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Pembrolizumab before and after melanoma surgery boosts outcomes



Giving pembrolizumab (Keytruda) both before and after surgery for advanced melanoma significantly improves event-free survival, show results from the phase 2 SWOG S1801 trial.

The trial involved 319 patients with operable stage IIIB to stage IV melanoma. The investigators found that patients who received pembrolizumab both before and after surgery (i.e., neoadjuvant and adjuvant therapy) fared better than those who received the drug only after surgery: The 2-year event-free survival rates were 72% vs. 49%, respectively.

The research was published in the New England Journal of Medicine, but similar results had already been presented at the European Society for Medical Oncology 2022 annual Meeting.

“It’s not just what you give; it’s when you give it,” said lead author Sapna Patel, MD, in a press release issued by the University of Texas MD Anderson Cancer Center, echoing comments she gave at ESMO 2022.

The study, she continued, “demonstrates the same treatment for resectable melanoma given before surgery can generate better outcomes.”

On the basis of their findings, Dr. Patel, who is associate professor of melanoma medical oncology at the University of Texas MD Anderson Cancer Center, Houston, said that 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.”

The mechanism of action of PD-1 blockade “relies on the presence of preexisting anti-tumor T cells attempting to attack cancer cells,” with the immunotherapy allowing the anti-tumor cells to proliferate and mediate clinical responses.

Resection of the bulk of the tumor is therefore “likely to take away some or even most of the potential anti-tumor T cells that would proliferate after PD-1 blockade,” they write.

Likely to apply also to nivolumab

Approached for comment, Jeffrey S. Weber, MD, PhD, professor of medicine, NYU Langone Medical Center, New York, said that outside of trials, both pembrolizumab and ipilimumab (Yervoy)/nivolumab (Opdivo) are already being used neoadjuvantly.

He thinks that the findings for neoadjuvant and adjuvant pembrolizumab could also apply to nivolumab because “the drugs are quite similar in efficacy.”

Dr. Weber told this news organization that, “even though the S1801 trial was not accepted as a registration trial by the FDA, I think that its results could very well change practice and confirm it for others who already use neoadjuvant therapy for palpable stage III melanoma.”

One question that is being addressed to an extent in the NADINA trial is whether adjuvant immunotherapy can be avoided all together and patients receive only neoadjuvant therapy, although Dr. Weber said, “I doubt that will be the case.”

Study details

In this study, patients were randomly assigned to either surgery followed by 18 doses of adjuvant pembrolizumab, or to receive 3 doses of neoadjuvant pembrolizumab followed by surgery and then 15 additional doses of adjuvant pembrolizumab.

After a median duration of follow-up of 14.7 months, there were 38 events in the neoadjuvant-adjuvant group and 67 in the adjuvant-only group.

“Events” were defined as disease progression, toxic effects, or complications that precluded surgery or the initiation of adjuvant therapy within 84 days of surgery, as well as the inability to fully resect the gross disease, melanoma recurrence, and death.

The team calculated that event-free survival was significantly longer in the neoadjuvant-adjuvant group (P = .004), with 2-year event-free survival at 72% vs. 49% in the adjuvant-only group.

“The benefit of neoadjuvant pembrolizumab was seen across all subgroups of patients,” the investigators note.

At the data cut-off, there were 14 deaths in the neoadjuvant-adjuvant group vs. 22 in the adjuvant-only group, which the researchers say is too few to allow “definitive comparison” in terms of overall survival.

Definitive surgery had been performed in 88% of neoadjuvant-adjuvant patients and in 95% of those assigned to adjuvant-only pembrolizumab. The most common reason for not undergoing surgery was disease progression.

Among the patients for whom safety data were available, 7% in the neoadjuvant-adjuvant group had at least one grade 3 or 4 adverse event related to pembrolizumab, whereas 7% had at least one grade 3 or 4 adverse event related to surgery.

In the adjuvant-only arm, 4% of patients had at least one grade 3 adverse event related to surgery, with no grade 4 adverse events reported.

The rates of grade 3 or 4 adverse events during adjuvant therapy were similar in the two groups, at 12% in patients assigned to neoadjuvant-adjuvant therapy and 14% in those given adjuvant-only pembrolizumab.

“Future studies can explore deescalation strategies for both surgery and adjuvant therapy, as well as approaches for patients whose melanoma does not respond to neoadjuvant therapy,” the researchers commented.

The study was funded by the National Cancer Institute and Merck Sharp and Dohme.

Dr. Patel reports numerous relationships with industry, including with Merck, manufacturer of pembrolizumab; other coauthors also have numerous relationships with industry. Dr. Weber is a regular columnist for this news organization and lists his disclosures in his Weber on Oncology column.

A version of this article first appeared on

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