Triple combination of two targeted therapies + immunotherapy is more effective in advanced melanoma

A groundbreaking new triple combination therapy shows promising signs of more effectively controlling advanced melanoma than previous BRAF + MEK inhibitor or BRAF inhibitor + immunotherapy combinations alone. The triple combination has increased immune response and fewer side effects. It was described in Science Translational Medicine (2015; doi:10.1126/scitranslmed.aaa4691).

An estimated 70,000 new cases of metastatic melanoma are diagnosed each year in the United States, and of those, 8,000 cases will result in death from the disease. Approximately 50% of these men and women (or 35,000 persons a year) have a mutated protein called a BRAF mutation, which in most cases allows melanoma to eventually build up a resistance to many drug therapies.

In the new study led by University of California Los Angeles (UCLA) Jonsson Comprehensive Cancer Center member Antoni Ribas, MD, PhD, and colleague Siwen Hu-Lieskovan, MD, PhD, scientists combined targeted therapies utilizing a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) with immunotherapy. The three together are shown to be more effective treatments by sensitizing the patient's own immune system to enhance immunotherapy, and together they reduce the probability of the melanoma eventually developing resistance.

This is a significant advance compared to previous drug combination findings, in which a combined BRAF inhibitor (vemurafenib) with immunotherapy (ipilimumab) caused serious liver toxicity in some patients, and the targeted therapies (BRAF and/or MEK inhibitors) became less effective and reactivated cancer cell growth.

“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,” said Ribas, a professor of hematology and oncology.

“We have made incredible progress in the last 3 years of treating advanced melanoma, with six new drug therapies approved by the 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.”

“The triple combination of targeted therapies BRAF (dabrafinib) and MEK (trametinib) inhibitors with immunotherapy (tumor antigen-specific adoptive cell transfer or anti-PD1 antibody) makes immune therapy more effective at killing cancerous tumors and causes less toxicity ” said Hu-Lieskovan, a UCLA clinical instructor of hematology and oncology.

“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.”

Ribas and Hu-Lieskovan have opened two clinical trials to test the effectiveness of the triple combination therapy in advanced melanoma patients. The first reported findings will be presented at the American Society of Clinical Oncology (ASCO) annual meeting in May 2015.

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