Somatic mutations in BRCA2, NFE2L2, ARID1A and NOTCH1 sensitize to anti-PDL1 therapy in multiple tumor types

Abstract

Background Tumor mutation burden (TMB) has emerged as a promising predictive biomarker for anti-PD1/L1; however, whether somatic mutations in specific genes can sensitize to immunotherapy is poorly understood. We explored association between mutations detectable in circulating tumor DNA (ctDNA) and outcomes on anti-PDL1 (D; durvalumab) therapy. Methods NCT01693562, NCT02087423, and NCT02207530 were nonrandomized phase 2 trials evaluating D (10 mpk Q2W) in pts with advanced solid tumors, NSCLC, or PDL1+ HNSCC, respectively. Using a next-generation sequencing panel comprised of 73 genes, we examined ctDNA mutations in a discovery set of 116 NSCLC and 33 urothelial carcinoma (UC) pre-treatment. Seven genes were identified harboring muts that enriched for response (RECIST v1.1). These genes were tested in a validation cohort of 217 NSCLC, 130 UC, 48 gastroesophageal, 36 HCC, 52 MSI+, 40 ovarian, 32 pancreatic, 50 HNSCC, 34 TNBC, 16 SCLC, 18 ST sarcoma, 21 HPV cancers, 22 uveal melanoma, 18 cutaneous melanoma and 6 nasopharyngeal carcinoma. Results In the discovery cohort, pts who responded to D had higher prevalence of muts in BRCA2, NFE2L2, NOTCH1, PIK3CA, ARID1A, APC, and BRCA1 compared to non-responders (OR = 1.3-9). Consistent associations with BRCA2, NFE2L2, NOTCH1 and ARID1A muts and response were observed in the validation cohort comprised of multiple tumor types (OR = 1.9-2.3; Table 1). Pts in the validation cohort with BRCA2 muts had longer numerical median DoR of 12.4 compared to wildtype of 8.4 months across all tumors. Muts in NFE2L2 occurred in the Neh2 domain, which binds the negative regulator KEAP1, activating this transcription pathway. Muts in these genes were associated with significantly higher TMB in multiple tumor types in TCGA. Prevalence ranged from 0-26% or 0-20% in TCGA or a ctDNA clinical database, respectively. Conclusions Somatic muts in specific genes sensitize to anti-PDL1 treatment in multiple tumor types (Table).Table: 2O Objective response by genes harboring muts in validation cohort Gene (mut type) Mutant N, ORR % (95% CI) Wildtype N, ORR % (95% CI) p BRCA2 (inactivate) 70, 26% (16%, 38%) 670, 13% (11%, 16%) 0.006 NFE2L2 (activate) 30, 27% (12%, 46%) 710, 14% (11%, 16%) 0.059 NOTCH1 (both) 39, 23% (11%, 39%) 701, 14% (11%, 16%) 0.10 ARID1A (inactivate) 122, 21% (4%, 48%) 618, 13% (10%, 16%) 0.022