Pembrolizumab FDA Applications Resubmitted for Updated Dosing Schedule

Supplemental biologics license applications have been resubmitted to the FDA for pembrolizumab to include an every-6-weeks option at 400 mg over 30-minute infusions across multiple indications.

Merck (MSD) has resubmitted supplemental biologics license applications (sBLAs) to the FDA for an updated dosing schedule for pembrolizumab (Keytruda) to include an every-6-weeks option at 400 mg over 30-minute infusions across all indications in adult patients.1

In February 2020, Merck received a Complete Response Letter (CRL) from the FDA regarding these sBLAs, and these resubmissions address the issues in the CRL, the company explained in a press release.

The new dosage would be 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, which is also administered over a 30-minute infusion.

“The oncology community is rapidly adapting cancer care during the COVID-19 pandemic in order to minimize exposure and keep cancer patients as safe as possible. Now more than ever, we believe it is critical to pursue a 6-week dosing schedule for KEYTRUDA,” Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said in the press release. “We appreciate FDA’s guidance during the resubmission period and look forward to working closely with the agency as they continue their review.”

The sBLAs were 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 (Cmin). 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 would be updated:

  • 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.


  1. Merck Resubmits Supplemental Biologics License Applications (sBLAs) for KEYTRUDA® (pembrolizumab) Six-Week Dosing Schedule. Published April 23, 2020. Accessed April 23, 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.