Can overall survival (OS) benefit be predicted from improvements in progression-free survival (PFS) for previously untreated metastatic colorectal cancer (mCRC)?

Abstract

222 Background: With improvements in treatment of mCRC, OS maintains its gold standard efficacy measure but takes longer to mature than intermediate endpoints. This study analyzed the association between treatment effects on PFS and OS using aggregate-level data from RCTs in previously untreated mCRC patients. Methods: A systematic literature review identified RCTs in previously untreated mCRC patients published from 2010–2021 reporting hazard ratios on PFS (HR PFS ) and OS (HR OS ). All treatments in comparison to chemotherapy alone or chemotherapy with anti-VEGF (bevacizumab) or anti-EGFR (cetuximab) targeted therapy were considered. Correlation between HR PFS and HR OS was evaluated using bivariate random-effects meta-analysis (BRMA) and weighted linear regression (WLR). Predictive performance of the surrogacy equations from WLR was assessed using leave-one-out cross-validation (LOOCV). Surrogate threshold effects (STE), defined as the minimum PFS benefit that would translate into a statistically significant OS benefit with 95% probability, were also derived to gauge the practical utility of the models. Primary analysis consisted of all included trials. Sensitivity analyses omitted trials that (I) had anti-EGFR medications, (II) had anti-VEGF medications, (III) violated proportional hazards assumptions, and (IV) permitted treatment crossover. Results: In the primary analysis 47 trials were included. The estimated correlation between PFS and OS was 0.67 (95% CI: 0.48–0.80) using BRMA and 0.70 (95% CI: 0.48–0.84) using WLR. The surrogacy equation derived from WLR was log(HR OS ) = −0.03 + 0.56 log(HR PFS ) with a statistically insignificant intercept and significant slope. Estimated STEs corresponding to sample sizes of 200 and 300 patients were 0.55 and 0.62, respectively. Observed HR OS ’s were within their 95% prediction intervals predicted from HR PFS for 93.6% of studies in LOOCV. Sensitivity analyses produced moderate correlations with >90% coverage in LOOCV (Table). Conclusions: Moderate correlations were found between HR PFS and HR OS using both modeling approaches, highlighting the stability of the findings. Cross-validations of surrogacy equations indicated promising predictive value of PFS benefit for OS benefit in previously untreated mCRC. Analysis Set​ # of Studies​ Correlation (95% CI) STE LOOCV​Coverage Rate​ BRMA WLR N = 200 N = 300 Sensitivity Analysis I​ 34​ 0.75 ​(0.57, 0.86)​ 0.78 ​(0.55, 0.90)​ 0.55​ 0.61​ 94.1​% Sensitivity Analysis II​ 14​ 0.44 ​(-0.08, 0.77)​ 0.62 ​(-0.05, 0.90)​ 0.44​ 0.52​ 92.9​% Sensitivity Analysis III​ 36​ 0.61 ​(0.36, 0.77)​ 0.59 ​(0.26, 0.80)​ 0.46​ 0.55​ 94.4​% Sensitivity Analysis IV 43​ 0.68 ​(0.48, 0.81)​ 0.67​(0.41, 0.83)​ 0.52​ 0.60​ 93.0​%