TROPION-Breast02: Datopotamab deruxtecan for locally recurrent inoperable or metastatic triple-negative breast cancer

Abstract

Despite recent treatment advances, the prognosis for patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) remains poor. The antibody–drug conjugate datopotamab deruxtecan (Dato-DXd) is composed of a humanized anti-TROP2 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload via a stable, cleavable linker. The phase III TROPION-Breast02 trial in patients previously untreated for locally recurrent inoperable or metastatic TNBC, who are not candidates for PD-1/PD-L1 inhibitors is evaluating efficacy and safety of Dato-DXd versus investigator’s choice of chemotherapy (ICC). Approximately 600 patients will be randomized 1:1 to Dato-DXd 6 mg/kg iv. every 3 weeks or ICC (paclitaxel, nab-paclitaxel, carboplatin, capecitabine or eribulin mesylate). Dual primary end points are progression-free survival by blinded independent central review and overall survival.

Plain language summary

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is hard to treat. Tumors lack receptors for estrogen and progesterone, which means that standard endocrine therapy is ineffective, and it does not express HER2, so HER2 therapies are also not appropriate. However, the majority of TNBC tumors do possess a cell surface protein called TROP2 which provides a way of directing treatment inside tumor cells that is more selective than traditional chemotherapy.

Datopotamab deruxtecan (Dato-DXd) is a drug that consists of two parts: datopotamab (an antibody) and DXd (the cancer-cell killing toxic component), which are joined via a stable linker. Datopotamab binds to the TROP2 protein found on TNBC tumors and is taken into the cell. The linker is then broken and releases DXd, which kills the tumor cell. By binding to cancer cells before releasing the payload, treatment is directed to the tumor, minimizing side effects in the rest of the body.

The TROPION-Breast02 study aims to discover whether Dato-DXd is more effective than standard-of-care chemotherapy, allowing patients with TNBC to live longer without their breast cancer getting worse. This study is also looking at how Dato-DXd may affect patients’ overall functioning and quality of life. TROPION-Breast02 will recruit approximately 600 patients who:

• Have cancer that has spread from the original site (metastatic), or cancer that returned to the same site (locally recurrent) that cannot be surgically removed

• Have not received any prior treatment for this stage of cancer

• Cannot receive an alternative type of anticancer treatment called PD-(L)1 inhibitors

• Had any length of time between their last treatment with the aim of cure and return of their disease

Eligible patients will be randomly assigned to a treatment group in equal numbers to either Dato-DXd or an appropriate chemotherapy (one of five available options, chosen by the treating doctor). Each patient will generally continue to receive their designated treatments if the tumor is controlled by the drug, there are no unacceptable side effects, or the patient chooses to stop treatment.

Clinical Trial Registration: NCT05374512 (ClinicalTrials.gov)

Keywords::

• antibody–drug conjugate (ADC)
• datopotamab deruxtecan (Dato-DXd)
• PD-1/PD-L1
• triple-negative breast cancer
• Trophoblast cell surface antigen 2 (TROP2)

Author contributions

Conception and design: MJ Maxwell, P Vukovic, D Mapiye, P Schmid, RA Dent, J Cortés; Manuscript writing, final approval of manuscript, accountable for all aspects of the work: all authors.

Financial & competing interests disclosure

The TROPION-Breast02 trial (NCT05374512) is sponsored by AstraZeneca. In July 2020, Daiichi-Sankyo entered into a global development and commercialization collaboration with AstraZeneca for datopotamab deruxtecan (Dato-DXd).

RA Dent has received consulting fees from AstraZeneca, Merck Sharp & Dohme (MSD), Roche, Pfizer, Eisai, Novartis, and Lilly in the last 24 months. DW Cescon has received consulting fees from AstraZeneca, Exact Sciences, Eisai, Gilead, GlaxoSmithKline (GSK), Lilly, Merck, Novartis, Pfizer, and Roche in the last 24 months; research funding to institution from AstraZeneca, Gilead, GSK, Inivata, Knight Therapeutics, Merck, Pfizer, and Roche; patent (US62/675,228) for methods of treating cancers characterized by a high expression level of spindle and kinetochore associated complex subunit 3 (ska3) gene. T Bachelot has received consulting fees from Seagen, Novartis, Daiichi-Sankyo, AstraZeneca, Pfizer, and Lilly in the last 24 months. KH Jung has received consulting fees from Daiichi-Sankyo, Everest Medicine, MSD, Novartis, Pfizer, and Roche in the last 24 months. Z-M Shao has no conflicts of interest to disclose. S Saji has received consulting fees from AstraZeneca, Chugai, Eli Lilly, Kyowa Kirin, MSD, Ono, and Pfizer; conducted contracted research for AstraZeneca, Chugai, Daiichi-Sankyo, MSD, and Taiho; received fees for non-CME services directly from commercial interest or their agents from AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eli Lilly, Eisai, Kyowa Kirin, MSD, Novartis, Ono, Pfizer, and Taiho in the last 24 months. TA Traina has received consulting fees from AstraZeneca, Daiichi-Sankyo, Gilead, Pfizer, Novartis, and Genentech (DSMB); conducted contracted research for AstraZeneca, Astellas Pharma, Genentech, Roche, Daiichi-Sankyo, and Ayala Pharmaceuticals in the last 24 months. P Vukovic is an employee and ownership interest holder of AstraZeneca. D Mapiye is an employee of AstraZeneca. MJ Maxwell is an employee of AstraZeneca. P Schmid has received consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma, Roche, Eisai, and Celgene; conducted contracted research for Astellas, AstraZeneca, Genentech, Novartis, OncoGenex Pharmaceuticals, Roche, and Medivation in the last 24 months. J Cortés has received consulting fees from Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi-Sankyo, Erytech, Athenex, Polyphor, Lilly, MSD, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, and Reveal Genomics; conducted contracted research for Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GmbH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffmann-La Roche, Guardant Health, MSD, Pfizer, Piqur Therapeutics, and Puma on behalf of Queen Mary University of London; received fees for non-CME services received directly from commercial interest or their agents from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, MSD, and Daiichi-Sankyo; ownership interest in MedSIR, Nektar Pharmaceuticals, and Leuko stocks in the last 24 months; holds patents WO 2014/199294 A and US 2019/0338368 A1. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Catherine Crookes of Ashfield MedComms (Macclesfield, UK), an Inizio company, and was funded by AstraZeneca.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Data sharing statement

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Data for studies directly listed on Vivli can be requested through Vivli at www.vivli.org. Data for studies not listed on Vivli could be requested through Vivli at https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/. AstraZeneca Vivli member page is also available outlining further details: https://vivli.org/ourmember/astrazeneca/.

Additional information

Funding

Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Catherine Crookes of Ashfield MedComms (Macclesfield, UK), an Inizio company, and was funded by AstraZeneca.