Multinational phase 1-2a study of puxitatug samrotecan in patients with advanced/metastatic solid tumors

B7-H4 is a promising antibody-drug conjugate (ADC) target with high expression in several 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. Puxitatug samrotecan (Puxi-Sam; AZD8205) is a novel B7-H4-directed ADC with a stable cleavable linker and a bystander-capable topoisomerase-1 inhibitor payload. In the multinational, first-in-human, phase 1-2a BLUESTAR 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, and to determine the maximum tolerated dose and/or the recommended phase 2 dose (RP2D). The most common treatment-related adverse events were nausea (51.1%), neutropenia (48.9%), and anemia (38.3%). At 3.2 mg/kg, dosee-limiting neutropenia and thrombocytopenia were observed. In patients treated at ≥1.6 mg/kg, partial responses were observed in ovarian, endometrial, and breast cancer (ORR 20.5%; 9/44). The authors conclude that these findings demonstrate manageable safety and promising efficacy with Puxi-Sam in heavily pretreated patients.