Vaccine-immunotherapy combination extends RFS in high-risk melanoma
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Key takeaways:
- The addition of a personalized mRNA-based cancer vaccine to pembrolizumab improved RFS among patients with resected high-risk melanoma.
- The regimen conferred benefit regardless of tumor mutational burden.
The addition of an mRNA-based cancer vaccine to pembrolizumab extended RFS among patients with resected high-risk melanoma, according to study results presented at American Association for Cancer Research Annual Meeting.
The benefit with the combination persisted regardless of patients’ tumor mutational burden status, findings of the randomized phase 2B KEYNOTE-942 trial showed.
“This randomized trial involved patients who had surgery to remove melanoma and were at high risk [for] the disease returning,” Jeffrey S. Weber, MD, PhD, deputy director of NYU Langone Perlmutter Cancer Center, as well as Laura and Isaac Perlmutter professor of oncology at NYU Grossman School of Medicine, told Healio. “Because the study participants all had their tumors removed, their cells were analyzed for molecules that could be recognized by the immune system and were specific to each melanoma, allowing a ‘personalized’ vaccine to be created for each patient.”
The results of the study — which suggest the addition of an mRNA neoantigen vaccine may augment the benefit of PD-1 blockade without increasing significant high-grade toxicity — are “extraordinarily important” because they provide hope that this novel treatment strategy may provide clinical benefit, Weber added.
Background and methods
Prior research showed use of T cells to target mutation-derived neoantigens can drive antitumor immune responses.
mRNA-4157/V940 (Moderna Inc./Merck) — a novel mRNA-based personalized cancer vaccine — encodes up to 34 patient-specific tumor neoantigens.
“Vaccine strategies over the last 25 years attempted to induce immune responses against tumor-associated antigens that are not absolutely specific to the tumor,” Weber said in a press release. “More recent cancer vaccine approaches have focused on targeting neoantigens originated from individual tumor mutations, which are unique to cancer cells.”
Weber and colleagues hypothesized the addition of mRNA-4157 to the anti-PD-1 antibody pembrolizumab (Keytruda, Merck) in the adjuvant setting would have a synergistic effect that could extend RFS among patients with resected stage IIIB, IIIC, IIID or IV melanoma.
The open-label KEYNOTE-942 trial included 157 patients with completely resected, high-risk cutaneous melanoma.
Researchers randomly assigned 107 patients to mRNA-4157 — dosed at 1 mg intramuscularly every 3 weeks for nine doses — in combination with pembrolizumab dosed at 200 mg via IV every 3 weeks for up to 18 cycles. The other 50 received pembrolizumab monotherapy, the standard adjuvant treatment for this population.
RFS in the intention-to-treat population served as the primary endpoint. Safety served as a secondary endpoint.
Researchers conducted the primary analysis for RFS after all patients completed at least 12 months on study and a minimum 40 RFS events had been reported.
Results
Median follow-up was 101 weeks in the combination group and 105 weeks in the pembrolizumab monotherapy group. At that time, 24 (22.4%) patients in the combination group and 20 (40%) in the pembrolizumab monotherapy group had developed recurrence or died.
Results showed a protocol-defined statistically significant improvement in RFS with the combination (HR = 0.56; 95% CI, 0.3-1), with stratified log-rank test 1-sided P value of .0266.
Researchers reported 18-month RFS rates of 78.6% with the combination and 62.2% with pembrolizumab alone.
Most treatment-related adverse events were grade 1 or grade 2, with a comparable percentage of patients in the combination and pembrolizumab monotherapy groups experiencing grade 3 or higher adverse events (25% vs. 18%). The most common grade 3 adverse event related to mRNA-4157 was fatigue. Researchers reported no grade 4 or grade 5 events related to mRNA-4157.
The addition of mRNA-4157 to pembrolizumab did not result in increased immune-mediated adverse events, according to investigators.
Investigators assessed baseline biopsies from KEYNOTE-942 participants to examine how tumor mutational burden related to RFS. They used 10 mutations per megabase as the threshold for tumor mutational burden-high status.
Results showed the vaccine-pembrolizumab combination conferred a comparable reduction in risk for recurrence or death among patients with high tumor mutational burden and low tumor mutational burden (35% vs. 41%).
Researchers acknowledged study limitations, including relatively short follow-up. The small number of patients and modest statistical power mean results must be interpreted with caution, Weber added.
Next steps
A randomized phase 3 study to assess this regimen for patients with melanoma will be conducted, Weber said.
Planned studies also will further examine the association between this treatment strategy and tumor mutational burden, as well as whether certain biomarkers — such as PD-L1 expression or gene-expression profiles — are associated with improved outcomes.
“These results are the first to demonstrate improvement of RFS over adjuvant standard-of-care PD-1 blockade in resected high-risk melanoma and provide the first randomized evidence that a personalized neoantigen approach is potentially beneficial for [patients with cancer],” Weber and colleagues wrote.
References:
- Adding a personalized mRNA cancer vaccine to immunotherapy may prolong recurrence-free survival in patients with high-risk melanoma (AACR press release). Published April 16, 2023. Accessed April 16, 2023.
- Khattak A, et al. Abstract CT001. Presented at: American Association for Cancer Research Annual Meeting; April 14-19, 2023; Orlando.
Perspective
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Thomas U. Marron, MD, PhD
The concept of personalized vaccines such as this is not new, but this is the largest trial reported to date and the first randomized trial of its kind to demonstrate the additive benefit of adding a vaccine to standard checkpoint-blocking immunotherapy.
Although this is very promising, the real excitement is the development of this technology for life-threatening metastatic melanoma and other metastatic cancers. This trial demonstrates the feasibility, and as this technology improves — both in the computational algorithm to predict optimal targets, as well as in the ability to rapidly create these vaccines — we will hopefully be able to introduce this into patients with metastatic cancers.
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Khattak A, et al. Abstract CT001. Presented at: American Association for Cancer Research Annual Meeting; April 14-19, 2023; Orlando.
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