Abstract

Background MK-3475A is pembrolizumab with berahyaluronidase alfa for subcutaneous administration (pembrolizumab SC). The phase 1 study 3475A-C18 (NCT05017012) assessed the pharmacokinetic and safety profiles of pembrolizumab SC. Methods The study had 4 arms that enrolled participants with unresectable or advanced melanoma (arms 1, 2, and 4), metastatic NSCLC (arms 1–3), or advanced or metastatic RCC (arms 1 and 2). Participants received pembrolizumab SC 650 mg Q6W at solution strengths of 165 mg/mL (arms 1 and 3), 130 mg/mL (arm 2), or pembrolizumab SC 395 mg Q3W at 165 mg/mL (arm 4). Key endpoints included pembrolizumab SC bioavailability, pharmacokinetics, immunogenicity, and safety and tolerability. Results 140 participants received study treatment. Across all arms, mean bioavailability of pembrolizumab SC was 61 % (95 % CI, 58 % 64 %; CV%, 22.4 %) and absorption rate was 0.30/day (95 % CI, 0.28–0.32/day; CV%, 43.7 %). Pharmacokinetic exposure, bioavailability, and absorption rate did not differ meaningfully with pembrolizumab SC by solution strength. Treatment-emergent anti-drug antibodies against pembrolizumab and berahyaluronidase occurred in 1 % and 2 % of participants, respectively. Injection site AEs with pembrolizumab SC occurred in 16 % of participants; all were grade 1/2 in severity. Immune-mediated AEs occurred in 41 % of participants in arms 1–3 and 18 % of participants in arm 4. Conclusion Results from study 3475A-C18 informed selection of pembrolizumab SC 790 mg Q6W at 165 mg/mL for further clinical development to ensure that all patients have the appropriate pembrolizumab exposure to derive expected clinical benefit. Arm 4 results provided key clinical data supporting the pembrolizumab SC 395 mg Q3W dosing regimen. Trial registration ClinicalTrials.gov, NCT05017012 © 2025 The Authors.