ASCO: Moderna, Merck melanoma vaccine set for phase 3

Moderna’s move into personalised cancer therapy continues to proceed at a rapid pace, with Merck & Co-partnered melanoma vaccine mRNA-4157 heading for a pivotal phase 3 programme after a phase 2b data drop at ASCO.

In the study, mRNA-4157 (V940) – which targets dozens of unique tumour-associated antigens or neoantigens that are expressed by a patient’s cancer cells – was combined with Merck’s PD-1 inhibitor Keytruda and compared to Keytruda alone in patients with high-risk stage 3 or 4 melanoma who were given the therapy as an adjuvant treatment after surgery.

There was a 65% reduction in the risk of distant metastasis or death for the combination compared to Keytruda alone, a key secondary endpoint in the 157-subject KEYNOTE-942 study. At 18 months, distant recurrence or death was seen in 8.4% and 24% of patients, respectively.

In April, the partners reported the first efficacy results from the study, including a 44% improvement in recurrence-free survival (RFS), the study’s primary endpoint, which came in at nearly 79% for the combination and 62% for Keytruda alone at the 18-month timepoint.

Moderna and Merck will start a phase 3 trial of the combination in adjuvant melanoma therapy later this year, and the proof-of-concept for this personalised neoantigen vaccine approach means that studies will follow in other cancers, focusing on those where immunotherapy with drugs like Keytruda is known to have an effect.

The results reinforce the view that after decades of stuttering development, mRNA-based vaccines spanning many neoantigens that can be developed within weeks could usher in a new era of cancer vaccines, supported by checkpoint inhibitors that boost immune responses.

KEYNOTE-942 has already earned the combination a breakthrough designation from the FDA and PRIME status from the EMA, both of which could accelerate the vaccine’s progress through the review process.

Also announced at ASCO was some intriguing new data on circulating tumour DNA (ctDNA) – fragments of genetic material from cancer cells – that can indicate the presence of minimal residual disease (MRD), i.e. the lingering presence of some tumour material.

A subgroup of 125 patients from KEYNOTE-942 had ctDNA measured using NeoGenomics’ RaDaR sequencing assay, and found that most patients (88%) had no ctDNA present at the start of the study. In that group, RFS was higher than for the overall study population, reduced by 78%.

A similar trend was seen in the ctDNA-negative group, although the number of patients here was too low to generate a statistically reliable result. Moderna and Merck said the association between MRD patterns and the effect of mRNA-4157 therapy will be explored in future studies.

Merck took up an option to partner with Moderna on mRNA-4157 last October, its first under a 2016 alliance aimed at finding individually tailored cancer vaccines for patients across a spectrum of cancers. Merck paid $200 million to activate the programme, and another $250 million to license the melanoma vaccine.

Fuelled with the windfall cash from its massively successful COVID-19 shot, Moderna has been accelerating development of its R&D pipeline, focusing on vaccines for other respiratory diseases, including flu, respiratory syncytial virus (RSV), and cytomegalovirus (CMV), as well as therapeutics for cancer, rare disease, and cardiovascular indications.