Cambridge's Moderna and Merck Report Personalized Cancer Vaccine Cut Melanoma Recurrence Risk 42% in Phase 3 Trial

Moderna, the Cambridge-based biotechnology company, and drugmaker Merck have released detailed results from a Phase 3 trial showing that their personalized mRNA cancer vaccine, given with Merck's immunotherapy Keytruda, reduced the risk of melanoma recurrence or death by 42% compared with Keytruda alone in patients whose tumors had been surgically removed, the companies said.

The vaccine, intismeran autogene, also known as V940 or mRNA-4157, also reduced the risk of distant metastasis or death by 38%, according to the companies' announcement. The trial, called INTerpath-001, enrolled 1,137 patients with completely resected stage IIB to stage IV melanoma, according to Healio.

The data had been scheduled for public release during a presidential symposium at the European Society for Medical Oncology Congress in Madrid on Saturday, Oct. 24. After a leak on Oct. 22, the companies released the findings early, Healio reported. CNBC reported that partial data spread on social media Thursday before the companies released the detailed results that day.

Moderna shares fell as much as 25% Thursday before regaining some ground, according to CNBC. The network said the stock had risen nearly 600% this year on optimism about the cancer vaccine, creating more room for disappointment. Investors had hoped the combination would match an earlier Phase 2 trial that showed a roughly 49% reduction in the risk of recurrence or death at five years, RBC Capital Markets analyst Trung Huynh wrote in a note, according to CNBC. Huynh called the Phase 3 results clinically meaningful and likely to support approval, but said the primary efficacy result was at the low end of investor expectations.

Six melanoma specialists told CNBC the results represent a clinically meaningful advance that could become a standard of care for patients who have surgery first and have not received immunotherapy before their operation.

"This has the potential to be a major breakthrough in melanoma treatment and also cancer immunotherapy in general that will open the door to greater outcomes for patients," Dr. Sekwon Jang of Inova Schar Cancer, a principal investigator at one of the trial's U.S. sites, told CNBC. Dr. Michael Postow, chief of the Melanoma Service at Memorial Sloan Kettering Cancer Center, said, "If we can essentially cure more patients with earlier-stage melanoma and never have to deal with unresectable metastatic disease, that's a wonderful advance."

In the trial, 757 patients received 400 milligrams of pembrolizumab, the generic name for Keytruda, by IV every six weeks for nine cycles plus 1 milligram of intismeran by injection every three weeks for up to nine doses, Healio reported. The other 380 patients received pembrolizumab plus a placebo. Treatment lasted about 56 weeks or until the disease progressed or side effects became unacceptable.

At the primary analysis, after a median follow-up of 24.6 months, the hazard ratio for recurrence or death was 0.58, the companies said. Two-year recurrence-free survival was 82.2% in the combination group, compared with 70% with Keytruda alone, and two-year distant metastasis-free survival was 88.5% compared with 80.2%, according to Healio.

The benefit did not appear right away. In the first six months, the combination performed about the same as Keytruda alone, according to the companies. After six months, following the vaccination regimen, a pre-specified sensitivity analysis showed the combination reduced the risk of recurrence or death by 58% and cut the risk of distant metastasis or death by half.

Dr. George Ansstas of Washington University in St. Louis told CNBC the delay may reflect that each vaccine must be custom-manufactured, which can take roughly six weeks, and that the immune system needs time and repeated doses to respond. CNBC noted that explanation is a hypothesis rather than proof. Ansstas also said the Phase 3 trial included some lower-risk patients than the Phase 2 study, which may have tempered the results.

Overall survival data are not yet mature, though the companies said they had observed a favorable trend. Nearly all patients had treatment-related side effects, 95.8% with the combination and 90% with Keytruda alone, according to Healio, while serious adverse events of grade 3 or higher occurred at similar rates, 14.2% and 13.4%. The most common side effects with the combination were fever, injection-site pain and fatigue.

Moderna CEO Stéphane Bancel told CNBC the company is finishing a regulatory filing as it aims for full approval next year. "It's a very, very happy moment for the field, for patients," he said. The companies said the results have been accepted for publication in The New England Journal of Medicine.

Questions remain. The trial tested the vaccine after surgery rather than against immunotherapy given before surgery, an approach increasingly used for eligible patients, so the data do not show whether the vaccine approach is more or less effective than that option, CNBC reported. Dr. Adil Daud of the University of California San Francisco, the lead investigator on the Phase 3 trial, told CNBC that producing an individual vaccine for each patient is labor-intensive. "There is the time and expense, and it's probably going to cost like a lot of money," he said. The companies have not disclosed manufacturing costs.