Background: Pembrolizumab is approved for use across multiple cancers at a dose of 200 mg or 2 mg/kg Q3W or 400 mg Q6W administered as an IV infusion. Alternative subcutaneous (SC) formulations can provide added convenience and flexibility in the clinic. KEYNOTE-555 (NCT03665597) Cohort A is an open-label, phase 1 study examining the relative bioavailability of 2 different concentrations of pembrolizumab SC formulations versus pembrolizumab IV. Methods: Patients with advanced melanoma were randomly assigned to receive (in a cross-over design) 1 dose of pembrolizumab 200 mg IV and 2 doses of pembrolizumab 285 mg SC (one of each SC formulation) during the first 3 treatment cycles; thereafter, all patients receive pembrolizumab IV for up to 2 years. Bayesian analysis of pembrolizumab serum concentration data collected from 31 patients through cycles 1, 2, and 3 in the current study and previously published pembrolizumab IV data were used to characterize the pharmacokinetics (PK) of pembrolizumab SC. Distribution and elimination parameters, time-dependent clearance, and covariate effects from the previously established pembrolizumab IV PK model were used, as these phases were expected to be similar for IV and SC administrations. Injection site reactions were evaluated by monitoring patients for local skin reactions approximately 1 hour after pembrolizumab SC or IV administration during the first 3 cycles, and through use of a pt questionnaire following monitoring. Results: The model simultaneously described pembrolizumab PK after IV and SC administrations. The SC absorption was characterized by a first-order absorption rate with lag time and bioavailability parameters. The PK of both pembrolizumab SC formulations were similar with an estimated bioavailability of 64% (95% CI, 54-74); this is consistent with the reported bioavailability of other SC monoclonal antibodies that range from 50% to 85%. Inclusion of a covariate effect of the SC formulation on bioavailability, lag time, or absorption rate was not statistically significant, indicating no significant difference between the 2 SC formulations in the absorption phase. In addition, no anti-drug antibody was observed after 3 treatment cycles. In general, pembrolizumab SC formulations were well tolerated over the first 3 cycles, with no significant injection-site reactions. Two grade 2 adverse events (AEs) of pruritus and rash were reported from the SC formulations and IV infusion, respectively; the other AEs were grade 1. Conclusions: The bioavailability of SC pembrolizumab was characterized from KEYNOTE-555 Cohort A data. SC formulations will be further assessed clinically in other tumor types.

Citation Format: Conrad R. Jacobs, Bernardo Leon Rapoport, Graham Lawrence Cohen, Mallika Lala, Carolina De Miranda Silva, Pavan Vaddady, Ferdous Gheyas, Dinesh de Alwis, Vikram Sinha, Omobolaji Oyekunle Akala, Elliot Chartash, Lokesh Jain. Pembrolizumab bioavailability after subcutaneous administration: analysis from the KEYNOTE-555 Cohort A in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT143.