FDA Grants Breakthrough Therapy Designation to mRNA-4157/V940 Plus Pembrolizumab in High-Risk Melanoma

The FDA has granted a breakthrough therapy designation to the investigational personalized mRNA cancer vaccine mRNA-4157/V940 in combination with pembrolizumab (Keytruda) for the adjuvant treatment of patients with high-risk melanoma following complete resection.¹

The designation was based on data from the phase 2b KEYNOTE-942 trial (NCT03897881). Findings showed that the combination reduced the risk of recurrence or death by 44% compared with pembrolizumab alone (HR, 0.56; 95% CI, 0.31-1.08; one-sided P = .0266), meeting the trial’s primary end point for recurrence-free survival (RFS).²

“The FDA’s breakthrough designation for mRNA-4157/V940 in combination with [pembrolizumab] reflects the excitement that we have for the potential promise of individualized cancer treatments,” Stephen Hoge, MD, president of Moderna, stated in a news release.¹ “mRNA-4157/V940 in combination with [pembrolizumab] provided the first demonstration of efficacy for an investigational mRNA cancer treatment in a randomized clinical trial and potentially represents a new frontier in treating melanoma and other cancers. We look forward to publishing the full data set and sharing the results at an upcoming oncology medical conference, as well as continuing discussions with health authorities. We are grateful to the FDA for this designation.”

mRNA-4157/V940 consists of a single synthetic mRNA coding for up to 34 neoantigens designed and produced using the unique mutational signature for a specific patient’s tumor. Upon injection, the vaccine’s neoantigen sequences are endogenously translated and undergo natural cellular antigen processing and presentation.

The open-label KEYNOTE-942trial enrolled 157 patients with stage III/IV melanoma. Patients were required to have resectable cutaneous melanoma at high risk of recurrence, have complete resection within 13 weeks of the first dose of pembrolizumab, be disease free at study entry with no loco-regional relapse or distant metastasis, and have no clinical evidence of brain metastases.

Additionally, patients needed to have FFPE tumor samples available for sequencing, an ECOG performance status of 0 or 1, and normal organ/bone marrow function at screening.²

Following resection, patients were randomly assigned to receive 9 total doses of mRNA-4157/V940 plus 200 mg of pembrolizumab every 3 weeks for 18 cycles, or pembrolizumab alone. Along with the primary end point of RFS, key secondary end points included distant metastasis–free survival and safety.

Regarding safety, adverse effects (AEs) were consistent with previously reported data for mRNA-4157/V940 and pembrolizumab. Serious treatment-related AEs occurred in 14.4% of patients who received mRNA-4157/V940 plus pembrolizumab compared with 10% for patients treated with pembrolizumab alone.

Moderna and Merck previously announced that the companies plan to share data from KEYNOTE-942 with regulatory agencies and initiate a phase 3 study of mRNA-4157/V940 in patients with melanoma in 2023.

References

1. 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/
2. Moderna and Merck announce mRNA-4157/V940, an investigational personalized mRNA cancer vaccine, in combination with Keytruda® (pembrolizumab), met primary efficacy endpoint in phase 2b KEYNOTE-942 trial. News release. Moderna. December 13, 2022. Accessed February 23, 2023. https://www.merck.com/news/