Effects of Vemurafenib ± Cobimetinib on Intratumoral and Host Immunity in Patients With BRAFV600 Mutant Melanoma: Implications for Combination With Immunotherapy

BACKGROUND: Prior studies in patients with BRAF-mutant melanoma have shown increased density of tumor infiltrating lymphocytes (TIL) after 2 weeks of BRAF (BRAFi) ± MEK inhibition (MEKi), but did not characterize the functional state or clonal diversity of TIL over time. We evaluated sequential tumor biopsies during therapy to test the hypotheses that BRAF/MEKi would increase TIL to day 29, with increases in IFNγ signatures and T-cell homing receptor ligands and expansion of functional intratumoral tumor-reactive CD8 T-cells and TIL clonality in the tumor microenvironment. METHODS: Subjects with biopsy-accessible BRAF-mutant advanced melanoma received vemurafenib+/-cobimetinib. Tumor biopsies were obtained at baseline and days 8, 15, and 29 on therapy. Tumors were analyzed by quantitative immunofluorescence (QIF), NanoString, and TCRseq. RESULTS: TIL density increased by day 8 or 15 per QIF and continued to increase at day 29 in two. Gene expression data showed upregulation of genes/pathways associated with immunologic rejection of cancer, including Class I and II MHC expression, antigen processing/presentation, and critical T-cell attracting chemokines. TCRvβ clonal expansion was observed in 3 patients, but most diminished after day 15. CONCLUSIONS: Data from this study provides provocative evidence that, while BRAF+/-MEK inhibitor therapy produces an increase in overall and clonal T cell infiltrates, there is limited evidence for generation of new or persistent tumor immunity. Thus, BRAFi/MEKi therapy may enable tumor-reactive T cells to infiltrate tumors but tumor control does not appear to depend on priming new immune responses.