BRAF/MEK Versus Immunotherapy: Which to Use First in Melanoma?

Weber, deputy director of the Laura and Isaac Perlmutter Cancer Center, co-director of the Melanoma Program, and head of Experimental Therapeutics at NYU Langone Medical Center, explains FDA-approved BRAK/MEK combinations such as dabrafenib (Tafinlar) plus trametinib (Mekinist) or vemurafenib (Zelboraf) plus cobimetinib (Cotellic), have proven efficacy over the past few years. However, these combinations they may not be as useful as certain immunotherapy combinations as a front-line treatment, such as the recently approved nivolumab (Opdivo) and ipilimumab (Yervoy) regimen.

In an interview with Targeted Oncology, Weber explains the merits of each combination and which would be beneficial to utilize as a front-line treatment in BRAF-mutated melanoma.

What are some of the current combination therapies in melanoma?

There have been two combination therapies in melanoma approved by the FDA. One of them was approved 2 years ago and the other was just recently cleared at the end of 2015. We had dabrafenib and trametinib approved several years ago, and then vemurafenib and cobimetinib were recently approved.

The revelation a few years back was that adding a BRAF inhibitor and a MEK inhibitor together in patients with metastatic disease not only augmented the efficacy of the treatment, but clearly decreased the toxicities, particularly the skin toxicities. Over the last couple of years, BRAF/MEK combination therapy has become the standard of care when treating patients with BRAF-mutated melanoma.

Keep in mind that if you do not have the BRAF mutation in the tumor, it's inappropriate to use these BRAF drugs. If you have the mutation, which occurs in 40% to 50% of all melanomas and interestingly occurs in patients who have an onset of the malignancy at a young age, the combination can be very effective with its high response rates and long survival.

Have there been recent developments in these BRAF/MEK drugs?

The data I presented at12th Annual International Symposium on Melanoma and Other Cutaneous Malignancies®described the long-term follow-up of the original phase II and phase III trials suggesting a couple of things about the BRAF/MEK drugs.

First, dabrafenib and trametinib have been tested over a long 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/MEK drugs had a high response rate, but almost all the patients would progress quickly, progression-free survival would be short, less than 1 year, and most patients would have to go on to receive other therapies or die of their disease. That's not exactly true — the urban legend is just that.

There does appear to be a plateau on the curve at about 30% for the patients who receive dabrafenib and trametinib, and I'm sure it will be virtually identical for the patients who receive vemurafenib and cobimetinib because their track records are very similar. We now have mature follow-up data for both these combinations showing that you have about a 25 month median survival in patients treated upfront with metastatic melanoma who are BRAF mutated, who received these drugs. Very impressive.

The interesting data from the long term follow-up from dabrafenib and trametinib show there's an obvious association between having a high tumor burden, a poorer performance status, a high LDH, and not doing well with these drugs. Meaning you do best with combination BRAF/MEK inhibitors if you have a low disease burden with a normal LDH, a performance status of 0, a few symptoms, et cetera. Very interesting, and not exactly unlike that which you see with combination immunotherapies.

Where do the BRAK/MEK drugs belong in the sequencing of treatment for melanoma?

In the recent, randomized phase III trial of ipilimumab with nivolumab versus either drug alone, for the combination arm there wasn't a very strong association between LDH and outcome, which is interesting. You do very well whether you have a high burden or not with immunotherapy. With targeted therapy, that's not the case, so it's very interesting. It suggests that you probably want to intervene with BRAF/MEK drugs earlier rather than later.

If the BRAF/MEK drugs work best with a low-disease burden, but the immunotherapy can work with either a low-disease burden or a high-disease burden, the argument would be that you go first with the BRAF/MEK drug, and only if they progress or fail do you come in with the immunotherapy. The immunotherapy is going to work whether you have a high disease burden or not. The targeted therapy won't work as well if you [administer?] the immunotherapy first, then you progress, have a high LDH, and have a high disease burden. Then you're disadvantaged. Interestingly, the association of doing well with targeted therapy with a low disease burden bodes well for starting with targeted therapy and only immunotherapy in the second-line.

That goes against the current urban legend that you should administer immunotherapy upfront whether you're BRAF-mutated or BRAF-wild type, because those are the patients who are going to be found under the long tail of the curve for survival. That may not be true for two reasons. As I said, the BRAF/MEK patients may also have that tail on the curve and, since you do more poorly with a high-disease burden with the targeted drugs clearly shown in the most recent compilation, you probably want to use it first in the BRAF-mutated patients, rather than immunotherapy.

Are there trials exploring the hypothesis of using targeted therapies early?

There is a well-conceived trial that is a randomized phase III study in which patients will be randomly allocated to get upfront immunotherapy with ipilimumab plus nivolumab, or dabrafenib and trametinib , versus the reciprocal if they have BRAF-mutated melanoma. So you either get BRAF/MEK drugs and if you progress you switch to immunotherapy, or you get the immunotherapy first and then when you progress, you switch to BRAF/MEK.

The endpoint there has got to be either the second progression or survival, and that's going to take a long time. These are both very effective regimens. Each one of them has well over a 50% response rate and each one of them has a 2-year median survival. The implication here is that we're going to have to wait a long time to see a difference.

At the end of the day, you might not see that much of a difference, but I'm not betting either way. My position in the debate would be in favor of the use of the targeted therapy first, but there are arguments either way that are meritorious. We'll have to see.

What does this mean for patients?

I don't think you're delaying progression with these drugs. I think you're going to cure some patients. That's the meaning of the tail on the curve. If you look at the original AJCC data from 2009, which reflected the experience in melanoma over the prior decade before we had these drugs, for stage IV melanoma the tail on the curve was at 10%. Those were the patients who were probably cured who had isolated metastases, that sort of thing. With ipilimumab in a paper in 2010, you had the tail on the curve up to 20%.

Currently, with pembrolizumab and nivolumab PD-1 blockade, that tail is probably up to about 30%. With ipilimumab plus nivolumab, it could be higher. We don't know because we don't have enough long-term follow-up with that combination, but that tail on the curve keeps inching up and up. We're not just prolonging relapse. We're probably curing some of these patients.

So for the first time in the melanoma field, we dare to use the word 'cure' with our patients.