FDA Issues Complete Response Letter for Updated Pembrolizumab Dosing Schedule

The FDA has issued a complete response letter (CRL) to 6 supplemental biologics license applications (sBLAs) that would have updated the dosing schedule for pembrolizumab (Keytruda) to include an every-6-weeks option at 400 mg over 30-minute infusions across multiple indications.¹

Merck, the developer of the PD-1 inhibitor, stated in a press release that it is reviewing the CRL and will discuss next steps with the FDA. The new dosage would have been applicable for the PD-1 inhibitor’s indications in melanoma, Merkel cell carcinoma, gastric cancer, hepatocellular carcinoma, classical Hodgkin lymphoma, and primary mediastinal large B-cell lymphoma.

Pembrolizumab’s current standard dosing schedule is 200 mg every 3 weeks, which is also administered over a 30-minute infusion.

The sBLA was based on 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 (Cavg 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.

For the sBLAs, the dosing schedule would have been 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).

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. Merck receives complete response letter from the US FDA for supplemental biologics license applications (sBLAs) for Keytruda (pembrolizumab) six-week dosing schedule [news release]: Kenilworth, NJ. Merck. Published February 18, 2020. https://bit.ly/2HzEn5Y. Accessed February 18, 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.