A U.S. Food and Drug Administration–pooled Analysis of Frontline Combination Treatment Survival Benefits by Risk Groups in Metastatic Renal Cell Carcinoma

While frontline immuno-oncology/tyrosine kinase inhibitor (IO/TKI) combination therapy has established a benefit in metastatic renal cell carcinoma (mRCC), this may differ by International Metastatic RCC Database Consortium (IMDC) risk grouping. Looking at individual trials, we noted an apparently smaller magnitude of benefit for favorable-risk disease. We aimed to assess treatment benefit by risk groupings, especially in favorable-risk, augmenting patient numbers via a pooled analysis. We pooled four frontline mRCC trials of IO/TKI combinations including 3,098 patients (839 favorable-risk) with approvals from 2019 to 2021. All trials used IO/TKI combinations as the treatment option and sunitinib as the control. We analyzed progression-free survival (PFS) and overall survival (OS) by IMDC groupings. To specifically address the favorable-risk group, we combined all others into an intermediate/poor-risk group. In this exploratory analysis adjusted for baseline covariates, IO/TKI combinations have yet to demonstrate an OS benefit in favorable-risk (hazard ratio [HR] 1.24; 95% confidence interval [CI]: 0.86, 1.78) despite demonstrating an OS benefit in the intermediate/poor-risk group (HR 0.64; 95% CI: 0.55, 0.75). In contrast, IO/TKI demonstrated a PFS benefit for both the favorable-risk (HR 0.63; 95% CI: 0.50, 0.79) and the intermediate/poor-risk (HR 0.52; 95% CI: 0.45, 0.60) group. For objective response rate, a smaller difference was observed between the combination and sunitinib arms in favorable-risk (68.2% vs 49.9%) versus intermediate/poor-risk (59.9% vs 36.5%) groups, while the difference in complete response rate was larger for favorable-risk (15.3% vs 6.0%) versus intermediate/poor-risk (9.1% vs 3.4%) groups. The frontline IO/TKI combination therapy benefit was shown to be greater in the intermediate/poor-risk group than in the favorable-risk group. The OS benefit observed with IO/TKI for mRCC has yet to be demonstrated for favorable-risk patients; longer follow-up is needed. Patients with intermediate/poor-risk metastatic renal cell carcinoma derive an overall survival benefit from immuno-oncology/tyrosine kinase inhibitor combinations, while data for favorable-risk remain immature.