Following the initial announcement of positive Phase 2b KEYNOTE-942 trial results in December 2022, the companies have this week released further data from the trial as they look to the next steps of development.
A Phase 3 study is expected to get underway this year, while the companies will also ‘rapidly expand’ development to additional tumor types, including non-small cell lung cancer.
Detailed data provides 'further encouragement'
The personalized cancer vaccine, mRNA-4157, is the most advanced candidate in Moderna’s cancer vaccine portfolio and is being jointly developed with Merck.
The investigational individualized neoantigen therapy (INT) is being trialed with Merck’s blockbuster anti-PD-1 therapy, Keytruda, in patients with resected high-risk melanoma (stage III/IV).
The US Food and Drug Administration and European Medicines Agency have granted the combination Breakthrough Therapy Designation and the PRIME scheme, respectively, for mRNA-4157 (V940) in combination with Keytruda for the adjuvant treatment of patients with high-risk melanoma following complete resection.
Detailed data from the Phase 2b trial is being presented during the American Association for Cancer Research (AACR) Annual Meeting this week.
“These results provide further encouragement for the potential of mRNA as an individualized neoantigen therapy to positively impact patients with high-risk resected melanoma,” said Dr. Kyle Holen, M.D. Moderna's Senior Vice President and Head of Development, Therapeutics and Oncology.
“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. We look forward to starting the Phase 3 melanoma trial soon and expanding testing to lung cancer and beyond.”
Fighting melanoma earlier
Merck, which has more than 1,600 trials studying Keytruda across a wide variety of cancers and treatment settings, emphasizes the potential of the cancer vaccine and Keytruda combo across a variety of early-stage cancers.
“Data from KEYNOTE-942 provide evidence for the potential of mRNA-4157 (V940) in combination with Keytruda to improve recurrence-free survival when given to patients with resected high-risk melanoma,” said Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories.
“These data support the potential of mRNA-4157 (V940) in combination with Keytruda to help fight melanoma earlier and warrant investigation of the combination in a larger Phase 3 trial. We also look forward to studying mRNA-4157 (V940) and Keytruda in a variety of other early-stage cancers.”
Primary endpoint: RFS
The rates of melanoma, the most serious form of skin cancer, have been rising over the past few decades, with nearly 325,000 new cases diagnosed worldwide in 2020.
In the US, 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 US in 2022). The five-year survival rates are estimated to be 60.3% for stage III and 16.2% for stage IV.
The primary endpoint of the Phase 2b KEYNOTE study is recurrence-free survival (RFS), compared to Keytruda alone, with secondary endpoints including distant metastasis-free survival and safety, and exploratory endpoints including distribution of tumor mutational burden (TMB) expression in baseline tumor samples across study arms and their association with the primary RFS endpoint.
The trial demonstrated a ‘statistically significant and clinically meaningful improvement’ in recurrence-free survival (RFS), and reduced the risk of recurrence or death by 44%, compared with Keytruda alone.
107 patients received mRNA-4157 (V940) in combination with Keytruda and 50 patients were treated with Keytruda alone.
Recurrence or death was reported in 22.4% of patients (n=24/107) in the combination arm compared with 40% of patients (n=20/50) who received KEYTRUDA alone with a median follow-up of 23 and 24 months, respectively.
The 12-month RFS rate was 83.4% (95% CI, 74.7-89.3) and 77.1% (95% CI, 62.5-86.6) in the combination and control arms, respectively. The 18-month RFS rate was 78.6% (95% CI, 69.0-85.6) and 62.2% (95% CI, 46.9-74.3) in the combination and control arms, respectively.
Adverse events reported with mRNA-4157 (V940) in KEYNOTE-942 were consistent with those previously observed in a Phase 1 clinical trial.
Data from an exploratory subgroup analysis of KEYNOTE-942/mRNA-4157-P201 showed that improvement in RFS was observed with mRNA-4157 (V940) in combination with KEYTRUDA compared to KEYTRUDA alone regardless of tumor mutational burden (TMB) status.
The RFS benefit of mRNA-4157 (V940) in combination with KEYTRUDA compared to KEYTRUDA alone observed in the intention-to-treat population was maintained across both TMB high (HR=0.65; 95% CI: 0.284-1.494) and TMB non-high (HR=0.59; 95% CI: 0.243-1.425) subpopulations.
The association between TMB and mRNA-4157 (V940) treatment effect will be further explored in upcoming planned studies.