During the 2023 American Association for Cancer Research Annual Meeting, researchers presented results from a phase 2b clinical trial demonstrating significant improvement in recurrence-free survival (RFS) in patients with high-risk melanoma who were treated with a combination of an investigational personalized mRNA-based vaccine plus the immune checkpoint inhibitor pembrolizumab (Keytruda), compared with pembrolizumab alone.1
“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 blockage, without adding significant high-grade toxicity. This study is extraordinary, because it gives hope that the novel [personalized] strategy will provide clinical benefit,” said Jeffrey S. Weber, MD, PhD, Deputy Director, Langone Perlmutter Cancer Center, and Laura and Isaac Perlmutter Professor of Oncology, Grossman School of Medicine, New York University, New York City, and the study’s lead investigator.
The use of mRNA technology to develop the COVID-19 vaccine paved the way for the investigational vaccine mRNA-4157/V940, which is tailored to target tumor mutations in a specific patient. It is comprised of a nanoparticle-encapsulated mRNA molecule, encoding up to 34 patient-specific tumor neoantigens picked by a computerized algorithm. Upon intramuscular injection, these neoantigen sequences undergo processing and presentation, ultimately inducing cytotoxic and memory T cells into tumor-targeting action.
“Over the last 25 years, vaccine strategies have attempted to induce immune responses against tumor-associated antigens that are not absolutely specific to the tumor. More recent cancer vaccine approaches have focused on targeting neoantigens that originate from tumor mutations, which are unique to cancer cells,” Dr Weber explained.
The randomized, open-label, phase 2b KEYNOTE-942 trial assessed the efficacy of mRNA-4157/V940 for prolonging RFS when given in combination with pembrolizumab (the standard of care) in patients with resected stages IIIB/IIIC/IIID and IV cutaneous melanoma. Patients were randomized (2:1) to 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 9 injections, and pembrolizumab was given every 3 weeks for up to 18 cycles.
According to the results of the primary trial analysis, after 12 months, RFS rates were 83.4% in patients treated with mRNA-4157/V940 plus pembrolizumab versus 77.1% in those treated with pembrolizumab monotherapy. At 18 months, RFS rates were 78.6% versus 62.2%, respectively, for a significant 44% reduction in the risk for recurrence or death in patients who received the combination of mRNA-4157/V940 and pembrolizumab.
Regarding safety, the combination of mRNA-4157/V940 plus pembrolizumab was well tolerated and consistent with the toxicity profiles of each agent alone. Grade ≥3 treatment-related adverse events (AEs) occurred in 25% of patients in the mRNA-4157/V940 plus pembrolizumab arm and 18% of those in the pembrolizumab monotherapy arm; serious AEs occurred in 14.4% and 10.0% of patients, respectively. Grade ≥3 immune-mediated AEs were reported in 10.6% and 14% of patients in the combination and pembrolizumab alone arms, respectively.
Dr Weber noted that although the trial was randomized, it was still a phase 2b study with modest statistical power. “Overall, it is a small number of patients, and one needs to be cautious with the interpretation of the results,” he said. “A larger, phase 3 randomized study to confirm our findings will begin soon.” Additional limitations included relatively short follow-up time and some setbacks, including cancer vaccine shortages, during the COVID-19 pandemic.
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