EU Approves Subcutaneous Pembrolizumab in All Approved Indications

The subcutaneous pembrolizumab formulation received approval in the US in September 2025 and is approved for use in adult patients across all solid tumor indications.

The European Commission has approved a subcutaneous formulation of pembrolizumab (Keytruda) and berahyaluronidase alfa-pmph (Keytruda QLEXTM) in all previously approved indications for pembrolizumab, including unresectable or metastatic melanoma, metastatic nonsquamous non–small cell lung cancer (NSCLC) in combination with pemetrexed and platinum-based chemotherapy, and microsatellite instability-high or mismatch repair deficient colorectal cancer, according to a news release from the developer, Merck.1

Findings supporting the regulatory decision came from the phase 3 3475A-D77 trial (NCT05722015) revealed comparable pharmacokinetic exposure levels between the subcutaneous and intravenous delivery methods in patients with treatment-naive metastatic NSCLC without EGFR, ALK, or ROS1 genomic tumor aberrations. Additionally, the overall response rate (ORR) was similar between both treatment modalities, at 45% (95% CI, 39%-52%) with the subcutaneous formulation and 42% (95% CI, 33%-51%) with the intravenous formulation. Furthermore, no significant differences in overall survival (OS) or progression-free survival (PFS) were observed in the trial.

The approval follows a positive recommendation for the subcutaneous formulation of pembrolizumab by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) in September 2025. This formulation also received approval in the USin September 2025 and is approved for use in adult patients across all solid tumor indications.2

“We are honored to introduce [pembrolizumab/berahyaluronidase alfa], the first and only subcutaneous immune checkpoint inhibitor in Europe that can be administered in 1 minute every 3 weeks or in 2 minutes every 6 weeks,” Marjorie Green, MD, senior vice president and head of Oncology and Global Clinical Development at Merck Research Laboratories, stated in the release on the approval.1 “We are committed to discovering patient-focused innovations for people with cancer like [pembrolizumab/berahyaluronidase alfa], which offers faster administration than [intravenous pembrolizumab], 2 dosing options and allows patients more choices of health care settings where they can receive therapy.”

Patients in the phase 3 3475A-D77 trial were randomly assigned 2:1 to receive the subcutaneous or intravenous formulations of pembrolizumab both given with platinum-doublet chemotherapy.3 In the subcutaneous arm, pembrolizumab was given at 790 mg in the abdominal area or thigh every 6 weeks at a solution strength of 165 mg/mL in addition to berahyaluronidase alfa at 2000 U/mL for up to 18 cycles. Additionally, intravenous pembrolizumab was given at 400 mg every 6 weeks as a 30-minute infusion for up to 18 cycles.

Patients with nonsquamous NSCLC received a maximum of 4 pemetrexed infusions at 500 mg/m2 every 3 weeks with investigators choice of 75 mg/m2 of cisplatin or carboplatin area under the concentration curve (AUC) of 5 every 3 weeks followed by pemetrexed maintenance. Those with squamous NSCLC received up to 4 infusions of carboplatin AUC 5 every 3 weeks with either paclitaxel at 200 mg/m2 every 3 weeks or nab-paclitaxel at 100 mg/m2 on days 1, 8, 15, 22, 29, and 36 of the first 2 treatment cycles.

The dual primary end points of the trial were cycle 1 AUC and steady-state trough concentrations of pembrolizumab. Secondary pharmacokinetic end points included cycle 1 peak concentration, steady-state trough concentrations AUC at week 0 to 6 and peak concentration up to cycle 3, and cycle 1 and steady-state model-based trough concentrations of pembrolizumab. Additional secondary end points included ORR, OS, PFS, duration of response, and safety.

Safety findings revealed a consistent safety profile between the 2 pembrolizumab formulations, with similar incidences of any-grade treatment related adverse effects (TRAEs), grade 3 to 5 TRAEs, and serious TRAEs similar between arms. Dose discontinuations due to TRAEs occurred in 8.4% of the subcutaneous arm and 8.7% of the intravenous arm.

Moreover, 10.4% vs 9.5% of the respective arms experienced AEs resulting in death. A total of 3.6% vs 2.4% of patients died due to TRAEs in each arm.

References

1. European Commission approves subcutaneous administration of KEYTRUDA® (pembrolizumab) for all adult indications approved in the European Union. News release. Merck. November 19, 2025. Accessed November 19, 2025. https://tinyurl.com/mryvhu56
2. FDA approves pembrolizumab and berahyaluronidase alfa-pmph for subcutaneous injection. Release. FDA. September 19, 2025. Accessed November 19, 2025. https://tinyurl.com/4ns5e8j7
3. 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 III 3475A-D77 trial. Ann Oncol. 2025;36(7):775-785. doi:10.1016/j.annonc.2025.03.012