Merck, Moderna cue up phase 3 trials for mRNA cancer shot

Moderna and partner Merck & Co have fleshed out the data from their clinical trial of personalised mRNA vaccine for melanoma, saying the results support the start of a phase 3 programme.

The two partners have presented updated results from the phase 2b KEYNOTE-942 trial of the mRNA-4157 vaccine, given in combination with Merck’s PD-1 inhibitor Keytruda (pembrolizumab) to patients with advanced melanoma who had surgery to remove the primary tumour, but who were considered at high risk of relapse.

After 18 months’ follow-up of 157 patients, relapse-free survival was 78.6% for a group receiving the vaccine and Keytruda as a combination therapy, compared to 62.2% for Keytruda alone, which was equivalent to a 44% reduction in the risk of recurrence or death.

After two years, the cancer had returned in just over 22% of patients in the combination arm, compared to 40% of those on Keytruda alone, according to new results presented over the weekend at the American Association of Cancer Research (AACR) congress.

“The profound observed reduction in the risk of recurrence-free survival suggests this combination may be a novel means of potentially extending the lives of patients with high-risk melanoma,” commented Dr Kyle Holen, head of development for Moderna’s therapeutics and oncology unit.

“We look forward to starting the phase 3 melanoma trial soon and expanding testing to lung cancer and beyond,” he added.

mRNA-4157 is a personalised vaccine consisting of 34 mRNAs, each targeting ‘neoantigens’ identified by gene sequencing that are thought to be driving a patient’s cancer. The vaccine is designed to prime the immune system to attack the tumour cells, while Keytruda blocks an immunological ‘brake’ that protects the cancer.

A key finding in the study was that the combination seemed to have efficacy regardless of patients’ tumour mutational burden (TMB) – the number of mutations that can provide the neoantigen targets for the individualised vaccine – although Moderna and Merck have suggested there will likely be lower threshold below which the vaccine will be less effective.

Early data from 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.

The key obstacle facing the partners is how the individual production approach can be scaled up so that it could become a viable, affordable option for health systems.

At the moment, the time from a biopsy to harvesting cells for sequencing to the administration of the personalised shot is upwards of eight weeks, and efforts are ongoing to reduce that time to around a month. Access to sequencing could, however, be a major obstacle at the population level.

The plan is to start a phase 3 study in melanoma later this year, and add in a mid-stage trial in non-small cell lung cancer (NSCLC) and preliminary studies to identify other potential indications.