ESMO 2024: Breakthroughs in Melanoma Treatment Regimens

Dr Jeffrey Weber discusses recent abstracts focused on melanoma, as presented at ESMO.

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Hello. I'm Dr Jeffrey Weber. I'm a medical oncologist at the Laura and Isaac Perlmutter Cancer Center in New York City at NYU Langone Health. I'd like to report to you today on three abstracts from the recent ESMO meeting. I think they are of some interest to both practicing doctors and those interested in the academic melanoma world.

First is an update on the SECOMBIT trial, a clinical trial in which patients with metastatic melanoma were randomly allocated to get either targeted therapy with encorafenib and imatinib first and then on progression get ipilimumab/nivolumab (ipi/nivo)(arm A); or to get ipi/nivo first and then get targeted therapy second (arm B).

Arm C was the sandwich arm: Patients got 8 weeks of encorafenib and imatinib and then had a forced switch to immunotherapy; if they progressed, they went on potentially to get targeted therapy. The preliminary results of that have already been presented.

What we saw here at ESMO were follow-up data at 5 years. Guess which arms were the winners. It was arms B and C. It was immunotherapy first or immunotherapy in the sandwich, where patients got targeted therapy and then immunotherapy, and then only targeted therapy if they progressed.

It looks like there was about a 50% progression-free survival (PFS) rate at 5 years, which is a phenomenal number, equivalent to what you would see in the much larger and older CheckMate 067 study, and the 5-year PFS for the targeted therapy–first arm was much inferior at only 27%. Those PFS curves broke apart, came apart quickly, and stayed apart. There were clear winners, as arms B and C were much better than arm A.

If you look at overall survival (OS), it was a very favorable 57% for arm C and 52% at 5 years for arm B. Those are the two arms where you had either immunotherapy first in arm B or the sandwich approach, with targeted therapy for 8 weeks, a forced switch to immunotherapy, and then on to targeted therapy if the patient progressed in arm C. There was more than 50% 5-year survival, which again is looking almost as good as CheckMate 067, where the median survival was about 72 months.

We may see that kind of median survival in this study. It's a much smaller study; we're talking about only 200-plus patients total, whereas CheckMate 067 had over 300 patients per arm times three. Again, these are very favorable data suggesting that in the sandwich, patients do very well and they also do very well getting immunotherapy first. Again, more grist for the mill, suggesting that your frontline strategy generally should be immunotherapy first followed by targeted therapy.

Now, for the first time, we look at those who had brain metastases. In the SECOMBIT trial, again, we saw the same pattern. Arms B and C were the winners, with a 5-year brain metastasis–free survival of 80% and 85%, respectively. Those are very nice numbers. The rate was significantly inferior if you got targeted therapy first, at 56%. Unfortunately, if you look at survival after developing brain metastases, if you only go to, say, 24 months, it's less than 10% for targeted therapy first, and it's about 1 in 3 or maybe 30% for either sandwich or immunotherapy first. We all agree that patients don't do as well, but they do much better if they get immunotherapy or sandwich therapy.

Finally, the 5-year rates of PFS and OS were much better with sandwich or immuno-first therapy compared with targeted first, which confirms the data of DREAMseq. Again, you're at a much higher risk of developing brain metastases if you get targeted therapy first. OS and brain metastasis–free survival were clearly better in arms B and C, with the sandwich and with the immunotherapy first. The patients who are tumor mutational burden–high and an active JAK/STAT, whatever the treatment, always do better. There's no question. It just reinforces the idea that, whatever the patient's situation, they're going to do better either with a sandwich or with immunotherapy first.

Let's switch gears and talk about uveal melanoma. Generally, we don't see a lot of uveal trials presented because not many of them are positive. In fact, the most interesting trial that I heard at the ESMO meeting in uveal melanoma was presented by Meredith McKean from MD Anderson, which utilized, surprisingly, a targeted approach with a protein kinase C (PKC) inhibitor and a c-MET inhibitor. PKC is activated in patients with GNA11 and GNAQ mutations, which are very common in uveal melanoma.

Transcript in its entirety can be found by clicking here: