Adjuvant pembrolizumab (Keytruda) for resected stage II melanoma significantly prolonged recurrence-free survival (RFS) compared with placebo, according to results from the KEYNOTE-716 trial.

At a median follow-up of 14.4 months, pembrolizumab for resected stage IIB and IIC melanoma decreased the risk of disease recurrence or death by 35% compared with placebo (hazard ratio 0.65, 95% CI 0.46-0.92), with median PFS not reach for either group by the time of this analysis, reported Jason J. Luke, MD, of UPMC Hillman Cancer Center in Pittsburgh.

In addition, there were fewer cases of distant recurrences in patients in the pembrolizumab arm compared with placebo, with a safety profile that was consistent with previous clinical trials, said Luke in a presentation at the European Society for Medical Oncology (ESMO) virtual meeting.

“And all of this data suggests that adjuvant pembrolizumab is an effective treatment option with a favorable benefit/risk profile for patients with high-risk stage II melanoma,” he stated.

But the study leaves oncologists with many unanswered questions, according to ESMO discussant Omid Hamid, MD, of the Angeles Clinic and Research Institute in Los Angeles.

“With a proposed [regulatory] approval, we will have a lot more patients in an earlier time to treat,” he said. “And then questions about how we treat on relapse, and how we treat in the metastatic setting, having exhausted single-agent PD-1. And thoughts about where melanoma therapeutics, and earlier therapy, takes us in other solid tumors that are just coming to the adjuvant PD-1 paradigm.”

In 2019, the FDA approved pembrolizumab for the adjuvant treatment of patients with melanoma with lymph-node involvement of lymph node following complete resection. In April 2021, the agency granted priority review for pembrolizumab for the adjuvant treatment of adult and pediatric (ages ≥12 years) patients with stage IIB or IIC melanoma following complete resection.

Pembrolizumab has been shown in previous trials to prolong RFS and distant metastases-free survival compared with placebo as an adjuvant treatment for stage III melanoma, with a sustained RFS benefit.

KEYNOTE-716 “is the first phase III, randomized, double-blind study of an anti-PD-1 therapy…compared with placebo for patients with resected stage IIB and IIC melanoma,” Luke stated.

In this study, 976 patients (ages ≥12 years) with complete resection of cutaneous IIB or IIC melanoma, and with negative sentinel lymph node biopsy, were randomized 1:1 to either pembrolizumab 200 mg every 3 weeks (2 mg/kg for pediatric patients) or placebo every 3 weeks, with each group receiving 17 cycles of treatment for up to a year. Treatment continued until disease recurrence or unacceptable toxicity.

Prespecified subgroups were comparably matched in terms of age, sex, T-category, and disease stage.

RFS plotted over time with Kaplan-Meier analysis, showed that at 6 months the curves began to separate, resulting in RFS rates of 90.5% for pembrolizumab-treated patients at 12 months versus 83.1% in patients receiving the placebo, Luke reported, and “this was highly statistically significant, with the hazard ratio of 0.65.”

In addition, 54 patients (11.1%) on pembrolizumab had a recurrence compared with 82 patients (16.8%) on placebo. Of those pembrolizumab patients who had disease recurrence, 31 (6.4%) had skin and/or local regional recurrence versus 41 (8.4%) of patients on placebo. Also, 23 patients (4.7%) on pembrolizumab had distant recurrence compared with 38 (7.8%) of patients on placebo.

As for safety, the number of any adverse events (AEs) were similar between the two groups (93% for pembrolizumab vs 89.1% for placebo), while treatment-related AEs were higher in the pembrolizumab group (79.9% vs 60.9%).

“Importantly, grade 3 or 4 AEs, or those that led to discontinuation [16.1% and 15.3%, respectively, in the pembrolizumab arm], are similar to what would be expected with pembrolizumab based on other adjuvant clinical trials,” Luke said.

Immune-mediated AEs occurred in 36.2% of pembrolizumab patients versus 8.4% of placebo patients, with the most common hypothyroidism and hyperthyroidism. Most of these were grade 1 or 2.

Luke and colleagues found that 18.6% of pembrolizumab patients had an AE that required hormonal management, most of which were thyroid events. Approximately 5% of patients had a significant thyroid event (hypophysitis, adrenal insufficiency, type 1 diabetes) requiring hormonal supplementation.

The investigators also assessed global health status/quality of life over time, and found that these scores were similar between the treatment groups at all time points.