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Moderna, Merck data support claim of cancer vaccine’s promise

An experimental vaccine may help stop tumors from recurring in people with a common form of skin cancer, detailed results from a mid-stage study run by biotechnology company Moderna show.

The data, from a Phase 2 trial testing Moderna’s vaccine alongside Merck & Co.’s immunotherapy Keytruda, are being presented at the American Association for Cancer Research annual meeting in Orlando. They’ve been eagerly anticipated since Moderna and Merck said the study succeeded in December, as they suggest a shot made from messenger RNA could amplify the effects of immune-boosting drugs often used to treat cancer.

Collectively known as checkpoint inhibitors, Keytruda and other drugs like it have changed the outlook for people diagnosed with melanoma since their arrival more than a decade ago.

“Around 10 to 12 years ago, there were no therapies that could extend a patient with melanoma’s life,” said Alexander Huang, an oncologist with the University of Pennsylvania. Checkpoint inhibitors can be curative for some people, he added.

While checkpoint inhibitors were initially approved for patients whose cancer had metastasized, drugmakers have more recently tested them earlier, before patients’ cancers spread and become more difficult to treat. Keytruda, for example, is now prescribed in the “adjuvant” setting, when it’s given after surgery to delay cancer’s return. Its approval was based on study data showing treatment reduced the risk of death or recurrence by 43% when compared to placebo.

Merck aims to improve on that benefit by adding Moderna’s vaccine. Code-named mRNA-4157, the personalized shot is designed to spur immune responses against protein targets identified in samples of a patient’s tumor. Merck acquired an option to Moderna’s program in 2016 and last year paid the biotech $250 million to license rights.

The results disclosed at AACR help to show why Merck was willing to make that investment.

In the study, 157 patients were randomized two-to-one to receive either Keytruda and the vaccine or Merck’s drug alone. To qualify for the study, patients’ cancer had to have spread from the skin to a lymph node prior to surgery. Participants also needed to be judged at high risk of recurrence because of their tumor’s size or other characteristics.

Patients who received Keytruda and mRNA-4157 received nine doses of the vaccine — one shot every three weeks — and up to 18 doses of Keytruda given 21 days apart.

Trial investigators tracked whether the combination reduced the risk of death or cancer recurrence following surgical removal of a tumor. This measure, known as “recurrence-free survival,” was evaluated after all patients completed 12 months on the study and at least 40 had progressed or died.

In December, Moderna and Merck reported the Keytruda-mRNA-4157 combination reduced the risk of recurrence or death by 44% compared to Keytruda alone.

Data revealed for the first time Sunday add important new details. In the group taking the combination, 24, or 22.4%, experienced disease recurrence or died after one year, compared to 20, or 40%, of those who only received Keytruda. Additionally, 79% of patients taking the combination were alive and cancer-free after 18 months, versus 62% of Keytruda recipients.

Adverse events classified as “Grade 3” — medically significant, but not immediately life threatening — or higher occurred among 25% of trial participants given the combination, versus 18% of those on just Keytruda.

The most common Grade 3 adverse event attributed to Moderna’s shot was fatigue, and the vaccine didn’t worsen the immune-related side effects associated with drugs like Keytruda.

Huang, who isn’t involved with the trial, believes melanoma treatment could again change if these types of results are replicated in further testing. “The fact that there are much better outcomes than the standard of care is extremely promising,” he said.

Still, Moderna’s results drew some skepticism when they were summarized by the companies in December. The 44% difference in recurrence-free survival was calculated as statistically significant, but researchers used a type of analysis that doesn’t account for the possibility that Keytruda might have performed better. The approach led to criticism from observers, although it was prespecified as part of the trial’s design.

Eric Rubin, an oncologist who serves as Merck’s vice president of clinical oncology, said that kind of analysis is typical of Phase 2 trials meant to be “signal finding.” A Phase 3 trial set to start by the end of this year will be more rigorous, he added.

In the meantime, the findings could renew optimism about the potential for cancer vaccines. Past attempts have resulted in shots capable of stimulating an immune response, yet that failed to help patients, Huang said. This led large drugmakers like GSK to back away from the field, while biotechs like Vical, Celldex Therapeutics and Oncothyreon reported high-profile study failures.

Moderna’s vaccine is different. It uses messenger RNA technology to encode for up to 34 “neoantigens,” or unique proteins derived from cancer cell mutations, to turn disease-fighting T cells against tumors.

Researchers hypothesize the approach may lead to better outcomes. “Looking at only one antigen may not be sufficient to stimulate the full power of the immune system,” Rubin said.

Huang holds a similar view. “That’s part of the reason why this particular vaccine is so compelling,” he said.