Adoption of Extended-Interval Dosing of Single-Agent Pembrolizumab and Comparative Effectiveness vs Standard Dosing in Time-to-Treatment Discontinuation

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Abstract
The immune checkpoint inhibitor pembrolizumab, first approved by the US Food and Drug Administration (FDA) in 2014, is a standard treatment for nearly 20 diseases. Registrational pembrolizumab trials administered doses every 3 weeks (standard interval) of 200 mg (flat) or 2 mg per kg (weight based).1 Pharmacokinetic modeling2 led the European Medicines Agency to approve 400 mg every 6 weeks dosing (extended interval) of pembrolizumab in March 2019.1 The FDA rejected a supplemental biologics license application for extended-interval pembrolizumab in February 2020 owing to concern that lower trough concentrations would reduce efficacy.3 However, the FDA reversed course in April 2020, approving extended-interval pembrolizumab after preliminary nonprespecified analysis of KEYNOTE-555 cohort B—a single-arm cohort of patients outside of the US (n = 44) receiving extended-interval pembrolizumab for melanoma—demonstrated response and immune-related adverse event rates approximately equivalent to historic standard-interval controls.4

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