The relationship between BRAF/NRAS/KIT genomic driver mutations and anti-PD1 immunotherapy responses in patients with advanced melanoma

Background: Anti-PD1 immunotherapy, when used alone or in combination (combo) with anti-CTLA4, prolongs overall (OS) and progression-free survival (PFS) of patients (pts) with advanced melanoma, compared to single-agent (SA) anti-CTLA4. Combo immunotherapy is more toxic than SA anti-PD1, therefore it is of interest to identify patients most likely benefit from SA anti-PD1 to spare these pts the toxicity of combo immunotherapy. We asked whether genomic driver mutations (mts) in BRAF, NRAS or KIT could predict anti-PD1 responses in melanoma pts. Methods: We preformed a single-center retrospective analysis of 292 melanoma pts who received SA or combo anti-PD1 immunotherapy at Princess Margaret Hospital between 2012-17. BRAF/NRAS/KIT mts and other covariates were abstracted from chart review. Multivariable Cox models were used to assess differences in OS/PFS. Results: We identified 209 and 83 melanoma patients who received SA-anti-PD1 or combo immunotherapy, respectively. Pt characteristics were: mean age 59 yrs; 56% male; 77% cutaneous/unknown primary 23% uveal or mucosal; 17% brain metastases; 34% stage M0/M1a/M1b, 66% stage M1c/M1d, 51% BRAF/NRAS/KIT mt. Among pts receiving SA anti-PD1, presence of a BRAF, NRAS, or KIT mt was an independent predictor of poor PFS (HR 1.84; 95% CI 1.21-2.81) and OS (HR 1.93; 95% CI 1.17-3.22) in multivariate models. Other negative predictors of poor survival were: elevated LDH, multiple previous lines of therapy, 3 or more sites of metastasis, and uveal or mucosal histology. Combo immunotherapy was independently associated with longer OS compared to SA anti-PD1 in BRAF/NRAS/KIT mt pts (HR 0.43; 95% CI 0.20-0.90), but not in BRAF/NRAS/KIT wild-type pts (HR 1.34; 95% CI 0.46-3.90). Conclusions: In this retrospective study, the presence of a BRAF NRAS or KIT mt was an independent predictor of poor PFS/OS in melanoma pts treated with SA anti-PD1. Combo immunotherapy prolonged survival vs SA anti-PD1 in BRAF/NRAS/KIT mt melanoma, but not in BRAF/NRAS/KIT wild-type melanoma. These data suggest that BRAF/NRAS/KIT wild-type melanoma pts may derive less added benefit from combo immunotherapy (vs single agent anti-PD1) compared to pts with BRAF/NRAS/KIT mutations. Validation analyses are on-going. Citation Format: April A.N. Rose, Susan M. Armstrong, David Hogg, Marcus Butler, Anthony M. Joshua, Danny Ghazarian, Suzanne Kamel-Reid, Ayman Al Habeeb, Mary Anne Chappell, Kendra Ross, Eitan Amir, Phillippe L. Bedard, Lillian Siu, Anna Spreafico. The relationship between BRAF/NRAS/KIT genomic driver mutations and anti-PD1 immunotherapy responses in patients with advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3141.