mRNA-4157/V940, a novel investigational, personalized, messenger ribonucleic acid (mRNA)-based personalized cancer vaccine that encodes up to 34 patient-specific tumor neoantigens, is designed to stimulate an immune response by generating specific T cell responses based on the unique mutational signature of a patient’s tumor.

In combination with the immune checkpoint inhibitor pembrolizumab (Keytruda®; Merck & Co*) the novel vaccine, being jointly developed by Moderna and Merck & Co, demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of recurrence-free survival (RFS) compared with pembrolizumab alone in patients with high-risk, stage III/IV melanoma following complete resection. The clinical benefit was observed regardless of the tumor mutational burden (TMB) status.

Adjuvant treatment with mRNA-4157/V940 in combination with pembrolizumab reduced the risk of recurrence or death by 44% (HR=0.56 [95% CI, 0.31-1.08]; one-sided p-value=0.0266) compared with pembrolizumab alone.

These results from the phase IIb KEYNOTE-942 clinical trial were presented at the AACR Annual Meeting 2023, held April 14-19.

The KEYNOTE-942 study was funded by Moderna and Merck.

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Skin cancer
Melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of pigment-producing cells.

The rates of melanoma have been rising over the past few decades, with nearly 325,000 new cases diagnosed worldwide in 2020. It is estimated that skin melanoma accounted for 4% of all new cancer diagnoses in the 27 countries of the European Union in 2020 (all cancers, excluding non-melanoma skin cancers) and for 1.3% of all deaths due to cancer.

This made it the sixth most frequently occurring cancer (after breast, colorectal, prostate, lung, and bladder cancers) and one of the 20 most frequent causes of cancer death.

Personalized cancer vaccines
Personalized cancer vaccines are designed to prime the immune system so that a patient can generate a tailored anti-tumor response specific to their tumor mutation signature.

“Vaccine strategies over the last 25 years attempted to induce immune responses against tumor-associated antigens that are not absolutely specific to the tumor,” said presenting author Jeffrey Weber, MD, PhD, deputy director of the NYU Langone Perlmutter Cancer Center and Laura and Isaac Perlmutter Professor of Oncology at NYU Grossman School of Medicine.

“More recent cancer vaccine approaches have focused on targeting neo-antigens originated from individual tumor mutations, which are unique to cancer cells.”

Stimulating an immune response
The combination of mRNA-4157/V940 with pembrolizumab potentially provides an additive benefit and enhance T cell-mediated destruction of tumor cells.

Upon administration, the algorithmically derived and mRNA-encoded neo-antigen sequences are endogenously translated and undergo natural cellular antigen processing and presentation, a key step in adaptive immunity.

“Hence, in addition to encoding the target antigens, mRNA vaccines also provide adjuvant properties that amplify the immune response,” Weber explained.

Trial design
The randomized KEYNOTE-942 trial assessed the efficacy of mRNA-4157/V940 in prolonging RFS in patients with resected, stages IIIB/IIIC/IIID and IV melanoma when given in combination with pembrolizumab, the standard-of-care adjuvant therapy in this patient population. Patients were randomly assigned (2:1) to receive mRNA-4157/V940 in combination with pembrolizumab (107 patients) or pembrolizumab alone (50 patients). The vaccine was administered every three weeks for a total of nine doses, and pembrolizumab was given every three weeks for up to 18 cycles.

According to the results of the primary trial analysis, after 18 months, the RFS was 78.6% in the combination arm and 62.2% in the pembrolizumab arm, corresponding to a 44% reduction in the risk of recurrence or death in patients who received both mRNA-4157/V940 and pembrolizumab compared to those who only received pembrolizumab.

The majority of treatment-related adverse events were mild, and the rates of serious adverse events were comparable between the two arms, Weber said.

“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 Weber.

“This study is extraordinarily important, because it gives hope that this novel strategy will provide clinical benefit.”

In an additional analysis of KEYNOTE-942, baseline biopsies from the trial participants were assessed for TMB and how it relates to RFS across the study arms. The threshold utilized to define TMB-high status for the analysis was 10 mutations per megabase.

“We focused on the TMB because it has been shown to be a predictor of response to immune checkpoint inhibitor therapy and it is relevant to a neoantigen vaccine product—theoretically, if you have a higher TMB, there will be more neoepitopes to target,” said presenting author Ryan Sullivan, MD, associate director of the Melanoma Program at Mass General Cancer Center and associate professor at Harvard Medical School.

Reduction in the risk of recurrence
The vaccine-pembrolizumab combination led to a similar reduction in the risk of recurrence or death in patients with high and low TMB (35% and 41%, respectively).

“Patients who were treated with the combination of vaccine and pembrolizumab had better outcomes than those treated with just pembrolizumab, independent of their TMB,” Sullivan said.

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.”

The association between this treatment approach and TMB will be further explored in upcoming planned studies. Additional analyses are ongoing to identify biomarkers potentially associated with better outcomes, including gene expression profiles and PD-L1 expression.

“The relevance of this study is the impact it could have not just for melanoma patients but for other cancers as well,” Sullivan said. “From a general cancer therapeutic standpoint, this is a potential major breakthrough.”

According to Weber, one limitation of the KEYNOTE-942 trial is that, although randomized, it is a phase IIb study with modest statistical power.

“Overall, it is a small number of patients, and one has to be cautious with the interpretation of the results,” Weber said. “A larger, phase III randomized study to confirm our findings will begin soon.” Additional limitations include relatively short follow-up time and some setbacks, including cancer vaccine shortage, during the COVID-19 pandemic.

According to Sullivan, a technical limitation of the neoantigen vaccine approach is that it is based on DNA and RNA sequencing of tumor tissue, therefore it may not be applicable to patients with earlier-stage disease, whose tumors may be smaller and not provide enough tissue.

Ongoing development
mRNA-4157/V940 in combination with pembrolizumab was granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA) for the adjuvant treatment of patients with high-risk melanoma following complete resection. The FDA granted Breakthrough Therapy Designation based on positive data from the Phase 2b KEYNOTE-942/mRNA-4157-P201 trial.

In addition, in early April 2023, the combination was also granted Priority Medicines (PRIME) scheme designation by the European Medicines Agency (EMA) for the adjuvant treatment of patients with high-risk stage III/IV melanoma following complete resection. The EMA granted PRIME scheme designation based on positive data from the Phase 2b KEYNOTE-942/mRNA-4157-P201 trial.**

“Prime scheme designation for mRNA-4157/V940 in combination with pembrolizumab highlights the potential promise of individualized cancer treatments in a population with limited alternatives,” noted Stephen Hoge, M.D., Moderna’s President.

“There is a high unmet need for therapies in melanoma, as it can be a life-threatening condition where available therapies may not be sufficiently effective in a significant proportion of patients.”

“This milestone underscores the potential for personalized approaches to help improve outcomes for people living with certain types of melanoma,” concluded Eric H. Rubin, senior vice president, global clinical development, Merck Research Laboratories. “We look forward to working with the EMA, in collaboration with Moderna, to advance our clinical development program for mRNA-4157/V940 in combination with pembrolizumab.

Technology platform
One of the key advantages of the mRNA technology platform being developed by Moderna, is that it allows for novel, investigational medicines that combine in a single mRNA therapy several different approaches to activate the immune system to attack cancer, either with mRNA encoding for common tumor proteins found across cancer types or multiple mRNAs encoding for various immunomodulatory proteins. This approach helps researchers to revolutionize drug development, and create potential mRNA treatments in shorter periods of time for previously untreatable and emerging diseases.

* Known as MSD outside of the United States and Canada.
** The Priority Medicines (PRIME) scheme designation is a regulatory mechanism run by the European Medicines Agency (EMA) that provides support for the development of medicines that target an unmet medical need. Through PRIME, the EMA offers early and proactive support to help optimize the generation of robust data on a medicine’s benefits and risks and speed up the development and evaluation of medicines applications, with the objective of helping patients benefit as early as possible from therapies that may significantly improve their quality of life.

Clinical trials
An Efficacy Study of Adjuvant Treatment With the Personalized Cancer Vaccine mRNA-4157 and Pembrolizumab in Participants With High-Risk Melanoma (KEYNOTE-942) – NCT03897881

Highlights of Prescribing information
Pembrolizumab (Keytruda®; Merck & Co) [Prescribing Information]

[1] Khattak A, Carlino M, Meniawy T, Ansstas G, Medina T, Taylor MH, Kim KB, McKean M, Long GV, Sullivan RJ, Faries M, Tran T, Cowey C, Pecora A, Segar J, Atkinson V, Gibney GT, Luke J, Thomas S, Buchbinder E, Hou P, Zhu L, Zaks T, Brown M, Aanur P, Meehan RS, Weber JS. A personalized cancer vaccine, mRNA-4157, combined with pembrolizumab versus pembrolizumab in patients with resected high-risk melanoma: Efficacy and safety results from the randomized, open-label Phase 2 mRNA-4157-P201/Keynote-942 trial. In: Proceedings of the 114th Annual Meeting of the American Association for Cancer Research; 2023 April 14-19; Orlando, FL. Philadelphia (PA): AACR; 2023. Abstract nr. CT001
[2] Sullivan RJ, Carlino M, Weber JS, Meniawy T, Taylor MH, Kim K, McKean M, Long GV, Faries M, Cowey CL, Pecora A, Gibney GT, Luke J, Thomas S, Sehgal V, Feldman I, Aanur P,  Brown M, Meehan RS, Robert-Tissot C, Khattak A. mRNA-4157, a personalized cancer vaccine, in combination with pembrolizumab, demonstrates trend for improved recurrence free survival compared to pembrolizumab alone in adjuvant melanoma patients across tumor mutational burden subgroups.In: Proceedings of the 114th Annual Meeting of the American Association for Cancer Research; 2023 April 14-19; Orlando, FL. Philadelphia (PA): AACR; 2023. Abstract nr CT224 / 14.

Featured image: The AACR 2016 Annual Meeting in New Orleans, LA, Photo courtesy: 2016 – 2023 © AACR/Scott Morgan. Used with permission

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