Distant metastasis-free survival results from the randomized, phase 2 mRNA-4157-P201/KEYNOTE-942 trial.
Adnan Khattak, Jeffrey S. Weber, Tarek Meniawy, Matthew H. Taylor, George Ansstas, Kevin B. Kim, Meredith McKean, Georgina V. Long, Ryan J. Sullivan, Mark B. Faries, Thuy Tran, Charles Lance Cowey, Theresa Medina, Jennifer Segar, Victoria Atkinson, Geoffrey T. Gibney, Jason J. Luke, Elizabeth I. Buchbinder, Robert Meehan, Matteo S. Carlino, on behalf of Moderna Author's Group
Abstract
LBA9503 Background: mRNA-4157 is a novel mRNA-based personalized cancer vaccine which encodes up to 34 patient-specific tumor neoantigens. The open-label randomized Phase 2 mRNA-4157-P201/Keynote-942 trial met its primary endpoint of recurrence free survival (RFS) in patients with resected high-risk stage IIIB/C/D and IV melanoma. The study has shown a statistically significant and clinically meaningful improvement in RFS in the combination therapy compared to pembrolizumab monotherapy, with a reduction in the risk of recurrence or death by 44% (HR = 0.561; 95% CI: (0.309, 1.017); 1-sided p-value of 0.0266). This report provides the first analysis of the secondary efficacy endpoint of distant metastasis-free survival (DMFS). Methods: mRNA-4157-p201 is an ongoing multicenter, open-label, randomized Phase II trial in patients with completely resected, high-risk Stage IIIB/C/D and IV cutaneous melanoma. Patients were randomized 2:1 (stratified by stage) to receive mRNA-4157 in combination with pembrolizumab or pembrolizumab alone. mRNA-4157 (1mg) was administered intramuscularly every 3 weeks for a total of 9 doses and pembrolizumab (200mg) intravenously was given every 3 weeks for up to 18cycles. The primary endpoint was investigator-assessed RFS, defined as local, locoregional, distant recurrence, or new primary melanoma. The secondary endpoint of DMFS was pre-specified and hierarchically tested following positive RFS. All tests were performed at 1-sided alpha = 0.99. Results: 157 patients were randomized to the combination of mRNA-4157 with pembrolizumab (n = 107) or pembrolizumab monotherapy (n = 50). The primary analysis for the primary endpoint occurred after all patients completed a minimum of 12 months on study and 44 RFS events were observed. At a median follow-up of 23 (combination) and 24 (pembrolizumab) months in the primary analysis, RFS events were reported in 22.4% (24/107) of patients in the combination arm and in 40% (20/50) of patients in the monotherapy arm. The 18-month RFS rates (95% CI) were 78.6% (69.0%, 85.6%) vs 62.2% (46.9%,74.3%) in the combination and monotherapy arms respectively. There was also a statistically and clinically significant improvement in DMFS for the combination versus pembrolizumab monotherapy (HR = 0.347; 95% CI: (0.145, 0.828); 1-sided p-value 0.0063). Distant recurrence or death was reported in 8.4% (9/107) and 24% (12/50) of patients, with 18-month DMFS rates (95% CI) were 91.8% (84.2%, 95.8%) vs 76.8% (61.0%, 86.8%) in the combination and monotherapy arm, respectively. Conclusions: mRNA-4157 in combination with pembrolizumab as adjuvant therapy for resected high-risk melanoma significantly prolonged DMFS compared to pembrolizumab. These results provide further evidence that a personalized neoantigen approach is potentially beneficial for cancer patients. A phase 3 randomized study will be initiated in patients with melanoma. Clinical trial information: NCT03897881 .