FDA Greenlights BTD of a Personalized mRNA Vaccine for High-Risk Melanoma

Positive data from the phase 2b KEYNOTE-942 trial (NCT03897881) have led to the FDA to grant a breakthrough therapy designation to mRNA-4157/V940 in combination with pembrolizumab (Keytruda) for the adjuvant treatment of patients with high-risk melanoma following complete resection, according to Moderna, Inc.¹

mRNA-4157/V940 is a novel investigational messenger ribonucleic acid (mRNA)-based personalized cancer vaccine made of a single synthetic mRNA coding for up to 34 neoantigens. The vaccine works by stimulating an immune response through generating specific T cell responses based on the unique mutational signature of a patient’s tumor.

Early clinical studies have shown that the combination of mRNA-4157/V940 with pembrolizumab may potentially produce an additive benefit and enhance T cell-mediated destruction of tumor cells.

“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,” said Stephen Hoge, MD, president of Moderna, in the press release. “mRNA-4157/V940 in combination with Keytruda 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.”

KEYNOTE-942 is an ongoing randomized, open-label phase 2b trial of 157 patients with stage III/IV melanoma. Patients were randomized to receive mRNA-4157/V940 following complete surgical resection. Nine total doses of mRNA-4157/V940 were administered to patients in addition to pembrolizumab at 200 mg every 3 weeks up to 18 cycles for approximately 1 year or pembrolizumab alone for approximately 1 year until disease recurrence or unacceptable toxicity.²

Enrollment in the trial was open to patients with resectable cutaneous melanoma at high-risk of recurrence, those who had complete resection within 13 weeks before receiving the first dose of pembrolizumab, and those who were disease free at the time of study entry and after surgery. Patients must not have had loco-regional relapse or distant metastasis, and no clinical evidence of brain metastases.

Findings from KEYNOTE-942 were reported in December 2022 and showed that there was a 44% reduction in risk recurrence or death (HR, 0.56; 95% CI, 0.31-1.08; one-sided P = .0266) among patients who received the mRNA vaccine plus pembrolizumab compared with pembrolizumab alone.

Regarding safety, mRNA-4157 was well tolerated and its adverse event (AE) profile was consistent with the phase 1 results.1 AEs from pembrolizumab were also consistent with past trials. Serious treatment-related AEs occurred in 14.4% of patients who received mRNA-4157 plus pembrolizumab versus 10% with pembrolizumab alone.

"The data from a phase 1 study of the neoantigen mRNA vaccine plus PD-1 antibody pembrolizumab, then recent data from a phase 2b randomized study of neoantigen mRNA vaccine plus PD-1 antibody pembrolizumab vs pembrolizumab alone showing increased recurrence-free survival for the combination compared to PD-1 antibody alone were submitted to the FDA, which granted this breakthrough designation. This means that there will be frequent and close consultation between IND sponsors like Moderna and Merck and the FDA to expedite regulatory issues and shorten the time to getting larger registration trials of the neoantigen mRNA plus PD-1 antibody strategy underway," Jeffrey S. Weber MD PhD, deputy director and co-director of the melanoma program, Laura and Isaac Perlmutter Professor of Oncology, Department of Medicine, NYU Langone’s Perlmutter Cancer Center, told Targeted Oncology^TM.

According to the press release, Moderna, Inc, and Merck will continue to discuss data from KEYNOTE-942 with regulatory authorities, initiate a phase 3 study with the agent for patients with adjuvant melanoma this year, and expand to evaluate additional tumor types, including non–small cell lung cancer.

“This is an important milestone in the development of mRNA-4157/V940 in combination with Keytruda,” said Eric H. Rubin, MD, senior vice president, global clinical development, Merck Research Laboratories, in the press release. “We look forward to working with the FDA, in collaboration with Moderna, to conduct a rigorous and rapid clinical development program with a focus on addressing the needs of this important patient population.”

REFERENCES:

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. February 22, 2023. Accessed February 23, 2023. https://bit.ly/3xJZLiS

Moderna and Merck announce mRNA-4157/V940, an investigational personalized mRNA cancer vaccine, in combination with Keytruda(R) (pembrolizumab), met primary efficacy endpoint in phase 2b KEYNOTE-942 trial. Moderna. December 13, 2022. Accessed December 14, 2022. https://bit.ly/3Pwoake