Subcutaneous Versus Intravenous Pembrolizumab, in Combination With Chemotherapy, for Treatment of Metastatic Non-Small Cell Lung Cancer: The Phase 3 3475A-D77 Trial
Mené sur 377 patients atteints d'un cancer du poumon non à petites cellules de stade métastatique, cet essai de phase III compare l'efficacité, du point de vue de mesures pharmacocinétiques, et la toxicité, en fonction du mode d'administration (voie sous-cutanée ou voie intraveineuse), du pembrolizumab en combinaison avec une chimiothérapie
Background: Pembrolizumab with berahyaluronidase alfa is for subcutaneous (SC) administration. The phase 3 open-label 3475A-D77 study (NCT05722015) assessed SC pembrolizumab versus intravenous (IV) pembrolizumab, plus chemotherapy, for treatment of metastatic non–small-cell lung cancer (mNSCLC).
Participants 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 SC 790 mg every 6 weeks (Q6W) or pembrolizumab IV 400 mg Q6W (18 cycles), each given with platinum doublet chemotherapy. Dual primary endpoints were pharmacokinetics exposure measures of cycle 1 area-under-the-curve (AUC0-6wks) and steady-state trough concentration (Ctrough) of pembrolizumab. The noninferiority margin for AUC0-6wks and Ctrough geometric mean ratios (GMR) of pembrolizumab SC versus IV was specified as 0.8. Secondary endpoints included additional pharmacokinetics exposure measures, pembrolizumab immunogenicity, efficacy, and safety.
Results: 377 participants were randomized to the pembrolizumab SC (n=251) or IV (n=126) arms. Median time from randomization to data cutoff (12Jul2024) was 9.6 months (range 6.2-16.4). Median injection time for pembrolizumab SC was 2.0 minutes (range 1-12). The GMR (96% CI) for cycle 1 AUC0-6wks was 1.14 (1.06-1.22); P<0.0001. The GMR (94% CI) for steady-state Ctrough was 1.67 (1.52-1.84); P<0.0001. Secondary pharmacokinetics endpoints were within established bounds for pembrolizumab. Anti-pembrolizumab antibodies were detected in 1.4% (pembrolizumab SC arm) and 0.9% (pembrolizumab IV arm) of participants. For the pembrolizumab SC versus IV arms, objective response rates were 45.4% vs 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 SC 790 mg Q6W were noninferior to those of pembrolizumab IV 400 mg Q6W given with chemotherapy in participants with treatment-naïve mNSCLC. Results support pembrolizumab SC as a treatment option in all indications where pembrolizumab IV can be used.