Moderna and Merck announced Monday that an individualized neoantigen therapy in combination with PD-1 therapy Keytruda blunted the risk of cancer metastasis or death by 65% among high-risk melanoma patients.

The companies shared results on distant metastasis-free survival (DMFS) from the Phase 2b KEYNOTE-942 trial of a treatment featuring mRNA-4157 (V940) plus Keytruda. 

Moderna and Merck said the treatment led to a statistically significant and clinically meaningful improvement in DMFS, a key secondary endpoint, in patients with stage III and IV melanoma who had already undergone complete resection. The trial results are set to be presented Monday afternoon as a late-breaker at the American Society for Clinical Oncology (ASCO).

Moderna’s SVP/head of development, therapeutics and oncology Kyle Holen called the result “exceptional” in DMFS. 

“Patients who experience metastases at distant sites typically have worse survival outcomes and a poor prognosis, thus these results showing a reduction in the risk of distant recurrence underscore the potential of neoantigen therapy,” Holen said in a media release.

Based on the data, and following the positive primary endpoint of recurrence-free survival (RFS) released at April’s American Association for Cancer Research (AACR) meeting, Moderna and Merck reiterated their plan to start a Phase 3 study in the adjuvant setting in patients with high-risk melanoma in 2023. The two organizations also plan to seek expansion into other tumor types, including non-small cell lung cancer.

KEYNOTE-942 is the first ever randomized neoantigen vaccine study with positive clinical outcomes. In April, upon seeing the V940-Keytruda combo’s Phase 2b RFS data in adjuvant melanoma, SVB Securities analyst Mani Foroohar hailed it as “arguably the most significant cancer vaccine study read-out ever” and “a strong and exciting proof-of-concept signal for personalized vaccination.” 

The combo led to clinically meaningful outcomes with a 16.4 percentage point improvement in RFS versus Keytruda alone at 18 months. 

“To place this into context, no other immuno-oncology (IO) agent has demonstrated proven benefit on top of anti-PD(L)1 in the adjuvant setting,” Foroohar explained.

That said, Moderna and Merck face “a longish and complex path” to bring their vaccine to melanoma patients, he cautioned. For one, neoantigen vaccines, like CAR-T, are personalized products, which adds complexity.

In addition, as the first vaccine process/personalized product of its kind to enter registration trials, the field lacks certain baseline information, such as markers of biologic activity which correlate to clinical benefit. 

“It would be very helpful for this study (or others) to provide goal-posts for future development of this and other vaccines: what are we solving for to drive better outcomes (e.g., is there a minimal number of neoantigens or quality of T cell response necessary)?” Foroohar posited.

To that end, later in the day at ASCO, Moderna management plans to present results from an ancillary analysis from the KEYNOTE-942 trial of circulating tumor DNA (ctDNA) monitoring data. The analysis is evaluating ctDNA as a biomarker of RFS in resected high-risk melanoma patients treated with the V940-Keytruda combo. 

Of evaluable patients, 88% were ctDNA negative at baseline and 14.4% of the combination arm were ctDNA positive versus 5.7% in the monotherapy arm. While these data could be a helpful start in helping answer whether ctDNA has prognostic value, the companies said the small sample size of the ctDNA subgroups limits the interpretation of these results.

This marks the latest promising clinical data to emerge from Moderna and Merck.

In December, the two companies announced that a combination of an investigational personalized mRNA cancer vaccine and Keytruda showed efficacy in patients with Stage III/IV melanoma.