4836 - The Role of Tumor Neoantigens in the Differential Response to Immunotherapy (IO) in EGFR and BRAF Mutated Lung Cancers - Quantity or Quality?

Background

Lung cancer patients with activating EGFR mutations tend to respond poorly to IO, but this is not true for all activating mutation driven lung cancers. Recent data show that patients with BRAF mutations tend to respond better to IO. Our study estimated the tumor neoantigen burden in these tumors, and the likelihood of their presentation to cytotoxic T cells by estimating their binding affinity to major histocompatibility complex (MHC).

Methods

Whole exome data for 68 patients with EGFR mutant lung adenocarcinoma and 33 with BRAF mutations were extracted from the Cancer Genome Atlas. MAFTOOLs was used to determine the tumor mutational load. Nonamers were estimated by simulating possible nonamer neoantigens from MAF files. The neoantigen (M_T) and wildtype (W_T) binding affinities to MHC-I were calculated using the NetMHC 4.0 server. The differential binding affinity of the neoantigens in comparison to wildtype was calculated as mean differential agretopicity index (DAI) = W_T - M_T. Patient survival was estimated by the Kaplan-Meier method.

Results

Patients with mutated BRAF had higher median mutational burden (445, range 165-776) than those with EGFR mutations (90.5, range 60.5-219.5, p = 0.001). The median number of simulated neoantigens was higher in the BRAF (9536.5, range 3839.5-14626.0) vs the EGFR group (1895.5, range 1148.5-4766.5, p < 0.001). Mean DAI for BRAF and EGFR patients were 1046 and 1033, respectively, p = 0.86. In the BRAF mutant group, patients with DAI < 1,000 had significantly better 5-year survival (80% vs 40%, p = 0.022) compared to patients with DAI > 1,000. No such survival benefit was identified in the EGFR mutant group (56% vs 58%, p = 0.81).

Conclusions

BRAF mutant lung cancers are characterized by higher neoantigen burden, but their neoantigen differential binding affinity to MHC-I complex was not different from EGFR mutant lung cancers. Our analysis suggests that the improved response to IO in the BRAF mutant population is due to increased quantity in neoantigen burden and not a qualitative difference in MHC-I binding. Further, DAI had a prognostic impact in the BRAF population suggesting that it may be a measure of tumor neoantigen immunogenicity.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

J. Subramanian: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Paradigm; Speaker Bureau / Expert testimony: Lilly; Research grant / Funding (institution): Biocept. All other authors have declared no conflicts of interest.