<p>Patients with BRAF-mutated melanoma can benefit from immunotherapy and targeted therapies, and ongoing trials are investigating these therapies in combination and in sequence. At the <strong>2024 ASCO Annual Meeting</strong>, key data from several of these trials were presented.</p> <p> </p> <p><em>Following these presentations, featured expert Elizabeth I. Buchbinder, MD, was interviewed by </em>Conference Reporter<em> Editor-in-Chief Tom Iarocci, MD. Dr Buchbinder’s clinical perspectives on these findings are presented here.</em></p>

The DREAMSeq and SECOMBIT trials really confirmed for us that patients have the best long-term survival when they get immunotherapy up front, specifically combination immunotherapy. However, interesting data from the EBIN trial looking at starting with targeted therapy for a short course and then going to immunotherapy were presented at ASCO 2024, suggesting that there was not a progression-free survival difference between doing this and starting on immunotherapy without a short course of targeted therapy (abstract LBA9503). I think that these data show us that if you do not think you have time to wait for something like ipilimumab plus nivolumab to work, you can give the patient targeted therapy and then switch to combination immunotherapy, but you do not want to wait for progression. Regarding whether that switch happens at 9 weeks or slightly later, I think that either is reasonable.

 

In terms of combining immunotherapy with targeted therapy, we are not seeing what we need to see in some of the data with triplet combinations, such as a BRAF inhibitor, an MEK inhibitor, and anti–PD-1 therapy, to consider combining these therapies up front (abstract LBA9513). We are seeing over and over again that it is better to give immunotherapy doublets and not worry so much about combining immunotherapy with targeted therapies.

 

In terms of sequencing, what we are running into now is that we administer many lines of immunotherapy before thinking about targeted therapy. I think that this is somewhat of a disservice to patients because some never get exposed to targeted therapy, which can be effective. There are data suggesting that patients with less disease may do better with targeted therapy, so at some point after combination immunotherapy, we should consider giving targeted therapy.

 

The COMBI-AD study results presented at ASCO 2024 were very thought provoking (abstract 9500). The issue is that we have never seen an overall survival (OS) benefit with immunotherapy in the adjuvant setting. Often, for patients with stage III BRAF-mutant disease, we favor targeted therapy because, previously, it had an OS benefit. With this final analysis, however, the OS benefit lost statistical significance, which was quite interesting. So, if you do not see an OS benefit with a therapy because your salvages are so good, is it worth the potential toxicity exposure to treat everybody in the adjuvant setting? However, the long-term, relapse-free survival numbers still look good, and, for now, many of us will keep using this therapy.

 

The S1801 trial showed that the use of neoadjuvant-plus-adjuvant pembrolizumab is better than using only adjuvant pembrolizumab. The NADINA trial, results of which were presented at ASCO 2024, showed that neoadjuvant ipilimumab plus nivolumab followed by response-driven adjuvant treatment is better than adjuvant treatment alone (abstract LBA2). We still do not know whether it is better to give neoadjuvant anti–PD-1 therapy or neoadjuvant ipilimumab plus nivolumab, and I think that anti–PD-1 alone is still a very reasonable regimen to consider in this space. We cannot easily make a cross-trial comparison since these trials use slightly different outcomes in that they defined events differently. However, the NADINA trial showed us that patients with bulky resectable disease should receive some sort of neoadjuvant immunotherapy regardless of BRAF status. Further, although the median follow-up was only 9.9 months, the data provide us with some confidence that we can probably choose not to give additional adjuvant therapy to patients who get a deep pathologic complete response or near pathologic complete response.

 

Although some experts in Europe feel that neoadjuvant ipilimumab plus nivolumab is the new standard of care based on the NADINA trial, I think that it is a new standard of care but not the new standard of care. I think that we are a bit more skeptical in the United States, and there is a lot of talk about the risk of hypophysitis and other severe immune-related toxicities with ipilimumab plus nivolumab. Occasionally with hypophysitis, there is a need for lifelong adrenal replacement, and patients are at risk of going into adrenal crisis anytime they get sick or need surgery, and it can be really dangerous. These are not mild potential long-term toxicities, so I think that this needs to be considered, given the fact that we are not sure how much benefit the combination adds. Who are we going to choose to receive one treatment vs the other? I think that the decision should be made after a discussion with the patient.