The number of therapies that are available for melanoma has increased dramatically over the past 13 years, raising hope for an eventual cure for the disease. At the 2024 ASCO Annual Meeting, researchers presented clinical trial data on novel therapies and combinations for melanoma in the adjuvant and metastatic settings.

Following these presentations, featured expert John M. Kirkwood, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Kirkwood’s clinical perspectives on these findings are presented here.

I think it is important to reflect that 13 years ago, in early 2011, we had no potential curative therapies for melanoma, and we had only 1 US Food and Drug Administration (FDA)–approved adjuvant treatment, interferon alpha. Since then, we have seen an avalanche of more than 15 new therapies for metastatic disease and easily 12 trials in the adjuvant space aimed at having a curative impact on melanoma.

Curative impact may be interpreted in different ways. I think that it can mean relapse-free survival in the adjuvant setting and progression-free survival in metastatic disease. Overall survival benefit is something that we have only recently dared to think that we can achieve. After 5 years of waiting, overall survival benefit has been reported in the CheckMate 067 trial, which really makes that a benchmark in metastatic disease.

Now we are considering the possibility of adding targeted therapies such as BRAF/MEK inhibitors to immunotherapies or adding tumor-infiltrating lymphocytes (TILs). Melanoma has paved the way for TILs with the first FDA approval for lifileucel in February 2024. And so, the question now is: How can we improve upon the impact of double checkpoint blockade with ipilimumab and nivolumab, which I think is the standard for the field?

I think that we have a first-line treatment for metastatic disease in the combination of relatlimab and nivolumab, which achieved statistical significance over nivolumab monotherapy for progression-free survival in the 3-year follow-up from the RELATIVITY-047 trial, results of which were presented at ASCO 2024 (abstract 9524). The toxicity with this regimen is probably half of what we have seen with the ipilimumab-plus-nivolumab regimen.

We also saw data from the RELATIVITY-048 trial at ASCO 2024 with the triplet combination of nivolumab, relatlimab, and ipilimumab in patients with relatively limited follow-up (abstract 9504). These data were really underwhelming, however, with small patient numbers and benefits that are not more than what we already have. In fact, the toxicities are probably a little worse than relatlimab plus nivolumab but are perhaps not as daunting as the ipilimumab-plus-nivolumab toxicities.

The biggest gap in the field is related to what to do for people who have failed single-agent anti–PD-1 therapy, either nivolumab or pembrolizumab, or the combination of anti–PD-1 and anti–CTLA-4 therapies. Maybe you need a combination such as the combination of anti–LAG-3 and anti–PD-1 therapies from RELATIVITY-047. The attempt to cure the disease with the addition of BRAF/MEK inhibitors to anti–PD-1 therapy did not achieve the benefits we wanted, and, sadly, all had significantly greater toxicity than anti–PD-1 alone followed by the BRAF/MEK inhibitors or the reverse sequencing.

It is very clear in metastatic disease that the algorithm should be immunotherapy first, followed by targeted therapy. The same cannot be said for adjuvant therapy. Since double immunotherapy is better than double-targeted therapy up front in metastatic disease, some people make the inference that the same may be true in the adjuvant setting, but that also is not true. One of the striking presentations on the first day of ASCO 2024 was that of the results of the COMBI-AD trial, which studied dabrafenib plus trametinib for 1 year vs placebo for 1 year in patients with resected, stage III, BRAF-mutated melanoma (abstract 9500). At the 10-year follow-up, there was a 20% risk reduction in the deaths of patients who received dabrafenib and trametinib as adjuvant therapy. Although it did not reach statistical significance, this is clearly highly active therapy. What this means to patients in an adjuvant setting is that if the disease is positive for BRAF V600E/K mutation, we know that dabrafenib and trametinib is as durable, robust, and every bit as good as anti–PD-1 immunotherapy. So, I think that the field is maturing nicely, and the benefits that we have with ICIs in the adjuvant setting are complemented nicely by the benefits that we see with BRAF and MEK inhibitors.

We saw a very small study of the combination of PD-1 plus TIL presented at ASCO 2024 called IOV-COM-202 (abstract 9505), which is a flicker of hope, and that combination is now being tested in the much larger, phase 3 TILVANCE-301 trial. We will have to await those results to really draw any firm conclusions about whether PD-1 blockade will be a lot more effective.

We have identified many biomarkers in melanoma that are of potential interest. For example, PRAME has been targeted with T-cell bispecifics, which are in active exploration (abstracts 9507 and TPS9602). The problem is that we have to match for the HLA type, and it has to be HLA-A*02:01, which only approximately half of the population manifests—and therefore can benefit from this therapy. Also, we have to do the tissue typing before we can consider the eligibility, which slows things down, but we are used to that. That is the very same fraction of the population with BRAF-mutated disease, and we have certainly been able to establish the efficacy of those approaches.