Background: Prior studies in pts with BRAFmM have shown increased density of tumor infiltrating lymphocytes (TIL) at 2 weeks (wks) with BRAF +/- MEK inhibition(i), but did not fully characterize kinetics or functional state of the TIL. To better assess the impact of BRAFi +/- MEKi on the tumor microenvironment, we conducted a study to evaluate serial tumor biopsies (Bx) and blood through the first 4 wks of V+/-C therapy (Tx). Methods: Subjects with Bx-accessible BRAFmM received either V alone or V+C Tx. Staging CT scans were performed at baseline, wks 6, 12 and q12 weeks until PD or study withdrawal. Tumor Bx and heparinized blood samples were obtained at baseline, day (d) 8, 15, and 29. Bx samples were formalin-fixed paraffin-embedded (FFPE), frozen in OCT, and processed for TIL. PBMC and plasma were isolated from blood. FFPE slides were analyzed by quantitative immunofluorescence (QIF), NanoString 770 Immune Panel and TCRseq (Adaptive). Frozen tumors were analyzed for single cell (sc)RNAseq. TIL and PBMC were analyzed by flow cytometry. Results: 5 pts (4M/1F) with BRAFmM were enrolled (3 received V and 2 V+C). All had initial tumor response (2 CR, 3 PR) and subsequent PD. No unusual or G4-5 toxicities were observed. In 4 of 5 tumors, CD8⁺ and CD4⁺ TIL increased by d8 or d15 by QIF and NanoString, waning thereafter. %CD4⁺ cells expressing CD45RO⁺ decreased over time suggesting a dominance of naïve T cells in new infiltrates. No specific change in %CD8⁺ TIL expression of CD45RO⁺ was seen. NanoString showed no significant change in FoxP3, arginase or TGFB1 expression and no change in IFNG, granzyme B or Caspase 3. Other analyses are in process. Conclusions: BRAFi +/- MEKi leads to tumor T cell infiltration by d8 that peaks at d15. CD4⁺ cells are increasingly antigen-inexperienced, while CD8 cells do not change. CD8 infiltrates are not accompanied by inflammatory or apoptotic response. Immune cell influx is not required for tumor response. The data suggest that T cell influx is not related to the generation of new anti-tumor immunity and that BRAF/MEKi Rx may, at best, augment an existing immune response rather than priming a new one. Clinical trial information: NCT01813214