Abstract
Tumor measurements can be used to estimate time to nadir and depth of nadir as potential surrogates for overall survival (OS). To assess time to nadir and depth of nadir as surrogates for OS in metastatic colorectal cancer. 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. 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. 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). 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.
Highlights
The availability of active treatments for use in subsequent lines have called into question the use of overall survival (OS) as a primary end point in phase 3 trials on first-line therapy for metastatic colorectal cancer.[1]
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
Tumor measurements consisted of the longest diameters of target lesions, used in the original trials according to the Response Evaluation Criteria in Solid Tumors (RECIST) guideline, version 1.1.32 Eight trials involved only chemotherapy; of the 12 trials that had at least 1 biological agent, 6 evaluated antiangiogenic agents as the only biological, 4 investigated an anti–epidermal growth factor receptor agent as the only biological, and 2 trials had both an anti-ANG and anti-EGFR agent
Summary
The availability of active treatments for use in subsequent lines have called into question the use of overall survival (OS) as a primary end point in phase 3 trials on first-line therapy for metastatic colorectal cancer (mCRC).[1]. In work published in abstract form, the depth of response was found to be associated with OS at the patient level in first-line cetuximab-based therapy.[10] That study was based on 2 randomized trials and did not assess the trial-level surrogacy. To obtain a more in-depth view of this question, we assessed the individualand trial-level surrogacy for OS of 2 continuous tumor-size–based end points in first-line treatment of mCRC
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