[ASCO2024] Moderna's individualized neoantigen therapy shows broad efficacy in cancer treatment

CHICAGO, Ill. -- By Lee Han-soo/Korea Biomedical Review correspondent -– Moderna, in collaboration with Merck, also known as MSD outside of the U.S. and Canada, has unveiled promising data from their phase 2b KEYNOTE-942/mRNA 4157-P201 study during the ASCO 2024 Annual Meeting.

This study evaluates Moderna’s mRNA-4157 (V940), an individualized neoantigen therapy (INT), in combination with Keytruda, MSD’s anti-PD-1 therapy, for patients with resected high-risk melanoma.

With an extensive follow-up of nearly three years, the combination therapy has shown significant and sustained improvements in recurrence-free survival (RFS) and distant metastasis-free survival (DMFS), providing a new potential in cancer treatment.

Against this backdrop, Korea Biomedical Review interviewed Moderna's Head of Development of Oncology and Therapeutics, Kyle Holen, to delve deeper into these findings and their implications for the future of oncology.

Holen started by explaining the core concept behind mRNA-4157 (V940) and how it enhances the efficacy of immune checkpoint inhibitors like Keytruda.

"Immune checkpoint inhibitors were a major breakthrough in oncology, effectively unleashing T cells to target cancer cells,” Holen said. “However, these T cells often lack precise direction, which can lead to immune-related adverse events.”

Moderna’s individualized neoantigen therapy (INT) trains T cells to specifically target cancer cells, providing a more precise and effective treatment approach, he added.

Highlights from the KEYNOTE-942/mRNA 4157-P201 study

The phase 2b study enrolled patients with high-risk melanoma who had undergone complete surgical resection. These patients were randomized to receive either the combination of mRNA-4157 (V940) and Keytruda or Keytruda alone.

The results, presented at the 2024 ASCO Annual Meeting, were compelling.

"The combination therapy reduced the risk of recurrence or death by 49 percent and the risk of distant metastasis or death by 62 percent compared to Keytruda alone," Holen shared. "These findings confirm the substantial benefits we observed in our earlier analysis."

Additionally, the study revealed an improvement in overall survival (OS), with a 2.5-year OS rate of 96 percent for the combination therapy compared to 90.2 percent for Keytruda alone.

Holen emphasized the importance of these results by stating that every endpoint that the company evaluated has shown dramatically positive outcomes, indicating a real impact on patients' lives.

Commercialization and future trials

Looking ahead, Holen discussed the ongoing phase 3 INTerpath-001 trial and Moderna's commercialization plans.

"We are actively enrolling patients in our phase 3 trial and expect full enrollment by the end of the year," he said. "Our commercialization timeline depends on regulatory approvals, and we are in active discussions with regulators worldwide."

When asked if there are any unique manufacturing challenges given the personalized nature of mRNA-4157, Holen explained the intricate process.

"We take a tumor sample and perform whole exome sequencing and RNA-Seq to identify unique mutations and neoantigens,” he said. “This data is fed into a proprietary algorithm that predicts which proteins will elicit the strongest immune response and then synthesize an mRNA vaccine targeting the top-ranked 34 neoantigens, put them in an mRNA, wrap it in LNP, and deliver it to the patient."

Despite the complexity, Moderna has streamlined this process to deliver treatments within six weeks.

"Currently, our manufacturing is based in the U.S., but we have been able to ship globally without significant delays," Holen said. “That may change in the future; we might not be able to manufacture it all in the U.S. if the capacity increases.”

However, the company has not made any decisions in terms of expanding, he added.

When asked if the six-week manufacturing process could delay treatment, Holen emphasized that Moderna’s studies are conducted in the adjuvant setting, meaning there hasn't been a significant delay in starting treatment as it begins after surgical recovery.

“However, I imagine if someone has metastatic cancer that's growing quite rapidly, that might be a setting where someone wouldn't be able to wait four to six weeks for their therapy,” he said. “As a result, we do have to be careful which indications we think we might move forward.”

Holen also expressed optimism about the potential of INT to treat a wide range of cancers.

"INT is not limited to any specific type of cancer,” he said. “We are exploring its use in cutaneous squamous cell carcinoma, bladder cancer, renal cell carcinoma, lung cancer, and more.”

The flexibility of INT, driven by its ability to target cancer-specific mutations, opens up possibilities across various cancer types, he added.

Notably, for blood cancer, Holen stressed that he believes INT can provide a safer alternative to traditional chemotherapy, particularly in early-stage cancers where patients might benefit from a less toxic treatment option.

Another significant area of interest is how INT can improve outcomes for patients with specific genetic mutations, such as EGFR mutations, which often pose challenges for traditional immunotherapies.

"We've looked at various types of patients,” he said. “We've examined those with high and low tumor mutational burden (TMB), high and low tumor inflammatory scores, different HLA haplotypes, BRAF status, and ctDNA positive.”

So far, the company has yet to find a subgroup where INT does not provide a benefit, he added.

This broad efficacy across various genetic backgrounds and tumor characteristics underscores the versatility and potential of INT.

"It's possible that future studies might reveal a subgroup that does not respond as well, but our current data is very promising," Holen said.