High response rate and durability driven by HLA genetic diversity in patients with kidney cancer treated with lenvatinib and pembrolizumab

Chung Han Lee, Renzo G. DiNatale, Diego Chowell, Chirag Krishna, Vladimir Makarov, Cristina Valero, Lynda Vuong, Mark Lee, Kate Weiss, Doug Hoen, Luc Morris, Ed Reznik, Samuel Murray, Ritesh Kotecha, Martin H. Voss, Maria I. Carlo, Darren Feldman, Pallavi Sachdev, Yusuke Adachi, Yukinori MinoshimaJunji Matsui, Yasuhiro Funahashi, Kenichi Nomoto, A. Ari Hakimi, Robert J. Motzer, Timothy A. Chan

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Immune checkpoint blockade (ICB) therapy has substantially improved the outcomes of patients with many types of cancers, including renal cell carcinoma (RCC). Initially studied as monotherapy, immunotherapy-based combination regimens have improved the clinical benefit achieved by ICB monotherapy and have revolutionized RCC treatment. While biomarkers like PD-L1 and tumor mutational burden (TMB) are FDA approved as biomarkers for ICB monotherapy, there are no known biomarkers for combination immunotherapies. Here, we describe the clinical outcomes and genomic determinants of response from a phase Ib/II clinical trial on patients with advanced RCC evaluating the efficacy of lenvatinib, a multi-kinase inhibitor mainly targeting VEGFR and FGFR plus pembrolizumab, an anti-PD1 immunotherapy. 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. While tumor mutational burden (TMB) did not predict for clinical benefit, germline HLA-I diversity strongly impacted treatment efficacy. Specifically, HLA-I evolutionary divergence (HED), which measures the breadth of a patient's immunopeptidome, was associated with both improved clinical benefit and durability of response. Our results identify lenvatinib plus pembrolizumab as a highly active treatment strategy in RCC and reveal HLA-I diversity as a critical determinant of efficacy for this combination. HED also predicted better survival in a separate cohort of patients with RCC following therapy with anti-PD-1-based combination therapy. Implications: These findings have substantial implications for RCC therapy and for understanding immunogenetic mechanisms of efficacy and warrants further investigation.

Original languageEnglish
Pages (from-to)1510-1521
Number of pages12
JournalMolecular Cancer Research
Issue number9
StatePublished - Sep 2021
Externally publishedYes


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