Regulatory Decision Summary for Keytruda

Authorization was based on the results of a Phase III, randomized, double-blind, placebo-controlled, multicenter trial (Keynote-716) designed to assess the efficacy and safety of pembrolizumab versus placebo in the adjuvant treatment of patients with Stage IIB or IIC melanoma following complete resection. A total of 976 patients were randomized (1:1) to receive pembrolizumab (n = 487) or placebo (n = 489). This included one pediatric patient in each treatment arm. Adult patients were treated with 200 mg of pembrolizumab intravenously every 3 weeks. Pediatric (12 years and older) patients were treated with 2 mg/kg (up to a maximum of 200 mg) of pembrolizumab intravenously every 3 weeks.

The study met its primary objective of demonstrating a statistically significant and clinically meaningful improvement in Recurrence-Free Survival (RFS) compared to placebo in all randomized patients. The median Recurrence-Free Survival (RFS) was not reached in either treatment arm. The estimated hazard ratio (HR) was 0.65, representing a 35% reduction in the risk of recurrence or death with pembrolizumab.

The most commonly reported adverse events (AEs) in at least 15% of patients treated with pembrolizumab in Keynote-716 were fatigue, diarrhea, pruritus, rash, and hypothyroidism. Other common adverse events (AEs) were arthralgia, headache and hyperthyroidism. All of these adverse events (AEs) are known adverse reactions that are associated pembrolizumab. Adverse events (AEs) of special interest reported were similar to the established pembrolizumab monotherapy safety profile, and consisted of immune-mediated endocrinopathies, mainly hypothyroidism. Most were low Grade (Grades 1-2). No new safety signals were identified. Overall, the safety of pembrolizumab is well characterized and manageable. The risks and management strategies have been adequately communicated in the Product Monograph.

The inclusion of the pediatric population, 12 years of age or older, was based on an extrapolation of the results observed in adult patients with Stage IIB or IIC melanoma to pediatric patients with the same disease. The mechanism of action of pembrolizumab is expected to be similar for pediatric and adult melanoma patients. Extrapolation was justified based on a rationale outlining the similarities of the adult and pediatric Stage IIB and IIC melanoma, similarities in clinical pharmacology, and the observed safety of pembrolizumab, administered at the recommended dosage regimen of 2 mg/kg once every 3 weeks, as observed in pediatric patients. Based on the assessment of the totality of evidence, it was recommended that the authorization of pembrolizumab include pediatric patients 12 years of age and older.

The recommended dose regimen of Keytruda for adult patients is 200 mg administered as an intravenous infusion every 3 weeks or 400 mg administered as an intravenous infusion every 6 weeks. The recommended dose for pediatric patients (12 years and older) is 2 mg/kg (up to a maximum of 200 mg) every 3 weeks. For both adult and pediatric patients, it is recommend that treatment continue until disease progression, unacceptable toxicity, or for up to 12 months (1 year).

Overall, the benefit/risk profile of the pembrolizumab therapy is considered positive for adult and pediatric (12 years and older) patients with Stage IIB or IIC melanoma following complete resection.