Starting pembrolizumab before surgery instead of waiting until after surgery significantly improves the outlook for patients with stage III-IV melanoma.

Patients with high-risk melanoma who received pembrolizumab both before and after surgery had a significantly lower risk of their cancer recurring than patients who received the drug only after surgery.

These results, published today in the New England Journal of Medicine, are from a research study led by the SWOG Cancer Research Network, a cancer clinical trials group funded by the National Cancer Institute (NCI). The findings originally were presented at a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2022.

The study, known as S1801, was led by Sapna Patel, M.D., chair of the SWOG melanoma committee and associate professor of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center.

“It's not just what you give, it's when you give it. The S1801 study demonstrates the same treatment for resectable melanoma given before surgery can generate better outcomes,” Patel says in a news release. “In this case, we used the immune checkpoint inhibitor pembrolizumab. This treatment relies on the presence of pre-existing T cells coming in contact with cancer cells in the body to generate an immune response, and we found that starting treatment before the melanoma is removed – and with it the bulk of tumor-specific T cells – leads to a greater response than giving it after surgery.”

The S1801 researchers hypothesized that there would be a larger anti-tumor immune response and longer immunologic memory if pembrolizumab was administered while the melanoma tumor was still in the body as opposed to after that tumor had been removed, when the immune system would be responding primarily to micrometastatic cancer cells.

To test this hypothesis, S1801 investigators enrolled 345 participants with stage IIIB through stage IV melanoma that was deemed operable. Participants ages 18-90 were randomized to receive either upfront surgery followed by 200 mg of pembrolizumab every three weeks (adjuvant-only) for a total of 18 doses, or to 200 mg of pembrolizumab every three weeks for three doses leading up to surgery (neoadjuvant-adjuvant), then an additional 15 doses following surgery.

The primary endpoint measured was the duration of event-free survival, defined as the time from randomization to the occurrence of one of the following: disease progression or toxicity that resulted in not receiving surgery, failure to begin adjuvant therapy within 84 days of surgery, melanoma recurrence after surgery, or death from any cause.

With a median follow-up of 14.7 months, event-free survival was significantly longer in the neoadjuvant-adjuvant therapy arm, with a hazard ratio of 0.58 when compared to the adjuvant therapy arm, which corresponds to a 42% lower event rate in the patients receiving the neoadjuvant regimen.

“Our study noted a significant improvement in event-free survival in the neoadjuvant regimen compared to the adjuvant regimen,” Patel says. “Importantly, a similar number of patients in both arms experienced events before initiating adjuvant pembrolizumab, but the rate of events after initiating adjuvant therapy was higher (worse) in the adjuvant arm.”

The researchers found that the benefit from neoadjuvant therapy was consistent across a range of factors including patient age, sex, performance status, and stage of disease. They also found that the rates of adverse events (side effects) were similar across both arms of the study and that neoadjuvant pembrolizumab did not result in an increase in adverse events related to surgery.

“Based on the findings from S1801, patients with high-risk melanoma should start immunotherapy prior to surgery to generate an immune response while the bulk of the melanoma and the anti-tumor T cells are intact,” Patel says. “Future studies can explore de-escalation strategies for both surgery and adjuvant therapy, as well as approaches for patients whose melanoma does not respond to neoadjuvant therapy.

Vernon Sondak, M.D. is a study co-author and chair of Moffitt’s Department of Cutaneous Oncology. “The dramatic successes we’ve seen with drug treatments for melanoma have led us to use them earlier and earlier in the patient’s course. Neoadjuvant therapy brings the powerful drugs to bear on the tumor even before surgery and has a lot of potential advantages. But many surgeons were reluctant to put off surgery for fear that the tumor would grow or spread and they would miss the opportunity for surgical cure,” he adds in a news release.

“Our trial results shows that the timing of administration of an immune checkpoint inhibitor relative to surgery can have a large effect on patient outcomes. These new landmark data are practice-changing and will impact how clinicians treat patients with advanced melanoma that can be surgically removed. We have been using neoadjuvant therapy extensively for several years now, but these results exceeded even my lofty expectations,” Sondak says. “The next step is to use neoadjuvant therapy to lessen the amount of surgery patients might need and shorten the length of drug treatment they might otherwise require. We’re working on precisely that right now.”

Study senior author Dr. Antoni Ribas, director of the Tumor Immunology Program at UCLA Jonsson Comprehensive Cancer Center says that this is the first clinical trial demonstrating that neoadjuvant therapy is superior to the same therapy given in the adjuvant setting – after surgery. “This is because it is best to turn on the immune system inside the cancer before it is taken out with the surgery,” he says in a news release.

“Based on this understanding, removing the bulk of the tumor, along with the tumor-infiltrating immune cells contained in the surgical specimen, is likely to take away some or even most of the potential antitumor immune cells that would proliferate after PD-1 blockade,” says Ribas, who was chair of the SWOG Cancer Research Network’s melanoma committee when the study was designed and launched. “Our theory has been – and this study confirms it – that starting anti-PD-1 blocking therapy before surgery could activate more antitumor immune cells and improve clinical outcomes compared with the same amount of drug delivered after the surgery.”

CAPTION

Sapna Patel, M.D.

CREDIT

MD Anderson Cancer Center