Malignant Melanoma: Contemporary Management - Episode 10

Clinical Trials for Frontline Therapy in Melanoma


Jeffrey S. Weber, MD, PhD: Jason, speaking of frontline targeted therapy, we now have longer-term data that will be presented at this ASCO [American Society of Clinical Oncology Annual Meeting]. I think it’s an oral presentation. What can you tell us about that abstract and what it says?

Jason J. Luke, MD, FACP: These are the 4- to 5-year follow-up data on dabrafenib-trametinib phase III clinical trials. And I think the data actually are pretty impressive, and I think it’s really worth highlighting them, although they have to be put into context. I always like the term that you often throw out about the urban legend that all patients who get targeted therapy eventually progress. I think what we can really, definitively say, based on this abstract, is that’s not true. At 4 and 5 years, we saw that the progression-free survival was around 20%. That means that about one-fifth of the patients never progressed on targeted therapy, and I think that’s really important. That really is a change from the way people have commonly thought of that. And the overall survival for those patients is sort of in the mid-30s, and that’s pretty good as well considering the historical experience in melanoma.

Another really important aspect of this, just to note, is the stratification within this analysis, which is to say that a low LDH [lactate dehydrogenase]—which is a blood biomarker that we use in melanoma—strongly stratified the outcomes of the patients. At 4 to 5 years, the patients with low LDH were 40% progression-free compared with those with a high LDH, who were less than 10%.

Jeffrey S. Weber, MD, PhD: A 50-year-old marker is still 1 of the most important prognostic factors in melanoma?

Jason J. Luke, MD, FACP: Exactly.

Jeffrey S. Weber, MD, PhD: Well, how far we’ve come.

Jason J. Luke, MD, FACP: Yeah.

Jeffrey S. Weber, MD, PhD: Interesting.

Vernon K. Sondak, MD: Yet most people say give BRAF/MEK to the high-LDH patients because they’ve got the highest tumor burden.

Jeffrey S. Weber, MD, PhD: Which is an absolute contradiction when you think about it.

Ryan J. Sullivan, MD: Contradiction.

Vernon K. Sondak, MD: When you think about it.

Ryan J. Sullivan, MD: An argument could be made that if we had a biomarker to identify who those 40% of patients would be, we would know which patients we should be offering BRAF/MEK to, other than high LDH. Obviously, LDH identifies the 40% who are going to be progression-free for a while, but if you had something to just say, “I don’t have to worry about immunotherapy yet for this person; I can just give targeted therapy,” it would be really useful.

Jeffrey S. Weber, MD, PhD: One thought is that you should combine these. In fact, I think Georgina Long has an abstract, Hussein, at this [American Society of Clinical Oncology Annual] Meeting. And there will be preliminary data from the COMBI-i study, which again is spartalizumab-dabrafenib-trametinib. What can you tell us about that?

Hussein A. Tawbi, MD, PhD: On the surface it sounds as if we have so much frustration deciding whether targeted or immunotherapy, so why not give them all? Why is this the approach? The reality is this is heavily based on some really compelling translational data that [show] that BRAF-targeted therapy actually improves, potentially, the outcome of immunotherapy by making the tumor microenvironment more favorable for immunotherapy and for T-cells to infiltrate for T-cells to actually kill tumors as well. And so based on those data, there have been several trials that have combined BRAF-targeted therapy with PD-1 [programmed cell death protein 1] antibodies that have shown some promising efficacy. And that approaches now in phase III testing.

COMBI-i is essentially a phase III trial that is designed to test the question of whether spartalizumab, an anti—PD-1 antibody, combined with dabrafenib and trametinib can actually be more effective in the first-line setting for BRAF-mutant patients, versus dabrafenib and trametinib alone. That study was designed in a way that had 3 parts. The phase III trial that I just discussed was part 3, but part 1 was designed to determine the safety and make sure that those 3 drugs could be given at full doses in this population, and it did meet the primary endpoint, and that’s how that evolved to part 2 and part 3. Part 2 was a 27-patient study that was a translational study with biomarkers. The patients had to have biopsiable disease and had to have biopsies before and after.

What is being presented at this meeting is actually some safety and efficacy data from those 2 parts. It was 36 patients, a sizable population in terms of looking at that question specifically, the safety. And it was clear that the triplet combination has a higher rate of toxicity, there is no question about that. However, when you do some dose interruptions and dose reductions, and follow some algorithms that have been developed as part of the study, you can still deliver the 3 drugs together. And so about 17% of patients discontinued all 3 drugs, but again, that means that the other 83% managed to get them.

Interestingly, from an efficacy perspective, there was an overall response rate of 75%. Thirty-three percent were complete responses, which is higher than what you would expect from dabrafenib and trametinib alone. They’re really intriguing data, and I think they get us even more excited about seeing what the triplet therapies are going to do in the phase III trials.

Transcript Edited for Clarity