Investigational Individualized Neoantigen Therapy, Pembrolizumab Improve Distant Metastasis-Free Survival in Melanoma

New data presented at the American Society of Clinical Oncology 2023 Annual Meeting demonstrate that treatment with mRNA-4157 (V940, Moderna) in combination with pembrolizumab (Keytruda, Merck) demonstrated a statistically significant and clinically meaningful improvement in distant metastasis-free survival (DMFS) in patients with high-risk stage 3/4 melanoma following complete resection.

Credit: Evgeniy Kalinovskiy - stock.adobe.com

mRNA-4157 consists of a single synthetic mRNA coding for up to 34 neoantigens and is designed and produced based on the unique mutational signature of the DNA sequence of the patient’s tumor. Upon administration, the algorithmically derived and messenger ribonucleic acid (RNA)-encoded neoantigen sequences are endogenously translated and undergo natural cellular antigen processing and presentation—an important step in adaptive immunity.

Individualized neoantigen therapies are designed to prime the immune system so that patients can generate an antitumor response specific to their tumor. mRNA-4157 generates specific T cell responses based on the tumor, whereas pembrolizumab increases the ability of the body’s immune system to help detect and fight tumor cells.

According to the new data, in the overall intention-to-treat population, adjuvant treatment with mRNA-4157 in combination with pembrolizumab demonstrated a statistically significant and clinically meaningful improvement in DMFS, a key secondary endpoint, compared with pembrolizumab alone. This endpoint, defined as the time from the first dose of pembrolizumab until the date of first distant recurrence or death from any cause, was pre-specified for statistical testing following the positive primary endpoint of recurrence-free survival (RFS).

The combination also reduced the risk of developing distant metastasis or death by 65%.

“Patients with stage 3 and 4 melanoma can be at high risk of having their cancer recur or metastasize to other sites,” said Eric H. Rubin, MD, senior vice president of global clinical development at Merck Research Laboratories, in a press release. “These new DMFS results build upon the positive [RFS] data previously observed from this phase 2b study, and we look forward to working with Moderna to initiate a phase 3 study in melanoma later this year.”

An exploratory subgroup analysis evaluated minimal residual disease (MRD) by circulating tumor DNA (ctDNA) as a biomarker of RFS in patients with resected high-risk melanoma treated with mRNA-4157 and pembrolizumab. The ctDNA-evaluable population across both study arms was representative of the total intention-to-treat population and the majority of these patients were ctDNA-negative at baseline (88%).

In ctDNA-negative patients at baseline, RFS was higher with mRNA-4157 in combination with pembrolizumab versus pembrolizumab monotherapy, demonstrating a 78% reduction in recurrence or death. A similar trend was observed for ctDNA-positive patients at baseline, although the investigators noted that the small sample size of the ctDNA subgroups limits the interpretation of these results. The association between MRD patterns and mRNA-4157 treatment effect will be explored more in upcoming studies.

Adverse events (AEs) reported with mRNA-4157 in the KEYNOTE-942 trial were consistent with those previously observed in a phase 1 clinical trial, and the safety profile of pembrolizumab was consistent with findings from previous studies. The number of patients reporting treatment related grade 3 or higher AEs were similar between the investigational and placebo arms, at 25% and 18%, respectively. The most common AEs of any grade attributed to either mRNA-4157 or the combination of both drugs were fatigue (60.6%), injection site pain (55.8%), and chills (50%).

“Patients who experience metastases at distant sites typically have worse survival outcomes and a poor prognosis, thus these results showing a reduction in the risk of distant recurrence underscore the potential of neoantigen therapy,” said Kyle Holen, MD, senior vice president and head of development, therapeutics, and oncology, at Moderna, in the press release. “These results add to the emerging picture of how individualized neoantigen therapy may advance melanoma treatment and the promise it may hold for other types of cancer.”

REFERENCE

Moderna and Merck Announce mRNA-4157 (V940) in Combination With Keytruda (pembrolizumab) Demonstrated a Statistically Significant and Clinically Meaningful Improvement in Distant Metastasis-Free Survival (DMFS) in Patients with High-Risk Stage III/IV Melanoma Following Complete Resection Versus Keytruda. News release. Merck. June 5, 2023. Accessed June 5, 2023. https://www.merck.com/news/moderna-and-merck-announce-mrna-4157-v940-in-combination-with-keytruda-pembrolizumab-demonstrated-a-statistically-significant-and-clinically-meaningful-improvement-in-distant-metastasis-free/