A personalized mRNA melanoma vaccine seems to cut recurrence or death by 42% in Merck and Moderna’s Phase 3 trial

A vaccine built from each patient’s own tumor seems to have kept melanoma from returning in more people than standard treatment alone, according to the companies. On Thursday, Oct. 22, Merck and Moderna announced detailed results from their Phase 3 INTerpath-001 trial, which pairs Moderna’s personalized mRNA therapy, intismeran autogene, with Merck’s immunotherapy drug Keytruda (pembrolizumab). According to the companies, the combination cut the risk of the cancer coming back or of death by 42% compared with Keytruda alone, after a median follow-up of 24.6 months.

The trial enrolled 1,137 people whose high-risk melanoma, stage IIB to IV, surgeons had fully removed, according to the Merck release; the trial’s registry entry still shows an estimated enrollment of 1,089. Researchers randomly assigned them, two to one, to receive either the vaccine plus Keytruda or a placebo plus Keytruda. Patients in the vaccine arm got 1 mg of intismeran every three weeks for up to nine doses, alongside 400 mg of Keytruda every six weeks for up to nine cycles, the release says. Each dose of intismeran carries mRNA coding for up to 34 neoantigens, markers found in a patient’s cancer cells but not in healthy cells, which the companies select using information from each patient’s tumor and normal DNA, the release says.

The headline numbers come from the companies. At two years, 82.2% of patients on the combination remained alive without recurrence, against 70.0% on Keytruda alone, the release says, a hazard ratio of 0.58. The combination also cut the risk of distant metastasis, the cancer spreading elsewhere in the body, or death by 38%, with two-year rates of 88.5% versus 80.2%. The companies add that the two arms showed comparable results in the first six months (a hazard ratio of 0.99), but that after the six-month immunization course, a pre-specified analysis found a 58% cut in the risk of recurrence or death. A separate analysis that left out patients who never got a dose of intismeran or placebo found a 49% cut.

Some numbers remain missing. Overall survival data “are not yet mature, but a favorable trend in OS with intismeran plus KEYTRUDA has been observed,” the companies write, and the study continues. Karen Knudsen, chief executive of the Parker Institute for Cancer Immunotherapy, told Scientific American that the findings do not yet include overall survival. “Did people who got the vaccine live longer than people who didn't? And what was their quality of life?” she asks, while calling the results “really encouraging.” Merck and Moderna say The New England Journal of Medicine has accepted the full results for publication, and that “we are engaging with regulatory authorities.”

Side effects seem broadly similar between the arms, according to the companies. Treatment-related adverse events hit 95.8% of patients on the combination and 90.0% on Keytruda alone, and grade 3 to 5 events hit 14.2% versus 13.4%, the release says. The most common: fever (52.2%), injection-site pain (51.0%) and fatigue (38.5%). BioSpace reports eight deaths in the treatment arm, and says five came before patients had received intismeran while the other three got no attribution to the vaccine. Dr. Hussein Tawbi, a trial investigator at MD Anderson Cancer Center, told CNBC: “This is a huge development for our patients.”

The rollout did not go as planned. The data had a slot for Saturday at the European Society for Medical Oncology congress, which Ars Technica places in Madrid, but, according to Ars Technica, “an oncology news site reported the results early, breaking the embargo,” so the companies released them on Thursday. Scientific American says the data “leaked on social media,” and BioSpace says the leaked results “were quickly removed after the erroneous posting.” Merck’s release carries a time stamp of 2:59 p.m. EDT.

Investors seem to have wanted more. Moderna shares dropped as much as 25% on Thursday, CNBC reports, while BioSpace says the stock fell 21% to $193.65 and Merck fell just over 1%. BioSpace, citing RBC Capital Markets, writes that investors had hoped for a result close to the hazard ratio of 0.51 seen in an earlier Phase 2 study, which left 0.58 “at the low end of expectations.” Ars Technica notes that a five-year Phase 2 trial had shown a 49% cut in the risk of recurrence or death. Still, BMO Capital Markets analyst Evan Seigerman wrote in a research note, according to CNBC: “We assert this relative reduction in recurrence/death is clinically meaningful.” CNBC also reports that Moderna shares had risen more than 530% this year as of Thursday afternoon.

Company leaders frame the result as a turning point. Dean Y. Li, president of Merck Research Laboratories, calls INTerpath-001 “one of the most significant advances in melanoma treatment since the advent of immunotherapy,” according to the release. Moderna chief executive Stéphane Bancel says the results “reinforce our conviction that mRNA has the potential to fundamentally change how we treat cancer.” Li struck a more cautious note with CNBC about other cancers: “Knocking one tree does not give you a cabin or a village.” The companies say they run nine Phase 2 and Phase 3 trials of intismeran, including three Phase 3 trials in non-small cell lung cancer.

This desk read the companies’ release, the trial registry and five news reports; it did not see the full trial data, which Ars Technica and BioSpace say had a Saturday presentation slot, and it relied on Merck and Moderna for every efficacy and safety figure above.