Adding a Personalized mRNA Cancer Vaccine to Immunotherapy May Prolong Recurrence-free Survival in Patients With High-risk Melanoma

Clinical benefit was independent of patients’ tumor mutational burden  

ORLANDO, Fla. – mRNA-4157/V940, a personalized mRNA-based cancer vaccine, in combination with the immune checkpoint inhibitor pembrolizumab (Keytruda) improved recurrence-free survival (RFS) compared with pembrolizumab alone in patients with high-risk melanoma, and the clinical benefit was observed regardless of the tumor mutational burden (TMB) status, according to results from the phase IIb KEYNOTE-942 clinical trial presented at the AACR Annual Meeting 2023, held April 14-19.

“Vaccine strategies over the last 25 years attempted to induce immune responses against tumor-associated antigens that are not absolutely specific to the tumor,” said presenting author Jeffrey Weber, MD, PhD, deputy director of the NYU Langone Perlmutter Cancer Center and Laura and Isaac Perlmutter Professor of Oncology at NYU Grossman School of Medicine. “More recent cancer vaccine approaches have focused on targeting neoantigens originated from individual tumor mutations, which are unique to cancer cells.”

mRNA-4157/V940 is a novel mRNA-based personalized cancer vaccine that encodes up to 34 patient-specific tumor neoantigens. In addition to encoding the target antigens, mRNA vaccines also provide adjuvant properties that amplify the immune response, Weber explained.

The randomized KEYNOTE-942 trial assessed the efficacy of mRNA-4157/V940 in prolonging RFS in patients with resected, stages IIIB/IIIC/IIID and IV melanoma when given in combination with pembrolizumab, the standard-of-care adjuvant therapy in this patient population. Patients were randomly assigned (2:1) to receive mRNA-4157/V940 in combination with pembrolizumab (107 patients) or pembrolizumab alone (50 patients). The vaccine was administered every three weeks for a total of nine doses, and pembrolizumab was given every three weeks for up to 18 cycles.

According to the results of the primary trial analysis, after 18 months, the RFS was 78.6% in the combination arm and 62.2% in the pembrolizumab arm, corresponding to a 44% reduction in the risk of recurrence or death in patients who received both mRNA-4157/V940 and pembrolizumab compared to those who only received pembrolizumab. The majority of treatment-related adverse events were mild, and the rates of serious adverse events were comparable between the two arms, Weber said.

“For the first time in a randomized study with a control arm, the addition of an mRNA neoantigen vaccine

appeared to augment the benefit of PD-1 blockade, without adding significant high-grade toxicity,” said Weber. “This study is extraordinarily important, because it gives hope that this novel strategy will provide clinical benefit.”

In an additional analysis of KEYNOTE-942, baseline biopsies from the trial participants were assessed for TMB and how it relates to RFS across the study arms. The threshold utilized to define TMB-high status for the analysis was 10 mutations per megabase.

“We focused on the TMB because it has been shown to be a predictor of response to immune checkpoint inhibitor therapy and it is relevant to a neoantigen vaccine product—theoretically, if you have a higher TMB, there will be more neoepitopes to target,” said presenting author Ryan Sullivan, MD, associate director of the Melanoma Program at Mass General Cancer Center and associate professor at Harvard Medical School.

The vaccine-pembrolizumab combination led to a similar reduction in the risk of recurrence or death in patients with high and low TMB (35% and 41%, respectively).

“Patients who were treated with the combination of vaccine and pembrolizumab had better outcomes than those treated with just pembrolizumab, independent of their TMB,” Sullivan said.

According to Sullivan, this observation suggests that an algorithm efficient in choosing the target neoantigens can potentially enable the vaccine to induce a robust immune response regardless of the TMB. “There likely is a certain TMB threshold below which our ability to successfully create a neoantigen vaccine is reduced, but our findings indicate that, above that threshold, the benefit of adding vaccination to pembrolizumab was similar regardless of the TMB.”

The association between this treatment approach and TMB will be further explored in upcoming planned studies. Additional analyses are ongoing to identify biomarkers potentially associated with better outcomes, including gene expression profiles and PD-L1 expression.

“The relevance of this study is the impact it could have not just for melanoma patients but for other cancers as well,” Sullivan said. “From a general cancer therapeutic standpoint, this is a potential major breakthrough.”

According to Weber, one limitation of the KEYNOTE-942 trial is that, although randomized, it is a phase IIb study with modest statistical power. “Overall, it is a small number of patients, and one has to be cautious with the interpretation of the results,” Weber said. “A larger, phase III randomized study to confirm our findings will begin soon.” Additional limitations include relatively short follow-up time and some setbacks, including cancer vaccine shortage, during the COVID-19 pandemic.

According to Sullivan, a technical limitation of the neoantigen vaccine approach is that it is based on DNA and RNA sequencing of tumor tissue, therefore it may not be applicable to patients with earlier-stage disease, whose tumors may be smaller and not provide enough tissue.  

The study was funded by Moderna Inc. and Merck.

Weber consults for and has received less than $10,000 per year from Merck, Genentech, AstraZeneca, GSK, Novartis, Nektar, Celldex, Incyte, Biond Biologics, Moderna, ImCheck, Sellas Life Sciences, Evaxion Biotech, Pfizer, Regeneron, and EMD Serono; has received $10,000-25,000 from Bristol Myers Squibb for membership on advisory boards; he holds equity in Biond, Evaxion, OncoC4, and Instil Bio; and is on scientific advisory boards for CytoMx, Incyte, ImCheck, Biond, Sellas, Instil Bio, OncoC4, and Neximmune, for which he is remunerated between $10,000-$50,000. NYU received research support from BMS, Merck, GSK, Moderna, Pfizer, Novartis, and AstraZeneca; Weber is one of the co-authors on two patents filed by Moffitt Cancer Center and one patent filed by Biodesix and receives less than $6,000 yearly in royalties.

Sullivan has served as a paid consultant for Merck, Novartis, and Pfizer, an unpaid consultant for BMS in the past two years, and has received research funding from Merck.

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