A tweak in timing may make an immune-system therapy much more effective for patients undergoing surgery for advanced melanoma, a new clinical trial has found.
Researchers showed that giving the therapy -- a drug called Keytruda (pembrolizumab) -- both before and after surgery slashed the risk of a melanoma recurrence over the next two years. That was in comparison to the standard approach of giving the drug only after surgery.
The benefit was so substantial that experts said they expect it to change the care of such patients going forward.
The trial, published March 2 in the New England Journal of Medicine, involved patients with "high-risk" melanoma that had spread from the skin to the lymph nodes but was still operable.
In those cases, the standard treatment is to surgically remove as much of the cancer as possible, then give additional therapies to try to wipe out any remaining tumor cells. That often means drugs called PD-1 inhibitors, which include Keytruda.
PD-1 inhibitors are a type of immunotherapy, which refers to any treatment that harnesses the immune system's natural cancer-fighting abilities. PD-1 inhibitors work by taking certain "brakes" off the immune response, freeing up T-cells to seek and destroy tumor cells.
The researchers on the new trial reasoned that starting a PD-1 inhibitor before surgery, rather than waiting until after, would work even better.
Lead researcher Dr. Sapna Patel explained the basic premise: Using the drugs before surgery would unleash the T-cell response when the tumor is still in the body -- which might allow the immune system to better "see" what it's up against, and have a stronger memory of it.
When a PD-1 inhibitor is given only after surgery, Patel said, the immune system is essentially searching for "micrometastases" -- small numbers of cancer cells that have spread beyond the primary tumor that was removed.
"So it's not just what you give, but when you give it," said Patel, an associate professor at the University of Texas MD Anderson Cancer Center, in Houston.
To put that concept to the test, the researchers randomly assigned 313 patients with high-risk melanoma to one of two groups: One went straight into surgery, followed by 18 doses of Keytruda, given by infusion every three weeks; patients in the other group had three doses of the drug before surgery, and then 15 afterward.
Patel stressed that the tactic did not require patients to undergo extra treatment -- just a different ordering of things.
That change, the trial found, proved key.
At the two-year mark, 72% of patients who'd received pre-surgery Keytruda were free of a cancer recurrence. That compared with 49% of patients whose Keytruda doses were delayed until after surgery. (Most trial patients were still alive, so researchers could not gauge whether there was any survival advantage.)
Keytruda can cause side effects like fatigue, muscle pain, diarrhea and skin rash. But splitting the doses to before and after surgery did not increase the risk of those problems, Patel said.
"We do think this is enough evidence to change practice," she said.
"The differences are profound. These results are quite remarkable," said Dr. Michael Postow, chief of the melanoma service at Memorial Sloan Kettering Cancer Center in New York City.
Postow, who was not involved in the trial, said doctors at Sloan Kettering and some other medical centers are already giving immunotherapy before surgery to high-risk melanoma patients. But this trial shows it's more effective than heading straight into surgery.
"Now we can tell patients we have proof that this is better," Postow said.
Dr. Vernon Sondak heads the department of cutaneous oncology at Moffitt Cancer Center, in Tampa, Fla., and was part of the trial.
"These results were better than even the most optimistic person would've predicted," he said.
Sondak, who is a surgeon, said that cancer surgeons and patients alike have the urge to cut the tumor out as soon as possible. And that is, in fact, the longstanding approach in cancer treatment in general.
But these trial findings "change the dynamic," Sondak said: Patients who are nervous about delaying surgery can be reassured that immunotherapy first is more effective at delaying a recurrence.
All of the doctors stressed that the results apply to patients with melanoma that has spread to the lymph nodes. For people with earlier-stage melanoma, surgery is still the go-to.
While this trial used Keytruda, other immunotherapy drugs are also commonly used to treat melanoma. And Postow said it's not yet clear which pre-surgery immunotherapy regimen may be best.
Another question, Sondak said, is whether some patients who have immunotherapy before surgery can skip the course afterward. An international trial is underway to test that idea.
The current study was funded by the U.S. National Cancer Institute and Merck, which makes Keytruda.
More information
The American Cancer Society has an overview of melanoma treatment.
SOURCES: Sapna Patel, MD, associate professor, melanoma medical oncology, University of Texas MD Anderson Cancer Center, Houston; Michael Postow, MD, chief, melanoma service, Memorial Sloan Kettering Cancer Center, New York City; Vernon Sondak, MD, chair, department of cutaneous oncology, Moffitt Cancer Center, Tampa, Fla.; New England Journal of Medicine, March 2, 2023
