The search for an effective cancer vaccine has been frustrating, but finally there may be light at the end of the tunnel. Adjuvant use of an investigational personalized mRNA vaccine (mRNA-4157) plus the PD-1 inhibitor pembrolizumab improved recurrence-free survival vs pembrolizumab alone in patients with high-risk melanoma, according to the results of the phase II mRNA-4157-P201/KEYNOTE-942 trial presented at the American Association for Cancer Research (AACR) Annual Meeting 2023.¹ In a second presentation based on the study, clinical benefit was observed regardless of tumor mutational burden (TMB) status.²

In the analysis of the primary trial, after 18 months, the rate of recurrence-free survival was 78.6% with the vaccine plus pembrolizumab vs 62.2% with pembrolizumab alone, reflecting a significant 44% reduction in the risk of recurrence or death in patients treated with the vaccine plus pembrolizumab vs pembrolizumab alone (one-sided P = .0266).

“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.”

— Jeffrey Weber, MD, PhD

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“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. This study is extraordinary, because it gives hope that the novel [personalized] strategy will provide clinical benefit,” said lead 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.

The mRNA-4157-P201/KEYNOTE-942 trial was designed to target an individual patient’s unique tumor mutations. The vaccine comprises a nanoparticle-encapsulated mRNA molecule, which is highly personalized, 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. Dr. Weber pointed out that although the vaccine encodes for 34 neoantigens, the bottom line is that the number of neoantigens is not as important as having the right one[s].

“Over the past 25 years, vaccine strategies have attempted to induce immune responses against tumor-associated antigens that are not 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. “Neoantigen-based vaccines may overcome the failure of previous cancer vaccine trials.

Study Details and Results

The randomized mRNA-4157-P201/KEYNOTE-942 trial assessed the efficacy of mRNA-4157 in prolonging recurrence-free survival in patients with fully resected stages IIIB, IIIC, IIID, and IV cutaneous melanoma. The vaccine was given with pembrolizumab at 200 mg every 3 weeks intravenously (n = 150), the standard of care for this patient population, and compared with pembrolizumab alone (n = 50). The vaccine was given every 3 weeks for a total of 9 injections, with pembrolizumab given every 3 weeks for up to 18 cycles vs the same regimen of pembrolizumab alone.

The 12-month recurrence-free survival rate was 83.4% for the vaccine-containing arm vs 77.% for pembrolizumab alone. At 18 months, the corresponding rate was 78.6% vs 62.2%, respectively.

“The curves separate at 8 to 9 months and remain separated after about 2 years. There is a 16% difference in recurrence-free survival at 18 months, which is clinically significant to me,” Dr. Weber said.

Most side effects were mild and consistent with the respective monotherapy safety profiles. No severe immune-mediated toxicities due to vaccine were reported. A total of 100% of patients in the vaccine arm and 94% in the placebo arm experienced an adverse event. Serious treatment-related adverse events were reported in 14% and 10%, respectively. Immune-mediated adverse events occurred in about 36% of patients in each arm, and grade 3 or higher immune-mediated adverse events were reported in 11% and 14%, respectively. No grade 4 or 5 events related to the vaccine were reported, and no potentiation of immune-mediated adverse events was observed when the vaccine was added to pembrolizumab.

Ryan Sullivan, MD

“For the first time with a melanoma vaccine, we have randomized data showing a hint of benefit; past trials with different approaches—peptides, dendritic cells, viral vectors—all failed,” said Ryan Sullivan, MD, Associate Professor, Medicine, Harvard Medical School; Associate Professor, Hematology/Oncology, Massachusetts General Hospital. “The question now is, are we seeing benefit because this vaccine serves as a nice adjunct to pembrolizumab, providing more T-cell populations with antitumor activity? Or is the key the mRNA platform itself, which seems to be a potent delivery system?”

TMB, Tumor Inflammation Score, and PD-L1

Dr. Sullivan reported findings from a subset analysis of KEYNOTE-942 using patients’ baseline biopsies to assess the relevance of tumor mutational burden (TMB) to a neoantigen vaccine. The TMB-high threshold was defined as 10 mutations/megabase.

This assessment showed that patients whose tumors were TMB-high had improved outcomes, but the combination was effective in all patient subsets. Compared with the control arm, patients given the vaccine plus pembrolizumab “did similarly better, independent of TMB,” he said. The recurrence risk was reduced by 35% and 41%, respectively, in TMB-high and TMB-low cohorts.

Further studies of mRNA-4157 are planned, including a larger phase III trial to confirm KEYNOTE-942, which will launch this summer.

Clinical Implications

At a press conference where these data were presented, Dr. Weber noted the personalized mRNA vaccine strategy “should also be applicable to virtually any solid tumor type that is operable, sensitive to PD-1 blockade, and generates neoantigens,” including non–small cell lung cancer, hepatocellular carcinoma, and triple-negative breast cancer, among others.

During the press conference, Dr. Weber explained the personalized vaccine takes 7 to 8 weeks to develop and patients receive the standard of care while it is being manufactured. “About 90% of patients can have the vaccine made, so there is no real impediment to give it as adjuvant therapy. The use of pembrolizumab as adjuvant therapy helps prevent recurrence during the time it takes to make the vaccine.”

“This mRNA-4157 vaccine has absolutely breathed new life into the cancer vaccine field. I say that as a bona fide skeptic who has put hundreds of patients on prior trials and seen no evidence of benefit until now,” Dr. Weber stated. 

DISCLOSURE: Dr. Weber has served as a consultant to Merck, Genentech, AstraZeneca, BMS, GSK, Novartis, Nektar, Celldex Therapeutics, Incyte, Biond, Moderna, ImCheck Therapeutics, Sellas, Evaxion Biotech, Pfizer, Regeneron, and EMD Serono; has received institutional research support from BMS, Merck, GSK, Moderna, Pfizer, Novartis, and AstraZeneca. Dr. Sullivan has served as a consultant to BMS, Merck, Novartis, Pfizer, and Marengo Therapeutics; and has received institutional research support from Merck.

REFERENCES

1. Khattak A, Carlino M, Meniawy T, et al: A personalized cancer vaccine, mRNA-4157, combined with pembrolizumab versus pembrolizumab in patients with resected high-risk melanoma: Efficacy and safety results from the randomized open-label phase 2 mRNA-4157-P201/KEYNOTE-942 trial. AACR Annual Meeting 2023. Abstract CT001. Presented April 16, 2023.

2. Sullivan R, Carlino M, Weber JS, et al: mRNA-4157, a personalized cancer vaccine, in combination with pembrolizumab, demonstrates trend for improved recurrence free survival compared to pembrolizumab alone in adjuvant melanoma patients across tumor mutational burden subgroups. AACR Annual Meeting 2023. Abstract CT224. Presented April 18, 2023.