Weber Compares BRAF/MEK, Immunotherapy Combos in Melanoma

Jeffrey S. Weber, MD, PhD

With 2 different BRAF/MEK combination regimens approved by the FDA, as well as an immunotherapy combination, treatment and sequencing decisions for metastatic BRAF-mutated melanoma can be difficult, says Jeffrey S. Weber, MD, PhD, 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.

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.

“I am not taking bets; there are arguments for both sides,” he explains. “But, I do think all of these combinations are not only going to delay progression with these agents, but we are going to cure some of these patients.“

OncLive: How has the role of combination therapies in melanoma evolved in recent years?

In an interview with OncLive, Weber discusses recent long-term follow-up data of dabrafenib and trametinib that may shed some light on sequencing questions for BRAF-mutated patients. He also discusses an ongoing randomized trial of a head-to-head comparison of BRAF/MEK inhibitors and immunotherapy as first-line treatment.Weber: There have been 2 combination therapies approved by the FDA recently for melanoma: dabrafenib plus trametinib and vemurafenib plus cobimetinib, which was approved in 2015.

Back in 2011, there was a revolution that adding a MEK inhibitor to a BRAF inhibitor in patients with metastatic disease not only augmented the efficacy of the treatment, but also clearly decreased the toxicities, particularly with skin toxicities. Over the next several years, combination MEK plus BRAF therapy has become the standard of care for treating patients with BRAF-mutated melanoma.

What were the most significant findings from the long-term follow-up?

However, 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.The follow-up research suggests a couple of things. First, dabrafenib and trametinib have been tested over a longer period of time, so we have longer follow-up. Second, there appears to be a plateau on the curve as you get out in time—in terms of survival follow-up—for dabrafenib and trametinib.

The “urban legend” was that the BRAF and MEK inhibitors had a high response rate, but almost all of the patients would progress quickly, progression-free survival would be less than 1 year, and most patients would have to go on another therapy or would die of their disease.

That’s not exactly true. 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.

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.

This means that patients who do best with the combination of BRAF/MEK inhibitors have low disease burden with a normal LDH, few symptoms, etc.

Do these findings make it any easier for oncologists to determine frontline treatment for BRAF-mutated patients with melanoma?

This is very interesting, and not exactly like what we have seen with combination immunotherapies. With the combination of ipilimumab and nivolumab, there was not a strong association between LDH—which is a surrogate for tumor burden—and outcome. Patients did very well whether they had a high tumor burden or not. With targeted therapy, that is not the case.These findings suggest that oncologists probably want to intervene with BRAF and MEK drugs earlier 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.

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.

Are there trials exploring sequencing of targeted therapies and immunotherapy agents for BRAF-mutated patients?

This goes against the current “urban legend” that patients should have immunotherapy upfront whether they are BRAF-mutated or BRAF wild-type because those are the patients who are going to get the long tail on the curve in terms of survival. That may not be true.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.

The endpoint there is either second-progression or survival; that is going to take a long time. They are both very effective regimens. Each one of them has at least a 2-year median survival and over a 50% response rate. The implication here is we are going to have to wait a long time to see a difference.