Comparative and Critical Analysis of Immune-based Combinations for First-line Treatment of Metastatic Renal Cell Carcinoma.

INTRODUCTION

The 4 immuno-combinations currently approved in first-line metastatic renal cell carcinoma were not compared in head-to-head randomized controlled trials (RCTs). We compared the efficacy, statistical robustness, and censoring patterns of 4 phase 3 RCTs investigating these combinations versus sunitinib.

PATIENTS AND

METHODS

Patient-level data on progression-free survival (PFS) and overall survival (OS) were extracted from the latest available updates of these studies (CheckMate-214, nivolumab + ipilimumab; CheckMate-9ER, nivolumab + cabozantinib; KEYNOTE-426, pembrolizumab + axitinib; CLEAR, pembrolizumab + lenvatinib). Censoring patterns were assessed using reverse Kaplan-Meier analyses. the restricted-mean survival time difference (RMST-D) was calculated. The survival-inferred fragility index (SIFI) for significant results was determined by reassigning the longest survivors from intervention to control until significance was lost.

RESULTS

The 58-month RMST-D for OS ranged from 3.5 (CLEAR) to 5.1 months (CheckMate-9ER) across the four trials. All studies showed significant control arm censoring in PFS. Before adjusting for censoring, the RMST-D for OS for the complete follow-up was statistically significant for all evaluated studies; after adjustment, only CLEAR lost OS benefit. The highest calculated SIFI for OS was in CheckMate-214 (2.2%).

CONCLUSIONS

Nivolumab-based combinations and pembrolizumab + axitinib had more robust OS results compared to pembrolizumab + lenvatinib. While exploratory, this analysis provides a critical framework for contextualizing evidence where head-to-head data are lacking.