A novel combination of three therapies has demonstrated evidence of improved antitumor activity in advanced melanoma compared with previous treatment combinations in a new preclinical study. The combination of dabrafenib, trametinib and an immunotherapy agent was investigated by researchers at University of California Los Angeles’ Jonsson Comprehensive Cancer Center (CA, USA) and their findings were published last week in Science Translational Medicine.
“We have made incredible progress in the last 3 years of treating advanced melanoma, with six new drug therapies approved by the [US] FDA. Half are immunotherapies and the other half are BRAF or MEK inhibitors. The next step is to figure out how to rationally combine them and merge their benefits in the clinic,” commented study lead Antoni Ribas of the Jonsson Comprehensive Cancer Center.
This use of an immunotherapy in combination with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib is believed to increase the efficacy of the immune response, as well as reduce toxicities compared with other BRAF inhibitor combinations. A previous clinical study investigating combined therapy with the BRAF inhibitor vemurafenib and the CTLA4 antibody ipilimumab was stopped prior to completion due to serious liver toxicity in some patients.
“The two drug combination of BRAF and MEK inhibitors works synergistically and decreases the side effects of the BRAF inhibitor or normal cells. We reasoned that this combo would allow us to synergize with immunotherapy without increasing toxicities,” continued Ribas.
Specifically, in a mouse model of BRAFV600E-driven melanoma, this triple combination promoted complete tumor regression, improved T-cell infiltration and increased in vivo cytotoxicity. The therapy also promoted global upregulation of immune-related genes and increased expression of melanosomal antigens.
“We’re trying to take advantage of the high response rate of the targeted therapy and durability of the immune therapy to induce a response that lasts in the majority of patients,” commented investigator Siwen Hu-Lieskovan (Jonsson Comprehensive Cancer Center).
The Jonsson team suggest that their findings provide evidence for investigating this combination in patients with advanced melanoma and as such they have opened two clinical trials, the intial findings of which will be reported at the 2015 American Society of Clinical Oncology annual meeting.
Written by Emily Brown
Sources: Hu-Lieskovan S, Mok S, Homet Moreno B et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma. Science Translational Medicine DOI: 10.1126/scitranslmed.aaa4691 (2015); University of California Los Angeles press release