Tumor response and progression-free survival as potential surrogate endpoints for overall survival in extensive stage small-cell lung cancer: findings on the basis of North Central Cancer Treatment Group trials

Abstract

Background: The authors investigated the putative surrogate endpoints of best response, complete response (CR), confirmed response, and progression-free survival (PFS) for associations with overall survival (OS), and as possible surrogate endpoints for OS.

Methods: Individual patient data from 870 untreated extensive stage small-cell lung cancer patients participating in 6 single-arm (274 patients) and 3 randomized trials (596 patients) were pooled. Patient-level associations between putative surrogate endpoints and OS were assessed by Cox models using landmark analyses. Trial-level surrogacy of putative surrogate endpoints were assessed by the association of treatment effects on OS and individual putative surrogate endpoints. Trial-level surrogacy measures included: R(2) from weighted least squares regression model, Spearman correlation coefficient, and R(2) from bivariate survival model (Copula R(2) ).

Results: Median OS and PFS were 9.6 (95% confidence interval [CI], 9.1-10.0) and 5.5 (95% CI, 5.2-5.9) months, respectively; best response, CR, and confirmed response rates were 44%, 22%, and 34%, respectively. Patient-level associations showed that PFS status at 4 months was a strong predictor of subsequent survival (hazard ratio [HR], 0.42; 95% CI, 0.35-0.51; concordance index 0.63; P < .01), with 6-month PFS being the strongest (HR, 0.41; 95% CI, 0.35-0.49; concordance index, 0.66, P < .01). At the trial level, PFS showed the highest level of surrogacy for OS (weighted least squares R(2) = 0.79; Copula R(2) = 0.80), explaining 79% of the variance in OS. Tumor response endpoints showed lower surrogacy levels (weighted least squares R(2) ≤0.48).

Conclusions: PFS was strongly associated with OS at both the patient and trial levels. PFS also shows promise as a potential surrogate for OS, but further validation is needed using data from a larger number of randomized phase 3 trials.

Figure I

Landmark analyses survival curves for progression status at the following time points: (A) 4 months (N=728) and (B) 6 months (N=651).

Figure II

Plot of the log of the hazard ratios (HRs) for the endpoints of Progression-Free Survival (PFS) and Overall Survival (OS) for the centers included in the 3 randomized trials. The sizes of the circles are proportional to the sample size within each center or unit. Excluding the bolded outlier yielded similar results (WLS R² = 0.73, Spearman rank correlation coefficient = 0.73, Copula R² = 0.75).

Figure III

Plot of the log of the hazard ratios for Overall Survival (OS) versus the log of the odds ratios for (A) best response (BR) and (B) confirmed response (CoR) endpoints. The sizes of the circles are proportional to the sample size within each center or unit included in the 3 randomized trials. Excluding the bolded outliers for (A) yielded values of 0.55 and 0.47 for WLS R² and Spearman rank correlation coefficients, respectively. Excluding the bolded outliers from (B) yielded values of 0.46 and 0.46 for WLS R² and Spearman rank correlation coefficients, respectively.