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The investigator, Daniel Olson, MD, of the University of Chicago, presented the study results as part of the American Society of Clinical Oncology virtual scientific program.
Pembrolizumab plus ipilimumab at 1 mg/kg generated a response rate of 27%, Dr. Olson reported. This is higher than the 15% response rate observed in historical controls who received ipilimumab alone after primary PD-1 failure (Lancet Oncol. 2019 Sep;20[9]:1239-1251), he noted.
“Treatment-related grade 3 to 4 toxicity occurred in 27% of patients” in the current trial, Dr. Olson added. He said this compares favorably to ipilimumab given at 3 mg/kg in combination with a PD-1 antibody first line, which produced a grade 3/4 adverse event rate of 59% in a prior trial (N Engl J Med 2017; 377:1345-1356).
Preserving efficacy while limiting toxicity
“The combination of PD-1 and CTLA-4 blockade is an incredibly potent combination, not only in melanoma, but across cancer types,” said Douglas Johnson, MD, an assistant professor at Vanderbilt University in Nashville, Tenn., and the discussant on Dr. Olson’s presentation.
Dr. Johnson noted, however, that the combination produces a high incidence of serious immune-related adverse events.
The goal of recent research has been finding a way to preserve the efficacy but limit the toxicity. The tack taken in the current study was to wait until primary PD-1 antibody failure to initiate the combination, then do so with an ipilimumab dose lower than the standard 3 mg/kg used in melanoma.
“The response rate was quite good,” Dr. Johnson said. “I think these are very favorable results.”
“It does seem like the sequential approach does decrease the total number of toxicities compared to using both agents in the front line,” he added. “Should we use 1 mg/kg or 3 mg/kg [ipilimumab] in this sort of sequential-type approach? I would say, at this point, they’re still both viable.”
However, for “patients who really need an upfront response ... we might favor giving combination upfront,” Dr. Johnson said.
Patients and treatment
The trial (NCT02743819) enrolled 70 patients with unresectable or metastatic melanoma that had progressed on a PD-1 antibody after a median treatment duration of 4.8 months. Patients had no prior exposure to a CTLA4 antibody.
Prior to entry, 86% of subjects had been treated with a PD-1 antibody alone, 14% with a PD-1 antibody in a non-CTLA4 antibody combination, and 7% with BRAF-directed therapy prior to PD-1 antibody treatment.
The patients’ median age was 64 years, and 67% were men. Overall, 89% of subjects had cutaneous melanoma, 10% acral melanoma, and 1% mucosal melanoma.
Half of patients had stage IV M1c or M1d disease. Ten percent had treated brain metastases at baseline, 24% had liver metastases, 28% had baseline lactate dehydrogenase (LDH) above the upper limit of normal, and 29% had BRAF mutations.
The patients were treated with ipilimumab at 1 mg/kg every 3 weeks for four doses. They received pembrolizumab at 200 mg every 3 weeks for up to 2 years.
Response details
There were 61 subjects evaluable for response, but all 70 patients were considered in the response rate. There were 5 complete responses and 14 partial responses, for a response rate of 27% (19/70). The median duration of response was 18.5 months.
“We did observe a substantially higher response rate among the PD-L1 negative subgroup, as compared to PD-L1-positive,” Dr. Olson said. “The responses observed in some of these higher-risk patients, and especially the responses we saw among many PD-L1-negative tumors, suggested that we might be capturing atypical responders with [pembrolizumab plus ipilimumab].”
“Most responses occurred in non-T-cell-inflamed or intermediate tumors,” Dr. Olson added. “Our trial enriched for non-T-cell inflamed tumor phenotypes, where we then observe[d] responses.”
“These patients responded across BRAF mutation status,” Dr. Johnson noted. “Patients who had elevated LDH, those who had liver metastases, brain metastases, also had comparable response rates to those lacking those more adverse prognostic features.”
Survival and safety
The median progression-free survival was 5 months, and the median overall survival was 24.7 months.
“The multiple durable responses we observed did translate into long-term survival for some patients,” Dr. Olson said.
Eighteen subjects (26%) had grade 3 adverse events at least possibly related to treatment. The most common were colitis/diarrhea in 9%, rash in 6%, and ALT/AST elevations in 6%. There was one grade 4 adverse event, a lipase elevation.
The median time to onset of high-grade adverse events was 55 days, which would fall between cycles 2 and 3 of ipilimumab “and is similar to the experience with [ipilimumab] in the front-line setting,” Dr. Olson said.
This study was funded by an investigator-initiated grant from Merck. Dr. Olson had no disclosures. Some of his coinvestigators reported ties to the company. Dr. Johnson is an advisor for Merck.
SOURCE: Olson D et al. ASCO 2020, Abstract 10004.
The investigator, Daniel Olson, MD, of the University of Chicago, presented the study results as part of the American Society of Clinical Oncology virtual scientific program.
Pembrolizumab plus ipilimumab at 1 mg/kg generated a response rate of 27%, Dr. Olson reported. This is higher than the 15% response rate observed in historical controls who received ipilimumab alone after primary PD-1 failure (Lancet Oncol. 2019 Sep;20[9]:1239-1251), he noted.
“Treatment-related grade 3 to 4 toxicity occurred in 27% of patients” in the current trial, Dr. Olson added. He said this compares favorably to ipilimumab given at 3 mg/kg in combination with a PD-1 antibody first line, which produced a grade 3/4 adverse event rate of 59% in a prior trial (N Engl J Med 2017; 377:1345-1356).
Preserving efficacy while limiting toxicity
“The combination of PD-1 and CTLA-4 blockade is an incredibly potent combination, not only in melanoma, but across cancer types,” said Douglas Johnson, MD, an assistant professor at Vanderbilt University in Nashville, Tenn., and the discussant on Dr. Olson’s presentation.
Dr. Johnson noted, however, that the combination produces a high incidence of serious immune-related adverse events.
The goal of recent research has been finding a way to preserve the efficacy but limit the toxicity. The tack taken in the current study was to wait until primary PD-1 antibody failure to initiate the combination, then do so with an ipilimumab dose lower than the standard 3 mg/kg used in melanoma.
“The response rate was quite good,” Dr. Johnson said. “I think these are very favorable results.”
“It does seem like the sequential approach does decrease the total number of toxicities compared to using both agents in the front line,” he added. “Should we use 1 mg/kg or 3 mg/kg [ipilimumab] in this sort of sequential-type approach? I would say, at this point, they’re still both viable.”
However, for “patients who really need an upfront response ... we might favor giving combination upfront,” Dr. Johnson said.
Patients and treatment
The trial (NCT02743819) enrolled 70 patients with unresectable or metastatic melanoma that had progressed on a PD-1 antibody after a median treatment duration of 4.8 months. Patients had no prior exposure to a CTLA4 antibody.
Prior to entry, 86% of subjects had been treated with a PD-1 antibody alone, 14% with a PD-1 antibody in a non-CTLA4 antibody combination, and 7% with BRAF-directed therapy prior to PD-1 antibody treatment.
The patients’ median age was 64 years, and 67% were men. Overall, 89% of subjects had cutaneous melanoma, 10% acral melanoma, and 1% mucosal melanoma.
Half of patients had stage IV M1c or M1d disease. Ten percent had treated brain metastases at baseline, 24% had liver metastases, 28% had baseline lactate dehydrogenase (LDH) above the upper limit of normal, and 29% had BRAF mutations.
The patients were treated with ipilimumab at 1 mg/kg every 3 weeks for four doses. They received pembrolizumab at 200 mg every 3 weeks for up to 2 years.
Response details
There were 61 subjects evaluable for response, but all 70 patients were considered in the response rate. There were 5 complete responses and 14 partial responses, for a response rate of 27% (19/70). The median duration of response was 18.5 months.
“We did observe a substantially higher response rate among the PD-L1 negative subgroup, as compared to PD-L1-positive,” Dr. Olson said. “The responses observed in some of these higher-risk patients, and especially the responses we saw among many PD-L1-negative tumors, suggested that we might be capturing atypical responders with [pembrolizumab plus ipilimumab].”
“Most responses occurred in non-T-cell-inflamed or intermediate tumors,” Dr. Olson added. “Our trial enriched for non-T-cell inflamed tumor phenotypes, where we then observe[d] responses.”
“These patients responded across BRAF mutation status,” Dr. Johnson noted. “Patients who had elevated LDH, those who had liver metastases, brain metastases, also had comparable response rates to those lacking those more adverse prognostic features.”
Survival and safety
The median progression-free survival was 5 months, and the median overall survival was 24.7 months.
“The multiple durable responses we observed did translate into long-term survival for some patients,” Dr. Olson said.
Eighteen subjects (26%) had grade 3 adverse events at least possibly related to treatment. The most common were colitis/diarrhea in 9%, rash in 6%, and ALT/AST elevations in 6%. There was one grade 4 adverse event, a lipase elevation.
The median time to onset of high-grade adverse events was 55 days, which would fall between cycles 2 and 3 of ipilimumab “and is similar to the experience with [ipilimumab] in the front-line setting,” Dr. Olson said.
This study was funded by an investigator-initiated grant from Merck. Dr. Olson had no disclosures. Some of his coinvestigators reported ties to the company. Dr. Johnson is an advisor for Merck.
SOURCE: Olson D et al. ASCO 2020, Abstract 10004.
The investigator, Daniel Olson, MD, of the University of Chicago, presented the study results as part of the American Society of Clinical Oncology virtual scientific program.
Pembrolizumab plus ipilimumab at 1 mg/kg generated a response rate of 27%, Dr. Olson reported. This is higher than the 15% response rate observed in historical controls who received ipilimumab alone after primary PD-1 failure (Lancet Oncol. 2019 Sep;20[9]:1239-1251), he noted.
“Treatment-related grade 3 to 4 toxicity occurred in 27% of patients” in the current trial, Dr. Olson added. He said this compares favorably to ipilimumab given at 3 mg/kg in combination with a PD-1 antibody first line, which produced a grade 3/4 adverse event rate of 59% in a prior trial (N Engl J Med 2017; 377:1345-1356).
Preserving efficacy while limiting toxicity
“The combination of PD-1 and CTLA-4 blockade is an incredibly potent combination, not only in melanoma, but across cancer types,” said Douglas Johnson, MD, an assistant professor at Vanderbilt University in Nashville, Tenn., and the discussant on Dr. Olson’s presentation.
Dr. Johnson noted, however, that the combination produces a high incidence of serious immune-related adverse events.
The goal of recent research has been finding a way to preserve the efficacy but limit the toxicity. The tack taken in the current study was to wait until primary PD-1 antibody failure to initiate the combination, then do so with an ipilimumab dose lower than the standard 3 mg/kg used in melanoma.
“The response rate was quite good,” Dr. Johnson said. “I think these are very favorable results.”
“It does seem like the sequential approach does decrease the total number of toxicities compared to using both agents in the front line,” he added. “Should we use 1 mg/kg or 3 mg/kg [ipilimumab] in this sort of sequential-type approach? I would say, at this point, they’re still both viable.”
However, for “patients who really need an upfront response ... we might favor giving combination upfront,” Dr. Johnson said.
Patients and treatment
The trial (NCT02743819) enrolled 70 patients with unresectable or metastatic melanoma that had progressed on a PD-1 antibody after a median treatment duration of 4.8 months. Patients had no prior exposure to a CTLA4 antibody.
Prior to entry, 86% of subjects had been treated with a PD-1 antibody alone, 14% with a PD-1 antibody in a non-CTLA4 antibody combination, and 7% with BRAF-directed therapy prior to PD-1 antibody treatment.
The patients’ median age was 64 years, and 67% were men. Overall, 89% of subjects had cutaneous melanoma, 10% acral melanoma, and 1% mucosal melanoma.
Half of patients had stage IV M1c or M1d disease. Ten percent had treated brain metastases at baseline, 24% had liver metastases, 28% had baseline lactate dehydrogenase (LDH) above the upper limit of normal, and 29% had BRAF mutations.
The patients were treated with ipilimumab at 1 mg/kg every 3 weeks for four doses. They received pembrolizumab at 200 mg every 3 weeks for up to 2 years.
Response details
There were 61 subjects evaluable for response, but all 70 patients were considered in the response rate. There were 5 complete responses and 14 partial responses, for a response rate of 27% (19/70). The median duration of response was 18.5 months.
“We did observe a substantially higher response rate among the PD-L1 negative subgroup, as compared to PD-L1-positive,” Dr. Olson said. “The responses observed in some of these higher-risk patients, and especially the responses we saw among many PD-L1-negative tumors, suggested that we might be capturing atypical responders with [pembrolizumab plus ipilimumab].”
“Most responses occurred in non-T-cell-inflamed or intermediate tumors,” Dr. Olson added. “Our trial enriched for non-T-cell inflamed tumor phenotypes, where we then observe[d] responses.”
“These patients responded across BRAF mutation status,” Dr. Johnson noted. “Patients who had elevated LDH, those who had liver metastases, brain metastases, also had comparable response rates to those lacking those more adverse prognostic features.”
Survival and safety
The median progression-free survival was 5 months, and the median overall survival was 24.7 months.
“The multiple durable responses we observed did translate into long-term survival for some patients,” Dr. Olson said.
Eighteen subjects (26%) had grade 3 adverse events at least possibly related to treatment. The most common were colitis/diarrhea in 9%, rash in 6%, and ALT/AST elevations in 6%. There was one grade 4 adverse event, a lipase elevation.
The median time to onset of high-grade adverse events was 55 days, which would fall between cycles 2 and 3 of ipilimumab “and is similar to the experience with [ipilimumab] in the front-line setting,” Dr. Olson said.
This study was funded by an investigator-initiated grant from Merck. Dr. Olson had no disclosures. Some of his coinvestigators reported ties to the company. Dr. Johnson is an advisor for Merck.
SOURCE: Olson D et al. ASCO 2020, Abstract 10004.
FROM ASCO 2020
Key clinical point: Low-dose ipilimumab (1 mg/kg) plus pembrolizumab given immediately after progression on a PD-1 antibody alone demonstrated antitumor activity and tolerability in patients with advanced melanoma, according to an investigator.
Major finding: There were 5 complete responses and 14 partial responses, for a response rate of 27%. The rate of grade 3/4 adverse events was 27%.
Study details: Phase 2 study of 70 patients, 61 of whom were evaluable for response.
Disclosures: The study was funded by an investigator-initiated grant from Merck. Dr. Olson had no disclosures. Some of his coinvestigators reported ties to the company.
Source: Olson D et al. ASCO 2020, Abstract 10004.