Abstract OT1-03-05: TROPION-Breast02: Phase 3, open-label, randomized study of first-line datopotamab deruxtecan versus chemotherapy in patients with locally recurrent inoperable or metastatic TNBC who are not candidates for anti-PD-(L)1 therapy
Authors: Dent Rebecca , Cescon David W. , Bachelot Thomas , Jung Kyung Hae , Shao Zhi-Ming , Saji Shigehira , Traina Tiffany A. , Vuković Petra , Mapiye Darlington , Maxwell Micah , Schmid Peter , Cortés Javier 
Published: March 2023

Introduction: Despite recent treatment advances, the prognosis for patients diagnosed with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) remains poor. Single-agent chemotherapy has been the mainstay of treatment for metastatic TNBC for many years, with very limited treatment options for patients who are not candidates for anti-PD-1/PD-L1 therapy; consequently, there remains an urgent unmet need. Trophoblast cell surface protein 2 (TROP2) is a type I transmembrane glycoprotein highly expressed on various solid tumors, including breast. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) composed of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to an exatecan derivative (DXd) – a highly potent topoisomerase I inhibitor payload – via a stable, tumor-selective, tetrapeptide-based cleavable linker. Dato-DXd has previously been evaluated in TROPION-PanTumor01 (NCT03401385) – an ongoing Phase I clinical trial across multiple advanced solid tumors, including heavily-pretreated, metastatic TNBC. As of the July 30, 2021 cut-off date, the objective response rate (ORR) by blinded independent central review (BICR) was 34% (15/44) in all patients with TNBC and 52% (14/27) in those patients treatment-naïve to topoisomerase I inhibitor-based ADC therapies, with measurable disease (per RECIST 1.1) at baseline. Furthermore, a manageable safety profile was reported, with no new safety signals identified; low grade nausea and stomatitis were most frequent, with neutropenia and diarrhea being uncommon. The aim of the phase 3 TROPION-Breast02 trial is to evaluate the efficacy and safety of Dato-DXd versus investigator’s choice of chemotherapy (ICC) in patients with TNBC who are not candidates for PD-1/PD-L1 inhibitor therapy. Methods: TROPION-Breast02 (NCT05374512) is an ongoing Phase 3, open-label, randomized study of Dato-DXd versus ICC in first-line treatment of patients with locally recurrent inoperable or metastatic TNBC. Approximately 600 patients will be randomized 1:1 to receive either Dato-DXd 6 mg/kg IV every three weeks or ICC (paclitaxel, nab-paclitaxel, carboplatin, capecitabine, or eribulin mesylate). Patients ≥18 years with histologically/cytologically confirmed TNBC who have not received prior chemotherapy or targeted systemic therapy for metastatic or locally recurrent inoperable disease are eligible for inclusion. Patients are also required to have an ECOG PS of 0 or 1 and be eligible for treatment with one of the ICC options per investigator assessment. Patients must have ≥1 measurable lesion per RECIST v1.1 not previously irradiated, along with a formalin-fixed and paraffin-embedded tumor sample available. Those with a previously treated neoplastic spinal cord compression or clinically inactive brain metastases can be included. Key exclusion criteria are history of another primary malignancy; persistent toxicity from previous anti-cancer treatments; uncontrolled infections; current/prior interstitial lung disease/pneumonitis or clinically severe pulmonary function compromise; clinically significant corneal disease; and prior treatment with topoisomerase I inhibitors, TROP2-targeted therapy, or the same chemotherapy agent chosen for on-study ICC. The dual primary endpoints are progression free survival (PFS) per RECIST 1.1 by BICR, and OS. Secondary endpoints include ORR, duration of response, PFS by investigator assessment, time to deterioration for patient-reported outcomes, time to first subsequent therapy, time to second subsequent therapy, time to second progression or death, pharmacokinetics and immunogenicity of Dato-DXd, and safety. Recruitment for this study is ongoing as of June 2022.

Citation Format: Rebecca Dent, David W. Cescon, Thomas Bachelot, Kyung Hae Jung, Zhi-Ming Shao, Shigehira Saji, Tiffany A. Traina, Petra Vuković, Darlington Mapiye, Micah Maxwell, Peter Schmid, Javier Cortés. TROPION-Breast02: Phase 3, open-label, randomized study of first-line datopotamab deruxtecan versus chemotherapy in patients with locally recurrent inoperable or metastatic TNBC who are not candidates for anti-PD-(L)1 therapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-03-05.