BRAF/MEK and Immunotherapy Combos in the Melanoma Treatment Paradigm

Within the treatment paradigm of melanoma, 2 different BRAF/MEK combination regimens, those being dabrafenib plus trametinib and vemurafenib plus cobimetinib, and an immunotherapy combination regimen have recently approved by the FDA. It is still unclear whether BRAF/MEK combinations, such as dabrafenib (Tafinlar) plus trametinib (Mekinist) or vemurafenib (Zelboraf) plus cobimetinib (Cotellic), or immunotherapy combinations, such as the recently approved nivolumab (Opdivo) and ipilimumab (Yervoy) regimen, should be the standard first-line treatment for BRAF-mutated patients, says Weber.

Weber cites the BRAF/MEK inhibitor surge as beginning in 2011, where the combination proved efficacious with little toxicities. This revolution in the treatment paradigm for melanoma eventually led to the BRAF/MEK combination to becoming the standard of care within BRAF-mutated melanoma, though the treatment isn't a blanket answer.

"For patients who do not have the BRAF mutation in the tumor, it is inappropriate to use these BRAF drugs. For patients who have the mutation, which occurs in about 40% to 50% of all melanomas, the combination of the BRAF and the MEK drugs can be very effective, with high response rates and long survival. I recently presented data on the long-term follow-up of the original phase II and phase III trials looking at the combination of a MEK inhibitor with a BRAF inhibitor," said Weber, deputy director of the Laura and Isaac Perlmutter Cancer Center, codirector of the Melanoma Program, and head of Experimental Therapeutics at NYU Langone Medical Center.

Honing in on one specific combination within the aformentioned armamentarium, recent long-term followup data on the dabrafenib and trametinib combination may aid oncologists in determining sequences when treating patients.

Weber says the dabrafenib and trametinib combination appears to produce a "plateau on the curve" as time wears on in the data in terms of survival.

"There does appear to be a plateau in the curve at about 30% for the patients who receive dabrafenib and trametinib. I am sure it will be virtually identical for vemurafenib and cobimetinib, which have a very similar median survival and 1-year survival track record as dabrafenib and trametinib," he said.

"We now have mature follow-up data from both dabrafenib and trametinib and vemurafenib and cobimetinib showing that we have about a 25-month median survival in patients treated upfront with metastatic melanoma that is BRAF-mutated who receive these drugs. That is very impressive. The interesting data from the longer follow-up of dabrafenib and trametinib showed that there is an obvious association between having a high tumor burden, poor performance status, a high LDH, and not doing well with these drugs."

The FDA approved the dabrafenib and trametinib combination in January 2016 for patients with unresectable or metastatic melanoma who harbor a BRAF V600E or V600K mutation. The approval for the combination was based on results from an open-label phase I/II trial, which showed the combination nearly doubled the duration of response and significantly improved overall response rates (ORR) when compared with dabrafenib alone.

Dabrafenib and trametinib were each approved as single agents in May 2013 along with a companion diagnostic. The approval of the agents in combination marks the first for a targeted therapy combination in advanced melanoma.

Weber says these findings suggest that oncologists may want to employ BRAF/MEK drugs earlier in their treatment paradigm, rather than later.

"If the BRAF and MEK drugs only work in patients with low disease burden, but the immunotherapy drugs can work with either a low or high disease burden, the argument would be in a mutated patient to first give BRAF/MEK and then immunotherapy if the patient progressed or failed," he said.

"The targeted therapy will not work as well if patients are receiving immunotherapy first, then they progress, have high LDH, and high disease burden. The association of patients doing well with targeted therapy with low disease burden bodes well for starting with targeted therapy and using immunotherapy in the second-line setting."

Despite the knowledge garnered through these studies, and FDA approvals, Weber says there is stil some way to go. He adds that there are trials exploring sequencing of targeted therapies and immunotherapies in BRAF-mutated melanoma as well.

"There is an ongoing randomized phase III trial examining this. One group of patients will get upfront immunotherapy with ipilimumab and nivolumab, and at progression, they will receive BRAF/MEK inhibitors. Other patients in the study will receive upfront dabrafenib and trametinib, and then ipilimumab and nivolumab at progression," he said.