An individualized mRNA cancer therapy built from each patient’s own tumor mutations reduced the risk of melanoma recurrence or death by 42% when added to the immunotherapy Keytruda after surgery, in the first phase 3 trial of such a treatment to succeed, Merck and Moderna announced Oct. 22. Full results were presented Oct. 24 at the European Society for Medical Oncology (ESMO) Congress in Madrid, and the companies say the data have been accepted for publication in The New England Journal of Medicine.
The INTerpath-001 trial randomized 1,137 patients with completely resected, high-risk stage IIB to IV cutaneous melanoma 2:1 to intismeran autogene plus pembrolizumab (Keytruda) or placebo plus pembrolizumab. Intismeran, also known as V940 or mRNA-4157, is a synthetic mRNA encoding up to 34 neoantigens selected by sequencing the patient’s tumor and normal DNA. It was given at 1 mg every three weeks for up to nine doses, alongside pembrolizumab 400 mg every six weeks for about a year. The trial was double-blind and placebo-controlled and was funded by the two companies. Until the journal paper appears, the results are a company announcement and a conference presentation rather than a peer-reviewed publication.
At a median follow-up of 24.6 months, the hazard ratio for recurrence-free survival, the primary endpoint, was 0.58 (95% confidence interval 0.45 to 0.75; p<0.001). Two-year recurrence-free survival was 82.2% with the combination versus 70.0% with pembrolizumab alone. Distant metastasis-free survival, a key secondary endpoint, improved by a similar margin: hazard ratio 0.62 (0.45 to 0.85; p=0.002), with two-year rates of 88.5% versus 80.2%. Overall survival data are immature; according to OncLive, the interim hazard ratio was 0.77 (0.45 to 1.31; p=0.33) and did not cross the prespecified boundary.
The survival curves overlapped for the first six months, with a recurrence-free survival hazard ratio of 0.99 in that window, and separated afterwards, with a hazard ratio of 0.42 beyond month six. Presenter Georgina Long of Melanoma Institute Australia attributed the delay to the wait before the first dose, a median of 64 days, and the time needed to build a T-cell response, OncLive reported. Manufacturing succeeded for more than 99% of patients in the combination arm, and 91% of randomized patients had the maximum 34 neoantigens identified, according to CancerNetwork.
Treatment-related adverse events occurred in 95.8% of patients on the combination and 90.0% on pembrolizumab alone; grade 3 to 5 treatment-related events were 14.2% versus 13.4%. Fever (52.2% versus 8.2%), injection-site pain (51.0% versus 9.5%) and flu-like illness (25.4% versus 9.2%) were the main additions, described by investigators as low grade and transient. Discontinuation of any study drug because of adverse events was 16.6% versus 9.5%. Two treatment-related deaths occurred in the combination arm, both attributed to pembrolizumab. “INTerpath-001 sets a new benchmark for adjuvant treatment in melanoma,” Long said at the symposium, OncLive reported.
Why it matters
Cancer vaccines have a long record of failure; at ESMO, Vinod Balachandran of Memorial Sloan Kettering Cancer Center called their history “long and sordid,” STAT reported. INTerpath-001 is the first positive phase 3 result for an individualized neoantigen therapy, and it validates an approach, sequencing a tumor and encoding its mutations in mRNA, that could in principle be applied elsewhere. James Larkin of the Royal Marsden Hospital in London, scientific co-chair of the meeting, told a press conference that “in principle, this type of approach may be applicable to other types of tumors,” according to STAT.
Most melanoma recurrences occur within two years of surgery, and more than half involve distant metastases, Merck notes, so a 38% reduction in distant metastasis or death is clinically meaningful if it holds. The companies say they are engaging with regulators. Nine phase 2 and phase 3 INTerpath trials are running across tumor types, including three phase 3 studies in non-small cell lung cancer.
The caveats
Overall survival has not been shown; the benefit so far is in recurrence and spread, and follow-up continues. The results come from the sponsors and a conference presentation, with peer-reviewed publication still to come. Several smaller subgroups had confidence intervals crossing 1, CancerNetwork noted, and 302 of 1,749 screened patients (17.3%) were excluded because their tumor sample was inadequate for sequencing, which limits who can receive the therapy. The 64-day median wait to first dose and the per-patient manufacturing process raise questions of cost and scalability that the trial does not answer.
What to watch
Publication in The New England Journal of Medicine, which OncLive reports is scheduled for Nov. 11, 2026; regulatory submissions; and maturing overall survival data from the trial, registered as NCT05933577.
This article is for general information and does not replace advice from a qualified clinician. Corrections: email the editor using the address on the Contact page.
