Scot Ebbinghaus, MD
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for a new extended dosing schedule for pembrolizumab (Keytruda) for all of the PD-1 inhibitor’s monotherapy indications in the European Union.1
The recommendation supports a new suggested dose of single-agent pembrolizumab at 400 mg every 6 weeks delivered as an intravenous (IV) infusion over 30 minutes. If approved by the European Commission, the every-6-weeks dose would be available in addition to the currently indicated dose of 200 mg every 3 weeks that is infused over 30 minutes.
The European Commission will now review the CHMP’s opinion, and a final decision on a marketing authorization is expected in the second quarter of 2019, according to Merck, the developer of the checkpoint inhibitor.
“Merck remains committed to improving the lives of people living with cancer, which includes the pursuit of innovative options for administering Keytruda to address the unique needs of patients and healthcare providers,” said Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories. “Importantly, the positive CHMP opinion supports the approval of a 6-week dosing option across all 8 approved KEYTRUDA monotherapy indications in Europe, spanning 5 cancer types. If approved by the European Commission, the Keytruda 400 mg every 6 weeks dose will provide both physicians and patients with greater flexibility in their treatment plans.”
Results of a study that were presented at the 2018 ASCO Annual Meeting evaluated the 6-weekly dosing schedule of pembrolizumab using a modeling- and simulation-based approach to determine whether a longer dosing interval would provide greater flexibility and convenience to patients and healthcare providers.2
In the study, efficacy of the every-6-weeks dosing schedule was bridged via examining projections of both pharmacokinetic drivers of efficacy, such as the average concentration over the dosing interval (Cavg or AUC) and trough concentration (Cmin). Additionally, an exposure-response analysis was conducted to predict overall survival at the longer dosing interval in melanoma and non–small cell lung cancer (NSCLC) for comparison at the standard 200 mg every-3-weeks dose. Moreover, safety was bridged based on an established exposure-safety analysis anchored on the maximum clinically administered and well-tolerated dose on 10 mg/kg every 2 weeks.
Results showed that the 400 mg every-6-weeks dosing regimen is expected to produce similar efficacy and safety results in all clinical treatment settings where 200 mg (or 2 mg/kg) of pembrolizumab every 3 weeks is currently indicated. Additionally, a PBPK model-based prediction of pembrolizumab tumor target engagement showed that, at 400 mg every 6 weeks, the tumor target engagement profile is similar to that for 2 mg/kg or 200 mg every 3 weeks. All doses maintained target engagement above 90% throughout the dosing interval.
The authors concluded that the 2 dosing regimens are expected to have a similar benefit-risk profile, suggesting physicians could have the flexibility to dose at a frequency that is tailored toward patients’ needs and/or personal preferences.
Pembrolizumab is currently approved by the FDA as a single agent in the following areas:
- First-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression with a tumor proportion score (TPS) ≥50% as determined by an FDA-approved test with no EGFR or ALK abnormalities; Patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy;
- Patients with unresectable or metastatic melanoma;
- Adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection; For the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma;
- Patients with recurrent or metastatic head and neck squamous cell carcinoma with disease progression on or after platinum-containing chemotherapy;
- Patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 with a combined positive score (CPS) ≥10, or in patients who are ineligible for platinum-containing chemotherapy regardless of PD-L1 status;
- Patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant therapy with platinum-containing chemotherapy;
- Patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 (CPS ≥1);
- Adult and pediatric patients with refractory classical Hodgkin lymphoma, or who have relapsed after 3 or more prior lines of therapy;
- Adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma, or who have relapsed following ≥2 lines of prior therapy;
- Adult and pediatric patients with unresectable or metastatic microsatellite instability—high or mismatch repair deficient solid tumors that have progressed on prior treatment and who have no alternative therapy options, or in colorectal cancer that has progressed on treatment with fluoropyrimidine, oxaliplatin, and irinotecan;
- Patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1);
- Patients with hepatocellular carcinoma who have been previously treated with sorafenib (Nexavar).
- European Medicines Agency Adopts Positive Opinion for Merck’s KEYTRUDA® (pembrolizumab) for Six-Week Dosing Schedule Across All Current Monotherapy Indications. Merck. Published March 4, 2019. https://bit.ly/2UkbGP5. Accessed March 4, 2019.
- Lala M, Li M, Sinha V, de Alwis D, Chartash E, Jain L. A six-weekly (Q6W) dosing schedule for pembrolizumab based on an exposure-response (E-R) evaluation using modeling and simulation. J Clin Oncol. 2018;36 (suppl; abstr 306). doi: 10.1200/JCO.2018.36.15_suppl.3062.