New data from Merck and Moderna underscore the phase 2 victory of their therapeutic cancer vaccine, adding momentum to the treatment’s clinical development as the companies prepare to launch a phase 3 trial before the end of the year.
More than three-quarters of patients (78.6%) with high-risk melanoma treated with mRNA-4157 in addition to Keytruda had recurrence-free survival at 18 months compared to 62.2% of patients in the comparator arm, which received Keytruda alone, according to new data presented at the 2023 American Association for Cancer Research (AACR) annual meeting. That equates to a 44% reduction in recurrence or death. There were no grade 4 or 5 side effects due to the mRNA-4157 reported in treated patients. The 157-patient trial was randomized 2:1.
“This is quite a remarkable achievement, and I'm really quite proud to be part of this,” said Eric Rubin, M.D., senior vice president of oncology early development for Merck Research Labs. “In fact, it reminds me a little bit of the early days of Keytruda.”
Merck and Moderna have plans to launch into a phase 3 trial before the end of the year. Rubin wouldn’t comment on previous teases from Moderna’s top brass that the companies were working with regulators on using the accelerated approval pathway, noting only that mRNA-4157's FDA breakthrough designation gives it a leg up.
Originally, Rubin said, the companies were planning on first testing the combination in patients with metastatic lung cancer. But they pivoted to melanoma even though a trial testing mRNA-4157 as an adjuvant therapy could take longer to accrue cases of recurrence. Rubin says that ultimately the move to melanoma was a “really fortuitous decision.”
In fact, Rubin added, data coming from an ongoing, single-arm phase 1 solid tumor trial "doesn't look as promising as what we've seen in the adjuvant melanoma space." That trial remains ongoing, but recruitment ended in February, according to the clinical trial record.
The premise of cancer vaccines—a bit of a misnomer compared to their infectious disease counterparts—is relatively simple. Because cancer is so heterogenous, successful therapies are likely those most tailored to an individual patient and their tumors. That’s exactly what mRNA-4157 does, with the time between drawing a patient's blood for analysis to when the therapy is ready for use being just six weeks, Rubin noted. And mRNA-4157 is designed to be able to encode up to 34 patient-specific tumor neoantigens. That carrying capacity is critical to the current and future clinical program, with Rubin explaining that the plan is to prioritize cancers with high mutational burdens.
The data did, however, also provide a bit of promise for patients with low tumor burdens, albeit with less confidence. The reduction in the risk of recurrence or death was 35% in patients with high tumor mutation burdens (TMB)—defined as 10 or more mutations—compared to 41% for those with lower burdens. Rubin couched that the confidence interval was bigger in the lower mutation burden group.
“I think the feeling is that if you get into TMB low states, you might not be able to get to 34 [neoantigens],” he said. “That’s another reason why I think at least initially, we're going to be interested in tumor types that tend to have higher TMB levels.”
Beyond melanoma, the company is working to circle back and launch a trial in non-small cell lung cancer patients this year. Rubin says next up would be a host of signal-finding studies with additional phase 3s in the next year or two depending on results.