In the phase IIb KEYNOTE-942 trial reported in The Lancet, Jeffrey S. Weber, MD, PhD, and colleagues found that the addition of adjuvant mRNA-4157—a novel mRNA-based individualized neoantigen therapy—to pembrolizumab numerically improved recurrence-free survival in patients with completely resected high-risk cutaneous melanoma.
Jeffrey S. Weber, MD, PhD
Study Details
In the open-label trial, 157 patients from sites in the United States and Australia were randomly assigned 2:1 between July 2019 and September 2021 to receive mRNA-4157 plus pembrolizumab (n = 107) or pembrolizumab monotherapy (n = 50). Patients in the combination group received pembrolizumab at 200 mg every 3 weeks during mRNA-4157 manufacturing; upon availability, 1 mg of mRNA-4157 was administered intramuscularly for a maximum of 9 doses together with pembrolizumab (maximum of 18 doses) in 3-week cycles. Pembrolizumab monotherapy at 200 mg was given every 3 weeks for up to 18 doses. The primary endpoint of the trial was recurrence-free survival in the intention-to-treat population.
Recurrence-Free Survival
Median follow-up was 23 months in the combination group and 24 months in the control group. At data cutoff, recurrence or death had occurred in 24 patients (22%) in the combination group vs 20 patients (40%) in the control group; the hazard ratio for recurrence-free survival for the combination group vs the control group was 0.561 (95% confidence interval [CI] = 0.309–1.017, P = .053); rates at 12 and 18 months were 83% vs 77% and 79% vs 62%, respectively. An increased separation of the recurrence-free survival curves was observed over time, with supportive analysis indicating a trend for improved piecewise hazard ratio after 40 weeks.
Distant metastasis–free survival was extended in the combination group (hazard ratio = 0.347, 95% CI = 0.145–0.828, P = .013); rates at 12 and 18 months were 93% vs 89% and 92% vs 77%, respectively.
KEY POINTS
- Recurrence-free survival events occurred in 22% of those in the mRNA-4157 plus pembrolizumab group vs 40% of the pembrolizumab monotherapy group.
- Recurrence-free survival rates at 12 and 18 months were 83% vs 77% and 79% vs 62%, respectively.
Adverse Events
Grade ≥ 3 treatment-related adverse events occurred in 25% of patients in the combination group vs 18% of the control group. In the combination group, mRNA-4157–related grade 3 events occurred in 12% of patients (no grade 4 or 5 events were reported), and pembrolizumab-related grade ≥ 3 adverse events occurred in 23%. The most common mRNA-4157–related events of any grade were fatigue (61%), injection-site pain (56%), and chills (50%). Immune-mediated adverse events of any grade occurred in 36% of patients in each group and were grade ≥ 3 in 11% vs 14% of patients.
The investigators concluded: “Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival vs pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualized neoantigen therapy might be beneficial in the adjuvant setting.”
Dr. Weber, of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Health, New York, is the corresponding author of The Lancet article.
Disclosure: The study was funded by Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co. For full disclosures of the study authors, visit thelancet.com.
