Five years after surgery, patients with high-risk melanoma who received a personalized mRNA-based therapy alongside pembrolizumab continued to experience fewer recurrences than those treated with pembrolizumab alone, according to new follow-up data reported by Moderna and Merck.
The results come from a pre-planned analysis of the Phase IIb KEYNOTE-942/mRNA-4157-P201 trial and show a sustained improvement in the study’s primary endpoint of recurrence-free survival.
The study is examining whether adding an individualized neoantigen therapy to PD-1 blockade can further reduce the risk of relapse in patients who remain at substantial risk of recurrence after complete tumor resection. Recurrence remains a major concern for patients with stage III and IV melanoma even in the era of adjuvant immune checkpoint inhibition.
KEYNOTE-942 is an ongoing, randomized, open-label Phase IIb trial that enrolled 157 patients with resected stage III or IV cutaneous melanoma. Participants were randomized 2:1, stratified by disease stage, to receive intismeran autogene plus pembrolizumab or pembrolizumab alone in the adjuvant setting.
Intismeran autogene was administered once every three weeks for a total of nine doses. Pembrolizumab was given on the same schedule at 200 mg for up to one year, or until disease recurrence or unacceptable toxicity. All patients were disease-free at baseline and had tumor tissue available for sequencing to generate the individualized neoantigen construct.
The primary endpoint was recurrence-free survival, measured as the time from starting pembrolizumab to the return of cancer at any site, the development of a new primary melanoma or death from any cause. Secondary endpoints included distant metastasis-free survival and safety. Exploratory analyses are also assessing whether baseline tumor features, such as tumor mutational burden, are associated with recurrence-free survival.
At a median follow-up of five years, patients who received intismeran autogene in combination with pembrolizumab had about half the risk of their cancer returning or of death compared with those treated with pembrolizumab alone. This corresponded to a hazard ratio of 0.51 (95% CI, 0.29-0.89), with a one-sided nominal p value of 0.0075 for recurrence-free survival. The benefit, first observed at earlier two- and three-year analyses, remained consistent at this pre-specified long-term follow-up.
Results for secondary endpoints, including distant metastasis-free survival, were not detailed in the current announcement. Moderna and Merck said additional analyses of both primary and secondary endpoints are planned for presentation at a future scientific meeting.
No new safety signals were observed with longer follow-up. The safety profile of the combination remained consistent with what has previously been reported, and overall tolerability was in line with the known immune-related safety profile of PD-1 inhibition, including events such as fatigue, gastrointestinal symptoms, skin reactions and endocrine disorders.
Intismeran autogene is an individualized mRNA-based neoantigen therapy encoding up to 34 tumor-specific targets, designed to stimulate tumor-directed T-cell responses when administered alongside PD-1 blockade.
Building on the Phase IIb findings, Moderna and Merck are continuing to advance the program in later-stage and expanded studies. A randomized Phase III trial in the adjuvant melanoma setting, INTerpath-001, is fully enrolled. Additional Phase II and Phase III studies are ongoing across multiple tumor types and treatment settings, including non-small cell lung cancer (NSCLC), bladder cancer and renal cell carcinoma, in both adjuvant and metastatic disease. The sponsors said these studies are intended to further define the clinical role of individualized neoantigen therapies in combination with PD-1 inhibition.
Recent policy changes in the US, including revisions to federal vaccination recommendations and funding priorities under the Department of Health and Human Services (HHS), have reshaped the landscape for vaccine development.
In this context, Moderna has said it is adjusting its broader mRNA development strategy. In recent public remarks, CEO Stéphane Bancel stated that the company does not plan to initiate new late-stage vaccine trials, citing regulatory delays and reduced government support for mRNA-based vaccine research, which he said have affected the commercial and development outlook for this area.
The five-year KEYNOTE-942 results highlight the continued clinical development of mRNA-based therapies beyond infectious disease.
Merck is also advancing a Phase III program in lung cancer, evaluating an oral KRAS G12C inhibitor in combination with pembrolizumab for first-line treatment of advanced NSCLC.
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