By Deborah Borfitz

July 18, 2023 | Messenger RNA (mRNA) vaccines “personalized” to the genetics of a tumor look promising for improving the treatment of melanomas, based on results of a phase 2 clinical trial recently presented at the American Society of Oncology congress in Chicago. Cancer treatment is moving into a “new, exciting phase” where the right individuals will be treated with the right drug at the right time—"in other words, one drug for one patient,” says Adnan Khattak, clinical professor at Edith Cowan University’s Center for Precision Health in Perth, Western Australia, and an investigator at nearby One Clinical Research.  

The study enrolled 157 participants, about 90% of whom had high-risk stage 3 melanomas, he says. The remainder were resected stage 4 cases. Of these, 50 were treated with standard immunotherapy (pembrolizumab, branded Keytruda by Merck) alone and 107 in combination with the mRNA vaccine (made by Moderna, the trial sponsor). 

Patents in the combination arm of the study had much better cancer-free survival (78.6% versus 62.2% after 18 months) and disease recurrence rates (22.4% versus 40% who died or had their cancer return after two years), Khattak reports. Moreover, after an average of two years, those getting the vaccine saw a 44% lower risk of death or melanoma returning to the same area of the body and a 65% reduction in the risk of death or the cancer recurrence in a different area of the body, with no additional side effects seen. 

In most cases, the vaccine was given with cycle three or four of pembrolizumab, roughly six to nine weeks after the start of treatment, he says. The protocol called for a total of nine doses of the vaccine, since repeated vaccine dosing generates a stronger antitumor immune response leading to better relapse risk reduction. 

The survival rate began to look better in the patient group receiving both immunotherapy and the vaccine after the first 40 weeks, by which time they had received two or three doses of the vaccine, says Khattak. Early relapses happened among all participants.  

Neoantigens—up to 34 of them—are the active ingredient in Moderna’s personalized mRNA vaccines, Khattak says. Tumor and blood samples from patients in the study were sent to a central lab in the United States where whole exome sequencing was done to predict their cancer-specific “fingerprint” that was then encoded into a single-stranded mRNA vaccine and sent to the study site for administration. That vaccine development process typically took between six and eight weeks. 

Prior trials, where patients were treated with pembrolizumab alone, pegged the relapse-free survival rate at about 55%, compared to 38% with placebo, meaning cancer came back in about 45% of cases. “We need better therapies,” says Khattak, “[and] we wanted to take a more personalized approach through a personalized cancer vaccine custom-designed for an individual patient.” 

Further details about the trial are expected to be shared in a “high-impact factor scientific journal,” where the study is currently undergoing peer review, he says. 

Phase 3 Trial 

A large, randomized phase 3 trial is now set to begin this month to confirm findings from the phase 2 study, Khattak says. “At this stage, we [One Clinical Research] hope to be the first site globally to be activated for this study,” he adds, noting that it was the highest recruiting site globally for the phase 2 study.  

The new trial, sponsored by Merck, will be focused on stage 2B; stage 2C; stage 3A, 3B, 3C, and 3D; and resected stage 4 melanoma cases, he continues. The phase 2 study did not include any stage 2B, 2C, 3A, or 3B cases.   

Moderna’s mRNA vaccine used in combination with Merck’s Keytruda received PRIME designation in April from the European Medicines Agency as well as Breakthrough Therapy Designation from the U.S. Food and Drug Administration in February. Both designations are “an attempt to fast-track novel therapies so that they can be provided promptly to deserving patients,” says Khattak. 

Studies of the personalized vaccine approach are planned in lung cancer, kidney cancer, and gastrointestinal cancers, he says. Merck will again be the sponsor.