433TiP - Phase III, randomized, open-label TroFuse-010 Study of sacituzumab tirumotecan (sac-TMT) alone and with pembrolizumab vs treatment of physician’s choice chemotherapy (TPC) in patients with HR+/HER2- unresectable locally advanced or metastatic breast cancer (mBC)

Background

Trophoblast cell surface antigen 2 (TROP2) is commonly overexpressed in patients (pts) with HR+/HER2- 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, IV sac-TMT alone had antitumor activity in pts with previously treated HR+/HER2- mBC (ORR, 36.8%). TroFuse-010 evaluates sac-TMT alone or with pembrolizumab (pembro) vs TPC in pts with HR+/HER2- unresectable locally advanced or mBC.

Trial design

This phase 3, randomized, open-label study (NCT06312176) is enrolling pts ≥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. Pts are candidates for chemotherapy (ChT) and had either (a) PD after ≥1 line of endocrine therapy (ET), 1 of which was with a CDK4/6 inhibitor (CKD4/6i), (b) PD ≤6 mo after starting 1L ET + CDK4/6i where the CDK4/6i was discontinued before the PD, (c) PD >6 mo after starting 1L ET + CKD4/6i (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 ChT in the metastatic setting and, if treated with prior (neo)adjuvant ChT, recurrence ≤6 mo after completion of ChT. Pts are randomized 3:3:2 to receive IV sac-TMT 4 mg/kg Q2W, IV sac-TMT 4 mg/kg Q2W + pembro 400 mg Q6W, or TPC (paclitaxel, nab-paclitaxel, capecitabine, or liposomal doxorubicin) until radiographic PD, unacceptable toxicity, pt withdrawal, or discontinuation criteria are met. Primary endpoints are PFS per RECIST v1.1 by BICR with sac-TMT vs TPC and sac-TMT + pembro vs TPC. Secondary endpoints include OS, PFS per RECIST v1.1 by BICR with sac-TMT + pembro vs sac-TMT, ORR, DOR, PROs, and safety. Recruitment began in April 2024.

Clinical trial identification

NCT06312176; 2023-504918-29.

Editorial acknowledgement

Medical writing assistance was provided by Susan Tyree of ICON plc (Blue Bell, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Funding

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad board participant/consultant: ARC Therapeutics, Daichii Sankyo, Eisai, Genentech/Roche, Gilead, Novartis, Sanofi, Seagen; Financial Interests, Personal, Other, Consulting: Aadi BioPharma, Hengrui USA; Financial Interests, Personal, Advisory Board, Ad board participation: Artios, Incyte Corp, BeyondSprings; Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board, Advisory Board participation: Bayer, Infinity Therapeutics, Sumitovant Biopharmaceuticals, OncXerna, Umoja Biopharma, Zentalis, Natera; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol-Myers Squibb; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Advisory Board, Advisory Board participation/consulting: Menarini/Stemline; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pfizer; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Personal, Advisory Board, Advisory board/consulting: Jazz Pharma; Financial Interests, Personal, Advisory Board: Tango Therapeutics, Systimmune, eFFECTOR, Cullinan Oncology, Arvinas; Financial Interests, Institutional, Funding, And steering committing: AstraZeneca; Financial Interests, Institutional, Funding, And steering committee: Eli Lilly; Financial Interests, Institutional, Funding: Pfizer, Sanofi, Seagen, Odonate, Cyclacel, Exelixis, Bristol Myers Squibb, Eisai, Merck, Novartis; Financial Interests, Personal and Institutional, Steering Committee Member: CytomX; Financial Interests, Institutional, Funding, and steering committee: Gilead, Genentech/Roche; Financial Interests, Institutional, Local PI: Stemline/Menarini. P. D’Amico: Financial Interests, Personal and Institutional, Stocks/Shares: Merck Sharp & Dohme LLC. L. Jia: Financial Interests, Personal and Institutional, Stocks/Shares: Merck Sharp & Dohme LLC. K.M. Hirshfield: Financial Interests, Personal, Full or part-time Employment, Salary and stock: MSD; Financial Interests, Personal, Stocks/Shares, Stock: MSD. F. Cardoso: Financial Interests, Personal, Other, Consultancy: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GSK, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, Prime Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva; Financial Interests, Personal, Advisory Board: Gilead, Iqvia, Touchime; Financial Interests, Institutional, Local PI: Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers-Squibb, Bayer, Daiichi, Eisai, Fresenius GmbH, Genentech, GSK, Ipsen, Incyte, Nektar Therapeutics, Nerviano, Novartis, Macrogenics, Medigene, MedImmune, Merck, Millenium, Pfizer, Pierre-Fabre, Roche, Sanofi-Aventis, Sonus, Taiho Oncology, Tesaro, Tigris, Wilex, Wyeth, Gilead; Non-Financial Interests, Leadership Role, President: ABC Global Alliance and ABC Consensus Conference and Guidelines; Non-Financial Interests, Member: ESMO, ESO, EORTC, BCG, IBCSG, SOLTI, ASCO, AACR, EACR, SIS, ASPIC.