Key Biomarker Analysis Highlights Effectiveness of Pembrolizumab, Axitinib in Advanced Renal Cell Carcinoma

A recent analysis of the phase 3 KEYNOTE-426 study, led by Brian I. Rini, MD, FASCO, of Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, and presented at the 2024 American Society of Clinical Oncology Annual Meeting, provides insights into the effectiveness of the combination therapy of pembrolizumab and axitinib versus sunitinib for patients with advanced renal cell carcinoma (RCC). This exploratory biomarker analysis focused on RNA sequencing (RNAseq), whole-exome sequencing (WES), and PD-L1 expression.

The KEYNOTE-426 trial previously established that the combination of pembrolizumab and axitinib improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) compared with sunitinib in patients with treatment-naive advanced RCC. This new biomarker analysis aimed to explore the underlying genetic and molecular factors contributing to these outcomes.

In the study, 861 patients with advanced RCC were randomly assigned to receive either pembrolizumab plus axitinib or sunitinib. Of these, 369 patients in the pembrolizumab plus axitinib group and 361 in the sunitinib group had archival samples available for RNAseq, while 347 and 351 patients, respectively, had samples for WES. Additionally, PD-L1 combined positive score was evaluated using immunohistochemistry.

A key finding was the strong positive association of the T-cell–inflamed gene signature (Tcell_infGEP) with clinical outcomes for patients treated with pembrolizumab plus axitinib. Higher Tcell_infGEP was significantly associated with improved OS, PFS, and ORR, suggesting that patients with a robust immune response benefit more from the combination therapy. Angiogenesis, another important factor, was positively associated with OS in both treatment groups, but its impact was more pronounced in patients receiving sunitinib. For pembrolizumab plus axitinib, angiogenesis was only associated with OS, while sunitinib showed strong positive associations with OS, PFS, and ORR.

Additional RNA signatures revealed varied associations with clinical outcomes. For pembrolizumab plus axitinib, a positive association with myeloid-derived suppressor cells was found for PFS and ORR. For sunitinib, positive associations were observed with hypoxia and negative associations were observed with MYC and proliferation, highlighting the differential impact of these signatures on treatment outcomes.

Analysis of DNA mutations also revealed significant associations with treatment outcomes. For pembrolizumab plus axitinib, PBRM1 mutation was positively associated with ORR and PFS. For sunitinib, positive associations with OS were found for VHL and PBRM1 mutations, while a negative association was observed for BAP1 mutation.

These findings underscore the importance of the immune microenvironment and genetic alterations in determining the efficacy of combination therapies in advanced RCC. The strong relationship between Tcell_infGEP and clinical outcomes with pembrolizumab plus axitinib highlights the potential for personalized treatment strategies based on immune profiles.