Surrogate endpoints for overall survival in randomized clinical trials testing antibody-drug conjugates.

Background: The surrogacy of overall response-rate (ORR) or progression-free survival (PFS) for overall survival (OS) at the trial-level in randomized clinical trials (RCTs) testing antibody-drugs conjugates (ADC) has never been investigated.

Methods: RCTs testing ADCs in patients with advanced solid tumors and reporting data on OS and PFS and/or ORR were analyzed.The main objective was to assess the trial-level association between the surrogate endpoints (ORR or PFS) and the reference endpoint (OS), overall and in subgroups of trials defined by tumor type, number of previous lines of systemic treatments, and specific ADC features.

Results: Twenty-five RCTs, for a total of 26 treatment comparisons and 11,729 patients, were included in the analysis. In 21 comparisons the ADC was administered as monotherapy, and in 16 was tested in patients with breast cancer.The association between the hazard ratio for OS and relative risk of ORR was moderate: the R2 from a model adjusted by tumor type was 0.47 (95%CI,0.11-0.83).The association between the hazard ratios for OS and PFS was strong: the R2 from the adjusted model was 0.79 (95%CI,0.66-0.92).Cross-validation analyses showed similar results. Consistent results were obtained across all the subgroups analyzed, with the notable exception of the subgroup of trials testing ADCs for breast cancer, where the association between OS and ORR appeared strong (R2=0.77; 95%CI,0.51-0.90).

Conclusions: In RCTs evaluating ADCs in advanced solid tumors, PFS serves as a robust surrogate endpoint for OS, offering greater reliability than ORR and adequately supporting accelerated approval of ADCs in future trials.