FDA pooled analysis of OS according to depth of response in frontline advanced IO RCC trials.

Abstract

Background: Retrospective analyses of studies of immune-oncology (IO)-containing combinations for advanced renal cell carcinoma (aRCC) suggest that depth of response (DepOR) is associated with overall survival (OS), but have methodologic limitations. We investigated the relationship of Week 12 DepOR as a continuous variable with OS.

Methods: Pooling data from patients with treatment (tx)-naïve aRCC enrolled in randomized IO-containing frontline aRCC trials submitted to FDA that included Week 12 imaging assessment, we developed 36-month (mo) OS prediction models based on Week 12 DepOR (reduction from baseline in target lesion diameters) using Cox proportional hazards with natural spline in IO combination and sunitinib (SUN) groups. To avoid guarantee-time bias, only patients in follow-up at Week 12 scan were included. OS was defined from Week 12 imaging date.

Results: Among the 4 trials meeting inclusion criteria, 1364 patients in IO combination and 1267 patients in SUN group had Week 12 imaging.DepOR and 36-month OS were correlated throughout the entire range of DepOR in both tx groups, with no plateau in OS as DepOR approached complete response. Across the range of DepOR, estimated 36-mo OS was higher in IO combination group.

Conclusion: Deeper response was associated with better 36-month OS in this pooled exploratory analysis of tx-naive aRCC patients treated with IO combination or SUN.Further work characterizing the relationship between DepOR and OS at the trial level may advance understanding of the utility of DepOR as a pharmacodynamic response biomarker or early endpoint in signal-seeking trials and to facilitate efficient drug development.