Subcutaneous Pembrolizumab Shows Non-inferiority to IV Pembrolizumab for Metastatic NSCLC

Subcutaneous pembrolizumab demonstrated non-inferiority to IV pembrolizumab in patients with metastatic non-small cell lung cancer (NSCLC), according to data presented at the European Lung Cancer Congress 2025.

Enriqueta Felip, MD, PhD, of the Vall d’Hebron University Hospital, presented the findings during a mini oral abstract session that was followed by an invited discussant by Rosalyn Juergens, MD, PhD.

The subcutaneous formulation is comprised of pembrolizumab with berahyaluronidase alfa, which is a variant of human hyaluronidase. The phase 3 open-label MK-3475A-D77 study compared the subcutaneous formulation with the intravenous formulation, plus chemotherapy, in patients with newly diagnosed stage IV squamous or non-squamous NSCLC with no sensitizing EGFR, ALK, or ROS1 alterations.

The study investigators randomly assigned 377 patients 2:1 to receive to subcutaneous pembrolizumab 790 mg every 6 weeks (n=251) or intravenous pembrolizumab 400 mg every 6 weeks (n=126) for 18 cycles, plus platinum doublet chemotherapy. The median time from randomization to data cut-off was 9.6 months (range, 6.2 to 16.4 months).

The dual primary endpoints of the study were cycle one pemrbolizumab area-under-the-curve (AUC_0-6wks) and steady-state trough concentration (C_trough). The non-inferiority margin concerning the AUC_0-6wks and C_trough geometric mean ratios (GMR) of subcutaneous versus intravenous pembrolizumab was specified as 0.8. Secondary endpoints included overall response rate (ORR), progression-free survival (PFS) per RECIST v1.1 by blinded independent central review, overall survival (OS), and safety.

The cycle 1 GMR for AUC_0-6wks was 1.14 (96% CI, 1.06–1.22) and the GMR for steady-state C_trough was 1.67 (94% CI, 1.52–1.84). Both were above the non-inferiority margin with P < 0.0001. Among patients receiving subcutaneous pembrolizumab, the ORR was 45.4%, compared with 42.1% in those receiving intravenous pembrolizumab (ORR ratio, 1.08; 95% CI, 0.85–1.37). The median PFS was 8.1 months in those receiving subcutaneous pembrolizumab, compared with 7.8 months in those receiving intravenous pembrolizumab (hazard ratio [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).

Similar proportions (47% vs 47.6%) of patients receiving subcutaneous and intravenous pembrolizumab had grade 3 or higher drug-related adverse events (AEs), with similar percentages (8.4% vs 8.7%) discontinuing treatment due to drug-related AEs, respectively. Injection site AEs were reported in 2.4% of patients receiving subcutaneous pembrolizumab. The researchers reported that pembrolizumab anti-drug antibodies were detected in 1.4% of those receiving subcutaneous treatment, compared with 0.9% of those receiving intravenous treatment. MK-5180 anti-drug antibodies were detected in 1.5% patients who were receiving subcutaneous treatment.

Based on these findings, the study authors concluded that subcutaneous pembrolizumab resulted in “exposure and trough concentrations that were non-inferior” to intravenous pembrolizumab, with “similar” efficacy. The safety profile of subcutaneous pembrolizumab plus chemotherapy was also found to be “manageable and consistent” with the safety profile of intravenous pembrolizumab plus chemotherapy. The results suggest that subcutaneous pembrolizumab is “a viable treatment option in indications” where pembrolizumab has approval, the study authors concluded.

Reference

Felip E, Rojas C, Schenker M, et al. Subcutaneous (SC) versus intravenous (IV) pembrolizumab (Pembro) plus chemotherapy (CT) in metastatic non-small cell lung cancer (mNSCLC): Phase III MK-3475A-D77 trial. Abstract 8MO. Presented at the European Lung Cancer Congress 2025, March 26-29; Paris, France.

In the photo at top, Rosalyn Juergens, MD, PhD, leads an invited discussant on the data presented by Enriqueta Felip, MD, PhD, at the European Lung Cancer Congress 2025. (Photo courtesy of the European Society for Medical Oncology)