SC vs IV pembrolizumab: Which route is better for metastatic NSCLC?

In patients with treatment-naive metastatic nonsmall cell lung cancer (NSCLC), subcutaneous (SC) pembrolizumab (pembro) demonstrates comparable efficacy to that of intravenous (IV) pembro as regards overall exposure and trough concentration, reports a study presented at ELCC 2025. 

“The [phase III] MK-3475A-D77 study successfully demonstrated that pembro SC was noninferior to pembro IV with respect to cycle 1 overall exposure and steady-state trough concentration (Ctrough) in participants with treatment-naive metastatic NSCLC,” said lead author Dr Enriqueta Felip, Department of Oncology, Vall d’Hebron Institute of Oncology, Barcelona, Spain. 

A total of 377 eligible patients with newly diagnosed stage IV squamous or nonsquamous NSCLC with no sensitizing EGFR, ALK, or ROS1 alterations were randomly allocated 2:1 to either pembro SC 790 mg Q6W (n=251) or pembro IV 400 mg Q6W (n=126) for 18 cycles, in addition to platinum doublet chemotherapy. The median time from randomization to data cutoff (12 July 2024) was 9.6 months. 

The primary endpoints were cycle 1 pembro exposure and Ctrough. The noninferiority margin was set to 0.8. Other endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), safety, and pembro and berahyaluronidase alfa (MK-5180) antidrug antibodies (ADAs). 

The geometric mean ratios for cycle 1 pembro exposure (1.14, 96 percent confidence interval [CI], 1.06–1.22) and for steady-state Ctrough (1.67, 94 percent CI, 1.52–1.84) were above the specified noninferiority margin (p<0.0001 for both). [ELCC 2025, abstract 8MO] 

With regard to the secondary outcomes, the ORR (45.4 percent vs 42.1 percent; ORR ratio, 1.08, 95 percent CI, 0.85–1.37) and the median PFS (8.1 vs 7.8 months; hazard ratio [HR], 1.05, 95 percent CI, 0.78–1.43) did not significantly differ between pembro SC and pembro IV. The median OS was not reached in both arms (HR, 0.81, 95 percent CI, 0.53–1.22). 

“Our findings demonstrate that pembro SC is a treatment option in all indications where pembro IV can be used,” Felip said. 

Safety profile 

Grade ≥3 treatment-related adverse events (AEs) occurred in 47.0 percent of patients in the SC arm and 47.6 percent of those in the IV arm. The discontinuation rate was comparable between the two treatment groups (8.4 percent with pembro SC vs 8.7 with pembro IV). 

In addition, 2.4 percent of patients in the pembro SC arm had injection-site AEs, but these reactions were infrequent, mild in severity, and nonserious. The median injection time for pembro SC was 2 min. 

Pembro ADAs were also noted in 1.4 percent and 0.9 percent of patients in the SC and IV arms, respectively, while MK-5180 ADAs were observed in 1.5 percent of those administered with pembro SC. 

“Pembro SC provides the same proven efficacy and established safety profile of pembro IV while enhancing the patient experience and reducing time demands, potentially streamlining treatment centre workflows and lowering healthcare resource utilization,” Felip said. [ELCC 2025, abstract 33P] 

“Pembro for SC dosing is pembro with MK-5180, a variant of human hyaluronidase developed and manufactured by Alteogen Inc,” she noted.