A Comparison of Response Patterns for Progression-Free Survival and Overall Survival Following Treatment for Cancer With PD-1 Inhibitors: A Meta-analysis of Correlation and Differences in Effect Sizes.

ABSTRACT:

Importance

Based on efficacy results from pivotal randomized clinical trials, PD-1 (programmed cell death 1) inhibitors, such as nivolumab and pembrolizumab, have been approved to treat various cancers. Response patterns with varying effects on progression-free survival (PFS) and overall survival (OS) have been reported for these drugs.

Objective

To compare 2 outcomes for PD-1 inhibitors: the correlation between PFS and OS and the differences in treatment effect size between PFS and OS.

Data sources

A systematic search of PubMed, Google Scholar, the Cochrane Library, Web of Science, and conference abstracts for randomized clinical trials of nivolumab and pembrolizumab published in English.

Study selection

Randomized clinical trials of nivolumab or pembrolizumab in adults with solid-tissue cancers with a nonimmunotherapy control.

Data extraction and synthesis

Two reviewers screened the studies for selection and extracted data on medians and hazard ratios (HRs) for PFS and OS. A pooled meta-analysis was conducted.

Main outcomes and measures

Across all trials, correlation coefficients between median PFS and median OS and between PFS benefit and OS benefit as well as the HRs of PFS and OS were assessed. The difference in treatment effect sizes between PFS and OS was assessed using a ratio of HRs (rHR). Subgroup analyses were conducted to observe differences based on drug, tumor type, and timing of therapy.

Results

Ten randomized clinical trials that included 4653 patients and met inclusion criteria were identified, as were 2 others (comprising 764 patients) in which nivolumab or pembrolizumab was used following treatment with ipilimumab. The correlations between median PFS and median OS (r?=?0.676; R2?=?0.457; P?=?.09) and the correlations between the change in PFS and the change in OS (r?=?0.474; R2?=?0.225; P?=?.28) were not significant. However, the correlation between HRs of PFS and OS was significant (r?=?0.637; R2?=?0.406; P?=?.048). Using random-effects meta-analysis, the protective effects of treatment were greater for OS than for PFS (pooled rHR, 1.18; 95% CI, 1.06-1.31; P?=?.002). There was no statistical evidence for heterogeneity across the studies (Q?=?6.24; P?=?.72; I2?=?0%). Subgroup analyses showed some differences in the treatment effect sizes based on drug type, tumor type, and line of therapy.

Conclusions and relevance

There was no significant correlation between OS and PFS in terms of medians and gains in medians, but their HRs were significantly correlated. The protective effects of treatment were greater for OS than for PFS. Traditional Response Evaluation Criteria in Solid Tumors-based PFS cannot capture the benefit of PD-1 inhibitors in patients with solid tumors, and OS should remain the gold standard.

SUBMITTER: Gyawali B 

PROVIDER: S-EPMC6324401 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature