MURANO study (NCT02005471), the investigators evaluated whether time-limited therapy with venetoclax/rituximab could improve PFS over bendamustine/rituximab.
Patients 18 and older with CLL who had been treated with one to three prior lines of therapy, including at least one chemotherapy-containing regimen, were enrolled. Prior treatment with bendamustine was allowed only if patients had had a duration of response of at least 24 months.
After stratification by del17p status, responsiveness to prior therapy, and geographic region, 389 patients were randomly assigned to receive rituximab 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2 through 6, plus either bendamustine 70 mg/m2 on days 1 and 2 of each of six cycles, or venetoclax 400 mg orally once daily until disease progression, cessation for toxicity, or up to a maximum of 2 years starting from day 1 of cycle 1.
As noted,
The respective 1- and 2-year PFS rates with venetoclax were 91.2% and 82.8%, compared with 74.1% and 37.4% with bendamustine.
The venetoclax/rituximab combination was also significantly superior across all subgroups, regardless of the number of prior therapies, refractory vs. relapsed after most recent prior therapy, del17p status, TP53 mutational status, or baseline immunoglobulin heavy chain variable (IGHV) mutated or unmutated status
Response rates assessed by both investigators and independent reviewers were also better with venetoclax. The investigator-assessed overall response rate (ORR) was 93.3%, compared with 67.7% for bendamustine/rituximab, including 26.8% complete responses (CR), compared with 8.2%. Independent reviewers decreed an ORR of 92.3% for venentoclax, vs. 72.3% for bendamustine, including respective CR rates of 8.2% and 3.6%.
The investigators also found that the percentage of MRD negativity was higher with venetoclax/rituximab, with 62% of patients in this group being MRD negative at 9 months. This rate remained fairly constant at 12-, 15- and 18-month follow-ups (60%, 57%, and 60%, respectively).
In contrast, 13% of patients treated with bendamustine were MRD negative at 9 months, and the rates gradually declined over time to 10%, 9%, and 5%.
Investigators also saw a clinically meaningful improvement in overall survival with the venetoclax/rituximab duo, although survival data are still not mature in this ongoing trial. The median OS had not been reached in either group at the time of data cutoff.
Respective 1- and 2-year OS rates with venetoclax were 95.9% and 91.9%, and with bendamustine were 91.1% and 86.6%.
At the time of this interim analysis, the hazard ratio favoring venetoclax/rituximab was 0.48 (P = .0186).
Drug discontinuation was more frequent with venetoclax/rituximab (25% vs, 17%), with disease progression and adverse events without progression being the most frequent reasons for stopping in each arm.
Serious adverse events occurred in 46% of patients on venetoclax/rituximab and 43% on bendamustine/rituximab. A higher percentage of patients on venetoclax/rituximab had grade 3 or 4 adverse events (82% vs, 70%). Ten patients (5%) in the venetoclax/rituximab arm died, and 11 patients (6%) on bendamustine/rituximab died.
Events with a greater than 2% difference included more frequent neutropenia, tumor lysis syndrome, hyperglycemia and hypogammaglobulinema with venetoclax/rituximab, and more frequent anemia, thrombocytopenia, febrile neutropenia, pneumonia, infusion-related reactions, and hypotension with bendamustine/rituximab.
In the question-and-response portion following Dr. Seymour’s presentation, an audience member commented that the continuation of venetoclax/rituximab beyond the initial treatment cycles amounted to a maintenance strategy, and that patients in the experimental arm were in treatment longer, which likely influenced the results.
“You’re absolutely correct that the treatment duration differed, although, of course, the capacity to deliver more than six cycles of bendamustine/rituximab would have been problematic,” Dr. Seymour replied.
“There are some data that antibody treatment may prolong progression-free survival. However, when this study was designed in 2013 that data was certainly not available, and I believe currently even maintenance antibodies are not an accepted standard of treatment,” he added.
The MURANO trial was funded by AbbVie and Genentech. Dr. Seymour disclosed honoraria, speakers bureau, research funding, and advisory activities with AbbVie and other companies.
SOURCE: Seymour J et al. ASH 2017 LBA-2.
ATLANTA – In patients with relapsed/refractory chronic lymphocytic leukemia (CLL), a combination of venetoclax (Venclexta) and rituximab was superior to bendamustine (Treanda) and rituximab for prolonging progression-free survival (PFS), with effects consistent across subgroups, regardless of mutational status, and a clinically meaningful improvement in overall survival.
An interim analysis from the phase 3 MURANO trial showed that after a median follow-up of 23.8 months, the median PFS for patients randomized to venetoclax/rituximab had not been reached, compared with 17 months for patients assigned to bendamustine/rituximab, reported John F. Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre at the University of Melbourne.
Relapsed/refractory CLL often has a suboptimal response to conventional chemotherapy because of adverse biological features that can accumulate in cells, he said.
The combination of bendamustine and rituximab has been associated with about 60% overall responses rates, a median PFS of approximately 15 months, and overall survival of nearly 3 years in patients with CLL, he noted.
The rationale for pairing venetoclax with rituximab in this population comes from evidence showing efficacy of the monoclonal antibody, an oral B-cell lymphoma–2 (BCL-2) inhibitor, as monotherapy in patients with relapsed/refractory CLL, including those with poor prognostic features such as the 17p deletion (del17p).
Dr. Seymour and his colleagues recently published results from a phase 1b trial of venetoclax/rituximab in patients with relapsed/refractory CLL. The combination was associated with a 51% complete response rate, and a 28% rate of negative marrow minimal residual disease (MRD) (Lancet Oncol. 2017 Feb;18[2]:230-40)
In the MURANO study (NCT02005471), the investigators evaluated whether time-limited therapy with venetoclax/rituximab could improve PFS over bendamustine/rituximab.
Patients 18 and older with CLL who had been treated with one to three prior lines of therapy, including at least one chemotherapy-containing regimen, were enrolled. Prior treatment with bendamustine was allowed only if patients had had a duration of response of at least 24 months.
After stratification by del17p status, responsiveness to prior therapy, and geographic region, 389 patients were randomly assigned to receive rituximab 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2 through 6, plus either bendamustine 70 mg/m2 on days 1 and 2 of each of six cycles, or venetoclax 400 mg orally once daily until disease progression, cessation for toxicity, or up to a maximum of 2 years starting from day 1 of cycle 1.
As noted,
The respective 1- and 2-year PFS rates with venetoclax were 91.2% and 82.8%, compared with 74.1% and 37.4% with bendamustine.
The venetoclax/rituximab combination was also significantly superior across all subgroups, regardless of the number of prior therapies, refractory vs. relapsed after most recent prior therapy, del17p status, TP53 mutational status, or baseline immunoglobulin heavy chain variable (IGHV) mutated or unmutated status
Response rates assessed by both investigators and independent reviewers were also better with venetoclax. The investigator-assessed overall response rate (ORR) was 93.3%, compared with 67.7% for bendamustine/rituximab, including 26.8% complete responses (CR), compared with 8.2%. Independent reviewers decreed an ORR of 92.3% for venentoclax, vs. 72.3% for bendamustine, including respective CR rates of 8.2% and 3.6%.
The investigators also found that the percentage of MRD negativity was higher with venetoclax/rituximab, with 62% of patients in this group being MRD negative at 9 months. This rate remained fairly constant at 12-, 15- and 18-month follow-ups (60%, 57%, and 60%, respectively).
In contrast, 13% of patients treated with bendamustine were MRD negative at 9 months, and the rates gradually declined over time to 10%, 9%, and 5%.
Investigators also saw a clinically meaningful improvement in overall survival with the venetoclax/rituximab duo, although survival data are still not mature in this ongoing trial. The median OS had not been reached in either group at the time of data cutoff.
Respective 1- and 2-year OS rates with venetoclax were 95.9% and 91.9%, and with bendamustine were 91.1% and 86.6%.
At the time of this interim analysis, the hazard ratio favoring venetoclax/rituximab was 0.48 (P = .0186).
Drug discontinuation was more frequent with venetoclax/rituximab (25% vs, 17%), with disease progression and adverse events without progression being the most frequent reasons for stopping in each arm.
Serious adverse events occurred in 46% of patients on venetoclax/rituximab and 43% on bendamustine/rituximab. A higher percentage of patients on venetoclax/rituximab had grade 3 or 4 adverse events (82% vs, 70%). Ten patients (5%) in the venetoclax/rituximab arm died, and 11 patients (6%) on bendamustine/rituximab died.
Events with a greater than 2% difference included more frequent neutropenia, tumor lysis syndrome, hyperglycemia and hypogammaglobulinema with venetoclax/rituximab, and more frequent anemia, thrombocytopenia, febrile neutropenia, pneumonia, infusion-related reactions, and hypotension with bendamustine/rituximab.
In the question-and-response portion following Dr. Seymour’s presentation, an audience member commented that the continuation of venetoclax/rituximab beyond the initial treatment cycles amounted to a maintenance strategy, and that patients in the experimental arm were in treatment longer, which likely influenced the results.
“You’re absolutely correct that the treatment duration differed, although, of course, the capacity to deliver more than six cycles of bendamustine/rituximab would have been problematic,” Dr. Seymour replied.
“There are some data that antibody treatment may prolong progression-free survival. However, when this study was designed in 2013 that data was certainly not available, and I believe currently even maintenance antibodies are not an accepted standard of treatment,” he added.
The MURANO trial was funded by AbbVie and Genentech. Dr. Seymour disclosed honoraria, speakers bureau, research funding, and advisory activities with AbbVie and other companies.
SOURCE: Seymour J et al. ASH 2017 LBA-2.
REPORTING FROM ASH 2017
Key clinical point: Compared with bendamustine/rituximab, venetoclax/rituximab was associated with significantly superior progression-free survival of relapsed/refractory chronic lymphocytic leukemia.
Major finding: The hazard ratio for PFS with venetoclax/rituximab was 0.17 (P less than .001).
Data source: A randomized phase 3, open-label trial in 389 patients with relapsed/refractory CLL.
Disclosures: The MURANO trial was funded by AbbVie and Genetech. Dr. Seymour disclosed honoraria, speakers bureau, research funding, and advisory activities with AbbVie and other companies.
Source: Seymour J et al. ASH 2017 LBA-2.
VIDEO: Venetoclax/rituximab prolongs PFS in relapsed/refractory CLL
ATLANTA – Relapsed or refractory chronic lymphocytic leukemia (CLL) often has a suboptimal response to conventional chemotherapy, because of adverse biological features that can accumulate in cells.
The combination of bendamustine (Treanda) and rituximab has been associated with about 60% overall responses rates, median progression-free survival of approximately 15 months, and overall survival of nearly 3 years in patients with CLL, and there is now evidence that substituting venetoclax (Venclexta) for bendamustine could improve outcomes even further.
In a video interview at the annual meeting of the American Society of Hematology, comparing bendamustine plus rituximab with venetoclax plus rituximab in patients with relapsed/refractory CLL.
Venetoclax/rituximab was superior to bendamustine/rituximab for prolonging progression-free survival, with effects consistent across subgroups, regardless of mutation status, and for having a clinically meaningful improvement in overall survival.
The MURANO trial was funded by AbbVie. Dr. Seymour reported honoraria, research funding, and advisory committee and speakers bureau participation for AbbVie and other companies.
ATLANTA – Relapsed or refractory chronic lymphocytic leukemia (CLL) often has a suboptimal response to conventional chemotherapy, because of adverse biological features that can accumulate in cells.
The combination of bendamustine (Treanda) and rituximab has been associated with about 60% overall responses rates, median progression-free survival of approximately 15 months, and overall survival of nearly 3 years in patients with CLL, and there is now evidence that substituting venetoclax (Venclexta) for bendamustine could improve outcomes even further.
In a video interview at the annual meeting of the American Society of Hematology, comparing bendamustine plus rituximab with venetoclax plus rituximab in patients with relapsed/refractory CLL.
Venetoclax/rituximab was superior to bendamustine/rituximab for prolonging progression-free survival, with effects consistent across subgroups, regardless of mutation status, and for having a clinically meaningful improvement in overall survival.
The MURANO trial was funded by AbbVie. Dr. Seymour reported honoraria, research funding, and advisory committee and speakers bureau participation for AbbVie and other companies.
ATLANTA – Relapsed or refractory chronic lymphocytic leukemia (CLL) often has a suboptimal response to conventional chemotherapy, because of adverse biological features that can accumulate in cells.
The combination of bendamustine (Treanda) and rituximab has been associated with about 60% overall responses rates, median progression-free survival of approximately 15 months, and overall survival of nearly 3 years in patients with CLL, and there is now evidence that substituting venetoclax (Venclexta) for bendamustine could improve outcomes even further.
In a video interview at the annual meeting of the American Society of Hematology, comparing bendamustine plus rituximab with venetoclax plus rituximab in patients with relapsed/refractory CLL.
Venetoclax/rituximab was superior to bendamustine/rituximab for prolonging progression-free survival, with effects consistent across subgroups, regardless of mutation status, and for having a clinically meaningful improvement in overall survival.
The MURANO trial was funded by AbbVie. Dr. Seymour reported honoraria, research funding, and advisory committee and speakers bureau participation for AbbVie and other companies.
REPORTING FROM ASH 2017
VIDEO: Daratumumab gives kick to standard first-line myeloma therapy
ATLANTA – The VMP regimen, consisting of bortezomib, melphalan, and prednisone, is a standard of care in Europe for frontline therapy for patients with multiple myeloma who, for reasons of age or infirmity, are not good candidates for autologous stem cell transplant.
In this video interview at the annual meeting of the American Society of Hematology, Jesus San-Miguel, MD, of the Clinical University of Navarra in Pamplona, Spain, discusses the results of the phase 3 international ALCYONE trial, comparing VMP with the same regimen plus the addition of the anti-CD38 monoclonal antibody daratumumab (Darzalex).
Adding daratumumab to VMP regimen as first-line therapy for 706 patients with multiple myeloma cut in half the risk of disease progression or death and substantially improved the rate of minimal residual disease negativity, Dr. San-Miguel reported. There were no new safety signals from adding the monoclonal antibody to VMP.
The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others.
ATLANTA – The VMP regimen, consisting of bortezomib, melphalan, and prednisone, is a standard of care in Europe for frontline therapy for patients with multiple myeloma who, for reasons of age or infirmity, are not good candidates for autologous stem cell transplant.
In this video interview at the annual meeting of the American Society of Hematology, Jesus San-Miguel, MD, of the Clinical University of Navarra in Pamplona, Spain, discusses the results of the phase 3 international ALCYONE trial, comparing VMP with the same regimen plus the addition of the anti-CD38 monoclonal antibody daratumumab (Darzalex).
Adding daratumumab to VMP regimen as first-line therapy for 706 patients with multiple myeloma cut in half the risk of disease progression or death and substantially improved the rate of minimal residual disease negativity, Dr. San-Miguel reported. There were no new safety signals from adding the monoclonal antibody to VMP.
The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others.
ATLANTA – The VMP regimen, consisting of bortezomib, melphalan, and prednisone, is a standard of care in Europe for frontline therapy for patients with multiple myeloma who, for reasons of age or infirmity, are not good candidates for autologous stem cell transplant.
In this video interview at the annual meeting of the American Society of Hematology, Jesus San-Miguel, MD, of the Clinical University of Navarra in Pamplona, Spain, discusses the results of the phase 3 international ALCYONE trial, comparing VMP with the same regimen plus the addition of the anti-CD38 monoclonal antibody daratumumab (Darzalex).
Adding daratumumab to VMP regimen as first-line therapy for 706 patients with multiple myeloma cut in half the risk of disease progression or death and substantially improved the rate of minimal residual disease negativity, Dr. San-Miguel reported. There were no new safety signals from adding the monoclonal antibody to VMP.
The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others.
REPORTING FROM ASH 2017
Daratumumab plus VMP boosts PFS, MRD-negativity in de novo myeloma
ATLANTA – Adding the anti-CD38 monoclonal antibody daratumumab (Darzalex) to the standard VMP regimen as first-line therapy for patients with multiple myeloma cut in half the risk of disease progression or death and substantially improved the rate of minimal residual disease (MRD) negativity, investigators in the ALCYONE trial reported.
This difference translated into a hazard ratio for progression or death with D-VMP of 0.50 (P less than .0001), said Jesus San-Miguel, MD, from the Clinical University of Navarra in Pamplona, Spain.
“This result clearly indicated for the first time that, in a phase 3 randomized study conducted with a monoclonal antibody in newly diagnosed myeloma patients, the addition of daratumumab to the standard of care reduced the risk of progression or death by 50%, and this is associated with significantly deeper responses, including a threefold higher MRD negativity rate,” he said at a media briefing prior to presentation of the data in a late-breaking abstract session at the annual meeting of the American Society of Hematology.
The VMP regimen is used more commonly in Europe than the United States as first-line therapy for patients with previously untreated multiple myeloma who are aged 65 years or older or are otherwise not suitable candidates for autologous stem cell transplants (ASCT).
In the ALCYONE trial, patients who met this definition were enrolled and stratified by International Staging System scores, region, and age (younger or older than 75 years) and were then randomized to 6-week cycles of VMP, with or without daratumumab. In the experimental arm, daratumumab was given at 16 mg/kg IV weekly for cycle 1, every 3 weeks for cycles 2-9, and every 4 weeks for cycles 10 and beyond (post VMP-treatment phase) until disease progression.
As noted before, the primary endpoint of investigator-assessed PFS significantly favored the addition of daratumumab. Dr. San-Miguel attributed this difference to the overall response rates, which were 91%, including 43% complete responses with daratumumab, vs. 74% ORR with 24% CR, without the monoclonal antibody.
The rate of MRD negativity, measured with a threshold sensitivity of 10–5, was also significantly higher with daratumumab at 22% vs. 6% (P less than .0001).
Among all patients who achieved MRD negativity, regardless of treatment, there was a lower risk of progression or death, Dr. San-Miguel said.
The rate of treatment discontinuation because of infection was higher with VMP (1.4%) than with D-VMP (0.9%). One patient in each trial arm discontinued therapy because of pneumonia. Rates of any serious adverse event were higher with D-VMP (42%, compared with 33%). Infusion-related reactions occurred in 27.7% of patients assigned to daratumumab.
Rates of grade 3 or 4 hematologic and nonhematologic toxicities were generally similar between the treatment arms, and there were no new safety signals with daratumumab, Dr. San-Miguel said.
The ALCYONE trial is one of several ongoing studies looking at the addition of daratumumab to standard therapies in the frontline, including the phase 3 MAIA trial (with daratumumab added to lenalidomide and dexamethasone), the phase 3 CASSIOPEIA trial (with the antibody added to bortezomib, thalidomide, and dexamethasone), the phase 2 GRIFFIN trial (with daratumumab plus lenalidomide, bortezomib, and dexamethasone), and the phase 2 LYRA trial (with the antibody added to cyclophosphamide, bortezomib, and dexamethasone).
The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others. Multiple coauthors disclosed similar relationships.
SOURCE: Mateos MV et al. ASH Abstract LBA-4.
ATLANTA – Adding the anti-CD38 monoclonal antibody daratumumab (Darzalex) to the standard VMP regimen as first-line therapy for patients with multiple myeloma cut in half the risk of disease progression or death and substantially improved the rate of minimal residual disease (MRD) negativity, investigators in the ALCYONE trial reported.
This difference translated into a hazard ratio for progression or death with D-VMP of 0.50 (P less than .0001), said Jesus San-Miguel, MD, from the Clinical University of Navarra in Pamplona, Spain.
“This result clearly indicated for the first time that, in a phase 3 randomized study conducted with a monoclonal antibody in newly diagnosed myeloma patients, the addition of daratumumab to the standard of care reduced the risk of progression or death by 50%, and this is associated with significantly deeper responses, including a threefold higher MRD negativity rate,” he said at a media briefing prior to presentation of the data in a late-breaking abstract session at the annual meeting of the American Society of Hematology.
The VMP regimen is used more commonly in Europe than the United States as first-line therapy for patients with previously untreated multiple myeloma who are aged 65 years or older or are otherwise not suitable candidates for autologous stem cell transplants (ASCT).
In the ALCYONE trial, patients who met this definition were enrolled and stratified by International Staging System scores, region, and age (younger or older than 75 years) and were then randomized to 6-week cycles of VMP, with or without daratumumab. In the experimental arm, daratumumab was given at 16 mg/kg IV weekly for cycle 1, every 3 weeks for cycles 2-9, and every 4 weeks for cycles 10 and beyond (post VMP-treatment phase) until disease progression.
As noted before, the primary endpoint of investigator-assessed PFS significantly favored the addition of daratumumab. Dr. San-Miguel attributed this difference to the overall response rates, which were 91%, including 43% complete responses with daratumumab, vs. 74% ORR with 24% CR, without the monoclonal antibody.
The rate of MRD negativity, measured with a threshold sensitivity of 10–5, was also significantly higher with daratumumab at 22% vs. 6% (P less than .0001).
Among all patients who achieved MRD negativity, regardless of treatment, there was a lower risk of progression or death, Dr. San-Miguel said.
The rate of treatment discontinuation because of infection was higher with VMP (1.4%) than with D-VMP (0.9%). One patient in each trial arm discontinued therapy because of pneumonia. Rates of any serious adverse event were higher with D-VMP (42%, compared with 33%). Infusion-related reactions occurred in 27.7% of patients assigned to daratumumab.
Rates of grade 3 or 4 hematologic and nonhematologic toxicities were generally similar between the treatment arms, and there were no new safety signals with daratumumab, Dr. San-Miguel said.
The ALCYONE trial is one of several ongoing studies looking at the addition of daratumumab to standard therapies in the frontline, including the phase 3 MAIA trial (with daratumumab added to lenalidomide and dexamethasone), the phase 3 CASSIOPEIA trial (with the antibody added to bortezomib, thalidomide, and dexamethasone), the phase 2 GRIFFIN trial (with daratumumab plus lenalidomide, bortezomib, and dexamethasone), and the phase 2 LYRA trial (with the antibody added to cyclophosphamide, bortezomib, and dexamethasone).
The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others. Multiple coauthors disclosed similar relationships.
SOURCE: Mateos MV et al. ASH Abstract LBA-4.
ATLANTA – Adding the anti-CD38 monoclonal antibody daratumumab (Darzalex) to the standard VMP regimen as first-line therapy for patients with multiple myeloma cut in half the risk of disease progression or death and substantially improved the rate of minimal residual disease (MRD) negativity, investigators in the ALCYONE trial reported.
This difference translated into a hazard ratio for progression or death with D-VMP of 0.50 (P less than .0001), said Jesus San-Miguel, MD, from the Clinical University of Navarra in Pamplona, Spain.
“This result clearly indicated for the first time that, in a phase 3 randomized study conducted with a monoclonal antibody in newly diagnosed myeloma patients, the addition of daratumumab to the standard of care reduced the risk of progression or death by 50%, and this is associated with significantly deeper responses, including a threefold higher MRD negativity rate,” he said at a media briefing prior to presentation of the data in a late-breaking abstract session at the annual meeting of the American Society of Hematology.
The VMP regimen is used more commonly in Europe than the United States as first-line therapy for patients with previously untreated multiple myeloma who are aged 65 years or older or are otherwise not suitable candidates for autologous stem cell transplants (ASCT).
In the ALCYONE trial, patients who met this definition were enrolled and stratified by International Staging System scores, region, and age (younger or older than 75 years) and were then randomized to 6-week cycles of VMP, with or without daratumumab. In the experimental arm, daratumumab was given at 16 mg/kg IV weekly for cycle 1, every 3 weeks for cycles 2-9, and every 4 weeks for cycles 10 and beyond (post VMP-treatment phase) until disease progression.
As noted before, the primary endpoint of investigator-assessed PFS significantly favored the addition of daratumumab. Dr. San-Miguel attributed this difference to the overall response rates, which were 91%, including 43% complete responses with daratumumab, vs. 74% ORR with 24% CR, without the monoclonal antibody.
The rate of MRD negativity, measured with a threshold sensitivity of 10–5, was also significantly higher with daratumumab at 22% vs. 6% (P less than .0001).
Among all patients who achieved MRD negativity, regardless of treatment, there was a lower risk of progression or death, Dr. San-Miguel said.
The rate of treatment discontinuation because of infection was higher with VMP (1.4%) than with D-VMP (0.9%). One patient in each trial arm discontinued therapy because of pneumonia. Rates of any serious adverse event were higher with D-VMP (42%, compared with 33%). Infusion-related reactions occurred in 27.7% of patients assigned to daratumumab.
Rates of grade 3 or 4 hematologic and nonhematologic toxicities were generally similar between the treatment arms, and there were no new safety signals with daratumumab, Dr. San-Miguel said.
The ALCYONE trial is one of several ongoing studies looking at the addition of daratumumab to standard therapies in the frontline, including the phase 3 MAIA trial (with daratumumab added to lenalidomide and dexamethasone), the phase 3 CASSIOPEIA trial (with the antibody added to bortezomib, thalidomide, and dexamethasone), the phase 2 GRIFFIN trial (with daratumumab plus lenalidomide, bortezomib, and dexamethasone), and the phase 2 LYRA trial (with the antibody added to cyclophosphamide, bortezomib, and dexamethasone).
The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others. Multiple coauthors disclosed similar relationships.
SOURCE: Mateos MV et al. ASH Abstract LBA-4.
REPORTING FROM ASH 2017
Key clinical point:
Major finding: The hazard ratio for progression or death with daratumumab plus VMP was 0.50 (P less than .0001).
Study details: Randomized phase 3 trial in 706 patients with multiple myeloma who were ineligible for transplant.
Disclosures: The ALCYONE study was supported by Janssen Research & Development. Dr. San-Miguel reported serving as an adviser to the company and several others. Multiple coauthors disclosed similar relationships.
Source: Mateos MV et al. ASH Abstract LBA-4.
Novel PARP inhibitor boosts PFS in HER2- breast cancer with BRCA mutations
SAN ANTONIO – In women with advanced HER2-negative breast cancer with germline BRCA mutations, an investigational oral PARP inhibitor talazoparib was associated with a near doubling in progression-free survival (PFS) when compared with single-agent chemotherapy, results of the phase 3 EMBRACA trial show.
After a median follow-up of 11.2 months, the median PFS by blinded central review – the primary endpoint – was 8.6 months for patients assigned to receive talazoparib, compared with 5.6 months for patients randomized to receive the physician’s choice of either capecitabine, eribulin, gemcitabine, or vinorelbine, reported Jennifer K. Litton, MD, from the University of Texas MD Anderson Cancer Center in Houston.
“Patients who were assigned to talazoparib had an improvement in their global health status versus patients who had deterioration when randomized.”
Talazoparib is an oral inhibitor of poly ADP-ribose polymerase (PARP) with a dual mechanism of action: It both inhibits the PARP enzyme directly and traps PARP on single-stranded DNA breaks, preventing repair of DNA damage and leading to the death of malignant cells.
In the phase 2 ABRAZO trial, the PARP inhibitor showed “encouraging” efficacy and safety in patients with germline BRCA1/BRCA2 mutations who had received platinum-based chemotherapy or at least three prior cytotoxic regimens.
Dr. Litton reported results of the EMBRACA trial, a phase 3 study in patients with locally advanced or metastatic HER2 negative breast cancer a germline BRCA1 or BRCA2 mutation. Patients were stratified by number of prior chemotherapy regimens, by having triple-negative breast cancer or hormone receptor-positive breast cancer, and by having a history of either central nervous system metastases or no CNS metastases; they were then randomized on a 2:1 basis to either oral talazoparib 1 mg daily (287 patients) or to the physician’s choice of therapy with one of the agents noted before.
The patient characteristics were generally well balanced, although there was a higher percentage of patients aged younger than 50 years in the talazoparib group than in the group treated with other agents (63.4% vs. 46.5%, respectively), slightly more CNS metastases (15% vs. 13.9%), and a higher percentage of patients with a disease-free interval (time from initial diagnosis to advanced breast cancer) shorter than 12 months (37.6% vs. 29.2%).
The primary endpoint of PFS by blinded central review showed the aforementioned significant benefit of talazoparib. A PFS by subgroup analysis showed that talazoparib was significantly better in all parameters except for patients who had previously received platinum-based therapy.
The trial was also powered to show overall survival as a secondary endpoint, but the data are not mature, Dr. Litton said. An interim OS analysis showed an apparent trend favoring the PARP inhibitor, with a median of 22.3 months, compared with 19.5 months with physician’s choice of treatment.
The 24- and 36-month probabilities of survival were 45% and 34% respectively for patients treated with talazoparib, compared with 37% and 0% for patients treated with other agents.
The objective response rate by investigator rating was 62.6% with talazoparib, compared with 27.2% for other drugs (odds ratio, 4.99; P less than .0001).
Anemia was the most common hematologic adverse event, with grade 3 or greater occurring in 39.2% of patients on the PARP inhibitor, compared with 4.8% of patients treated with other agents.
Talazoparib, unlike other PARP inhibitors, was also associated with grade 1 or 2 alopecia, which occurred in 25.2% of those patients, compared with 27.8% of those receiving the physician’s choice of treatment.
Grade 3 or 4 serious adverse events occurred in about 25.5% of patients in each study arm. Events leading to permanent drug discontinuation were more common with physician’s choice agents at 9.5%, compared with 7.7% of patients treated with talazoparib.
Kent Osborne, MD, the director of the Dan L. Duncan Cancer Center at Baylor College of Medicine, Houston, who moderated a briefing where Dr. Litton presented the data, commented that patients may not be as enthusiastic about the results as investigators seem to be.
“I’ve heard doctors like you and I say ‘This is really great, we’ve got some activity from a PARP inhibitor;’ patients look at it and say ‘Gee, a few more responses and a 3-month prolongation on average of my time to progression is not a very big advantage,’ ” he said to Dr. Litton.
“So what’s the next step in the development of these drugs? Are they going to be used in combinations? Are we going to come up with a mechanism of resistance that we can then overcome to extend the duration of their benefit?” he asked.
Dr. Litton replied that she was encouraged by fact that the tails of the survival curves appear to be separating and that some patients have complete responses and some have relatively durable responses.
“One of the things that we’re going to be looking at are the correlatives, trying to identify who these extraordinary responders are and the mechanisms of resistance as best we can,” she said.
This study was funded by Pfizer, which developed the inhibitor. Dr. Litton has disclosed research funding with EMD Serono, AstraZeneca, Pfizer, Genentech, and GlaxoSmithKline, and serves on advisory boards for Pfizer and AstraZeneca, all uncompensated.
SOURCE: Litton et al. SABCS 2017 Abstract GS6-07.
SAN ANTONIO – In women with advanced HER2-negative breast cancer with germline BRCA mutations, an investigational oral PARP inhibitor talazoparib was associated with a near doubling in progression-free survival (PFS) when compared with single-agent chemotherapy, results of the phase 3 EMBRACA trial show.
After a median follow-up of 11.2 months, the median PFS by blinded central review – the primary endpoint – was 8.6 months for patients assigned to receive talazoparib, compared with 5.6 months for patients randomized to receive the physician’s choice of either capecitabine, eribulin, gemcitabine, or vinorelbine, reported Jennifer K. Litton, MD, from the University of Texas MD Anderson Cancer Center in Houston.
“Patients who were assigned to talazoparib had an improvement in their global health status versus patients who had deterioration when randomized.”
Talazoparib is an oral inhibitor of poly ADP-ribose polymerase (PARP) with a dual mechanism of action: It both inhibits the PARP enzyme directly and traps PARP on single-stranded DNA breaks, preventing repair of DNA damage and leading to the death of malignant cells.
In the phase 2 ABRAZO trial, the PARP inhibitor showed “encouraging” efficacy and safety in patients with germline BRCA1/BRCA2 mutations who had received platinum-based chemotherapy or at least three prior cytotoxic regimens.
Dr. Litton reported results of the EMBRACA trial, a phase 3 study in patients with locally advanced or metastatic HER2 negative breast cancer a germline BRCA1 or BRCA2 mutation. Patients were stratified by number of prior chemotherapy regimens, by having triple-negative breast cancer or hormone receptor-positive breast cancer, and by having a history of either central nervous system metastases or no CNS metastases; they were then randomized on a 2:1 basis to either oral talazoparib 1 mg daily (287 patients) or to the physician’s choice of therapy with one of the agents noted before.
The patient characteristics were generally well balanced, although there was a higher percentage of patients aged younger than 50 years in the talazoparib group than in the group treated with other agents (63.4% vs. 46.5%, respectively), slightly more CNS metastases (15% vs. 13.9%), and a higher percentage of patients with a disease-free interval (time from initial diagnosis to advanced breast cancer) shorter than 12 months (37.6% vs. 29.2%).
The primary endpoint of PFS by blinded central review showed the aforementioned significant benefit of talazoparib. A PFS by subgroup analysis showed that talazoparib was significantly better in all parameters except for patients who had previously received platinum-based therapy.
The trial was also powered to show overall survival as a secondary endpoint, but the data are not mature, Dr. Litton said. An interim OS analysis showed an apparent trend favoring the PARP inhibitor, with a median of 22.3 months, compared with 19.5 months with physician’s choice of treatment.
The 24- and 36-month probabilities of survival were 45% and 34% respectively for patients treated with talazoparib, compared with 37% and 0% for patients treated with other agents.
The objective response rate by investigator rating was 62.6% with talazoparib, compared with 27.2% for other drugs (odds ratio, 4.99; P less than .0001).
Anemia was the most common hematologic adverse event, with grade 3 or greater occurring in 39.2% of patients on the PARP inhibitor, compared with 4.8% of patients treated with other agents.
Talazoparib, unlike other PARP inhibitors, was also associated with grade 1 or 2 alopecia, which occurred in 25.2% of those patients, compared with 27.8% of those receiving the physician’s choice of treatment.
Grade 3 or 4 serious adverse events occurred in about 25.5% of patients in each study arm. Events leading to permanent drug discontinuation were more common with physician’s choice agents at 9.5%, compared with 7.7% of patients treated with talazoparib.
Kent Osborne, MD, the director of the Dan L. Duncan Cancer Center at Baylor College of Medicine, Houston, who moderated a briefing where Dr. Litton presented the data, commented that patients may not be as enthusiastic about the results as investigators seem to be.
“I’ve heard doctors like you and I say ‘This is really great, we’ve got some activity from a PARP inhibitor;’ patients look at it and say ‘Gee, a few more responses and a 3-month prolongation on average of my time to progression is not a very big advantage,’ ” he said to Dr. Litton.
“So what’s the next step in the development of these drugs? Are they going to be used in combinations? Are we going to come up with a mechanism of resistance that we can then overcome to extend the duration of their benefit?” he asked.
Dr. Litton replied that she was encouraged by fact that the tails of the survival curves appear to be separating and that some patients have complete responses and some have relatively durable responses.
“One of the things that we’re going to be looking at are the correlatives, trying to identify who these extraordinary responders are and the mechanisms of resistance as best we can,” she said.
This study was funded by Pfizer, which developed the inhibitor. Dr. Litton has disclosed research funding with EMD Serono, AstraZeneca, Pfizer, Genentech, and GlaxoSmithKline, and serves on advisory boards for Pfizer and AstraZeneca, all uncompensated.
SOURCE: Litton et al. SABCS 2017 Abstract GS6-07.
SAN ANTONIO – In women with advanced HER2-negative breast cancer with germline BRCA mutations, an investigational oral PARP inhibitor talazoparib was associated with a near doubling in progression-free survival (PFS) when compared with single-agent chemotherapy, results of the phase 3 EMBRACA trial show.
After a median follow-up of 11.2 months, the median PFS by blinded central review – the primary endpoint – was 8.6 months for patients assigned to receive talazoparib, compared with 5.6 months for patients randomized to receive the physician’s choice of either capecitabine, eribulin, gemcitabine, or vinorelbine, reported Jennifer K. Litton, MD, from the University of Texas MD Anderson Cancer Center in Houston.
“Patients who were assigned to talazoparib had an improvement in their global health status versus patients who had deterioration when randomized.”
Talazoparib is an oral inhibitor of poly ADP-ribose polymerase (PARP) with a dual mechanism of action: It both inhibits the PARP enzyme directly and traps PARP on single-stranded DNA breaks, preventing repair of DNA damage and leading to the death of malignant cells.
In the phase 2 ABRAZO trial, the PARP inhibitor showed “encouraging” efficacy and safety in patients with germline BRCA1/BRCA2 mutations who had received platinum-based chemotherapy or at least three prior cytotoxic regimens.
Dr. Litton reported results of the EMBRACA trial, a phase 3 study in patients with locally advanced or metastatic HER2 negative breast cancer a germline BRCA1 or BRCA2 mutation. Patients were stratified by number of prior chemotherapy regimens, by having triple-negative breast cancer or hormone receptor-positive breast cancer, and by having a history of either central nervous system metastases or no CNS metastases; they were then randomized on a 2:1 basis to either oral talazoparib 1 mg daily (287 patients) or to the physician’s choice of therapy with one of the agents noted before.
The patient characteristics were generally well balanced, although there was a higher percentage of patients aged younger than 50 years in the talazoparib group than in the group treated with other agents (63.4% vs. 46.5%, respectively), slightly more CNS metastases (15% vs. 13.9%), and a higher percentage of patients with a disease-free interval (time from initial diagnosis to advanced breast cancer) shorter than 12 months (37.6% vs. 29.2%).
The primary endpoint of PFS by blinded central review showed the aforementioned significant benefit of talazoparib. A PFS by subgroup analysis showed that talazoparib was significantly better in all parameters except for patients who had previously received platinum-based therapy.
The trial was also powered to show overall survival as a secondary endpoint, but the data are not mature, Dr. Litton said. An interim OS analysis showed an apparent trend favoring the PARP inhibitor, with a median of 22.3 months, compared with 19.5 months with physician’s choice of treatment.
The 24- and 36-month probabilities of survival were 45% and 34% respectively for patients treated with talazoparib, compared with 37% and 0% for patients treated with other agents.
The objective response rate by investigator rating was 62.6% with talazoparib, compared with 27.2% for other drugs (odds ratio, 4.99; P less than .0001).
Anemia was the most common hematologic adverse event, with grade 3 or greater occurring in 39.2% of patients on the PARP inhibitor, compared with 4.8% of patients treated with other agents.
Talazoparib, unlike other PARP inhibitors, was also associated with grade 1 or 2 alopecia, which occurred in 25.2% of those patients, compared with 27.8% of those receiving the physician’s choice of treatment.
Grade 3 or 4 serious adverse events occurred in about 25.5% of patients in each study arm. Events leading to permanent drug discontinuation were more common with physician’s choice agents at 9.5%, compared with 7.7% of patients treated with talazoparib.
Kent Osborne, MD, the director of the Dan L. Duncan Cancer Center at Baylor College of Medicine, Houston, who moderated a briefing where Dr. Litton presented the data, commented that patients may not be as enthusiastic about the results as investigators seem to be.
“I’ve heard doctors like you and I say ‘This is really great, we’ve got some activity from a PARP inhibitor;’ patients look at it and say ‘Gee, a few more responses and a 3-month prolongation on average of my time to progression is not a very big advantage,’ ” he said to Dr. Litton.
“So what’s the next step in the development of these drugs? Are they going to be used in combinations? Are we going to come up with a mechanism of resistance that we can then overcome to extend the duration of their benefit?” he asked.
Dr. Litton replied that she was encouraged by fact that the tails of the survival curves appear to be separating and that some patients have complete responses and some have relatively durable responses.
“One of the things that we’re going to be looking at are the correlatives, trying to identify who these extraordinary responders are and the mechanisms of resistance as best we can,” she said.
This study was funded by Pfizer, which developed the inhibitor. Dr. Litton has disclosed research funding with EMD Serono, AstraZeneca, Pfizer, Genentech, and GlaxoSmithKline, and serves on advisory boards for Pfizer and AstraZeneca, all uncompensated.
SOURCE: Litton et al. SABCS 2017 Abstract GS6-07.
REPORTING FROM SABCS 2017
Key clinical point: The investigational PARP inhibitor talazoparib extended progression-free survival of advanced HER2-negative breast cancer with germline BRCA mutations.
Major finding: Talazoparib was associated with a 46% reduction in risk for progression when compared with standard single agent therapies.
Data source: Randomized clinical trial in 431 patients with advanced, previously treated breast cancer with germline BRCA1 and BRCA2 mutations.
Disclosures: This study was funded by Pfizer, which developed the inhibitor. Dr. Litton disclosed that she has received research funding from EMD Serono, AstraZeneca, Pfizer, Genentech, and GlaxoSmithKline and that she serves on advisory boards for Pfizer and AstraZeneca, all uncompensated.
Source: Litton J et al. SABCS 2017 Abstract GS6-07.
Extra years of adjuvant bisphosphonate not needed in early breast cancer
SAN ANTONIO – When it comes to adjuvant bisphosphonate therapy following adjuvant chemotherapy for high-risk early breast cancer, more is not better than less, phase 3 data from the randomized SUCCESS A study suggest.
Among 3,421 patients randomized to adjuvant bisphosphonate therapy following chemotherapy, there was barely a speck of difference in either disease-free survival (DFS) or overall survival (OS) between patients randomized to either 2 years or 5 years of adjuvant bisphosphonate therapy with zoledronate, reported Wolfgang Janni, MD, from University Hospital Ulm (Germany).
“We conclude 5 years of adjuvant zoledronate treatment should not be considered currently in these patients in the absence of decreased bone density,” he said at the San Antonio Breast Cancer Symposium.
Adjuvant bisphosphonate therapy in patients with early breast cancer is associated with improved breast cancer–specific survival and reduced rates of breast cancer recurrence in bone, especially for postmenopausal patients, as shown in a meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group, Dr. Janni noted.
German breast cancer guidelines state that postmenopausal women should be offered bisphosphonates as part of their adjuvant systemic therapy, but the optimal duration of therapy is uncertain, prompting the investigators to examine the issue in a randomized trial.
SUCCESS A was a multicenter, phase 3, randomized trial with a multifactorial 2 x 2 design, in patients with high-risk node-negative and node-positive disease. Patients were randomized to FEC100 chemotherapy followed by docetaxel with or without gemcitabine. Chemotherapy was followed by endocrine therapy with 2 years of tamoxifen followed by 3 years of anastrozole (Arimidex). At the start of endocrine therapy, patients were further randomized to receive either 2 or 5 years of adjuvant zoledronate, 4 mg intravenously every 3 months for 2 years, or the same schedule over 2 years, followed by 4 mg every 6 months for 3 years.
A total of 2,987 of the 3,421 patients randomized to a zoledronate schedule were available for inclusion in the analysis.
As noted, adapted DFS and OS, measured starting from 2 years after the start of zoledronate with a maximum observation time of 48 months, were virtually identical between the two treatment groups, with respective P values of .827 and .713. Similarly, in a multivariate regression analysis model adjusted for age, body mass index, menopausal status, tumor size, nodal stage, histological grade and type, hormone receptor status, HER2 status, surgery type, and chemotherapy regimen, the hazard ratio for 5 vs. 2 years was 0.97 for DFS and 0.98 for OS. Neither endpoint was significantly different between the groups.
Similarly, there was no significant differences in the number of bone recurrences as first distant recurrences or in premenopausal vs. postmenopausal women.
Adverse events of any grade were significantly higher with 5 years of bisphosphonate therapy (46.2% vs. 27.2%, P less than .001), including significantly higher grade 3 or greater adverse events (7.6% vs. 5.1%, P = .006).
Following presentation of the data in an oral session, moderator Sibylle Loibl, MD, PhD, of the German Breast Group in Neu-Isenburg, Germany, questioned whether the follow-up was long enough to detect a clinically meaningful difference.
“The negative result of this study might be due to the small observation time,” Dr. Janni conceded.”We have a quite intensive drug regimen for the first 2 years, so this might also be a contributing factor [as to why] we did not see any difference.”
The SUCCESS A study was supported by AstraZeneca, Chugai, Janssen Diagnostics, Lilly, Novartis, and Sanofi-Aventis. Dr. Janni has reported financial relationships with AstraZeneca, Chugai, Janssen, Lilly, Novartis, and Sanofi.
SOURCE: Janni et al. SABCS 2017 Abstract GS1-06
SAN ANTONIO – When it comes to adjuvant bisphosphonate therapy following adjuvant chemotherapy for high-risk early breast cancer, more is not better than less, phase 3 data from the randomized SUCCESS A study suggest.
Among 3,421 patients randomized to adjuvant bisphosphonate therapy following chemotherapy, there was barely a speck of difference in either disease-free survival (DFS) or overall survival (OS) between patients randomized to either 2 years or 5 years of adjuvant bisphosphonate therapy with zoledronate, reported Wolfgang Janni, MD, from University Hospital Ulm (Germany).
“We conclude 5 years of adjuvant zoledronate treatment should not be considered currently in these patients in the absence of decreased bone density,” he said at the San Antonio Breast Cancer Symposium.
Adjuvant bisphosphonate therapy in patients with early breast cancer is associated with improved breast cancer–specific survival and reduced rates of breast cancer recurrence in bone, especially for postmenopausal patients, as shown in a meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group, Dr. Janni noted.
German breast cancer guidelines state that postmenopausal women should be offered bisphosphonates as part of their adjuvant systemic therapy, but the optimal duration of therapy is uncertain, prompting the investigators to examine the issue in a randomized trial.
SUCCESS A was a multicenter, phase 3, randomized trial with a multifactorial 2 x 2 design, in patients with high-risk node-negative and node-positive disease. Patients were randomized to FEC100 chemotherapy followed by docetaxel with or without gemcitabine. Chemotherapy was followed by endocrine therapy with 2 years of tamoxifen followed by 3 years of anastrozole (Arimidex). At the start of endocrine therapy, patients were further randomized to receive either 2 or 5 years of adjuvant zoledronate, 4 mg intravenously every 3 months for 2 years, or the same schedule over 2 years, followed by 4 mg every 6 months for 3 years.
A total of 2,987 of the 3,421 patients randomized to a zoledronate schedule were available for inclusion in the analysis.
As noted, adapted DFS and OS, measured starting from 2 years after the start of zoledronate with a maximum observation time of 48 months, were virtually identical between the two treatment groups, with respective P values of .827 and .713. Similarly, in a multivariate regression analysis model adjusted for age, body mass index, menopausal status, tumor size, nodal stage, histological grade and type, hormone receptor status, HER2 status, surgery type, and chemotherapy regimen, the hazard ratio for 5 vs. 2 years was 0.97 for DFS and 0.98 for OS. Neither endpoint was significantly different between the groups.
Similarly, there was no significant differences in the number of bone recurrences as first distant recurrences or in premenopausal vs. postmenopausal women.
Adverse events of any grade were significantly higher with 5 years of bisphosphonate therapy (46.2% vs. 27.2%, P less than .001), including significantly higher grade 3 or greater adverse events (7.6% vs. 5.1%, P = .006).
Following presentation of the data in an oral session, moderator Sibylle Loibl, MD, PhD, of the German Breast Group in Neu-Isenburg, Germany, questioned whether the follow-up was long enough to detect a clinically meaningful difference.
“The negative result of this study might be due to the small observation time,” Dr. Janni conceded.”We have a quite intensive drug regimen for the first 2 years, so this might also be a contributing factor [as to why] we did not see any difference.”
The SUCCESS A study was supported by AstraZeneca, Chugai, Janssen Diagnostics, Lilly, Novartis, and Sanofi-Aventis. Dr. Janni has reported financial relationships with AstraZeneca, Chugai, Janssen, Lilly, Novartis, and Sanofi.
SOURCE: Janni et al. SABCS 2017 Abstract GS1-06
SAN ANTONIO – When it comes to adjuvant bisphosphonate therapy following adjuvant chemotherapy for high-risk early breast cancer, more is not better than less, phase 3 data from the randomized SUCCESS A study suggest.
Among 3,421 patients randomized to adjuvant bisphosphonate therapy following chemotherapy, there was barely a speck of difference in either disease-free survival (DFS) or overall survival (OS) between patients randomized to either 2 years or 5 years of adjuvant bisphosphonate therapy with zoledronate, reported Wolfgang Janni, MD, from University Hospital Ulm (Germany).
“We conclude 5 years of adjuvant zoledronate treatment should not be considered currently in these patients in the absence of decreased bone density,” he said at the San Antonio Breast Cancer Symposium.
Adjuvant bisphosphonate therapy in patients with early breast cancer is associated with improved breast cancer–specific survival and reduced rates of breast cancer recurrence in bone, especially for postmenopausal patients, as shown in a meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group, Dr. Janni noted.
German breast cancer guidelines state that postmenopausal women should be offered bisphosphonates as part of their adjuvant systemic therapy, but the optimal duration of therapy is uncertain, prompting the investigators to examine the issue in a randomized trial.
SUCCESS A was a multicenter, phase 3, randomized trial with a multifactorial 2 x 2 design, in patients with high-risk node-negative and node-positive disease. Patients were randomized to FEC100 chemotherapy followed by docetaxel with or without gemcitabine. Chemotherapy was followed by endocrine therapy with 2 years of tamoxifen followed by 3 years of anastrozole (Arimidex). At the start of endocrine therapy, patients were further randomized to receive either 2 or 5 years of adjuvant zoledronate, 4 mg intravenously every 3 months for 2 years, or the same schedule over 2 years, followed by 4 mg every 6 months for 3 years.
A total of 2,987 of the 3,421 patients randomized to a zoledronate schedule were available for inclusion in the analysis.
As noted, adapted DFS and OS, measured starting from 2 years after the start of zoledronate with a maximum observation time of 48 months, were virtually identical between the two treatment groups, with respective P values of .827 and .713. Similarly, in a multivariate regression analysis model adjusted for age, body mass index, menopausal status, tumor size, nodal stage, histological grade and type, hormone receptor status, HER2 status, surgery type, and chemotherapy regimen, the hazard ratio for 5 vs. 2 years was 0.97 for DFS and 0.98 for OS. Neither endpoint was significantly different between the groups.
Similarly, there was no significant differences in the number of bone recurrences as first distant recurrences or in premenopausal vs. postmenopausal women.
Adverse events of any grade were significantly higher with 5 years of bisphosphonate therapy (46.2% vs. 27.2%, P less than .001), including significantly higher grade 3 or greater adverse events (7.6% vs. 5.1%, P = .006).
Following presentation of the data in an oral session, moderator Sibylle Loibl, MD, PhD, of the German Breast Group in Neu-Isenburg, Germany, questioned whether the follow-up was long enough to detect a clinically meaningful difference.
“The negative result of this study might be due to the small observation time,” Dr. Janni conceded.”We have a quite intensive drug regimen for the first 2 years, so this might also be a contributing factor [as to why] we did not see any difference.”
The SUCCESS A study was supported by AstraZeneca, Chugai, Janssen Diagnostics, Lilly, Novartis, and Sanofi-Aventis. Dr. Janni has reported financial relationships with AstraZeneca, Chugai, Janssen, Lilly, Novartis, and Sanofi.
SOURCE: Janni et al. SABCS 2017 Abstract GS1-06
REPORTING FROM SABCS 2017
Key clinical point: Five years of adjuvant bisphosphonate therapy offered no survival advantages over 2 years of therapy for women with early breast cancers.
Major finding: Neither adapted disease-free survival nor overall survival were significantly better with 3 extra years of zoledronate therapy.
Data source: Randomized phase 3 trial.
Disclosures: The SUCCESS A study was supported by AstraZeneca, Chugai, Janssen Diagnostics, Lilly, Novartis, and Sanofi-Aventis. Dr. Janni has reported financial relationships with AstraZeneca, Chugai, Janssen, Lilly, Novartis, and Sanofi.
Source: Janni et al., SABCS 2017 abstract GS1-06