Following resection of advanced melanoma, combining a personalized mRNA vaccine with pembrolizumab was shown to reduce the risk of recurrence or death by 44 percent compared to pembrolizumab alone, according to results from the KEYNOTE-942 trial presented at the American Association for Cancer Research (AACR) Annual Meeting 2023.
The study represents a landmark in the advancement of personalized cancer vaccines, being the first randomized clinical trial with a control arm to show that a personalized mRNA vaccine improved clinical outcomes compared to an existing treatment.
“These data provide the first evidence that we can improve upon the rates of recurrence-free survival achieved by PD-1 blockade in resected high-risk melanoma.”Jeffrey S. Weber, MD, PhD
“These data provide the first evidence that we can improve upon the rates of recurrence-free survival achieved by PD-1 blockade in resected high-risk melanoma,” Jeffrey S. Weber, MD, PhD, principal investigator of the study and deputy director of NYU Langone Health’s Perlmutter Cancer Center, said in a statement.
“These findings also provide the first randomized evidence that a personalized neoantigen approach is potentially beneficial for cancer patients.”
Directing T cells to the Tumor
With the capacity to encode a tailored combination of up to 34 neoantigen sequences, the mRNA vaccine is designed to initiate an immune response to cancer based on a patient’s unique tumor mutations. According to vaccine developers, the optimal combination of neoantigen sequences is identified in only two hours using an algorithm that analyzes DNA and RNA sequencing data, and roughly six weeks is required for vaccine manufacturing.
Once administered, the neoantigen sequences are translated and undergo antigen processing and presentation, directing T cells to attack the cancer.
Improved Outcomes, Well Tolerated
The study enrolled 157 patients with cutaneous melanoma metastatic to a lymph node or to distant sites and at high risk of recurrence. All patients had complete resection of their melanoma and were randomly assigned 2:1 to receive either the combination treatment or pembrolizumab alone, with the mRNA vaccine administered for a total of 9 doses.
In addition to improved recurrence-free survival, the mRNA vaccine was well tolerated, and the adverse event profiles for both the vaccine and pembrolizumab were consistent with past trials. The majority of adverse events were low grade, and the most common vaccine-related adverse event was fatigue. Furthermore, no potentiation of immune-mediated adverse events was seen with the addition of the mRNA vaccine to pembrolizumab.
Based on the promising findings, a phase 3 trial will open in 2023 for patients with melanoma, with plans to launch trials of the vaccine in other cancer types soon.
Dr. Weber is a paid consultant for Merck and Moderna.