Simple SummaryMost melanoma patients have non-overlapping “driver” mutations in either BRAF, NRAS, or NF1 genes based on Next-Gen sequencing. Other overlapping genetic changes, termed “passenger mutations” may also be identified. The impact of these mutations on cancer immunotherapy outcome is currently not well understood. We evaluated the outcome of checkpoint inhibitor-based immunotherapy in 73 patients. Rare patients with BRAF fusion genes or internal rearrangements had a significantly reduced progression-free and overall survival. No other “driver” or “passenger” mutations appeared to influence outcome in a multivariate analysis. The strongest predictor of long-term survival in our study appeared to be development of a complete response as assessed at 12 months from the start of treatment.AbstractBackground: Non-overlapping somatic mutations in BRAF, NRAS, or NF1 genes occur in 85% of metastatic melanoma patients. It is not known whether these mutations affect immunotherapy outcome. Materials and methods: Next-Gen sequencing of 324 oncogenes was performed in 73 metastatic melanoma patients. A retrospective review of immunotherapy outcome was performed. Results: BRAF fusions/internal rearrangements, BRAF V600E, NRAS, NF1 mutations, and triple-negative genotypes occurred in 6.9%, 30.1%, 17.8%, 32.9%, and 12.3% of patients, respectively. Median potential follow-up was 41.0 months. Patients with BRAF fusion/rearrangement had decreased progression-free and overall survival (p= 0.015). The other genotypes each had similar progression-free and overall survival. Patients who achieved a complete best objective response at 12 months (n= 36, 49.3%) were found to have significantly improved survival compared those who failed to achieve remissions (n= 37, 50.7%,p< 0.001). Conclusions: The most important determinant of long-term survival was achievement of a complete response by 12 months following immunotherapy. PR and SD were not a stable type of response and generally resulted in progression and death from melanoma. Rare patients with BRAF fusions or rearrangements had decreased progression-free and overall survival following initial immunotherapy. Other BRAF, NRAS, or NF1 mutations were not associated with significant differences in outcome.