FDA Grants Breakthrough Designation to mRNA Vaccine for Resected Melanoma

The FDA has granted breakthrough therapy designation to the investigational vaccine mRNA-4157-P201 in combination with pembrolizumab (Keytruda) as an adjuvant treatment for patients with high-risk melanoma following complete resection, according to a press release from Moderna and Merck.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," according to the manufacturers of the mRNA-4157/V940 vaccine.

Findings from the phase 2b KEYNOTE-942/mRNA-4157-P201 trial (NCT03897881) supported the breakthrough therapy designation. In the trial, mRNA-4157/V940 plus pembrolizumab yielded a statistically significant and clinically meaningful improvement in the primary end point of recurrence-free survival (RFS) compared with pembrolizumab alone.² Additionally, mRNA-4157/V940 plus pembrolizumab lowered the risk of recurrence or death by 44% vs pembrolizumab monotherapy (HR, 0.56; 95% CI, 0.31-1.08; P = .0266).

Serious treatment-related adverse effects (TRAEs) occurred in 14.4% of patients receiving the mRNA-4157-P201 vaccine plus pembrolizumab vs 10.0% of those receiving pembrolizumab alone. AEs observed with the mRNA vaccine were comparable with those previously reported in a phase 1 clinical trial, and the safety profile of pembrolizumab was consistent with those previously reported of the agent.

The manufacturers of mRNA-4157-P201 plan to discuss the results of KEYNOTE-942 with regulatory authorities, initiate a phase 3 trial in adjuvant melanoma in 2023, and investigate additional diseases including non–small cell lung cancer.

“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,” Stephen Hoge, MD, president of Moderna, said in the press release. “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.”

The novel, personalized mRNA-4157/V940 vaccine consists of a single synthetic mRNA coding for up to 34 neoantigens and was designed and produced based on the unique mutational signature of a patient’s tumor. The vaccine stimulates an immune response by generating specific T-cell responses based on unique mutational signature.

Investigators of the ongoing, randomized, open-label phase 2b KEYNOTE-942 trial have enrolled 157 patients with stage III or IV melanoma following complete resection. Patients were randomly assigned to receive either 9 total doses of the mRNA-4157/V940 vaccine plus 200 mg of pembrolizumab every 3 weeks for up to 18 cycles or pembrolizumab alone until unacceptable toxicity or recurrent disease.

Secondary end points of the trial included distant metastasis-free survival, AEs, and number of patients who discontinued treatment due to AEs.

Patients 18 years and older with cutaneous metastatic melanoma at high risk of recurrence who underwent a complete resection within 13 weeks before beginning study treatment were eligible for enrollment on the trial. Additional inclusion criteria included having a formalin fixed paraffin embedded tumor sample available for sequencing, an ECOG performance status of 0 or 1, and normal organ and marrow function at time of screening.

Patients who had a prior malignancy or received a presvious systemic anti-cancer therapy were unable to enroll on the trial. Patients were also unsuitable for enrollment if they received a live vaccine within 30 days of beginning study treatment, had active autoimmune disease, a solid organ or allogeneic bone marrow transplant, pneumonitis, prior interstitial lung disease, clinically significant heart failure, or active infection requiring treatment.

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, Merck. February 22, 2023. Accessed February 23, 2023. http://bit.ly/3YV63rZ
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, Merck. December 13, 2022. Accessed February 23, 2023. http://bit.ly/3xNrI9B