• Biomarker analysis of the phase 3 KEYNOTE-426 study of pembrolizumab (P) plus axitinib (A) versus sunitinib (S) for advanced renal cell carcinoma (RCC).

Background: P + A improved OS, PFS, and ORR over S in 1L advanced RCC in KEYNOTE-426 (NCT02853331).Here, we present exploratory biomarker results including RNAseq, WES, and PD-L1. Methods: Patients (pts) with treatment-naive advanced RCC were randomly assigned 1:1 to P + A or S. Association between T-cell–inflamed gene signature (TcellinfGEP), angiogenesis gene signature (RNAseq), and PD-L1 CPS (22C3 IHC) with clinical outcomes were tested at prespecified α=0.05. Other RNA signatures (Cristescu et al. Clin Cancer Res. 2022. 2022;28:1680) and molecular subtypes, based on clustering identified from IMmotion151 (Motzer et al. Cancer Cell. 2020;38:803), were tested at prespecified α = 0.10 after multiplicity adjustment. DNA mutations (VHL, PBRM1, SETD2, and BAP1) by WES were tested at prespecified α = 0.10 after multiplicity adjustment. Results: Of 861 pts, 369 (P + A) and 361 (S) had archival samples for RNAseq; 347 (P + A) and 351 (S) had WES samples. PD-L1 CPS was negatively associated with OS (P=0.013) for S. There was a strong positive association of TcellinfGEP with OS (P=0.003), PFS (P<0.0001), and ORR (P<0.0001) for P + A. Angiogenesis was positively associated with OS (P=0.013) for P + A; there was a strong positive association with OS (P<0.0001), PFS (P<0.001), and ORR (P=0.002) for S. For other RNA signatures, positive association with mMDSC was found for PFS (P=0.018) and ORR (P=0.093) with P + A. For S, positive association was found with hypoxia (OS, P=0.034; ORR, P=0.071) and negative associations with MYC (OS, P<0.001; PFS, P=0.012) and proliferation (OS, P=0.002). Across all molecular clusters, ORR favored P + A over S, with the highest P + A ORR in the immune/proliferative cluster (Table). By WES, PBRM1 mutation had positive association with ORR (P=0.004) and PFS (P=0.079) for P + A. For S, positive associations were observed with OS for VHL (P=0.073) and PBRM1 (P=0.001) mutations and a negative one observed for BAP1 mutation (P=0.046). P + A improved ORR over S regardless of mutational status. Conclusions: There was a strong relationship of TcellinfGEP with clinical outcomes with P + A. Angiogenesis was positively associated with outcomes with S and only with OS with P + A. Further understanding the role of the immune microenvironment in combination therapy will be critical to advance treatment strategies. Clinical trial information: NCT02853331.