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Obinutuzumab-CHOP not superior to rituximab-CHOP in new DLBCL
Obinutuzumab with CHOP therapy did not improve progression-free survival, compared with rituximab plus CHOP, in patients with previously untreated diffuse large B-cell lymphoma (DLBCL), according to results from a phase 3 trial published in the Journal of Clinical Oncology. (2017 Aug 10. doi: 10.1200/JCO.2017.73.3402)
The findings suggest that obinutuzumab, a glycoengineered, type II, anti-CD20 monoclonal antibody, might not offer a benefit over standard treatment with rituximab, an anti-CD20 monoclonal antibody, when used with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone).
A total of 1,418 patients were enrolled at 207 centers in 29 countries in the GOYA trial and were randomly assigned to one regimen or the other. The mean duration of exposure to the drugs was 25 weeks for both. The progression-free survival was 69.6% for obinutuzumab-CHOP – also known as G-CHOP – and 66.9% for rituximab-CHOP, not a statistically significant difference, wrote Umberto Vitolo, MD, of University-Hospital Città della Salute e della Scienza, Torino, Italy, and his fellow investigators.
The rate of adverse events was similar between the two groups. The lack of superiority of obinutuzumab comes after findings of its superiority in untreated follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). The investigators suggested that this may be a sign that obinutuzumab’s efficacy is best seen in less aggressive disease types.
“Given the advantages of G-based therapy in patients with FL and CLL, the lack of benefit of G-CHOP in patients with DLBCL in the GOYA study was unexpected, and the reasons for it are unclear,” they wrote. “This lack of benefit might simply have resulted from the differences in biologic and clinical profiles between indolent lymphoproliferative diseases, such as FL and CLL, and aggressive ones, such as DLBCL.”
The study was sponsored by F. Hoffman-La Roche, the manufacturer of the two drugs, and had support from Fondazione Italiana Linfomi.
Obinutuzumab with CHOP therapy did not improve progression-free survival, compared with rituximab plus CHOP, in patients with previously untreated diffuse large B-cell lymphoma (DLBCL), according to results from a phase 3 trial published in the Journal of Clinical Oncology. (2017 Aug 10. doi: 10.1200/JCO.2017.73.3402)
The findings suggest that obinutuzumab, a glycoengineered, type II, anti-CD20 monoclonal antibody, might not offer a benefit over standard treatment with rituximab, an anti-CD20 monoclonal antibody, when used with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone).
A total of 1,418 patients were enrolled at 207 centers in 29 countries in the GOYA trial and were randomly assigned to one regimen or the other. The mean duration of exposure to the drugs was 25 weeks for both. The progression-free survival was 69.6% for obinutuzumab-CHOP – also known as G-CHOP – and 66.9% for rituximab-CHOP, not a statistically significant difference, wrote Umberto Vitolo, MD, of University-Hospital Città della Salute e della Scienza, Torino, Italy, and his fellow investigators.
The rate of adverse events was similar between the two groups. The lack of superiority of obinutuzumab comes after findings of its superiority in untreated follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). The investigators suggested that this may be a sign that obinutuzumab’s efficacy is best seen in less aggressive disease types.
“Given the advantages of G-based therapy in patients with FL and CLL, the lack of benefit of G-CHOP in patients with DLBCL in the GOYA study was unexpected, and the reasons for it are unclear,” they wrote. “This lack of benefit might simply have resulted from the differences in biologic and clinical profiles between indolent lymphoproliferative diseases, such as FL and CLL, and aggressive ones, such as DLBCL.”
The study was sponsored by F. Hoffman-La Roche, the manufacturer of the two drugs, and had support from Fondazione Italiana Linfomi.
Obinutuzumab with CHOP therapy did not improve progression-free survival, compared with rituximab plus CHOP, in patients with previously untreated diffuse large B-cell lymphoma (DLBCL), according to results from a phase 3 trial published in the Journal of Clinical Oncology. (2017 Aug 10. doi: 10.1200/JCO.2017.73.3402)
The findings suggest that obinutuzumab, a glycoengineered, type II, anti-CD20 monoclonal antibody, might not offer a benefit over standard treatment with rituximab, an anti-CD20 monoclonal antibody, when used with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone).
A total of 1,418 patients were enrolled at 207 centers in 29 countries in the GOYA trial and were randomly assigned to one regimen or the other. The mean duration of exposure to the drugs was 25 weeks for both. The progression-free survival was 69.6% for obinutuzumab-CHOP – also known as G-CHOP – and 66.9% for rituximab-CHOP, not a statistically significant difference, wrote Umberto Vitolo, MD, of University-Hospital Città della Salute e della Scienza, Torino, Italy, and his fellow investigators.
The rate of adverse events was similar between the two groups. The lack of superiority of obinutuzumab comes after findings of its superiority in untreated follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). The investigators suggested that this may be a sign that obinutuzumab’s efficacy is best seen in less aggressive disease types.
“Given the advantages of G-based therapy in patients with FL and CLL, the lack of benefit of G-CHOP in patients with DLBCL in the GOYA study was unexpected, and the reasons for it are unclear,” they wrote. “This lack of benefit might simply have resulted from the differences in biologic and clinical profiles between indolent lymphoproliferative diseases, such as FL and CLL, and aggressive ones, such as DLBCL.”
The study was sponsored by F. Hoffman-La Roche, the manufacturer of the two drugs, and had support from Fondazione Italiana Linfomi.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Obinutuzumab with CHOP therapy did not improve progression-free survival for diffuse large B-cell lymphoma, compared with standard treatment with rituximab used with CHOP.
Major finding: The estimated PFS was 69.6% for obinutuzumab-CHOP and 66.9% for rituximab-CHOP, an insignificant difference.
Data source: A randomized phase 3 trial of 1,418 patients at 207 centers in 29 countries.
Disclosures: The study was sponsored by F. Hoffman-La Roche, the manufacturer of the two drugs, and had support from Fondazione Italiana Linfomi..
Analysis reveals poor outcomes in refractory DLBCL
Results from the SCHOLAR-1 study revealed poor outcomes of salvage therapy in patients with refractory diffuse large B-cell lymphoma (DLBCL).
This retrospective study included data on patients enrolled in 2 randomized trials and 2 academic databases.
The patients had primary refractory disease, were refractory to second-line or later therapy, or had relapsed within 12 months of autologous stem cell transplant (ASCT).
Twenty-six percent of patients responded to salvage therapy, with 7% achieving a complete response (CR).
The median overall survival (OS) was 6.3 months, and 20% of patients were still alive at 2 years’ follow-up.
Christian Gisselbrecht, MD, of Saint Louis Hospital in Paris, France, and his colleagues reported these findings in Blood. SCHOLAR-1 was funded through an unrestricted grant from Kite Pharma.
“SCHOLAR-1 demonstrates the uniformly poor treatment outcomes for patients with aggressive non-Hodgkin lymphoma and emphasizes the need for breakthrough therapies for these refractory patients,” Dr Gisselbrecht said.
Patient characteristics
The study included pooled, patient-level data from 2 phase 3 trials and 2 databases:
- The Canadian Cancer Trials Group study LY.12 (n=219)
- The Lymphoma Academic Research Organization’s CORAL study (n=170)
- A cohort from MD Anderson Cancer Center (n=165)
- A cohort from the Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (n=82).
There were a total of 636 patients who met criteria for refractory DLBCL, which included primary mediastinal B-cell lymphoma and transformed follicular lymphoma.
Twenty-eight percent of patients were primary refractory, 50% were refractory to second-line or later therapy, and 22% had relapsed within 12 months of transplant.
The patients’ median age was 55 (range, 19-81), and 64% were male. Seventy-three percent had an ECOG performance status of 0-1, 14% had a status of 2-4, and 13% were missing this data. Seventy-two percent of patients had stage III-IV disease, 27% had stage I-II disease, and less than 1% were missing this data.
Treatments
The MD Anderson cohort included patients who were relapsed/refractory to initial rituximab-containing chemotherapy, had failed salvage platinum-containing chemotherapy, and received a second salvage therapy at MD Anderson.
The University of Iowa/Mayo Clinic cohort included unselected, newly diagnosed patients with lymphoma who entered prospective documentation of primary and subsequent treatments and outcomes.
In the LY.12 study, patients were enrolled upon relapse after anthracycline-containing therapy and randomized to 1 of 2 salvage regimens, with a goal of consolidative ASCT.
The CORAL study enrolled patients in their first relapse or whose lymphoma was refractory to first-line therapy. They were randomized to 1 of 2 salvage regimens, with a goal of consolidative ASCT.
In the LY.12 and CORAL studies, eligible patients with CD20+ lymphoma were randomized to rituximab maintenance or observation post-ASCT.
Response
In all, 523 patients were evaluated for response. The overall response rate (ORR) was 26%, with a 7% CR rate and an 18% partial response rate.
Among patients with primary refractory disease, the ORR was 20%, and the CR rate was 3%.
Among patients who were refractory to second-line or later therapy, the ORR was 26%, and the CR rate was 10%.
Among patients who relapsed after transplant, the ORR was 34%, and the CR rate was 15%.
Survival
A total of 603 patients were evaluated for survival.
The median OS from the start of salvage therapy was 6.3 months (range, 5.9-7.0). The 1-year OS rate was 28%, and the 2-year OS was 20%.
Among primary refractory patients, the median OS was 7.1 months (range, 6.0-8.1), 1-year OS was 29%, and 2-year OS was 24%.
Among patient who were refractory to second-line or later therapy, the median OS was 6.1 months (range, 5.2-7.0), 1-year OS was 26%, and 2-year OS was 17%.
Among patients who relapsed after transplant, the median OS was 6.2 months (range, 5.2-7.6), 1-year OS was 32%, and 2-year OS was 19%.
“Although 60% to 70% of non-Hodgkin lymphoma patients survive 5 years after rituximab-based chemotherapy and autologous stem cell transplant, nearly half of them either do not respond or relapse shortly after transplant,” Dr Gisselbrecht noted.
“SCHOLAR-1 provides a rigorous measure of outcomes for these patients who do not benefit from currently available therapies, and this landmark study will serve as an important historical control for evaluating new therapeutic candidates in the field of non-Hodgkin lymphoma.” 
Results from the SCHOLAR-1 study revealed poor outcomes of salvage therapy in patients with refractory diffuse large B-cell lymphoma (DLBCL).
This retrospective study included data on patients enrolled in 2 randomized trials and 2 academic databases.
The patients had primary refractory disease, were refractory to second-line or later therapy, or had relapsed within 12 months of autologous stem cell transplant (ASCT).
Twenty-six percent of patients responded to salvage therapy, with 7% achieving a complete response (CR).
The median overall survival (OS) was 6.3 months, and 20% of patients were still alive at 2 years’ follow-up.
Christian Gisselbrecht, MD, of Saint Louis Hospital in Paris, France, and his colleagues reported these findings in Blood. SCHOLAR-1 was funded through an unrestricted grant from Kite Pharma.
“SCHOLAR-1 demonstrates the uniformly poor treatment outcomes for patients with aggressive non-Hodgkin lymphoma and emphasizes the need for breakthrough therapies for these refractory patients,” Dr Gisselbrecht said.
Patient characteristics
The study included pooled, patient-level data from 2 phase 3 trials and 2 databases:
- The Canadian Cancer Trials Group study LY.12 (n=219)
- The Lymphoma Academic Research Organization’s CORAL study (n=170)
- A cohort from MD Anderson Cancer Center (n=165)
- A cohort from the Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (n=82).
There were a total of 636 patients who met criteria for refractory DLBCL, which included primary mediastinal B-cell lymphoma and transformed follicular lymphoma.
Twenty-eight percent of patients were primary refractory, 50% were refractory to second-line or later therapy, and 22% had relapsed within 12 months of transplant.
The patients’ median age was 55 (range, 19-81), and 64% were male. Seventy-three percent had an ECOG performance status of 0-1, 14% had a status of 2-4, and 13% were missing this data. Seventy-two percent of patients had stage III-IV disease, 27% had stage I-II disease, and less than 1% were missing this data.
Treatments
The MD Anderson cohort included patients who were relapsed/refractory to initial rituximab-containing chemotherapy, had failed salvage platinum-containing chemotherapy, and received a second salvage therapy at MD Anderson.
The University of Iowa/Mayo Clinic cohort included unselected, newly diagnosed patients with lymphoma who entered prospective documentation of primary and subsequent treatments and outcomes.
In the LY.12 study, patients were enrolled upon relapse after anthracycline-containing therapy and randomized to 1 of 2 salvage regimens, with a goal of consolidative ASCT.
The CORAL study enrolled patients in their first relapse or whose lymphoma was refractory to first-line therapy. They were randomized to 1 of 2 salvage regimens, with a goal of consolidative ASCT.
In the LY.12 and CORAL studies, eligible patients with CD20+ lymphoma were randomized to rituximab maintenance or observation post-ASCT.
Response
In all, 523 patients were evaluated for response. The overall response rate (ORR) was 26%, with a 7% CR rate and an 18% partial response rate.
Among patients with primary refractory disease, the ORR was 20%, and the CR rate was 3%.
Among patients who were refractory to second-line or later therapy, the ORR was 26%, and the CR rate was 10%.
Among patients who relapsed after transplant, the ORR was 34%, and the CR rate was 15%.
Survival
A total of 603 patients were evaluated for survival.
The median OS from the start of salvage therapy was 6.3 months (range, 5.9-7.0). The 1-year OS rate was 28%, and the 2-year OS was 20%.
Among primary refractory patients, the median OS was 7.1 months (range, 6.0-8.1), 1-year OS was 29%, and 2-year OS was 24%.
Among patient who were refractory to second-line or later therapy, the median OS was 6.1 months (range, 5.2-7.0), 1-year OS was 26%, and 2-year OS was 17%.
Among patients who relapsed after transplant, the median OS was 6.2 months (range, 5.2-7.6), 1-year OS was 32%, and 2-year OS was 19%.
“Although 60% to 70% of non-Hodgkin lymphoma patients survive 5 years after rituximab-based chemotherapy and autologous stem cell transplant, nearly half of them either do not respond or relapse shortly after transplant,” Dr Gisselbrecht noted.
“SCHOLAR-1 provides a rigorous measure of outcomes for these patients who do not benefit from currently available therapies, and this landmark study will serve as an important historical control for evaluating new therapeutic candidates in the field of non-Hodgkin lymphoma.”
Results from the SCHOLAR-1 study revealed poor outcomes of salvage therapy in patients with refractory diffuse large B-cell lymphoma (DLBCL).
This retrospective study included data on patients enrolled in 2 randomized trials and 2 academic databases.
The patients had primary refractory disease, were refractory to second-line or later therapy, or had relapsed within 12 months of autologous stem cell transplant (ASCT).
Twenty-six percent of patients responded to salvage therapy, with 7% achieving a complete response (CR).
The median overall survival (OS) was 6.3 months, and 20% of patients were still alive at 2 years’ follow-up.
Christian Gisselbrecht, MD, of Saint Louis Hospital in Paris, France, and his colleagues reported these findings in Blood. SCHOLAR-1 was funded through an unrestricted grant from Kite Pharma.
“SCHOLAR-1 demonstrates the uniformly poor treatment outcomes for patients with aggressive non-Hodgkin lymphoma and emphasizes the need for breakthrough therapies for these refractory patients,” Dr Gisselbrecht said.
Patient characteristics
The study included pooled, patient-level data from 2 phase 3 trials and 2 databases:
- The Canadian Cancer Trials Group study LY.12 (n=219)
- The Lymphoma Academic Research Organization’s CORAL study (n=170)
- A cohort from MD Anderson Cancer Center (n=165)
- A cohort from the Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (n=82).
There were a total of 636 patients who met criteria for refractory DLBCL, which included primary mediastinal B-cell lymphoma and transformed follicular lymphoma.
Twenty-eight percent of patients were primary refractory, 50% were refractory to second-line or later therapy, and 22% had relapsed within 12 months of transplant.
The patients’ median age was 55 (range, 19-81), and 64% were male. Seventy-three percent had an ECOG performance status of 0-1, 14% had a status of 2-4, and 13% were missing this data. Seventy-two percent of patients had stage III-IV disease, 27% had stage I-II disease, and less than 1% were missing this data.
Treatments
The MD Anderson cohort included patients who were relapsed/refractory to initial rituximab-containing chemotherapy, had failed salvage platinum-containing chemotherapy, and received a second salvage therapy at MD Anderson.
The University of Iowa/Mayo Clinic cohort included unselected, newly diagnosed patients with lymphoma who entered prospective documentation of primary and subsequent treatments and outcomes.
In the LY.12 study, patients were enrolled upon relapse after anthracycline-containing therapy and randomized to 1 of 2 salvage regimens, with a goal of consolidative ASCT.
The CORAL study enrolled patients in their first relapse or whose lymphoma was refractory to first-line therapy. They were randomized to 1 of 2 salvage regimens, with a goal of consolidative ASCT.
In the LY.12 and CORAL studies, eligible patients with CD20+ lymphoma were randomized to rituximab maintenance or observation post-ASCT.
Response
In all, 523 patients were evaluated for response. The overall response rate (ORR) was 26%, with a 7% CR rate and an 18% partial response rate.
Among patients with primary refractory disease, the ORR was 20%, and the CR rate was 3%.
Among patients who were refractory to second-line or later therapy, the ORR was 26%, and the CR rate was 10%.
Among patients who relapsed after transplant, the ORR was 34%, and the CR rate was 15%.
Survival
A total of 603 patients were evaluated for survival.
The median OS from the start of salvage therapy was 6.3 months (range, 5.9-7.0). The 1-year OS rate was 28%, and the 2-year OS was 20%.
Among primary refractory patients, the median OS was 7.1 months (range, 6.0-8.1), 1-year OS was 29%, and 2-year OS was 24%.
Among patient who were refractory to second-line or later therapy, the median OS was 6.1 months (range, 5.2-7.0), 1-year OS was 26%, and 2-year OS was 17%.
Among patients who relapsed after transplant, the median OS was 6.2 months (range, 5.2-7.6), 1-year OS was 32%, and 2-year OS was 19%.
“Although 60% to 70% of non-Hodgkin lymphoma patients survive 5 years after rituximab-based chemotherapy and autologous stem cell transplant, nearly half of them either do not respond or relapse shortly after transplant,” Dr Gisselbrecht noted.
“SCHOLAR-1 provides a rigorous measure of outcomes for these patients who do not benefit from currently available therapies, and this landmark study will serve as an important historical control for evaluating new therapeutic candidates in the field of non-Hodgkin lymphoma.”
CHMP recommends new indication for obinutuzumab
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for obinutuzumab (Gazyvaro).
The new proposed indication is for obinutuzumab in combination with chemotherapy for patients with previously untreated, advanced follicular lymphoma (FL). This would be followed by obinutuzumab maintenance in patients who achieved a response.
The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 2 to 3 months’ of the CHMP’s recommendation.
The decision will be applicable to all member states of the European Union, plus Iceland, Liechtenstein, and Norway.
If approved for this new indication, obinutuzumab will be authorized for use in the European Economic Area as follows:
- In combination with chlorambucil for the treatment of adults with previously untreated chronic lymphocytic leukemia and comorbidities making them unsuitable for full-dose fludarabine-based therapy.
- In combination with bendamustine, followed by obinutuzumab maintenance, for the treatment of patients with FL who did not respond to, or who progressed during or up to 6 months after, treatment with rituximab or a rituximab-containing regimen.
- In combination with chemotherapy, followed by obinutuzumab maintenance in responders, for the treatment of patients with previously untreated, advanced FL.
GALLIUM trial
The CHMP’s recommendation is based on results of the phase 3 GALLIUM trial, which were presented at the 2016 ASH Annual Meeting.
The study enrolled 1401 patients with previously untreated, indolent non-Hodgkin lymphoma, including 1202 with FL.
Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).
The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), CVP (cyclophosphamide, vincristine, and prednisolone), and bendamustine.
Patients who received obinutuzumab had significantly better progression-free survival than patients who received rituximab. The 3-year progression-free survival rate was 73.3% in the rituximab arm and 80% in the obinutuzumab arm (hazard ratio [HR]=0.66, P=0.0012).
There was no significant difference between the treatment arms with regard to overall survival. The 3-year overall survival was 92.1% in the rituximab arm and 94% in the obinutuzumab arm (HR=0.75, P=0.21).
The overall incidence of adverse events (AEs) was 98.3% in the rituximab arm and 99.5% in the obinutuzumab arm. The incidence of serious AEs was 39.9% and 46.1%, respectively.
The incidence of grade 3 or higher AEs was higher among patients who received obinutuzumab.
Grade 3 or higher AEs occurring in at least 5% of patients in either arm (rituximab and obinutuzumab, respectively) included neutropenia (67.8% and 74.6%), leukopenia (37.9% and 43.9%), febrile neutropenia (4.9% and 6.9%), infections and infestations (3.7% and 6.7%), and thrombocytopenia (2.7% and 6.1%).
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for obinutuzumab (Gazyvaro).
The new proposed indication is for obinutuzumab in combination with chemotherapy for patients with previously untreated, advanced follicular lymphoma (FL). This would be followed by obinutuzumab maintenance in patients who achieved a response.
The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 2 to 3 months’ of the CHMP’s recommendation.
The decision will be applicable to all member states of the European Union, plus Iceland, Liechtenstein, and Norway.
If approved for this new indication, obinutuzumab will be authorized for use in the European Economic Area as follows:
- In combination with chlorambucil for the treatment of adults with previously untreated chronic lymphocytic leukemia and comorbidities making them unsuitable for full-dose fludarabine-based therapy.
- In combination with bendamustine, followed by obinutuzumab maintenance, for the treatment of patients with FL who did not respond to, or who progressed during or up to 6 months after, treatment with rituximab or a rituximab-containing regimen.
- In combination with chemotherapy, followed by obinutuzumab maintenance in responders, for the treatment of patients with previously untreated, advanced FL.
GALLIUM trial
The CHMP’s recommendation is based on results of the phase 3 GALLIUM trial, which were presented at the 2016 ASH Annual Meeting.
The study enrolled 1401 patients with previously untreated, indolent non-Hodgkin lymphoma, including 1202 with FL.
Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).
The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), CVP (cyclophosphamide, vincristine, and prednisolone), and bendamustine.
Patients who received obinutuzumab had significantly better progression-free survival than patients who received rituximab. The 3-year progression-free survival rate was 73.3% in the rituximab arm and 80% in the obinutuzumab arm (hazard ratio [HR]=0.66, P=0.0012).
There was no significant difference between the treatment arms with regard to overall survival. The 3-year overall survival was 92.1% in the rituximab arm and 94% in the obinutuzumab arm (HR=0.75, P=0.21).
The overall incidence of adverse events (AEs) was 98.3% in the rituximab arm and 99.5% in the obinutuzumab arm. The incidence of serious AEs was 39.9% and 46.1%, respectively.
The incidence of grade 3 or higher AEs was higher among patients who received obinutuzumab.
Grade 3 or higher AEs occurring in at least 5% of patients in either arm (rituximab and obinutuzumab, respectively) included neutropenia (67.8% and 74.6%), leukopenia (37.9% and 43.9%), febrile neutropenia (4.9% and 6.9%), infections and infestations (3.7% and 6.7%), and thrombocytopenia (2.7% and 6.1%).
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the marketing authorization for obinutuzumab (Gazyvaro).
The new proposed indication is for obinutuzumab in combination with chemotherapy for patients with previously untreated, advanced follicular lymphoma (FL). This would be followed by obinutuzumab maintenance in patients who achieved a response.
The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 2 to 3 months’ of the CHMP’s recommendation.
The decision will be applicable to all member states of the European Union, plus Iceland, Liechtenstein, and Norway.
If approved for this new indication, obinutuzumab will be authorized for use in the European Economic Area as follows:
- In combination with chlorambucil for the treatment of adults with previously untreated chronic lymphocytic leukemia and comorbidities making them unsuitable for full-dose fludarabine-based therapy.
- In combination with bendamustine, followed by obinutuzumab maintenance, for the treatment of patients with FL who did not respond to, or who progressed during or up to 6 months after, treatment with rituximab or a rituximab-containing regimen.
- In combination with chemotherapy, followed by obinutuzumab maintenance in responders, for the treatment of patients with previously untreated, advanced FL.
GALLIUM trial
The CHMP’s recommendation is based on results of the phase 3 GALLIUM trial, which were presented at the 2016 ASH Annual Meeting.
The study enrolled 1401 patients with previously untreated, indolent non-Hodgkin lymphoma, including 1202 with FL.
Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).
The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), CVP (cyclophosphamide, vincristine, and prednisolone), and bendamustine.
Patients who received obinutuzumab had significantly better progression-free survival than patients who received rituximab. The 3-year progression-free survival rate was 73.3% in the rituximab arm and 80% in the obinutuzumab arm (hazard ratio [HR]=0.66, P=0.0012).
There was no significant difference between the treatment arms with regard to overall survival. The 3-year overall survival was 92.1% in the rituximab arm and 94% in the obinutuzumab arm (HR=0.75, P=0.21).
The overall incidence of adverse events (AEs) was 98.3% in the rituximab arm and 99.5% in the obinutuzumab arm. The incidence of serious AEs was 39.9% and 46.1%, respectively.
The incidence of grade 3 or higher AEs was higher among patients who received obinutuzumab.
Grade 3 or higher AEs occurring in at least 5% of patients in either arm (rituximab and obinutuzumab, respectively) included neutropenia (67.8% and 74.6%), leukopenia (37.9% and 43.9%), febrile neutropenia (4.9% and 6.9%), infections and infestations (3.7% and 6.7%), and thrombocytopenia (2.7% and 6.1%).
IMiD/Anti-CD20 combo induces complete responses in r/r NHL
Lugano, Switzerland – A combination of obinutuzumab (Gazyva) and the experimental immunomodulatory agent CC-122 showed “clinically meaningful” activity against relapsed/refractory diffuse large B cell lymphoma (DLBCL) and indolent non-Hodgkin lymphoma (NHL) in a phase 1b study.
Among 38 patients with heavily pretreated, relapsed/refractory DLBCL, follicular lymphoma (FL), or marginal zone lymphoma (MZL), the overall response rate was 66%, including 12 patients (32%) with a complete response (CR), reported Jean-Marie Michot, MD, from the Goustave-Roussy Cancer Center in Villejuif, France.
CC-122 is a thalidomide analog that shares a molecular target with its cousin lenalidomide (Revlimid). Both molecules bind to the protein cereblon to cause degradation of the lymphoid transcription factors Aiolos and Ikaros.
As a single agent, CC-122 has been shown to have immunomodulatory effects on T-cell and natural killer (NK)–cell functions and has shown clinical activity in heavily pretreated patients with relapsed refractory NHL, including various cell-of-origin–based DLBCL subtypes, Dr, Michot said.
In preclinical studies, the combination of CC-122 and obinutuzumab, an anti-CD20 monoclonal antibody, has shown synergistic effects against FL and greater antilymphoma effects against DLBCL than either agent alone, he added.
In a multicenter, open-label, phase 1b dose-escalation and expansion study, investigators enrolled 19 patients with FL or MZL for whom at least one prior regimen had failed and 19 patients with relapsed/refractory DLBCL following at least two prior regimens and failed autologous stem cell transplant.
The patients received oral CC-122 at different dose levels for 5 of 7 days in each 28 day treatment cycle, plus intravenous obinutuzumab 1000 mg on days 2, 8, and 15 of cycle 1 and day 1 of cycles 2 through 8.
Responses were assessed according to International Working Group 2007 revised response criteria for malignant lymphoma.
Among all 38 patients, 25 (66%) had a response. Responses consisted of 12 CR (3 in patients with DLBCL, and 9 in patients with FL/MZL) and 13 partial responses (six and seven patients, respectively),
The median time to best response was 57 days. Responses were seen in 23 of the 30 patients who received CC-122 at dose level of 3 mg or higher.
“To date, patients receiving CC-122 at a dose of 3 mg and higher have the best and more durable responses to CC-122 plus obinutuzumab,” Dr. Michot said.
Patients generally tolerated the combination well. The most common grade 3 or 4 adverse events were hematologic and included grade 4 febrile neutropenia in two patients. Two patients discontinued treatment because of adverse events.
There was a dose-limiting toxicity, grade 4 neutropenia in one patient who received CC-122 at the 3 mg dose level, and one death from a tumor flare reaction in a patient treated at the 4 mg dose level.
The dose-escalation arm of the study has completed, and investigators are enrolling patients in a dose expansion phase at the 3 mg level.
The study was sponsored by Celgene. Hoffman La-Roche contributed obinutuzumab for the study. Dr. Michot reported serving as an advisor to Bristol-Myers Squibb and receiving travel grants from BMS, Pfizer, and Roche. Seven coauthors are Celgene employees and stockholders.
Lugano, Switzerland – A combination of obinutuzumab (Gazyva) and the experimental immunomodulatory agent CC-122 showed “clinically meaningful” activity against relapsed/refractory diffuse large B cell lymphoma (DLBCL) and indolent non-Hodgkin lymphoma (NHL) in a phase 1b study.
Among 38 patients with heavily pretreated, relapsed/refractory DLBCL, follicular lymphoma (FL), or marginal zone lymphoma (MZL), the overall response rate was 66%, including 12 patients (32%) with a complete response (CR), reported Jean-Marie Michot, MD, from the Goustave-Roussy Cancer Center in Villejuif, France.
CC-122 is a thalidomide analog that shares a molecular target with its cousin lenalidomide (Revlimid). Both molecules bind to the protein cereblon to cause degradation of the lymphoid transcription factors Aiolos and Ikaros.
As a single agent, CC-122 has been shown to have immunomodulatory effects on T-cell and natural killer (NK)–cell functions and has shown clinical activity in heavily pretreated patients with relapsed refractory NHL, including various cell-of-origin–based DLBCL subtypes, Dr, Michot said.
In preclinical studies, the combination of CC-122 and obinutuzumab, an anti-CD20 monoclonal antibody, has shown synergistic effects against FL and greater antilymphoma effects against DLBCL than either agent alone, he added.
In a multicenter, open-label, phase 1b dose-escalation and expansion study, investigators enrolled 19 patients with FL or MZL for whom at least one prior regimen had failed and 19 patients with relapsed/refractory DLBCL following at least two prior regimens and failed autologous stem cell transplant.
The patients received oral CC-122 at different dose levels for 5 of 7 days in each 28 day treatment cycle, plus intravenous obinutuzumab 1000 mg on days 2, 8, and 15 of cycle 1 and day 1 of cycles 2 through 8.
Responses were assessed according to International Working Group 2007 revised response criteria for malignant lymphoma.
Among all 38 patients, 25 (66%) had a response. Responses consisted of 12 CR (3 in patients with DLBCL, and 9 in patients with FL/MZL) and 13 partial responses (six and seven patients, respectively),
The median time to best response was 57 days. Responses were seen in 23 of the 30 patients who received CC-122 at dose level of 3 mg or higher.
“To date, patients receiving CC-122 at a dose of 3 mg and higher have the best and more durable responses to CC-122 plus obinutuzumab,” Dr. Michot said.
Patients generally tolerated the combination well. The most common grade 3 or 4 adverse events were hematologic and included grade 4 febrile neutropenia in two patients. Two patients discontinued treatment because of adverse events.
There was a dose-limiting toxicity, grade 4 neutropenia in one patient who received CC-122 at the 3 mg dose level, and one death from a tumor flare reaction in a patient treated at the 4 mg dose level.
The dose-escalation arm of the study has completed, and investigators are enrolling patients in a dose expansion phase at the 3 mg level.
The study was sponsored by Celgene. Hoffman La-Roche contributed obinutuzumab for the study. Dr. Michot reported serving as an advisor to Bristol-Myers Squibb and receiving travel grants from BMS, Pfizer, and Roche. Seven coauthors are Celgene employees and stockholders.
Lugano, Switzerland – A combination of obinutuzumab (Gazyva) and the experimental immunomodulatory agent CC-122 showed “clinically meaningful” activity against relapsed/refractory diffuse large B cell lymphoma (DLBCL) and indolent non-Hodgkin lymphoma (NHL) in a phase 1b study.
Among 38 patients with heavily pretreated, relapsed/refractory DLBCL, follicular lymphoma (FL), or marginal zone lymphoma (MZL), the overall response rate was 66%, including 12 patients (32%) with a complete response (CR), reported Jean-Marie Michot, MD, from the Goustave-Roussy Cancer Center in Villejuif, France.
CC-122 is a thalidomide analog that shares a molecular target with its cousin lenalidomide (Revlimid). Both molecules bind to the protein cereblon to cause degradation of the lymphoid transcription factors Aiolos and Ikaros.
As a single agent, CC-122 has been shown to have immunomodulatory effects on T-cell and natural killer (NK)–cell functions and has shown clinical activity in heavily pretreated patients with relapsed refractory NHL, including various cell-of-origin–based DLBCL subtypes, Dr, Michot said.
In preclinical studies, the combination of CC-122 and obinutuzumab, an anti-CD20 monoclonal antibody, has shown synergistic effects against FL and greater antilymphoma effects against DLBCL than either agent alone, he added.
In a multicenter, open-label, phase 1b dose-escalation and expansion study, investigators enrolled 19 patients with FL or MZL for whom at least one prior regimen had failed and 19 patients with relapsed/refractory DLBCL following at least two prior regimens and failed autologous stem cell transplant.
The patients received oral CC-122 at different dose levels for 5 of 7 days in each 28 day treatment cycle, plus intravenous obinutuzumab 1000 mg on days 2, 8, and 15 of cycle 1 and day 1 of cycles 2 through 8.
Responses were assessed according to International Working Group 2007 revised response criteria for malignant lymphoma.
Among all 38 patients, 25 (66%) had a response. Responses consisted of 12 CR (3 in patients with DLBCL, and 9 in patients with FL/MZL) and 13 partial responses (six and seven patients, respectively),
The median time to best response was 57 days. Responses were seen in 23 of the 30 patients who received CC-122 at dose level of 3 mg or higher.
“To date, patients receiving CC-122 at a dose of 3 mg and higher have the best and more durable responses to CC-122 plus obinutuzumab,” Dr. Michot said.
Patients generally tolerated the combination well. The most common grade 3 or 4 adverse events were hematologic and included grade 4 febrile neutropenia in two patients. Two patients discontinued treatment because of adverse events.
There was a dose-limiting toxicity, grade 4 neutropenia in one patient who received CC-122 at the 3 mg dose level, and one death from a tumor flare reaction in a patient treated at the 4 mg dose level.
The dose-escalation arm of the study has completed, and investigators are enrolling patients in a dose expansion phase at the 3 mg level.
The study was sponsored by Celgene. Hoffman La-Roche contributed obinutuzumab for the study. Dr. Michot reported serving as an advisor to Bristol-Myers Squibb and receiving travel grants from BMS, Pfizer, and Roche. Seven coauthors are Celgene employees and stockholders.
AT 14-ICML
Key clinical point: A combination of the experimental immunomodulator CC-122 and obinutuzumab showed significant activity against relapsed/refractory non-Hodgkin lymphoma.
Major finding: The overall response rate was 66%, including 32% complete responses.
Data source: A multicenter open-label phase 1b dose-escalation study in 19 patients with DLBCL and 19 with follicular lymphoma or marginal zone lymphoma.
Disclosures: The study was sponsored by Celgene. Hoffman La-Roche contributed obinutuzumab for the study. Dr. Michot reported serving as an advisor to Bristol-Myers Squibb and receiving travel grants from BMS, Pfizer, and Roche. Seven coauthors are Celgene employees and stockholders.
Copanlisib makes inroads against relapsed/refractory follicular lymphoma
LUGANO, SWITZERLAND – Copanlisib, an investigational intravenous inhibitor of phosphatidylinositol 3-kinase (PI3K), was associated with “promising” efficacy and a better safety profile than has been seen with oral PI3K inhibitors in patients with relapsed or refractory indolent lymphomas.
In a phase 2 trial of the drug as monotherapy in patients with indolent lymphomas, copanlisib was associated with an overall response rate of 58.6% among 104 patients with follicular lymphoma (FL), including 14.4% complete responses (CR) and 44.2% partial responses (PR), reported Martin Dreyling, MD, of the Universität München-Grosshadern in Munich, Germany.
“The favorable risk-benefit profile of this compound suggests further [need for] testing in follicular lymphoma. My personal interpretation is that the different safety profile is due to the intermittent dosing and the IV application, avoiding adverse cause-effect both in the gut and the liver,” he said at the 14th International Conference on Malignant Lymphoma.
Dr. Dreyling noted that the oral PI3K inhibitor idelalisib (Zydelig) is approved for the treatment of patients with relapsed chronic lymphocytic leukemia in combination with rituximab and in patients with relapsed FL or small lymphocytic lymphomas (SLL) who have received at least two prior lines of systemic therapy. This agent, however, carries a black box warning about fatal and serious toxicities, including hepatic events, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation.
Copanlisib inhibits all isoforms of P13K but is predominantly active against the alpha and delta isoforms of the kinase. The alpha form, expressed in many cell types, is involved in insulin signaling and angiogenesis and in resistance mechanisms to lymphoma. The delta form, expressed in leukocytes, is involved in B-cell signaling, development, and survival, making PIK3 an attractive target, Dr. Dreyling explained.
The study included patients with indolent B-cell lymphomas, including FL grades 1-3a, marginal zone lymphoma, SLL, or lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) for whom at least two prior lines of therapy had failed.
The patients received copanlisib 60 mg IV on days 1, 8, and 15 of each 28-day cycle until disease progression or unacceptable toxicity.
Of 142 assigned to and started on treatment, 46 patients (32.3%) remained on treatment at the time of data cutoff. Of the 96 patients (67.7%) who discontinued, 35 did so because of adverse events, 36 discontinued for radiologic or clinical evidence of progression, 16 withdrew, 5 were discontinued on the treating physician’s decision, and 4 stopped for other, unspecified reasons.
Among all 142 patients, the median duration of therapy was 22 weeks and the median number of cycles was 5.5. In all, 26.1% of patients required a dosage reduction to 45 mg, and 5.6% required reduction to 30 mg.
As noted, the objective tumor response rate (ORR) among patients was 58.6% for 104 patients with FL. For the 23 patients with marginal zone lymphoma, the ORR was 69.6%, consisting of two complete and 14 partial responses. Among eight patients with SLL, there were six partial responses and no complete responses. For the six patients with LPL/WM, there was one partial response.
The overall median duration of response was 22.6 months. Among patients with refractory disease and in all patients with FL the median duration of response was 12.2 months.
The median progression-free survival after 24 months of follow-up was 11.2 months for all patients. The median overall survival has not been reached.
The most frequent adverse events of grade 3 or 4 were hyperglycemia in 40.1% (33.1% grade 3 and 7.0% grade 4) and hypertension in 22.5% (all grade 3).
Grade 3 diarrhea, a significant problem with idelalisib, occurred in 4.2% of patients, and there were no grade 4 events.
Grade 3 pneumonitis was seen in two patients, and one had grade 4 colitis. There were three drug related deaths, including one patient each from lung infection, respiratory failure, or thromboembolic event..
The study was supported by Bayer. Dr. Dreyling disclosed receiving honoraria from the company and serving on a scientific/advisory board for the company.
LUGANO, SWITZERLAND – Copanlisib, an investigational intravenous inhibitor of phosphatidylinositol 3-kinase (PI3K), was associated with “promising” efficacy and a better safety profile than has been seen with oral PI3K inhibitors in patients with relapsed or refractory indolent lymphomas.
In a phase 2 trial of the drug as monotherapy in patients with indolent lymphomas, copanlisib was associated with an overall response rate of 58.6% among 104 patients with follicular lymphoma (FL), including 14.4% complete responses (CR) and 44.2% partial responses (PR), reported Martin Dreyling, MD, of the Universität München-Grosshadern in Munich, Germany.
“The favorable risk-benefit profile of this compound suggests further [need for] testing in follicular lymphoma. My personal interpretation is that the different safety profile is due to the intermittent dosing and the IV application, avoiding adverse cause-effect both in the gut and the liver,” he said at the 14th International Conference on Malignant Lymphoma.
Dr. Dreyling noted that the oral PI3K inhibitor idelalisib (Zydelig) is approved for the treatment of patients with relapsed chronic lymphocytic leukemia in combination with rituximab and in patients with relapsed FL or small lymphocytic lymphomas (SLL) who have received at least two prior lines of systemic therapy. This agent, however, carries a black box warning about fatal and serious toxicities, including hepatic events, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation.
Copanlisib inhibits all isoforms of P13K but is predominantly active against the alpha and delta isoforms of the kinase. The alpha form, expressed in many cell types, is involved in insulin signaling and angiogenesis and in resistance mechanisms to lymphoma. The delta form, expressed in leukocytes, is involved in B-cell signaling, development, and survival, making PIK3 an attractive target, Dr. Dreyling explained.
The study included patients with indolent B-cell lymphomas, including FL grades 1-3a, marginal zone lymphoma, SLL, or lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) for whom at least two prior lines of therapy had failed.
The patients received copanlisib 60 mg IV on days 1, 8, and 15 of each 28-day cycle until disease progression or unacceptable toxicity.
Of 142 assigned to and started on treatment, 46 patients (32.3%) remained on treatment at the time of data cutoff. Of the 96 patients (67.7%) who discontinued, 35 did so because of adverse events, 36 discontinued for radiologic or clinical evidence of progression, 16 withdrew, 5 were discontinued on the treating physician’s decision, and 4 stopped for other, unspecified reasons.
Among all 142 patients, the median duration of therapy was 22 weeks and the median number of cycles was 5.5. In all, 26.1% of patients required a dosage reduction to 45 mg, and 5.6% required reduction to 30 mg.
As noted, the objective tumor response rate (ORR) among patients was 58.6% for 104 patients with FL. For the 23 patients with marginal zone lymphoma, the ORR was 69.6%, consisting of two complete and 14 partial responses. Among eight patients with SLL, there were six partial responses and no complete responses. For the six patients with LPL/WM, there was one partial response.
The overall median duration of response was 22.6 months. Among patients with refractory disease and in all patients with FL the median duration of response was 12.2 months.
The median progression-free survival after 24 months of follow-up was 11.2 months for all patients. The median overall survival has not been reached.
The most frequent adverse events of grade 3 or 4 were hyperglycemia in 40.1% (33.1% grade 3 and 7.0% grade 4) and hypertension in 22.5% (all grade 3).
Grade 3 diarrhea, a significant problem with idelalisib, occurred in 4.2% of patients, and there were no grade 4 events.
Grade 3 pneumonitis was seen in two patients, and one had grade 4 colitis. There were three drug related deaths, including one patient each from lung infection, respiratory failure, or thromboembolic event..
The study was supported by Bayer. Dr. Dreyling disclosed receiving honoraria from the company and serving on a scientific/advisory board for the company.
LUGANO, SWITZERLAND – Copanlisib, an investigational intravenous inhibitor of phosphatidylinositol 3-kinase (PI3K), was associated with “promising” efficacy and a better safety profile than has been seen with oral PI3K inhibitors in patients with relapsed or refractory indolent lymphomas.
In a phase 2 trial of the drug as monotherapy in patients with indolent lymphomas, copanlisib was associated with an overall response rate of 58.6% among 104 patients with follicular lymphoma (FL), including 14.4% complete responses (CR) and 44.2% partial responses (PR), reported Martin Dreyling, MD, of the Universität München-Grosshadern in Munich, Germany.
“The favorable risk-benefit profile of this compound suggests further [need for] testing in follicular lymphoma. My personal interpretation is that the different safety profile is due to the intermittent dosing and the IV application, avoiding adverse cause-effect both in the gut and the liver,” he said at the 14th International Conference on Malignant Lymphoma.
Dr. Dreyling noted that the oral PI3K inhibitor idelalisib (Zydelig) is approved for the treatment of patients with relapsed chronic lymphocytic leukemia in combination with rituximab and in patients with relapsed FL or small lymphocytic lymphomas (SLL) who have received at least two prior lines of systemic therapy. This agent, however, carries a black box warning about fatal and serious toxicities, including hepatic events, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation.
Copanlisib inhibits all isoforms of P13K but is predominantly active against the alpha and delta isoforms of the kinase. The alpha form, expressed in many cell types, is involved in insulin signaling and angiogenesis and in resistance mechanisms to lymphoma. The delta form, expressed in leukocytes, is involved in B-cell signaling, development, and survival, making PIK3 an attractive target, Dr. Dreyling explained.
The study included patients with indolent B-cell lymphomas, including FL grades 1-3a, marginal zone lymphoma, SLL, or lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) for whom at least two prior lines of therapy had failed.
The patients received copanlisib 60 mg IV on days 1, 8, and 15 of each 28-day cycle until disease progression or unacceptable toxicity.
Of 142 assigned to and started on treatment, 46 patients (32.3%) remained on treatment at the time of data cutoff. Of the 96 patients (67.7%) who discontinued, 35 did so because of adverse events, 36 discontinued for radiologic or clinical evidence of progression, 16 withdrew, 5 were discontinued on the treating physician’s decision, and 4 stopped for other, unspecified reasons.
Among all 142 patients, the median duration of therapy was 22 weeks and the median number of cycles was 5.5. In all, 26.1% of patients required a dosage reduction to 45 mg, and 5.6% required reduction to 30 mg.
As noted, the objective tumor response rate (ORR) among patients was 58.6% for 104 patients with FL. For the 23 patients with marginal zone lymphoma, the ORR was 69.6%, consisting of two complete and 14 partial responses. Among eight patients with SLL, there were six partial responses and no complete responses. For the six patients with LPL/WM, there was one partial response.
The overall median duration of response was 22.6 months. Among patients with refractory disease and in all patients with FL the median duration of response was 12.2 months.
The median progression-free survival after 24 months of follow-up was 11.2 months for all patients. The median overall survival has not been reached.
The most frequent adverse events of grade 3 or 4 were hyperglycemia in 40.1% (33.1% grade 3 and 7.0% grade 4) and hypertension in 22.5% (all grade 3).
Grade 3 diarrhea, a significant problem with idelalisib, occurred in 4.2% of patients, and there were no grade 4 events.
Grade 3 pneumonitis was seen in two patients, and one had grade 4 colitis. There were three drug related deaths, including one patient each from lung infection, respiratory failure, or thromboembolic event..
The study was supported by Bayer. Dr. Dreyling disclosed receiving honoraria from the company and serving on a scientific/advisory board for the company.
AT 14-ICML
Key clinical point: Copanlisib, an intravenous PI3K inhibitor, was active against relapsed/refractory follicular lymphoma (FL).
Major finding: The overall response rate among 104 patients was 58.6%
Data source: A multicenter international phase 2 study in patients with relapsed/refractory indolent lymphomas
Disclosures: The study was supported by Bayer. Dr. Dreyling disclosed receiving honoraria from the company and serving on a scientific/advisory board for the company.
Combo demonstrates activity in CLL/SLL and FL
LUGANO, SWITZERLAND—Results of a phase 1 study suggest a 2-drug combination may be safe and effective in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and follicular lymphoma (FL).
The ongoing study is a test of the BTK inhibitor BGB-3111 and the anti-CD20 antibody obinutuzumab.
The overall response rate (ORR) with this combination was 81% in the entire study population, 89% in treatment-naïve CLL/SLL patients, 92% in relapsed/refractory CLL/SLL patients, and 73% in relapsed/refractory FL patients.
The rate of serious adverse events (AEs) was 24% in both CLL/SLL and FL patients.
These results were presented at the 14th International Conference on Malignant Lymphoma (ICML). The research was sponsored by BeiGene, Ltd.
“This clinical trial is supported by preclinical work suggesting that BGB-3111 may combine well with antibodies that rely on antibody-dependent cell-mediated cytotoxicity, such as obinutuzumab, because of less off-target inhibition of interleukin-2-inducible T-cell kinase,” said study investigator Constantine Tam, MD, of St. Vincent’s Hospital in Melbourne, Australia.
“The preliminary clinical results to date suggest that the combination is well tolerated and highly active in patients with CLL or SLL and FL. Complete responses have already been observed in patients with both disease types, including CLL or SLL patients with high-risk features, despite a very short follow-up time.”
The trial consists of a dose-escalation phase and a dose-expansion phase in disease-specific cohorts, which include treatment-naive or relapsed/refractory CLL/SLL and relapsed/refractory FL.
The dose-escalation component is testing BGB-3111 at 320 mg once daily or 160 mg twice daily in 28-day cycles, in combination with obinutuzumab. Obinutuzumab is administered in line with standard CLL dosing (3 loading doses of 1000 mg weekly, followed by 1000 mg on day 1 of cycles 2 to 6).
The ongoing dose-expansion component is testing doses of BGB-3111 at 160 mg twice daily with the same obinutuzumab schedule.
As of the data cutoff (March 31, 2017), 45 patients with CLL/SLL and 17 patients with FL were enrolled in the trial.
Patient characteristics
The median age was 68 (range, 28-82) in the CLL/SLL patients and 56 (range, 41-86) in the FL patients.
ECOG performance status was 0 in 42% of CLL/SLL patients, 1 in 56% of these patients, and 2 in 2%. ECOG performance status was 0 in 82% of FL patients, 1 in 12% of these patients, and 2 in 6%.
Twenty CLL/SLL patients were treatment-naïve, and 25 had relapsed/refractory disease. All 17 FL patients had relapsed/refractory disease.
The median number of prior therapies was 1 (range, 1-4) in the relapsed/refractory CLL/SLL patients and 3 (range, 1-7) in the FL patients.
Safety
At the time of the data cutoff, BGB-3111 was deemed well tolerated in patients with CLL/SLL and FL.
The most frequent AEs of any cause occurring in at least 15% of patients with CLL/SLL were petechiae/purpura/contusion (33%), neutropenia (31%), thrombocytopenia (22%), fatigue (18%), pyrexia (18%), upper respiratory tract infection (18%), and diarrhea (16%).
Most of these events were grade 1/2. The exceptions were grade 3/4 neutropenia (20%) and grade 3/4 thrombocytopenia (4%).
The most frequent AEs in FL patients were petechiae/purpura/contusion (35%), fatigue (29%), cough (18%), diarrhea (18%), dizziness (18%), headache (18%), insomnia (18%), nausea (18%), and upper respiratory tract infection (18%). All of these events were grade 1/2.
Serious AEs occurred in 24% of both the CLL/SLL patients and the FL patients.
Infusion-related reactions occurred in 24% of CLL/SLL patients and 6% of FL patients. Nearly all cases were grade 1/2. The exception was 1 grade 4 case in a CLL/SLL patient.
There were no cases of serious hemorrhage (≥ grade 3 hemorrhage or central nervous system hemorrhage of any grade) or atrial fibrillation.
One patient discontinued treatment due to an AE—squamous cell carcinoma. This patient had a prior history of squamous cell carcinoma.
Efficacy
At the time of the data cutoff, 43 patients with CLL/SLL (18 treatment-naive, 25 relapsed/refractory) and 15 patients with relapsed/refractory FL had greater than 12 weeks of follow-up and were evaluable for efficacy.
In treatment-naive CLL/SLL, after a median follow-up of 7.0 months (range, 2.8–11.8 months), the ORR was 89%. The complete response (CR) rate was 22%, the rate of partial response (PR) was 67%, and the rate of stable disease (SD) was 11%.
In relapsed/refractory CLL/SLL, at a median follow-up of 8.0 months (range, 3.8–14.0 months) the ORR was 92%. The CR rate was 16%, the PR rate was 76%, and 4% of patients had SD.
One patient (4%) with relapsed/refractory CLL/SLL had progressive disease (Richter’s transformation).
In relapsed/refractory FL, at a median follow-up of 6.2 months (range, 1.2–10.7 months), the ORR was 73%. The CR rate was 33%, the PR rate was 40%, and 13% of patients had SD.
Two patients (13%) with relapsed/refractory FL had progressive disease.
On the basis of these data, BeiGene plans to expand its global registrational program for BGB-3111 to include a phase 2 trial of BGB-3111 in combination with obinutuzumab compared to obinutuzumab alone in patients with relapsed/refractory FL.
The company is also planning a phase 3 trial comparing BGB-3111 with bendamustine plus rituximab in patients with treatment-naive CLL.
LUGANO, SWITZERLAND—Results of a phase 1 study suggest a 2-drug combination may be safe and effective in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and follicular lymphoma (FL).
The ongoing study is a test of the BTK inhibitor BGB-3111 and the anti-CD20 antibody obinutuzumab.
The overall response rate (ORR) with this combination was 81% in the entire study population, 89% in treatment-naïve CLL/SLL patients, 92% in relapsed/refractory CLL/SLL patients, and 73% in relapsed/refractory FL patients.
The rate of serious adverse events (AEs) was 24% in both CLL/SLL and FL patients.
These results were presented at the 14th International Conference on Malignant Lymphoma (ICML). The research was sponsored by BeiGene, Ltd.
“This clinical trial is supported by preclinical work suggesting that BGB-3111 may combine well with antibodies that rely on antibody-dependent cell-mediated cytotoxicity, such as obinutuzumab, because of less off-target inhibition of interleukin-2-inducible T-cell kinase,” said study investigator Constantine Tam, MD, of St. Vincent’s Hospital in Melbourne, Australia.
“The preliminary clinical results to date suggest that the combination is well tolerated and highly active in patients with CLL or SLL and FL. Complete responses have already been observed in patients with both disease types, including CLL or SLL patients with high-risk features, despite a very short follow-up time.”
The trial consists of a dose-escalation phase and a dose-expansion phase in disease-specific cohorts, which include treatment-naive or relapsed/refractory CLL/SLL and relapsed/refractory FL.
The dose-escalation component is testing BGB-3111 at 320 mg once daily or 160 mg twice daily in 28-day cycles, in combination with obinutuzumab. Obinutuzumab is administered in line with standard CLL dosing (3 loading doses of 1000 mg weekly, followed by 1000 mg on day 1 of cycles 2 to 6).
The ongoing dose-expansion component is testing doses of BGB-3111 at 160 mg twice daily with the same obinutuzumab schedule.
As of the data cutoff (March 31, 2017), 45 patients with CLL/SLL and 17 patients with FL were enrolled in the trial.
Patient characteristics
The median age was 68 (range, 28-82) in the CLL/SLL patients and 56 (range, 41-86) in the FL patients.
ECOG performance status was 0 in 42% of CLL/SLL patients, 1 in 56% of these patients, and 2 in 2%. ECOG performance status was 0 in 82% of FL patients, 1 in 12% of these patients, and 2 in 6%.
Twenty CLL/SLL patients were treatment-naïve, and 25 had relapsed/refractory disease. All 17 FL patients had relapsed/refractory disease.
The median number of prior therapies was 1 (range, 1-4) in the relapsed/refractory CLL/SLL patients and 3 (range, 1-7) in the FL patients.
Safety
At the time of the data cutoff, BGB-3111 was deemed well tolerated in patients with CLL/SLL and FL.
The most frequent AEs of any cause occurring in at least 15% of patients with CLL/SLL were petechiae/purpura/contusion (33%), neutropenia (31%), thrombocytopenia (22%), fatigue (18%), pyrexia (18%), upper respiratory tract infection (18%), and diarrhea (16%).
Most of these events were grade 1/2. The exceptions were grade 3/4 neutropenia (20%) and grade 3/4 thrombocytopenia (4%).
The most frequent AEs in FL patients were petechiae/purpura/contusion (35%), fatigue (29%), cough (18%), diarrhea (18%), dizziness (18%), headache (18%), insomnia (18%), nausea (18%), and upper respiratory tract infection (18%). All of these events were grade 1/2.
Serious AEs occurred in 24% of both the CLL/SLL patients and the FL patients.
Infusion-related reactions occurred in 24% of CLL/SLL patients and 6% of FL patients. Nearly all cases were grade 1/2. The exception was 1 grade 4 case in a CLL/SLL patient.
There were no cases of serious hemorrhage (≥ grade 3 hemorrhage or central nervous system hemorrhage of any grade) or atrial fibrillation.
One patient discontinued treatment due to an AE—squamous cell carcinoma. This patient had a prior history of squamous cell carcinoma.
Efficacy
At the time of the data cutoff, 43 patients with CLL/SLL (18 treatment-naive, 25 relapsed/refractory) and 15 patients with relapsed/refractory FL had greater than 12 weeks of follow-up and were evaluable for efficacy.
In treatment-naive CLL/SLL, after a median follow-up of 7.0 months (range, 2.8–11.8 months), the ORR was 89%. The complete response (CR) rate was 22%, the rate of partial response (PR) was 67%, and the rate of stable disease (SD) was 11%.
In relapsed/refractory CLL/SLL, at a median follow-up of 8.0 months (range, 3.8–14.0 months) the ORR was 92%. The CR rate was 16%, the PR rate was 76%, and 4% of patients had SD.
One patient (4%) with relapsed/refractory CLL/SLL had progressive disease (Richter’s transformation).
In relapsed/refractory FL, at a median follow-up of 6.2 months (range, 1.2–10.7 months), the ORR was 73%. The CR rate was 33%, the PR rate was 40%, and 13% of patients had SD.
Two patients (13%) with relapsed/refractory FL had progressive disease.
On the basis of these data, BeiGene plans to expand its global registrational program for BGB-3111 to include a phase 2 trial of BGB-3111 in combination with obinutuzumab compared to obinutuzumab alone in patients with relapsed/refractory FL.
The company is also planning a phase 3 trial comparing BGB-3111 with bendamustine plus rituximab in patients with treatment-naive CLL.
LUGANO, SWITZERLAND—Results of a phase 1 study suggest a 2-drug combination may be safe and effective in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and follicular lymphoma (FL).
The ongoing study is a test of the BTK inhibitor BGB-3111 and the anti-CD20 antibody obinutuzumab.
The overall response rate (ORR) with this combination was 81% in the entire study population, 89% in treatment-naïve CLL/SLL patients, 92% in relapsed/refractory CLL/SLL patients, and 73% in relapsed/refractory FL patients.
The rate of serious adverse events (AEs) was 24% in both CLL/SLL and FL patients.
These results were presented at the 14th International Conference on Malignant Lymphoma (ICML). The research was sponsored by BeiGene, Ltd.
“This clinical trial is supported by preclinical work suggesting that BGB-3111 may combine well with antibodies that rely on antibody-dependent cell-mediated cytotoxicity, such as obinutuzumab, because of less off-target inhibition of interleukin-2-inducible T-cell kinase,” said study investigator Constantine Tam, MD, of St. Vincent’s Hospital in Melbourne, Australia.
“The preliminary clinical results to date suggest that the combination is well tolerated and highly active in patients with CLL or SLL and FL. Complete responses have already been observed in patients with both disease types, including CLL or SLL patients with high-risk features, despite a very short follow-up time.”
The trial consists of a dose-escalation phase and a dose-expansion phase in disease-specific cohorts, which include treatment-naive or relapsed/refractory CLL/SLL and relapsed/refractory FL.
The dose-escalation component is testing BGB-3111 at 320 mg once daily or 160 mg twice daily in 28-day cycles, in combination with obinutuzumab. Obinutuzumab is administered in line with standard CLL dosing (3 loading doses of 1000 mg weekly, followed by 1000 mg on day 1 of cycles 2 to 6).
The ongoing dose-expansion component is testing doses of BGB-3111 at 160 mg twice daily with the same obinutuzumab schedule.
As of the data cutoff (March 31, 2017), 45 patients with CLL/SLL and 17 patients with FL were enrolled in the trial.
Patient characteristics
The median age was 68 (range, 28-82) in the CLL/SLL patients and 56 (range, 41-86) in the FL patients.
ECOG performance status was 0 in 42% of CLL/SLL patients, 1 in 56% of these patients, and 2 in 2%. ECOG performance status was 0 in 82% of FL patients, 1 in 12% of these patients, and 2 in 6%.
Twenty CLL/SLL patients were treatment-naïve, and 25 had relapsed/refractory disease. All 17 FL patients had relapsed/refractory disease.
The median number of prior therapies was 1 (range, 1-4) in the relapsed/refractory CLL/SLL patients and 3 (range, 1-7) in the FL patients.
Safety
At the time of the data cutoff, BGB-3111 was deemed well tolerated in patients with CLL/SLL and FL.
The most frequent AEs of any cause occurring in at least 15% of patients with CLL/SLL were petechiae/purpura/contusion (33%), neutropenia (31%), thrombocytopenia (22%), fatigue (18%), pyrexia (18%), upper respiratory tract infection (18%), and diarrhea (16%).
Most of these events were grade 1/2. The exceptions were grade 3/4 neutropenia (20%) and grade 3/4 thrombocytopenia (4%).
The most frequent AEs in FL patients were petechiae/purpura/contusion (35%), fatigue (29%), cough (18%), diarrhea (18%), dizziness (18%), headache (18%), insomnia (18%), nausea (18%), and upper respiratory tract infection (18%). All of these events were grade 1/2.
Serious AEs occurred in 24% of both the CLL/SLL patients and the FL patients.
Infusion-related reactions occurred in 24% of CLL/SLL patients and 6% of FL patients. Nearly all cases were grade 1/2. The exception was 1 grade 4 case in a CLL/SLL patient.
There were no cases of serious hemorrhage (≥ grade 3 hemorrhage or central nervous system hemorrhage of any grade) or atrial fibrillation.
One patient discontinued treatment due to an AE—squamous cell carcinoma. This patient had a prior history of squamous cell carcinoma.
Efficacy
At the time of the data cutoff, 43 patients with CLL/SLL (18 treatment-naive, 25 relapsed/refractory) and 15 patients with relapsed/refractory FL had greater than 12 weeks of follow-up and were evaluable for efficacy.
In treatment-naive CLL/SLL, after a median follow-up of 7.0 months (range, 2.8–11.8 months), the ORR was 89%. The complete response (CR) rate was 22%, the rate of partial response (PR) was 67%, and the rate of stable disease (SD) was 11%.
In relapsed/refractory CLL/SLL, at a median follow-up of 8.0 months (range, 3.8–14.0 months) the ORR was 92%. The CR rate was 16%, the PR rate was 76%, and 4% of patients had SD.
One patient (4%) with relapsed/refractory CLL/SLL had progressive disease (Richter’s transformation).
In relapsed/refractory FL, at a median follow-up of 6.2 months (range, 1.2–10.7 months), the ORR was 73%. The CR rate was 33%, the PR rate was 40%, and 13% of patients had SD.
Two patients (13%) with relapsed/refractory FL had progressive disease.
On the basis of these data, BeiGene plans to expand its global registrational program for BGB-3111 to include a phase 2 trial of BGB-3111 in combination with obinutuzumab compared to obinutuzumab alone in patients with relapsed/refractory FL.
The company is also planning a phase 3 trial comparing BGB-3111 with bendamustine plus rituximab in patients with treatment-naive CLL.
Tazemetostat active against follicular lymphoma with EZH2 mutation
LUGANO, SWITZERLAND – Tazemetostat, a first-in-class experimental agent that inhibits an oncogenic protein, shows efficacy in patients with heavily pretreated, relapsed/refractory follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL), interim results from a phase II study suggest.
Among patients with relapsed/refractory FL who had mutations in EZH2 (enhancer of zeste homolog 2), a member of a family of proteins that are involved in epigenetic gene silencing, the overall response rate (ORR) was 92%, reported Franck Morschhauser, MD, PhD, of the University of Lille, France.
“What we observed is a four-fold increase in [ORR in] follicular lymphoma-mutated patients compared to wild-type patients, a two-fold increase in DLBCL patients mutated compared to wild-type patients,” he said.
“But if we had focused [only] on the actionable mutation, we would have missed those other complete responders in the wild-type setting,” he added.
EZH2, an epigenetic regulator of gene expression, had been shown in preclinical studies to play an important role in multiple forms of cancers, and activating mutations of EZH2 have been shown to be oncogenic drivers in approximately 20% of FL and germinal center B-cell–like DLBCL, Dr. Morschhauser explained.
EZH2 has also been shown to be over-expressed in leukemia-initiating cells in patients with chronic myeloid leukemia, and EZH2 inhibitors are being explored as a possible therapy for patients with chronic myeloid leukemia that has become resistant to tyrosine kinase inhibitors.
Large multicenter study
Dr. Morschhauser reported interim results from a global, multi-center open-label study of tazemetostat in six cohorts of patients with relapsed/refractory FL (two monotherapy cohorts of 45 patients each) or DLBCL (three monotherapy cohorts of 60 patients each). A sixth cohort consisting of 70 patients with DLBCL treated with tazemetostat and prednisolone was added in 2017.
In the ongoing trial, patients receive oral tazemetostat 800 mg twice daily until disease progression or withdrawal from study, and are being followed for ORR, progression-free survival, overall survival, duration-of response, safety, and pharmacokinetics.
The longest follow-up at the time of data cutoff was approximately 18 months. Among 13 evaluable patients with FL with EZH2 mutations, the ORR was 92%, including one complete response (CR) and 11 partial responses (PR). In contrast, the ORR for 54 patients with FL and wild-type EZH2 was 28%, consisting of three CRs and 11 PRs. One patient with mutated EZH2 and 23 with wild-type EZH2 had stable disease.
Among 17 patients with DLBCL and EZH2 mutations, the ORR was 29%, consisting of 5 PR. For 119 patients with wild-type EZH2, the ORR was 15%, consisting of 10 CR and 8 PR. Six patients with mutations and 22 with wild-type EZH2 had stable disease.
Among the patients with FL, 75% had significant reduction in tumor burden.
The time to response ranged from 2 months to 1 year, with a median of approximately 4 months.
The variability in time to response “makes it a little bit tricky to calculate response duration,” Dr. Morschhauser said.
The drug had a “favorable” safety profile, with treatment-related adverse events of grade 3 or greater in more than 5% of patients including thrombocytopenias in 6% of patients, anemias in 4%, and neutropenias in 6%. Treatment-emergent adverse events leading to dose reductions occurred in 4% of patients, and those leading to drug discontinuation or study withdrawal occurred in 12% of patients.
In a retrospective analysis, the investigators performed molecular profiling studies using next-generation sequencing to look for predictors of response to tazemetostat. They found that patients most likely to respond to tazemetostat were those with activating mutations in EZH2 and MYD88. In contrast, patients with mutations HIST1H1E or MYC were not likely to respond.
Thomas E. Witzig, MD, of the Mayo Clinic in Rochester, Minn., the invited discussant, said that the study is important because “it provides proof of principle that attacking the methylation issue, attacking one of these enzymes, is very important and can produce single-agent responses.
“It also demonstrates the value of mutation status, and this trial knowledge of that mutation status has actually changed the trial design, so that now they are only putting patients on with mutations,” he said.
The trial also raises the possibility of targeting other parts of the methylation pathway to treat cancer, he added.
The study was sponsored by Epizyme, the maker of tazemetostat. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies. Dr. Witzig has disclosed grants for clinical trials from Novartis and Wyeth, and he has served on advisory boards for Cephalon, Novartis, and Wyeth.
LUGANO, SWITZERLAND – Tazemetostat, a first-in-class experimental agent that inhibits an oncogenic protein, shows efficacy in patients with heavily pretreated, relapsed/refractory follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL), interim results from a phase II study suggest.
Among patients with relapsed/refractory FL who had mutations in EZH2 (enhancer of zeste homolog 2), a member of a family of proteins that are involved in epigenetic gene silencing, the overall response rate (ORR) was 92%, reported Franck Morschhauser, MD, PhD, of the University of Lille, France.
“What we observed is a four-fold increase in [ORR in] follicular lymphoma-mutated patients compared to wild-type patients, a two-fold increase in DLBCL patients mutated compared to wild-type patients,” he said.
“But if we had focused [only] on the actionable mutation, we would have missed those other complete responders in the wild-type setting,” he added.
EZH2, an epigenetic regulator of gene expression, had been shown in preclinical studies to play an important role in multiple forms of cancers, and activating mutations of EZH2 have been shown to be oncogenic drivers in approximately 20% of FL and germinal center B-cell–like DLBCL, Dr. Morschhauser explained.
EZH2 has also been shown to be over-expressed in leukemia-initiating cells in patients with chronic myeloid leukemia, and EZH2 inhibitors are being explored as a possible therapy for patients with chronic myeloid leukemia that has become resistant to tyrosine kinase inhibitors.
Large multicenter study
Dr. Morschhauser reported interim results from a global, multi-center open-label study of tazemetostat in six cohorts of patients with relapsed/refractory FL (two monotherapy cohorts of 45 patients each) or DLBCL (three monotherapy cohorts of 60 patients each). A sixth cohort consisting of 70 patients with DLBCL treated with tazemetostat and prednisolone was added in 2017.
In the ongoing trial, patients receive oral tazemetostat 800 mg twice daily until disease progression or withdrawal from study, and are being followed for ORR, progression-free survival, overall survival, duration-of response, safety, and pharmacokinetics.
The longest follow-up at the time of data cutoff was approximately 18 months. Among 13 evaluable patients with FL with EZH2 mutations, the ORR was 92%, including one complete response (CR) and 11 partial responses (PR). In contrast, the ORR for 54 patients with FL and wild-type EZH2 was 28%, consisting of three CRs and 11 PRs. One patient with mutated EZH2 and 23 with wild-type EZH2 had stable disease.
Among 17 patients with DLBCL and EZH2 mutations, the ORR was 29%, consisting of 5 PR. For 119 patients with wild-type EZH2, the ORR was 15%, consisting of 10 CR and 8 PR. Six patients with mutations and 22 with wild-type EZH2 had stable disease.
Among the patients with FL, 75% had significant reduction in tumor burden.
The time to response ranged from 2 months to 1 year, with a median of approximately 4 months.
The variability in time to response “makes it a little bit tricky to calculate response duration,” Dr. Morschhauser said.
The drug had a “favorable” safety profile, with treatment-related adverse events of grade 3 or greater in more than 5% of patients including thrombocytopenias in 6% of patients, anemias in 4%, and neutropenias in 6%. Treatment-emergent adverse events leading to dose reductions occurred in 4% of patients, and those leading to drug discontinuation or study withdrawal occurred in 12% of patients.
In a retrospective analysis, the investigators performed molecular profiling studies using next-generation sequencing to look for predictors of response to tazemetostat. They found that patients most likely to respond to tazemetostat were those with activating mutations in EZH2 and MYD88. In contrast, patients with mutations HIST1H1E or MYC were not likely to respond.
Thomas E. Witzig, MD, of the Mayo Clinic in Rochester, Minn., the invited discussant, said that the study is important because “it provides proof of principle that attacking the methylation issue, attacking one of these enzymes, is very important and can produce single-agent responses.
“It also demonstrates the value of mutation status, and this trial knowledge of that mutation status has actually changed the trial design, so that now they are only putting patients on with mutations,” he said.
The trial also raises the possibility of targeting other parts of the methylation pathway to treat cancer, he added.
The study was sponsored by Epizyme, the maker of tazemetostat. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies. Dr. Witzig has disclosed grants for clinical trials from Novartis and Wyeth, and he has served on advisory boards for Cephalon, Novartis, and Wyeth.
LUGANO, SWITZERLAND – Tazemetostat, a first-in-class experimental agent that inhibits an oncogenic protein, shows efficacy in patients with heavily pretreated, relapsed/refractory follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL), interim results from a phase II study suggest.
Among patients with relapsed/refractory FL who had mutations in EZH2 (enhancer of zeste homolog 2), a member of a family of proteins that are involved in epigenetic gene silencing, the overall response rate (ORR) was 92%, reported Franck Morschhauser, MD, PhD, of the University of Lille, France.
“What we observed is a four-fold increase in [ORR in] follicular lymphoma-mutated patients compared to wild-type patients, a two-fold increase in DLBCL patients mutated compared to wild-type patients,” he said.
“But if we had focused [only] on the actionable mutation, we would have missed those other complete responders in the wild-type setting,” he added.
EZH2, an epigenetic regulator of gene expression, had been shown in preclinical studies to play an important role in multiple forms of cancers, and activating mutations of EZH2 have been shown to be oncogenic drivers in approximately 20% of FL and germinal center B-cell–like DLBCL, Dr. Morschhauser explained.
EZH2 has also been shown to be over-expressed in leukemia-initiating cells in patients with chronic myeloid leukemia, and EZH2 inhibitors are being explored as a possible therapy for patients with chronic myeloid leukemia that has become resistant to tyrosine kinase inhibitors.
Large multicenter study
Dr. Morschhauser reported interim results from a global, multi-center open-label study of tazemetostat in six cohorts of patients with relapsed/refractory FL (two monotherapy cohorts of 45 patients each) or DLBCL (three monotherapy cohorts of 60 patients each). A sixth cohort consisting of 70 patients with DLBCL treated with tazemetostat and prednisolone was added in 2017.
In the ongoing trial, patients receive oral tazemetostat 800 mg twice daily until disease progression or withdrawal from study, and are being followed for ORR, progression-free survival, overall survival, duration-of response, safety, and pharmacokinetics.
The longest follow-up at the time of data cutoff was approximately 18 months. Among 13 evaluable patients with FL with EZH2 mutations, the ORR was 92%, including one complete response (CR) and 11 partial responses (PR). In contrast, the ORR for 54 patients with FL and wild-type EZH2 was 28%, consisting of three CRs and 11 PRs. One patient with mutated EZH2 and 23 with wild-type EZH2 had stable disease.
Among 17 patients with DLBCL and EZH2 mutations, the ORR was 29%, consisting of 5 PR. For 119 patients with wild-type EZH2, the ORR was 15%, consisting of 10 CR and 8 PR. Six patients with mutations and 22 with wild-type EZH2 had stable disease.
Among the patients with FL, 75% had significant reduction in tumor burden.
The time to response ranged from 2 months to 1 year, with a median of approximately 4 months.
The variability in time to response “makes it a little bit tricky to calculate response duration,” Dr. Morschhauser said.
The drug had a “favorable” safety profile, with treatment-related adverse events of grade 3 or greater in more than 5% of patients including thrombocytopenias in 6% of patients, anemias in 4%, and neutropenias in 6%. Treatment-emergent adverse events leading to dose reductions occurred in 4% of patients, and those leading to drug discontinuation or study withdrawal occurred in 12% of patients.
In a retrospective analysis, the investigators performed molecular profiling studies using next-generation sequencing to look for predictors of response to tazemetostat. They found that patients most likely to respond to tazemetostat were those with activating mutations in EZH2 and MYD88. In contrast, patients with mutations HIST1H1E or MYC were not likely to respond.
Thomas E. Witzig, MD, of the Mayo Clinic in Rochester, Minn., the invited discussant, said that the study is important because “it provides proof of principle that attacking the methylation issue, attacking one of these enzymes, is very important and can produce single-agent responses.
“It also demonstrates the value of mutation status, and this trial knowledge of that mutation status has actually changed the trial design, so that now they are only putting patients on with mutations,” he said.
The trial also raises the possibility of targeting other parts of the methylation pathway to treat cancer, he added.
The study was sponsored by Epizyme, the maker of tazemetostat. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies. Dr. Witzig has disclosed grants for clinical trials from Novartis and Wyeth, and he has served on advisory boards for Cephalon, Novartis, and Wyeth.
AT 14-ICML
Key clinical point: The experimental drug tazemetostat induced responses in patients with heavily pretreated follicular lymphoma (FL) with mutations in EZH2.
Major finding: The overall response rate among patients with FL with mutated EZH2 was 92%.
Data source: Multicenter, open-label phase II study in patients with relapsed/refractory FL and diffuse large B cell lymphoma.
Disclosures: The study is sponsored by Epizyme. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies. Dr. Witzig has disclosed grants for clinical trials from Novartis and Wyeth, and he has served on advisory boards for Cephalon, Novartis, and Wyeth.
CAR T-cell therapy shows early promise in DLBCL
LUGANO, SWITZERLAND—The chimeric antigen receptor (CAR) T-cell therapy JCAR017 can produce “potent and durable” responses in patients with relapsed/refractory, aggressive diffuse large B-cell lymphoma (DLBCL), according to an investigator from the TRANSCEND NHL 001 trial.
In this phase 1 trial, JCAR017, given after lymphodepleting chemotherapy, produced an overall response rate (ORR) of 76% and a complete response (CR) rate of 52%.
At 3 months of follow-up, the ORR was 51%, and the CR rate was 39%.
Responses were seen even in poor-risk subgroups, noted study investigator Jeremy Abramson, MD, of Massachusetts General Hospital Cancer Center in Boston.
“TRANSCEND NHL 001 is the first multicenter study of a CD19-directed CAR T-cell product with a fixed CD4 and CD8 composition to deliver potent and durable responses in high-risk subsets in DLBCL,” Dr Abramson said.
He presented data from the trial at the 2017 International Conference on Malignant Lymphoma (ICML) as abstract 128. The research was sponsored by Juno Therapeutics, the company developing JCAR017.
Patients
Dr Abramson presented data on 55 patients with relapsed/refractory non-Hodgkin lymphoma. Forty patients had DLBCL not otherwise specified, 14 had transformed DLBCL, and 1 had grade 3B follicular lymphoma. Fifteen patients had double- or triple-hit lymphoma.
The patients’ median age was 61 (range, 29-82), and 69% were male. Eighty-seven percent of patients (n=48) had an ECOG status of 0 to 1. Two patients had central nervous system involvement.
The patients had received a median of 3 prior lines of therapy (range, 1-11). Seventy-six percent of patients (n=42) were chemo-refractory, 7% (n=4) had received an allogeneic transplant, and 44% (n=24) had received an autologous transplant.
Treatment
Patients received 1 of 2 doses of JCAR017 after fludarabine/cyclophosphamide lymphodepletion.
Thirty patients received a single dose of JCAR017 at 5 x 107 CAR cells (dose-level 1, single [DL1S]).
Six patients received 2 doses of 5 x 107 CAR cells (dose-level 1, double [DL1D]).
Nineteen patients received a single dose of 1 x 108 CAR cells (dose-level 2, single [DL2S]).
Safety
More than 90% of patients experienced a treatment-emergent adverse event (AE), and 60% had a treatment-related AE.
Treatment-emergent AEs occurring in more than 20% of patients included cytokine release syndrome (CRS), fatigue, nausea, constipation, decreased appetite, diarrhea, hypotension, neutropenia, anemia, and thrombocytopenia.
One patient had a grade 5 AE of diffuse alveolar damage that was thought to be related to fludarabine, cyclophosphamide, and JCAR017.
Another patient had a grade 5 AE of multiorgan failure that was considered unrelated to study treatment and due to disease progression.
The rate of grade 1/2 CRS was 33% (n=18), and the rate of grade 3/4 CRS was 2% (n=1). The rate of grade 1/2 neurotoxicity was 6% (n=3), and the rate of grade 3/4 neurotoxicity was 16% (n=9).
There were no deaths from CRS or neurotoxicity. The median time to onset of CRS was 5 days (range, 1-23), and the median time to onset of neurotoxicity was 11 days (range, 5-23).
“JCAR017 toxicities have, thus far, been relatively low and highly manageable at all dose levels tested, with a favorable safety profile that may enable outpatient administration,” Dr Abramson said.
Response
Fifty-four patients were evaluable for response. The ORR was 76%, and the CR rate was 52%. At 3 months of follow-up, the ORR was 51%, and the CR rate was 39%.
Dr Abramson noted that there was a dose-response relationship.
Overall, in the DL1S cohort, the ORR was 80%, and the CR rate was 53%. In the DL2S cohort, the ORR was 72%, and the CR rate was 50%. In the DL1D cohort, the ORR was 67%, and the CR rate was 50%.
At 3 months, in the DL1S cohort, the ORR was 46%, and the CR rate was 33%. In the DL2S cohort, the ORR was 64%, and the CR rate was 46%. In the DL1D cohort, the ORR and CR rate were both 50%.
Dr Abramson also noted that JCAR017 could produce a high response rate in poor-risk subgroups.
At 3 months, the ORR was 91% in patients who relapsed less than 12 months after transplant, 82% in patients with double- or triple-hit lymphoma, 48% in patients who had never achieved a CR, 47% in chemo-refractory patients, 31% in patients with primary refractory lymphoma, and 24% in patients with stable disease or progression after last chemotherapy.
LUGANO, SWITZERLAND—The chimeric antigen receptor (CAR) T-cell therapy JCAR017 can produce “potent and durable” responses in patients with relapsed/refractory, aggressive diffuse large B-cell lymphoma (DLBCL), according to an investigator from the TRANSCEND NHL 001 trial.
In this phase 1 trial, JCAR017, given after lymphodepleting chemotherapy, produced an overall response rate (ORR) of 76% and a complete response (CR) rate of 52%.
At 3 months of follow-up, the ORR was 51%, and the CR rate was 39%.
Responses were seen even in poor-risk subgroups, noted study investigator Jeremy Abramson, MD, of Massachusetts General Hospital Cancer Center in Boston.
“TRANSCEND NHL 001 is the first multicenter study of a CD19-directed CAR T-cell product with a fixed CD4 and CD8 composition to deliver potent and durable responses in high-risk subsets in DLBCL,” Dr Abramson said.
He presented data from the trial at the 2017 International Conference on Malignant Lymphoma (ICML) as abstract 128. The research was sponsored by Juno Therapeutics, the company developing JCAR017.
Patients
Dr Abramson presented data on 55 patients with relapsed/refractory non-Hodgkin lymphoma. Forty patients had DLBCL not otherwise specified, 14 had transformed DLBCL, and 1 had grade 3B follicular lymphoma. Fifteen patients had double- or triple-hit lymphoma.
The patients’ median age was 61 (range, 29-82), and 69% were male. Eighty-seven percent of patients (n=48) had an ECOG status of 0 to 1. Two patients had central nervous system involvement.
The patients had received a median of 3 prior lines of therapy (range, 1-11). Seventy-six percent of patients (n=42) were chemo-refractory, 7% (n=4) had received an allogeneic transplant, and 44% (n=24) had received an autologous transplant.
Treatment
Patients received 1 of 2 doses of JCAR017 after fludarabine/cyclophosphamide lymphodepletion.
Thirty patients received a single dose of JCAR017 at 5 x 107 CAR cells (dose-level 1, single [DL1S]).
Six patients received 2 doses of 5 x 107 CAR cells (dose-level 1, double [DL1D]).
Nineteen patients received a single dose of 1 x 108 CAR cells (dose-level 2, single [DL2S]).
Safety
More than 90% of patients experienced a treatment-emergent adverse event (AE), and 60% had a treatment-related AE.
Treatment-emergent AEs occurring in more than 20% of patients included cytokine release syndrome (CRS), fatigue, nausea, constipation, decreased appetite, diarrhea, hypotension, neutropenia, anemia, and thrombocytopenia.
One patient had a grade 5 AE of diffuse alveolar damage that was thought to be related to fludarabine, cyclophosphamide, and JCAR017.
Another patient had a grade 5 AE of multiorgan failure that was considered unrelated to study treatment and due to disease progression.
The rate of grade 1/2 CRS was 33% (n=18), and the rate of grade 3/4 CRS was 2% (n=1). The rate of grade 1/2 neurotoxicity was 6% (n=3), and the rate of grade 3/4 neurotoxicity was 16% (n=9).
There were no deaths from CRS or neurotoxicity. The median time to onset of CRS was 5 days (range, 1-23), and the median time to onset of neurotoxicity was 11 days (range, 5-23).
“JCAR017 toxicities have, thus far, been relatively low and highly manageable at all dose levels tested, with a favorable safety profile that may enable outpatient administration,” Dr Abramson said.
Response
Fifty-four patients were evaluable for response. The ORR was 76%, and the CR rate was 52%. At 3 months of follow-up, the ORR was 51%, and the CR rate was 39%.
Dr Abramson noted that there was a dose-response relationship.
Overall, in the DL1S cohort, the ORR was 80%, and the CR rate was 53%. In the DL2S cohort, the ORR was 72%, and the CR rate was 50%. In the DL1D cohort, the ORR was 67%, and the CR rate was 50%.
At 3 months, in the DL1S cohort, the ORR was 46%, and the CR rate was 33%. In the DL2S cohort, the ORR was 64%, and the CR rate was 46%. In the DL1D cohort, the ORR and CR rate were both 50%.
Dr Abramson also noted that JCAR017 could produce a high response rate in poor-risk subgroups.
At 3 months, the ORR was 91% in patients who relapsed less than 12 months after transplant, 82% in patients with double- or triple-hit lymphoma, 48% in patients who had never achieved a CR, 47% in chemo-refractory patients, 31% in patients with primary refractory lymphoma, and 24% in patients with stable disease or progression after last chemotherapy.
LUGANO, SWITZERLAND—The chimeric antigen receptor (CAR) T-cell therapy JCAR017 can produce “potent and durable” responses in patients with relapsed/refractory, aggressive diffuse large B-cell lymphoma (DLBCL), according to an investigator from the TRANSCEND NHL 001 trial.
In this phase 1 trial, JCAR017, given after lymphodepleting chemotherapy, produced an overall response rate (ORR) of 76% and a complete response (CR) rate of 52%.
At 3 months of follow-up, the ORR was 51%, and the CR rate was 39%.
Responses were seen even in poor-risk subgroups, noted study investigator Jeremy Abramson, MD, of Massachusetts General Hospital Cancer Center in Boston.
“TRANSCEND NHL 001 is the first multicenter study of a CD19-directed CAR T-cell product with a fixed CD4 and CD8 composition to deliver potent and durable responses in high-risk subsets in DLBCL,” Dr Abramson said.
He presented data from the trial at the 2017 International Conference on Malignant Lymphoma (ICML) as abstract 128. The research was sponsored by Juno Therapeutics, the company developing JCAR017.
Patients
Dr Abramson presented data on 55 patients with relapsed/refractory non-Hodgkin lymphoma. Forty patients had DLBCL not otherwise specified, 14 had transformed DLBCL, and 1 had grade 3B follicular lymphoma. Fifteen patients had double- or triple-hit lymphoma.
The patients’ median age was 61 (range, 29-82), and 69% were male. Eighty-seven percent of patients (n=48) had an ECOG status of 0 to 1. Two patients had central nervous system involvement.
The patients had received a median of 3 prior lines of therapy (range, 1-11). Seventy-six percent of patients (n=42) were chemo-refractory, 7% (n=4) had received an allogeneic transplant, and 44% (n=24) had received an autologous transplant.
Treatment
Patients received 1 of 2 doses of JCAR017 after fludarabine/cyclophosphamide lymphodepletion.
Thirty patients received a single dose of JCAR017 at 5 x 107 CAR cells (dose-level 1, single [DL1S]).
Six patients received 2 doses of 5 x 107 CAR cells (dose-level 1, double [DL1D]).
Nineteen patients received a single dose of 1 x 108 CAR cells (dose-level 2, single [DL2S]).
Safety
More than 90% of patients experienced a treatment-emergent adverse event (AE), and 60% had a treatment-related AE.
Treatment-emergent AEs occurring in more than 20% of patients included cytokine release syndrome (CRS), fatigue, nausea, constipation, decreased appetite, diarrhea, hypotension, neutropenia, anemia, and thrombocytopenia.
One patient had a grade 5 AE of diffuse alveolar damage that was thought to be related to fludarabine, cyclophosphamide, and JCAR017.
Another patient had a grade 5 AE of multiorgan failure that was considered unrelated to study treatment and due to disease progression.
The rate of grade 1/2 CRS was 33% (n=18), and the rate of grade 3/4 CRS was 2% (n=1). The rate of grade 1/2 neurotoxicity was 6% (n=3), and the rate of grade 3/4 neurotoxicity was 16% (n=9).
There were no deaths from CRS or neurotoxicity. The median time to onset of CRS was 5 days (range, 1-23), and the median time to onset of neurotoxicity was 11 days (range, 5-23).
“JCAR017 toxicities have, thus far, been relatively low and highly manageable at all dose levels tested, with a favorable safety profile that may enable outpatient administration,” Dr Abramson said.
Response
Fifty-four patients were evaluable for response. The ORR was 76%, and the CR rate was 52%. At 3 months of follow-up, the ORR was 51%, and the CR rate was 39%.
Dr Abramson noted that there was a dose-response relationship.
Overall, in the DL1S cohort, the ORR was 80%, and the CR rate was 53%. In the DL2S cohort, the ORR was 72%, and the CR rate was 50%. In the DL1D cohort, the ORR was 67%, and the CR rate was 50%.
At 3 months, in the DL1S cohort, the ORR was 46%, and the CR rate was 33%. In the DL2S cohort, the ORR was 64%, and the CR rate was 46%. In the DL1D cohort, the ORR and CR rate were both 50%.
Dr Abramson also noted that JCAR017 could produce a high response rate in poor-risk subgroups.
At 3 months, the ORR was 91% in patients who relapsed less than 12 months after transplant, 82% in patients with double- or triple-hit lymphoma, 48% in patients who had never achieved a CR, 47% in chemo-refractory patients, 31% in patients with primary refractory lymphoma, and 24% in patients with stable disease or progression after last chemotherapy.
Ibrutinib/buparlisib looks good for relapsed mantle cell lymphoma
LUGANO, SWITZERLAND – A combination of the Bruton’s tyrosine kinase (BTK) ibrutinib (Imbruvica) and the pan-phosphoinositide 3-kinase (PI3K) inhibitor buparlisib showed clinical activity superior to that of single-agent ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL).
In a phase I/IB dose escalation study and expansion cohort testing the combination in patients with diffuse large B cell lymphoma (DLBCL), follicular lymphoma, and MCL, the overall response rate (ORR) among patients with MCL was 100%, consisting of complete responses (CR) in 8 of 11 patients, and partial responses (PR) in 3 patients, reported Connie Lee Batlevi, MD, of Memorial Sloan Kettering Cancer Center in New York.
In contrast, the response rate to ibrutinib monotherapy among patients with relapsed MCL is around 20%, she said.
Preclinical studies have demonstrated synergism between BTK inhibitors and PI3K inhibitors in B-cell non-Hodgkin lymphoma (NHL), prompting the investigators to look into the combination in patients with relapsed or refractory DLBCL, follicular lymphoma (FL), and MCL.
They enrolled 25 patients (9 with DLBCL, 5 with FL, and 11 with MCL). The patients received escalating doses of once daily ibrutinib and buparlisib in three dose levels (ibrutinib 420-560 mg; buparlisib 80-100 mg). Dose level 3, consisting of ibrutinib 560 mg and buparlisib 100 mg, was selected for dose expansion based on one of six patients developing a dose-limiting toxicity.
Using the Lugano Response Criteria, the overall ORR (all histologies) was 52%. Among nine patients with DLBCL, the ORR was 11%, with one CR and no PR. Among five patients with FL, the ORR was 20%, consisting of one CR and no PR.
Among 11 patients with MCL, however, the ORR was far more impressive, at 100%, including eight CR and three PR. No patients with MCL had either stable or progressive disease.
Under the RECIL (International Working Group) criteria, the ORR was 48% including one CR each for DLBCL and FL, and eight CR and two PR for patients with MCL.
In the safety analysis, there were two dose-limiting toxicities in the lowest and highest dose groups, but none at dose level 2 (ibrutinib 560 mg and buparlisib 80 mg).
Grade 3 or greater adverse events occurred in 63% of patients. The most common events were hyperglycemia and rash in 19% each, and diarrhea, anorexia, and neurologic changes in 11% each,
The grade 3 neurologic changes included depression, agitation, mood swings, confusion and memory impairment, all of which resolved after buparlisib was withdrawn.
Dr. Batlevi showed scans of two patients with representative clinical responses in MCL. One 55-year-old man with blastoid MCL who had relapsed 18 months after frontline therapy with ofatumumab and bendamustine had near total clearance of lesions after two cycles of ibrutinib and buparlisib. He remains in CR after 12 months on the combination.
A second patient, a 77-year-old man with MCL that relapsed 10 years after R-CHOP and rituximab maintenance followed by autologous stem cell transplant, showed a complete response upon restaging after two cycles of ibrutinib/buparlisib.
The investigators are currently enrolling patients for phase IB expansions, with the goal of better estimating the safety and efficacy of the combination.
Memorial Sloan Kettering Cancer Center sponsored the study, with support from Janssen and Novartis. Dr. Batlevi reported no conflicts of interest.
LUGANO, SWITZERLAND – A combination of the Bruton’s tyrosine kinase (BTK) ibrutinib (Imbruvica) and the pan-phosphoinositide 3-kinase (PI3K) inhibitor buparlisib showed clinical activity superior to that of single-agent ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL).
In a phase I/IB dose escalation study and expansion cohort testing the combination in patients with diffuse large B cell lymphoma (DLBCL), follicular lymphoma, and MCL, the overall response rate (ORR) among patients with MCL was 100%, consisting of complete responses (CR) in 8 of 11 patients, and partial responses (PR) in 3 patients, reported Connie Lee Batlevi, MD, of Memorial Sloan Kettering Cancer Center in New York.
In contrast, the response rate to ibrutinib monotherapy among patients with relapsed MCL is around 20%, she said.
Preclinical studies have demonstrated synergism between BTK inhibitors and PI3K inhibitors in B-cell non-Hodgkin lymphoma (NHL), prompting the investigators to look into the combination in patients with relapsed or refractory DLBCL, follicular lymphoma (FL), and MCL.
They enrolled 25 patients (9 with DLBCL, 5 with FL, and 11 with MCL). The patients received escalating doses of once daily ibrutinib and buparlisib in three dose levels (ibrutinib 420-560 mg; buparlisib 80-100 mg). Dose level 3, consisting of ibrutinib 560 mg and buparlisib 100 mg, was selected for dose expansion based on one of six patients developing a dose-limiting toxicity.
Using the Lugano Response Criteria, the overall ORR (all histologies) was 52%. Among nine patients with DLBCL, the ORR was 11%, with one CR and no PR. Among five patients with FL, the ORR was 20%, consisting of one CR and no PR.
Among 11 patients with MCL, however, the ORR was far more impressive, at 100%, including eight CR and three PR. No patients with MCL had either stable or progressive disease.
Under the RECIL (International Working Group) criteria, the ORR was 48% including one CR each for DLBCL and FL, and eight CR and two PR for patients with MCL.
In the safety analysis, there were two dose-limiting toxicities in the lowest and highest dose groups, but none at dose level 2 (ibrutinib 560 mg and buparlisib 80 mg).
Grade 3 or greater adverse events occurred in 63% of patients. The most common events were hyperglycemia and rash in 19% each, and diarrhea, anorexia, and neurologic changes in 11% each,
The grade 3 neurologic changes included depression, agitation, mood swings, confusion and memory impairment, all of which resolved after buparlisib was withdrawn.
Dr. Batlevi showed scans of two patients with representative clinical responses in MCL. One 55-year-old man with blastoid MCL who had relapsed 18 months after frontline therapy with ofatumumab and bendamustine had near total clearance of lesions after two cycles of ibrutinib and buparlisib. He remains in CR after 12 months on the combination.
A second patient, a 77-year-old man with MCL that relapsed 10 years after R-CHOP and rituximab maintenance followed by autologous stem cell transplant, showed a complete response upon restaging after two cycles of ibrutinib/buparlisib.
The investigators are currently enrolling patients for phase IB expansions, with the goal of better estimating the safety and efficacy of the combination.
Memorial Sloan Kettering Cancer Center sponsored the study, with support from Janssen and Novartis. Dr. Batlevi reported no conflicts of interest.
LUGANO, SWITZERLAND – A combination of the Bruton’s tyrosine kinase (BTK) ibrutinib (Imbruvica) and the pan-phosphoinositide 3-kinase (PI3K) inhibitor buparlisib showed clinical activity superior to that of single-agent ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL).
In a phase I/IB dose escalation study and expansion cohort testing the combination in patients with diffuse large B cell lymphoma (DLBCL), follicular lymphoma, and MCL, the overall response rate (ORR) among patients with MCL was 100%, consisting of complete responses (CR) in 8 of 11 patients, and partial responses (PR) in 3 patients, reported Connie Lee Batlevi, MD, of Memorial Sloan Kettering Cancer Center in New York.
In contrast, the response rate to ibrutinib monotherapy among patients with relapsed MCL is around 20%, she said.
Preclinical studies have demonstrated synergism between BTK inhibitors and PI3K inhibitors in B-cell non-Hodgkin lymphoma (NHL), prompting the investigators to look into the combination in patients with relapsed or refractory DLBCL, follicular lymphoma (FL), and MCL.
They enrolled 25 patients (9 with DLBCL, 5 with FL, and 11 with MCL). The patients received escalating doses of once daily ibrutinib and buparlisib in three dose levels (ibrutinib 420-560 mg; buparlisib 80-100 mg). Dose level 3, consisting of ibrutinib 560 mg and buparlisib 100 mg, was selected for dose expansion based on one of six patients developing a dose-limiting toxicity.
Using the Lugano Response Criteria, the overall ORR (all histologies) was 52%. Among nine patients with DLBCL, the ORR was 11%, with one CR and no PR. Among five patients with FL, the ORR was 20%, consisting of one CR and no PR.
Among 11 patients with MCL, however, the ORR was far more impressive, at 100%, including eight CR and three PR. No patients with MCL had either stable or progressive disease.
Under the RECIL (International Working Group) criteria, the ORR was 48% including one CR each for DLBCL and FL, and eight CR and two PR for patients with MCL.
In the safety analysis, there were two dose-limiting toxicities in the lowest and highest dose groups, but none at dose level 2 (ibrutinib 560 mg and buparlisib 80 mg).
Grade 3 or greater adverse events occurred in 63% of patients. The most common events were hyperglycemia and rash in 19% each, and diarrhea, anorexia, and neurologic changes in 11% each,
The grade 3 neurologic changes included depression, agitation, mood swings, confusion and memory impairment, all of which resolved after buparlisib was withdrawn.
Dr. Batlevi showed scans of two patients with representative clinical responses in MCL. One 55-year-old man with blastoid MCL who had relapsed 18 months after frontline therapy with ofatumumab and bendamustine had near total clearance of lesions after two cycles of ibrutinib and buparlisib. He remains in CR after 12 months on the combination.
A second patient, a 77-year-old man with MCL that relapsed 10 years after R-CHOP and rituximab maintenance followed by autologous stem cell transplant, showed a complete response upon restaging after two cycles of ibrutinib/buparlisib.
The investigators are currently enrolling patients for phase IB expansions, with the goal of better estimating the safety and efficacy of the combination.
Memorial Sloan Kettering Cancer Center sponsored the study, with support from Janssen and Novartis. Dr. Batlevi reported no conflicts of interest.
AT 14-ICML
Key clinical point: The combination of ibrutinib and buparlisib showed efficacy against mantle cell lymphoma in a dose-escalation and safety study,
Major finding: The overall response rate to the combination among 11 patients with relapsed MCL was 100%.
Data source: Open label phase I/IB study of 25 patients with B-cell lymphomas.
Disclosures: Memorial Sloan Kettering Cancer Center sponsored the study, with support from Janssen and Novartis. Dr. Batlevi reported no conflicts of interest.
Pembrolizumab + rituximab boost response rates in relapsed follicular lymphoma
LUGANO, SWITZERLAND – A novel combination of the anti-programmed death 1 (PD-1) checkpoint inhibitor pembrolizumab (Keytruda) and the anti-CD20 monoclonal antibody rituximab was associated with a high overall response rate (ORR) in patients with relapsed follicular lymphoma in a phase II clinical trial.
Among 20 patients evaluable for efficacy, the overall response rate to the combination was 65%, including 50% complete responses (CR) reported Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“Follicular lymphoma is probably one of the best examples of targeting the immune system and also one of the earliest examples. Over the last few years we’ve learned a great deal about the different mechanisms of not only negative impact on infiltrating T cells, but also immune escape and T-cell exhaustion,” she said at the International Conference on Malignant Lymphoma.
Although biopsies of follicular lymphoma tumors have demonstrated infiltration of anti-tumor T cells, these cells are typically impeded by immune checkpoints, including PD-1 and its ligand (PD-L1).
The use of anti-PD-1 checkpoint inhibitors such as pembrolizumab has been shown to enhance the function of antitumor T cells in follicular lymphoma, and blocking PD-1 on natural killer cells enhances the antibody-dependent cell-mediated cytotoxicity of the natural killer cells, she said.
Because rituximab, a mainstay of therapy for non-Hodgkin lymphomas, induces antibody-dependent cell-mediated cytotoxicity, the investigators reasoned that combining it with pembrolizumab would simultaneously and synergistically stimulate activation of innate and adaptive immunity.
They designed a phase II, single-arm study in 30 patients with relapsed follicular lymphoma following one or more prior lines of therapy. The patients also had to have rituximab-sensitive disease, defined as a complete response (CR) or partial response lasting for at least 6 months following the most recent rituximab-containing therapy.
The patients were treated with rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1, and pembrolizumab 200 mg IV every 3 weeks for up to 16 cycles starting on day 2 of cycle 1.
The investigators expected that the combination would improve ORR, the primary endpoint, to at least 60%, compared with 40% for historical controls treated with repeat courses of rituximab.
At the data cutoff for the interim analysis, 32 patients had been enrolled, 30 were evaluable for safety, and 20 for efficacy after a median follow-up of 8.2 months.
Among the 20 patients (median age 64) in the efficacy analysis, 10 (50%) had a CR, and 3 (15%) had a partial response, for an ORR of 65%. Three additional patients had stable disease, and four had disease progression as best responses.
Among the patients with CRs, the duration of response ranged from nearly 275 days to more than 600 days.
“This does appear to be durable, and it is time dependent in terms of response. We did see early response, and we also saw deepening of response over time,” Dr. Nastoupil said.
Four patients were discontinued from the study because of immune-related adverse events. All four patients had achieved a CR at the time of study removal, and all four have ongoing CRs.
Among the 30 patients evaluable for safety, there were no grade 4 adverse events, no deaths, and few grade 3 events. Most events were grade 1 or 2, and included fatigue, eye pain/blurred vision/watery eye, nausea and vomiting, diarrhea dyspnea, rash, cough, and lymphopenia.
The investigators also looked at potential biomarkers for response, including PD-L1 expression in tumors prior to treatment. They found in samples from three patients who went on to achieve CRs that PD-L1 expression in tumor cells was low, ranging from 0% to 8%, suggesting that PD-L1 expression may not be necessary to generate a response with the combination.
They then looked at the association between CD8-positive T effector cells and responses in 12 patients, and found that patients with higher levels of expression had better ORR and CR rates.
“These interim results warrant further investigation of this combination in follicular lymphoma, and an expansion to include patients with refractory follicular lymphoma is planned,” Dr. Nastoupil concluded.
The Leukemia & Lymphoma Society supported the study. Dr Nastoupil has disclosed consulting fees from Celgene and contracted research for Abbvie, Janssen, and TG Therapeutics.
LUGANO, SWITZERLAND – A novel combination of the anti-programmed death 1 (PD-1) checkpoint inhibitor pembrolizumab (Keytruda) and the anti-CD20 monoclonal antibody rituximab was associated with a high overall response rate (ORR) in patients with relapsed follicular lymphoma in a phase II clinical trial.
Among 20 patients evaluable for efficacy, the overall response rate to the combination was 65%, including 50% complete responses (CR) reported Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“Follicular lymphoma is probably one of the best examples of targeting the immune system and also one of the earliest examples. Over the last few years we’ve learned a great deal about the different mechanisms of not only negative impact on infiltrating T cells, but also immune escape and T-cell exhaustion,” she said at the International Conference on Malignant Lymphoma.
Although biopsies of follicular lymphoma tumors have demonstrated infiltration of anti-tumor T cells, these cells are typically impeded by immune checkpoints, including PD-1 and its ligand (PD-L1).
The use of anti-PD-1 checkpoint inhibitors such as pembrolizumab has been shown to enhance the function of antitumor T cells in follicular lymphoma, and blocking PD-1 on natural killer cells enhances the antibody-dependent cell-mediated cytotoxicity of the natural killer cells, she said.
Because rituximab, a mainstay of therapy for non-Hodgkin lymphomas, induces antibody-dependent cell-mediated cytotoxicity, the investigators reasoned that combining it with pembrolizumab would simultaneously and synergistically stimulate activation of innate and adaptive immunity.
They designed a phase II, single-arm study in 30 patients with relapsed follicular lymphoma following one or more prior lines of therapy. The patients also had to have rituximab-sensitive disease, defined as a complete response (CR) or partial response lasting for at least 6 months following the most recent rituximab-containing therapy.
The patients were treated with rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1, and pembrolizumab 200 mg IV every 3 weeks for up to 16 cycles starting on day 2 of cycle 1.
The investigators expected that the combination would improve ORR, the primary endpoint, to at least 60%, compared with 40% for historical controls treated with repeat courses of rituximab.
At the data cutoff for the interim analysis, 32 patients had been enrolled, 30 were evaluable for safety, and 20 for efficacy after a median follow-up of 8.2 months.
Among the 20 patients (median age 64) in the efficacy analysis, 10 (50%) had a CR, and 3 (15%) had a partial response, for an ORR of 65%. Three additional patients had stable disease, and four had disease progression as best responses.
Among the patients with CRs, the duration of response ranged from nearly 275 days to more than 600 days.
“This does appear to be durable, and it is time dependent in terms of response. We did see early response, and we also saw deepening of response over time,” Dr. Nastoupil said.
Four patients were discontinued from the study because of immune-related adverse events. All four patients had achieved a CR at the time of study removal, and all four have ongoing CRs.
Among the 30 patients evaluable for safety, there were no grade 4 adverse events, no deaths, and few grade 3 events. Most events were grade 1 or 2, and included fatigue, eye pain/blurred vision/watery eye, nausea and vomiting, diarrhea dyspnea, rash, cough, and lymphopenia.
The investigators also looked at potential biomarkers for response, including PD-L1 expression in tumors prior to treatment. They found in samples from three patients who went on to achieve CRs that PD-L1 expression in tumor cells was low, ranging from 0% to 8%, suggesting that PD-L1 expression may not be necessary to generate a response with the combination.
They then looked at the association between CD8-positive T effector cells and responses in 12 patients, and found that patients with higher levels of expression had better ORR and CR rates.
“These interim results warrant further investigation of this combination in follicular lymphoma, and an expansion to include patients with refractory follicular lymphoma is planned,” Dr. Nastoupil concluded.
The Leukemia & Lymphoma Society supported the study. Dr Nastoupil has disclosed consulting fees from Celgene and contracted research for Abbvie, Janssen, and TG Therapeutics.
LUGANO, SWITZERLAND – A novel combination of the anti-programmed death 1 (PD-1) checkpoint inhibitor pembrolizumab (Keytruda) and the anti-CD20 monoclonal antibody rituximab was associated with a high overall response rate (ORR) in patients with relapsed follicular lymphoma in a phase II clinical trial.
Among 20 patients evaluable for efficacy, the overall response rate to the combination was 65%, including 50% complete responses (CR) reported Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“Follicular lymphoma is probably one of the best examples of targeting the immune system and also one of the earliest examples. Over the last few years we’ve learned a great deal about the different mechanisms of not only negative impact on infiltrating T cells, but also immune escape and T-cell exhaustion,” she said at the International Conference on Malignant Lymphoma.
Although biopsies of follicular lymphoma tumors have demonstrated infiltration of anti-tumor T cells, these cells are typically impeded by immune checkpoints, including PD-1 and its ligand (PD-L1).
The use of anti-PD-1 checkpoint inhibitors such as pembrolizumab has been shown to enhance the function of antitumor T cells in follicular lymphoma, and blocking PD-1 on natural killer cells enhances the antibody-dependent cell-mediated cytotoxicity of the natural killer cells, she said.
Because rituximab, a mainstay of therapy for non-Hodgkin lymphomas, induces antibody-dependent cell-mediated cytotoxicity, the investigators reasoned that combining it with pembrolizumab would simultaneously and synergistically stimulate activation of innate and adaptive immunity.
They designed a phase II, single-arm study in 30 patients with relapsed follicular lymphoma following one or more prior lines of therapy. The patients also had to have rituximab-sensitive disease, defined as a complete response (CR) or partial response lasting for at least 6 months following the most recent rituximab-containing therapy.
The patients were treated with rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1, and pembrolizumab 200 mg IV every 3 weeks for up to 16 cycles starting on day 2 of cycle 1.
The investigators expected that the combination would improve ORR, the primary endpoint, to at least 60%, compared with 40% for historical controls treated with repeat courses of rituximab.
At the data cutoff for the interim analysis, 32 patients had been enrolled, 30 were evaluable for safety, and 20 for efficacy after a median follow-up of 8.2 months.
Among the 20 patients (median age 64) in the efficacy analysis, 10 (50%) had a CR, and 3 (15%) had a partial response, for an ORR of 65%. Three additional patients had stable disease, and four had disease progression as best responses.
Among the patients with CRs, the duration of response ranged from nearly 275 days to more than 600 days.
“This does appear to be durable, and it is time dependent in terms of response. We did see early response, and we also saw deepening of response over time,” Dr. Nastoupil said.
Four patients were discontinued from the study because of immune-related adverse events. All four patients had achieved a CR at the time of study removal, and all four have ongoing CRs.
Among the 30 patients evaluable for safety, there were no grade 4 adverse events, no deaths, and few grade 3 events. Most events were grade 1 or 2, and included fatigue, eye pain/blurred vision/watery eye, nausea and vomiting, diarrhea dyspnea, rash, cough, and lymphopenia.
The investigators also looked at potential biomarkers for response, including PD-L1 expression in tumors prior to treatment. They found in samples from three patients who went on to achieve CRs that PD-L1 expression in tumor cells was low, ranging from 0% to 8%, suggesting that PD-L1 expression may not be necessary to generate a response with the combination.
They then looked at the association between CD8-positive T effector cells and responses in 12 patients, and found that patients with higher levels of expression had better ORR and CR rates.
“These interim results warrant further investigation of this combination in follicular lymphoma, and an expansion to include patients with refractory follicular lymphoma is planned,” Dr. Nastoupil concluded.
The Leukemia & Lymphoma Society supported the study. Dr Nastoupil has disclosed consulting fees from Celgene and contracted research for Abbvie, Janssen, and TG Therapeutics.
AT 14-ICML
Key clinical point: The combination of pembrolizumab and rituximab increased responses compared with repeat rituximab in patients with relapsed follicular lymphoma.
Major finding: The overall response rate with the combination was 65%, including 50% complete responses.
Data source: Open-label, phase II, single-arm study in 32 patients with relapsed follicular lymphoma (20 for efficacy, 30 for safety analysis).
Disclosures: The Leukemia & Lymphoma Society supported the study. Dr Nastoupil has disclosed consulting fees from Celgene and contracted research for Abbvie, Janssen, and TG Therapeutics.