In a phase III 3475A-D77 study, overall exposure and trough concentration of subcutaneous pembrolizumab were non-inferior to those of intravenous pembrolizumab; furthermore, similar efficacy and consistent safety profiles were found between the subcutaneous and intravenous treatment arms, each administered in combination with platinum-doublet chemotherapy in patients with previously untreated, metastatic squamous and non-squamous non-small cell lung cancer (NSCLC).
The immunogenicity of subcutaneous pembrolizumab was low, and local injection-site adverse events were infrequent, mild, and non-serious. Injection administration time was notably short with the potential to reduce time demands in the clinic according to Dr. Enriqueta Felip of the Vall d’Hebron University Hospital in Barcelona, Spain and colleagues, who published the findings on 27 March 2025 in the Annals of Oncology.
Pembrolizumab administered by intravenous infusion is approved globally for the treatment of multiple tumour types, including NSCLC. Pembrolizumab administered subcutaneously would have the potential to increase convenience for patients and providers, increase patient satisfaction, and improve clinic efficiency, the authors wrote in the background.
MK-3475A is pembrolizumab with berahyaluronidase alfa (MK-5180), a variant of human hyaluronidase developed for subcutaneous administration. Berahyaluronidase alfa acts as a permeation enhancer that temporarily degrades hyaluronan in the extracellular matrix surrounding the injection area, increasing dispersion and enabling subcutaneous administration of pembrolizumab.
The phase I 3475A-C18 study assessed the bioavailability, pharmacokinetics, safety, and tolerability of subcutaneous pembrolizumab in patients with advanced or metastatic melanoma, renal cell carcinoma, and NSCLC; the study results informed the selection of the pembrolizumab dose and the subcutaneous pembrolizumab solution strength, subcutaneous pembrolizumab 790 mg at 165 mg/mL once every 6 weeks for further clinical development.
In the phase III open-label 3475A-D77 study, patients with newly diagnosed stage IV squamous or non-squamous NSCLC without sensitising EGFR, ALK, or ROS1 alterations were randomised 2:1 to subcutaneous pembrolizumab 790 mg every 6 weeks or intravenous pembrolizumab 400 mg every 6 weeks for 18 cycles, each given with platinum doublet chemotherapy.
Dual primary endpoints were pharmacokinetics exposure measures of cycle 1 area-under-the-curve (AUC0-6wks) and steady-state trough concentration (Ctrough) of pembrolizumab. The non-inferiority margin for AUC0-6wks and Ctrough geometric mean ratios (GMR) of subcutaneous pembrolizumab versus intravenous pembrolizumab was specified as 0.8. Secondary endpoints included additional pharmacokinetics exposure measures, pembrolizumab immunogenicity, efficacy, and safety.
A total of 377 patients were randomised, of whom 251 to subcutaneous pembrolizumab and 126 to the intravenous pembrolizumab arm. Median time from randomisation to data cut-off on 12 July 2024 was 9.6 months (range, 6.2-16.4). Median injection time for subcutaneous pembrolizumab was 2.0 minutes (range, 1-12). The GMR (96% confidence interval [CI]) for cycle 1 AUC0-6wks was 1.14 (1.06-1.22; p < 0.0001). The GMR (94% CI) for steady-state Ctrough was 1.67 (1.52-1.84; p < 0.0001).
Secondary pharmacokinetics endpoints were within established bounds for pembrolizumab. Anti-pembrolizumab antibodies were detected in 1.4% of patients in the subcutaneous pembrolizumab arm and 0.9% in the intravenous pembrolizumab arm. For the subcutaneous versus intravenous pembrolizumab arms, objective response rates (ORR) were 45.4% versus 42.1% (ORR ratio 1.08; 95% CI 0.85-1.37). Other efficacy measures were similar and safety profiles were consistent between treatment arms.
The authors concluded that the overall exposure and trough concentrations of subcutaneous pembrolizumab were non-inferior to those of intravenous pembrolizumab. The study results demonstrate that subcutaneous pembrolizumab is a treatment option for all indications where intravenous pembrolizumab can be used, with the potential to improve the patient experience and reduce time demands in the clinic, which may streamline treatment centre workflows and reduce healthcare resource utilisation.
This study was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Reference
Felip E, Rojas CI, Schenker M, et al. Subcutaneous Versus Intravenous Pembrolizumab, in Combination With Chemotherapy, for Treatment of Metastatic Non–Small Cell Lung Cancer: The Phase 3 3475A-D77 Trial. Annals of Oncology; Published online 27 March 2025. DOI: 10.1016/j.annonc.2025.03.012