Abstract P4-08-09: Phase 3, Randomized, Open-label TroFuse-010 Study of Sacituzumab Tirumotecan (sac-TMT) Alone & W/ Pembrolizumab vs. Treatment of Physician’s Choice Chemotherapy in Patients With HR+/HER2- Unresectable Locally Advanced or Metastatic Breast Cancer

Abstract Background: Additional therapies are needed to improve outcomes in patients with HR+/HER2- breast cancer that progressed on endocrine therapy (ET) plus CDK4/6 inhibitors (CDK4/6i). Trophoblast cell surface antigen 2 (TROP2) is commonly overexpressed in patients with HR+/HER2- metastatic breast cancer (mBC) and is associated with poor prognosis. Sac-TMT (also known as MK-2870/SKB264) is a novel anti-TROP2 antibody-drug conjugate composed of an anti-TROP2 antibody coupled to a cytotoxic belotecan derivative via a novel linker (average drug/antibody ratio, 7.4). In a phase 1/2 study, intravenous (IV) sac-TMT alone had antitumor activity in patients with previously treated HR+/HER2- mBC (ORR, 36.8%). TroFuse-010 evaluates sac-TMT alone or with pembrolizumab vs treatment of physician’s choice chemotherapy (TPC) in patients with HR+/HER2- unresectable locally advanced or mBC who have not previously received chemotherapy. Methods: This phase 3, randomized, open-label study (NCT06312176) is enrolling patients ≥18 y with HR+/HER2- unresectable locally advanced or mBC, ECOG PS ≤1, and a tumor sample for central assessment of TROP2 expression and HR, HER2, and PD-L1 status. Patients are candidates for chemotherapy and had either (a) PD after ≥1 line of ET, 1 of which was with a CDK4/6i, (b) PD ≤6 mo after starting 1L ET plus CDK4/6i where the CDK4/6i was discontinued before the PD, (c) PD >6 mo after starting 1L ET plus CDK4/6i (where the CDK4/6i was discontinued before the PD) and PD on an additional ET (either as monotherapy or combined with a PI3K or mTOR inhibitor), or (d) relapse during or ≤12 mo after completing CDK4/6i given as adjuvant therapy together with ET. Key exclusion criteria are prior treatment with chemotherapy in the metastatic setting and, if treated with prior (neo)adjuvant chemotherapy, recurrence ≤6 mo after completion of chemotherapy. Patients are randomized 3:3:2 to receive IV sac-TMT 4 mg/kg Q2W, IV sac-TMT 4 mg/kg Q2W plus pembrolizumab 400 mg Q6W, or TPC (paclitaxel, nab-paclitaxel, capecitabine, or liposomal doxorubicin) until radiographic PD, unacceptable toxicity, patient withdrawal, or discontinuation criteria are met. Randomization is stratified by PD-L1 combined positive score (<1 vs 1-9 vs ≥10), TROP2 expression (low/medium vs high), and region (Western Europe vs North America vs Rest of World). Primary endpoints are PFS per RECIST v1.1 by blinded independent central review (BICR) with sac-TMT vs TPC and sac-TMT plus pembrolizumab vs TPC. Secondary endpoints include OS, PFS per RECIST v1.1 by BICR with sac-TMT plus pembrolizumab vs sac-TMT, ORR, duration of response, patient-reported outcomes, and safety. Tumor imaging occurs at baseline, Q9W through week 54, and Q12W thereafter. Recruitment began in April 2024. Citation Format: Sara M. Tolaney, Paolo D’Amico, Liyi Jia, Kim M. Hirshfield, Fatima Cardoso. Phase 3, Randomized, Open-label TroFuse-010 Study of Sacituzumab Tirumotecan (sac-TMT) Alone & W/ Pembrolizumab vs. Treatment of Physician’s Choice Chemotherapy in Patients With HR+/HER2- Unresectable Locally Advanced or Metastatic Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-08-09.