Subcutaneous versus intravenous pembrolizumab, in combination with chemotherapy, for treatment of metastatic non-small-cell lung cancer: the phase III 3475A-D77 trial

Abstract

Background: Pembrolizumab with berahyaluronidase alfa is for subcutaneous (s.c.) administration. The phase III open-label 3475A-D77 study (NCT05722015) assessed s.c. pembrolizumab versus intravenous (i.v.) pembrolizumab, plus chemotherapy, for treatment of metastatic non-small-cell lung cancer (mNSCLC).

Patients and methods: Participants with newly diagnosed stage IV squamous or nonsquamous NSCLC without sensitizing EGFR, ALK, or ROS1 alterations were randomized 2 : 1 to pembrolizumab s.c. 790 mg every 6 weeks (q6w) or pembrolizumab i.v. 400 mg q6w (18 cycles), each given with platinum-doublet chemotherapy. Dual primary endpoints were pharmacokinetic exposure measures of cycle 1 area under the curve (AUC_{0-6 weeks}) and steady-state trough concentration (C_trough) of pembrolizumab. The noninferiority margin for AUC_{0-6 weeks} and C_trough geometric mean ratios (GMRs) of pembrolizumab s.c. versus i.v. was specified as 0.8. Secondary endpoints included additional pharmacokinetic exposure measures, pembrolizumab immunogenicity, efficacy, and safety.

Results: In total 377 participants were randomized to the pembrolizumab s.c. (n = 251) or i.v. (n = 126) arms. The median time from randomization to data cut-off (12 July 2024) was 9.6 months (range 6.2-16.4 months). The median injection time for pembrolizumab s.c. was 2.0 min (range 1-12 min). The GMR [96% confidence interval (CI)] for cycle 1 AUC_{0-6 weeks} was 1.14 (1.06-1.22); P < 0.0001. The GMR (94% CI) for steady-state C_trough was 1.67 (1.52-1.84); P < 0.0001. Secondary pharmacokinetic endpoints were within established bounds for pembrolizumab. Anti-pembrolizumab antibodies were detected in 1.4% (pembrolizumab s.c. arm) and 0.9% (pembrolizumab i.v. arm) of participants. For the pembrolizumab s.c. versus i.v. arms, objective response rates (ORRs) were 45.4% versus 42.1% (ORR ratio 1.08, 95% CI 0.85-1.37). Other efficacy measures were similar and safety profiles were consistent between treatment arms.

Conclusions: Overall exposure and trough concentrations of pembrolizumab s.c. 790 mg q6w were noninferior to those of pembrolizumab i.v. 400 mg q6w given with chemotherapy in participants with treatment-naive mNSCLC. Results support pembrolizumab s.c. as a treatment option in all indications where pembrolizumab i.v. can be used.

Keywords: immunotherapy; non-small-cell lung cancer; pembrolizumab; phase III; programmed cell death protein 1; subcutaneous.