Several clinical trials are evaluating neoadjuvant and adjuvant immunotherapies for melanoma alone and in combination in an attempt to improve upon current regimens. Researchers at the 2024 ASCO Annual Meeting presented data from some of these trials.

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.

As a field, I think we have learned that we should not consider any one trial to be the be-all and end-all. To be fair, the phase 3 NADINA trial of neoadjuvant ipilimumab plus nivolumab vs standard of care, results of which were presented at ASCO 2024 in abstract LBA2, was preceded by a couple of very small trials in Europe (ie, the OpACIN-neo and the PRADO trials). The use of anti–CTLA-4 and anti–PD-1 therapies together is certainly not new. In the NADINA trial, if a patient had a major pathologic response, the investigators accepted this as a sufficient indication that they required no further therapy. That is certainly not the current standard of care in the United States, although it may be in the future. Determining that would require a special trial and follow-up that we do not have from NADINA.

Further, among patients from NADINA who did not have a major pathologic response, those with BRAF wild-type tumors were assigned to nivolumab, which would be a standard approach here. Those who were BRAF mutated were assigned to BRAF/MEK inhibitors. The hazard ratio of 0.32 for the primary end point of event-free survival means a 68% reduction in event-free impact, and this is very notable. The 12-month estimated event-free survival of 83.7% for the neoadjuvant arm vs 57.2% for the adjuvant arm is as good as we have seen. But this is just one trial. It does come after the SWOG S1801 trial. It was multicenter, and it was robust in numbers.

And, while the data are good, I think that the comparator might well have been anti–PD-1 neoadjuvant therapy vs anti–PD-1/anti–CTLA-4. I am sure that this will happen in the future, but we need further data. I think that NADINA is a trial that will be discussed for some time to come and that investigators across the country will begin to think about the use of ipilimumab plus nivolumab. While the combination of ipilimumab and nivolumab is something that is clearly growing, is it the zenith? Or is that ipilimumab, nivolumab, and relatlimab? What is the role of these combinations in the adjuvant treatment of melanoma? That is also being discussed.

At ASCO 2024, the results of the phase 3 PIVOTAL trial examining neoadjuvant intratumoral therapy with daromun (a combination of the antibody-cytokine fusions L19IL2 and L19TNF) vs immediate surgery were presented in abstract LBA9501 by Hauschild et al. This study had really interesting data for us to consider. Since, for locally advanced disease, it is difficult to assure a curative impact with just surgery, it may well be reasonably treated with this therapy. And I think that this treatment is one that we have not really thought about in the United States. There was a significant impact in relapse-free survival, with a median relapse-free survival of 16.7 months in the treatment arm vs 6.9 months in the control arm by a blinded independent review board.

I think that neoadjuvant therapy in stage III melanoma has come of age. Anti–PD-1 therapy is currently widely considered in this country and will be for some time because we do not yet know if a nivolumab-plus-ipilimumab regimen is that much better than anti–PD-1 alone, and it is potentially more toxic.

A big question for the field moving forward is: How do we treat high-risk patients with stage IB/IIA melanoma? We need additional trial data in these populations. The good thing about the US Food and Drug Administration (FDA) approvals for both pembrolizumab and nivolumab in stage IIB/C melanoma is that the population of patients who may benefit from immunotherapies will nearly double.

The best way to encapsulate the risk-benefit ratio is to talk about the number needed to treat for benefit and the number needed to harm for adverse impacts. I think that we should really openly present all the data regarding the toxicities in the adjuvant setting. They are mostly reversible. Patients may not be the best candidates for immunotherapy if they have underlying autoimmune disorders or a history of colitis or hepatitis.