Exploring One Medicine for One Patient: Individualized Neoantigen Therapies
Each person’s cancer is different because cancer cells have genetic mutations that make them unique, which can make the cancer difficult to treat. That's why we, in collaboration with Merck, are researching mRNA medicines that are designed specifically for an individual patient. Individualized neoantigen therapies (INTs) are an innovative approach that tailor treatment to each patient's individual cancer.
This week, we are participating in the American Society for Clinical Oncology (ASCO) Annual Meeting, where distant metastasis-free survival (DMFS) results 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, will be presented. The ASCO Annual Meeting is the world’s largest oncology conference, and we are honored to share these new data with the global oncology community.
We are incredibly grateful to the participants in our clinical trials and the investigators and clinical trial staff who are helping to advance this important cancer research.
One Medicine for One Patient: Individualizing Cancer Research
Even after 50 years of clinical trials, cancer vaccine-based approaches have had little success, as no cancer vaccine containing regimen has shown recurrence-free survival benefit compared to the traditional standard of care.¹
Developments in the field of immunotherapy have transformed our understanding of the immune system’s role in fighting certain types of cancer. By building on developments in immunologic understanding and cancer biology, we are researching and developing an individualized treatment approach specific to each patient’s own tumor. Moderna, in collaboration with Merck, is exploring INTs as a therapeutic option designed to potentially train and activate the immune system to increase its ability to fight cancer. With this work, we hope to further advance the field of immuno-oncology.
Cancer cells express abnormal proteins, or neoantigens, that are not usually seen in normal cells. These cancer proteins make up a patient’s cancer “fingerprint.” Individualized neoantigen therapies are designed with the goal of specifically matching one patient's unique 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 FDA-approved individualized neoantigen therapies.
How are Investigational mRNA Individualized Neoantigen Therapies Made?
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.
Data Being Presented at the ASCO Annual Meeting
Today, we are presenting distant metastasis-free survival (DMFS) results from the Phase 2b randomized KEYNOTE-942/mRNA-4157-P201 study. In the overall intention-to-treat population, adjuvant treatment with mRNA-4157 (V940) in combination with KEYTRUDA demonstrated a statistically significant and clinically meaningful improvement in DMFS, a key secondary endpoint of the study, compared with KEYTRUDA alone and reduced the risk of developing distant metastases or death by 65% (HR = 0.347 [95% CI, 0.145- 0.828]); one-sided p value=0.0063). The secondary endpoint of DMFS, defined as the time from the first dose of KEYTRUDA 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).
Adverse events reported with mRNA-4157 (V940) in KEYNOTE-942 were consistent with those previously observed in a Phase 1 clinical trial. The safety profile of KEYTRUDA was consistent with findings from previous 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 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%).
At ASCO, we are also presenting data from an exploratory subgroup analysis of KEYNOTE-942/mRNA-4157-P201, evaluating minimal residual disease (MRD) by circulating tumor DNA (ctDNA) as a biomarker of recurrence-free survival (RFS) in resected high-risk melanoma patients treated with mRNA-4157 (V940) in combination with KEYTRUDA.
Phase 2b Study of mRNA Individualized Neoantigen Therapy: Recurrence-Free Survival
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 KEYNOTE-942/mRNA-4157-P201 study because it is considered a standard of care in adjuvant melanoma. 107 patients received the combination of our investigational mRNA-4157 (V940) with KEYTRUDA and 50 patients were treated with KETRUDA alone.
In April at the American Association for Cancer Research (AACR) Annual Meeting, we presented data on the recurrence-free survival (RFS) primary endpoint of the KEYNOTE-942/mRNA-4157-P201 Phase 2b study in patients with stage III/IV melanoma following complete resection. These data showed that mRNA-4157 (V940) in combination with KEYTRUDA demonstrated a statistically significant and clinically meaningful improvement in RFS versus KEYTRUDA alone.
Specifically, individualized neoantigen therapy 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.
Adverse events reported with mRNA-4157 (V940) in KEYNOTE-942 previously presented at AACR were consistent with those currently shared at ASCO.
Based on data from the Phase 2b study, mRNA-4157 (V940) in combination with KEYTRUDA for the adjuvant treatment of patients with high-risk melanoma following complete resection was granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA) and was granted Priority Medicines (PRIME) scheme by the European Medicines Agency.
These results add greater insight into the potential promise of an mRNA individualized
neoantigen approach to addressing cancer. Looking ahead, in collaboration 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. We will continue to research individualized neoantigen approaches with the goal of potentially helping more patients with cancer.