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mRNA-4157 (V940) in combination with KEYTRUDA reduced the risk of distant metastasis or death by 65% (HR=0.347 [95% CI, 0.145-0.828]); one-sided p value=0.0063) compared to KEYTRUDA alone
The DMFS results, a key secondary endpoint of the Phase 2b KEYNOTE-942 study, will be presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting
Companies plan to initiate a Phase 3 study in the adjuvant setting in patients with high-risk melanoma in 2023, and rapidly expand to additional tumor types, including non-small cell lung cancer
CAMBRIDGE, MA and RAHWAY, NJ / ACCESSWIRE / June 5, 2023 /Moderna, Inc. (NASDAQ:MRNA), a biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines, and Merck (NYSE:MRK), known as MSD outside of the United States and Canada, today announced distant metastasis-free survival (DMFS) results from the Phase 2b randomized KEYNOTE-942/mRNA-4157-P201 study, a clinical trial evaluating mRNA-4157 (V940), an investigational individualized neoantigen therapy (INT), in combination with KEYTRUDA, Merck's anti-PD-1 therapy, in patients with resected high-risk melanoma (stage III/IV). In the overall intention-to-treat (ITT) 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 metastasis 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). These late-breaking data are being presented for the first time today at 5:00 p.m. ET during an oral abstract session at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract #LBA9503).
"We are excited to be sharing these results with the oncology community and thrilled to see such an exceptional result in distant melanoma recurrence or death. 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, M.D. Moderna's Senior Vice President and Head of Development, Therapeutics and Oncology. "These results add to the emerging picture of how individualized neoantigen therapy may transform melanoma treatment and the promise it may hold for other types of cancer. Together with Merck, we are rapidly advancing our efforts to move this forward for patients."
"Patients with stage III and IV melanoma can be at high risk of having their cancer recur or metastasize to other sites," said Dr. Eric H. Rubin, senior vice president, global clinical development, Merck Research Laboratories. "These new DMFS results build upon the positive recurrence-free survival 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."
Based on data from KEYNOTE-942/mRNA-4157-P201, the U.S. Food and Drug Administration and European Medicines Agency granted Breakthrough Therapy Designation and the Priority Medicines (PRIME) scheme, respectively, for mRNA-4157 (V940) in combination with KEYTRUDA for the adjuvant treatment of patients with high-risk melanoma following complete resection. The companies recently announced the first presentation of the study's primary endpoint, RFS, from the Phase 2 KEYNOTE-942/mRNA-4157-P201 trial in April 2023 at the American Association for Cancer Research (AACR) Annual Meeting.
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%).
Exploratory Subgroup Analysis Evaluating Minimal Residual Disease by ctDNA
Data from an exploratory subgroup analysis of KEYNOTE-942/mRNA-4157-P201 (Abstract #LBA9515) evaluating minimal residual disease (MRD) by circulating tumor DNA (ctDNA) as a biomarker of RFS in resected high-risk melanoma patients treated with mRNA-4157 (V940) in combination with KEYTRUDA were also presented. For ctDNA assessments, tumor core biopsies and matched whole-blood samples were subjected to whole-exome sequencing to identify patient-specific somatic variants. The personalized amplicon-based next-generation sequencing assay from NeoGenomics (RaDaR®) was used to select up to 48 variants most suitable for MRD detection and analysis of ctDNA in baseline plasma samples. The ctDNA-evaluable population (n=125) across both study arms was representative of the total ITT population (n=157). The majority of ctDNA-evaluable patients were ctDNA-negative at baseline (88.0%, n=110/125), compared to ctDNA-positive patients at baseline (12.0%, n=15/125). In ctDNA-negative patients at baseline, RFS was higher with mRNA-4157 (V940) in combination with KEYTRUDA (n=77) versus KEYTRUDA monotherapy (n=33), representing a 78% reduction in recurrence or death (HR=0.225 [95% CI 0.095-0.531]). A similar trend was observed for ctDNA-positive patients (n=13 for the combination arm; n=2 for KEYTRUDA only) at baseline. However, the small sample size of the ctDNA subgroups limits the interpretation of these results. The association between MRD patterns and mRNA-4157 (V940) treatment effect will be further explored in upcoming planned studies.
About mRNA-4157 (V940)
mRNA-4157 (V940) is a novel investigational messenger ribonucleic acid (mRNA)-based individualized neoantigen therapy1 consisting of a single synthetic mRNA coding for up to 34 neoantigens that is designed and produced based on the unique mutational signature of the DNA sequence of the patient's tumor. Upon administration into the body, the algorithmically derived and RNA-encoded neoantigen sequences are endogenously translated and undergo natural cellular antigen processing and presentation, a key step in adaptive immunity.
Individualized neoantigen therapies are designed to prime the immune system so that a patient can generate an antitumor response specific to their tumor mutation signature. mRNA-4157 (V940) is designed to stimulate an immune response by generating specific T cell responses based on the unique mutational signature of a patient's tumor. KEYTRUDA is an immunotherapy that works by increasing the ability of the body's immune system to help detect and fight tumor cells. Based on early clinical studies, combining mRNA-4157 (V940) with KEYTRUDA may potentially provide an additive benefit and enhance T cell-mediated destruction of tumor cells.
About KEYNOTE-942/mRNA-4157-P201 (NCT03897881)
KEYNOTE-942 is an ongoing randomized, open-label Phase 2b trial that enrolled 157 patients with high-risk stage III/IV melanoma. Following complete surgical resection, patients were randomized 2:1 (stratified by stage) to receive mRNA-4157 (V940) (1 mg every three weeks for nine doses) and KEYTRUDA (200 mg every three weeks up to 18 cycles [for approximately one year]) versus KEYTRUDA alone for approximately one year until disease recurrence or unacceptable toxicity. The primary endpoint is RFS, defined as the time from first dose of KEYTRUDA until the date of first recurrence (local, regional, or distant metastasis), a new primary melanoma, or death from any cause in the intention-to-treat population. Secondary endpoints include DMFS and safety, and exploratory endpoints include distribution of TMB expression in baseline tumor samples across study arms and their association with the primary RFS endpoint.
Key eligibility criteria for the trial included: patients with resectable cutaneous melanoma metastatic to a lymph node and at high risk of recurrence, patients with complete resection within 13 weeks prior to the first dose of KEYTRUDA, patients were disease free at study entry (after surgery) with no loco-regional relapse or distant metastasis and no clinical evidence of brain metastases, patients had a formalin fixed paraffin embedded (FFPE) tumor sample available suitable for sequencing, Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 and patients with normal organ and marrow function reported at screening.
About melanoma
Melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of pigment-producing cells. The rates of melanoma have been rising over the past few decades, with nearly 325,000 new cases diagnosed worldwide in 2020. In the U.S., skin cancer is one of the most common types of cancer diagnosed, and melanoma accounts for a large majority of skin cancer deaths. It is estimated there will be nearly 100,000 new cases of melanoma diagnosed and almost 8,000 deaths resulting from the disease in the U.S. in 2023. The five-year survival rates are estimated to be approximately 60.3% for stage III and 16.2% for stage IV.
About KEYTRUDA® (pembrolizumab) injection, 100 mg
KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body's immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Merck has the industry's largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.
Selected KEYTRUDA® (pembrolizumab) Indications in the U.S.
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.
KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB, IIC, or III melanoma following complete resection.
See additional selected indications for KEYTRUDA in the U.S. after the Selected Important Safety Information
Selected Important Safety Information for KEYTRUDA
Severe and Fatal Immune-Mediated Adverse Reactions
KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.
Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti-PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.
Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.
Pneumonitis occurred in 41 (7%) patients, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. In adult patients who received adjuvant therapy for NSCLC, patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (
