Subcutaneous versus intravenous pembrolizumab, in combination with chemotherapy, for treatment of metastatic non-small-cell lung cancer: the phase III 3475A-D77 trial
Published report from the trial registered as NCT05722015, in Annals of Oncology (2025), chosen as the most cited paper whose own text cites the registry id.
Overview
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.
Indexed on Europe PMC as PubMed record 40157574 (DOI 10.1016/j.annonc.2025.03.012). Its abstract cites the registry id NCT05722015, which is how it was matched to this trial; no figure has been checked by an editor.
This is the paper Europe PMC returns for registry id NCT05722015 with the most citations, so it is the natural first reading for anyone following the trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand.
- Matched to the trial by the registry id cited in the Europe PMC record; the summary reproduces the record's abstract and no figure has been verified against the full paper.