Adjuvant mRNA-4157 Plus Pembrolizumab Improves RFS in Resected High-Risk Melanoma

Jeffrey S. Weber, MD, PhD

The personalized mRNA-based cancer vaccine mRNA-4157 (V940) in combination with pembrolizumab (Keytruda) improved recurrence-free survival (RFS) compared with pembrolizumab alone when used as an adjuvant treatment in patients with resected high-risk melanoma, regardless of tumor mutational burden (TMB), according to findings from the open-label, randomized, phase 2b mRNA-4157-P201/KEYNOTE-942 trial (NCT03897881).¹

The findings, which were presented during the 2023 AACR Annual Meeting, showed that the overall 18-month RFS rate was 78.6% (95% CI, 69.0%-85.6%) with the combination vs 62.2% (95% CI, 46.9%-74.3%) with pembrolizumab alone, leading to a 44% reduction in the risk of disease recurrence or death (HR, 0.561; 95% CI, 0.309-1.017; 1-sided P = .0266). These data, which were presented in a press briefing by senior author Jeffrey S. Weber, MD, PhD, were found to be statistically significant and clinically meaningful.

“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,” Weber, who is deputy director of the NYU Langone Perlmutter Cancer Center and Laura and Isaac Perlmutter Professor of Oncology at NYU Grossman School of Medicine, in New York, New York, as well as a 2016 Giant of Cancer Care® winner in melanoma, stated in a press release.² “This study is extraordinarily important, because it gives hope that this novel strategy will provide clinical benefit.”

Additionally, in patients with high TMB, there was a 35% reduction in the risk of recurrence or death with the combination (HR, 0.642; 95% CI, 0.284-1.494); this reduction was 41% in those with low TMB (HR, 0.586; 95% CI, 0.243-1.415), suggesting that the vaccine can elicit robust responses regardless of TMB, said Ryan Sullivan, MD, who presented the data alongside Weber in the press briefing.

Ryan Sullivan, MD

“The relevance of this study is the impact it could have not just for patients [with melanoma] but for other cancers, as well,” Sullivan, who is an associate director of the Melanoma Program at Massachusetts General Cancer Center and associate professor at Harvard Medical School, stated in the press release. “From a general cancer therapeutic standpoint, this is a potential major breakthrough.”

In February 2023, the FDA granted a breakthrough therapy designation to mRNA-4157/V940 in combination with pembrolizumab for the adjuvant treatment of patients with high-risk melanoma following complete resection.³

As part of the trial, patients’ normal and tumor tissue samples were extracted and analyzed, followed by sequencing to identify mutations in protein neoantigen. mRNA-4157 is designed to target a patient’s unique tumor mutations, with individualized mRNA encoding for up to 34 neoantigens. Upon manufacturing to 1 lot per patient, the vaccine is administered.

In the mRNA-4157-P201/KEYNOTE-942 study, patients were randomly assigned 2:1 to receive mRNA-4157 at 1 mg intramuscularly every 3 weeks for up to 9 doses plus pembrolizumab at 200 mg intravenously every 3 weeks for up to 18 cycles (n = 107) or pembrolizumab alone (n = 50). Patients were stratified by disease stage.

The primary end point was RFS and secondary end points were safety, tolerability, and distant metastasis–free survival. Follow-up for RFS was up to 3 years following the first pembrolizumab dose.

The study had 80% power to detect a hazard ratio (HR) of 0.5 with at least 40 RFS events and a 1-sided alpha of 0.1. The median follow-up was 23 months and 24 months for the combination and pembrolizumab-alone arms, respectively.

To be eligible for enrollment, patients had to have stage IIIB, IIIC, IIID, or IV cutaneous melanoma and have undergone complete surgical resection within 13 weeks before the first pembrolizumab dose. Patients must have been disease free at study entry, had an ECOG performance status of 0 or 1, and had tissue available for next-generation sequencing.

Additional findings showed that the 12-month RFS rate was 83.4% with the combination and 77.1% with single-agent pembrolizumab. Disease recurrence or death occurred in 22.4% of patients on the combination regimen and 40% of those on the monotherapy arm at a median follow-up of 101 and 105 weeks, respectively.

Regarding safety, the combination was found to be well tolerated and consistent with the safety profiles of each agent alone. Treatment-related adverse effects (AEs) that were grade 3 or higher occurred in 25.0% of patients on mRNA-4157/pembrolizumab vs 18.0% of those on pembrolizumab monotherapy; serious AEs occurred in 14.4% and 10.0% of patients, respectively. Grade 3 or higher immune-mediated AEs were reported in 10.6% and 14.0% of patients on the combination and pembrolizumab alone, respectively.

Grade 3 or higher mRNA-4157–related AEs that occurred in more than 20% of patients were fatigue (4.8%), pyrexia (1.0%), and myalgia (1.0%). Grade 3 or higher pembrolizumab-related AEs in more than 20% of patients were fatigue (5.8%) and diarrhea (1.9%).

Weber and Sullivan noted that the link between the vaccine/PD-1 inhibitor combination and TMB will continue to be explored in future studies, and additional analyses will aim to identify predictive biomarkers of response.

TMB, tumor inflammation score (TIS), and PD-L1 expression were measured at baseline. Sullivan explained that whole-exome sequencing were performed from formalin-fixed paraffin embedded (FFPE) and germline from peripheral blood mononuclear cells in order to identify patient-specific mutations. The TMB threshold that was used was 175/exome (10 mutations/megabase per F1Cx).

For TIS, RNA sequencing was performed to identify tumor transcriptome, and the TIS computed weighted average was 18 genes used in the gene expression profile score. The cutoff for TIS was based on median values across the entire study population.

FFPE biopsies were stained for PD-L1, and the combined positivity score (CPS) across tumor and infiltrating cells were used; a CPS of 1 or greater was identified as positive.

It was noted that patients randomized to the combination at baseline were more likely to have higher TMB vs those who were on the PD-1 inhibitor alone. No difference in PD-L1 expression or TIS was observed in the 2 groups.

The RFS benefit with the combination vs single-agent pembrolizumab was observed in TIS-high tumors (HR, 0.576; 95% CI, 0.209-1.591) and TIS–non-high tumors (HR, 0.528; 95% CI, 0.253-1.101). In PD-L1–positive tumors, the HR was 0.485 (95% CI, 0.226-1.039) and was 0.162 (95% CI, 0.038-0.685) in PD-L1–negative tumors.

Limitations of the study were that KEYNOTE-942 was a phase 2b trial with “modest statistical power,” and that the neoantigen vaccine is based on DNA and RNA sequencing of tissue. Because of this, it may not be an optimal therapy for those with earlier-stage disease since there may be a lack of tissue available for patients with tumors smaller in size.

A phase 3 trial of the combination in this patient population is planned.

Dr Weber cited disclosures for consulting roles with Merck, Genentech, AstraZeneca, GSK, Novartis, Nektar, Celldex, Incyte, Biond, Moderna, ImCheck, Sellas, Evaxion, Pfizer, Regeneron, EMD Serono, and Bristol-Myers Squibb; equity roles in Biond, Evaxion, OncoC4, and Instill Bio; and scientific advisory roles with CytomX, Incyte, ImCheck, Biond, Sellas, Instill Bio, OncoC4, and NexImmune.

Dr Sullivan cited disclosures for paid consulting roles with Merck, Novartis, and Pfizer; an unpaid consultant for BMS in the past 2 years; and research funding 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. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT001.
2. Adding a personalized mRNA cancer vaccine to immunotherapy may prolong recurrence-free survival in patients with high-risk melanoma. News release. American Association of Cancer Research. April 16, 2023. Accessed April 16, 2023. https://aacr.ent.box.com/s/j9b0dx6d6px08llj6rqw87m99qbqd0fe
3. Moderna and Merck announce mRNA-4157/V940, an investigational personalized mRNA cancer vaccine, in combination with Keytruda® (pembrolizumab), was granted breakthrough therapy designation by the FDA for adjuvant treatment of patients with high-risk melanoma following complete resection. News release. Moderna. February 22, 2023. Accessed February 23, 2023. https://www.merck.com/news/