Regulatory Decision Summary for Keytruda

Keytruda (pembrolizumab) is a potent and highly selective humanized monoclonal antibody of the immunoglobulin G4/kappa isotype designed to directly block the interaction between programmed cell death -1 (PD-1) and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumor regression and, ultimately, immune rejection.

Authorization was based on the pre-defined interim efficacy results from an open label single arm pivotal Phase II study in adult patients with rrPMBCL, and from a single-arm supportive study of adult patients with rrPMBCL. In the pivotal study, 53 patients were enrolled, and interim data were obtained in 29 patients for efficacy and 49 patients for safety. In the supportive phase Ib trial in patients with hematological malignancies, a cohort of 21 patients with rrPMBCL was reviewed.

The primary efficacy endpoint was objective response rate (ORR) based on fluorodeoxyglucose positron emission tomography (FDG PET/CT). In the pivotal study, ORR was 41% (95% CI: 24, 61) based on the interim analysis (n = 29), with the median follow-up duration of 6.6 months. For the 12 responders, the median time to first objective response was 2.9 months (range 2.4 to 8.5 months). In the supporting study ORR was 47.6% (95% CI, 25.7%-70.2%) with a median duration of follow-up of 17.1 months.

The promising efficacy results are expected to be confirmed by the final study report including the entire enrolled patient population (n = 53).

The most commonly reported drug-related adverse events in the pivotal trial included neutropenia (18.4%), asthenia (6.1%), hypothyroidism (6.1%), and pyrexia (6.1%). The overall safety profile is comparable to the established Keytruda data from prior clinical trials with other indications. The higher rate of neutropenia in the rrPMBCL patients as compared with the neutropenia rate in other indications was attributed to multiple lines of prior myelotoxic therapy and by prior administration of rituximab and was captured in the product monograph.

Pediatric PMBCL is a rare disease. The assessment of efficacy in pediatric patients is based on extrapolation from the adult rrPMBCL population. Extrapolation is justified based on rationale explaining the similarities of the adult and pediatric forms of PMBCL, a population pharmacokinetic bridging analysis, 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 (n = 87).

The recommended dose regimen of Keytruda administered as an intravenous infusion over 30 minutes every 3 weeks is 200 mg in adults and 2 mg/kg (up to a maximum of 200 mg) in pediatric patients.

This application was reviewed under the advance consideration of the Notice of Compliance with conditions (NOC/c). The market authorization of this NOC/c was granted based on the promising clinical benefit of Keytruda in rrPMBCL patients.