Dual Targeted or Immunotherapy for BRAF-Mutant Melanoma

Transcript:Jeffrey S. Weber, MD, PhD: Georgina, at your institution, what kind of biomarker testing do you do at the time of diagnosis? Let’s say you see a new patient in clinic; what kind of genetic testing are you going to order?

Georgina Long, MD, PhD: Genetic testing must be done for all patients with stage 4 disease. That’s critical. We also do somatic genetic testing, checking the tumor. We also do it for very high-risk stage III patients. So, the next question is, what test do you use? The most important thing is that you understand the test you’ve got so you can interpret it and know whether or not you need to do more tests. For example, at our institution, we routinely do an immunohistochemistry test for V600E, because we can get that back within a couple of hours to very quickly know whether or not the patient has the more common V600E mutation. However, you must complement that with a genetic test. Sometimes, there can be staining difficulties in less experienced hands. But, if it’s negative, there are these other V600 mutations—V600K, V600R—and they’re rarer, so you must complement that with the genetic test, particularly if the immunohistochemistry is negative.

There are several different platforms. There are some PCR-based tests. There’s the next-generation sequencing panel. The advantage of that is that you can get an idea of other mutations, although we have no drugs specifically targeting other mutations. We do have clinical trials in NRAS-mutant metastatic melanoma. So, I think the most important test you can get is a BRAF test that covers all the V600 BRAF mutations. A panel may give you some more information, particularly for the NRAS mutations in melanoma, and we may increasingly have other drugs for other targets within melanoma.

Jeffrey S. Weber, MD, PhD: So, the first thing you’ll do is to genetically test them. Then the question becomes—and this is a controversial one—how do you decide whom to put on targeted therapy and whom to put on immunotherapy? Obviously, if they’re wild type, it’s a moot point. But, in the BRAF-mutated setting, 50% of the population you see in clinic, how do you decide? Mike, take that first.

Michael A. Davies, MD, PhD: I think it’s one of the dominant questions in the field at this point. And I think, for a newly diagnosed patient with BRAF-mutant metastatic melanoma, we have very good results with targeted therapy, and we have very good results with immunotherapy. The fact of the matter is that none of us absolutely know from the start which one of those treatments is going to be better. And I think it comes down to there being a lot of things now that go into the decision making between those 2 agents or strategies. Traditionally, in the field, what we’ve seen is that patients with a low burden of disease are preferentially getting treated with immunotherapy. Long-term follow-up data from the targeted therapy trial show that’s actually a population of patients who can do very well for a very long time with targeted therapy, as well.

For patients who have large, bulky disease that appears to be very aggressive, the bias over time has been to put those patients on targeted therapy because it has a higher chance of getting an initial response. But we actually know now that the majority of those responses are actually quite short-lived; whereas, if you actually get a response to immunotherapy in those patients, it can be quite durable. So, I think it’s really an open question.

Certainly, the other hypothesis that’s now being evaluated in clinical trials is the third option, which is combining targeted therapy and immunotherapy together. And the question for each of those therapies is, can we identify clinical molecular immune biomarkers that help us personalize how we actually pick the initial therapy? What I would also add to this is one of the things that I talk about with my patients: regardless of which therapy we decide to start with, we know that if it doesn’t work, these other therapies can work in the second-line setting. And so, in many ways, although we often struggle with what treatment is first, the fact of the matter is that it’s a bit of a luxury for the BRAF-mutant patients that you actually have multiple lines of effective therapy to offer.

Jeffrey S. Weber, MD, PhD: Georgina has published on the issue of which patients indeed might benefit the most from targeted therapy versus immunotherapy. So, Georgina, could you just summarize the data that were presented today at ASCO? Because it really relates to debunking that urban legend that all patients who get BRAF/MEK inhibitors are going to progress and die within the first couple of years.

Georgina Long, MD, PhD: I’ll just back up on what Mike said about the decision between the 2. I have to say, we do have to wait a little longer to see the emerging data, and what we’re really going to be interested in is the size of the tail on the progression-free survival curves for all of these treatments. But to summarize the data and answer your question, today we presented the 5-year overall survival data for the combination of dabrafenib and trametinib—you presented that, Jeff—from a phase I/II trial, particularly focusing on the randomized portion in the phase II trial. So, what we saw overall in that group was that at 5 years, the progression-free survival was 13%. That’s the landmark at 5 years.

If we look at the subgroup who had a normal LDH at baseline and less than 3 metastatic sites—and that was not a small proportion of patients, actually; surprisingly enough, it was around the 40% mark of the total population—their 5-year progression-free survival was 25%, and their overall survival was 51%. I am cautious of the interpretation of overall survival landmarks these days, because we so often treat with other therapies after patients progress. So, I think to get a really good sense of the drug’s activity, the progression-free survival landmarks really say it all, because you only fall off of that curve if you either progress or change treatment—but you don’t even have to be on treatment. So, 25% in less than 3 metastatic sites and a normal LDH.

Jeffrey S. Weber, MD, PhD: Jason, another issue is whether or not we should ever be using BRAF inhibitors alone. Do you have any views on that?

Jason J. Luke, MD: We should not be using BRAF inhibitors alone.

Jeffrey S. Weber, MD, PhD: I agree with you, but actually, I hear about this happening in the community every once in a while, so I think we have to convince our practicing colleagues.

Jason J. Luke, MD: If I could make a point to back up what Georgina said there—I think it argues to a point about the multidisciplinary approach to a patient. Many of the patients are doing quite well over a period of time on targeted therapy. Perhaps they have intermittently had to have 1 lesion taken care of that progressed. So, considering a multidisciplinary approach to patients, both at the beginning but also throughout their care, is something that we’re going to have to get back to thinking about a lot in the way that it used to be: that the surgeons really were involved in the management of metastatic melanoma throughout their care. Because I think we’re starting to see signs that if we can get the more aggressive lesions under control, these therapies that we have can really convey very long-term benefits in our patients.

Transcript Edited for Clarity