An ongoing clinical trial will assess whether the adjuvant combination of the personalized cancer vaccine mRNA-4157 and pembrolizumab improves recurrence-free survival compared with pembrolizumab alone in patients with complete resection of cutaneous melanoma and a high-risk of recurrence.
Andrew L. Pecora, MD, editor in chief,John Theurer Cancer Center at Hackensack Meridian Health
Andrew L. Pecora, MD
An ongoing clinical trial will assess whether the adjuvant combination of the personalized cancer vaccine mRNA-4157 and pembrolizumab (Keytruda) improves recurrence-free survival (RFS) compared with pembrolizumab alone in patients with complete resection of cutaneous melanoma and a high-risk of recurrence.1
Seventeen sites are enrolling patients on the multicenter, international trial KEYNOTE-942 trial (NCT03897881), including John Theurer Cancer Center.
"Pembrolizumab and other checkpoint inhibitors have been shown to reduce disease recurrence among patients with high-risk melanoma that was surgically removed. However, in many patients, the cancer eventually comes back," study investigator Andrew L. Pecora, MD, FACP, CPE, hematologist/oncologist at John Theurer Cancer Center and associate dean, Technology and Innovation, Hackensack Meridian School of Medicine at Seton Hall University, stated in a press release. "Reducing the rate of relapse would address a significant unmet medical need for these patients."
mRNA-4157 uses a novel and gene-based technology, and is designed by comparing patient's normal cell DNA sequence to that of their tumor, and identifying tumor specific changes to the DNA. By combining with pembrolizumab, researchers hypothesize that the vaccine can prime the immune system to be more responsive to the PD-1 inhibitor and reduce the risk of disease recurrence.
In the trial, patients are randomized to receive a combination of mRNA-4157 and intravenous pembrolizumab or pembrolizumab alone. To be eligible for enrollment, patients must be ≥18 years of age; have resectable melanoma that is at a high risk of recurrence; underwent complete resection within 13 weeks before study enrollment; be disease free at study entry and have no clinical evidence of brain metastases; have an formalin-fixed, paraffin-embedded tumor sample available that is suitable for sequencing; have an ECOG performance status of 0 or 1; and normal organ and marrow function reported at screening.
Those with a prior malignancy or received prior systemic anti-cancer treatment, received a live vaccine ≤30 days prior to the first pembrolizumab dose, had a blood transfusion or administration of colony stimulating factors ≤2 weeks of screening blood sample, an active autoimmune condition ≤7 days prior to the first pembrolizumab dose, have undergone solid organ or allogeneic bone marrow transplant, active or history of pneumonitis, prior interstitial lung disease, clinically significant heart failure, an active infection requiring treatment, or a history of HIV or active hepatitis B or C disease, could not enroll on the study.
The primary endpoint of the trial is RFS, and secondary endpoints include distant metastasis-free survival at 3 years, incidence and severity of adverse events (AEs) ≤90 days after last pembrolizumab dose, discontinuation of treatment due to AEs, and overall survival.
Phase I activity with the combination was presented during the 2019 ASCO Annual Meeting.2 In the trial, mRNA-4157 was evaluated as adjuvant monotherapy (n = 33) or in combination with pembrolizumab (n = 20) in patients with resectable advanced or metastatic solid tumors, including: melanoma, bladder cancer, HPV-negative head and neck squamous cell carcinoma, non—small cell lung cancer, small cell lung cancer, and microsatellite instability–high or tumor mutational burden–high cancers.
Patients received ≤9 cycles of mRNA-4157 by intramuscular injection, at doses ranging from 0.04 mg to 1 mg. In the combination arm, pembrolizumab was administered at 200 mg for 2 cycles prior to the addition of mRNA-4157.
At a median follow-up of 8 months, results showed that 11 patients on the monotherapy arm remained disease free. On the combination arm, 6 of 20 patients had clinical responses to the combination; this included 1 complete response and 5 partial responses. Six patients had stable disease and 8 had disease progression.
All treatment-related adverse events with mRNA-4157 were reversible and of low grade; no treatment-related grade ≥3 AEs were observed, demonstrating the safety and tolerability of the vaccine alone.
"Immunotherapy is revolutionizing cancer care, but challenges remain. This is a very exciting customized anticancer vaccine using a novel technology," Martin E. Gutierrez, MD, director of Drug Discovery and the Phase I Unit, chief of Thoracic Oncology at John Theurer Cancer Center, also stated in the press release. "We are encouraged by the phase I findings and are hopeful that the phase II study results will show a similar positive outcome for these patients."