Evaluation of Continuous Tumor-Size-Based End Points as Surrogates for Overall Survival in Randomized Clinical Trials in Metastatic Colorectal Cancer

Key Points Question Can end points based on the kinetics of tumor size after treatment be used as surrogates for overall survival in metastatic colorectal cancer? Findings In this pooled analysis of data from 20 randomized clinical trials, time to nadir and depth of nadir were modeled and assessed as potential surrogates for overall survival at the patient and trial levels. The associations found were weak or moderate; there were notable differences in tumor-size kinetics between antiangiogenic agents and anti–epidermal growth factor receptor agents. Meaning The implications of these results for early drug development and clinical practice are unclear and warrant further studies; the findings of this study reinforce the need to develop more reliable end points that reflect tumor biology and patient benefit.
Importance Tumor measurements can be used to estimate time to nadir and depth of nadir as potential surrogates for overall survival (OS). Objective To assess time to nadir and depth of nadir as surrogates for OS in metastatic colorectal cancer. Design, Setting, and Participants Pooled analysis of 20 randomized clinical trials within the Aide et Recherche en Cancerologie Digestive database, which contains academic and industry-sponsored trials, was conducted. Three sets of comparisons were performed: chemotherapy alone, antiangiogenic agents, and anti–epidermal growth factor receptor agents in first-line treatment for patients with metastatic colorectal cancer. Main Outcomes and Measures Surrogacy of time to nadir and depth of nadir was assessed at the trial level based on joint modeling of relative tumor-size change vs baseline and OS. Treatment effects on time to nadir and on depth of nadir were defined in terms of between-arm differences in time to nadir and in depth of nadir, and both were assessed in linear regressions for their correlation with treatment effects (hazard ratios) on OS within each set. The strengths of association were quantified using sample-size–weighted coefficients of determination (R2), with values closer to 1.00 indicating stronger association. At the patient level, the correlation was assessed between modeled relative tumor-size change and OS. Results For 14 chemotherapy comparisons in 4289 patients, the R2 value was 0.63 (95% CI, 0.30-0.96) for the association between treatment effects on time to nadir and OS and 0.08 (95% CI, 0-0.37) for depth of nadir and OS. For 11 antiangiogenic agent comparisons (4854 patients), corresponding values of R2 were 0.25 (95% CI, 0-0.72) and 0.06 (95% CI, 0-0.35). For 8 anti–epidermal growth factor receptor comparisons (2684 patients), corresponding values of R2 were 0.24 (95% CI, 0-0.83) and 0.21 (95% CI, 0-0.78). Conclusions and Relevance In contrast with early reports favoring depth of response as a surrogate, these results suggest that neither time to nadir nor depth of nadir is an acceptable surrogate for OS in the first-line treatment of metastatic colorectal cancer.
This study examines the use of time to nadir and depth of nadir as surrogate end points for overall survival in phase 3 randomized clinical trials evaluating first-line treatment in patients with metastatic colorectal cancer.