Abstract CT035: Pharmacokinetics (PK), safety, and tolerability of pembrolizumab with berahyaluronidase alfa administered subcutaneously Q3W in participants with advanced melanoma

Abstract Background: Pembrolizumab is approved for use across multiple cancers at doses of 200 mg Q3W, 2 mg/kg Q3W, or 400 mg Q6W administered as an intravenous (IV) infusion. Alternative subcutaneous (SC) formulations can provide added convenience and flexibility in the clinic. MK-3475A is pembrolizumab with berahyaluronidase alfa (MK-5180), a variant of human hyaluronidase developed and manufactured by Alteogen Inc., for SC administration of pembrolizumab (hereafter referred to as “pembro SC”). The purpose of this arm of the phase 1, nonrandomized, multi-arm, open-label 3475A-C18 study is to generate the first clinical data for pembro SC administered Q3W, with PK exposure measures as the primary endpoint. PK data will be used to validate model-based predictions and confirm Q3W SC dosing regimen. Methods: In arm 4 of this phase 1 study (NCT05017012), adults with unresectable advanced melanoma received pembro SC 395 mg Q3W for up to 35 cycles. Using serum concentration data collected in cycles 1-6, the primary objective was to characterize the PK profile of pembro SC administered Q3W in cycle 1 and cycle 6 (steady state). Other objectives included the evaluation of anti-drug antibodies (ADA) against pembro SC (secondary), characterization of the safety and tolerability of pembro SC (secondary), and evaluation of the systemic concentrations of and ADA against MK-5180 (tertiary). Results: 44 participants were treated with pembro SC 395 mg. Median (range) age was 60 years (30-89) and 50% were male. Median (range) pembro PK exposure measures in cycle 1 and at steady state were: Cmax 34.1 µg/mL (10.6-63.7) and 80.7 µg/mL (30.9-162); Ctrough 21.1 µg/mL (9.7-40.5) and 54.6 µg/mL (21.7-123); AUC0-3wks 567 µg·day/mL (192-979) and 1446 µg·day/mL (604-3050); Tmax 5 days (2-10) and 4 days (2-8). ADAs against pembro were detected in 1 of 40 (3%) evaluable participants, with no effect on pembro exposure observed. No samples had detectable MK-5180 levels, and ADAs against MK-5180 were not detected. On physical exam, 9 (20.5%) participants had injection site AEs, most frequently erythema (n=4) and injection site reaction (n=2). All injection site reactions were nonserious, grade 1, and effectively managed. Eight (18%) participants had an immune-mediated AE, most commonly hypothyroidism (n=3, 7%). Conclusions: The PK exposures of pembro SC Q3W in this study were generally consistent with model-based predictions and with PK exposures for pembro SC 790 mg Q6W and pembro IV 200 mg Q3W dosing regimens, thereby validating the model and confirming 395 mg Q3W as a dosing regimen for pembro SC. The overall systemic safety profile of pembro SC Q3W was consistent with the known safety profile of pembrolizumab monotherapy. Citation Format: Corlia Coetzee, Richard Khanyile, Graham Cohen, Georgina McAdam, Cathryn Walton, Sze Wai Chan, Bernardo Rapoport, Christian Caglevic, Patricio Yañez, Mallika Lala, Gina Song, Julia W. Cohen, Carlos Rojas. Pharmacokinetics (PK), safety, and tolerability of pembrolizumab with berahyaluronidase alfa administered subcutaneously Q3W in participants with advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT035.