The FDA approved pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex; Merck) for subcutaneous injection on September 19, 2025, marking a significant advancement in cancer immunotherapy delivery. The approval covers all previously approved solid tumor indications for intravenous pembrolizumab in adult and pediatric patients aged 12 years and older.
Clinical Trial Demonstrates Non-Inferior Pharmacokinetics
The approval is supported by data from the phase 3 MK-3475A-D77 trial (NCT05722015), which enrolled 377 patients with treatment-naïve metastatic non-small cell lung cancer (NSCLC). The open-label, multi-center study randomly assigned patients 2:1 to receive either subcutaneous pembrolizumab with chemotherapy (n = 251) or intravenous pembrolizumab in combination with chemotherapy (n = 126).
The trial's dual primary endpoints were Cycle 1 area under the curve (AUC) and steady-state trough concentration (Ctrough) at Cycle 3. The subcutaneous formulation met predefined acceptance margins for pharmacokinetic endpoints, with geometric mean ratios exceeding the pre-specified threshold of 0.8 for comparability.
Specifically, subcutaneous pembrolizumab demonstrated non-inferior AUC exposure during the first dosing cycle, with a geometric mean ratio of 1.14 (96% CI, 1.06 to 1.22; P < .0001). The subcutaneous formulation also showed non-inferiority in steady-state trough concentration, with a geometric mean ratio of 1.67 (94% CI, 1.52 to 1.84; P < .0001).
Comparable Efficacy Outcomes
Secondary efficacy endpoints were comparable between both treatment arms. The objective response rate was 45.4% (95% CI, 39.1 to 51.8) with the subcutaneous formulation versus 42.1% (95% CI, 33.3 to 51.2) with the intravenous formulation. The median duration of response was 9.1 months (95% CI, 6.9 to not reached) in the subcutaneous arm versus 8.0 months (95% CI, 7.4 to not reached) in the intravenous arm.
Both progression-free survival and overall survival demonstrated comparable outcomes. The median progression-free survival was 8.1 months (95% CI, 6.3-8.3) in the subcutaneous arm versus 7.8 months (95% CI, 6.2-9.7) in the intravenous arm (HR, 1.05; 95% CI, 0.78 to 1.43). Median overall survival was not reached in either arm (HR, 0.81; 95% CI, 0.53 to 1.22).
Significant Reduction in Treatment Burden
The subcutaneous formulation offers substantial practical advantages for patients and healthcare systems. The median injection time for subcutaneous pembrolizumab (4.8 mL) was 2 minutes. In the phase 3 study, the subcutaneous formulation reduced patient time spent in-chair and in the treatment room by 49.7% and 47.4%, respectively. The formulation also reduced total active time spent by healthcare professionals on treatment preparation, administration process, and patient monitoring by 45.7%.
Dosing and Safety Profile
The FDA-recommended dosage for the subcutaneous formulation is 395 mg of pembrolizumab and 4800 units of berahyaluronidase alfa-pmph every 3 weeks or 790 mg of pembrolizumab and 9600 units of berahyaluronidase alfa-pmph every 6 weeks until disease progression or unacceptable toxicity.
Safety profiles were comparable between formulations. Grade 3 or higher adverse events were reported in 47% of patients who received subcutaneous pembrolizumab versus 47.6% of patients who received intravenous pembrolizumab. According to research published in ESMO Annals of Oncology, very few patients developed antibodies against the drug in either group.
The prescribing information includes warnings and precautions for immune-mediated adverse reactions, hypersensitivity and administration-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity.
Dr. Enriqueta Felip, section chief at the Vall d'Hebron University Hospital and head of the Vall d' Hebron Institute of Oncology's Thoracic Tumors Group, concluded that results support subcutaneous Keytruda "as a treatment option in all indications where intravenous Keytruda can be used."
