Personalized Cancer Vaccine Cuts Melanoma Relapse Risk by 42 Percent in Landmark Trial

A vaccine designed for one patient alone, built from the cancer inside that patient’s own body, cut the risk of melanoma coming back by 42 percent in a landmark trial. The full results were unveiled October 24 at Europe’s largest cancer meeting.The experimental shot from Moderna and Merck is the first personalized cancer vaccine to succeed in a large final-stage trial, known as Phase 3. Patients with melanoma, the deadliest form of skin cancer, received it after surgery along with Keytruda, a Merck drug that helps the immune system find and attack cancer. They were less likely to see the disease return than patients who got Keytruda alone.After two years, about 82 percent of patients on the combination were still cancer-free, compared with 70 percent on Keytruda alone. The results were presented at the European Society for Medical Oncology congress at Madrid and have been accepted by the New England Journal of Medicine.The milestone matters more because the field has a long record of disappointment.“It’s huge,” an associate professor of medicine at Harvard Medical School, Dr. Ryan Sullivan, tells The New York Sun. “The cancer vaccine field in general has been ongoing for decades and has had a number of false starts, with promising Phase 2 data that never panned out in Phase 3.”A Vaccine Built From One Patient’s TumorSo how does a vaccine made for one patient work, and how close is it to the people who need it?The therapy, intismeran autogene, is not a preventive shot. Researchers sequence a sample of the patient’s tumor to find mutations unique to that cancer. They then manufacture a synthetic mRNA that codes for up to 34 tumor markers, known as neoantigens. Think of them as flags that mark cancer cells as foreign.The aim is to train the immune system to recognize cells carrying those flags, while Keytruda helps it attack the disease more broadly. Every dose is made for one person, using the same class of technology behind the Covid vaccines.The trial, called INTerpath-001, enrolled 1,137 patients with completely resected stage IIB to IV melanoma, meaning surgeons had removed all visible cancer. They were randomly assigned 2:1 to receive the vaccine plus Keytruda or a placebo plus Keytruda.After a median follow-up of about two years, the combination reduced the risk of recurrence or death by 42 percent. It reduced the risk of cancer spreading to distant organs, or death, by 38 percent. About 89 percent of patients on the combination were free of distant spread at two years, compared with 80 percent on Keytruda alone.The benefit did not show up right away. For the first six months, while patients were still receiving their nine doses, the two groups fared about the same. After that, the vaccine group’s risk of recurrence or death fell by 58 percent.Whether patients also live longer is unsettled. Survival data are still immature, and the early trend toward fewer deaths did not reach statistical significance. The trial continues to track it.Side effects were mostly the short-lived kind familiar from other mRNA shots. Fever and injection-site pain each hit about half of patients on the combination. Serious treatment-related side effects ran at about the same rate in both groups, roughly 14 percent. More patients on the combination stopped treatment because of side effects, 14 percent versus about 9 percent. Two treatment-related deaths in the vaccine group were attributed to Keytruda, not the vaccine.An earlier, smaller study had set expectations. A five-year follow-up of 157 patients, presented at the American Society of Clinical Oncology meeting in June, found a 49 percent lower risk of recurrence or death. It also found a 59 percent lower risk of distant spread or death than with Keytruda alone.Dr. Sullivan says the earlier trial “was remarkable for being the first anti-PD-1-based combination in the adjuvant setting to show benefit over anti-PD-1 monotherapy in a randomized trial.”Before the Phase 3 numbers came out, he flagged the questions that mattered: “It will be important to see if the data approximates the Phase 2 data. Is the magnitude of difference similar? Is the safety similar?”The answer is largely yes. In the full trial population, the benefit came in somewhat smaller than the earlier study’s 49 percent. But among patients who received at least one dose as planned, it matched it. Serious side effects were about the same in both groups.The health threat posed by melanoma is serious. About 112,000 invasive melanoma cases and 8,510 deaths are expected in the United States this year, according to American Cancer Society estimates. But the impact of the new treatment may not stop at melanoma.Lung, Pancreas and What Comes NextMerck and Moderna are running nine Phase 2 and Phase 3 trials of intismeran for treatment of melanoma, lung, bladder and kidney cancer. Three of them are Phase 3 lung cancer trials, including one in high-risk stage I disease. The companies also presented early data at Madrid from a small pancreatic cancer study, pairing the vaccine with chemotherapy after surgery.Lung cancer is where a melanoma win could matter most, since melanoma is far rarer.“If there is a significant improvement in recurrence free survival we will be more excited about the upcoming lung cancer studies, as this could be a huge game changer for lung cancer patients undergoing surgery who — despite significant improvements with the advent of immunotherapy in this setting — still have a significant chance, about 50 percent, of the cancer coming back and taking a patient’s life,” the director of the Early Phase Trials Unit and a professor of medicine at the Icahn School of Medicine at Mount Sinai, Dr. Thomas Marron, tells the Sun.In other words, even after surgery and today’s best drugs, roughly half of patients with early lung cancer see it return. A vaccine that lowered that risk would reach far more patients than melanoma does.Pancreatic cancer is a steeper climb. Dr. Marron calls it “a higher bar where no form of immunotherapy has ever helped.” However, he points to early data suggesting that “a similar approach post-operatively in pancreatic cancer works.”A rival pairing, BioNTech and Genentech, is further along with its candidate autogene cevumeran.Pancreatic cancer has a five-year survival rate of about 13 percent. In a Phase 1 trial led by Vinod Balachandran at Memorial Sloan Kettering Cancer Center, eight of 16 treated patients developed an immune response. Seven of those eight were alive at six-year follow-up, according to data presented in April. A randomized Phase 2 trial, IMCODE003, is now testing that vaccine with chemotherapy and immunotherapy against chemotherapy alone after surgery. It has not reported results.In simple terms, pancreatic cancer is among the hardest to treat, and in that small early study the vaccine appeared to teach some patients’ immune systems to keep watch for years. It is far too early to say it works.The path from here, however, is long.The Road to PatientsNo regulator has yet approved the melanoma vaccine. Merck and Moderna say they are now engaging with regulators, the step before agencies such as the Food and Drug Administration review the evidence for approval. The full trial report is slated to appear in the New England Journal of Medicine on November 11. Until approval, the only way to get the vaccine is through a clinical trial, so patients interested should ask their care teams whether one is available to them.Even approval would only start the work of getting it to patients, according to Dr. Sullivan.“The first hurdle is FDA-approval,” he says. After that, the “process for optimizing samples for analysis, chain of ownership of tissue and then the product, will be critically important since every vaccine developed is personalized for individual patients.”The trial offers early clues on that front. The companies manufactured the vaccine successfully for more than 99 percent of patients assigned to it. The median wait from enrollment to first dose was 64 days. But about one in six patients screened for the trial was turned away because their tumor sample was not good enough to build a vaccine from.What is at stake is a new way to keep cancer from returning after surgery, when many patients are most vulnerable. If the numbers hold up, the shot could become an add-on to an established treatment, and researchers could try the same approach in cancers that have resisted immunotherapy.What has to happen next is plain. Regulators must review the data, the trial must show whether patients live longer, and drugmakers must prove they can produce a one-patient medicine reliably and at scale.Skepticism is still warranted. The survival question is open, and the history of cancer vaccines is full of early hopes that faded. Other mRNA cancer efforts have stumbled. On October 13, a BioNTech mRNA therapy for head and neck cancer failed to improve progression-free survival significantly.That setback followed the company’s halt in August of a colorectal cancer trial of its personalized vaccine, given on its own, after more patients died in the vaccine group than in the comparison group.For now, the promise is confined to patients whose tumors have already been removed, a limit Dr. Marron says his own studies share. The aim, he says, is to go further, and “hopefully we will learn a lot from these initial vaccines so that we can eventually identify the optimal way to move these vaccines into the metastatic setting, and into the treatment of other tough-to-treat cancers like pancreatic cancer.”Whatever the survival numbers show, one thing is already settled.“The fact that there is a positive phase 3 trial is an amazing accomplishment and should provide a huge boost to the field in general,” Dr. Sullivan says.

Personalized Cancer Vaccine Cuts Melanoma Relapse Risk by 42 Percent in Landmark Trial

Personalized Cancer Vaccine Cuts Melanoma Relapse Risk by 42 Percent in Landmark Trial

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