Triple Therapy for Melanoma

The addition of a dual targeted combination of a BRAF plus MEK inhibitor to immunotherapy enhanced the effects of the immunotherapy in a mouse model of melanoma.

The immunotherapy ipilimumab (Yervoy, Bristol-Myers Squibb), is currently approved for metastatic melanoma by the US Food and Drug Administration (FDA). The combination of two targeted oral agents, dabrafenib (Tafinlar, GlaxoSmithKline), a BRAF inhibitor, plus trametinib (Mekinist, GlaxoSmithKline), a MEK inhibitor, is also approved for metastatic melanoma, but only in those patients whose tumors harbor a BRAF V600 mutation.

A prior human clinical trial testing ipilimumab plus the BRAF inhibitor, vemurafenib, showed that the combination results in a high level of liver toxicity. The current study, while preclinical, suggests that this triple combination may have fewer side effects compared to prior combinations, and could be effective in the control of advanced melanoma.

The results are published in the March 18, 2015 issue of Science Translational Medicine.  

The new study, by Antoni Ribas, MD, PhD and Siwen Hu-Lieskovan, MD, PhD, both of the of the University of California Los Angeles, and colleagues provides evidence that the targeted agents may work by sensitizing the immune system to boost the effectiveness of immunotherapy.

The BRAF plus MEK inhibitor combination has previously been shown in preclinical and human clinical trials to synergistically shrink BRAF-positive melanoma tumors, as well as to decrease the skin-related toxicities experienced by patients treated with a BRAF inhibitor alone. "We reasoned that this combo would allow us to synergize with immunotherapy without increasing toxicities," said Ribas in a statement. While immunotherapies-ipilimumab, nivolumab (Opdivo, Bristol-Myers Squibb), and pembrolizumab (Keytruda, Merck)-and BRAF and MEK inhibitors are approved for the treatment of metastatic melanoma, combinations of targeted agents and immunotherapies are still being explored in clinical trials. 

Researchers used a mouse model of BRAF V600E-driven melanoma and treated the mice with trametinib, dabrafenib, and adoptive cell transfer (ACT). The triple combination increased T-cell infiltration, caused complete tumor regression, and resulted in better in vivo cytotoxicity. The triple combination also resulted in increased melanoma antigens, as well as a global immune-related gene upregulation.

It was previously thought that MEK inhibitors are detrimental to T-cell function in vivo, but what was surprising, Hu-Lieskovan told OncoTherapy Network, was that combining the MEK inhibitor with the other two agents did not inhibit T-cell function.

The current results need to be validated with human clinical trials, but the data suggest that adding a MEK inhibitor to the BRAF inhibitor plus immunotherapy combination could improve responses to treatment, according to the study authors.

"Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAF V600E mutant metastatic melanoma," concluded the authors.

According to Ribas, two clinical trials have been initiated based on this work. One phase I/II trial, the KEYNOTE 022 trial, will examine the triple combination of pembrolizumab with dabrafenib and trametinib in patients with BRAF-mutated advanced melanoma. The second is testing MEDI4736, an experimental anti-PD-L1 antibody with trametinib and dabrafenib (NCT02027961). Both trials are currently enrolling patients.