High Response Rate and Durability Driven by HLA Genetic Diversity in Patients with Kidney Cancer Treated with Lenvatinib and Pembrolizumab.

Abstract

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.

• Authors: 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 Minoshima, Junji Matsui, Yasuhiro Funahashi, Kenichi Nomoto, A Ari Hakimi, Robert J Motzer, Timothy A Chan
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 19 Issue 9 Pg. 1510-1521 (09 2021) ISSN: 1557-3125 [Electronic] United States
• PMID: 34039647 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal, Humanized
• Biomarkers, Tumor
• HLA Antigens
• Phenylurea Compounds
• Quinolines
• pembrolizumab
• lenvatinib

Topics

• Aged
• Antibodies, Monoclonal, Humanized (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor (genetics)
• Carcinoma, Renal Cell (drug therapy, genetics, pathology)
• Female
• Follow-Up Studies
• Genetic Variation
• HLA Antigens (genetics)
• Humans
• Kidney Neoplasms (drug therapy, genetics, pathology)
• Male
• Middle Aged
• Phenylurea Compounds (administration & dosage)
• Prognosis
• Quinolines (administration & dosage)
• Survival Rate