B7-H4‒directed antibody-drug conjugate AZD8205 (puxitatug samrotecan) in patients with advanced/metastatic solid tumors: the Phase 1/2a (BLUESTAR), first-in-human study

B7-H4 is a promising antibody-drug conjugate (ADC) target with high expression in several solid tumors and limited expression in normal tissue. B7-H4 negatively regulates T-cell function, and high expression of B7-H4 is associated with disease progression. AZD8205 (puxitatug samrotecan [Puxi-Sam]) is a novel B7-H4–directed ADC with a stable cleavable linker and a bystander-capable topoisomerase-1 (TOP1) inhibitor payload. In this first-in-human study, 47 patients with advanced/metastatic B7-H4−positive endometrial cancer, ovarian cancer, breast cancer or cholangiocarcinoma received intravenous Puxi-Sam at 0.8–3.2 mg/kg every 3 weeks. The primary objectives were to evaluate the safety and tolerability of Puxi-Sam (incidence of adverse events [AE], serious AEs and dose-limiting toxicities), and to determine the maximum tolerated dose and/or recommended phase 2 dose of Puxi-Sam. Secondary objectives included characterizing the pharmacokinetics, assessing the antitumor activity (objective response rate [ORR]), and determining the pharmacodynamics of Puxi-Sam. The most common treatment-related adverse events were nausea (51.1%), neutropenia (48.9%) and anemia (38.3%). At 3.2 mg/kg, dose-limiting neutropenia and thrombocytopenia were observed. In patients treated at ≥1.6 mg/kg (predicted efficacious range), partial responses were observed in ovarian, endometrial and breast cancer (ORR 20.5% [9/44]). Translational data indicated selective localization of the TOP1 inhibitor payload to B7-H4–expressing tumor cells and induction of target-dependent DNA damage. Our findings demonstrate manageable safety and promising efficacy with Puxi-Sam in heavily pretreated patients; further development is ongoing. ClinicalTrials.gov: NCT05123482. B7-H4 is a promising therapeutic target in solid tumors because of its frequent expression in cancer cells, limited normal tissue distribution, and immunosuppressive functions. In this first-in-human trial, the authors report safety and efficacy outcomes for B7-H4–directed antibody-drug conjugate AZD8205 (puxitatug samrotecan) in patients with heavily pretreated ovarian, endometrial, and breast cancers, and cholangiocarcinoma.