Personalized mRNA Cancer Vaccine Cuts Melanoma Recurrence Risk by 42% in Merck and Moderna Phase 3 Trial

A cancer treatment built from each patient’s own tumor has cleared its first big test. Merck and Moderna’s experimental mRNA therapy, intismeran autogene, lowered the risk of melanoma returning, or of death, by 42% when it was added to the immunotherapy Keytruda, according to phase 3 results presented Saturday at the European Society for Medical Oncology (ESMO) Congress in Madrid.

The trial, called INTerpath-001, is the first phase 3 study of an individualized mRNA cancer therapy to show a benefit, ESMO said in its summary of the presentation. The data were featured in the meeting’s Presidential Symposium, a slot reserved for the most consequential studies, and the companies said the results have been accepted for publication in The New England Journal of Medicine.

Merck and Moderna said they are now talking with regulators about the results. The therapy is not approved anywhere, and the companies have not said when they might file for approval with the Food and Drug Administration.

What did the phase 3 trial find?

The study enrolled 1,137 patients with stage IIB to IV melanoma whose tumors had been fully removed by surgery. That group still faces a real chance of the cancer returning, which is why many receive a year of Keytruda afterward. Two-thirds of the patients were randomly assigned to get intismeran plus Keytruda, and one-third got Keytruda with a placebo.

After a median follow-up of about two years, 82.2% of patients in the intismeran group were alive and free of recurrence, compared with 70% of those on Keytruda alone, according to the companies’ detailed results. The combination also cut the risk of the cancer spreading to distant organs, or of death, by 38%.

The benefit did not show up right away. In the first six months, the two groups looked about the same, which researchers attribute to the time it takes the immune system to respond to a full course of the vaccine. After six months, in a pre-planned analysis, the risk of recurrence or death was 58% lower in the intismeran group.

Overall survival data are not mature yet. The companies reported a favorable trend but no final numbers, and the study is continuing.

How does a personalized mRNA cancer vaccine work?

Each dose is made for one patient. Doctors send a sample of the patient’s removed tumor for genetic sequencing, and the mutations unique to that tumor are used to design an mRNA sequence that encodes a set of those abnormal proteins, called neoantigens. The finished therapy teaches the immune system to recognize cells carrying them, while Keytruda takes the brakes off the immune response.

Making a custom drug for every patient was one of the big doubts hanging over the approach. Moderna said intismeran was successfully manufactured for more than 99% of patients randomized to receive it in the trial.

In the study, patients received intismeran every three weeks for up to nine doses, alongside Keytruda every six weeks for roughly a year.

What did doctors and the companies say?

“The transformative INTerpath-001 results have the potential to make a foundational shift in how we treat patients with earlier-stage melanoma in the adjuvant setting,” said Professor Georgina Long, the study’s principal investigator and medical director of Melanoma Institute Australia, in the companies’ announcement. She said the findings support treatment tailored to “the unique mutational signature of a patient’s tumor.”

Dr. Dean Li, president of Merck Research Laboratories, called the study one of the most significant advances in melanoma treatment since immunotherapy arrived. Moderna CEO Stéphane Bancel said the results “mark a defining moment” for the company’s bet that mRNA can be used to treat cancer.

Independent experts at the meeting were already looking beyond melanoma. “In principle, this type of approach may be applicable to other types of tumors,” James Larkin of London’s Royal Marsden Hospital, the meeting’s scientific co-chair, said at an opening press conference, STAT reported.

What are the side effects?

Side effects were common in both groups but mostly mild to moderate. Treatment-related side effects of grade 3 or higher, the more serious kind, occurred in 14.2% of patients on the combination and 13.4% of those on Keytruda alone. The most common complaints with intismeran were fever, injection-site pain and fatigue. The companies said no new safety concerns emerged.

What does this mean for patients?

For now, intismeran is available only through clinical trials. Merck and Moderna are running nine phase 2 and phase 3 studies of the therapy, including three phase 3 trials in non-small cell lung cancer, plus early work in pancreatic and stomach cancers. Patients with melanoma who are interested can ask their oncologist about trials or search ClinicalTrials.gov.

Cost will be a major question if the therapy is approved. A drug manufactured for a single patient is expensive to produce, and it would be given on top of Keytruda. HNC recently reported on an ICER analysis showing new drug launch prices topping $250,000 a year, and how long it takes Medicare patients to get them.

The result also adds to a run of immunotherapy advances this fall, including the FDA’s approval of Jemperli for some rectal cancer patients who may avoid surgery.

Key Takeaways

• Merck and Moderna’s personalized mRNA therapy intismeran, added to Keytruda, cut the risk of melanoma recurrence or death by 42% in a phase 3 trial of 1,137 patients.
• After about two years, 82.2% of patients on the combination were recurrence-free, compared with 70% on Keytruda alone.
• The benefit appeared after the first six months of treatment; overall survival data are not yet mature.
• Serious side effects were similar in both groups. Fever, injection-site pain and fatigue were the most common.
• The therapy is not approved. The companies say they are talking with regulators and have not given a filing date.

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