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Objective response rate (ORR) correlated poorly with overall survival (OS), but 6-month progression-free survival was a better predictor of 12-month OS, according to a systematic review and meta-analysis of phase 2 and phase 3 trials of checkpoint inhibitors in advanced solid cancers.
Six-month progression-free survival is recommended in place of objective response rate as an endpoint in future phase 2 checkpoint-inhibitor trials, investigators wrote. The report was published in JAMA Oncology.
Appropriate selection of a primary endpoint in phase 2 checkpoint-inhibitor trials is critical to proceed to phase 3 testing. In checkpoint inhibitor trials, the validity of ORR, as determined by RECIST, and PFS as surrogates for OS remains unclear.
The investigators conducted a systematic search of electronic databases for trial results from January 2000 to January 2017, identified through PREMEDLINE, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. In addition, abstracts and conference presentations on the European Society for Medical Oncology and American Society of Clinical Oncology websites were hand-searched, wrote Georgia Ritchie, MBBS, of the Cancer Care Centre, St. George Hospital, Sydney, and associates.
Inclusion criteria comprised trials that used checkpoint inhibitors in advanced solid cancers in single-arm or randomized controlled trials of phase 2 and phase 3 designs.
Within the checkpoint inhibitor arms of the trials, r correlation coefficients between ORR with 6-month PFS, ORR with 12-month OS, and 6-month PFS with 12-month OS were 0.37 (95% confidence interval, −0.06 to 0.95), 0.08 (95% confidence interval, −0.17 to 0.70), and 0.74 (95% confidence interval, 0.57-0.92), respectively, Dr. Ritchie and associates reported. To validate an OS prediction model, the investigators found a good calibration between 6-month PFS and actual and predicted 12-month OS. However, when ORR was used to predict 6-month PFS and 12-month OS rates, the actual vs. predicted rates calibrated poorly, they said.
A strength of the study is its generalizability, because of a heterogeneous population of patients with advanced cancer. “Future phase 2 trials might require a larger sample size, and more resources to report on this result than RECIST ORR,” reported the authors. Further research is required to assess the validity of milestone analysis with 6-month PFS as a potential surrogate for OS in treatment comparisons between checkpoint inhibitors and standard of care therapy, they added.
The authors reported no conflicts of interest.
SOURCE: Ritchie G et al., JAMA Oncol. 2018 Feb 22 doi: 10.1001/jamaoncol.2017.5236.
Objective response rate (ORR) correlated poorly with overall survival (OS), but 6-month progression-free survival was a better predictor of 12-month OS, according to a systematic review and meta-analysis of phase 2 and phase 3 trials of checkpoint inhibitors in advanced solid cancers.
Six-month progression-free survival is recommended in place of objective response rate as an endpoint in future phase 2 checkpoint-inhibitor trials, investigators wrote. The report was published in JAMA Oncology.
Appropriate selection of a primary endpoint in phase 2 checkpoint-inhibitor trials is critical to proceed to phase 3 testing. In checkpoint inhibitor trials, the validity of ORR, as determined by RECIST, and PFS as surrogates for OS remains unclear.
The investigators conducted a systematic search of electronic databases for trial results from January 2000 to January 2017, identified through PREMEDLINE, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. In addition, abstracts and conference presentations on the European Society for Medical Oncology and American Society of Clinical Oncology websites were hand-searched, wrote Georgia Ritchie, MBBS, of the Cancer Care Centre, St. George Hospital, Sydney, and associates.
Inclusion criteria comprised trials that used checkpoint inhibitors in advanced solid cancers in single-arm or randomized controlled trials of phase 2 and phase 3 designs.
Within the checkpoint inhibitor arms of the trials, r correlation coefficients between ORR with 6-month PFS, ORR with 12-month OS, and 6-month PFS with 12-month OS were 0.37 (95% confidence interval, −0.06 to 0.95), 0.08 (95% confidence interval, −0.17 to 0.70), and 0.74 (95% confidence interval, 0.57-0.92), respectively, Dr. Ritchie and associates reported. To validate an OS prediction model, the investigators found a good calibration between 6-month PFS and actual and predicted 12-month OS. However, when ORR was used to predict 6-month PFS and 12-month OS rates, the actual vs. predicted rates calibrated poorly, they said.
A strength of the study is its generalizability, because of a heterogeneous population of patients with advanced cancer. “Future phase 2 trials might require a larger sample size, and more resources to report on this result than RECIST ORR,” reported the authors. Further research is required to assess the validity of milestone analysis with 6-month PFS as a potential surrogate for OS in treatment comparisons between checkpoint inhibitors and standard of care therapy, they added.
The authors reported no conflicts of interest.
SOURCE: Ritchie G et al., JAMA Oncol. 2018 Feb 22 doi: 10.1001/jamaoncol.2017.5236.
Objective response rate (ORR) correlated poorly with overall survival (OS), but 6-month progression-free survival was a better predictor of 12-month OS, according to a systematic review and meta-analysis of phase 2 and phase 3 trials of checkpoint inhibitors in advanced solid cancers.
Six-month progression-free survival is recommended in place of objective response rate as an endpoint in future phase 2 checkpoint-inhibitor trials, investigators wrote. The report was published in JAMA Oncology.
Appropriate selection of a primary endpoint in phase 2 checkpoint-inhibitor trials is critical to proceed to phase 3 testing. In checkpoint inhibitor trials, the validity of ORR, as determined by RECIST, and PFS as surrogates for OS remains unclear.
The investigators conducted a systematic search of electronic databases for trial results from January 2000 to January 2017, identified through PREMEDLINE, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. In addition, abstracts and conference presentations on the European Society for Medical Oncology and American Society of Clinical Oncology websites were hand-searched, wrote Georgia Ritchie, MBBS, of the Cancer Care Centre, St. George Hospital, Sydney, and associates.
Inclusion criteria comprised trials that used checkpoint inhibitors in advanced solid cancers in single-arm or randomized controlled trials of phase 2 and phase 3 designs.
Within the checkpoint inhibitor arms of the trials, r correlation coefficients between ORR with 6-month PFS, ORR with 12-month OS, and 6-month PFS with 12-month OS were 0.37 (95% confidence interval, −0.06 to 0.95), 0.08 (95% confidence interval, −0.17 to 0.70), and 0.74 (95% confidence interval, 0.57-0.92), respectively, Dr. Ritchie and associates reported. To validate an OS prediction model, the investigators found a good calibration between 6-month PFS and actual and predicted 12-month OS. However, when ORR was used to predict 6-month PFS and 12-month OS rates, the actual vs. predicted rates calibrated poorly, they said.
A strength of the study is its generalizability, because of a heterogeneous population of patients with advanced cancer. “Future phase 2 trials might require a larger sample size, and more resources to report on this result than RECIST ORR,” reported the authors. Further research is required to assess the validity of milestone analysis with 6-month PFS as a potential surrogate for OS in treatment comparisons between checkpoint inhibitors and standard of care therapy, they added.
The authors reported no conflicts of interest.
SOURCE: Ritchie G et al., JAMA Oncol. 2018 Feb 22 doi: 10.1001/jamaoncol.2017.5236.
FROM JAMA ONCOLOGY
Key clinical point: Immune checkpoint inhibitors activate anti-tumor T-cells to detect and destroy tumor cells and have become the standard of care for many patients with advanced solid cancers. The most appropriate primary endpoint in phase 2 trials of checkpoint inhibitors remains uncertain.
Major finding: In this systematic review and meta-analysis of phase 2 and phase 3 trials of checkpoint inhibitors in advanced solid cancers, objective response rate correlated poorly with overall survival, but 6-month progression-free survival was a better predictor of 12-month overall survival.
Study details: Trials listed in electronic databases from 2000 to 2017 (PREMEDLINE, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials).
Disclosures: None reported.
Source: Ritchie G et al. JAMA Oncol. 2018 Feb 22. doi: 10.1001/jamaoncol.2017.5236.