Tumor response and progression-free survival (PFS) as potential surrogate endpoints for overall survival (OS) in extensive-stage small cell lung cancer (ES-SCLC): Findings based on North Central Cancer Treatment Group (NCCTG) trials.

Abstract

7637 Background: We investigated the putative surrogate endpoints (PSEs) of best response (BR), confirmed response (CoR), and PFS for association with OS, and as possible surrogate endpoints for OS. Methods: Individual patient (pt) data for 870 untreated ES-SCLC pts from 6 single-arm (274 pts) and 3 randomized trials (596 pts from 32 participating centers) containing platinum or paclitaxel-based regimens were pooled. Patient-level associations between the PSEs and OS were assessed by Cox models using a landmark analyses at 2, 4, and 6 months post-study entry. Model discrimination was evaluated using the concordance (c) index. Trial-level surrogacy of PSEs was assessed by the association of the treatment effects on OS and individual PSEs. Treatment effects were estimated through log hazard ratios and log odds ratios. Trial-level surrogacy measures included: R2 from a weighted least squares regression model (R2 WLS), Spearman rank correlation coefficient (Spearman), and R2 from a bivariate survival model (R2 Copula). Results: The median OS and PFS were 9.6 and 5.5 months, respectively; the BR and CoR rates were 44% and 34%, respectively. Patient-level associations showed that PFS status at 4 months was a strong predictor of subsequent survival (HR=0.42 [95% CI: 0.35, 0.51]; c-index = 0.63; p < 0.01), with 6-month PFS being the strongest (HR=0.41 [95% CI: 0.35, 0.49]; c-index = 0.66; p < 0.01). At the trial level, PFS showed the highest level of surrogacy for OS (R2 WLS = 0.79; R2 Copula = 0.80), which indicates that PFS explained 79% of the variance in OS and is a good surrogacy measure (see Table). Conclusions: PFS was strongly associated with OS, where PFS status as early as 4 months was a strong predictor of subsequent survival. PFS also shows promise as a potential surrogate for OS, and needs further validation using data from a larger number of randomized phase III trials. This data, if substantiated, will allow faster yet valid evaluation of drugs for ES- SCLC. Trial-level surrogacy measures Endpoint R2 WLS R2 Copula Spearman PFS 0.79 0.80 (95% CI: 0.67, 0.93) 0.75 BR 0.21 NA 0.52 CoR 0.40 NA 0.60 No significant financial relationships to disclose.