Researchers have developed a personalized mRNA-based vaccine, mRNA-4157, that significantly delays disease recurrence in patients with resected high-risk melanoma when added to standard-of-care adjuvant pembrolizumab therapy.
“For the first time in a randomized study with a control arm, the addition of an mRNA neoantigen vaccine appeared to augment the benefit of PD-1 blockade, without adding significant high-grade toxicity,” said presenting author Jeffrey Weber, deputy director of the NYU Langone Perlmutter Cancer Center and Laura and Isaac Perlmutter Professor of Oncology at NYU Grossman School of Medicine, at the AACR Annual Meeting 2023 in Orlando, Florida.
He added that the phase 2 mRNA-4157-P201/Keynote-942 trial “is extraordinarily important, because it gives hope that this novel strategy will provide clinical benefit.”
The trial included 157 patients with completely resected stage IIIB, IIIC, IIID or IV cutaneous melanoma who were randomly assigned to receive the combination of mRNA-4157 plus pembrolizumab (n=107) or pembrolizumab monotherapy (n=50). The vaccine was administered intramuscularly every 3 weeks for a total of nine doses and pembrolizumab (200 mg) was given intravenously every 3 weeks for up to 18 cycles.
Weber explained that mRNA-4157 is a novel personalized cancer vaccine that is designed to target an individual patient’s unique tumor mutations. It is developed by sequencing tumor and normal tissue samples and using a computerized algorithm that identifies immunogenic neoepitopes, regions on tumor antigens (or neoantigens) that are recognized by the immune system as targets for T cells and can elicit immune response to cancer. The 34 neoantigens deemed most likely to produce an immune response are then assembled in into a single mRNA molecule that is made into a microencapsulated vaccine.
The whole process takes an average of 6 to 7 weeks per patient, during which time the patient continues to receive standard chemotherapy.
Over approximately 2 years of follow-up, 22.4% of patients in the combination arm and 40.0% of those in the monotherapy arm experienced disease recurrence or died. At 18 months, the recurrence-free survival rate was 78.6% among the patients who received the vaccine and 62.2% among those who did not.
“That’s a 16% difference, and to me that’s clinically significant,” Weber remarked.
The difference was not only clinically significant, but also corresponded to a statistically significant 44% lower risk for recurrence or death in favor of the vaccine.
Weber reported that the number of patients reporting grade 3 or worse treatment-related adverse events (AEs) was generally similar between the combination and monotherapy arms (25% vs 18%). No patients experienced a grade 4 or grade 5 event related to mRNA-4157, and the most-reported grade 3 event was fatigue. Furthermore, the addition of mRNA-4157 to pembrolizumab did not increase the likelihood of immune-mediated AEs, with 36% of patients in each arm experiencing this outcome.
Data from a subanalysis of the study was also presented at the meeting by Ryan Sullivan, associate director of the Melanoma Program at Mass General Cancer Center and associate professor at Harvard Medical School.
He reported that patients in the combination arm had better outcomes than those treated with just pembrolizumab, regardless of their tumor mutational burden (TMB), tumor inflammation score, or PD-L1 level. For example, the vaccine-pembrolizumab combination led to a similar reduction in the risk of recurrence or death in patients with high and low TMB, at 35% and 41%, respectively.
According to Sullivan, this observation suggests that an algorithm efficient in choosing the target neoantigens can potentially enable the vaccine to induce a robust immune response regardless of the TMB. “There likely is a certain TMB threshold below which our ability to successfully create a neoantigen vaccine is reduced, but our findings indicate that, above that threshold, the benefit of adding vaccination to pembrolizumab was similar regardless of the TMB,” he remarked.
Weber said that the data will now “encourage the initiation of a definitive large, randomized phase 3 trial that’s going to start hopefully in the next couple of months, certainly by the summer of 2023, which I think will definitively answer the question of whether the vaccine added to pembrolizumab causes increased clinical benefit defined as recurrence free survival and distant metastasis free survival.”
He also noted that he believes that the personalized vaccine approach “is absolutely applicable to any solid tumor that expresses neoantigens and that’s almost every solid tumor.” Hematologic malignancies carry fewer neoantigens than solid tumors, but Weber sees no reason the same vaccine strategy couldn’t be used for hematologic cancers “as long as you had a good algorithm for choosing the best neoantigens.”
The study’s first author, Professor Adnan Khattak, Cancer Clinical Trials Lead and Raine Foundation Research Fellow at Hollywood Private Hospital in Nedlands, Western Australia, told Inside precision Medicine that the vaccine will allow clinicians to “take a more personalised approach for high-risk melanoma patients in an effort to further improve the cure rate in addition to what is currently being offered by standard immunotherapy alone.”
Commenting on the data, Sandip Patel, professor of medical oncology at the University of California, San Diego, said he thinks that the personalized mRNA vaccine is “potentially a very exciting approach that may be applicable across multiple tumor types.” However, he cautioned that the data needs to be validated in larger randomized studies as the vaccine is currently only available in context of clinical trials. “If the trial results are positive, this may become a treatment option in future in melanoma as well as in other cancers,” he said.
