Abstract
Pooled analyses of chemotherapy trials in metastatic colorectal cancer (mCRC) have suggested that progression-free survival (PFS) is a surrogate endpoint for overall survival (OS). However, this has not been evaluated under current standard-of-care regimens of chemotherapy in combination with targeted therapies. We conducted an analysis of published mCRC trials of chemotherapy and targeted therapies from 2000 to evaluate the surrogacy of PFS and response rate (RR) for OS. Study-level data was pooled from 24 randomized mCRC trials that evaluated fluoropyrimidine-based regimens and included trials conducted with targeted agents (panitumumab, cetuximab, bevacizumab, and aflibercept). A total of 69 treatment arms with a sample size of 20,438 patients was included. Linear regression analysis was carried out to estimate the correlation of PFS and RR with OS. The correlation coefficient between PFS HRs and OS HRs was 0.86 for all trials, 0.89 for 12 phase III trials of targeted agents in combination with chemotherapy, 0.95 for 8 first-line phase III trials of targeted agents, and 0.83 for 9 trials of anti-EGFR-targeted agents. In all cases, correlation coefficients between RR and OS HRs were lower than those between PFS HRs and OS HRs (range, 0.42-0.81). In this study-level analysis of randomized mCRC trials of chemotherapy and targeted agents, improvements in PFS are strongly correlated with improvements in OS. This suggests that PFS remains a valid surrogate endpoint for OS with current treatment regimens in the mCRC setting.
Highlights
Overall survival (OS), the time from randomization/ first treatment to death from any cause, is often used as the primary endpoint for phase III trials and for regulatory approval
Thirteen of the 24 trials had targeted therapies in at least 1 arm with 9 of these trials evaluating anti-EGF receptor (EGFR) therapies in combination with chemotherapy (2 trials combined anti-EGFR therapies with bevacizumab)
When KRAS status was reported, patients with WT or mutant KRAS metastatic colorectal cancer (mCRC) were analyzed as separate treatment arms as the efficacy of anti-EGFR therapies is limited to patients with WT KRAS mCRC [22]
Summary
Overall survival (OS), the time from randomization/ first treatment to death from any cause, is often used as the primary endpoint for phase III trials and for regulatory approval. OS as an endpoint is clinically meaningful and objectively assessed. Trials using OS endpoints often require large patient numbers and protracted long-term follow-up, which may delay decisions about the effectiveness of new treatments. Given the growing number of efficacious treatments in later lines of therapy and crossover between therapies, improvements in OS for earlier lines of treatments may become increasingly confounded by effective poststudy therapies. OS as an endpoint may become less relevant in clinical trials as the standard of care may change by the time OS data are mature.
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