Overcoming Primary Resistance to Immunotherapy in Metastatic Melanoma

Treatment groups (single-arm): During Weeks 1-4 of the study, subjects will receive intravenous pembrolizumab 400 mg every 6 weeks (Q6W), oral encorafenib 450 mg once daily and oral binimetinib 45mg twice daily. From Week 5-13, participants will receive intravenous pembrolizumab 400 mg every 6 weeks. From Week 13 to 2 years, subjects with a response of stable disease or better (determined by CT every 3 months) will receive pembrolizumab 400mg Q6W until evident progressive disease by Response Evaluation Criteria In Solid Tumors (RECIST), unacceptable toxicity, withdrawal of consent, or until completion of 17 treatment cycles (approximately 2 years) with pembrolizumab. Participants who stop study treatment after receiving 17 administrations of pembrolizumab for reasons other than disease progression or intolerability, or participants who attain a complete response (CR) and stop study treatment may be eligible for up to 1 year of treatment with pembrolizumab (\~8 cycles) upon experiencing disease progression (Second Course Phase). Tumor biopsies and blood (peripheral blood mononuclear cells \[PMBC\] and plasma) will be obtained upon patient recruitment, during the screening period, after 4 weeks of treatment and at 13 weeks. Primary Translational Objectives \& Hypothesis: 1. To determine the decrease in nuclear c-MYC levels in situ in tumor biopsies and blood following treatment. 2. To determine the increase in mitochondrial activity protein profile (Acetyl-CoA acetyltransferase \[ACAT1\] and Hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha \[HADHA\]) in the tumor cells1 in situ following treatment. 3. To determine the increase in CD8+ counts in situ following treatment. Hypothesis: c-MYC impairs interferon gamma (IFNγ) responsiveness and drives anaerobic metabolism,which reduces antigenicity. MAPK activation through the BRAF V600 mutation leads to c-MYC activation and its nuclear translocation in MM patients, directly inhibiting aerobic metabolism in melanoma cells in-vitro. Thus, BRAF V600 seems to drive both mechanisms #1 and #2, highlighting its potential targeting to revert primary immune resistance. The investigators hypothesize that BRAF inhibition will deactivate c-MYC and drive tumor cell metabolism towards oxidative phosphorylation. c-MYC deactivation is expected to alleviate IFNγ resistance. Aerobic metabolism of tumor cells is expected to increase their immunogenicity. The combined effect is expected to overcome primary resistance and reinvigorate local immune response. This is expected to be evident by increased T cell influx, which is associated with successful checkpoint inhibition, and could be further perpetuated with PD-1 blockade. Primary Clinical Objectives \& Hypothesis: To determine the best overall response rate (BORR) to pembrolizumab. Hypothesis: The immunological alteration in the tumor and its microenvironment will provide the grounds for pembrolizumab to induce a clinical response.