mRNA-4157/V940, a personalized mRNA-based cancer vaccine, in combination with the immune checkpoint inhibitor pembrolizumab improved recurrence-free survival compared with pembrolizumab alone in patients with high-risk melanoma, and clinical benefit was observed regardless of tumor mutational burden (TMB) status, according to results from the phase IIb KEYNOTE-942 clinical trial presented by Khattak et al at the American Association for Cancer Research (AACR) Annual Meeting 2023 (Abstract CT001).
Jeffrey Weber, MD, PhD
“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 New York University (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, Dr. Weber explained.
More About KEYNOTE-942
The randomized KEYNOTE-942 trial assessed the efficacy of mRNA-4157/V940 in prolonging recurrence-free survival 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 (n = 107) or pembrolizumab alone (n = 50). The vaccine was administered every 3 weeks for a total of nine doses, and pembrolizumab was given every 3 weeks for up to 18 cycles.
Recurrence-Free Survival Results
According to the results of the primary trial analysis, after 18 months, the recurrence-free survival was 78.6% in the combination arm and 62.2% in the pembrolizumab-alone 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, Dr. 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 Dr. Weber. “This study is extraordinarily important, because it gives hope that this novel strategy will provide clinical benefit.”
TMB Analysis
In an additional analysis of KEYNOTE-942, baseline biopsies from the trial participants were assessed for TMB and how it relates to recurrence-free survival across the study arms. The threshold utilized to define TMB-high status for the analysis was 10 mutations per megabase.
Ryan Sullivan, MD
“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,” Dr. Sullivan said. According to Dr. 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,” he explained.
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 [patients with] melanoma, but for other cancers as well,” Dr. Sullivan said. “From a general cancer therapeutic standpoint, this is a potential major breakthrough.”
According to Dr. 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,” Dr. 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 Dr. 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.
Disclosure: The study was funded by Moderna Inc and Merck. For full disclosures of the study authors, visit abstractsonline.com.
