medwireNews: Adding a novel messenger (m)RNA-based individualized neoantigen therapy to adjuvant pembrolizumab could improve the outcomes of patients with completely resected, high-risk melanoma, suggests a phase 2b trial.
“Treatment with mRNA-4157 in combination with pembrolizumab showed a clinically meaningful improvement in both recurrence-free survival [RFS] and distant metastasis-free survival [MFS] compared with pembrolizumab monotherapy,” report the KEYNOTE-942 investigators in The Lancet.
The safety profile of the combination “was encouraging,” they continue, “with infrequent clinically meaningful adverse events reported compared with pembrolizumab monotherapy.”
These results “add to the growing body of evidence showing the clinical utility of individualised neoantigen therapy” in this patient population, and on the basis of the findings “a phase 3 registrational study has been initiated,” says the team.
Outlining the background to the trial, the study authors explain that “[n]eoantigens are immunogenic molecules generally arising from non-synonymous cancer-specific mutations in intracellular proteins that are processed and presented at the cell surface as peptides in association with major histocompatibility complex molecules.”
They add that although neoantigens could serve as anticancer treatment targets, “tumour mutations and their antigen-presenting molecules (ie, human leukocyte antigens) are unique to each patient.”
The researchers continue: “mRNA-4157 is an mRNA-based individualised neoantigen therapy encoding up to 34 neoantigens in a lipid nanoparticle formulation and is tailored specifically to an individual’s tumour mutanome and human leukocyte antigen type.”
A total of 157 patients with stage IIIB or IV cutaneous melanoma who had undergone a complete resection were randomly assigned to receive up to 18 doses of pembrolizumab 200 mg alongside up to nine doses of mRNA-4157 given intramuscularly every 3 weeks, or pembrolizumab alone.
The proportion of patients who experienced recurrence or death over a median follow-up of 23–24 months was lower with combination treatment than pembrolizumab monotherapy, at 22% versus 40%, and equated to a hazard ratio (HR) for recurrence or death of 0.56 in favor of mRNA-4157 use.
The 12-month RFS rates were 83% and 77%, respectively, while the 18-month rates were 79% and 62%.
Jeffrey Weber (Laura and Isaac Perlmutter Cancer Center at NYU Langone Health, New York, USA) and co-investigators point out that “there was delayed separation of the recurrence-free survival curves,” which “might be partly attributable to the manufacturing time of mRNA-4157, during which patients in both groups received pembrolizumab monotherapy.”
But “it might also indicate the induction of durable, functional, and robust antitumour neoantigen-specific T-cell responses and immunological memory that support sustained disease control beyond completion of treatment,” they add.
The second endpoint of distant MFS was similarly improved with the use of mRNA-4157 alongside pembrolizumab, with an HR for distant recurrence or death of 0.35. The distant MFS rate at 12 months was 93% in the combination arm and 89% in the monotherapy arm, with corresponding 18-month rates of 92% and 77%.
Regarding safety, the majority of adverse events (AEs) related to the neoantigen therapy were of grade 1 or 2, with events of grade 3 observed in 12% and no events of grade 4 or 5. The most frequently observed AE of grade 3 was fatigue, in 5% of patients.
Fifteen percent of participants discontinued mRNA-4157 as a result of AEs related to either drug, while the rates of discontinuation of pembrolizumab were 25% and 18% in the combination and monotherapy groups, respectively.
Immune-mediated AEs occurred in an identical 36% of patients in the combination and monotherapy study arms, with events of grade 3 or worse seen in a respective 11% and 14%.
“This safety profile supports testing of future combinations with mRNA-4157 in other cancer types and settings,” write Weber and colleagues.
Writing in a linked commentary, Mizue Terai and Takami Sato (both from Thomas Jefferson University in Philadelphia, Pennsylvania, USA) say that “[d]espite modest statistical power and a fairly short follow-up time, these results are encouraging and warrant further large-scale clinical trials to investigate whether newly developed neoantigen-targeting vaccine platforms can yield meaningful clinical outcomes.”
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Lancet 2024; doi:10.1016/S0140-6736(23)02268-7
Lancet 2024; doi:10.1016/S0140-6736(23)02463-7