Researchers at the University of California, Los Angeles (UCLA) recently published in the journal Science Translational Medicine results of a groundbreaking effective triple combination therapy for advanced melanoma. The study is entitled “Improved anti tumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma.”
Melanoma is the most dangerous form of skin cancer caused by damage to skin cells, which triggers mutations that are not repaired, allowing cells to rapidly multiply and generate malignant tumors. Melanoma is curable when detected and treated early; if it goes undetected or if it recurs, the cancer can proliferate and spread (metastasize) to other parts of the body, becoming more difficult to treat. In the United States, it is estimated that 70,000 new diagnoses of metastatic melanoma are made every year resulting in 8,000 deaths. Around half of the diagnosed individuals (men and women) carry a mutation in the BRAF gene, which can provide melanoma with a resistance mechanism against several drug therapies commonly based on BRAF inhibitors.
It has been shown that the combination of BRAF targeted therapy and immunotherapy improves antitumor activity, however, it was reported that the combination of vemurafenib (a BRAF inhibitor) and ipilimumab (as immunotherapy) causes serious liver toxicity, making the treatment unviable.
In this study, in order to enhance antitumor activity, researchers combined targeted therapies using a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib; MEK has been linked to the development of melanoma in BRAF mutated cells) together with immunotherapy.
“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,” explained the study’s senior author Dr. Antoni Ribas in a news release. “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 rationally combine them and merge their benefits in the clinic.”
Researchers found that the combination of the three strategies – BRAF inhibitor, MEK inhibitor and immunotherapy — yields a more effective treatment of advanced melanoma with complete tumor regression in comparison with treatments based on combinations of BRAF plus MEK inhibitors or BRAF inhibitor plus immunotherapy. This triple combination sensitizes the immune system of the patient, increasing the immune response and reducing the likelihood of resistance development by melanoma cells. The triple combination was also found to have improved cytotoxicity and fewer side effects.
“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 the study’s first author Dr. Siwen Hu-Lieskovan. “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.”
The research team is conducting two ongoing clinical trials to assess the efficacy of the triple combination therapy in patients with advanced melanoma. Preliminary findings of these trials will be presented in May at the 2015 American Society of Clinical Oncology (ASCO) annual meeting.
