UCLA researchers develop new combination therapy to fight melanoma

In June of 2020, UCLA Health writer Jocelyn Apodaca noticed that a mole on her leg had changed in size and color. (Photo courtesy of Jocelyn Apodaca)

UCLA cancer researchers have found that a new triple combination therapy shows promising signs of more effectively controlling advanced melanoma than previous treatments and also with fewer side effects.

An estimated 70,000 new cases of metastatic melanoma are diagnosed each year in the United States, and of those 8,000 people will die of the disease. About 50 percent of the total men and women diagnosed 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 UCLA Jonsson Comprehensive Cancer Center member Dr. Antoni Ribas and colleague Dr. Siwen Hu-Lieskovan, UCLA scientists combined targeted therapies utilizing the BRAF inhibitor drug dabrafenib and the MEK inhibitor drug trametinib, with immunotherapy, which is treatment that uses a person’s own immune system to help fight cancer.

Dabrafenib causes cancerous tumors to shrink in people whose metastatic melanoma has a BRAF gene change. Trametinib prevents the disturbance of the MAPK/ERK pathway that dabrafenib causes on cells without the BRAF mutation. That disturbance causes overactive cells to form a different type of skin cancer.

The combination of the three therapies, which was shown to be a more effective treatment, works by sensitizing a person’s own immune system to enhance immunotherapy, and reducing the probability of the melanoma eventually developing resistance.

This is a significant advance compared to previous drug combination findings, in which a combination of the BRAF inhibitor vemurafenib with an immunotherapy drug caused serious liver toxicity in some people, 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 on normal cells. We reasoned that this combo would allow us to synergize with immunotherapy without increasing toxicities,” said Ribas, a professor of hematology-oncology at UCLA. “We have made incredible progress in the last three 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 combine them and merge their benefits in the clinic.”

The triple combination of targeted therapies dabrafinib and trametinib inhibitors with immunotherapy (tumor antigen-specific adoptive cell transfer or anti-PD1 antibody) makes immune therapy more effective at killing cancerous tumors and it 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,” Hu-Lieskovan said.

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 annual meeting in May.

The study is available online today in the journal Science Translational Medicine.