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Pembrolizumab takes on r/r PMBCL
LUGANO, SWITZERLAND – Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL) have few good therapeutic options, but pembrolizumab (Keytruda) may be one of them, an interim analysis from a phase 2 trial suggests.
Six of 10 patients with relapsed/refractory PMBCL for whom autologous stem cell transplantation (ASCT) had failed had responses to salvage therapy with pembrolizumab, including three complete responses (CR) and three partial responses (PR), reported Pier Luigi Zinzani, MD, PhD, of the University of Bologna, Italy.
“In relapsed/refractory primary mediastinal large B-cell lymphoma including heavily pretreated patients in our series, pembrolizumab showed promising antitumor activity in these preliminary data from a phase 2 study, and a manageable safety profile,” Dr. Zinzani said at the International Conference on Malignant Lymphoma.
Although standard cytotoxic chemotherapy regimens are curative in approximately 80% of patients with PMBCL, those with relapsed/refractory disease have a poor prognosis and limited treatment options. In the United States, about 200 patients are diagnosed with relapsed/refractory PMBCL each year, Dr. Zinzani noted.
The rationale for using a programmed death-1 (PD-1) inhibitor such as pembrolizumab is that PMBCL tumors frequently harbor amplifications and/or translocations in the 9p24.1 locus that lead to overexpression of PD ligand 1 (PD-L1) or PD-L2. Pembrolizumab blocks interactions between PD-1 and its ligands.
In the Keynote-013 PMBCL cohort, the objective response rate (ORR) was 48%, including 24% CR.
Keynote 170 investigators are enrolling adults with relapsed/refractory PMBCL who are either ineligible for ASCT following at least two prior lines of therapy, or who had a relapse following a transplant.
Patients receive pembrolizumab 200 mg every 3 weeks. Those who achieve a complete response are allowed to discontinue after a minimum of 24 weeks on study, those with partial response or stable disease are treated for 35 cycles or until disease progression or intolerable toxicities, and those with disease progression are discontinued, but are allowed to remain on study until progression is confirmed.
Responses are assessed by PET and CT scans according to 2007 International Working Group criteria.
Among the 29 patients assessable for efficacy at the time of Dr. Zinzani’s presentations, the best response by blinded central review was 41% (12 patients: 4 CR and 8 PR). Three patients had stable disease, and eight had disease progression. Six patients died or discontinued participation prior to the first assessment.
In all, 16 of 22 patients had reductions in target lesions, and all but one of these patients had reductions greater than 50%.
After a median follow-up of 6.6 months, 10 patients had ongoing responses. The median time to response was 2.9 months. The median duration of response has not been reached.
Of the 10 patients for whom ASCT had failed, three had a CR, and three had a PR. Among 19 ASCT-ineligible patients, one had a CR and five had a PR.
The interim safety analysis included 49 patients. Of this group, only one discontinued treatment because of adverse events. There were 26 treatment-related adverse events, but no treatment-related deaths.
The most frequent adverse events were neutropenia, asthenia, hypothyroidism, and pyrexia.
The study is supported by Merck. Dr Zinzani disclosed serving on advisory boards for several companies.
LUGANO, SWITZERLAND – Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL) have few good therapeutic options, but pembrolizumab (Keytruda) may be one of them, an interim analysis from a phase 2 trial suggests.
Six of 10 patients with relapsed/refractory PMBCL for whom autologous stem cell transplantation (ASCT) had failed had responses to salvage therapy with pembrolizumab, including three complete responses (CR) and three partial responses (PR), reported Pier Luigi Zinzani, MD, PhD, of the University of Bologna, Italy.
“In relapsed/refractory primary mediastinal large B-cell lymphoma including heavily pretreated patients in our series, pembrolizumab showed promising antitumor activity in these preliminary data from a phase 2 study, and a manageable safety profile,” Dr. Zinzani said at the International Conference on Malignant Lymphoma.
Although standard cytotoxic chemotherapy regimens are curative in approximately 80% of patients with PMBCL, those with relapsed/refractory disease have a poor prognosis and limited treatment options. In the United States, about 200 patients are diagnosed with relapsed/refractory PMBCL each year, Dr. Zinzani noted.
The rationale for using a programmed death-1 (PD-1) inhibitor such as pembrolizumab is that PMBCL tumors frequently harbor amplifications and/or translocations in the 9p24.1 locus that lead to overexpression of PD ligand 1 (PD-L1) or PD-L2. Pembrolizumab blocks interactions between PD-1 and its ligands.
In the Keynote-013 PMBCL cohort, the objective response rate (ORR) was 48%, including 24% CR.
Keynote 170 investigators are enrolling adults with relapsed/refractory PMBCL who are either ineligible for ASCT following at least two prior lines of therapy, or who had a relapse following a transplant.
Patients receive pembrolizumab 200 mg every 3 weeks. Those who achieve a complete response are allowed to discontinue after a minimum of 24 weeks on study, those with partial response or stable disease are treated for 35 cycles or until disease progression or intolerable toxicities, and those with disease progression are discontinued, but are allowed to remain on study until progression is confirmed.
Responses are assessed by PET and CT scans according to 2007 International Working Group criteria.
Among the 29 patients assessable for efficacy at the time of Dr. Zinzani’s presentations, the best response by blinded central review was 41% (12 patients: 4 CR and 8 PR). Three patients had stable disease, and eight had disease progression. Six patients died or discontinued participation prior to the first assessment.
In all, 16 of 22 patients had reductions in target lesions, and all but one of these patients had reductions greater than 50%.
After a median follow-up of 6.6 months, 10 patients had ongoing responses. The median time to response was 2.9 months. The median duration of response has not been reached.
Of the 10 patients for whom ASCT had failed, three had a CR, and three had a PR. Among 19 ASCT-ineligible patients, one had a CR and five had a PR.
The interim safety analysis included 49 patients. Of this group, only one discontinued treatment because of adverse events. There were 26 treatment-related adverse events, but no treatment-related deaths.
The most frequent adverse events were neutropenia, asthenia, hypothyroidism, and pyrexia.
The study is supported by Merck. Dr Zinzani disclosed serving on advisory boards for several companies.
LUGANO, SWITZERLAND – Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL) have few good therapeutic options, but pembrolizumab (Keytruda) may be one of them, an interim analysis from a phase 2 trial suggests.
Six of 10 patients with relapsed/refractory PMBCL for whom autologous stem cell transplantation (ASCT) had failed had responses to salvage therapy with pembrolizumab, including three complete responses (CR) and three partial responses (PR), reported Pier Luigi Zinzani, MD, PhD, of the University of Bologna, Italy.
“In relapsed/refractory primary mediastinal large B-cell lymphoma including heavily pretreated patients in our series, pembrolizumab showed promising antitumor activity in these preliminary data from a phase 2 study, and a manageable safety profile,” Dr. Zinzani said at the International Conference on Malignant Lymphoma.
Although standard cytotoxic chemotherapy regimens are curative in approximately 80% of patients with PMBCL, those with relapsed/refractory disease have a poor prognosis and limited treatment options. In the United States, about 200 patients are diagnosed with relapsed/refractory PMBCL each year, Dr. Zinzani noted.
The rationale for using a programmed death-1 (PD-1) inhibitor such as pembrolizumab is that PMBCL tumors frequently harbor amplifications and/or translocations in the 9p24.1 locus that lead to overexpression of PD ligand 1 (PD-L1) or PD-L2. Pembrolizumab blocks interactions between PD-1 and its ligands.
In the Keynote-013 PMBCL cohort, the objective response rate (ORR) was 48%, including 24% CR.
Keynote 170 investigators are enrolling adults with relapsed/refractory PMBCL who are either ineligible for ASCT following at least two prior lines of therapy, or who had a relapse following a transplant.
Patients receive pembrolizumab 200 mg every 3 weeks. Those who achieve a complete response are allowed to discontinue after a minimum of 24 weeks on study, those with partial response or stable disease are treated for 35 cycles or until disease progression or intolerable toxicities, and those with disease progression are discontinued, but are allowed to remain on study until progression is confirmed.
Responses are assessed by PET and CT scans according to 2007 International Working Group criteria.
Among the 29 patients assessable for efficacy at the time of Dr. Zinzani’s presentations, the best response by blinded central review was 41% (12 patients: 4 CR and 8 PR). Three patients had stable disease, and eight had disease progression. Six patients died or discontinued participation prior to the first assessment.
In all, 16 of 22 patients had reductions in target lesions, and all but one of these patients had reductions greater than 50%.
After a median follow-up of 6.6 months, 10 patients had ongoing responses. The median time to response was 2.9 months. The median duration of response has not been reached.
Of the 10 patients for whom ASCT had failed, three had a CR, and three had a PR. Among 19 ASCT-ineligible patients, one had a CR and five had a PR.
The interim safety analysis included 49 patients. Of this group, only one discontinued treatment because of adverse events. There were 26 treatment-related adverse events, but no treatment-related deaths.
The most frequent adverse events were neutropenia, asthenia, hypothyroidism, and pyrexia.
The study is supported by Merck. Dr Zinzani disclosed serving on advisory boards for several companies.
AT 14-ICML
Key clinical point: Poor-prognosis relapsed/refractory primary mediastinal large B-cell lymphoma may respond to PD-1 inhibition.
Major finding: The best response by blinded central review was 41% (12 patients: 4 complete and 8 partial responses).
Data source: Interim analysis from a phase 2 study with 29 patients evaluable for efficacy, 49 for safety.
Disclosures: Merck supports the study. Dr Zinzani disclosed serving on advisory boards for several companies.
Avelumab induces response in Hodgkin lymphoma after failed allo-SCT
LUGANO, SWITZERLAND – The immune checkpoint inhibitor avelumab showed efficacy against classical Hodgkin lymphoma among patients with disease progression following allogeneic stem cell transplants (allo-SCT), based on results of a phase 1 trial.
Two of eight patients with disease progression following an allogeneic transplant (allo-SCT) had complete responses (CR) to the programmed death ligand-1 (PD-L1) inhibitor avelumab (Bavencio), three had partial responses (PRs), and two had stable disease, reported Robert Chen, MD, of City of Hope Medical Center in Duarte, California.
“The overall response rate observed in the postallo population of 62.5% suggests that the PD-L1 blockade inhibitor may potentiate a graft-vs.-lymphoma response,” he said at the 14th International Conference on Malignant Lymphoma.
Amplification of the chromosome 9p24.1 locus is frequent in classical Hodgkin lymphoma, and the amplicon contains the genes encoding for PD-L1 and PD-L2, resulting in the over expression of both ligands, Dr. Chen said.
Both nivolumab (Opdivo) and pembrolizumab (Keytruda) are indicated for the treatment of relapsed/refractory classical Hodgkin lymphoma. Both agents block the interactions between PD-1 and both PD-L1 and PD-L2.
“However, it has not been established whether blockade of the PD-1/PD-L1 interaction is necessary and/or sufficient for the therapeutic effect observed in classical Hodgkin lymphoma,” he said.
Avelumab is an anti–PD-L1, immunoglobulin G1 monoclonal antibody that inhibits PD-1/PD-L1 interactions but leaves PD-1/PD-L2 interactions intact. This agent, which recently received FDA approval for the treatment of Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma, targets tumor cells rather than the T cells targeted by nivolumab and pembrolizumab.
In the phase 1b JAVELIN Hodgkin study, patients with histologically confirmed relapsed/refractory classical Hodgkin lymphoma who were ineligible for transplant or for whom allogeneic or autologous stem cell transplants had failed were enrolled and were assigned to one of five cohorts to receive avelumab in doses ranging from 70 mg intravenously to 10 mg/kg IV every 2 weeks (or every 3 weeks for the 500 mg dose cohort).
A total of 31 patients were randomized in the dose-finding phase of the study. The median patient age was 38 years, 24 patients were younger than 65, and 7 were 65 or older. Only 1 of the 31 patients had received a single prior line of therapy. Of those, 3 had received two prior therapies, 7 had been treated with three prior lines, and 20 had four or more prior lines of therapy. All patients had received brentuximab vedotin (Adcetris).
The median follow-up was 43.3 weeks. In all, nine patients were continuing on avelumab at the time of the data analysis. Because of disease progression, 10 patients discontinued therapy. Additionally, four discontinued because of adverse events, two chose to withdraw, one was removed from the study by the treating physicians, one did not receive treatment, and four others discontinued because of unspecified reasons.
The median treatment duration was 16.9 weeks. The mean number of cycles was 8.6.
The objective response rate was 42%, including five CRs and eight PRs. Three of the CRs were in patients treated at the 70 mg every 2 week dose, and two were in patients treated at the 500 mg every 3 week level.
In all, 23 patients experienced some degree of tumor shrinkage, and 13 had shrinkage greater than 50%.
In an analysis of best overall response among patients whose disease progressed following SCT, the investigators found that two of eight patients (25%) who had disease progression following allo-SCT had a complete response. Three of these patients had a PR, two had stable disease, and one was not eligible for response evaluation.
In contrast, there was only one objective response, a PR, among five patients who had relapses following autologous SCT.
Grade 3 or 4 treatment-related adverse events occurred in 37% of patients. There were no treatment-related deaths. The incidence of treatment-related adverse events was similar across the five dosing cohorts.
“Based on the observed efficacy and safety profiles and unmet need, this study has recently been amended to focus the expansion of patients who progressed post allo-SCT,” Dr. Chen said.
The study was sponsored by Pfizer in collaboration with Merck KGaA, Germany. Dr. Chen has consulted and served in a speakers’ bureau for Seattle Genetics, Millennium, and Genentech. He has also received research funding from Pharmacyclics, Seattle Genetics, Millennium, and Merck.
LUGANO, SWITZERLAND – The immune checkpoint inhibitor avelumab showed efficacy against classical Hodgkin lymphoma among patients with disease progression following allogeneic stem cell transplants (allo-SCT), based on results of a phase 1 trial.
Two of eight patients with disease progression following an allogeneic transplant (allo-SCT) had complete responses (CR) to the programmed death ligand-1 (PD-L1) inhibitor avelumab (Bavencio), three had partial responses (PRs), and two had stable disease, reported Robert Chen, MD, of City of Hope Medical Center in Duarte, California.
“The overall response rate observed in the postallo population of 62.5% suggests that the PD-L1 blockade inhibitor may potentiate a graft-vs.-lymphoma response,” he said at the 14th International Conference on Malignant Lymphoma.
Amplification of the chromosome 9p24.1 locus is frequent in classical Hodgkin lymphoma, and the amplicon contains the genes encoding for PD-L1 and PD-L2, resulting in the over expression of both ligands, Dr. Chen said.
Both nivolumab (Opdivo) and pembrolizumab (Keytruda) are indicated for the treatment of relapsed/refractory classical Hodgkin lymphoma. Both agents block the interactions between PD-1 and both PD-L1 and PD-L2.
“However, it has not been established whether blockade of the PD-1/PD-L1 interaction is necessary and/or sufficient for the therapeutic effect observed in classical Hodgkin lymphoma,” he said.
Avelumab is an anti–PD-L1, immunoglobulin G1 monoclonal antibody that inhibits PD-1/PD-L1 interactions but leaves PD-1/PD-L2 interactions intact. This agent, which recently received FDA approval for the treatment of Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma, targets tumor cells rather than the T cells targeted by nivolumab and pembrolizumab.
In the phase 1b JAVELIN Hodgkin study, patients with histologically confirmed relapsed/refractory classical Hodgkin lymphoma who were ineligible for transplant or for whom allogeneic or autologous stem cell transplants had failed were enrolled and were assigned to one of five cohorts to receive avelumab in doses ranging from 70 mg intravenously to 10 mg/kg IV every 2 weeks (or every 3 weeks for the 500 mg dose cohort).
A total of 31 patients were randomized in the dose-finding phase of the study. The median patient age was 38 years, 24 patients were younger than 65, and 7 were 65 or older. Only 1 of the 31 patients had received a single prior line of therapy. Of those, 3 had received two prior therapies, 7 had been treated with three prior lines, and 20 had four or more prior lines of therapy. All patients had received brentuximab vedotin (Adcetris).
The median follow-up was 43.3 weeks. In all, nine patients were continuing on avelumab at the time of the data analysis. Because of disease progression, 10 patients discontinued therapy. Additionally, four discontinued because of adverse events, two chose to withdraw, one was removed from the study by the treating physicians, one did not receive treatment, and four others discontinued because of unspecified reasons.
The median treatment duration was 16.9 weeks. The mean number of cycles was 8.6.
The objective response rate was 42%, including five CRs and eight PRs. Three of the CRs were in patients treated at the 70 mg every 2 week dose, and two were in patients treated at the 500 mg every 3 week level.
In all, 23 patients experienced some degree of tumor shrinkage, and 13 had shrinkage greater than 50%.
In an analysis of best overall response among patients whose disease progressed following SCT, the investigators found that two of eight patients (25%) who had disease progression following allo-SCT had a complete response. Three of these patients had a PR, two had stable disease, and one was not eligible for response evaluation.
In contrast, there was only one objective response, a PR, among five patients who had relapses following autologous SCT.
Grade 3 or 4 treatment-related adverse events occurred in 37% of patients. There were no treatment-related deaths. The incidence of treatment-related adverse events was similar across the five dosing cohorts.
“Based on the observed efficacy and safety profiles and unmet need, this study has recently been amended to focus the expansion of patients who progressed post allo-SCT,” Dr. Chen said.
The study was sponsored by Pfizer in collaboration with Merck KGaA, Germany. Dr. Chen has consulted and served in a speakers’ bureau for Seattle Genetics, Millennium, and Genentech. He has also received research funding from Pharmacyclics, Seattle Genetics, Millennium, and Merck.
LUGANO, SWITZERLAND – The immune checkpoint inhibitor avelumab showed efficacy against classical Hodgkin lymphoma among patients with disease progression following allogeneic stem cell transplants (allo-SCT), based on results of a phase 1 trial.
Two of eight patients with disease progression following an allogeneic transplant (allo-SCT) had complete responses (CR) to the programmed death ligand-1 (PD-L1) inhibitor avelumab (Bavencio), three had partial responses (PRs), and two had stable disease, reported Robert Chen, MD, of City of Hope Medical Center in Duarte, California.
“The overall response rate observed in the postallo population of 62.5% suggests that the PD-L1 blockade inhibitor may potentiate a graft-vs.-lymphoma response,” he said at the 14th International Conference on Malignant Lymphoma.
Amplification of the chromosome 9p24.1 locus is frequent in classical Hodgkin lymphoma, and the amplicon contains the genes encoding for PD-L1 and PD-L2, resulting in the over expression of both ligands, Dr. Chen said.
Both nivolumab (Opdivo) and pembrolizumab (Keytruda) are indicated for the treatment of relapsed/refractory classical Hodgkin lymphoma. Both agents block the interactions between PD-1 and both PD-L1 and PD-L2.
“However, it has not been established whether blockade of the PD-1/PD-L1 interaction is necessary and/or sufficient for the therapeutic effect observed in classical Hodgkin lymphoma,” he said.
Avelumab is an anti–PD-L1, immunoglobulin G1 monoclonal antibody that inhibits PD-1/PD-L1 interactions but leaves PD-1/PD-L2 interactions intact. This agent, which recently received FDA approval for the treatment of Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma, targets tumor cells rather than the T cells targeted by nivolumab and pembrolizumab.
In the phase 1b JAVELIN Hodgkin study, patients with histologically confirmed relapsed/refractory classical Hodgkin lymphoma who were ineligible for transplant or for whom allogeneic or autologous stem cell transplants had failed were enrolled and were assigned to one of five cohorts to receive avelumab in doses ranging from 70 mg intravenously to 10 mg/kg IV every 2 weeks (or every 3 weeks for the 500 mg dose cohort).
A total of 31 patients were randomized in the dose-finding phase of the study. The median patient age was 38 years, 24 patients were younger than 65, and 7 were 65 or older. Only 1 of the 31 patients had received a single prior line of therapy. Of those, 3 had received two prior therapies, 7 had been treated with three prior lines, and 20 had four or more prior lines of therapy. All patients had received brentuximab vedotin (Adcetris).
The median follow-up was 43.3 weeks. In all, nine patients were continuing on avelumab at the time of the data analysis. Because of disease progression, 10 patients discontinued therapy. Additionally, four discontinued because of adverse events, two chose to withdraw, one was removed from the study by the treating physicians, one did not receive treatment, and four others discontinued because of unspecified reasons.
The median treatment duration was 16.9 weeks. The mean number of cycles was 8.6.
The objective response rate was 42%, including five CRs and eight PRs. Three of the CRs were in patients treated at the 70 mg every 2 week dose, and two were in patients treated at the 500 mg every 3 week level.
In all, 23 patients experienced some degree of tumor shrinkage, and 13 had shrinkage greater than 50%.
In an analysis of best overall response among patients whose disease progressed following SCT, the investigators found that two of eight patients (25%) who had disease progression following allo-SCT had a complete response. Three of these patients had a PR, two had stable disease, and one was not eligible for response evaluation.
In contrast, there was only one objective response, a PR, among five patients who had relapses following autologous SCT.
Grade 3 or 4 treatment-related adverse events occurred in 37% of patients. There were no treatment-related deaths. The incidence of treatment-related adverse events was similar across the five dosing cohorts.
“Based on the observed efficacy and safety profiles and unmet need, this study has recently been amended to focus the expansion of patients who progressed post allo-SCT,” Dr. Chen said.
The study was sponsored by Pfizer in collaboration with Merck KGaA, Germany. Dr. Chen has consulted and served in a speakers’ bureau for Seattle Genetics, Millennium, and Genentech. He has also received research funding from Pharmacyclics, Seattle Genetics, Millennium, and Merck.
AT 14-ICML
Key clinical point: Avelumab showed efficacy in patients with classical Hodgkin lymphoma that relapsed following allogeneic stem cell transplant.
Major finding: The objective response rate among all patients in the study was 41.9%.
Data source: A phase 1 dose-finding and expansion study in 31 patients with relapsed/refractory classical Hodgkin lymphoma who were ineligible for SCT or experienced relapses following SCT.
Disclosures: The study was sponsored by Pfizer in collaboration with Merck KGaA, Germany. Dr. Chen has consulted and served in a speakers’ bureau for Seattle Genetics, Millennium, and Genentech. He has also received research funding from Pharmacyclics, Seattle Genetics, Millennium, and Merck.
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.
All FDA panel members go thumbs up for CTL019 in relapsed/refractory childhood ALL
The answer to the billion dollar question – Does the chimeric antigen receptor T-cell (CAR T) construct CTL019 (tisagenlecleucel-T) have a favorable risk-benefit profile for the treatment of children and young adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia? – was a unanimous “yes” at a July 12 meeting of the Food and Drug Administration’s Oncologic Drugs Advisory Committee.
“This is the most exciting thing I have seen in my lifetime, and probably since the introduction of ‘multiagent total cancer care,’ as it was called then, for treatment of childhood leukemia,” remarked Timothy P. Cripe, MD, PhD, from Nationwide Children’s Hospital in Columbus, Ohio, and a temporary voting member of the ODAC.
Catherine M. Bollard, MD, MBChB, from the Children’s National Medical Center in Washington, also a temporary ODAC member, said that she voted “yes” because “this is a very poor-risk patient population, this is an unmet need in the pediatric population, and as you saw in the data [presented to ODAC] today, the clinical responses are remarkable. I think Novartis [the maker of CTL019] has done a great job putting together a plan for mitigating risk going forward.”
CTL019 was shown in a pivotal phase 2 clinical trial to induce an overall remission rate of 83% in children and young adults with relapsed/refractory ALL for whom at least two prior lines of therapy had failed. Based on these results, the FDA accepted a biologics license application for the agent from Novartis.
At the meeting, panel members initially seemed favorably disposed toward recommending approval but heard concerns from FDA scientists about the potential for severe or fatal adverse events such as the cytokine release syndrome (CRS); the possible generation of replication competent retrovirus (RCR); and the potential for secondary malignancies from insertional mutagenesis, the incorporation of portions of the lentiviral vector into the patient’s genome.
In his opening remarks, Wilson W. Bryan, MD, from the FDA’s Office of Tissue and Advanced Therapies and Center for Biologics Evaluation and Drug Research, commented that “the clinical development of tisagenlecleucel suggests that this is a life-saving product.”
He went on, however, to frame the FDA’s concerns: “Clinical trials are not always a good predictor of the effectiveness and safety of a marketed product,” he said. “In particular, we are concerned that the same benefit and safety seen in clinical trials may not carry over to routine clinical use.”
The purpose of the hearing was to focus on manufacturing issues related to product quality, including replicability of the product for commercial use and safety issues such as prevention of CRS and neurotoxicities.
“We are also concerned about the hypothetical risk of secondary malignancies. Therefore, we are asking for the committee’s recommendations regarding the nature and duration of follow-up of patients who would receive this product,” Dr. Bryan said.
“CTL019 is a living drug, which demonstrates activity after a single infusion,” said Samit Hirawat, MD, head of oncology global development for Novartis.
But the nature of CTL019 as a living drug also means that it is subject to variations in the ability of autologous T cells harvested via leukapheresis to be infected with the lentiviral vector and expanded into a population of CAR T cells large enough to have therapeutic value, said Xiaobin Victor Lu, PhD, a chemistry, manufacturing, and controls reviewer for the FDA.
Mitigation plan
Novartis’ proposed plan includes specific, long-term steps for mitigating the risk of CRS and neurologic events, such as cerebral edema, the latter of which caused the FDA to call for a clinical hold of the phase 2 ROCKET trial for a different CAR T-cell construct.
Among the proposed elements of the mitigation plan are a 15-year minimum pharmacovigilance program and long-term safety follow-up for adverse events related to the therapy, efficacy, immunogenicity, transgene persistence of CD19 CAR, and the incidence of second malignancies possibly related to insertional mutagenesis.
Novartis also will train treatment center staff on processes for cell collection, cryopreservation, transport, chain of identity, safety management, and logistics for handling the CAR T-cell product. The company proposes to provide on-site training of personnel on CRS and neurotoxicity risk and management, as well as to offer information to patients and caregivers about the signs and symptoms of adverse events of concern.
Dr. Cripe expressed his concerns that Novartis’ proposal to initially limit the mitigation plan to 30 or 35 treatment sites would create problems of access and economic disparities among patients, and could cause inequities among treatment centers even with the same city.
David Lebwohl, MD, head of the CAR T global program for Novartis, said that the planned number of sites for the mitigation program would be expanded after 6 to 12 months if the CAR T construct receives final approval and clinical implementation goes well.
There was nearly unanimous agreement among the panel members that the planned 15-year follow-up and other mitigation measures would be adequate for detecting serious short- and long-term consequences of CAR T-cell therapy.
Patient/advocate perspective
In the public comment section of the proceedings, panel members were urged to vote in favor of CTL019 by parents of children with ALL, including Don McMahon, whose son Connor received the therapy after multiple relapses, and Tom Whitehead, father of Emily Whitehead, the first patient to receive CAR T cells for ALL.
Both children are alive and doing well.
CTL019 is produced by Novartis.
The unanimous recommendation by the Food and Drug Administration's Oncologic Drugs Advisory Committee means that the FDA is likely to approve CTL019 (tisagenlecleucel-T), and that approval may come quickly, possibly before the end of 2017. This approval was based on compelling data showing that 83% of children and young adults with refractory or relapsed acute lymphocytic leukemia (ALL) achieved remission with this therapy. This is exciting news for ALL patients as well as for the cell and gene therapy community. What remains to be determined are the labelling for CTL019, the cost of the therapy, and whether all patients who might benefit from this therapy will have the coverage to be able to access it.
While the response rates in patients treated in the trials presented to the FDA are very encouraging there are also concerns with the risks for cytokine release syndrome and neurotoxicity which can affect up to half of treated patients. As a result, Novartis, the manufacturer of CTL019, has proposed an extensive mitigation strategy and education process for the cell therapy centers that will offer the therapy. Initially, this is likely to be limited to around 30 centers that will be geographically distributed throughout the United States with gradual roll out to more centers as there is more experience with the use of CTL019.
Another issue for the centers is going to be operationalizing a new paradigm where CTL019 will be offered as a standard of care rather than in the context of a research study. Most of the initial pediatric centers will likely provide CTL019, within their transplant infrastructure since procurement, initial processing and infusion of cells will utilize their cell processing and collection facilities. The Foundation for Accreditation of Cell Therapy (FACT) has also anticipated this approval by publishing new standards for Immune Effectors earlier this year to promote quality practice in immune effector cell administration.
One other question is whether CTL019 will be transplant enabling or transplant replacing. While the initial response rates are very high and there are some well publicized patients who remain in remission over 5 years after CTL019 without other therapy, other responders proceeded to transplant and there is also a significant relapse rate. It is therefore an open question whether treating physicians will be happy to watch patients who attain remission after this therapy or whether they will still recommend transplant because there is not yet enough follow up on this product to know what the long-term cure rate is going to be.
Another CAR T-cell product is scheduled to come before an FDA advisory committee in October. The indication for KTE-C19 (axicabtagene ciloleucel) from Kite is for relapsed/refractory diffuse large B-cell lymphoma, a much bigger indication with a potentially much larger number of patients. The response rates for KTE-C19 in DLBCL (and indeed for CTL019 in DLBCL) are not as high as those for CTL019 in ALL and follow-up time is shorter, so it is not yet clear how many patients will have sustained long term responses. Nevertheless the response rate in patients who have failed all other therapies is high enough that this product will also likely be approved.
Helen Heslop, MD, is the Dan L. Duncan Chair and Professor of Medicine and Pediatrics at Baylor College of Medicine, Houston. She also is the Director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital. Dr. Heslop is a member of the editorial advisory board of Hematology News.
The unanimous recommendation by the Food and Drug Administration's Oncologic Drugs Advisory Committee means that the FDA is likely to approve CTL019 (tisagenlecleucel-T), and that approval may come quickly, possibly before the end of 2017. This approval was based on compelling data showing that 83% of children and young adults with refractory or relapsed acute lymphocytic leukemia (ALL) achieved remission with this therapy. This is exciting news for ALL patients as well as for the cell and gene therapy community. What remains to be determined are the labelling for CTL019, the cost of the therapy, and whether all patients who might benefit from this therapy will have the coverage to be able to access it.
While the response rates in patients treated in the trials presented to the FDA are very encouraging there are also concerns with the risks for cytokine release syndrome and neurotoxicity which can affect up to half of treated patients. As a result, Novartis, the manufacturer of CTL019, has proposed an extensive mitigation strategy and education process for the cell therapy centers that will offer the therapy. Initially, this is likely to be limited to around 30 centers that will be geographically distributed throughout the United States with gradual roll out to more centers as there is more experience with the use of CTL019.
Another issue for the centers is going to be operationalizing a new paradigm where CTL019 will be offered as a standard of care rather than in the context of a research study. Most of the initial pediatric centers will likely provide CTL019, within their transplant infrastructure since procurement, initial processing and infusion of cells will utilize their cell processing and collection facilities. The Foundation for Accreditation of Cell Therapy (FACT) has also anticipated this approval by publishing new standards for Immune Effectors earlier this year to promote quality practice in immune effector cell administration.
One other question is whether CTL019 will be transplant enabling or transplant replacing. While the initial response rates are very high and there are some well publicized patients who remain in remission over 5 years after CTL019 without other therapy, other responders proceeded to transplant and there is also a significant relapse rate. It is therefore an open question whether treating physicians will be happy to watch patients who attain remission after this therapy or whether they will still recommend transplant because there is not yet enough follow up on this product to know what the long-term cure rate is going to be.
Another CAR T-cell product is scheduled to come before an FDA advisory committee in October. The indication for KTE-C19 (axicabtagene ciloleucel) from Kite is for relapsed/refractory diffuse large B-cell lymphoma, a much bigger indication with a potentially much larger number of patients. The response rates for KTE-C19 in DLBCL (and indeed for CTL019 in DLBCL) are not as high as those for CTL019 in ALL and follow-up time is shorter, so it is not yet clear how many patients will have sustained long term responses. Nevertheless the response rate in patients who have failed all other therapies is high enough that this product will also likely be approved.
Helen Heslop, MD, is the Dan L. Duncan Chair and Professor of Medicine and Pediatrics at Baylor College of Medicine, Houston. She also is the Director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital. Dr. Heslop is a member of the editorial advisory board of Hematology News.
The unanimous recommendation by the Food and Drug Administration's Oncologic Drugs Advisory Committee means that the FDA is likely to approve CTL019 (tisagenlecleucel-T), and that approval may come quickly, possibly before the end of 2017. This approval was based on compelling data showing that 83% of children and young adults with refractory or relapsed acute lymphocytic leukemia (ALL) achieved remission with this therapy. This is exciting news for ALL patients as well as for the cell and gene therapy community. What remains to be determined are the labelling for CTL019, the cost of the therapy, and whether all patients who might benefit from this therapy will have the coverage to be able to access it.
While the response rates in patients treated in the trials presented to the FDA are very encouraging there are also concerns with the risks for cytokine release syndrome and neurotoxicity which can affect up to half of treated patients. As a result, Novartis, the manufacturer of CTL019, has proposed an extensive mitigation strategy and education process for the cell therapy centers that will offer the therapy. Initially, this is likely to be limited to around 30 centers that will be geographically distributed throughout the United States with gradual roll out to more centers as there is more experience with the use of CTL019.
Another issue for the centers is going to be operationalizing a new paradigm where CTL019 will be offered as a standard of care rather than in the context of a research study. Most of the initial pediatric centers will likely provide CTL019, within their transplant infrastructure since procurement, initial processing and infusion of cells will utilize their cell processing and collection facilities. The Foundation for Accreditation of Cell Therapy (FACT) has also anticipated this approval by publishing new standards for Immune Effectors earlier this year to promote quality practice in immune effector cell administration.
One other question is whether CTL019 will be transplant enabling or transplant replacing. While the initial response rates are very high and there are some well publicized patients who remain in remission over 5 years after CTL019 without other therapy, other responders proceeded to transplant and there is also a significant relapse rate. It is therefore an open question whether treating physicians will be happy to watch patients who attain remission after this therapy or whether they will still recommend transplant because there is not yet enough follow up on this product to know what the long-term cure rate is going to be.
Another CAR T-cell product is scheduled to come before an FDA advisory committee in October. The indication for KTE-C19 (axicabtagene ciloleucel) from Kite is for relapsed/refractory diffuse large B-cell lymphoma, a much bigger indication with a potentially much larger number of patients. The response rates for KTE-C19 in DLBCL (and indeed for CTL019 in DLBCL) are not as high as those for CTL019 in ALL and follow-up time is shorter, so it is not yet clear how many patients will have sustained long term responses. Nevertheless the response rate in patients who have failed all other therapies is high enough that this product will also likely be approved.
Helen Heslop, MD, is the Dan L. Duncan Chair and Professor of Medicine and Pediatrics at Baylor College of Medicine, Houston. She also is the Director of the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital. Dr. Heslop is a member of the editorial advisory board of Hematology News.
The answer to the billion dollar question – Does the chimeric antigen receptor T-cell (CAR T) construct CTL019 (tisagenlecleucel-T) have a favorable risk-benefit profile for the treatment of children and young adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia? – was a unanimous “yes” at a July 12 meeting of the Food and Drug Administration’s Oncologic Drugs Advisory Committee.
“This is the most exciting thing I have seen in my lifetime, and probably since the introduction of ‘multiagent total cancer care,’ as it was called then, for treatment of childhood leukemia,” remarked Timothy P. Cripe, MD, PhD, from Nationwide Children’s Hospital in Columbus, Ohio, and a temporary voting member of the ODAC.
Catherine M. Bollard, MD, MBChB, from the Children’s National Medical Center in Washington, also a temporary ODAC member, said that she voted “yes” because “this is a very poor-risk patient population, this is an unmet need in the pediatric population, and as you saw in the data [presented to ODAC] today, the clinical responses are remarkable. I think Novartis [the maker of CTL019] has done a great job putting together a plan for mitigating risk going forward.”
CTL019 was shown in a pivotal phase 2 clinical trial to induce an overall remission rate of 83% in children and young adults with relapsed/refractory ALL for whom at least two prior lines of therapy had failed. Based on these results, the FDA accepted a biologics license application for the agent from Novartis.
At the meeting, panel members initially seemed favorably disposed toward recommending approval but heard concerns from FDA scientists about the potential for severe or fatal adverse events such as the cytokine release syndrome (CRS); the possible generation of replication competent retrovirus (RCR); and the potential for secondary malignancies from insertional mutagenesis, the incorporation of portions of the lentiviral vector into the patient’s genome.
In his opening remarks, Wilson W. Bryan, MD, from the FDA’s Office of Tissue and Advanced Therapies and Center for Biologics Evaluation and Drug Research, commented that “the clinical development of tisagenlecleucel suggests that this is a life-saving product.”
He went on, however, to frame the FDA’s concerns: “Clinical trials are not always a good predictor of the effectiveness and safety of a marketed product,” he said. “In particular, we are concerned that the same benefit and safety seen in clinical trials may not carry over to routine clinical use.”
The purpose of the hearing was to focus on manufacturing issues related to product quality, including replicability of the product for commercial use and safety issues such as prevention of CRS and neurotoxicities.
“We are also concerned about the hypothetical risk of secondary malignancies. Therefore, we are asking for the committee’s recommendations regarding the nature and duration of follow-up of patients who would receive this product,” Dr. Bryan said.
“CTL019 is a living drug, which demonstrates activity after a single infusion,” said Samit Hirawat, MD, head of oncology global development for Novartis.
But the nature of CTL019 as a living drug also means that it is subject to variations in the ability of autologous T cells harvested via leukapheresis to be infected with the lentiviral vector and expanded into a population of CAR T cells large enough to have therapeutic value, said Xiaobin Victor Lu, PhD, a chemistry, manufacturing, and controls reviewer for the FDA.
Mitigation plan
Novartis’ proposed plan includes specific, long-term steps for mitigating the risk of CRS and neurologic events, such as cerebral edema, the latter of which caused the FDA to call for a clinical hold of the phase 2 ROCKET trial for a different CAR T-cell construct.
Among the proposed elements of the mitigation plan are a 15-year minimum pharmacovigilance program and long-term safety follow-up for adverse events related to the therapy, efficacy, immunogenicity, transgene persistence of CD19 CAR, and the incidence of second malignancies possibly related to insertional mutagenesis.
Novartis also will train treatment center staff on processes for cell collection, cryopreservation, transport, chain of identity, safety management, and logistics for handling the CAR T-cell product. The company proposes to provide on-site training of personnel on CRS and neurotoxicity risk and management, as well as to offer information to patients and caregivers about the signs and symptoms of adverse events of concern.
Dr. Cripe expressed his concerns that Novartis’ proposal to initially limit the mitigation plan to 30 or 35 treatment sites would create problems of access and economic disparities among patients, and could cause inequities among treatment centers even with the same city.
David Lebwohl, MD, head of the CAR T global program for Novartis, said that the planned number of sites for the mitigation program would be expanded after 6 to 12 months if the CAR T construct receives final approval and clinical implementation goes well.
There was nearly unanimous agreement among the panel members that the planned 15-year follow-up and other mitigation measures would be adequate for detecting serious short- and long-term consequences of CAR T-cell therapy.
Patient/advocate perspective
In the public comment section of the proceedings, panel members were urged to vote in favor of CTL019 by parents of children with ALL, including Don McMahon, whose son Connor received the therapy after multiple relapses, and Tom Whitehead, father of Emily Whitehead, the first patient to receive CAR T cells for ALL.
Both children are alive and doing well.
CTL019 is produced by Novartis.
The answer to the billion dollar question – Does the chimeric antigen receptor T-cell (CAR T) construct CTL019 (tisagenlecleucel-T) have a favorable risk-benefit profile for the treatment of children and young adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia? – was a unanimous “yes” at a July 12 meeting of the Food and Drug Administration’s Oncologic Drugs Advisory Committee.
“This is the most exciting thing I have seen in my lifetime, and probably since the introduction of ‘multiagent total cancer care,’ as it was called then, for treatment of childhood leukemia,” remarked Timothy P. Cripe, MD, PhD, from Nationwide Children’s Hospital in Columbus, Ohio, and a temporary voting member of the ODAC.
Catherine M. Bollard, MD, MBChB, from the Children’s National Medical Center in Washington, also a temporary ODAC member, said that she voted “yes” because “this is a very poor-risk patient population, this is an unmet need in the pediatric population, and as you saw in the data [presented to ODAC] today, the clinical responses are remarkable. I think Novartis [the maker of CTL019] has done a great job putting together a plan for mitigating risk going forward.”
CTL019 was shown in a pivotal phase 2 clinical trial to induce an overall remission rate of 83% in children and young adults with relapsed/refractory ALL for whom at least two prior lines of therapy had failed. Based on these results, the FDA accepted a biologics license application for the agent from Novartis.
At the meeting, panel members initially seemed favorably disposed toward recommending approval but heard concerns from FDA scientists about the potential for severe or fatal adverse events such as the cytokine release syndrome (CRS); the possible generation of replication competent retrovirus (RCR); and the potential for secondary malignancies from insertional mutagenesis, the incorporation of portions of the lentiviral vector into the patient’s genome.
In his opening remarks, Wilson W. Bryan, MD, from the FDA’s Office of Tissue and Advanced Therapies and Center for Biologics Evaluation and Drug Research, commented that “the clinical development of tisagenlecleucel suggests that this is a life-saving product.”
He went on, however, to frame the FDA’s concerns: “Clinical trials are not always a good predictor of the effectiveness and safety of a marketed product,” he said. “In particular, we are concerned that the same benefit and safety seen in clinical trials may not carry over to routine clinical use.”
The purpose of the hearing was to focus on manufacturing issues related to product quality, including replicability of the product for commercial use and safety issues such as prevention of CRS and neurotoxicities.
“We are also concerned about the hypothetical risk of secondary malignancies. Therefore, we are asking for the committee’s recommendations regarding the nature and duration of follow-up of patients who would receive this product,” Dr. Bryan said.
“CTL019 is a living drug, which demonstrates activity after a single infusion,” said Samit Hirawat, MD, head of oncology global development for Novartis.
But the nature of CTL019 as a living drug also means that it is subject to variations in the ability of autologous T cells harvested via leukapheresis to be infected with the lentiviral vector and expanded into a population of CAR T cells large enough to have therapeutic value, said Xiaobin Victor Lu, PhD, a chemistry, manufacturing, and controls reviewer for the FDA.
Mitigation plan
Novartis’ proposed plan includes specific, long-term steps for mitigating the risk of CRS and neurologic events, such as cerebral edema, the latter of which caused the FDA to call for a clinical hold of the phase 2 ROCKET trial for a different CAR T-cell construct.
Among the proposed elements of the mitigation plan are a 15-year minimum pharmacovigilance program and long-term safety follow-up for adverse events related to the therapy, efficacy, immunogenicity, transgene persistence of CD19 CAR, and the incidence of second malignancies possibly related to insertional mutagenesis.
Novartis also will train treatment center staff on processes for cell collection, cryopreservation, transport, chain of identity, safety management, and logistics for handling the CAR T-cell product. The company proposes to provide on-site training of personnel on CRS and neurotoxicity risk and management, as well as to offer information to patients and caregivers about the signs and symptoms of adverse events of concern.
Dr. Cripe expressed his concerns that Novartis’ proposal to initially limit the mitigation plan to 30 or 35 treatment sites would create problems of access and economic disparities among patients, and could cause inequities among treatment centers even with the same city.
David Lebwohl, MD, head of the CAR T global program for Novartis, said that the planned number of sites for the mitigation program would be expanded after 6 to 12 months if the CAR T construct receives final approval and clinical implementation goes well.
There was nearly unanimous agreement among the panel members that the planned 15-year follow-up and other mitigation measures would be adequate for detecting serious short- and long-term consequences of CAR T-cell therapy.
Patient/advocate perspective
In the public comment section of the proceedings, panel members were urged to vote in favor of CTL019 by parents of children with ALL, including Don McMahon, whose son Connor received the therapy after multiple relapses, and Tom Whitehead, father of Emily Whitehead, the first patient to receive CAR T cells for ALL.
Both children are alive and doing well.
CTL019 is produced by Novartis.
VIDEO: Immune therapy effective, durable in treatment-naive melanoma brain metastases
CHICAGO – Immune therapy shows promise for use in the treatment of melanoma brain metastases, especially for treatment-naive patients, judging from the findings of a new phase II randomized study.
For patients with asymptomatic brain metastases from melanoma who had not had prior treatment, nivolumab combined with ipilimumab produced a 50% intracranial response rate after at least 12 weeks of therapy. When nivolumab alone was given to untreated patients, the intracranial response rate was 21%, Georgina Long MD, PhD, co–medical director of the Melanoma Institute Australia , said during a video interview at the annual meeting of the American Society of Clinical Oncology.
“If you look at progression-free survival by response, none of our complete responders have progressed,” said Dr. Long. “And this is with a median follow-up of 16.4 months.” The partial responders have also done well, with little progression, she said. “Remember, these patients usually survive only a few weeks.”
The Anti-PD1 Brain Collaboration study, a phase II clinical trial, enrolled patients with melanoma brain metastases at least 5 mm but less than 40 mm in diameter who had not received previous anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), anti-programmed cell death protein 1 (anti-PD-1), or anti-programmed death-ligand 1 (anti-PD-L1) therapies. Patients were permitted to have had previous BRAF and MEK inhibitor therapies. Asymptomatic patients who had no previous local brain therapy (i.e., radiation treatment or surgery) were randomized 1:1 to receive nivolumab alone, or nivolumab plus ipilimumab.
The nivolumab arm received 3 mg/kg by intravenous infusion every 2 weeks. The combination arm began with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks for four doses. After this, they also received nivolumab 3 mg/kg monotherapy every 2 weeks.
The third cohort – a small group of 15 patients who received nivolumab alone – either had symptomatic brain metastases or leptomeningeal disease and could have had previous brain surgery or radiotherapy. Unlike the first two cohorts, they were also permitted to be on up to 10 mg/day of prednisone; these patients received nivolumab alone at 3 mg/kg every 2 weeks.
For all patients, immune therapy was given until the disease progressed, consent was withdrawn, or patients experienced unacceptable toxicity or they died.
“We were most interested in the randomized cohorts,” said Dr. Long. Interestingly, she said, ipilimumab became available in Australia when 27 patients were enrolled in the nivolumab arm and 26 to the combination arm. “So we stopped the monotherapy arm, and the rest of the 60 patients to be recruited all went into the combination arm,” she said. A total of 76 patients were recruited, 33 into the combination arm, 27 to the asymptomatic nivolumab monotherapy arm, and 16 to the symptomatic and/or previously treated arm.
Data analysis from the point of the data cut included 67 patients who were followed for a period ranging from 5 to 34 months. Intracranial disease was evaluated by gadolinium-enhanced MRI and modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
“The results of the trial were very interesting,” said Dr. Long. The nivolumab plus ipilimumab combo resulted in an overall 42% intracranial response rate, while nivolumab alone produced an overall intracranial response rate of 21%. However, patients in either arm who had prior BRAF or MEK inhibitor exposure “didn’t do too well on immunotherapy,” said Dr. Long, noting that the response rate was just 16% for these patients. These were, she said, “small numbers, but still, an interesting signal there.”
When comparing the secondary endpoint of extracranial response to intracranial response on a per-patient basis, Dr. Long and her collaborators could see that “the intracranial and extracranial results were mostly concordant.”
Analysis of the additional secondary endpoints of progression-free survival (PFS) and overall survival (OS) also showed an interesting pattern, said Dr. Long. After an initial drop-off period of about 5 months, the curves for patients in all arms have stabilized, so that patients who were responders are maintaining that response. The overall 6-month PFS rate for the combination cohort was 47%, with a durable response: “If you look at the curve, it’s flattened out since that stage, and we haven’t had any progression since that time,” said Dr. Long. The PFS rate was 29% for the cohort receiving nivolumab alone. “Activity is highest when nivolumab and ipilimumab are given upfront,” said Dr. Long.
For asymptomatic patients pretreated with BRAF or MEK inhibitors, “activity is low,” said Dr. Long, with an intracranial response rate of 16% in both cohorts.
Symptomatic patients who were more heavily pretreated fared even worse: “The activity of nivolumab monotherapy is low after multiple modality therapy or in leptomeningeal melanoma,” said Dr. Long. The intracranial response rate in the third cohort was just 6%.
The combination therapy cohort had the most treatment-related adverse events, with 96% of patients experiencing some adverse event. About half (12/26, 46%) had grade 3 or 4 events, and the same number had a serious adverse event. Seven patients (27%) discontinued therapy because of treatment-related adverse events in the combination study arm. However, said Dr. Long, this side effect profile is in keeping with what has been seen in other studies of combination therapy with nivolumab and ipilimumab. “There were not unexpected adverse events,” she said.
Dr. Long reported relationships with Bristol-Myers Squibb, Merck, and Roche.
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CHICAGO – Immune therapy shows promise for use in the treatment of melanoma brain metastases, especially for treatment-naive patients, judging from the findings of a new phase II randomized study.
For patients with asymptomatic brain metastases from melanoma who had not had prior treatment, nivolumab combined with ipilimumab produced a 50% intracranial response rate after at least 12 weeks of therapy. When nivolumab alone was given to untreated patients, the intracranial response rate was 21%, Georgina Long MD, PhD, co–medical director of the Melanoma Institute Australia , said during a video interview at the annual meeting of the American Society of Clinical Oncology.
“If you look at progression-free survival by response, none of our complete responders have progressed,” said Dr. Long. “And this is with a median follow-up of 16.4 months.” The partial responders have also done well, with little progression, she said. “Remember, these patients usually survive only a few weeks.”
The Anti-PD1 Brain Collaboration study, a phase II clinical trial, enrolled patients with melanoma brain metastases at least 5 mm but less than 40 mm in diameter who had not received previous anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), anti-programmed cell death protein 1 (anti-PD-1), or anti-programmed death-ligand 1 (anti-PD-L1) therapies. Patients were permitted to have had previous BRAF and MEK inhibitor therapies. Asymptomatic patients who had no previous local brain therapy (i.e., radiation treatment or surgery) were randomized 1:1 to receive nivolumab alone, or nivolumab plus ipilimumab.
The nivolumab arm received 3 mg/kg by intravenous infusion every 2 weeks. The combination arm began with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks for four doses. After this, they also received nivolumab 3 mg/kg monotherapy every 2 weeks.
The third cohort – a small group of 15 patients who received nivolumab alone – either had symptomatic brain metastases or leptomeningeal disease and could have had previous brain surgery or radiotherapy. Unlike the first two cohorts, they were also permitted to be on up to 10 mg/day of prednisone; these patients received nivolumab alone at 3 mg/kg every 2 weeks.
For all patients, immune therapy was given until the disease progressed, consent was withdrawn, or patients experienced unacceptable toxicity or they died.
“We were most interested in the randomized cohorts,” said Dr. Long. Interestingly, she said, ipilimumab became available in Australia when 27 patients were enrolled in the nivolumab arm and 26 to the combination arm. “So we stopped the monotherapy arm, and the rest of the 60 patients to be recruited all went into the combination arm,” she said. A total of 76 patients were recruited, 33 into the combination arm, 27 to the asymptomatic nivolumab monotherapy arm, and 16 to the symptomatic and/or previously treated arm.
Data analysis from the point of the data cut included 67 patients who were followed for a period ranging from 5 to 34 months. Intracranial disease was evaluated by gadolinium-enhanced MRI and modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
“The results of the trial were very interesting,” said Dr. Long. The nivolumab plus ipilimumab combo resulted in an overall 42% intracranial response rate, while nivolumab alone produced an overall intracranial response rate of 21%. However, patients in either arm who had prior BRAF or MEK inhibitor exposure “didn’t do too well on immunotherapy,” said Dr. Long, noting that the response rate was just 16% for these patients. These were, she said, “small numbers, but still, an interesting signal there.”
When comparing the secondary endpoint of extracranial response to intracranial response on a per-patient basis, Dr. Long and her collaborators could see that “the intracranial and extracranial results were mostly concordant.”
Analysis of the additional secondary endpoints of progression-free survival (PFS) and overall survival (OS) also showed an interesting pattern, said Dr. Long. After an initial drop-off period of about 5 months, the curves for patients in all arms have stabilized, so that patients who were responders are maintaining that response. The overall 6-month PFS rate for the combination cohort was 47%, with a durable response: “If you look at the curve, it’s flattened out since that stage, and we haven’t had any progression since that time,” said Dr. Long. The PFS rate was 29% for the cohort receiving nivolumab alone. “Activity is highest when nivolumab and ipilimumab are given upfront,” said Dr. Long.
For asymptomatic patients pretreated with BRAF or MEK inhibitors, “activity is low,” said Dr. Long, with an intracranial response rate of 16% in both cohorts.
Symptomatic patients who were more heavily pretreated fared even worse: “The activity of nivolumab monotherapy is low after multiple modality therapy or in leptomeningeal melanoma,” said Dr. Long. The intracranial response rate in the third cohort was just 6%.
The combination therapy cohort had the most treatment-related adverse events, with 96% of patients experiencing some adverse event. About half (12/26, 46%) had grade 3 or 4 events, and the same number had a serious adverse event. Seven patients (27%) discontinued therapy because of treatment-related adverse events in the combination study arm. However, said Dr. Long, this side effect profile is in keeping with what has been seen in other studies of combination therapy with nivolumab and ipilimumab. “There were not unexpected adverse events,” she said.
Dr. Long reported relationships with Bristol-Myers Squibb, Merck, and Roche.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
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On Twitter @karioakes
CHICAGO – Immune therapy shows promise for use in the treatment of melanoma brain metastases, especially for treatment-naive patients, judging from the findings of a new phase II randomized study.
For patients with asymptomatic brain metastases from melanoma who had not had prior treatment, nivolumab combined with ipilimumab produced a 50% intracranial response rate after at least 12 weeks of therapy. When nivolumab alone was given to untreated patients, the intracranial response rate was 21%, Georgina Long MD, PhD, co–medical director of the Melanoma Institute Australia , said during a video interview at the annual meeting of the American Society of Clinical Oncology.
“If you look at progression-free survival by response, none of our complete responders have progressed,” said Dr. Long. “And this is with a median follow-up of 16.4 months.” The partial responders have also done well, with little progression, she said. “Remember, these patients usually survive only a few weeks.”
The Anti-PD1 Brain Collaboration study, a phase II clinical trial, enrolled patients with melanoma brain metastases at least 5 mm but less than 40 mm in diameter who had not received previous anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), anti-programmed cell death protein 1 (anti-PD-1), or anti-programmed death-ligand 1 (anti-PD-L1) therapies. Patients were permitted to have had previous BRAF and MEK inhibitor therapies. Asymptomatic patients who had no previous local brain therapy (i.e., radiation treatment or surgery) were randomized 1:1 to receive nivolumab alone, or nivolumab plus ipilimumab.
The nivolumab arm received 3 mg/kg by intravenous infusion every 2 weeks. The combination arm began with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks for four doses. After this, they also received nivolumab 3 mg/kg monotherapy every 2 weeks.
The third cohort – a small group of 15 patients who received nivolumab alone – either had symptomatic brain metastases or leptomeningeal disease and could have had previous brain surgery or radiotherapy. Unlike the first two cohorts, they were also permitted to be on up to 10 mg/day of prednisone; these patients received nivolumab alone at 3 mg/kg every 2 weeks.
For all patients, immune therapy was given until the disease progressed, consent was withdrawn, or patients experienced unacceptable toxicity or they died.
“We were most interested in the randomized cohorts,” said Dr. Long. Interestingly, she said, ipilimumab became available in Australia when 27 patients were enrolled in the nivolumab arm and 26 to the combination arm. “So we stopped the monotherapy arm, and the rest of the 60 patients to be recruited all went into the combination arm,” she said. A total of 76 patients were recruited, 33 into the combination arm, 27 to the asymptomatic nivolumab monotherapy arm, and 16 to the symptomatic and/or previously treated arm.
Data analysis from the point of the data cut included 67 patients who were followed for a period ranging from 5 to 34 months. Intracranial disease was evaluated by gadolinium-enhanced MRI and modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
“The results of the trial were very interesting,” said Dr. Long. The nivolumab plus ipilimumab combo resulted in an overall 42% intracranial response rate, while nivolumab alone produced an overall intracranial response rate of 21%. However, patients in either arm who had prior BRAF or MEK inhibitor exposure “didn’t do too well on immunotherapy,” said Dr. Long, noting that the response rate was just 16% for these patients. These were, she said, “small numbers, but still, an interesting signal there.”
When comparing the secondary endpoint of extracranial response to intracranial response on a per-patient basis, Dr. Long and her collaborators could see that “the intracranial and extracranial results were mostly concordant.”
Analysis of the additional secondary endpoints of progression-free survival (PFS) and overall survival (OS) also showed an interesting pattern, said Dr. Long. After an initial drop-off period of about 5 months, the curves for patients in all arms have stabilized, so that patients who were responders are maintaining that response. The overall 6-month PFS rate for the combination cohort was 47%, with a durable response: “If you look at the curve, it’s flattened out since that stage, and we haven’t had any progression since that time,” said Dr. Long. The PFS rate was 29% for the cohort receiving nivolumab alone. “Activity is highest when nivolumab and ipilimumab are given upfront,” said Dr. Long.
For asymptomatic patients pretreated with BRAF or MEK inhibitors, “activity is low,” said Dr. Long, with an intracranial response rate of 16% in both cohorts.
Symptomatic patients who were more heavily pretreated fared even worse: “The activity of nivolumab monotherapy is low after multiple modality therapy or in leptomeningeal melanoma,” said Dr. Long. The intracranial response rate in the third cohort was just 6%.
The combination therapy cohort had the most treatment-related adverse events, with 96% of patients experiencing some adverse event. About half (12/26, 46%) had grade 3 or 4 events, and the same number had a serious adverse event. Seven patients (27%) discontinued therapy because of treatment-related adverse events in the combination study arm. However, said Dr. Long, this side effect profile is in keeping with what has been seen in other studies of combination therapy with nivolumab and ipilimumab. “There were not unexpected adverse events,” she said.
Dr. Long reported relationships with Bristol-Myers Squibb, Merck, and Roche.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @karioakes
AT ASCO 2017
VIDEO: Immunotherapy ups disease control rate in relapsed mesothelioma
CHICAGO – Early data from a phase II trial of immune checkpoint inhibitors to treat relapsed mesothelioma give hope that immunotherapy may be an effective therapeutic option for the rapidly progressive, currently incurable cancer.
Reporting on 12 weeks of data from the randomized multicenter trial, Arnaud Scherpereel, MD, the study’s first author, said in a video interview, “We were very pleased to see that we were able to increase ... the disease control rate to 44% with nivolumab, and 50% with nivolumab plus ipilimumab. This was translated into a overall survival gain for these patients.” The best previous disease control rate seen with other therapies was less than 30%, said Dr. Scherpereel at the annual meeting of the American Society of Clinical Oncology.
Discussing the early results in a video interview, Dr. Scherpereel, head of the pulmonary and thoracic oncology department at the University Hospital of Lille, France noted that the median overall survival for the nivolumab patients was 10.4 months, and has not yet been reached for the nivolumab plus ipilimumab patients. Further, he said in a press briefing, “Tumors shrunk in 18% of patients treated with nivolumab and 26% of those treated with nivolumab plus ipilimumab.”
The French MAPS-2 study has enrolled 125 adult patients with malignant pleural mesothelioma who had measurable disease progression after one or two prior lines of chemotherapy, including pemetrexed/platinum doublet. Patients were randomized 1:1 to receive either nivolumab or nivolumab plus ipilimumab, until disease control or unacceptable toxicity was reached, for a maximum of 2 years. Patients were mostly (80%) male, with a median age of 71.8 years, and most had the epithelioid malignant pleural mesothelioma subtype.
In commentary at the press briefing announcing the findings, ASCO expert Michael Sabel, MD, said, “I need to emphasize that this is amazing, in that we are seeing [the use of] checkpoint inhibitors expanding beyond melanoma, to other cancers that we thought were not amenable to immunotherapy approaches.”
“This is a great example of how basic cancer research in one field can expand across others,” said Dr. Sabel of the departments of surgery and surgical oncology at the University of Michigan, Ann Arbor.
Most side effects were not severe, but there were three potentially drug-related deaths in the nivolumab-ipilimumab combo arm: one patient died of fulminant hepatitis, one from metabolic encephalitis, and one from acute renal failure. “There is no identified factor that is predictive” in terms of which patients will have the more significant known adverse effects of checkpoint inhibitors, said Dr. Scherpereel. Patients, caregivers, and health care professionals all need to be alert to the possibility of adverse events and act promptly if concerning symptoms crop up, he said.
Dr. Scherpereel said that though his study group has not yet reported the quality of life findings from MAPS-2, he sees that his patients who are study participants are doing better. “In my patients, they have a very good tolerance to this treatment compared to chemotherapy. They have less dyspnea, less chest pain. Clearly, we hope to get these drugs into the routine very quickly for them.”
Bristol-Myers Squibb manufactures both nivolumab and ipilimumab and provided the study drugs. Dr. Sabel disclosed a financial relationship with Merck. Dr. Scherpereel has no relevant financial disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @karioakes
CHICAGO – Early data from a phase II trial of immune checkpoint inhibitors to treat relapsed mesothelioma give hope that immunotherapy may be an effective therapeutic option for the rapidly progressive, currently incurable cancer.
Reporting on 12 weeks of data from the randomized multicenter trial, Arnaud Scherpereel, MD, the study’s first author, said in a video interview, “We were very pleased to see that we were able to increase ... the disease control rate to 44% with nivolumab, and 50% with nivolumab plus ipilimumab. This was translated into a overall survival gain for these patients.” The best previous disease control rate seen with other therapies was less than 30%, said Dr. Scherpereel at the annual meeting of the American Society of Clinical Oncology.
Discussing the early results in a video interview, Dr. Scherpereel, head of the pulmonary and thoracic oncology department at the University Hospital of Lille, France noted that the median overall survival for the nivolumab patients was 10.4 months, and has not yet been reached for the nivolumab plus ipilimumab patients. Further, he said in a press briefing, “Tumors shrunk in 18% of patients treated with nivolumab and 26% of those treated with nivolumab plus ipilimumab.”
The French MAPS-2 study has enrolled 125 adult patients with malignant pleural mesothelioma who had measurable disease progression after one or two prior lines of chemotherapy, including pemetrexed/platinum doublet. Patients were randomized 1:1 to receive either nivolumab or nivolumab plus ipilimumab, until disease control or unacceptable toxicity was reached, for a maximum of 2 years. Patients were mostly (80%) male, with a median age of 71.8 years, and most had the epithelioid malignant pleural mesothelioma subtype.
In commentary at the press briefing announcing the findings, ASCO expert Michael Sabel, MD, said, “I need to emphasize that this is amazing, in that we are seeing [the use of] checkpoint inhibitors expanding beyond melanoma, to other cancers that we thought were not amenable to immunotherapy approaches.”
“This is a great example of how basic cancer research in one field can expand across others,” said Dr. Sabel of the departments of surgery and surgical oncology at the University of Michigan, Ann Arbor.
Most side effects were not severe, but there were three potentially drug-related deaths in the nivolumab-ipilimumab combo arm: one patient died of fulminant hepatitis, one from metabolic encephalitis, and one from acute renal failure. “There is no identified factor that is predictive” in terms of which patients will have the more significant known adverse effects of checkpoint inhibitors, said Dr. Scherpereel. Patients, caregivers, and health care professionals all need to be alert to the possibility of adverse events and act promptly if concerning symptoms crop up, he said.
Dr. Scherpereel said that though his study group has not yet reported the quality of life findings from MAPS-2, he sees that his patients who are study participants are doing better. “In my patients, they have a very good tolerance to this treatment compared to chemotherapy. They have less dyspnea, less chest pain. Clearly, we hope to get these drugs into the routine very quickly for them.”
Bristol-Myers Squibb manufactures both nivolumab and ipilimumab and provided the study drugs. Dr. Sabel disclosed a financial relationship with Merck. Dr. Scherpereel has no relevant financial disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @karioakes
CHICAGO – Early data from a phase II trial of immune checkpoint inhibitors to treat relapsed mesothelioma give hope that immunotherapy may be an effective therapeutic option for the rapidly progressive, currently incurable cancer.
Reporting on 12 weeks of data from the randomized multicenter trial, Arnaud Scherpereel, MD, the study’s first author, said in a video interview, “We were very pleased to see that we were able to increase ... the disease control rate to 44% with nivolumab, and 50% with nivolumab plus ipilimumab. This was translated into a overall survival gain for these patients.” The best previous disease control rate seen with other therapies was less than 30%, said Dr. Scherpereel at the annual meeting of the American Society of Clinical Oncology.
Discussing the early results in a video interview, Dr. Scherpereel, head of the pulmonary and thoracic oncology department at the University Hospital of Lille, France noted that the median overall survival for the nivolumab patients was 10.4 months, and has not yet been reached for the nivolumab plus ipilimumab patients. Further, he said in a press briefing, “Tumors shrunk in 18% of patients treated with nivolumab and 26% of those treated with nivolumab plus ipilimumab.”
The French MAPS-2 study has enrolled 125 adult patients with malignant pleural mesothelioma who had measurable disease progression after one or two prior lines of chemotherapy, including pemetrexed/platinum doublet. Patients were randomized 1:1 to receive either nivolumab or nivolumab plus ipilimumab, until disease control or unacceptable toxicity was reached, for a maximum of 2 years. Patients were mostly (80%) male, with a median age of 71.8 years, and most had the epithelioid malignant pleural mesothelioma subtype.
In commentary at the press briefing announcing the findings, ASCO expert Michael Sabel, MD, said, “I need to emphasize that this is amazing, in that we are seeing [the use of] checkpoint inhibitors expanding beyond melanoma, to other cancers that we thought were not amenable to immunotherapy approaches.”
“This is a great example of how basic cancer research in one field can expand across others,” said Dr. Sabel of the departments of surgery and surgical oncology at the University of Michigan, Ann Arbor.
Most side effects were not severe, but there were three potentially drug-related deaths in the nivolumab-ipilimumab combo arm: one patient died of fulminant hepatitis, one from metabolic encephalitis, and one from acute renal failure. “There is no identified factor that is predictive” in terms of which patients will have the more significant known adverse effects of checkpoint inhibitors, said Dr. Scherpereel. Patients, caregivers, and health care professionals all need to be alert to the possibility of adverse events and act promptly if concerning symptoms crop up, he said.
Dr. Scherpereel said that though his study group has not yet reported the quality of life findings from MAPS-2, he sees that his patients who are study participants are doing better. “In my patients, they have a very good tolerance to this treatment compared to chemotherapy. They have less dyspnea, less chest pain. Clearly, we hope to get these drugs into the routine very quickly for them.”
Bristol-Myers Squibb manufactures both nivolumab and ipilimumab and provided the study drugs. Dr. Sabel disclosed a financial relationship with Merck. Dr. Scherpereel has no relevant financial disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @karioakes
AT ASCO 2017
VIDEO: Combined immunotherapy strategy shows promise in advanced solid tumors
CHICAGO – Adding an experimental immune-enhancing agent to a checkpoint inhibitor was safe and showed early promise of activity against advanced solid tumors in a phase I/IIa clinical trial.
BMS-986156 is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucorticoid-induced tumor necrosis factor receptor-related gene. The drug acts synergistically with the programmed-death 1 inhibitor (PD-1) nivolumab (Opdivo) by increasing survival of T effector cells, promoting regulatory T-cell depletion and reduction, and reducing regulatory T cell suppression of T effector cells to produce a more robust antitumor immune response.
In this video interview at the annual meeting of the American Society of Clinical Oncology, Lillian Siu, MD, from the Princess Margaret Hospital, Toronto, describes how the combination has induced durable partial responses in patients with tumors thought to be insensitive to immunotherapy, as well as patients who had disease progression while on a PD-1 inhibitor.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Adding an experimental immune-enhancing agent to a checkpoint inhibitor was safe and showed early promise of activity against advanced solid tumors in a phase I/IIa clinical trial.
BMS-986156 is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucorticoid-induced tumor necrosis factor receptor-related gene. The drug acts synergistically with the programmed-death 1 inhibitor (PD-1) nivolumab (Opdivo) by increasing survival of T effector cells, promoting regulatory T-cell depletion and reduction, and reducing regulatory T cell suppression of T effector cells to produce a more robust antitumor immune response.
In this video interview at the annual meeting of the American Society of Clinical Oncology, Lillian Siu, MD, from the Princess Margaret Hospital, Toronto, describes how the combination has induced durable partial responses in patients with tumors thought to be insensitive to immunotherapy, as well as patients who had disease progression while on a PD-1 inhibitor.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Adding an experimental immune-enhancing agent to a checkpoint inhibitor was safe and showed early promise of activity against advanced solid tumors in a phase I/IIa clinical trial.
BMS-986156 is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucorticoid-induced tumor necrosis factor receptor-related gene. The drug acts synergistically with the programmed-death 1 inhibitor (PD-1) nivolumab (Opdivo) by increasing survival of T effector cells, promoting regulatory T-cell depletion and reduction, and reducing regulatory T cell suppression of T effector cells to produce a more robust antitumor immune response.
In this video interview at the annual meeting of the American Society of Clinical Oncology, Lillian Siu, MD, from the Princess Margaret Hospital, Toronto, describes how the combination has induced durable partial responses in patients with tumors thought to be insensitive to immunotherapy, as well as patients who had disease progression while on a PD-1 inhibitor.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASCO 2017
Immune-agonist combo has activity against several tumor types
CHICAGO – A combination of the programmed death 1 (PD-1) inhibitor nivolumab (Opdivo) with an experimental immune-enhancing monoclonal antibody induced clinical responses in patients with several different solid tumor types, including some patients who had disease progression on a PD-1 inhibitor, investigators reported.
The investigational agent, euphoniously named BMS-986156 (986156), is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucocorticoid-induced tumor necrosis factor receptor–related gene (GITR).
BMS-986156156 “induces potent antitumor immunity by several mechanisms. First, it increases T-effector cell survival and function. Second, it promotes T-regulatory cell depletion and reduction through its conversion to other immune cells. As well, it reduces T-reg-mediated suppression of T-effector cells,” said Lillian L Siu, MD, from the Princess Margaret Hospital in Toronto.
In preclinical studies, the combination of an anti-GITR and an anti-PD-1 agent showed synergistic activity against murine tumor models.
Dr. Siu and colleagues conducted a phase I/IIa study of BMS-986156 with or without nivolumab in 66 patients with advanced solid tumors.
The 29 patients assigned to BMS-986156 monotherapy were started at 10 mg every 2 weeks, which was gradually titrated upward to find the maximum tolerated dose of 240 mg Q2 weeks.
The 37 patients assigned to the combination were started on a dose of 30-mg nivolumab and 240-mg BMS-986156. The nivolumab dose but not the BMS-986156 dose was then titrated upward to a maximum tolerated dose of 240 mg for each agent. This dose was based on pharmacodynamic and pharmacokinetic studies.
Tumor types included melanoma, cervical, colon, breast, renal, pancreatic, and ovarian cancers and cholangiocarcinoma.
Approximately one-third of patients in the monotherapy arm and nearly half of those in the combination arm had undergone three or more prior therapies for cancer. Seven patients in the monotherapy group and five in the combination group had previously received a PD-1 or PD-L1 inhibitor.
The median duration of treatment ranged from 7 to 15.5 weeks for 156 monotherapy and 8 to 18 weeks for the combination.
Safe and well tolerated
There were no dose-limiting toxicities or treatment-related deaths in either study arm, and patients tolerated both BMS-986156 monotherapy and the combination well. There were no grade 3 or 4 adverse events in the monotherapy arm.
“In the combination arm, the toxicity is very consistent with that observed with nivolumab monotherapy alone,” Dr. Siu said.
The only grade 4 event in this group was an increase in blood creatine phosphokinase. In this group, there were six grade 3 adverse events, including one each of colitis, dehydration, fatigue and increases in hepatic enzymes, lipase increase, and lung infection.
In pharmacokinetic studies, the action of the combinations was linear, with dose-related increases in exposure, and the combination had low immunogenicity, with no patients developing persistent antidrug antibodies.
The combination was also associated with increases in natural killer and CD8 cells in peripheral blood. Immunophenotyping of patients treated with the 240/240-mg dose of the combination showed increased proliferation and activation of CD8 effector cells, central memory cells, and CD4 cells.
Early promise
Dr. Siu reviewed interim efficacy results for the five patients treated with the combination who had responses.
For example, a 44-year-old woman with metastatic cervical cancer – a tumor type known to have high levels of GITR expression – had received more than three prior lines of therapy, including chemotherapy with a vascular endothelial growth factor inhibitor. She had a partial response with the combination, with an approximately 62% reduction in tumor burden. She had an ongoing response to the combination at the time of data cutoff in March 2017.
Two other patients had partial responses after progression on an anti-PD-1 agents, including one with nasopharyngeal cancer who had received three prior lines of therapy, including chemotherapy and a PD-1 inhibitor. This patient had an approximately 43% reduction in tumor burden, with a 17-week duration of response and ongoing response at data cutoff.
The other patient was a 59-year-old with malignant melanoma that had advanced on pembrolizumab (Keytruda). This patient too had received three prior lines of therapy, including a BRAF inhibitor, anti-PD-1, and BRAF/MEK inhibitor combination.
This patient had a response of 24-week duration at the time of data cutoff. It is ongoing, Dr. Liu said.
“This combination of immune agonists was safe with a low incidence of severe toxicity, and there was no maximum tolerated dose; however, the maximum administered dose may not be the most effective dose to move forward,” commented Siwen Hu-Lieskovan MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, the invited discussant.
She noted that activity of the combination has been seen in a wide range of tumor histologies but added that further biomarker studies will be critical for identifying patients who are likely to respond.
The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
CHICAGO – A combination of the programmed death 1 (PD-1) inhibitor nivolumab (Opdivo) with an experimental immune-enhancing monoclonal antibody induced clinical responses in patients with several different solid tumor types, including some patients who had disease progression on a PD-1 inhibitor, investigators reported.
The investigational agent, euphoniously named BMS-986156 (986156), is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucocorticoid-induced tumor necrosis factor receptor–related gene (GITR).
BMS-986156156 “induces potent antitumor immunity by several mechanisms. First, it increases T-effector cell survival and function. Second, it promotes T-regulatory cell depletion and reduction through its conversion to other immune cells. As well, it reduces T-reg-mediated suppression of T-effector cells,” said Lillian L Siu, MD, from the Princess Margaret Hospital in Toronto.
In preclinical studies, the combination of an anti-GITR and an anti-PD-1 agent showed synergistic activity against murine tumor models.
Dr. Siu and colleagues conducted a phase I/IIa study of BMS-986156 with or without nivolumab in 66 patients with advanced solid tumors.
The 29 patients assigned to BMS-986156 monotherapy were started at 10 mg every 2 weeks, which was gradually titrated upward to find the maximum tolerated dose of 240 mg Q2 weeks.
The 37 patients assigned to the combination were started on a dose of 30-mg nivolumab and 240-mg BMS-986156. The nivolumab dose but not the BMS-986156 dose was then titrated upward to a maximum tolerated dose of 240 mg for each agent. This dose was based on pharmacodynamic and pharmacokinetic studies.
Tumor types included melanoma, cervical, colon, breast, renal, pancreatic, and ovarian cancers and cholangiocarcinoma.
Approximately one-third of patients in the monotherapy arm and nearly half of those in the combination arm had undergone three or more prior therapies for cancer. Seven patients in the monotherapy group and five in the combination group had previously received a PD-1 or PD-L1 inhibitor.
The median duration of treatment ranged from 7 to 15.5 weeks for 156 monotherapy and 8 to 18 weeks for the combination.
Safe and well tolerated
There were no dose-limiting toxicities or treatment-related deaths in either study arm, and patients tolerated both BMS-986156 monotherapy and the combination well. There were no grade 3 or 4 adverse events in the monotherapy arm.
“In the combination arm, the toxicity is very consistent with that observed with nivolumab monotherapy alone,” Dr. Siu said.
The only grade 4 event in this group was an increase in blood creatine phosphokinase. In this group, there were six grade 3 adverse events, including one each of colitis, dehydration, fatigue and increases in hepatic enzymes, lipase increase, and lung infection.
In pharmacokinetic studies, the action of the combinations was linear, with dose-related increases in exposure, and the combination had low immunogenicity, with no patients developing persistent antidrug antibodies.
The combination was also associated with increases in natural killer and CD8 cells in peripheral blood. Immunophenotyping of patients treated with the 240/240-mg dose of the combination showed increased proliferation and activation of CD8 effector cells, central memory cells, and CD4 cells.
Early promise
Dr. Siu reviewed interim efficacy results for the five patients treated with the combination who had responses.
For example, a 44-year-old woman with metastatic cervical cancer – a tumor type known to have high levels of GITR expression – had received more than three prior lines of therapy, including chemotherapy with a vascular endothelial growth factor inhibitor. She had a partial response with the combination, with an approximately 62% reduction in tumor burden. She had an ongoing response to the combination at the time of data cutoff in March 2017.
Two other patients had partial responses after progression on an anti-PD-1 agents, including one with nasopharyngeal cancer who had received three prior lines of therapy, including chemotherapy and a PD-1 inhibitor. This patient had an approximately 43% reduction in tumor burden, with a 17-week duration of response and ongoing response at data cutoff.
The other patient was a 59-year-old with malignant melanoma that had advanced on pembrolizumab (Keytruda). This patient too had received three prior lines of therapy, including a BRAF inhibitor, anti-PD-1, and BRAF/MEK inhibitor combination.
This patient had a response of 24-week duration at the time of data cutoff. It is ongoing, Dr. Liu said.
“This combination of immune agonists was safe with a low incidence of severe toxicity, and there was no maximum tolerated dose; however, the maximum administered dose may not be the most effective dose to move forward,” commented Siwen Hu-Lieskovan MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, the invited discussant.
She noted that activity of the combination has been seen in a wide range of tumor histologies but added that further biomarker studies will be critical for identifying patients who are likely to respond.
The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
CHICAGO – A combination of the programmed death 1 (PD-1) inhibitor nivolumab (Opdivo) with an experimental immune-enhancing monoclonal antibody induced clinical responses in patients with several different solid tumor types, including some patients who had disease progression on a PD-1 inhibitor, investigators reported.
The investigational agent, euphoniously named BMS-986156 (986156), is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucocorticoid-induced tumor necrosis factor receptor–related gene (GITR).
BMS-986156156 “induces potent antitumor immunity by several mechanisms. First, it increases T-effector cell survival and function. Second, it promotes T-regulatory cell depletion and reduction through its conversion to other immune cells. As well, it reduces T-reg-mediated suppression of T-effector cells,” said Lillian L Siu, MD, from the Princess Margaret Hospital in Toronto.
In preclinical studies, the combination of an anti-GITR and an anti-PD-1 agent showed synergistic activity against murine tumor models.
Dr. Siu and colleagues conducted a phase I/IIa study of BMS-986156 with or without nivolumab in 66 patients with advanced solid tumors.
The 29 patients assigned to BMS-986156 monotherapy were started at 10 mg every 2 weeks, which was gradually titrated upward to find the maximum tolerated dose of 240 mg Q2 weeks.
The 37 patients assigned to the combination were started on a dose of 30-mg nivolumab and 240-mg BMS-986156. The nivolumab dose but not the BMS-986156 dose was then titrated upward to a maximum tolerated dose of 240 mg for each agent. This dose was based on pharmacodynamic and pharmacokinetic studies.
Tumor types included melanoma, cervical, colon, breast, renal, pancreatic, and ovarian cancers and cholangiocarcinoma.
Approximately one-third of patients in the monotherapy arm and nearly half of those in the combination arm had undergone three or more prior therapies for cancer. Seven patients in the monotherapy group and five in the combination group had previously received a PD-1 or PD-L1 inhibitor.
The median duration of treatment ranged from 7 to 15.5 weeks for 156 monotherapy and 8 to 18 weeks for the combination.
Safe and well tolerated
There were no dose-limiting toxicities or treatment-related deaths in either study arm, and patients tolerated both BMS-986156 monotherapy and the combination well. There were no grade 3 or 4 adverse events in the monotherapy arm.
“In the combination arm, the toxicity is very consistent with that observed with nivolumab monotherapy alone,” Dr. Siu said.
The only grade 4 event in this group was an increase in blood creatine phosphokinase. In this group, there were six grade 3 adverse events, including one each of colitis, dehydration, fatigue and increases in hepatic enzymes, lipase increase, and lung infection.
In pharmacokinetic studies, the action of the combinations was linear, with dose-related increases in exposure, and the combination had low immunogenicity, with no patients developing persistent antidrug antibodies.
The combination was also associated with increases in natural killer and CD8 cells in peripheral blood. Immunophenotyping of patients treated with the 240/240-mg dose of the combination showed increased proliferation and activation of CD8 effector cells, central memory cells, and CD4 cells.
Early promise
Dr. Siu reviewed interim efficacy results for the five patients treated with the combination who had responses.
For example, a 44-year-old woman with metastatic cervical cancer – a tumor type known to have high levels of GITR expression – had received more than three prior lines of therapy, including chemotherapy with a vascular endothelial growth factor inhibitor. She had a partial response with the combination, with an approximately 62% reduction in tumor burden. She had an ongoing response to the combination at the time of data cutoff in March 2017.
Two other patients had partial responses after progression on an anti-PD-1 agents, including one with nasopharyngeal cancer who had received three prior lines of therapy, including chemotherapy and a PD-1 inhibitor. This patient had an approximately 43% reduction in tumor burden, with a 17-week duration of response and ongoing response at data cutoff.
The other patient was a 59-year-old with malignant melanoma that had advanced on pembrolizumab (Keytruda). This patient too had received three prior lines of therapy, including a BRAF inhibitor, anti-PD-1, and BRAF/MEK inhibitor combination.
This patient had a response of 24-week duration at the time of data cutoff. It is ongoing, Dr. Liu said.
“This combination of immune agonists was safe with a low incidence of severe toxicity, and there was no maximum tolerated dose; however, the maximum administered dose may not be the most effective dose to move forward,” commented Siwen Hu-Lieskovan MD, PhD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, the invited discussant.
She noted that activity of the combination has been seen in a wide range of tumor histologies but added that further biomarker studies will be critical for identifying patients who are likely to respond.
The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
AT ASCO 2017
Key clinical point: A combination of a GITR-agonist and anti-PD-1 agent was safe and produced partial responses in patients with heavily pretreated advanced cancers.
Major finding: Two patients with cancers that had progression on a PD-1 inhibitor had durable partial responses.
Data source: A phase I/IIa dose-finding and safety study of BMS986156 alone or in combination with nivolumab (Opdivo).
Disclosures: The study was funded by Bristol-Myers Squibb. Dr. Siu disclosed research funding from the company and others and consulting/advising for several different companies. Dr. Hu-Lieskovan disclosed institutional research funding from BMS and other companies, as well as honoraria and consulting and serving in an advisory capacity for companies other than BMS. Several coauthors are employees of the company.
FDA approves pembrolizumab for advanced urothelial carcinoma
The Food and Drug Administration has granted regular approval to pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Accelerated approval was granted for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
Approval of pembrolizumab for the second-line indication was based on an improvement in overall survival and objective response rate (ORR) in the KEYNOTE-045 trial. Median overall survival was 10.3 months for patients randomized to receive pembrolizumab (n = 270) every 3 weeks, compared with 7.4 months for patients randomized to receive the investigator’s choice of a chemotherapy regimen (paclitaxel [n = 84], docetaxel [n = 84], or vinflunine [n = 87]) every 3 weeks (hazard ratio, 0.73; 95% confidence interval: 0.59-0.91, P =.004). ORR was 21% for pembrolizumab and 11% for chemotherapy (P = .002). All patients had locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. No statistically significant difference in progression-free survival between the two arms was observed, the FDA said in a statement.
The accelerated approval for the first-line indication was based on an ORR of 28.6% (95% CI, 24-34) in KEYNOTE-052, a single-arm, open-label trial in 370 patients with locally advanced or metastatic urothelial carcinoma who were deemed not eligible for cisplatin-containing chemotherapy. The median response duration was not reached (range, 1.4+-17.8+ months).
The most common adverse reactions reported for those receiving pembrolizumab in either of the two trials included fatigue, musculoskeletal pain, pruritus, decreased appetite, nausea, diarrhea, constipation, and rash. Discontinuation of pembrolizumab occurred in 8% of patients in KEYNOTE-045 and in 11% in KEYNOTE-052. Serious adverse reactions occurred in approximately 40% of pembrolizumab-treated patients, the FDA said.
The recommended pembrolizumab dose and schedule for the treatment of urothelial carcinoma is 200 mg as an intravenous infusion over 30 minutes every 3 weeks. Full prescribing information is available the FDA website.
The Food and Drug Administration has granted regular approval to pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Accelerated approval was granted for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
Approval of pembrolizumab for the second-line indication was based on an improvement in overall survival and objective response rate (ORR) in the KEYNOTE-045 trial. Median overall survival was 10.3 months for patients randomized to receive pembrolizumab (n = 270) every 3 weeks, compared with 7.4 months for patients randomized to receive the investigator’s choice of a chemotherapy regimen (paclitaxel [n = 84], docetaxel [n = 84], or vinflunine [n = 87]) every 3 weeks (hazard ratio, 0.73; 95% confidence interval: 0.59-0.91, P =.004). ORR was 21% for pembrolizumab and 11% for chemotherapy (P = .002). All patients had locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. No statistically significant difference in progression-free survival between the two arms was observed, the FDA said in a statement.
The accelerated approval for the first-line indication was based on an ORR of 28.6% (95% CI, 24-34) in KEYNOTE-052, a single-arm, open-label trial in 370 patients with locally advanced or metastatic urothelial carcinoma who were deemed not eligible for cisplatin-containing chemotherapy. The median response duration was not reached (range, 1.4+-17.8+ months).
The most common adverse reactions reported for those receiving pembrolizumab in either of the two trials included fatigue, musculoskeletal pain, pruritus, decreased appetite, nausea, diarrhea, constipation, and rash. Discontinuation of pembrolizumab occurred in 8% of patients in KEYNOTE-045 and in 11% in KEYNOTE-052. Serious adverse reactions occurred in approximately 40% of pembrolizumab-treated patients, the FDA said.
The recommended pembrolizumab dose and schedule for the treatment of urothelial carcinoma is 200 mg as an intravenous infusion over 30 minutes every 3 weeks. Full prescribing information is available the FDA website.
The Food and Drug Administration has granted regular approval to pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Accelerated approval was granted for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.
Approval of pembrolizumab for the second-line indication was based on an improvement in overall survival and objective response rate (ORR) in the KEYNOTE-045 trial. Median overall survival was 10.3 months for patients randomized to receive pembrolizumab (n = 270) every 3 weeks, compared with 7.4 months for patients randomized to receive the investigator’s choice of a chemotherapy regimen (paclitaxel [n = 84], docetaxel [n = 84], or vinflunine [n = 87]) every 3 weeks (hazard ratio, 0.73; 95% confidence interval: 0.59-0.91, P =.004). ORR was 21% for pembrolizumab and 11% for chemotherapy (P = .002). All patients had locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. No statistically significant difference in progression-free survival between the two arms was observed, the FDA said in a statement.
The accelerated approval for the first-line indication was based on an ORR of 28.6% (95% CI, 24-34) in KEYNOTE-052, a single-arm, open-label trial in 370 patients with locally advanced or metastatic urothelial carcinoma who were deemed not eligible for cisplatin-containing chemotherapy. The median response duration was not reached (range, 1.4+-17.8+ months).
The most common adverse reactions reported for those receiving pembrolizumab in either of the two trials included fatigue, musculoskeletal pain, pruritus, decreased appetite, nausea, diarrhea, constipation, and rash. Discontinuation of pembrolizumab occurred in 8% of patients in KEYNOTE-045 and in 11% in KEYNOTE-052. Serious adverse reactions occurred in approximately 40% of pembrolizumab-treated patients, the FDA said.
The recommended pembrolizumab dose and schedule for the treatment of urothelial carcinoma is 200 mg as an intravenous infusion over 30 minutes every 3 weeks. Full prescribing information is available the FDA website.
Pembrolizumab shows some activity against advanced endometrial cancer
In some women with heavily pretreated locally advanced or metastatic endometrial cancers, treatment with the immune checkpoint inhibitor pembrolizumab (Keytruda) produced partial, durable responses, investigators reported.
The women were participants in the KEYNOTE-028 trial, a multicohort, open-label phase Ib basket trial of patients with advanced solid tumors positive for programmed death ligand 1 (PD-L1). Of 24 women with PD-L1-positive endometrial tumors, 3 (13%) had confirmed partial responses, and 2 of these patients remained on therapy with a continued response at the time of data cutoff, reported Patrick A. Ott, MD, PhD, of Dana-Farber Cancer Institute, Boston, and his colleagues.
“[T]he results from the KEYNOTE-028 trial presented herein indicate that pembrolizumab shows promise as a treatment for advanced endometrial cancer, a disease for which current treatment options are limited,” they wrote (J Clin Oncol. 2017 May 10; doi: 10.1200/JCO.2017.72.5952).
Patients with advanced endometrial cancer have a poor prognosis, with 5-year survival rates below 50% for patients with lymph node metastases, and less than 20% for those with distant metastases or disease that has spread to the peritoneum, the investigators noted.
“Treatment options for patients presenting with advanced disease are limited, with no consensus on a standard regimen. Similarly, no optimal therapy for patients who experience progression during first-line therapy has been identified, with second-line chemotherapeutic options producing only modest activity,” they wrote.
PD-L1 was shown to be expressed on 83% of primary endometrial tumors and 100% of metastatic endometrial cancers in one study (Cancer Immunol Immunother. 2014;63[6]:545-57), suggesting that could be a viable target in this difficult-to-treat disease, noted Dr. Ott and his colleagues.
In their study, 24 women with locally advanced or metastatic PD-L1–positive endometrial cancer who had experienced progression after standard therapy were treated with pembrolizumab 10 mg/kg every 2 weeks for up to 24 months or until disease progression or unacceptable toxicity. As noted, 3 of the 24 patients met the primary efficacy endpoint of objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) with a partial response, with the median duration of response (a secondary endpoint) not reached at the time of data cutoff on Feb. 17, 2016.
Three other patients (13%) had stable disease, with a median duration of 24.6 weeks.
Safety, also a secondary endpoint, was comparable to that seen in other studies with pembrolizumab. Four patients had grade 3 treatment-related adverse events (AEs). There were no grade 4 AEs of any kind, no immune-mediated AEs of any grade, and no treatment-related deaths.
One of the patients who had a partial response was found through genomic profiling to have a polymerase E, or POLE mutation, and this patient had a rapid improvement after starting on pembrolizumab, with the response lasting longer than 14 months.
“These exceptional results support the theory that the presence of POLE mutations may aid in identifying patients for whom pembrolizumab may be particularly effective, a concept that should be investigated further,” wrote Dr. Ott and his colleagues.
Merck Sharp & Dohme sponsored the study. Dr. Ott and multiple coauthors disclosed institution research funding, honoraria, consulting, or advising with the company, and three are Merck employees..
In some women with heavily pretreated locally advanced or metastatic endometrial cancers, treatment with the immune checkpoint inhibitor pembrolizumab (Keytruda) produced partial, durable responses, investigators reported.
The women were participants in the KEYNOTE-028 trial, a multicohort, open-label phase Ib basket trial of patients with advanced solid tumors positive for programmed death ligand 1 (PD-L1). Of 24 women with PD-L1-positive endometrial tumors, 3 (13%) had confirmed partial responses, and 2 of these patients remained on therapy with a continued response at the time of data cutoff, reported Patrick A. Ott, MD, PhD, of Dana-Farber Cancer Institute, Boston, and his colleagues.
“[T]he results from the KEYNOTE-028 trial presented herein indicate that pembrolizumab shows promise as a treatment for advanced endometrial cancer, a disease for which current treatment options are limited,” they wrote (J Clin Oncol. 2017 May 10; doi: 10.1200/JCO.2017.72.5952).
Patients with advanced endometrial cancer have a poor prognosis, with 5-year survival rates below 50% for patients with lymph node metastases, and less than 20% for those with distant metastases or disease that has spread to the peritoneum, the investigators noted.
“Treatment options for patients presenting with advanced disease are limited, with no consensus on a standard regimen. Similarly, no optimal therapy for patients who experience progression during first-line therapy has been identified, with second-line chemotherapeutic options producing only modest activity,” they wrote.
PD-L1 was shown to be expressed on 83% of primary endometrial tumors and 100% of metastatic endometrial cancers in one study (Cancer Immunol Immunother. 2014;63[6]:545-57), suggesting that could be a viable target in this difficult-to-treat disease, noted Dr. Ott and his colleagues.
In their study, 24 women with locally advanced or metastatic PD-L1–positive endometrial cancer who had experienced progression after standard therapy were treated with pembrolizumab 10 mg/kg every 2 weeks for up to 24 months or until disease progression or unacceptable toxicity. As noted, 3 of the 24 patients met the primary efficacy endpoint of objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) with a partial response, with the median duration of response (a secondary endpoint) not reached at the time of data cutoff on Feb. 17, 2016.
Three other patients (13%) had stable disease, with a median duration of 24.6 weeks.
Safety, also a secondary endpoint, was comparable to that seen in other studies with pembrolizumab. Four patients had grade 3 treatment-related adverse events (AEs). There were no grade 4 AEs of any kind, no immune-mediated AEs of any grade, and no treatment-related deaths.
One of the patients who had a partial response was found through genomic profiling to have a polymerase E, or POLE mutation, and this patient had a rapid improvement after starting on pembrolizumab, with the response lasting longer than 14 months.
“These exceptional results support the theory that the presence of POLE mutations may aid in identifying patients for whom pembrolizumab may be particularly effective, a concept that should be investigated further,” wrote Dr. Ott and his colleagues.
Merck Sharp & Dohme sponsored the study. Dr. Ott and multiple coauthors disclosed institution research funding, honoraria, consulting, or advising with the company, and three are Merck employees..
In some women with heavily pretreated locally advanced or metastatic endometrial cancers, treatment with the immune checkpoint inhibitor pembrolizumab (Keytruda) produced partial, durable responses, investigators reported.
The women were participants in the KEYNOTE-028 trial, a multicohort, open-label phase Ib basket trial of patients with advanced solid tumors positive for programmed death ligand 1 (PD-L1). Of 24 women with PD-L1-positive endometrial tumors, 3 (13%) had confirmed partial responses, and 2 of these patients remained on therapy with a continued response at the time of data cutoff, reported Patrick A. Ott, MD, PhD, of Dana-Farber Cancer Institute, Boston, and his colleagues.
“[T]he results from the KEYNOTE-028 trial presented herein indicate that pembrolizumab shows promise as a treatment for advanced endometrial cancer, a disease for which current treatment options are limited,” they wrote (J Clin Oncol. 2017 May 10; doi: 10.1200/JCO.2017.72.5952).
Patients with advanced endometrial cancer have a poor prognosis, with 5-year survival rates below 50% for patients with lymph node metastases, and less than 20% for those with distant metastases or disease that has spread to the peritoneum, the investigators noted.
“Treatment options for patients presenting with advanced disease are limited, with no consensus on a standard regimen. Similarly, no optimal therapy for patients who experience progression during first-line therapy has been identified, with second-line chemotherapeutic options producing only modest activity,” they wrote.
PD-L1 was shown to be expressed on 83% of primary endometrial tumors and 100% of metastatic endometrial cancers in one study (Cancer Immunol Immunother. 2014;63[6]:545-57), suggesting that could be a viable target in this difficult-to-treat disease, noted Dr. Ott and his colleagues.
In their study, 24 women with locally advanced or metastatic PD-L1–positive endometrial cancer who had experienced progression after standard therapy were treated with pembrolizumab 10 mg/kg every 2 weeks for up to 24 months or until disease progression or unacceptable toxicity. As noted, 3 of the 24 patients met the primary efficacy endpoint of objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) with a partial response, with the median duration of response (a secondary endpoint) not reached at the time of data cutoff on Feb. 17, 2016.
Three other patients (13%) had stable disease, with a median duration of 24.6 weeks.
Safety, also a secondary endpoint, was comparable to that seen in other studies with pembrolizumab. Four patients had grade 3 treatment-related adverse events (AEs). There were no grade 4 AEs of any kind, no immune-mediated AEs of any grade, and no treatment-related deaths.
One of the patients who had a partial response was found through genomic profiling to have a polymerase E, or POLE mutation, and this patient had a rapid improvement after starting on pembrolizumab, with the response lasting longer than 14 months.
“These exceptional results support the theory that the presence of POLE mutations may aid in identifying patients for whom pembrolizumab may be particularly effective, a concept that should be investigated further,” wrote Dr. Ott and his colleagues.
Merck Sharp & Dohme sponsored the study. Dr. Ott and multiple coauthors disclosed institution research funding, honoraria, consulting, or advising with the company, and three are Merck employees..
Key clinical point: The anti-PD-L1 checkpoint inhibitor had some activity against locally advanced or metastatic endometrial cancer.
Major finding: Three of 24 patients had a partial response, and three had stable disease.
Data source: Cohort of patients with heavily pretreated advanced endometrial cancer in the multicohort, open-label, phase Ib basket trial KEYNOTE 028.
Disclosures: Merck Sharp & Dohme sponsored the study. Dr. Ott and multiple coauthors disclosed institution research funding, honoraria, consulting, or advising with the company, and three are Merck employees.