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. 2025 Feb 5:17:17588359251316176.
doi: 10.1177/17588359251316176. eCollection 2025.

TROPION-Breast04: a randomized phase III study of neoadjuvant datopotamab deruxtecan (Dato-DXd) plus durvalumab followed by adjuvant durvalumab versus standard of care in patients with treatment-naïve early-stage triple negative or HR-low/HER2- breast cancer

Heather L McArthur  1 , Sara M Tolaney  2 , Rebecca Dent  3 , Peter Schmid  4 , Jamil Asselah  5 , Qiang Liu  6 , Jane Lowe Meisel  7 , Naoki Niikura  8 , Yeon Hee Park  9 , Gustavo Werutsky  10 , Giampaolo Bianchini  11 , Jay C Andersen  12 , Robert Kozarski  13 , Nana Rokutanda  14 , Barbara Pistilli  15 , Sibylle Loibl  16
Affiliations

TROPION-Breast04: a randomized phase III study of neoadjuvant datopotamab deruxtecan (Dato-DXd) plus durvalumab followed by adjuvant durvalumab versus standard of care in patients with treatment-naïve early-stage triple negative or HR-low/HER2- breast cancer

Heather L McArthur et al. Ther Adv Med Oncol. .

Abstract

Background: Despite treatment advances for patients with early-stage triple-negative breast cancer (TNBC) and hormone receptor (HR)-low/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, treatments that improve clinical outcomes while mitigating toxicity are needed. Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate consisting of a humanized IgG1 monoclonal antibody attached via a plasma-stable cleavable linker to a topoisomerase-I inhibitor payload, has shown efficacy alone or in combination with durvalumab, a selective, high-affinity anti-programmed cell death ligand 1 antibody, in early-phase clinical studies.

Objectives: The primary objective of TROPION-Breast04 is to evaluate the efficacy and safety of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy versus standard of care in patients with previously untreated early-stage TNBC or HR-low/HER2- breast cancer.

Design: This is an ongoing, international, phase III, open-label, randomized controlled study.

Methods and analysis: Approximately 1728 patients (aged ⩾18 years) will be randomized 1:1 to eight cycles of neoadjuvant Dato-DXd (6 mg/kg intravenously (IV) every 3 weeks (Q3W)) plus durvalumab (1120 mg IV Q3W) followed by nine cycles of adjuvant durvalumab (1120 mg IV Q3W) with or without chemotherapy versus eight cycles of pembrolizumab (200 mg IV Q3W) plus chemotherapy followed by nine cycles of adjuvant pembrolizumab (200 mg IV Q3W) with or without chemotherapy. Dual primary endpoints are pathological complete response by blinded central review and event-free survival by investigator assessment. Secondary endpoints include overall survival (key), distant disease-free survival, patient-reported outcomes, and safety.

Ethics: The study is approved by independent ethics committees and/or institutional review boards at each study site. All patients will provide written informed consent.

Discussion: This study will evaluate the potential use of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy versus standard of care in patients with previously untreated early-stage TNBC or HR-low/HER2- breast cancer. The findings of this trial could lead to promising treatment options for these patients.

Trial registration: ClinicalTrials.gov identifier: NCT06112379.

Keywords: HR-low/HER2− breast cancer; antibody-drug conjugate; datopotamab deruxtecan; durvalumab; neoadjuvant; triple-negative breast cancer.

Plain language summary

TROPION-Breast04: a clinical study comparing datopotamab deruxtecan (Dato-DXd) plus durvalumab before surgery followed by durvalumab with or without chemotherapy after surgery, versus standard of care treatment in people with triple-negative breast cancer (TNBC) or hormone receptor (HR)-low/human epidermal growth factor receptor 2-negative (HER2−) breast cancer who have not received previous treatment People with TNBC have neither estrogen receptors and/or progesterone receptors nor a protein called HER2 expressed on their cancer cells. Standard treatment for early-stage TNBC that has not spread to other parts of the body and can be removed by surgery is pembrolizumab (a drug that makes cancer cells more susceptible to being killed by the immune system) plus chemotherapy before surgery, and pembrolizumab after surgery. People with HR-low/HER2− breast cancer (BC) do not have HER2 but have low levels of estrogen/progesterone receptors on their cancer cells and may be treated similarly to those with TNBC. Some people with high-risk early-stage TNBC or HR-low/HER2− BC experience a recurrence of their cancer after standard treatment. Therefore, new therapies that stop cancer returning and improve long-term outcomes are needed. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate that consists of an antibody (datopotamab) and an anticancer drug payload (DXd), joined via a stable cleavable linker. In people with TNBC that has spread to other parts of the body, promising outcomes have been observed with Dato-DXd alone or in combination with durvalumab (a drug that makes cancer cells more susceptible to being killed by the immune system). In the TROPION-Breast04 study, approximately 1700 people with early-stage TNBC or HR-low/HER2– BC who have not received previous treatment will be randomly assigned in equal numbers to receive Dato-DXd plus durvalumab followed by surgery and durvalumab with or without chemotherapy, or pembrolizumab plus chemotherapy followed by surgery and pembrolizumab with or without chemotherapy. TROPION-Breast04 will show if Dato-DXd plus durvalumab before surgery followed by durvalumab with or without chemotherapy after surgery can help people with early-stage TNBC and HR-low/HER2– BC live longer without their cancer returning versus pembrolizumab plus chemotherapy before surgery followed by pembrolizumab with or without chemotherapy.

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Conflict of interest statement

H.L.M. has participated in advisory boards with Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Pfizer, Puma, Spectrum Pharmaceuticals, Syndax Pharmaceuticals, Peregrine, Calithera, Daiichi-Sankyo, Seattle Genetics, AstraZeneca, Gilead, Crown Bioscience, and TapImmune; has received research grants (institution) from Bristol-Myers Squibb, BTG/Boston Scientific, and Merck. S.M.T. has acted as a consultant or advisor for Novartis, Pfizer (SeaGen), Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, CytomX Therapeutics, Daiichi-Sankyo, Gilead, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, Sumitovant Biopharma, Umoja Biopharma, Artios Pharma, Menarini/Stemline, Aadi Bio, Bayer, Incyte Corp, Jazz Pharmaceuticals, Natera, Tango Therapeutics, Systimmune, eFFECTOR, Hengrui USA, Cullinan Oncology, Circle Pharma, and Arvinas; has received research funding (institution) from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Gilead, Seattle Genetics, OncoPep, Daiichi-Sankyo; has received travel or accommodation expenses from Eli Lilly, Sanofi, Gilead, and Jazz Pharmaceuticals. R.D. has received consulting fees from AstraZeneca, MSD, Roche, Pfizer, Eisai, Novartis, and Lilly. P.S. 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. J.A. has no conflicts of interest to declare. Q.L. has acted as a speaker for Roche, AstraZeneca, Pfizer, Eisai, and Novartis; reports participation in speakers’ bureaus for Roche, AstraZeneca, Pfizer, Eisai, and Novartis; participated in advisory boards with AstraZeneca and Pfizer; has received funding from Eisai. J.L.M. has acted as a speaker for Prime Oncology and Targeted Oncology; participated in advisory boards with Sermonix; has acted as a Principal Investigator with Olema, Sermonix, and Seagen (now Pfizer); has acted as an advisor for Pfizer, Novartis, Puma, Seagen (now Pfizer), Olema, Genentech, GSK, AstraZeneca, and Sermonix. N.N. has received honoraria from AstraZeneca, Chugai Pharma, Daiichi-Sankyo/UCB Japan, Eisai, Kyowa Kirin, Lilly Japan, MSD, Novartis, Pfizer, and Taiho Pharmaceutical; has received research funding from Boehringer Ingelheim, Chugai Pharma, Daiichi-Sankyo, Eisai, Kyowa Kirin, Lilly Japan, Mochida Pharmaceutical Co. Ltd, Nihon Medi-Physics, Nippon Kayaku, Pfizer, Puma Biotechnology, Taiho Pharmaceutical, and Takeda. Y.H.P. has received honoraria from AstraZeneca, Daiichi-Sankyo, Eisai, Lilly, MSD, Novartis, Pfizer, and Roche; has acted as a consultant or advisor for AstraZeneca, Boryung, Daiichi-Sankyo, Eisai, Gilead Sciences, Lilly, Menarini, MSD, Novartis, Pfizer, and Roche; has received research funding from AstraZeneca, Gencurix, Genome Insight, NGeneBio, Pfizer, and Roche; has received travel and accommodation expenses from Gilead Sciences. G.W. has acted as a speaker for AstraZeneca, MSD, Pfizer, and Roche; participated in advisory boards with Novartis, Organon, Roche, MSD, and Daiichi-Sankyo; has received research grants from Astellas Pharma, AstraZeneca, Ipsen, Janssen, Novartis, Pfizer, Roche, Takeda, GlaxoSmithKline, Bayer, and Libbs; has acted as a Principal Investigator with AstraZeneca, BMS, Lilly, and MSD. G.B. has received honoraria from AstraZeneca/Daiichi-Sankyo, Eisai, Exact Sciences, Gilead Sciences, Lilly, Menarini, MSD, Novartis, Pfizer, Roche, and Seagen; has acted as a consultant or advisor for Agendia, AstraZeneca, AstraZeneca/Daiichi-Sankyo, Daiichi-Sankyo Europe GmbH, Eisai, Exact Sciences, Gilead Sciences, Lilly, MSD, Novartis, Pfizer, Roche, and Seagen; has received research funding (institution) from Gilead Sciences; has received travel or accommodations expenses from AstraZeneca/Daiichi-Sankyo, Gilead Sciences, Novartis, Pfizer, and Roche. J.C.A. has received honoraria from AstraZeneca, Genentech, Genomic Health, Novartis, and Puma Biotechnology; has acted as a consultant or advisor for AstraZeneca, Athenex, Daiichi-Sankyo Pharmaceutical, Genentech, Genomic Health, Immunomedics, Myriad Genetic Laboratories, Novartis, Pfizer, Puma Biotechnology, and Seagen; has participated in speakers’ bureaus with AstraZeneca, Genentech, Genomic Health, Novartis, and Puma Biotechnology. R.K. is an employee of AstraZeneca. N.R. is an employee of AstraZeneca. B.P. has received consulting fees (institutional) from AstraZeneca, Seagen, Gilead, Novartis, Lilly, MSD, Pierre Fabre (personal), and Daiichi-Sankyo (institutional/personal); has received research funding (institutional) from AstraZeneca, Daiichi-Sankyo, Gilead, Seagen, and MSD; has received travel support from AstraZeneca, Pierre Fabre, Lilly, Daiichi-Sankyo, and MSD. S.L. has acted as a consultant or advisor for AbbVie, Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, Celgene, Daiichi-Sankyo, EirGenix, Eisai Europe, GlaxoSmithKline, Lilly, Menarini Group, Merck KGaA, MSD Oncology, Novartis, Olema Pharmaceuticals, Pfizer, Pierre Fabre, Relay Therapeutics, Roche, Sanofi, and Seagen; reports participation in speakers’ bureaus for AstraZeneca, Daiichi-Sankyo Europe GmbH, Gilead Sciences, Novartis, Pfizer, Roche, and Seagen; has received research funding from AbbVie, AstraZeneca, Celgene, Daiichi-Sankyo, Gilead Sciences, Menarini Group, Molecular Health, Novartis, Pfizer, and Roche; reports patents, royalties, or other intellectual property: Digital Ki67 Evaluator, VM Scope GmbH, Patent Issued EP15702464.7, Patent Pending EP14153692.0, Patent Pending EP19808852.8, Patent Pending EP21152186.9.

Figures

Figure 1.
Figure 1.
Mechanism of action of Dato-DXd and durvalumab. ADC, antibody-drug conjugate; CD80, cluster of differentiation 80; Dato-DXd, datopotamab deruxtecan; PD-(L)1, programmed cell death protein (ligand) 1; TROP2, trophoblast cell-surface antigen 2.
Figure 2.
Figure 2.
Study design. [a]6 mg/kg IV Q3W; [b]1120 mg IV Q3W; [c]300 mg PO BID for 1 year; [d]200 mg IV Q3W; [e]AUC 5 mg/mL/min IV Q3W, OR AUC 1.5 mg/mL/min IV QW (based on investigator preference); [f]80 mg/m2 IV QW; [g]600 mg/m2 IV Q3W; [h]60 mg/m2 IV Q3W; [i]90 mg/m2 IV Q3W; [j]1000 or 1250 mg/m2 (based on standard institutional practice) PO BID on Days 1–14, Q3W. *TNBC defined as: ER and PR < 1% on IHC; negative for HER2 with 0 or 1+ intensity on IHC, or 2+ intensity on IHC and no evidence of amplification on ISH. HR-low/HER2− breast cancer defined as: ER 1% to <10% and/or PR 1% to <10% (neither HR may be ⩾10%); negative for HER2 with 0 or 1+ intensity on IHC, or 2+ intensity on IHC and no evidence of amplification on ISH. †Adjuvant therapy regimen will be based on pCR rates with neoadjuvant treatment. ‡Olaparib may be given for a total period of 1 year in patients with gBRCA-positive tumors and residual disease; treatment may overlap with the nine adjuvant cycles of durvalumab/pembrolizumab but may not be given concurrently with chemotherapy. §Adjuvant chemotherapy may be given in combination with durvalumab only if patients have residual disease. Chemotherapy may be one of four regimens: (1) Either doxorubicin[h] or epirubicin[i] + cyclophosphamide[g] for four cycles followed by paclitaxel[f] and carboplatin[e] for four cycles; (2) Either doxorubicin[h] or epirubicin[i] + cyclophosphamide[g] for four cycles followed by paclitaxel[f] for four cycles; (3) Carboplatin[e] + paclitaxel[f] for four cycles; (4) Capecitabine[j] for eight cycles. Capecitabine may be given in combination with pembrolizumab if patients have residual disease. AUC, area under the curve; BID, twice daily; Dato-DXd, datopotamab deruxtecan; DDFS, distant disease-free survival; ECOG PS, Eastern Cooperative Oncology Group performance status; EFS, event-free survival; ER, estrogen receptor; gBRCA, germline breast cancer resistance gene; HER2, human epidermal growth factor receptor-2; HR, hormone receptor; IHC, immunohistochemistry; ISH, in situ hybridization; IV, intravenous; pCR, pathologic complete response; PO, orally; PR, progesterone receptor; PROs, patient reported outcomes; QW, weekly; Q3W, every 3 weeks; TNBC, triple negative breast cancer.
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