The European Medicines Agency (EMA) has awarded Priority Medicines (PRIME) designation to the combination of the personalized cancer vaccine mRNA-4157/V940 and pembrolizumab (Keytruda) for adjuvant treatment in patients with high-risk, stage III or IV melanoma following complete resection. This designation aims to accelerate the development and assessment of this therapeutic approach, addressing a critical unmet need in melanoma treatment.
The PRIME designation is supported by data from the phase 2b KEYNOTE-942 trial (NCT03897881), where the combination therapy showed a statistically significant and clinically meaningful 44% reduction in the risk of disease recurrence or death compared to pembrolizumab monotherapy (HR, 0.56; 95% CI, 0.31-1.08; P = .0266).
Mechanism of Action and Clinical Rationale
mRNA-4157/V940 is a personalized cancer vaccine composed of a single synthetic mRNA that encodes for up to 34 neoantigens, designed and produced based on the unique mutational signature of each patient’s tumor. Once administered, the mRNA-encoded neoantigen sequences are translated and undergo natural cellular antigen processing and presentation, stimulating adaptive immunity. Preclinical and early clinical data suggest that combining mRNA-4157/V940 with pembrolizumab may enhance T-cell-mediated elimination of cancer cells, leading to additive clinical benefits.
KEYNOTE-942 Trial Details
The randomized, open-label, phase 2b KEYNOTE-942 trial enrolled 157 patients with high-risk resectable cutaneous melanoma. Eligible patients had an ECOG performance status of 0 or 1 and adequate organ and marrow function. They were required to have undergone complete resection within 13 weeks before the first pembrolizumab dose and be free of disease at study entry, without locoregional relapse or distant metastasis. Patients with brain metastases were excluded.
Participants were randomized to receive either 9 doses of mRNA-4157/V940 plus pembrolizumab 200 mg every 3 weeks for up to 18 cycles (approximately 1 year) or pembrolizumab monotherapy for the same duration, until recurrence or intolerable toxicity. The primary endpoint was recurrence-free survival, with key secondary endpoints including distant metastasis-free survival and safety.
Expert Commentary
Stephen Hoge, MD, president of Moderna, Inc., stated, "Prime scheme designation for mRNA-4157/V940 in combination with [pembrolizumab] highlights the potential promise of individualized cancer treatments in a population with limited alternatives. There is a high unmet need for therapies in melanoma, as it can be a life-threatening condition where available therapies may not be sufficiently effective in a significant proportion of patients."
Eric H. Rubin, MD, senior vice president of global clinical development at Merck Research Laboratories, added, "The milestone underscores the potential for personalized approaches to help improve outcomes for people living with certain types of melanoma. We look forward to working with the EMA, in collaboration with Moderna, to advance our clinical development program for mRNA-4157/V940 in combination with [pembrolizumab]."
Prior Regulatory Designations
In February 2023, the FDA granted breakthrough therapy designation to mRNA-4157/V940 plus pembrolizumab for the same adjuvant indication in high-risk melanoma patients after complete resection, also based on data from KEYNOTE-942.
