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.“
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.
OncLive: How has the role of combination therapies in melanoma evolved in recent years?
: 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
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.
What were the most significant findings from the long-term follow-up?
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.
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.
Do these findings make it any easier for oncologists to determine frontline treatment for BRAF-mutated patients with melanoma?
These findings suggest that oncologists probably want to intervene with BRAF and MEK drugs earlier rather than later.