Treatment Choices in Metastatic Melanoma

Michael A. Davies, MD, PhD:For a patient withBRAF-mutant metastatic melanoma, there are many FDA-approved therapeutic options available for this patient. Because this patient has aBRAF V600mutation, targeted therapies are certainly an option. At this time, the standard approach with targeted therapies is to use BRAF and MEK combination therapies as opposed to single-agent BRAF inhibitors. FDA options include the combination of dabrafenib and trametinib and vemurafenib and cobimetinib. In treatment-naïve metastatic melanoma patients with aBRAFmutation, the expected clinical response rates with these agents are in the range of 70% to 75%, with disease control rates of greater than 90%. The median progression-free survival on each of those combinations is approximately 1 year, and we’re building up more and more data about the long-term outcomes with those therapies.

In addition to targeted therapy, it’s also very reasonable to consider first-line immune therapies in a patient like this. And based on randomized trials, that’s really a decision between single-agent PD-1 therapy or combination immunotherapy with ipilimumab and nivolumab. Single-agent PD-1 therapy with either nivolumab or pembrolizumab has a response rate between 40% to 45% in treatment-naïve metastatic melanoma patients. And notably, most of those responses are quite durable, with most responses lasting at least 2 years.

The combination of ipilimumab and nivolumab has a response rate of close to 60%, and many of those responses appear to be quite durable. Interestingly, recent randomized clinical trial data from the CheckMate-067 study does suggest that 2-year overall survival with single-agent nivolumab and the ipilimumab/nivolumab combination is actually very similar. So, it’s hard to tell, at this point, how to pick specifically between single-agent PD-1 therapy and the ipilimumab/nivolumab combination in the frontline setting.

So, for this patient withBRAF-mutant metastatic melanoma, treatment with a BRAF/MEK combination, such as dabrafenib and trametinib, is a very reasonable therapeutic option. Overall, we know that the median progression-free survival with dabrafenib and trametinib is approximately 1 year. It’s clear that some patients have much better outcomes than that, while other patients have much worse outcomes than that.

Recent studies that have looked retrospectively at large clinical trials with both BRAF/MEK combinations that are approved for use in this disease have identified a number of factors that predict whether patients will have better or worse outcomes. Particularly relevant to this patient, it has actually been demonstrated that patients who have a normal LDH and a low tumor burden can actually do exceptionally well with BRAF/MEK combination therapy. Indeed, those patients have a very high chance of achieving a complete response. In patients who receive a complete response with dabrafenib and trametinib therapy, the 2-year survival rate was actually close to 80%.

So, in this patient who’s presenting with, again, what appears to be a very low burden of disease and a normal LDH, we would expect this patient to have a very high chance of an initial response, certainly even higher than the average response rate of 75%. And it’s very likely that this response will be quite durable in this patient. Therefore, the treatment with BRAF and MEK combination therapy was a very reasonable choice in this patient. However, we do also know that this low serum LDH and low tumor burden potentially also predict very good outcomes with immune therapies as well. So, again, this is a patient with a multitude of good treatment options, both in this setting and if the treatments are needed subsequently.

This is a patient withBRAF-mutant metastatic melanoma who has been started on combination targeted therapy with dabrafenib and trametinib. And, again, although the overwhelming majority of patients treated with this therapy in this clinical scenario will have not only a response, but very good responses, it is true that many of these patients will eventually progress. What would be the treatment options at that time? There would actually be multiple treatment options available.

Among FDA-approved treatment options, again, the primary options for this patient would be treatment with either single-agent PD-1 or the ipilimumab/nivolumab combination therapy. Both of those therapies are known to work inBRAF-mutant patients who are either treatment-naïve or after progression on targeted therapies. And so, they would remain very good treatment options for this patient, even after prior treatment with targeted therapy with dabrafenib and trametinib. Certainly, patients like this are also good candidates for clinical trials, which should also be considered in that clinical setting.

Transcript edited for clarity.

April 2017

• A 52-year-old female presented to her dermatologist with a pigmented lesion which had recently become darker; she had it removed for cosmetic reasons
  • Pathology revealed a melanoma with a depth of 2.3 mm
  • Genetic testing;BRAF V600mutation-positive
• LDH, WNL (174 UI/L)
• She underwent wide local excision and sentinel node mapping; staining is positive for melanoma in the right axillary node
• Complete dissection of the right axilla reveals no additional involved nodes
• CT of the chest, abdomen, and pelvis showed multiple masses in both lungs, the largest being 5 mm
• She underwent core-needle biopsy of the largest lung lesion
  • Pathology revealed metastatic melanoma
  • Mutation testing:BRAF-positive
• The patient is started on dabrafenib 150 mg bid and trametinib 2 mg qd