FDA Approves Updated Dosing Schedule for Pembrolizumab

The FDA has granted an accelerated approval to an updated dosing schedule for pembrolizumab (Keytruda) to include an every-6-weeks option at 400 mg across all indications in adult patients.¹

The new dosage is applicable to all approved single-agent and combination indications for the PD-1 inhibitor, including those in melanoma, Merkel cell carcinoma, gastric cancer, hepatocellular carcinoma, classical Hodgkin lymphoma, and primary mediastinal large B-cell lymphoma. The current standard dosing schedule for pembrolizumab is 200 mg every 3 weeks.

“The important social distancing measures for COVID-19 have created a number of challenges for people with cancer, including keeping to planned treatment schedules,” Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said in a press release. “Today’s approval of an every 6-week dosing schedule for Keytruda gives doctors an option to reduce how often patients are at the clinic for their treatment.”

The approval was supported by pharmacokinetic modeling and simulation data that were presented at the 2018 ASCO Annual Meeting; the trial was designed to determine whether a longer dosing interval would provide better flexibility and accessibility to patients and their healthcare providers.²

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 were 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.

These are some of the indications in adult patients that have been fupdated:

• 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 patients with recurrent locally advanced or metastatic Merkel cell carcinoma;
• Adult patients with refractory classical Hodgkin lymphoma, or who have relapsed after 3 or more prior lines of therapy;
• Adult 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).

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, head and neck squamous cell carcinoma, urothelial carcinoma, microsatellite instability–high or mismatch repair deficient solid tumors, and cervical cancer.

References

1. FDA Approves Merck’s KEYTRUDA® (pembrolizumab) for Use at an Additional Recommended Dose of 400 mg Every Six Weeks for All Approved Adult Indications. Published April 28, 2020. https://bit.ly/3aMyb6w. Accessed April 28, 2020.
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.