Adjuvant Pembrolizumab Extends DMFS in Resected Stage IIB/IIC Melanoma

Adjuvant treatment with pembrolizumab (Keytruda) showed improvement in distant metastasis-free survival (DMFS) in patients with resected stage IIB and IIC melanoma, meeting a secondary end point of the phase 3 KEYNOTE-716 trial, according to interim analysis results announced in a press release by Merck.¹

The difference in DMFS between the pembrolizumab arm and the placebo control arm was a hazard ratio (HR) of 0.60 (95% CI, 0.49-0.73; P < .001).

“Patients with melanoma that has spread to distant sites have a significantly worse prognosis and the goal of adjuvant therapy is to delay disease recurrence, especially distant metastases,” said Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, in a press release. “In KEYNOTE-716, adjuvant treatment with Keytruda first showed a significant improvement in recurrence-free survival and has now demonstrated a significant improvement in the time until the first diagnosis of a distant metastasis compared to placebo. The distant metastasis-free survival data from KEYNOTE-716 reinforce the evidence for Keytruda as adjuvant therapy in stage IIB and IIC melanoma.”

KEYNOTE-716 (NCT03553836) is a randomized, double-blind study of approximately 976 patients aged 12 years or older are randomly assigned to receive either pembrolizumab or placebo. The primary end point of the study is recurrence-free survival (RFS), and the secondary end points include DMFS, overall survival, the incidence of adverse events (AEs), and the incidence of discontinuations.

In part 1, pediatric patients in the pembrolizumab arm will be dosed with 2 mg/kg of the agent by intravenous (IV) infusion every 3 weeks (Q3W) for up to 17 cycles. Adult patients will receive a 200-mg dose of pembrolizumab by IV infusion Q3W for up to 17 cycles. A matching placebo is administered in the placebo arm in part 1. Patients who finish 17 cycles of placebo and experience disease recurrence may be eligible to receive pembrolizumab.²

In part 2 of the study, all patients will receive up to 17 cycles of pembrolizumab for local/distant recurrence following disease resection or up to 35 cycles of pembrolizumab for unresectable disease recurrence. Those with distant metastasis who undergo complete resection will receive 17 cycles of pembrolizumab but are permitted to receive up to 35 cycles of pembrolizumab for certain reasons.

Data for the primary end point were previously announced at the European Society of Medical Oncology Congress 2021. A 35% reduction in the risk of disease recurrence or death was observed with pembrolizumab versus placebo (HR, 0.57; 95% CI, 0.46, 0.70; P < .001). At a median follow-up of 14.4 months, patients treated with pembrolizumab had an 11.1% recurrence rate compared with a rate of 16.8% in the placebo arm. At 12 months, the RFS rate was 90.5% with pembrolizumab versus 83.1% with placebo.³

Safety data shows that pembrolizumab lead to grade ≥3 any-cause AEs in 25.9% of patients compared with 17.1% of patients in the placebo arm. Grade ≥ 3 treatment-related AEs occurred in 16.1% of the pembrolizumab arm compared with 4.3% of the placebo arm, and these events lead to treatment discontinuation in 15.3% versus 2.5%, respectively. There were no deaths because of AEs or treatment-related AEs in the pembrolizumab arm, but 4 AE-related deaths occurred in the placebo arm. There were also immune-mediated AEs in the study occurring in both the pembrolizumab arm and the placebo arm including hypothyroidism (15.7% vs 3.5%), and hyperthyroidism (10.4% vs 0.6%). Most of the immune-mediated AEs were low grade.

_REFERENCES:

_{1. Merck’s Keytruda® (pembrolizumab) demonstrated significant improvement in distant metastasis-free survival (DMFS) compared to placebo as adjuvant therapy for patients with resected stage IIB and IIC melanoma in phase 3 KEYNOTE-716 trial. News release. Merck. March 7, 2022. Accessed March 7, 2022.}

_{2. Safety and efficacy of pembrolizumab compared to placebo in resected high-risk stage ii melanoma (MK-3475-716/KEYNOTE-716). Clinicaltrials.gov. Accessed March 7, 2022.}

_{3. Luke JJ, Rutkowski P, Quierolo P, et al. LBA3_PR - Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: Efficacy and safety results from the KEYNOTE-716 double-blind phase III trial. Ann Oncol. 2021;32(suppl_5): S1283-S1346. doi: 10.1016/annonc/annonc741}