Datopotamab deruxtecan (Dato-DXd), a TROP2 antibody-drug conjugate, vs investigators' choice of chemotherapy (ICC) in previously-treated, inoperable or metastatic hormone-receptor (HR) positive, HER2-negative (HR+/HER2-) breast cancer: TROPION-Breast01

초록

Background Chemotherapy is the main treatment in patients (pts) with pretreated endocrine-resistant HR+/HER2– metastatic breast cancer (BC), but has limited efficacy and substantial toxicities. The antibody-drug conjugate Dato-DXd consists of a humanized IgG1 mAb targeting TROP2 attached via a stable cleavable linker to a topoisomerase I (TopI) inhibitor payload. The TROPION-PanTumor01 (NCT03401385) study of Dato-DXd in heavily pretreated, metastatic, triple-negative BC showed a manageable safety profile and highly encouraging objective response rates (ORR by blinded independent central review [BICR]: 34% in all pts; 52% in pts treatment-naïve to TopI inhibitor-based therapies). The metastatic HR+/HER2– BC cohort of TROPION-PanTumor01 has completed enrolment (n=41); data are currently maturing. Trial design TROPION-Breast01 (NCT05104866) is an ongoing, global, phase III, open-label, randomized trial evaluating efficacy and safety of Dato-DXd vs ICC in pts with inoperable or metastatic HR+/HER2– BC. Pts (n≈700) are randomized 1:1 to Dato-DXd 6 mg/kg IV Q3W or ICC (eribulin, capecitabine, vinorelbine, or gemcitabine) until progression. Adults with ECOG PS 0–1, who experienced progression on or are unsuitable for endocrine therapy, and received 1–2 prior lines of standard-of-care chemotherapy in the inoperable or metastatic setting are eligible. Inhibitors of mTOR, PD-[L]1, CDK4/6 and PARP do not count as prior chemotherapy lines. Pts must have ≥1 measurable lesion per RECIST 1.1 and an archival or fresh FFPE tumour sample. Clinically inactive brain metastases are permitted. Dual primary endpoints are progression-free survival (PFS) by BICR, and overall survival. Secondary endpoints include PFS per investigator, ORR, disease control rate, pt-reported outcomes, and Dato-DXd pharmacokinetics and immunogenicity. Exploratory endpoints include TROP2 expression and exposure–efficacy relationship. Pts are stratified by number of prior chemotherapy lines, prior CDK4/6 inhibitor use, and region. Enrolment is ongoing. Clinical trial identification NCT05104866