Moderna and Merck & Co. have presented positive mid-stage data at the American Association for Cancer Research (AACR) Annual Meeting 2023 for the combination of their personalized cancer vaccine (PCV) candidate—which Moderna calls mRNA-4157 and Merck calls V940—and Merck’s blockbuster cancer immunotherapy Keytruda® (pembrolizumab).

The companies presented the first detailed data from the Phase IIb KEYNOTE-942/ mRNA-4157-P201 trial (NCT03897881) showing that the PCV/Keytruda combination reduced the risk of recurrence or death by 44% compared to Keytruda alone in stage III/IV melanoma patients with high risk of recurrence following complete resection.

The companies hailed their results as a statistically significant and clinically meaningful improvement in recurrence-free survival (RFS).

“The profound observed reduction in the risk of recurrence-free survival suggests this combination may be a novel means of potentially extending the lives of patients with high-risk melanoma,” Kyle Holen, MD, Moderna’s senior vice president and head of development, therapeutics and oncology, said in a statement.

Holen added that the results, presented Sunday, “provide further encouragement for the potential of mRNA as an individualized neoantigen therapy to positively impact patients with high-risk resected melanoma.”

Moderna and Merck said they plan to advance the personalized cancer vaccine into a Phase III study in patients with adjuvant melanoma later this year, then “rapidly” expand their studies to additional tumor types, including non-small cell lung cancer.

At TD Cowen’s 43rd Annual Health Care Conference last month, Moderna president Stephen Hoge, MD, said the company was considering seeking accelerated approval for the mRNA-based personalized cancer vaccine.

Merck last October exercised an option to jointly develop and commercialize Moderna’s mRNA-based PCV, and agreed to pay Moderna $250 million upfront. Two months later, the companies trumpeted positive topline data from the trial, triggering a 72% surge in Moderna’s stock price.

mRNA-4157/V940 is designed to stimulate an immune response by generating T-cell responses based on the mutational signature of a patient’s tumor. Last month, the vaccine was granted the FDA’s Breakthrough Therapy designation

KEYNOTE-942/mRNA-4157-P201 is an ongoing, randomized, open-label trial that is fully enrolled with 157 high-risk melanoma patients. After complete surgical resection, patients were randomized to mRNA-4157/V940 (nine doses every three weeks) and Keytruda (200 mg every three weeks) versus Keytruda alone for approximately one year until disease recurrence or unacceptable toxicity. The primary endpoint was RFS, with secondary endpoints that included distant metastasis-free survival and overall survival.

In the trial, 107 patients received mRNA-4157 (V940) in combination with Keytruda, while the other 50 patients were treated with Keytruda alone. Recurrence or death was reported in 24 of 107 patients (22%) in the combination arm, versus 20 of 50 patients (40%) dosed with Keytruda alone. The median follow-up for patients was 23 and 24 months, respectively.

12-, 18-month RFS rates

The 12-month RFS rate was 83.4% in the PCV/Keytruda arm and 77.1% in the Keytruda-alone arm. At 18 months, the RFS rate was 78.6% and 62.2% in the combination and control arms, respectively.

Adverse events reported with the PCV were consistent with those previously seen in an earlier Phase I trial, while the safety profile of KEYTRUDA was also consistent with earlier studies. The number of patients reporting treatment-related Grade ≥ 3 adverse events were similar between the arms (25% for PCV-Keytruda, 18% for Keytruda alone). The most common adverse events of any grade attributed to either mRNA-4157 (V940) or the combination of mRNA-4157 (V940) and Keytruda were fatigue (60.6%), injection site pain (55.8%), and chills (50.0%).

Moderna and Merck also presented data from an exploratory subgroup analysis of KEYNOTE-942/mRNA-4157-P201 showing improved RFS among vaccine/Keytruda patients vs. patients taking Keytruda alone regardless of tumor mutational burden (TMB) status.

The RFS benefit of the vaccine/Keytruda combination compared to Keytruda alone that was seen in the intention-to-treat population was maintained across both TMB high and TMB non-high subpopulations. TMB was assessed using tumor biopsies analyzed by whole exome sequencing (WES) and whole transcriptome sequencing. According to the established WES genomic score for KEYTRUDA, TMB high was defined as ≥10 mut/Mb (175 mut/exome) assessed using the FoundationOne CDx assay.

Moderna and Merck added that the association between TMB and mRNA-4157 (V940) treatment effect will be further explored in upcoming planned studies.

Moderna and Merck are among the companies working to develop cancer vaccines. Last year, BioNTech reported positive follow-up Phase I/II data for its wholly-owned novel chimeric antigen receptor T-cell therapy (CAR-T) candidate BNT211 in patients with relapsed or refractory advanced solid tumors.

Besides Moderna-Merck and BioNTech, other companies working on PCVs include Roche and its Genentech subsidiary, which is developing RO7198457; Nykode, which expects to report updated interim Phase II data for its lead cancer vaccine candidate VB10.16 in the first half of 2023; Gritstone bio, which is pursuing two PCV programs, Slate (consisting of Slate v1 and Slate-KRAS) and Granite; as well as privately-held Nouscom, which has announced plans to present poster data Tuesday on its cancer vaccine candidate NOUS-PEV, which is based on patient-specific neoantigens sourced from individual patient tumor mutanomes.

Gritstone expects to report preliminary data from its Granite Phase II/III trial (NCT05141721) assessing its individualized vaccine for first-line microsatellite-stable colorectal cancer in the fourth quarter.


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