PracticeUpdate: What are the most exciting updates in targeted therapy for metastatic melanoma from this conference?
Dr. van Akkooi: At this year's ESMO, there have been a few important publications of studies with targeted therapies for metastatic melanoma. I think one of the first most prominent ones is the COMBI-i study, which is a study that is examining the triplet of spartalizumab, which is an anti–PD-1, plus dabrafenib and trametinib for BRAF-mutated melanoma versus dabrafenib and trametinib plus a placebo. The interesting thing about this study is that it is actually negative up until this point. The primary analysis looking at progression-free survival, although it seems to improve progression-free survival slightly, the triplet versus the doublet, with about 4 months was not statistically significant, according to the pre-specified statistical plan. This is interesting if you compare it to a previous study that was reported, which is the IMspire study of atezolizumab plus vemurafenib and cobimetinib, which was a positive triplet.
Although if you compare head to head the two studies, it doesn't seem that the difference between the two studies is too much. Here, the study didn't end up having a statistically significant benefit, whereas the IMspire study did. The question remains, is it clinically relevant? If we move from that to another study that was presented at this year's ESMO, it is the SECOMBIT trial. The SECOMBIT trial is a trial that examined three different treatment options, being either ipi/nivo or upfront targeted therapy with enco/bini, and then switching at progression, or the third, which is called the sandwich approach, where patients would receive 8 weeks of enco and bini and then follow with a planned switch after 8 weeks to ipi/nivo. The interesting thing about this trial is that none of the 3 groups seem to be superior to another group, so that all 3 options seem to be okay in patients with metastatic melanoma.
We still don't know what is the optimal first-line treatment approach. Of course, the progression-free survival was the best in the patients that were treated with enco/bini and it was lesser for the patients that started with upfront ipi/nivo. But after 2 years, there were no differences between the 3 groups. Still, we struggle to see what is the optimal approach to treat BRAF-mutated metastatic melanoma. Is that with a triplet, is that with upfront targeted therapy, or is that with upfront immunotherapy? I think there are still some studies needed for the future to see what the optimal approach will be.
PracticeUpdate: Did we learn anything new about adjuvant treatment from these presentations?
Dr. van Akkooi: The adjuvant treatment was also updated at this year's ESMO meeting. There have been two updates from pivotal phase III studies. The first being the EORTC 1325 study, a study of adjuvant pembrolizumab for a year vs placebo or the CheckMate 238 study, which was a study of adjuvant nivolumab for a year, but then compare it to the active comparator of high-dose ipi at 10 mg/kg. These studies showed us that with longer follow-up, there is a sustained benefit of anti–PD-1 adjuvant therapy at circa 3.5 to 4 years out now, and that, of course, anti–PD-1 is superior to a placebo or to high-dose ipilimumab treatment.
We didn't see any updates now at ESMO about the targeted therapies in adjuvant setting. Previously, we've seen that the COMBI-AD study with 5 years' follow-up showed that the combination of dabrafenib and trametinib is also still very effective, even 5 years on. For the choice of adjuvant treatments for BRAF-mutated melanomas, the jury is still out there. What is the optimal approach? Is it adjuvant targeted therapy, or is it adjuvant immunotherapy? Nobody knows, and both options can be discussed with the patient.
PracticeUpdate: Finally, are there any novel targeted therapies that we should keep our eyes on?
Dr. van Akkooi: The novel therapies this year at ESMO meeting for metastatic melanoma included, for instance, lenvatinib. Lenvatinib is a VEGFR inhibitor, and this was combined with an anti–PD-1 regimen for patients that were already resistant to first-line treatment. It was a phase II study, but it showed some efficacy of this combination in this highly difficult treatment group, which was already treatment-refractory to the first-line treatment. It might be interesting to see this move forward into a phase III study if this is a novel therapeutic approach for metastatic melanoma.