‘A major breakthrough’: Vaccine/medicine combo reveals a novel treatment strategy

Pharma News: Despite remarkable progress in oncology, malignant tumours remain the second leading cause of mortality worldwide. The combination of a personalised vaccine and immunotherapy has revealed a statistically significant improvement in survival for patients with advanced melanoma, according to results presented at the AACR Annual Meeting 2023, held April 14-19.

Moderna’s mRNA-4157/V940, a personalised mRNA-based cancer vaccine, in combination with the MSD’s immune checkpoint inhibitor Keytruda (pembrolizumab) improved recurrence-free survival (RFS) compared with Keytruda alone in patients with high-risk melanoma, and the clinical benefit was observed regardless of the tumour mutational burden (TMB) status.

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

“More recent cancer vaccine approaches have focused on targeting neoantigens originated from individual tumour mutations, which are unique to cancer cells.”

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 Keytruda arm, corresponding to a 44% reduction in the risk of recurrence or death for patients in the combination arm.

“For the first time in a randomised 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.

“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 Dr Ryan Sullivan, associate director of the Melanoma Program at Mass General Cancer Centre and associate professor at Harvard Medical School.

The vaccine-Keytruda 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,” Dr Sullivan said.

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,” Dr Sullivan said.

“From a general cancer therapeutic standpoint, this is a potential major breakthrough.”

One limitation of the KEYNOTE-942 trial is that, although randomised, 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. A larger, phase III randomised 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,” Dr Weber said.

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

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