Biomarker analyses from the phase III CheckMate 214 trial of nivolumab plus ipilimumab (N+I) or sunitinib (S) in advanced renal cell carcinoma (aRCC).

Abstract

5009 Background: In CheckMate 214 (NCT02231749), N+I demonstrated superior clinical outcomes vs S in patients (pts) with aRCC. Here, we report exploratory biomarker analyses of pretreatment tumor samples relative to outcomes. Methods: Formalin-fixed, paraffin-embedded aRCC samples were characterized by immunohistochemistry (tumor programmed death ligand 1 [PD-L1], n = 992; PD-L1 combined positive score [CPS], n = 980), whole exome sequencing (WES; tumor mutational burden, indel burden, HLA class I zygosity, and PBRM1 mutation status; n = 481), and RNAseq (n = 213). Gene signature scores were calculated as the median value of Z-scored expression for transcripts. Association with outcome was tested using Fisher’s exact test and Cox proportional hazards model. With ≥ 42 mo follow-up, prolonged progression-free survival (PFS) with N+I ( < or ≥ 18 mo; n = 82 vs 27, respectively) was analyzed by limma and gene set enrichment analysis of Hallmark gene sets (MSigDB). Results: PD-L1 CPS did not have improved predictive power over tumor PD-L1. The WES-derived biomarkers were not associated with outcomes in pts treated with N+I or S. For the RNAseq cohort, objective response rates (ORR) for pts with ≥ median scores, and hazard ratios (HR) relative to < median are shown (Table). A higher angiogenesis (Angio) gene signature score was associated with higher ORR and PFS for S; lower Angio score was associated with higher ORR in N+I. Immune signature scores were not predictive for ORR in N+I. Prolonged PFS with N+I (≥ 18 mo, n = 27) was associated with higher expression of Hallmark inflammatory response and Hallmark epithelial mesenchymal transition (EMT) gene sets (both adjusted P = 0.002). Conclusions: The Angio gene signature was associated with ORR for S (high score) and N+I (low score). Prolonged PFS in 27 pts receiving N+I was linked with inflammation (consistent with findings from PD-1 blockade monotherapy), but associated with EMT-related transcripts (in contrast with findings in other tumor types). Further validation of these exploratory analyses will be required. Clinical trial information: NCT02231749 . [Table: see text]