High response rate and determinants of efficacy in kidney cancer patients treated with combined VEGFR and PD-1 axis blockade via lenvatinib plus pembrolizumab

Immune checkpoint blockade (ICB) therapy has substantially improved the outcomes of patients with many types of cancers, including renal cell carcinoma (RCC). Immunotherapy based combination regimens can dramatically expand the clinical benefit achieved by ICB monotherapy. However, optimal therapeutic combinations have yet to be identified for RCC and molecular determinants of response remain unknown. These combination therapies have begun to revolutionize the treatment of RCC. Here, we describe the clinical outcomes and genomic determinants of response from a phase 1b/2 clinical trial with advanced RCC patients evaluating the efficacy of lenvatinib, a second generation vascular endothelial growth factor receptor (VEGFR) inhibitor plus pembrolizumab, an anti-PD1 immunotherapy. Strikingly, concurrent treatment with lenvatinib and pembrolizumab resulted in an objective response rate of 79% (19/24) and tumor shrinkage in 96% (23/24) of patients. The mutational landscape of patient tumors was characterized (n=24). While tumor mutation burden (TMB) did not predict for clinical benefit, germline HLA-I diversity strongly impacted treatment efficacy. Specifically, HLA-I evolutionary divergence (HED)9, which measures the breadth of a patient's immunopeptidome, was associated with both improved clinical benefit and durability of response. HED also predicted better survival in a second cohort of RCC patients following therapy with anti-PD-1/anti-PD-L1-based combination therapy. Our results identify lenvatinib plus pembrolizumab as a highly active treatment strategy and reveal HLA-I diversity as a critical determinant of efficacy for this immunotherapy-based combination.