Background: Vascular endothelial growth factor (VEGF) and immune checkpoint inhibitors (IO) combinations are a standard in mRCC. Molecular clusters of patients have been identified and correlated with outcomes in the phase 3 IMmotion151 (IM151) trial of atezolizumab + bevacizumab (IO+VEGF) vs. sunitinib (Sun) (Motzer, Cancer Cell 2020 &JAMA Oncol 2021). Avelumab+axitinib (AA) is an approved IO+VEGF combination in mRCC. This work aims to evaluate these clusters in patients from the phase 3 JAVELIN Renal 101 (JR101; NCT02684006 ) trial of AA vs. Sun. Methods: Bulk RNA-sequencing of primary and metastatic samples and clinical data (data cutoff: 28 January 2019) from JR101 were obtained. A random forest model designed to predict molecular clusters based on transcriptomic data was trained on the IM151 dataset. Using this model, patients from JR101 study were categorized into previously defined molecular subgroups. We then evaluated treatment outcomes including progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) from JR101 in relation to molecular subgroups. Results: The proportion of patients in each molecular subtype and across MSKCC risk groups were largely comparable between the 2 trials (accuracy: 81.6%; p=0.2). AA was generally superior to Sun. for PFS and ORR across all molecular subsets, including angiogenic and immune-based clusters (Table). Combining immune and/or cell cycle-enriched clusters 4+5 resulted in improved PFS (HR: 0.65; 95% CI: 0.44-0.97) for AA vs. Sun. Conclusions: We were able to largely validate the molecular clusters classification and some of the associations with survival outcomes from IM151 in the JR101 clinical trial cohort. Biomarkers of specific VEGF+IO combinations in mRCC should be prospectively validated in randomized trials.

Cluster 7 separately was excluded as it contains 1 patient per treatment arm.