The Food and Drug Administration Pooled Analysis of Overall Survival According to Depth of Response in Frontline Advanced Immune-Oncology Renal Cell Carcinoma Trials.

BACKGROUND:Retrospective analyses of studies of IO-containing combinations for advanced renal cell carcinoma (RCC) suggest that depth of response is associated with overall survival but have methodological limitations. We investigated the relationship of week 12 depth of response as a continuous variable with overall survival. METHODS:Pooling data from patients with treatment-naïve advanced RCC enrolled in randomized IO-containing frontline advanced RCC trials submitted to the US Food and Drug Administration that included week 12 imaging assessment, we developed 36-month overall survival prediction models based on week 12 depth of response (reduction from baseline in target lesion diameter) using Cox proportional hazards with natural spline in an IO combination group and a sunitinib group. To avoid guarantee-time bias, only patients in follow-up at the week 12 scan were included. Overall survival was defined from the week 12 imaging date. RESULTS:Among the 4 trials that met our inclusion criteria, 1364 patients in the IO combination group and 1267 patients in the sunitinib group had week 12 imaging. Depth of response and 36-month overall survival were correlated throughout the entire range of depth of response in both treatment groups, with no plateau in overall survival as depth of response approached complete response. Across this range, estimated 36-month overall survival was higher in the IO combination group. CONCLUSIONS:Deeper response was associated with better 36-month overall survival in this pooled exploratory analysis of treatment-naïve patients with advanced RCC treated with IO combination or sunitinib. Further work characterizing the relationship between depth of response and overall survival at the trial level may advance understanding of the utility of depth of response as a pharmacodynamic response biomarker or early endpoint in signal-seeking trials and to facilitate efficient drug development.