One Medicine for One Patient: An Investigational mRNA Individualized Neoantigen Therapy (INT)
We are thrilled to participate in the American Association for Cancer Research’s (AACR) Annual Meeting, in collaboration with Merck, where data will be presented during the plenary session from the Phase 2b study of our investigational mRNA individualized neoantigen therapy (mRNA-4157/V940) in combination with KEYTRUDA® (pembrolizumab), Merck’s anti-PD-1 therapy, for the adjuvant treatment of patients with high-risk stage III/IV melanoma following complete resection. These data will be presented today during AACR’s plenary session; additional subgroup analysis data will be presented during a poster session on Tuesday, April 18.
We expect to advance to a Phase 3 study in adjuvant melanoma with Merck this year and to rapidly begin additional studies in other tumor types including non-small cell lung cancer (NSCLC). mRNA-4157 (V940) is an investigational asset and has not been determined safe or effective by the FDA.
As we look ahead, we are evolving from calling mRNA-4157 (V940) a personalized cancer vaccine to an individualized neoantigen therapy, to better describe the goal of the program.
What are Individualized Neoantigen Therapies?
Each cancer is different – no two are the same – because cancer cells have genetic mutations that make them unique. Genetic mutations create neoantigens, pieces of proteins in cancer cells, that are not usually seen in normal cells. These cancer proteins make up a patient’s cancer “fingerprint.”
Individualized neoantigen therapies are made with the goal of specifically matching each patient's cancer fingerprint. The goal of individualized neoantigen therapies is to train a patient's immune cells to recognize the cancer fingerprint proteins and launch an immune response against the cancer cells.
Individualized neoantigen therapies are currently being studied in clinical trials. As of today, there are currently no approved individualized neoantigen therapies.
Manufacturing our Investigational mRNA Individualized Neoantigen Therapy
The process to make our individualized neoantigen therapy starts in the clinic, where a study participant has their blood drawn and their tumor biopsied. Sequencing is then performed in a lab to compare data from the tumor biopsy sample and the study participant’s healthy blood cells, which are not mutated, to identify the unique genetic mutations of that individual’s cancer.
A proprietary algorithm developed in collaboration with Merck then reviews these mutations and predicts up to 34 of those mutations that are believed to help the study participant’s immune system better recognize tumor cells and to launch an attack. Next, the investigational individualized neoantigen therapy is created to give cells instructions to make the “fingerprint” cancer protein, with the goal of helping the body recognize and attack that study participant’s unique cancer.
Following the design stage, this information is then sent to our manufacturing facility in Norwood, MA, where the individualized neoantigen therapy is manufactured. The individualized neoantigen therapy is then placed in a vial and shipped back to the clinical trial site where a healthcare professional administers it to the study patient via intramuscular injection.
Phase 2b Study of mRNA Individualized Neoantigen Therapy in Combination with KEYTRUDA for Adjuvant Treatment of Patients with Stage III/IV Melanoma
Today, Jeffrey Weber, MD, PhD; Deputy Director of the Perlmutter Cancer Center and Co-Director of the Melanoma Research Program at NYU Langone Health and Principal Investigator of the Phase 2b study will present these data during the plenary session at the AACR Annual Meeting.
mRNA-4157 (V940) in combination with KEYTRUDA demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of recurrence-free survival versus KEYTRUDA alone for the adjuvant treatment of patients with stage III/IV melanoma following complete resection. In the study, 107 patients received the combination of our investigational individualized neoantigen therapy with KEYTRUDA and 50 patients were treated with KETRUDA alone.
Adjuvant treatment with mRNA-4157 (V940) in combination with KEYTRUDA reduced the risk of recurrence or death by 44% (HR =0.56 [95% CI, 0.31-1.017]; one-sided p value =0.0266), compared with KEYTRUDA alone.
With Merck, we are studying our investigational mRNA individualized neoantigen therapy given in combination with KEYTRUDA compared to KEYTRUDA alone. We selected KEYTRUDA as the comparator in the trial because it is considered a standard of care in adjuvant melanoma.
Adverse events observed with mRNA-4157 (V940) in KEYNOTE-942 were consistent with those previously reported in a Phase 1 clinical trial. The safety profile of KEYTRUDA was consistent with that observed in previously reported studies. The number of patients reporting treatment related Grade ≥ 3 adverse events were similar between the arms (25% vs 18%, respectively). The most common adverse event of any grade attributed to either mRNA-4157 (V940) alone or to both mRNA-4157 (V940) and KEYTRUDA were fatigue (60.6%), injection site pain (55.8%) and chills (50.0%).
Collaborating with Merck to Advance This Program for Patients
In 2016, we entered into a strategic collaboration with Merck to evaluate novel mRNA-based personalized cancer vaccines, now known as individualized neoantigen therapies, and without KEYTRUDA for the treatment of multiple types of cancer. We have accelerated this program – we hired our first employee working on this program and filed our Investigational New Drug Application (IND) for mRNA-4157 (V940) with the U.S. FDA within 18 months. The first participant in the Phase 1 study of mRNA-4157 was dosed in November 2017. In October 2022, Merck exercised their option for joint development and commercialization mRNA-4157 (V940). We appreciate the ongoing, productive collaboration that we have had with Merck.
Our Next Steps
We are extremely grateful to the participants in our clinical trials and the investigators and staff at our trial sites who are helping to advance this important research. Looking ahead, with Merck, we plan to initiate a Phase 3 study in melanoma in 2023 and rapidly expand our efforts to study additional tumor types including non-small cell lung cancer.
At Moderna, we work collaboratively across the company to set ambitious goals and we continue to push past possible even when those goals are met. I would like to thank the incredible Moderna team for their dedication to positively impact human health globally.
We will continue to act with sense of deep sense of responsibility as we pursue our mission to deliver the greatest possible impact to people through mRNA medicines.