mRNA-4157 Plus Pembrolizumab Under Further Investigation in Phase 3 Trial in High-Risk Melanoma

The combination of mRNA-4157 (V940) and pembrolizumab (Keytruda) will be further evaluated as an adjuvant treatment option for patients with resected, high-risk, stage IIB to IV melanoma in the phase 3 V940-001 trial (NCT05933577).¹

The global, randomized, double-blind, placebo-controlled study will evaluate mRNA-4157 plus pembrolizumab vs placebo plus pembrolizumab in approximately 1089 patients with high-risk, stage IIB to IV melanoma following complete resection. Enrollment for the trial has commenced, with the first patients enrolling in Australia.

“As we continue our efforts to advance novel treatment options for patients with high-risk, stage IIB to IV melanoma, the initiation of the V940-001 phase 3 trial represents an important step forward in these efforts and our study of individualized neoantigen therapy,” Marjorie Green, MD, senior vice president and head of Late-Stage Oncology, Global Clinical Development, at Merck Research Laboratories, stated in a news release. “We look forward to continuing to collaborate with Moderna to evaluate this promising new approach with mRNA-4157, while also building on a standard of care laid by [pembrolizumab].”

mRNA-4157 is a novel investigational mRNA-based individualized neoantigen therapy comprised of a single synthetic mRNA coding for up to 34 neoantigens. The vaccine is designed to use the unique mutational signature of the DNA sequence from an individual patient’s tumor to stimulate an immune response via specific T-cell responses.

In February 2023, the FDA granted breakthrough therapy designation to mRNA-4157/V940 in combination with pembrolizumab for the adjuvant treatment of patients with high-risk melanoma following complete resection, based on data from the phase 2b KEYNOTE-942 trial (NCT03897881).²

Findings showed that KEYNOTE-942 met its primary end point for recurrence-free survival (RFS), with the combination reducing the risk of recurrence or death by 44% compared with pembrolizumab alone (HR, 0.561; 95% CI, 0.309-1.017; 1-sided P = .0266).^3,4 The 18-month RFS rates were 78.6% and 62.2% for mRNA-4157/pembrolizumab and pembrolizumab monotherapy, respectively.

Further data presented at the 2023 ASCO Annual Meeting showed that at a median follow-up of 23 months for mRNA-4157 plus pembrolizumab and 24 months for pembrolizumab monotherapy, the combination elicited an 18-month distant metastasis–free survival (DMFS) rate of 91.8% compared with 76.8% for pembrolizumab alone (HR, 0.347; 95% CI, 0.145-0.828; P = .0063).⁴

V940-001 is enrolling patients at least 18 years of age with surgically resected and histologically/pathologically confirmed stage IIB, IIC, III, or IV cutaneous melanoma who have not received prior systemic therapy for melanoma beyond surgical resection.⁵ Patients must not be more than 13 weeks removed from final surgical resection before the first dose of pembrolizumab.

Key exclusion criteria include ocular or mucosal melanoma, past or current cancer that has spread to other parts of the body, heart failure within 6 months prior to enrollment, or exposure to prior cancer therapy or another cancer vaccine.

Following complete resection, patients will be randomly assigned 2:1 to receive mRNA-4157 at 1 mg once every 3 weeks or placebo in combination with 400 mg of pembrolizumab once every 6 weeks for up to 9 cycles. Patients will continue treatment for up to 56 weeks, or until disease recurrence or unacceptable toxicity.¹

Investigator-assessed RFS will serve as the trial’s primary end point. Secondary end points will include DMFS, overall survival, safety, and quality of life.

References

1. Merck and Moderna initiate phase 3 study evaluating V940 (mRNA-4157) in combination with Keytruda (pembrolizumab) for adjuvant treatment of patients with resected high-risk (stage IIB-IV) melanoma. News release. Merck. July 16, 2023. Accessed July 26, 2023. https://www.merck.com/news/merck-and-moderna-initiate-phase-3-study-evaluating-v940-mrna-4157-in-combination-with-keytruda-pembrolizumab-for-adjuvant-treatment-of-patients-with-resected-high-riskstage-iib-iv-melanom/
2. 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 July 26, 2023. https://www.merck.com/news/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/
3. 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 July 26, 2023. https://www.merck.com/news/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-94/
4. Khattack A, Weber JS, Meniawy T, et al. Distant metastasis-free survival results from the randomized, phase 2 mRNA-4157-P201/KEYNOTE-942 trial. J Clin Oncol. 2023;41(suppl 17):LBA9503. doi:10.1200/JCO.2023.41.17_suppl.LBA9503
5. A clinical study of V940 plus pembrolizumab in people with high-risk melanoma (V940-001). ClinicalTrials.gov. Updated July 19, 2023. Accessed July 26, 2023. https://clinicaltrials.gov/study/NCT05933577