Merck, Moderna mRNA Melanoma Therapy Cuts Risk 42%

A cancer treatment built from each patient’s own tumour has passed its first phase 3 test. Merck and Moderna said on 22 October that adding intismeran autogene, an investigational mRNA therapy, to the immunotherapy Keytruda (pembrolizumab) cut the risk of recurrence or death by 42% in people whose high-risk melanoma had been surgically removed, compared with Keytruda alone.

The result, from the INTerpath-001 trial of 1,137 patients with completely resected stage IIB to IV melanoma, is, according to Melanoma Institute Australia, the first time an mRNA cancer treatment, and the first individualised neoantigen therapy, has been proven in a trial of this scale. It is not an approval. Overall survival data are not yet mature, the companies say, and the therapy remains investigational. The full data will be presented at the European Society for Medical Oncology (ESMO) Congress in Madrid on Saturday 24 October and have been accepted by The New England Journal of Medicine.

The headline figure comes from the trial’s primary analysis

After a median follow-up of 24.6 months, the combination reduced the risk of recurrence or death by 42% (hazard ratio 0.58; 95% confidence interval 0.45 to 0.75; two-sided p<0.001), according to the joint release, which went out at 19:59 BST on 22 October. It also cut the risk of distant metastasis or death, the cancer spreading to other organs, by 38% (hazard ratio 0.62).

In plain numbers, 82.2% of patients on the combination were alive and free of recurrence at two years, against 70.0% on Keytruda alone. For distant metastasis-free survival the two-year rates were 88.5% and 80.2%. Neither arm has yet reached a median, which means more than half of patients in each group had not relapsed or died when the data were analysed.

The companies report a split in timing. In the first six months the two arms performed about the same (hazard ratio 0.99). After six months, once patients had completed the immunisation regimen, a pre-specified sensitivity analysis showed a 58% lower risk of recurrence or death (hazard ratio 0.42) and a halving of the risk of distant metastasis or death.

Side effects were broadly similar. Treatment-related adverse events occurred in 95.8% of patients on the combination and 90.0% on Keytruda alone, with severe (grade 3 to 5) events in 14.2% and 13.4% respectively. The most common were fever, injection-site pain and fatigue. The companies say no new safety signals emerged.

Each dose is designed from a single patient’s tumour

Intismeran, also known as V940 or mRNA-4157, is made from a sample of the patient’s tumour. Merck says information from the tumour and from the patient’s normal DNA is used to create an individual “blueprint”, and each therapy is a synthetic mRNA coding for up to 34 neoantigens, the abnormal proteins that mark out that person’s cancer cells. Once injected, those sequences are presented to the immune system to train T cells against the cancer.

Melanoma Institute Australia, whose medical director Professor Georgina Long was the trial’s global principal investigator, calls it a personalised therapeutic cancer vaccine. “We analyse a sample of each patient’s tumour to read its unique neoantigen fingerprint, then create a ‘wanted poster’ of the cancer,” Long said in the institute’s release. Keytruda, by contrast, “is the same drug for everyone”, she said.

Patients in the double-blind trial were randomised two to one. One group received intismeran every three weeks for up to nine doses plus Keytruda for about a year, and the other received a placebo plus Keytruda. Recurrence-free survival was the primary endpoint; distant metastasis-free survival, overall survival and quality of life are among the secondary measures.

Dr Dean Li, president of Merck Research Laboratories, called INTerpath-001 “the first Phase 3 study to demonstrate a clinically meaningful improvement in RFS and DMFS over standard-of-care KEYTRUDA in patients with resected melanoma”. Moderna chief executive Stéphane Bancel called the results “a defining moment for that vision” of cancer treatments matched to each patient’s tumour.

Nine UK hospitals are listed as trial sites

Merck trades as MSD in the UK. The ClinicalTrials.gov record for the study lists nine UK sites, including the Royal Marsden and University College London Hospital in London, Addenbrooke’s in Cambridge, the Churchill in Oxford, The Christie in Manchester, St James’s in Leeds and the Western General in Edinburgh. The record does not say how many UK patients took part. A separate early-stage study of intismeran in pancreatic cancer will be presented at ESMO by David Pinato of London, according to Moderna’s conference announcement.

None of the sources names a UK regulatory filing. Merck says only that “based on these data, we are engaging with regulatory authorities”. Melanoma Institute Australia warns that regulatory review “may take several years, depending on the country”, and says: “Until then the treatment is not available.”

The trial sits within a wider programme of nine phase 2 and phase 3 studies, according to Merck, including three phase 3 trials in non-small cell lung cancer. TSN’s Tech for Good hub tracks other medical advances of this kind, from an AI-designed phage given to a single patient to a King’s College London model that reads ovarian cancer slides for a DNA-repair defect.

The six-month split is the result to watch at ESMO

The pattern in the numbers is as telling as the headline. A hazard ratio close to 1 in the first six months, followed by a much larger effect afterwards, fits the companies’ account that the benefit arrives once the immunisation course is complete. But the 58% figure comes from a sensitivity analysis rather than the trial’s primary endpoint, and clinicians will want to see the full curves before treating it as the real size of the effect. The 42% reduction across all randomised patients is the figure the trial was built to test, and it is a large one.

The absolute gap matters for patients. A 12-point difference in two-year recurrence-free survival means roughly one in eight treated patients avoided a relapse or death over that period who would not have done on Keytruda alone, if the curves hold. The modest rise in side effects, mostly fever and sore injection sites, looks a small price for that.

What the release leaves open is just as important. Survival is the measure that regulators and health systems weigh most heavily, and it is not yet mature. The companies give no turnaround time from biopsy to first dose and no cost, both of which will decide how widely a treatment made for one person at a time can be used. Software that tracks drug programmes is drawing big buyers too, as OpenAI’s purchase of Orchestra Bio showed this week.

The next marker is Saturday afternoon. Long presents the data in ESMO’s first Presidential Symposium at 15:30 BST on 24 October, and Moderna hosts an investor webcast at 18:00 BST the same day, giving investors their first chance to press the company on survival data and timelines.