Personalized mRNA melanoma vaccine cuts recurrence risk by 42% in largest trial yet

A personalized mRNA vaccine designed to match each patient's own tumor reduced the risk of melanoma returning — or of dying — by 42% compared with the current standard of care alone, according to results from the largest trial of the therapy to date. The findings, from a Phase 3 trial of 1,136 patients, were released by Moderna and Merck on Thursday ahead of a formal presentation at the European Society for Medical Oncology meeting in Madrid.

The companies said they are now 'engaging with regulatory authorities,' language that signals an FDA approval filing could be imminent.

This new vaccine is something that we've never really seen before in terms of the efficacy that it has demonstrated and the way that it works.— Dr. Michael Postow, chief of the melanoma service at Memorial Sloan Kettering Cancer Center

The vaccine, called intismeran autogene — also known as mRNA-4157 — uses the same mRNA platform as Moderna's Covid-19 vaccine, but instead of targeting a virus, it is engineered to attack cancer cells. After a patient's tumor is surgically removed, a sample is sequenced and the vaccine is custom-built around up to 34 tumor-specific markers, called neoantigens, most likely to trigger an immune response. Each dose is delivered as an intramuscular injection.

This personalized cancer vaccine is a specific type of treatment that boosts the body's immune response only against the cancer cells that are there, and therefore it is a much more targeted immune boost directly against that patient's individual tumor.— Dr. Michael Postow, chief of the melanoma service at Memorial Sloan Kettering Cancer Center

The trial enrolled patients with resected high-risk melanoma — stage IIIB through stage IV — who had already had their tumors surgically removed but faced a high probability of the cancer returning. All participants received Keytruda; two-thirds also received the experimental vaccine, while one-third received a placebo alongside Keytruda. The vaccine was given every three weeks for up to nine doses; Keytruda was administered by intravenous infusion every six weeks for up to about a year, according to CNN.

Keytruda (pembrolizumab) was itself considered a breakthrough when approved in 2014. It works by enabling the immune system to identify and attack cancer cells that had previously evaded detection. It was famously used to treat former President Jimmy Carter for melanoma that had spread to his liver and brain; Carter announced he was cancer-free in December 2015, according to CNN.

The Phase 3 results are somewhat less dramatic than those from an earlier, smaller Phase 2 trial — KEYNOTE-942 — which followed 157 patients for five years and found a 49% reduction in the risk of recurrence or death, and a 59% reduction in the risk of distant spread or death, according to MedPage Today. At four years in that study, 72.4% of vaccine recipients remained recurrence-free versus 49.1% in the Keytruda-only group. The Phase 3 trial's two-year snapshot is an earlier look at a larger, more diverse population, and the trial will continue.

The most critical question — whether the vaccine helps patients live longer overall — remains unanswered. The companies said overall survival data are not yet mature, but that 'a favorable trend' has been observed. In the Phase 2 data, four-year overall survival rates were 92.2% in the vaccine group versus 85.6% in the Keytruda-only group, though that difference was not statistically significant, according to MedPage Today.

Clinical experts welcomed the results while flagging real-world hurdles. At the American Society of Clinical Oncology meeting where the Phase 2 five-year data were presented, discussant Dr. Rodrigo Ramella Munhoz of Sírio Libanês Hospital in São Paulo noted that 'operational complexity, manufacturing timelines, and costs may limit broad applicability of the personalized vaccine approach,' according to MedPage Today. He also raised the question of where the vaccine would fit as treatment patterns shift toward giving immunotherapy before surgery rather than after.

A confirmatory Phase 3 trial called INTerpath-001, focused on high-risk melanoma, has fully enrolled, according to MedPage Today. The technology is also being tested in lung and pancreatic cancers, and in earlier-stage studies for other tumor types.

Wall Street's reaction to Thursday's data release was mixed. Moderna's stock fell 18% before the market closed, while Merck's shares declined 1.8%, according to CNN. Analysts at RBC Capital Markets noted the Phase 3 results were not quite as strong as the earlier Phase 2 data, but said the FDA is likely to approve the therapy next year. Even after Thursday's drop, Moderna's shares were up more than 500% year-to-date, according to CNN analyst commentary from William Blair's Myles Minter, who called the results 'great data.'

Among the 1,136 trial participants is Beth Ryzyk, 59, who was diagnosed with stage IIIC melanoma in December 2023 — meaning the cancer had reached a certain thickness and spread to her lymph nodes. More than a year after finishing treatment, she remains cancer-free, though she still does not know whether she received the vaccine or the placebo.

I'm good; sometimes I even forget about it. It's always in the back of your mind … but they're watching.— Beth Ryzyk, trial participant

Why it matters — If confirmed by ongoing survival data and approved by regulators, this would be the first personalized mRNA cancer vaccine cleared for use — potentially opening a new treatment model applicable across multiple cancer types beyond melanoma.

Reported by washingtonpost.com, medpagetoday.com, nytimes.com, cnn.com