MEK Inhibition Enhances Preclinical Activity of BRAF Inhibition and Immunotherapy Free

BRAF inhibitors stimulate immune responses and have been tested in combination with immunotherapy in BRAF-mutant melanoma, but only modest activity has been observed with significant toxicity. Adding MEK inhibitors to such combination regimens may be beneficial because MEK inhibitors potentiate the antitumor activity and mitigate the adverse effects of BRAF inhibitors, but MEK inhibition reduces T-cell functionality in vitro, so it is possible that MEK inhibitors may be detrimental in this setting. Hu-Lieskovan and colleagues evaluated whether the MEK inhibitor trametinib would improve the antitumor activity of the BRAF inhibitor dabrafenib in combination with immunotherapy in a syngeneic murine model of BRAF-mutant melanoma. Combined BRAF and MEK inhibition with adoptive cell transfer (ACT) had greater antitumor activity than ACT plus either drug alone and led to complete tumor regression. Dabrafenib and trametinib increased adoptively transferred T-cell infiltration into tumors, and, importantly, the addition of trametinib did not impair adoptively transferred T-cell functionality. Moreover, the addition of trametinib to dabrafenib and ACT reduced levels of tumor-associated macrophages and T regulatory cells, suggesting that reduced tumor infiltration of immunosuppressive cell populations may underlie the increased antitumor activity of the triple combination therapy. Gene expression profiling of tumors revealed that triple combination therapy not only induced expression of genes associated with T-cell activation but also induced expression of PD-L1, which binds to PD-1 on effector T cells to suppress T-cell function. The authors therefore evaluated the combination of dabrafenib and trametinib with PD-1 blockade and found that the combination of all three agents had significantly greater antitumor activity than any pair. In addition to providing preclinical evidence that MEK inhibition does not negatively affect T-cell function in vivo, these results provide a rationale for clinical evaluation of the triple combination of BRAF inhibition, MEK inhibition, and immunotherapy in patients with BRAF-mutant melanoma.

Hu-Lieskovan S, Mok S, Homet Moreno B, Tsoi J, Robert L, Goedert L, et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF^V600E melanoma. Sci Transl Med 2015;7:279ra41.