Genomic biomarkers of response to lenvatinib/pembrolizumab (Len/Pembro) in patients with advanced renal cell carcinoma.

Abstract

733 Background: A phase 1b/2 clinical trial indicated that len/pembro shows promise in the treatment of renal cell carcinoma (RCC) in both PD-1/PD-L1 immune checkpoint blockade (ICB)-naïve and pretreated patients (NCT02501096). The combination is being further investigated in a phase 3 clinical trial in RCC (NCT02811861). Tumor antigen presentation depends on multiple factors, including HLA diversity, which can be measured by HLA evolutionary divergence (HED). HED quantitates the capacity of a patient’s HLA genotype to present different peptide antigens. This study is investigating the genomic components of tumor antigen presentation in ICB-naïve patients who have RCC and are treated with len/pembro. Methods: Whole exome sequencing (WES) was performed on pretreatment tumor-derived DNA. Somatic mutations, tumor mutation burden (TMB), neoantigen (NA) load, germline HLA zygosity and somatic loss of heterozygosity (LOH), and HED were correlated with objective response rate (ORR) and progression-free survival (PFS). An updated clinical cutoff was March 29, 2019. Results: Twenty four (80%) of 30 ICB-naïve patients underwent WES. A top-quartile cutoff was used. Increased mean HED was associated with improved PFS, while HLA homozygosity or LOH trended toward worse PFS. Loss-of-function mutations in PBRM1 (PBRM1 LOF) trended toward improved PFS. However, TMB and NA load were not correlated to PFS. No genomic biomarkers were correlated to ORR. Conclusions: Increased HLA diversity was associated with improved PFS, while decreased HLA diversity may be associated with worse PFS. PBRM1 mutation may be associated with improved PFS; however, TMB and NA load were not correlated to outcomes. These findings warrant further examination in larger datasets to rule out possible artifacts from multiple testing in a small cohort. Clinical trial information: NCT02811861. [Table: see text]