FDA Approves Subcutaneous Pembrolizumab for Solid Tumors

The FDA has approved pembrolizumab and berahyaluronidase alfa-pmph (subcutaneous pembrolizumab; Keytruda Qlex) for subcutaneous injection for use in adult and pediatric (12 years and older) solid tumor indications approved for the intravenous formulation of pembrolizumab (Keytruda).1

The regulatory decision was supported by findings from the phase 3 open-label 3475A-D77 study (NCT05722015), in which subcutaneous pembrolizumab given in combination with chemotherapy demonstrated noninferior pharmacokinetics compared with the IV formulation plus chemotherapy in patients with metastatic non–small cell lung cancer (NSCLC).2

Findings supporting the approval showed that the trial met the predefined acceptance margin for the pharmacokinetic end points of Cycle 1 AUC0-6 weeks and Cycle 3 (Steady State) Ctrough.1

Efficacy and safety outcomes were comparable between the two treatment arms.2 Objective response rates (ORRs) were 45% (95% CI, 39%-52%) with subcutaneous pembrolizumab plus chemotherapy vs 42% (95% CI, 33%-51%) with IV pembrolizumab plus chemotherapy.1 There were no notable differences in progression-free survival (PFS) or overall survival (OS) between the groups

Previously reported data from the study showed that the median duration of response (DOR) was 9.1 months (95% CI, 6.9-not reached [NR]) vs 8.0 months (95% CI, 7.4-NR), respectively.2

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 NR in both arms (HR, 0.81; 95% CI, 0.53-1.22).

3475A-D77 Study Breakdown

To be eligible for enrollment, patients had to be at least 18 years old with previously untreated stage IV NSCLC lacking sensitizing EGFR, ALK, or ROS1 alterations.3 Additional requirements included an ECOG performance status of 0 or 1 and the absence of pneumonitis or interstitial lung disease.

Participants were randomly assigned in a 2:1 ratio to receive either subcutaneous pembrolizumab at 790 mg every 6 weeks plus platinum-doublet chemotherapy, or intravenous pembrolizumab at 400 mg every 6 weeks plus platinum-doublet chemotherapy. Following 2 initial cycles, patients continued treatment for up to 16 additional cycles of subcutaneous or intravenous pembrolizumab, with pemetrexed maintenance therapy administered to those with nonsquamous histology.

The study’s dual primary end points were cycle 1 area under the curve and steady-state trough concentration at cycle 3. Key secondary end points included immunogenicity, ORR, PFS, and DOR as assessed by blinded independent central review. Other secondary measures included OS, safety and tolerability, and health-related quality of life.

Safety Findings From 3475A-D77

Subcutaneous pembrolizumab demonstrated a safety profile consistent with its IV formulation, with infrequent injection-site reactions reported as mild in severity and nonserious. In the subcutaneous arm, injection-site adverse effects (AEs) occurred in 2.4% of patients and included erythema (0.4%), hemorrhage (0.4%), induration (0.4%), pain (0.4%), and reaction (0.8%).

Any-grade treatment-related AEs (TRAEs) were observed in 90.0% of patients in the experimental arm, including 47.0% of patients with grade 3 or higher TRAEs; 21.1% of AEs were considered serious. Treatment discontinuation due to TRAEs occurred in 8.4% of patients for subcutaneous pembrolizumab and 15.1% for chemotherapy. In the IV arm, any-grade TRAEs occurred in 96.0% of patients, including 47.6% with grade 3 or higher TRAEs; 19.8% of AEs were deemed serious. Discontinuation rates were 8.7% for IV pembrolizumab and 11.9% for chemotherapy.

The most frequent TRAEs reported in at least 10% of patients in the subcutaneous arm included anemia (52.2%), neutropenia (41.8%), thrombocytopenia (28.3%), leukopenia (27.9%), nausea (22.3%), increased aspartate aminotransferase (AST) levels (13.1%), fatigue (13.1%), hypothyroidism (12.4%), increased alanine aminotransferase (ALT) levels (11.6%), and pruritus (10.4%).

In the IV arm, rates of TRAEs were similar and included anemia (64.3%), neutropenia (31.0%), thrombocytopenia (27.0%), leukopenia (25.4%), nausea (21.4%), increased AST levels (9.5%), fatigue (11.9%), hypothyroidism (11.1%), increased ALT levels (10.3%), pruritus (7.9%), alopecia (10.3%), and decreased appetite (15.9%).

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. May 27, 2025. Accessed August 29, 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
3. Felip E, Rojas CI, Schenker M, et al. Subcutaneous versus intravenous pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer: the phase 3 3475A-D77 trial. Presented at: 2025 European Lung Cancer Congress; March 26-29, 2025; Paris, France. Abstract 8MO.