Ogct-01 Sacituzumab Tirumotecan to Treat Patients With Brain Metastases From Triple-Negative Breast Cancer

Abstract BACKGROUND Brain metastases occur in approximately a third of patients with metastatic triple-negative breast cancer (TNBC) and represent an unfavorable prognostic feature. Antibody-drug conjugates (ADCs) have shown intracranial activity in patients with brain metastases. Sacituzumab tirumotecan (Sac-TMT) is a novel, humanized anti-TROP2 ADC linked to a belotecan-derived topoisomerase I payload. In an early-phase study evaluating Sac-TMT as monotherapy in patients with metastatic TNBC, most of whom had received 3 prior systemic therapies, the median overall response rate (ORR) was 42.4% (53.1% in patients whose tumors were high expressors of TROP-2). However, patients with active brain metastases were not included in this study. This clinical gap and potential superior efficacy of Sac-TMT in treating patients with TNBC in comparison with other available ADCs provides the rationale for our study. STUDY DESIGN This is a prospective 3-arm parallel-cohort investigator-initiated study enrolling 46 patients with metastatic TNBC and active brain metastases (minimally symptomatic or asymptomatic), including patients with leptomeningeal disease. Patients will be accrued into 3 cohorts: cohort A (n=30): patients with prior ADC exposure; cohort B (n=10): patients without prior ADC exposure; cohort C (n=6): patients with leptomeningeal disease. Patients will receive Sac-TMT at 4 mg/kg IV every 2 weeks. Patients whose active brain metastases progress and/or become significantly symptomatic while on study can receive local therapy as appropriate and remain on study if systemic benefit from the drug is seen. The primary aim is to determine the intracranial overall response rate (ORR) of Sac-TMT. The secondary aims are to determine intracranial clinical benefit rate (CBR), extracranial ORR and extracranial clinical benefit rate (CBR), as well as progression-free survival (PFS), OS and safety. The exploratory aims are to evaluate biomarkers to predict therapy response and resistance to therapy, novel neuro-radiology modalities, as well as patient-reported outcomes and QoL data.