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

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) and steady-state trough concentration (C) of pembrolizumab. The noninferiority margin for AUC and C 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 was 1.14 (1.06-1.22); P < 0.0001. The GMR (94% CI) for steady-state C 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.