Interim data from cohort B of KEYNOTE-555, a phase I trial evaluating a 400 mg every 6-week dosing regimen of pembrolizumab (Keytruda) in patients with metastatic melanoma, was presented at the American Association for Cancer Research (AACR) Annual Virtual Meeting 2020, held from April 27-28, 2020.1
The preliminary pharmacokinetic, efficacy, and safety analyzed from this cohort validated the findings from the model-based assessment, of which a consistent benefit-risk profile was demonstrated for a dosing regimen of 400 mg every 6 weeks compared to the 200 mg (or 2 mg/kg) dosing every 3 weeks.
“This offers convenience and flexibility to both patients and providers, the need for which is particularly exemplified by the current COVID-19 pandemic,” Mallika Lala, PhD, associate principle scientist for the quantitative pharmacology and pharmacometrics group at Merck, the developer of the agent, said in a plenary session at AACR.2
In this ongoing trial, researchers are evaluating the alternative dosing regimen of 400 mg every 6 weeks for up to 2 years in a total of 101 patients with unresectable stage III or IV melanoma. Of the overall cohort, 37 patients had complete cycle 1 pharmacokinetic data available for interim analysis. Observed concentration-time profiles from cycle 1 were compared with predictions from the model, which was based on 2,993 patients from 5 clinical trials across tumors types.
The primary endpoint for cohort B is overall response rate (ORR), and secondary endpoints include pharmacokinetics, progression-free survival (PFS), and safety. There is also an additional exploratory endpoint of immunogenicity.
The observed concentrations for 400 mg every 6 weeks were found to be well within the 90% prediction intervals of simulated concentrations using the model. Further, the geometric mean of observed trough concentration at 6 weeks (Ctrough) at 400 mg every 6 weeks was 14.5 ug/mL, which is 18% lower than at 200 mg every 3 weeks (18.1 ug/mL) and 11% higher than at 2 mg/kg every 3 weeks (13.4 ug/mL). The geometric mean of observed peak concentration at the end of infusion at 400 mg every 6 weeks was 136 ug/mL, which is below (38% lower) the highest clinically tested dose of 10 mg/kg every 2 weeks (220 ug/mL).
Additionally, the ORR of KEYNOTE-555 cohort B was found to be comparable to the ORR in previous pembrolizumab studies in metastatic melanoma, suggesting similar efficacy between the regimens dosing at every 6 weeks and at every 3 weeks. Moreover, the safety of the 6-week regimen was comparable to the extensive safety profile of pembrolizumab that has been observed in over 12 tumor types.
“The totality of available clinical data validates the inference of a consistent benefit risk between the 400 mg Q6 week and 200 mg Q3 week regimens in all treatment settings of pembrolizumab as indicated previously by model-based assessments,” said Lala.
Merck resubmitted a supplemental biologics license application to the FDA supported by the KEYNOTE-555 data.3 The alternative dosing regimen of 400 mg every 6 weeks was just approved by the FDA across all adult indications as a monotherapy or in combination with other agents.
Markets including the European Union (EU), Australia, and New Zealand have also approved the 400 mg every 6-week dosing regimen based on pharmacokinetic modeling and simulation.
1. AACR. CT042 - Pembrolizumab 400 mg Q6W dosing: First clinical outcomes data from Keynote-555 cohort B in metastatic melanoma patients. AACR website. Published April 28, 2020. abstractsonline.com/pp8/#!/9045/presentation/10751. Accessed April 29, 2020.
2. AACR. Immunotherapy Clinical Trials 2. AACR website. Published April 28, 2020. aacr20.onlineeventpro.freeman.com/live-stream/15335381/Immunotherapy-Clinical-Trials-2. Accessed April 29, 2020.
3. Merck. 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, 2019. mrknewsroom.com/news-release/oncology/fda-approves-mercks-keytruda-pembrolizumab-use-additional-recommended-dose-400. Accessed April 29, 2019.