Immuno-oncology

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.

[email protected]

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.

[email protected]

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.

[email protected]

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.

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.

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.

[email protected]

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.

[email protected]

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.

[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.

[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.

[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.

[email protected]

On Twitter @karioakes

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.

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.

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.

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).

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.

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).

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.

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).

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.

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.

[email protected]

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.

[email protected]

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.

[email protected]

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..

[email protected]

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..

[email protected]

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..

[email protected]

GENEVA – Patients with stage IV non–small cell lung cancer (NSCLC) who have disease progression following treatment with an immune checkpoint inhibitor have a 30% better chance of achieving at least a partial response with salvage chemotherapy compared with patients who had received prior chemotherapy but not immunotherapy, according to Swiss and U.S. investigators.

In a study of 82 patients with advanced NSCLC, 18 of 67 patients (27%) who had progressed on an inhibitor of programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) had a partial response to combination chemotherapy, compared with just 1 of 15 (7%) of patients who had not received a checkpoint inhibitor, reported Sacha Rothschild, MD, PhD, of University Hospital Basel, Switzerland, and colleagues.

“The odds of achieving a partial response to salvage chemotherapy were significantly higher in patients with prior exposure to PD-1/PD-L1 inhibitors. This observed difference, however, warrants confirmation in larger cohorts. Ongoing investigations include the duration of response as well as evaluation of toxicity,” the researchers wrote in a scientific poster presented at the European Lung Cancer Conference.

Immune checkpoint inhibitors have been shown to be active in patients with late-stage NSCLC who have experienced disease progression following chemotherapy. To see whether salvage chemotherapy could offer any additional benefit to patients who had disease progression on immunotherapy, the investigators conducted a retrospective case-control study. They reviewed 355 patient records, and identified 82 patients – 46 men and 36 women – who met the study criteria.

Of this group, 67 patients had received a PD-1/PD-L1 checkpoint inhibitor, either nivolumab (Opdivo, 56 patients), pembrolizumab (Keytruda, 7), or atezolizumab (Tecentriq, 4). These patients were designated as cases. The remaining 15 patients, who had received prior chemotherapy or chemoradiotherapy only, were designated as controls.

Of all 82 patients, 63 (77%) had adenocarcinomas, 18 (22%) had squamous cell carcinomas, and 1 (1%) had a large-cell carcinoma.

Cases had a mean of 2.37 chemotherapy regimens prior to salvage chemotherapy, and controls had a mean of 1.93. Drugs used in the salvage regimens were docetaxel in 62% of patients, pemetrexed in 20%, gemcitabine in 12%, and paclitaxel in 6%.

GENEVA – Patients with stage IV non–small cell lung cancer (NSCLC) who have disease progression following treatment with an immune checkpoint inhibitor have a 30% better chance of achieving at least a partial response with salvage chemotherapy compared with patients who had received prior chemotherapy but not immunotherapy, according to Swiss and U.S. investigators.

In a study of 82 patients with advanced NSCLC, 18 of 67 patients (27%) who had progressed on an inhibitor of programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) had a partial response to combination chemotherapy, compared with just 1 of 15 (7%) of patients who had not received a checkpoint inhibitor, reported Sacha Rothschild, MD, PhD, of University Hospital Basel, Switzerland, and colleagues.

“The odds of achieving a partial response to salvage chemotherapy were significantly higher in patients with prior exposure to PD-1/PD-L1 inhibitors. This observed difference, however, warrants confirmation in larger cohorts. Ongoing investigations include the duration of response as well as evaluation of toxicity,” the researchers wrote in a scientific poster presented at the European Lung Cancer Conference.

Immune checkpoint inhibitors have been shown to be active in patients with late-stage NSCLC who have experienced disease progression following chemotherapy. To see whether salvage chemotherapy could offer any additional benefit to patients who had disease progression on immunotherapy, the investigators conducted a retrospective case-control study. They reviewed 355 patient records, and identified 82 patients – 46 men and 36 women – who met the study criteria.

Of this group, 67 patients had received a PD-1/PD-L1 checkpoint inhibitor, either nivolumab (Opdivo, 56 patients), pembrolizumab (Keytruda, 7), or atezolizumab (Tecentriq, 4). These patients were designated as cases. The remaining 15 patients, who had received prior chemotherapy or chemoradiotherapy only, were designated as controls.

Of all 82 patients, 63 (77%) had adenocarcinomas, 18 (22%) had squamous cell carcinomas, and 1 (1%) had a large-cell carcinoma.

Cases had a mean of 2.37 chemotherapy regimens prior to salvage chemotherapy, and controls had a mean of 1.93. Drugs used in the salvage regimens were docetaxel in 62% of patients, pemetrexed in 20%, gemcitabine in 12%, and paclitaxel in 6%.

GENEVA – Patients with stage IV non–small cell lung cancer (NSCLC) who have disease progression following treatment with an immune checkpoint inhibitor have a 30% better chance of achieving at least a partial response with salvage chemotherapy compared with patients who had received prior chemotherapy but not immunotherapy, according to Swiss and U.S. investigators.

In a study of 82 patients with advanced NSCLC, 18 of 67 patients (27%) who had progressed on an inhibitor of programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) had a partial response to combination chemotherapy, compared with just 1 of 15 (7%) of patients who had not received a checkpoint inhibitor, reported Sacha Rothschild, MD, PhD, of University Hospital Basel, Switzerland, and colleagues.

“The odds of achieving a partial response to salvage chemotherapy were significantly higher in patients with prior exposure to PD-1/PD-L1 inhibitors. This observed difference, however, warrants confirmation in larger cohorts. Ongoing investigations include the duration of response as well as evaluation of toxicity,” the researchers wrote in a scientific poster presented at the European Lung Cancer Conference.

Immune checkpoint inhibitors have been shown to be active in patients with late-stage NSCLC who have experienced disease progression following chemotherapy. To see whether salvage chemotherapy could offer any additional benefit to patients who had disease progression on immunotherapy, the investigators conducted a retrospective case-control study. They reviewed 355 patient records, and identified 82 patients – 46 men and 36 women – who met the study criteria.

Of this group, 67 patients had received a PD-1/PD-L1 checkpoint inhibitor, either nivolumab (Opdivo, 56 patients), pembrolizumab (Keytruda, 7), or atezolizumab (Tecentriq, 4). These patients were designated as cases. The remaining 15 patients, who had received prior chemotherapy or chemoradiotherapy only, were designated as controls.

Of all 82 patients, 63 (77%) had adenocarcinomas, 18 (22%) had squamous cell carcinomas, and 1 (1%) had a large-cell carcinoma.

Cases had a mean of 2.37 chemotherapy regimens prior to salvage chemotherapy, and controls had a mean of 1.93. Drugs used in the salvage regimens were docetaxel in 62% of patients, pemetrexed in 20%, gemcitabine in 12%, and paclitaxel in 6%.

GENEVA – Immune checkpoint inhibitors may improve survival in patients with non–small cell lung cancer (NSCLC) and brain metastases compared with chemotherapy, without adding unacceptable toxicities, pooled analyses of clinical trials suggest.

Among 1452 patients with NSCLC treated with the programmed death ligand-1 (PD-L1) inhibitor atezolizumab (Tecentriq), rates of treatment-related serious adverse events (SAEs) were similar between patients with brain metastases at baseline and those without brain metastases, reported Rimas V Lukas, MD, from the University of Chicago.

Neil Osterweil/Frontline Medical News

Neil Osterweil/Frontline Medical News

[email protected]

GENEVA – Immune checkpoint inhibitors may improve survival in patients with non–small cell lung cancer (NSCLC) and brain metastases compared with chemotherapy, without adding unacceptable toxicities, pooled analyses of clinical trials suggest.

Among 1452 patients with NSCLC treated with the programmed death ligand-1 (PD-L1) inhibitor atezolizumab (Tecentriq), rates of treatment-related serious adverse events (SAEs) were similar between patients with brain metastases at baseline and those without brain metastases, reported Rimas V Lukas, MD, from the University of Chicago.

Neil Osterweil/Frontline Medical News

Neil Osterweil/Frontline Medical News

[email protected]

GENEVA – Immune checkpoint inhibitors may improve survival in patients with non–small cell lung cancer (NSCLC) and brain metastases compared with chemotherapy, without adding unacceptable toxicities, pooled analyses of clinical trials suggest.

Among 1452 patients with NSCLC treated with the programmed death ligand-1 (PD-L1) inhibitor atezolizumab (Tecentriq), rates of treatment-related serious adverse events (SAEs) were similar between patients with brain metastases at baseline and those without brain metastases, reported Rimas V Lukas, MD, from the University of Chicago.

Neil Osterweil/Frontline Medical News

Neil Osterweil/Frontline Medical News

[email protected]