Safety and efficacy of puxitatug samrotecan (Puxi-Sam, AZD8205) in patients with biliary tract cancer (BTC): A first-in-human phase 1/2a study (BLUESTAR).

4106 Background: B7-H4 is a transmembrane glycoprotein that negatively regulates T-cell function and is highly expressed in many cancers, including BTC, making it an attractive target for an antibody–drug conjugate (ADC). Puxi-Sam (also known as AZD8205), a novel B7-H4–directed topoisomerase I inhibitor (TOP1i) ADC, demonstrated favorable toxicity and promising antitumor activity during the dose escalation phase of the first-in-human Phase 1/2a BLUESTAR (NCT05123482) trial. Here, we report the pooled analyses for patients with BTC in the dose-escalation and dose-expansion phase of BLUESTAR. Methods: Eligible patients were ≥18 years old with nonresectable, recurrent, or metastatic B7-H4-positive BTC, with measurable disease per RECIST v1.1, and an ECOG performance status of 0 or 1. B7-H4 positivity was defined as ≥25% tumor cell staining by central immunohistochemistry in archival tumor samples. Patients must have received prior adequate standard-of-care therapy; prior treatment with a TOP1i was not allowed for patients in the dose-expansion phase. Patients received Puxi-Sam 2.4 mg/kg IV Q3W until disease progression, unacceptable drug-related toxicity, or consent withdrawal. The primary objective was assessment of safety; secondary objectives included assessment of antitumor activity. Results: As of 30 October, 2025, 20 patients received 2.4 mg/kg Puxi-Sam. The median (min–max) age was 61.5 years (44–88) and patients had received a median (min–max) of 2 (1–4) prior lines of treatment. Sixteen (80.0%) patients had treatment-related adverse events (TRAE), most commonly nausea (55.0%), and anemia (50.0%). Eleven (55.0%) patients had Grade ≥3 TRAEs, most commonly anemia (50.0%) and neutropenia (30.0%). Dose interruptions, reductions, and discontinuations due to TRAEs were required in six, two, and one patient, respectively. Two patients achieved a partial response (PR), corresponding to a confirmed objective response rate (ORR) of 10.0%. Disease stabilization was observed in a meaningful proportion of patients; 10 patients (50%) had stable disease (SD), and 12-week disease control rate (DCR) was 25.0% (5/20). Median progression-free survival (PFS) was 2.2 months, with a median follow-up of 2.2 months, supporting early signals of disease control (Table). Conclusions: Puxi-Sam demonstrated a favorable safety profile and showed modest clinical activity with prolonged disease stabilization observed in a subset of heavily pretreated patients with nonresectable, recurrent, or metastatic BTC. Clinical trial information: NCT05123482 . Efficacy summary (interim response evaluable patients). Puxi-Sam2.4 mg/kgN=20 ORR, % (95% CI) 10.0 (1.2–31.7) PR, n (%) 2 (10.0) SD, n (%) 10 (50.0) PD, n (%) 7 (35.0) NE, n (%) 1 (5.0) DCR at 12 weeks, %(95% CI) 25.0(8.7–49.1) Median PFS, months(95% CI)* 2.2(1.4–4.6) * Full analysis set. NE, not evaluable; PD, progressive disease.