Case 2: Long-Term BRAF/MEK Data in Melanoma

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Ahmad Tarhini, MD, PhD:Dr Wong, would you like to review some of the recent data?

Deborah J. Wong, MD, PhD:Yes, I’d be happy to review recent data. Dr McKean alluded to how in the past decade or so we’ve really seen a vast expansion in the number of treatment options for metastatic melanoma, which has been very exciting to me as a clinician caring for such patients. This slide summarizes a timeline of the various agents and when they were approved for metastatic melanoma.

As you can see on the left, before 2011, we really had quite a limited number of options, dacarbazine and high-dose IL-2 [interleukin-2], which of course requires an ICU [intensive care unit] admission—very intensive therapy with a lot of adverse effects. There have been very few responses, but in a small number of patients with high-dose IL-2 we did see a few durable responses, which really paved the way for evaluating immunotherapy in this space.

Fast forward to 2011 where we had the approval of anti—CTLA-4 [anti–cytotoxic T-lymphocyte–associated protein 4] immune therapy, ipilimumab. That same year forBRAF-mutated melanoma, vemurafenib, a specific BRAF inhibitor, was approved. Two years later dabrafenib, another BRAF inhibitor, and trametinib, a MEK inhibitor, were approved as monotherapy forBRAF-mutated melanoma. Subsequent to that, the combination of dabrafenib plus trametinib, so BRAF-MEK inhibition, was approved.

That same year was an important year for immunotherapy as well where we saw approvals for pembrolizumab and nivolumab, anti—PD-1 [anti-programmed cell death protein 1] antibodies for metastatic melanoma.

In 2015, we had the approval of nivolumab plus ipilimumab. So now combination or dual immune checkpoint inhibition. In addition to that, the second of our combination targeted therapies was approved with vemurafenib and cobimetinib. That same year we also had TVEC [talimogene laherparepvec] as an option, which is an oncolytic virus delivered via intratumoral injection. Most recently in 2018, we now have a third option for BRAF-MEK inhibition forBRAF-mutated melanoma, with encorafenib in combination with binimetinib.

So really from before 2011 we were looking at quite a dismal 1-year overall survival rate of less than 25%. In today’s day and age, there is a 1-year overall survival exceeding 70%. This is definitely a very exciting time for patients and physicians.

How do we put this all together? These are the NCCN [National Comprehensive Cancer Network] guidelines that outline management options for advanced melanoma. On the left, if you have a patient with metastatic or unresectable melanoma, it would be very important to understand the status of their tumor in regard toBRAFmutation, because that of course outlines the treatment options.

Frontline therapy, irrespective ofBRAFmutation status, would include immune therapy. This would be either anti—PD-1 antibodies as monotherapy or in combination. We have nivolumab and ipilimumab. If the patient has aBRAFV600 activating mutation, we have 3 different choices for combination BRAF-MEK inhibition.

Of course for appropriate patients the option of participating in a clinical trial should also be discussed. Upon disease progression, or maximal clinical benefit, for example, withBRAF-targeted therapies, second-line or beyond therapies could include any of those options that weren’t used in the frontline setting.

The next series of slides summarize some of the recent data evaluating the use of BRAF and MEK inhibition forBRAF-activated metastatic melanoma. This was presented at the 2019 American Society of Clinical Oncology [ASCO] annual meeting, presenting a 5-year analysis of dabrafenib and trametinib for patients withBRAF-mutated melanoma.

This actually was a pooled analysis of 2 studies, the COMBI-d and the COMBI-v studies. Those study schemas are outlined here. Essentially, COMBI-d evaluated dabrafenib and trametinib versus dabrafenib and placebo, for treatment-naïveBRAF-mutated melanoma. Whereas COMBI-v evaluated the same BRAF-MEK combination compared to vemurafenib.

These are the 5-year progression-free-survival [PFS] curves. As we can see, the medium progression-free-survival with dabrafenib and trametinib was 11.1 months. At 5 years, 19% of such patients were still doing well on their first-line therapy.

If you now look at the overall survival curves at 5 years, the median overall survival of patients treated with dabrafenib and trametinib was 25.9 months—greater than 2 years. At 5 years, 34% of patients were still alive and doing well on their therapy.

Ahmad Tarhini, MD, PhD:It’s interesting in the study that patients who had low tumor burden, low LDH [lactate dehydrogenase], and 3 or less sites of distant metastatic disease also did better with targeted therapy. Although, historically we used to treat these patients with immunotherapy, but it’s interesting to see that they have a 5-year survival that approaches 50%, or a little bit more.

Deborah J. Wong, MD, PhD:This is exciting to see that even with targeted therapies, which we generally think about as relatively short-lived, that we are seeing long-term PFS as well as OS [overall survival] data.

Similar data were also seen in the COLUMBUS study, which evaluated encorafenib and binimetinib compared to vemurafenib. Presented at the 2019 ASCO annual meeting, the median progression-free survival for patients treated with binimetinib and encorafenib was 14.9 months compared to 7.3 months with vemurafenib. Again, very exciting data demonstrating the efficacy of BRAF-MEK inhibition. The overall response rates were very high for these targeted therapies in the COLUMBUS study, 75% of patients with an overall response rate by local review.

Transcript edited for clarity.