If all goes well, a major advance in preventing the spread of melanoma, the deadliest skin cancer, could be just months away from U.S. Food and Drug Administration approval.

Moderna and Merck announced on Aug. 19 that a major phase 3 clinical trial had tracked with the success of a smaller phase 2 trial whose results the pharmaceutical companies released in early June. Both trials involved patients who had had melanomas surgically removed but were at high risk of the cancer coming back and spreading to other organs.

The clinical trials combined Merck’s pembrolizumab (Keytruda) and Merck and Moderna’s jointly developed intismeran, an investigational, mRNA-based cancer vaccine. While the companies didn’t disclose the phase 3 numbers, the phase 2 results were striking: An average of five years after taking the drug combination for up to a year, those on the combination had a 49% lower chance of recurrence or death than those taking only Keytruda.

Not long ago, Keytruda alone brought a roughly 40% improvement on those fronts over prior melanoma treatments, said Dr. Theresa Medina, an oncologist specializing in melanoma at UCHealth University of Colorado Hospital. Medina, also an associate professor of medical oncology at University of Colorado Anschutz, led the phase 2 trial site at UCHealth, where about 20 patients participated.

“We’re very excited to have this, hopefully, as a future option,” Medina said.

The National Cancer Institute estimates that there will be about 112,000 new melanoma cases in the United States this year, with more than 8,500 deaths from melanoma’s spread to the lymph nodes, lungs, liver, bones, brain, and elsewhere. Colorado residents are at elevated risk given the thinner atmosphere to filter out ultraviolet rays that can lead to skin cancers.

How the Keytruda-intismeran combination works to fight melanoma

Both intismeran and Keytruda are immunotherapies. They work by helping the immune system see invaders — in this case, melanoma cancer cells — that use various tricks to hide from it.

Keytruda, which the FDA approved in September 2014, is a checkpoint-inhibitor immunotherapy. Melanoma and other cancer cells avoid immune system detection in part by producing proteins (PD-L1 and PD-L2) that bind to PD-1 receptors on the surface of immune system T cells. Those receptors normally are important “off” switches that stop T cells from attacking the body’s healthy tissue. Cancers exploit that. Keytruda works by binding to those PD-1 receptors before the cancer cells’ diversionary PD-L1 and PD-L2 proteins do. The T cells are then unblindfolded to the cancer cells and, ideally, attack them.

Intismeran works differently. Just as with Moderna’s mRNA coronavirus vaccine, intismeran sends tiny packets of messenger RNA into healthy cells. Those cells then crank out proteins based on the mRNA’s instructions.

With the coronavirus vaccine, those proteins mimic the COVID-19 spike protein. The immune system learns to recognize the vaccine-driven proteins as invaders, so if immune cells encounter an actual coronavirus, they recognize it and attack quickly, reducing the viral burden and the severity of subsequent illness.

The big difference with intismeran is that it’s tailored to the patient. Tissue from a patient’s surgically removed melanoma tumor goes to a lab, where staff sequence the DNA in the tumor. They look for sections of DNA that ultimately lead to the creation of “neoantigens.” These are proteins that cancer cells produce, but healthy cells don’t, and they end up on the surface of cancer cells. There they act like chemical flags that say, in effect, “I’m a cancer cell.”

How Moderna and Merck target neoantigens with intismeran

Various types of cancer cells produce thousands of different neoantigens, with a given cancer cell averaging about 150 of them. A key early step in making a patient-tailored batch of intismeran involves taking a snapshot, based on tumor DNA, of up to 34 of the neoantigens that tumor cells might produce.

In a process that takes about six weeks, staff then create millions of mRNA strands that will, once injected, cause the patient’s own healthy cells near the injection site to produce legions of proteins that look just like those up-to-34 different types of tumor-cell neoantigens. As with the coronavirus vaccine, the immune system recognizes the free-floating, mRNA-driven neoantigen proteins as invaders and learns to attack the cancer cells that have the actual neoantigens on their surfaces.

The Keytruda-intismeran combination isn’t the first where scientists have tried to combine Keytruda or Opdivo — another effective checkpoint inhibitor immunotherapy — with other drugs, but those trials came up empty, Medina said.

The FDA’s approval decision will hinge on those phase 3 results, Medina said, and potentially also on patient-survival data, which could push approval out years. But there’s precedent for the FDA acting more quickly on a promising drug without that survival-related data: the approvals of Keytruda and Opdivo.

The FDA approved Keytruda, just over six months after Merck filed. Bristol-Myers Squibb waited seven-and-a-half months from their filing to Opdivo’s approval in December 2014.

Since then, the FDA has greenlit Keytruda for more than two dozen types of cancer, and Opdivo for more than a dozen. Merck and Moderna see a similar path for their Keytruda-intismeran combination. They’re already running trials of it for non-small cell lung cancer, kidney cancer, and bladder cancer.

A lot of patients are already asking for this promising melanoma treatment, Medina said.

“I wish it was available now,” she said.