As Keytruda’s 2028 patent cliff looms large, Merck & Co.’s renewed R&D oncology strategy focuses on three strategies. One of those prongs is improving immune responses, a pillar that stars Moderna-shared cancer vaccine mRNA-4157.
“We're undergoing a pretty substantial transformation from a strategy that was focusing on developing Keytruda, which was really the right strategy at the time, obviously,” Eliav Barr, M.D., Merck’s senior vice president, head of global clinical development and chief medical officer, told Fierce Biotech at this year’s American Society of Clinical Oncology (ASCO) conference in Chicago. “But, now, we've pivoted to a multimodality, very diverse pipeline that can be divided into three pillars.”
The first pillar is improving immune response to cancers, an approach that features mRNA-4157 as the “star of the show,” according to Barr. The asset, in combination with Keytruda, leverages the anti-PD-1’s ability to “rev up the immune system.”
“It used to be that cancer vaccines just meant the graveyard of drug development, and everyone would run away from it screaming into the night,” the Merck leader said. “But, now, the world has changed dramatically. And I think that represents a new era.”
During ASCO, Merck and Moderna publicly presented three-year data on the joint cancer vax in a phase 2b trial for resected melanoma. The update comes from KEYNOTE-942, a trial assessing the individualized neoantigen therapy (INT) in combination with Keytruda for 157 patients with high-risk melanoma (stage 3/4) after complete resection.
At a median follow-up of 34.9 months, mRNA-4157 and Keytruda reduced the risk of recurrence or death by 49% compared to Keytruda by itself. This compares to the two-year top-line data that found a 44% recurrence-free survival rate.
“These data are very important, because they provide a strong efficacy and durable efficacy for patients,” Barr said. “This is a therapy designed for immunologic resetting, where you're trying to create anti-tumor immune responses that are very vigorous and can be used for long-term control of the tumor.”
When examining long-term efficacy, the key is to watch for any late relapses that could occur, Barr said. Relapses would indicate that the vaccine’s initial benefit stops or dissipates over time. That hasn’t been the case for mRNA-4157 in KEYNOTE-942.
“If anything, we see continued benefit for patients,” Bar said. “So, I think that the results are very, very encouraging, and allow us to hope that, in patients who've got a good immune response, the likelihood of recurrence is going to be relatively low.”
The vaccine-Keytruda arm did have a slightly elevated adverse event (AE) profile compared to Keytruda by itself, with immune-related AEs occurring among 37.5% of patients receiving the combo and 36% receiving Keytruda only.
The most common AEs attributed to the mRNA-4157 and Keytruda combo were fatigue (60.6%) and injection site pain (56.7%), with most events classified as grade 1 or 2 occurrences.
“This is a relatively well-tolerated drug,” Merck’s CMO said. “I don't think that the adverse experience profile we've seen with this drug warrants, for example, restriction in patient populations that might benefit. The INT is relatively similar to the profile you get with vaccines in general, because they're using the same materials.”
Merck and Moderna are currently enrolling patients “ahead of schedule” for a phase 3 trial assessing the vaccine with Keytruda in high-risk melanoma, according to Barr. The study has an anticipated enrollment of 1,089 patients and a primary completion date set for October 2029.
When asked about a potential biologics license application, Barr underscored the fact that the cancer vaccine is a new intervention.
“Regulators will scrutinize things quite carefully, simply because [it’s] first-in-class, first modality, the first time a cancer vaccine really actually works,” Barr said. “And my suspicion is that they're going to be most comfortable with the idea of a submission based on the phase 3 results.”
Barr said the breakthrough designation mRNA-4157 received in February 2023 allows Merck and Moderna to interact more with the FDA and therefore better understand what the agency may be looking for in a new drug application.
Beyond improving immune responses, the pharma’s second strategic pillar is targeting chemotherapy and other cancer-killing therapies to tumors. Lastly, the third focus is precision targeting therapies, or medicines designed to attack specific mutations in tumor cells that drive growth.