Somatic mutations in BRCA2, NFE2L2, ARID1A and NOTCH1 sensitize to anti-PDL1 therapy in multiple tumor types
Authors: M. Kuziora, H. Si, B. Higgs, P. Brohawn, K. Streicher, M. Jure-Kunkel, R. Raja, E. Helman, A. Franovic, Z. Cooper, Y. Shrestha, N. Holoweckyj, Y. Lee, I. Achour, J. Ye, P. Mukhopadhyay, P.A. Dennis, G. Melillo, S.E. Abdullah, K. Ranade
Journal: Annals of Oncology (2018)

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).Table2O Objective response by genes harboring muts in validation cohortGene (mut type)Mutant N, ORR % (95% CI)Wildtype N, ORR % (95% CI)pBRCA2 (inactivate)70, 26% (16%, 38%)670, 13% (11%, 16%)0.006NFE2L2 (activate)30, 27% (12%, 46%)710, 14% (11%, 16%)0.059NOTCH1 (both)39, 23% (11%, 39%)701, 14% (11%, 16%)0.10ARID1A (inactivate)122, 21% (4%, 48%)618, 13% (10%, 16%)0.022 Open table in a new tab Editorial acknowledgement: Editorial support was provided by Guardant Health. Clinical trial identification: NCT01693562/September 26, 2012; NCT02087423/March 14, 2014; NCT02207530/August 4, 2014. Legal entity responsible for the study: MedImmune. Funding: MedImmune. Disclosure: M. Kuziora: Employed by MedImmune; Stock: AstraZeneca; Patent B7H1-410-US-PSP pending. B. Higgs: Employed by MedImmune; Stock: AstraZeneca; Intellectual property interests: MedImmune. P. Brohawn, K. Streicher, R. Raja: Employed by MedImmune; Stock: AstraZeneca. M. Jure-Kunkel: Employed by MedImmune; Stock: AstraZeneca; Patents, royalties, or other intellectual property: Bristol-Meyers Squibb. E. Helman: Employed by, stock, intellectual property interests: Guardant Health. A. Franovic: Employed by Guardant Health. Z. Cooper, Y. Shrestha: Employed by MedImmune. Y. Lee: Employed by MedImmune; Stock: AstraZeneca. P. Mukhopadhyay, P.A. Dennis: Employed by, stock: AstraZeneca. G. Melillo: Employed by AstraZeneca. S.E. Abdullah: Employed by, travel, accommodations, or other expenses: MedImmune; Stock: AstraZeneca. K. Ranade: Employed by, intellectual property interests: MedImmune; Stock: AstraZeneca. All other authors have declared no conflicts of interest.