Adding mRNA vaccine to immunotherapy cuts risk for melanoma recurrence nearly in half
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Key takeaways:
- mRNA vaccine and pembrolizumab significantly improved RFS in patients with resected high-risk melanoma.
- Vaccine, pembrolizumab combination also showed late trend for improved OS, although more follow-up needed.
CHICAGO — Combining an mRNA-based cancer vaccine with standard-of-care pembrolizumab significantly improved RFS and distant metastasis-free survival among patients with resected high-risk melanoma, study results showed.
Extended follow-up of a randomized phase 2 trial presented at ASCO Annual Meeting showed individuals who received the mRNA-4157/V940 (Moderna/Merck) vaccine and pembrolizumab (Keytruda, Merck) had a 49% reduction of risk for recurrence or death and a decrease of 62% for distant recurrence or mortality.
“The mRNA vaccine with pembrolizumab showed a durable clinically significant and now statistically significant improvement in recurrence free and distant metastasis-free survival compared [with] standard single agent pembrolizumab,” 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, said during his presentation.
Background and methodology
The investigational agent mRNA-4157/V940 — a novel mRNA-based personalized cancer vaccine — encodes up to 34 patient-specific tumor neoantigens.
The open-label KEYNOTE-942 trial included 157 patients with completely resected, high-risk cutaneous stage IIIB, IIIC, IIID or IV melanoma.
Researchers randomly assigned patients in a 2:1 to one of two treatment groups. The experimental cohort had 107 patients dosed at 1 mg mRNA-4157 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 patients received pembrolizumab monotherapy, the standard adjuvant treatment for this population.
The vaccine takes between 5 and 6 weeks to manufacture.
“There’s no impact because you’re giving them adjuvant pembrolizumab anyway standard of care — and for the patients it’s great,” Weber told Healio. “I tell the patients, what do you have to lose?”
RFS in the intention-to-treat population served as the study’s primary endpoint. Safety and distant metastasis-free survival (DMFS) served as secondary endpoints.
Results and next steps
At a median follow-up of 34.9 months, the combination arm had significant risk reduction for recurrence and death (HR = 0.51; 95% CI, 0.288-0.906).
The experimental group had a superior 2.5-year RFS rate compared with pembrolizumab alone (74.8% vs. 55.6%), a widened gap from the 18-month update (79.4% vs. 62.2%).
“Nice looking data,” Weber said during his presentation. “The curves are widening out a little bit and we’re showing sustained improvement in recurrence-free survival.”
The mRNA-4157 cohort also had sustained improvement in DMFS (HR = 0.384; 95% CI, 0.172-0.858).
The investigative arm had an improved 2.5-year DMFS rate (89.3% vs. 68.7%). The DMFS curves also widened from the 18-month examination (90.9% vs. 76.8%).
The OS data had remained relatively similar for the first 2 years of the study but did have a late break around month 30 (96% vs. 90.2%), indicating the mRNA-4157 group may gain a benefit (HR = 0.425; 95% CI, 0.114-1.584).
“The numbers are small — whether they’re on the pembrolizumab arm or the combo arm they obviously did well — but these are encouraging data that merit follow-up,” Weber said.
Patients with a heterozygosity or homozygosity for HLA class 1 alleles both benefited from the combination treatment.
“The benefit of mRNA-4157 plus pembrolizumab continued to be overserved irrespective of PD-L1, tumor mutational burden and [circulating tumor DNA] status,” Weber said.
The combination treatment did not produce an increase in grade 3 or worse adverse events (34.6% in combo arm; 36% in control) or immune-related adverse events (10.6% vs. 14%).
The most common grade 3 or worse adverse events for the investigative arm included those related to mRNA-4157 (11.5%) and fatigue (4.8%).
A phase 3 trial is currently enrolling, and Weber said accrual will finish by the end of 2024.
“If I were a betting man, I would bet the phase 3 would be positive,” Weber told Healio. “I think it’s very encouraging that the randomized phase 2 gets better over time.”
However, Weber emphasized the need for an investigation into neoadjuvant therapy in the patient population.
“I think it should’ve happened already,” he said during a question-and-answer dialogue.
Weber later told Healio, “You don’t want to lose the 20% of patients with clinically detectable diseases.”
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Weber JS, et al. Abstract LBA9512. Presented at: ASCO Annual Meeting 2024; May 31-June 4, 2024; Chicago.
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