Patients with resected high-risk stage III melanoma had significantly longer recurrence-free survival (RFS) when given adjuvant pembrolizumab than those given placebo, according to results from the EORTC 1325/KEYNOTE-054 trial.1,2

The trial randomly assigned patients with completely resected stage III melanoma to 200 mg pembrolizumab every 3 weeks (514 patients) or placebo (505 patients) every 3 weeks for 18 doses or until disease recurrence or unacceptable toxicity. With a median follow-up of more than 1 year, pembrolizumab was associated with a 43% decreased risk for recurrence (hazard ratio [HR], 0.57; 95% CI, 0.43-0.74; P < .001) compared with placebo. The 1-year RFS rate was 75.4% for pembrolizumab vs 61.0% with placebo.

The improvement in RFS was seen both in patients with PD-L1-positive tumors (HR, 0.54; 95% CI, 0.42-0.69; P < .001) and in those with PD-L1-negative tumors or undetermined tumor PD-L1 expression.

A New Player

“Melanoma has long been the immunotherapy poster child despite many years with a lack of benefit,” said Brian Gastman, MD, director of Cleveland Clinic Melanoma Program in Ohio. “Now that we are into the PD-1 and PD-L1-based immunotherapies, responses have gotten a lot better with fewer side effects.”

Checkpoint inhibitors first had success in metastatic melanoma. Ipilimumab, a CTLA-4 inhibitor, and pembrolizumab and nivolumab, PD-1 inhibitors, are all US Food and Drug Administration (FDA)-approved for the treatment of unresectable stage III melanoma, stage IV melanoma, and recurrent melanoma.

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“As soon as ipilimumab was approved for stage IV disease, companies began to explore the use of these drugs in the adjuvant setting,” Dr Gastman said.

In 2015, ipilimumab was approved as an adjuvant treatment for melanoma. Two years later, results of CheckMate-238 showed significant improvements in RFS and toxicity with the use of adjuvant nivolumab compared with ipilimumab in this disease setting.3

Meanwhile, SWOG 1404 was launched to investigate the safety and efficacy of pembrolizumab for high-risk resected melanoma. The study is comparing standard-of-care high-dose interferon with pembrolizumab in patients with stage IIIa, IIIb, IIIc, or IV disease.4

“That study took a lot longer and we don’t yet know when results will be presented or published,” said Dr Gastman, an investigator for the SWOG 1404 study.

“What makes [KEYNOTE-054] a little different from CheckMate-238 was that nivolumab in that study was compared with ipilimumab, the best available therapy, not placebo,” Dr Gastman said. “However, what [KEYNOTE-054] did do was look at all stage III disease.”

Dr Gastman pointed out that the FDA has approved adjuvant nivolumab for all stage III disease, but the studies never looked at stage IIIa. In KEYNOTE-054, the benefit from pembrolizumab was similar in patients with stage IIIa, IIIB, and IIIc disease.