A cancer vaccine made separately for each patient, from the genetic makeup of their own tumor, lowered the chance that melanoma came back or killed them in a large trial. The results were presented at the European Society for Medical Oncology congress in Madrid1. Among people whose melanoma had been removed by surgery, adding the vaccine to the standard immune drug Keytruda (pembrolizumab) cut the risk of the cancer returning or death by 42% compared with Keytruda alone2.
The vaccine, called intismeran autogene (also known as V940 or mRNA-4157), was developed jointly by Merck and Moderna2. The results have been accepted for publication in the New England Journal of Medicine2. The companies first said in August that the trial had met its main goal, without giving numbers3. This is the first time the detailed data have been made public.
What the trial tested
The study, called INTerpath-001, was a Phase 3 trial, the last big stage of testing before a drug can be considered for approval. It enrolled 1,137 adults with stage IIB to IV melanoma, meaning higher-risk or more advanced skin cancer, whose tumors had been fully removed by surgery4. Melanoma makes up only about 1% of skin cancers but causes most deaths from them, and most recurrences show up in the first two to three years after treatment5.
Patients were assigned by chance: 757 got the vaccine plus Keytruda, and 380 got a placebo (a dummy shot) plus Keytruda4. Neither patients nor doctors knew who got which shot4. The vaccine was given every three weeks for up to nine doses, alongside Keytruda every six weeks, for about a year1.
To make each dose, researchers read the genetic code of a patient’s cancer cells, compare it with their healthy cells, and pick out up to 34 changes found only in the cancer6. The vaccine carries mRNA instructions for those changes inside a fatty particle, similar to Moderna’s COVID vaccine1. The idea is to teach the immune system what the patient’s cancer looks like. Keytruda, a type of drug called a checkpoint inhibitor, works differently: it takes the brakes off immune cells so they can attack tumor cells1.
The results so far
After a median follow-up of 24.6 months, the vaccine group had a 42% lower risk of the cancer coming back or death2. In plain numbers, an estimated 82.2% of patients on the combination were alive and free of cancer return at two years, compared with 70.0% on Keytruda alone7.
The combination also lowered the risk of the cancer spreading to distant parts of the body, or death, by 38%2. At two years, 88.5% of the vaccine group were free of distant spread, compared with 80.2% of the comparison group4. Investigators reported a similar benefit in less advanced and more advanced disease4.
The timing of the effect stood out. During the first six months, the two groups did about the same2. After the six-month vaccine course, a planned extra analysis found a 58% lower risk of return or death in the vaccine group2. Moderna’s chief development officer, David Berman, told TIME: “We think it’s because the immune system takes time to be activated”1. Another planned analysis that left out patients who never got a dose of vaccine or placebo as planned found a 49% lower risk2.
Side effects
Fever affected 52.2% of patients on the combination versus 8.2% on Keytruda alone; pain at the injection site, 51.0% versus 9.5%; and tiredness, 38.5% versus 29.7%4. Serious side effects judged to be caused by treatment occurred in 14.2% and 13.4%7. Side effects led patients to stop both treatments in 6.5% and 5.3% of cases4. The companies said no new safety signals were seen2.
What it does not show yet
The trial has not shown that the vaccine helps people live longer. Overall survival data are not yet mature, though the companies say they have seen a favorable trend2. A summary of the conference presentation noted that survival results were not reported in the abstract4. The study is continuing2.
The numbers so far come from the conference presentation and company releases; the full peer-reviewed paper has not appeared yet2. The results also apply only to melanoma that had been fully removed by surgery. Professor Georgina Long, the trial’s principal investigator, said in the companies’ statement that the findings are in that group, while adding that they will help inform research in other tumor types2.
The effect was smaller than in the earlier Phase 2 trial. That study reported a 49% lower risk of return or death and a 59% lower risk of distant spread or death over five years6. Berman told TIME he was surprised the new trial came so close, because it included a broader group of patients1.
Who is behind it
The trial was run by Merck and Moderna, which are developing the vaccine together. Keytruda is Merck’s own drug2. Long, the medical director of Melanoma Institute Australia and a melanoma oncologist at the University of Sydney, led the study and presented the results28. The trial ran at 157 sites around the world8.
Money is a large part of this story. When the companies first announced success in August, Moderna’s stock rose about 177% that day and Merck’s rose more than 12%5. Before the conference, the detailed results became public through an oncology website two days early, breaking the agreed release time4. The companies then put out the data6. Moderna shares fell 21% after the release, as the main result landed at the low end of investor expectations, according to BioSpace reporting cited by AJMC7.
Analysts were split on what it means. RBC Capital Markets called the data clinically meaningful and likely approvable, but questioned the vaccine’s value compared with immune treatment given before surgery, which may work about as well at lower cost7. BMO Capital Markets cautioned against assuming the results will carry over to other cancers7.
How it fits the field
The companies call this the first positive Phase 3 result for a personalized cancer vaccine of this kind and for any mRNA-based cancer therapy3. It uses the same mRNA technology that made the fast development of COVID-19 vaccines possible9. Experts are debating how widely the approach could apply to other cancers9.
That question is open for a reason. Several recent randomized trials testing mRNA vaccines in colorectal cancer and in head and neck cancer did not reduce recurrence8. Berman suggested the results could help explain why only about 30% of cancer patients respond to checkpoint inhibitors, arguing that in many patients the immune system has not learned to recognize the cancer1. That is his interpretation, not something this trial measured.
What to watch next
- The full paper in the New England Journal of Medicine, which will let outside experts check the details2.
- Survival data, as the trial continues to track whether people live longer2.
- Regulators. Merck and Moderna say they are engaging with regulatory authorities2. The vaccine is not available to patients in Australia or the United States, and a review could take several years depending on the country8.
- Other cancers. The companies are testing the vaccine in nine Phase 2 and Phase 3 trials, including three late-stage trials in non-small cell lung cancer7, as well as bladder and kidney cancer3.
