FDA approves pembrolizumab for subcutaneous injection for solid tumors

On September 19, 2025, the FDA approved pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex; Merck) for subcutaneous injection across previously approved solid tumor indications of intravenous pembrolizumab in adult and pediatric patients (12 years or older).¹

According to the FDA, the recommended dosage of the subcutaneous formulation is 395 mg of pembrolizumab and 4800 U of berahyaluronidase alfa-pmph every 3 weeks or 790 mg of pembrolizumab and 9600 U of berahyaluronidase alfa-pmph every 6 weeks until disease progression or unacceptable toxicity.

The approval is supported by data from the phase 3 MK-3475A-D77 trial (NCT05722015), in which the subcutaneous formulation of pembrolizumab demonstrated noninferior pharmacokinetics (PK) compared with the intravenous (IV) formulation in patients with treatment-naive metastatic non–small cell lung cancer (NSCLC).²

In total, the open-label, multicenter MK-3475A-D77 trial enrolled 377 patients who were randomly assigned 2:1 to receive either subcutaneous pembrolizumab administered with chemotherapy (n = 251) or IV pembrolizumab in combination with chemotherapy (n = 126). The dual primary end points for the study were cycle 1 area under the curve (AUC) and steady-state trough concentration (C_trough) at cycle 3.

The FDA noted that the trial met its predefined acceptance margin for the PK end points, with the lower boundary of the geometric mean ratios (96% CI for cycle 1 AUC_0-6weeks and 94% CI for cycle 3 C_trough) exceeding the prespecified threshold of 0.8 for comparability.

Specifically, subcutaneous pembrolizumab demonstrated noninferior AUC exposure during the first dosing cycle, with a geometric mean ratio of 1.14 (96% CI, 1.06-1.22; P < .0001). The subcutaneous formulation also showed noninferiority over the IV formulation in steady-state trough concentration, with a geometric mean ratio of 1.67 (94% CI, 1.52-1.84; P < .0001).

Secondary efficacy end points were also comparable between both arms. Overall, the objective response rate was 45.4% (95% CI, 39.1%-51.8%) with the subcutaneous formulation vs 42.1% (95% CI, 33.3%-51.2%) with the IV formulation. The median duration of response was 9.1 months (95% CI, 6.9-not reached [NR]) in the subcutaneous arm vs 8.0 months (95% CI, 7.4-NR) in the IV arm.

Both progression-free survival (PFS) and overall survival (OS) were also comparable. Specifically, the median PFS was 8.1 months (95% CI, 6.3-8.3) in the subcutaneous arm vs 7.8 months (95% CI, 6.2-9.7) in the IV arm (HR, 1.05; 95% CI, 0.78-1.43). The median OS was not reached in either arm (HR, 0.81; 95% CI, 0.53-1.22).

Notably, the median injection time for subcutaneous pembrolizumab (4.8 mL) was 2 minutes. In the phase 3 study, the subcutaneous formulation reduced the time for patients spent in chair and in the treatment room by 49.7% and 47.4%, respectively. The subcutaneous formulation also reduced the total active time spent by health care professionals on treatment preparation, administration process, and patient monitoring by 45.7%.

Grade 3 or higher adverse events were reported in 47% of patients who received subcutaneous pembrolizumab vs 47.6% of patients who received IV pembrolizumab.

The FDA also noted, “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.”

REFERENCES

1. FDA approves pembrolizumab and berahyaluronidase alfa-pmph for subcutaneous injection. FDA. September 19, 2025. Accessed September 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-and-berahyaluronidase-alfa-pmph-subcutaneous-injection

2. Merck’s investigational subcutaneous pembrolizumab with berahyaluronidase alfa demonstrates noninferior pharmacokinetics compared to intravenous (IV) KEYTRUDA (pembrolizumab) in pivotal 3475A-D77 trial. News release. Merck. March 27, 2025. Accessed September 19, 2025. https://www.businesswire.com/news/home/20250327895076/en/Mercks-Investigational-Subcutaneous-Pembrolizumab-With-Berahyaluronidase-Alfa-Demonstrates-Noninferior-Pharmacokinetics-Compared-to-Intravenous-IV-KEYTRUDA-pembrolizumab-in-Pivotal-3475A-D77-Trial