mRNA-based individualised neoantigen therapy added to PD-1 blockade might provide increased clinical benefit in the adjuvant treatment of high-risk resected melanoma compared with PD-1 blockade alone according to the results from an open-label, randomised, phase IIb, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy conducted in patients with completely resected high-risk cutaneous melanoma.
Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival (RFS) and showed a manageable safety profile according to Prof. Jeffrey S Weber of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Health in New York, NY, US, and colleagues who published the findings on 18 January 2024 in The Lancet.
Neoantigens can stimulate robust antitumour T-cell responses. They are potential targets for cancer therapies, but tumour mutations and their antigen-presenting molecules are unique to each patient. No recurrent neoantigen peptide sequences have yet predicted responder patient populations. Studies of tumour-associated antigen vaccines in resected melanoma and other cancers either did not show benefit or suggested a detrimental effect. However, an individualised neoantigen therapy designed to target a patient’s unique set of cancer neoantigens might overcome the limitations of previous approaches.
The authors wrote in the background that KEYNOTE-054, CheckMate 238, and COMBI A/D studies showed approximately 50% recurrence rate within 5 years in stage III melanoma following complete resection. Several biomarkers might be predictive of outcomes to adjuvant treatment, including TMB, PD-L1 tumour and immune cell expression, and ctDNA. TMB is associated with neoantigen load and might be a predictive biomarker for response to treatment with immune checkpoint inhibitors.
Based on its novel mechanism of action, the study team hypothesised that the mRNA-4157 (V940), individualised neoantigen therapy enhances the activity of immune checkpoint inhibitors by increasing endogenous T-cell responses and inducing de-novo T-cell responses, resulting in improved clinical benefit with minimal additional adverse events. They sequenced the genome of each patient’s tumour and, by using a proprietary algorithm established potentially immunogenic tumour-specific neoantigens.
Moderna’s modified mRNA platform was implemented for mRNA-1273, COVID-19 vaccine showing its utility and rapid adaptability. Preclinical studies initially characterised the immunogenicity and safety profile of mRNA-4157. These observations provided biological evidence of the novel mechanism of action of mRNA-4157 and formed the rationale for the randomised phase IIb assessment of mRNA-4157 in combination with pembrolizumab.
Patients with completely resected high-risk cutaneous melanoma (stage IIIB–IV) were enrolled into this ongoing study from multiple sites in the US and Australia and assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum 9 doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was RFS in the intention-to-treat population.
From 18 July 2019 to 30 September 2021, 157 patients were assigned to treatment, of whom 107 to mRNA-4157 plus pembrolizumab combination therapy and 50 to pembrolizumab monotherapy. Median follow-up was 23 months and 24 months, respectively. RFS was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death 0.561, 95% confidence interval [CI] 0.309–1.017; two-sided p = 0.053), with lower recurrence or death event rate (22% versus 40%); 18-month RFS was 79% (95% CI 69.0–85.6) versus 62% (46.9–74.3).
Distant metastasis-free survival (DMFS) was also longer with the combination therapy compared with monotherapy, with a numerically higher 18-month rate in the combination versus the monotherapy group. Longitudinal DMFS analysis showed that most patients who had a distant recurrence had it as the initial recurrence event, similar to previous studies that have shown that distant metastasis is often the site of first recurrence after melanoma resection. Although patients in both groups had a low risk of distant recurrence or death within the first year, patients in the combination therapy group appeared to have a delayed risk of distant recurrence after stopping pembrolizumab treatment.
Most treatment-related adverse events were grade 1–2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4–5 events. The most common mRNA-4157-related adverse events were influenza-like symptoms and local injection-site reactions, which were generally self-limited and decreased in subsequent dosing cycles.
There was no evidence of an increase in immune-mediated adverse events with the addition of mRNA-4157 to pembrolizumab, despite these being common with immuno-oncology combinations. This safety profile supports testing of future combinations with mRNA-4157 in other cancer types and settings.
The translational data from the study, although exploratory, supported the observed efficacy in terms of RFS and DMFS benefit of mRNA-4157 combination with pembrolizumab. As the focus of the study was clinical outcomes, it was not powered for biomarker and immunogenicity analyses, which were exploratory in nature and involved small sample sizes, but these merit further study.
Logistical complexity is intrinsic to personalised neoepitope selection and manufacture. Although inadequate tissue quantity or quality, or both, for mRNA-4157 manufacture was uncommon (<7% of those screened), future development must continue to optimise methods to ensure sufficient tissue collection, facilitate timely manufacturing, and coordinate patient schedules.
As the treatment paradigm is shifting, additional data in both neoadjuvant and adjuvant settings is needed to contextualise these findings and the potential role for mRNA-4157. This combination is being evaluated in an adjuvant phase III study.
In an accompanied comment, Drs. Mizue Terai and Takami Sato of the Department of Medical Oncology, Sidney Kimmel Medical College, Thomas Jefferson University in Philadelphia, PA, US wrote that the use of neoantigen-based cancer vaccines is likely to face competition from various fusion proteins targeting cancer cells, such as T-cell engagers and bispecific antibodies, and the expected commercialisation of tumour-infiltrating lymphocyte treatments. Furthermore, there are obvious remaining technical challenges for selecting suitable immunogenic epitopes and for the creation of personalised vaccine compounds for tumours with low TMB.
Nevertheless, the development of memory T cells against cancer cells is the most important goal for long-lasting antitumour immune response. In this regard, active specific immunotherapy with cancer neoantigens is one of the most reasonable approaches and should be further explored. Additionally, the combination of cancer-targeting vaccines with immune checkpoint inhibitors could enhance the immune response against cancer cells. Furthermore, various approaches to modify the tumour microenvironment should also be combined with individualised cancer vaccine therapy to break immune tolerance.
This study was funded by Moderna, in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.
