Adding new vaccine type to leading immunotherapy dramatically reduces melanoma recurrence

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Published: 3 May 2023
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Dr Jeffrey Weber - NYU Langone’s Perlmutter Cancer Center, Newyork, USA

Dr Jeffrey Weber speaks to ecancer about a personalised cancer vaccine, mRNA-4157, combined with pembrolizumab in patients with resected high-risk melanoma.

He discusses the efficacy and safety results from the randomised, open-label Phase 2b mRNA-4157-P201/Keynote-942 trial.

Immunotherapies are usually used for treating melanoma but their impact differs from patient to patient due to the evasiveness of cancer which lead to immunotherapy resistance.

This is why in this study they added immunotherapy with pembrolizumab.

Dr Weber says that our study shows that a neoantigen mRNA vaccine when used in combination with pembrolizumab, results in prolonged time without recurrence or death compared with pembrolizumab alone.

He concludes by discussing the significance of these findings and what the future is for this study.

The study that I recently reported on at the AACR meeting was a randomised phase II study of an adjuvant strategy that combined a neoantigen messenger RNA vaccine with a standard drug called pembrolizumab, which is an immunologic drug that is FDA approved as adjuvant therapy for high-risk, surgically resected melanoma, compared to just the pembrolizumab alone. So this was a randomised phase II study with a 2:1 randomisation that was designed to find out whether you could prolong the time to recurrence, or what we call recurrence-free survival, in patients who had what we call high-risk resected melanoma, meaning someone who after surgery would be free of disease but would have easily a 50% or more risk of relapse over the next five years.

What was the study design?

This was a classic 2:1 randomisation, meaning a total of 150 patients. So there ended up being 107 patients who got the combination of the mRNA vaccine 4157 with pembrolizumab and 50 who got pembrolizumab alone. Remember, in a randomised phase II study you don’t have enough patients to definitively answer a clinical question but you have enough patients to give you a high degree of assurance that if you did a randomised phase III study, a confirmatory study, the result would parallel that which you saw in the randomised phase II study.

What were the results?

The results were highly encouraging and showed that there was a clinically significant difference in recurrence free survival between the combination of the mRNA vaccine 4157 and pembrolizumab compared to pembrolizumab alone. Each arm had about two years of follow up and if you calculate, say, at 18 months, which is the so-called landmark recurrence free survival, it was 78% for the combination and only 62% for pembrolizumab alone. Now, that 62% at 18 months is consistent with what you would see with pembrolizumab alone in prior studies where it was compared in large studies to a placebo. 78% is pretty darn good and if you look over time and compare the recurrence free survival curves you can generate a hazard ratio. The hazard ratio was 0.56 over time, suggesting a 44% reduction in the risk of recurrence over time where the recurrence free survival curves were the same until about 8 months or so and then began to open up and then stayed open over the two years of follow up. 

In addition, when you looked at the toxicity, the so-called grade 3/4 immune-related adverse events, or the serious adverse events, were similar between the arms although if you calculated all toxicity obviously the vaccine carries with it its own toxicity, 89% of the patients who had vaccine toxicities, which is almost all patients, had grade 1 and 2 toxicities which means they were fairly well tolerated. Only one in nine, or 11% of patients, had a grade 3 vaccine-related toxicity, usually high fevers. But again, like the COVID vaccine that has some similarities to the neoantigen vaccine, you would have some vaccine-related side effects, as I have had when I got my COVID shot. That is, you’ll see some feverishness, chills, fatigue, lethargy, injection site rash and tenderness, muscle aches. Those are the classic vaccine-related side effects. So, overall, when you add all the toxicities up, of course there’s more toxicity in the combination arm than in the control arm, but if you look at the clinically significant, the high-grade serious adverse events, they were pretty much similar between the arms and the vaccine did not augment the so-called immune-related side effects of pembrolizumab.

How do you think these results can impact future research and treatment?

I think the study was a landmark in that it’s been the first reported study where a neoantigen vaccine approach, whether it be peptides, DNA, RNA, in this case, of course, mRNA, was compared to a control arm with a significant suggestion and evidence of clinical benefit for the vaccine when combined with the standard treatment of pembrolizumab compared to the control arm of pembrolizumab alone. All prior neoantigen vaccine strategies or studies have been in early phase studies, very small numbers of patients, designed as proof of concept to see whether you could actually induce an immune response.

Here you actually had evidence of clinical benefit and clinically significant evidence of benefit. I think that makes it a landmark and for the future it says neoantigen vaccine approaches need to be pursued in other cancers that express neoantigens, which is almost all cancers, especially those where there is benefit from PD-1 blockade, such as non-small cell lung cancer, head and neck cancer, gastroesophageal, hepatocellular, renal cell. All of those are fair game for vaccine trials. Bladder cancer. All places where there’s an approved adjuvant or most of them have an approved adjuvant treatment consisting of, at least in part, a PD-1 antibody, where you could add the vaccine approach to it. I think that will provoke large numbers of randomised phase III studies in the future. 

In addition, it gives hope to the neoantigen strategy in general, not just as a vaccine but it now provides evidence in a randomised study that neoantigen approaches will be useful in cancer and, of course, it resuscitates the cancer vaccine field, in my opinion, and will provoke lots of further phase III studies. The cancer vaccine field has been discouraging and I, for one, am certainly a person who would be regarded as a cancer vaccine sceptic but now these data really shift the pendulum back to one where we really would wish to develop multiple different trials of neoantigen cancer vaccines, especially mRNA vaccines.