FDA Approval Sought for Extended Pembrolizumab Dosing Schedule for Select Indications

The FDA has accepted 6 supplemental biologics license applications (sBLAs) for review to update the dosing schedule for pembrolizumab (Keytruda) to include an every-6-weeks option at 400 mg over 30-minute infusions.¹ The new dosage would be applicable for the PD-1 inhibitor’s following indications: melanoma, Merkel cell carcinoma, gastric cancer, hepatocellular carcinoma, classical Hodgkin lymphoma, and primary mediastinal large B-cell lymphoma.

If approved, the updated dosing schedule would be available in addition to the standard 200 mg every-3-weeks schedule, which is also administered over a 30-minute infusion. Under the Prescription Drug User Fee Act, the FDA must make a decision on the application by February 18, 2020, stated Merck, the developer of pembrolizumab, in a press release.

In March 2019, the European Commission approved the 400 mg every-6-week dosing schedule in all of pembrolizumab’s single-agent indications, which also include non—small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, urothelial carcinoma, microsatellite instability–high or mismatch repair deficient solid tumors, and cervical cancer.

“We are committed to improving cancer care, which includes identifying ways to ensure patients have a flexible dosing option that may reduce the amount of time they spend receiving treatment,” Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, stated in the press release. “If approved, the 6-week dosing schedule will provide physicians and patients with greater flexibility in their treatment plans across a variety of cancer types, including melanoma where Keytruda is indicated in both the adjuvant and metastatic settings. We look forward to working with the FDA to file additional Keytruda dosing sBLAs later this year.”

A study² evaluating the every-6-weeks dosing was presented at the 2018 ASCO Annual Meeting, highlighting a modeling- and simulation-based method to determine whether a longer dosing interval would provide better flexibility and accessibility to patients and their healthcare providers.

In the trial, 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 (C_avg or AUC) and trough concentration (C_min). Additionally, an exposure-response analysis was conducted to predict overall survival at the longer dosing interval in melanoma and 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.

Data 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 2 dosing regimens are expected to have a similar benefit-risk profile, suggesting that physicians could have the flexibility to dose at a frequency that is personalized toward patients’ needs and/or personal preferences.

For the sBLAs, the dosing schedule would be updated in the following indications:

• 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;
• 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;
• Patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 (CPS ≥1);
• Patients with hepatocellular carcinoma who have been previously treated with sorafenib (Nexavar).

References

1. FDA Accepts Merck’s Supplemental Biologics License Applications for KEYTRUDA® (pembrolizumab) Six-Week Dosing Schedule for Melanoma and Multiple Other Indications. Merck. Published July 9, 2019. https://bit.ly/2LbQtG5. Accessed July 9, 2019.
2. 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.