Moderna and Merck's mRNA vaccine cuts melanoma recurrence or death by 42% in phase 3

Moderna and Merck said their phase 3 INTerpath-001 trial met its primary endpoint of recurrence-free survival and a key secondary endpoint of distant metastasis-free survival. The companies announced top-line results in August and presented the detailed data at the European Society for Medical Oncology congress in Madrid on 24 October.

The trial enrolled 1,137 patients with completely resected stage IIB to IV cutaneous melanoma who had not received prior systemic therapy. Patients were randomized 2:1 to receive intismeran autogene, 1 mg every three weeks for up to nine doses, plus pembrolizumab for about a year, or pembrolizumab alone.

At a median follow-up of 24.6 months, the combination reduced the risk of recurrence or death by 42% compared with pembrolizumab alone, with a hazard ratio of 0.58 (95% CI 0.45 to 0.75), according to the ESMO presentation. It reduced the risk of distant metastasis or death by 38%, with a hazard ratio of 0.62 (95% CI 0.45 to 0.85). At two years, 82.2% of the combination group were alive without recurrence versus 70.0% on pembrolizumab alone.

The results leaked and spread on social media on Thursday, prompting the companies to release an early look, Scientific American reported. STAT reported the 42% figure that day. Overall survival data were not mature, according to the ESMO presentation.

The trial will continue to evaluate overall survival and other secondary endpoints, the companies said.

What the result means

The companies said this is the first positive phase 3 result for an mRNA-based cancer treatment and for an individualized neoantigen therapy. Intismeran autogene is made from each patient's tumor. Up to 34 tumor-specific neoantigens are encoded into one mRNA. It is given after surgery to attack cancer cells left behind, not to prevent cancer.

Melanoma is the deadliest form of skin cancer. More than 330,000 people were diagnosed worldwide in 2022 and more than 58,000 died, Technology Networks reported.

The result builds on the phase 2b KEYNOTE-942 trial in 157 patients, which reported a 49% reduction in recurrence or death at five years (HR 0.51, 95% CI 0.294 to 0.887). In that trial, 68.8% of the combination group remained cancer-free at five years versus 49.1% on pembrolizumab alone, NYU Langone Health reported. The phase 3 reduction is smaller than the phase 2b figure, but the phase 3 trial enrolled 1,137 patients versus 157.

Safety and the control arm

In the phase 3 trial, the most common side effects were fever and injection-site pain, and grade 3 or higher adverse events occurred in 23.6% of the combination group versus 20.3% in the control group, according to the ESMO presentation. The companies said no new safety signals emerged.

The trial measured the added benefit of the vaccine on top of standard immunotherapy, because the control arm also received pembrolizumab. Pembrolizumab alone is a standard adjuvant treatment after surgery for high-risk melanoma, but many patients still see the disease return.

What comes next

The results have been accepted for publication in the New England Journal of Medicine, Merck and Moderna said, though the peer-reviewed text has not been made public. The companies said they were engaging with regulatory authorities.

Moderna shares soared as much as 147% on the day of the August announcement, and Merck rose about 13%, NBC News reported. AJMC reported that Moderna added roughly $40 billion in market capitalization. Scientific American reported that the October data triggered a drop in Moderna's stock.