Tucatinib, trastuzumab, and capecitabine as second- or third-line therapy after trastuzumab deruxtecan in HER2-positive metastatic breast cancer: A multicenter retrospective study in France

Trastuzumab deruxtecan (T-DXd) is the current standard second-line therapy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), and it has been recently approved by FDA as first line therapy in combination with pertuzumab, following the results of the DESTINY-Breast09 trial. However, optimal treatment strategies following T-DXd remain undefined and data on subsequent therapies are limited. The present study evaluated the efficacy of combined treatment with tucatinib, trastuzumab, and capecitabine (TTC) after T-DXd. Patients with HER2-positive MBC who received TTC as second- or third-line therapy following T-DXd in the 17 participating centers were eligible. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were time to next treatment, overall survival (OS), and objective response rate. Between July 2021 and June 2025, 105 patients who received TTC as second- or third-line therapy following T-DXd were included in the study. The median age was 55.1 years, 41.0% had de novo metastatic disease, and 55.2% had brain metastases. Most patients (91.4%) received TTC as third-line therapy. During a median follow-up of 19.5 months, the median PFS, time to next treatment, and OS were 4.7, 6.6, and 15.3 months, respectively. Among evaluable patients, the objective response rate was 29.6%, with 9.2% achieving complete response. Patients with prior T-DXd exposure for >18 months had improved PFS (6.0 months) compared to those with prior T-DXd exposure for ≤18 months (3.8 months). TTC exhibited clinically meaningful activity following T-DXd in patients with HER2-positive MBC, particularly those with prolonged T-DXd response.

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Journal
The Breast
Published
2026-09-29
DOI
https://doi.org/10.1016/j.breast.2026.104939
Primary Topic
HER2/EGFR in Cancer Research
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article
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article

Tucatinib, trastuzumab, and capecitabine as second- or third-line therapy after trastuzumab deruxtecan in HER2-positive metastatic breast cancer: A multicenter retrospective study in France

Audrey Mailliez, Catherine Guérin‐Charbonnel, Barbara Pistilli, François Poumeaud et al.
The Breast
HER2/EGFR in Cancer Research
article

Tucatinib, trastuzumab, and capecitabine as second- or third-line therapy after trastuzumab deruxtecan in HER2-positive metastatic breast cancer: A multicenter retrospective study in France

Audrey Mailliez, Catherine Guérin‐Charbonnel, Barbara Pistilli, François Poumeaud, François Cherifi, Jean Zeghondy, Séverine Guiu, Jean‐Sébastien Frenel, Thomas Bachelot, Caroline Bailleux, Élise Deluche, Florence Dalenc, Anne Patsouris, Louis Larrouquère, Laurent Mathiot, Rayan Kabirian, Nicolás Isambert, Loïck Galland, Mónica Arnedos, Elsa Volant, François Bocquet, Delphine Loirat, Tevy San, Fanny Le Du, Alexandre de Nonnevile, Laura Poestch
article en

Abstract

Trastuzumab deruxtecan (T-DXd) is the current standard second-line therapy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), and it has been recently approved by FDA as first line therapy in combination with pertuzumab, following the results of the DESTINY-Breast09 trial. However, optimal treatment strategies following T-DXd remain undefined and data on subsequent therapies are limited. The present study evaluated the efficacy of combined treatment with tucatinib, trastuzumab, and capecitabine (TTC) after T-DXd. Patients with HER2-positive MBC who received TTC as second- or third-line therapy following T-DXd in the 17 participating centers were eligible. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were time to next treatment, overall survival (OS), and objective response rate. Between July 2021 and June 2025, 105 patients who received TTC as second- or third-line therapy following T-DXd were included in the study. The median age was 55.1 years, 41.0% had de novo metastatic disease, and 55.2% had brain metastases. Most patients (91.4%) received TTC as third-line therapy. During a median follow-up of 19.5 months, the median PFS, time to next treatment, and OS were 4.7, 6.6, and 15.3 months, respectively. Among evaluable patients, the objective response rate was 29.6%, with 9.2% achieving complete response. Patients with prior T-DXd exposure for >18 months had improved PFS (6.0 months) compared to those with prior T-DXd exposure for ≤18 months (3.8 months). TTC exhibited clinically meaningful activity following T-DXd in patients with HER2-positive MBC, particularly those with prolonged T-DXd response.

The BreastVol. 90
Centre National de la Recherche Scientifique (FR), Inserm (FR), Aix-Marseille Université (FR), Institut Gustave Roussy (FR), Centre Georges François Leclerc (FR), Centre Léon Bérard (FR), Institut de Cancérologie de l'Ouest (FR), Centre Eugène Marquis (FR), Centre Hospitalier Universitaire de Poitiers (FR), Polyclinique Bordeaux Nord Aquitaine (FR), Centre Hospitalier Universitaire de Limoges (FR), Centre François Baclesse (FR), Thion Medical (France) (FR), Institut Claudius Regaud (FR), Centre Oscar Lambret (FR), Institut Bergonié (FR), Centre de Recherche en Cancérologie de Marseille (FR), Institut Paoli-Calmettes (FR), Centre Antoine Lacassagne (FR), Institut Regional du Cancer de Montpellier (FR), Fondation Gustave Roussy (FR), Institut Curie (FR)
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Openalex Percentile: Top 15%
HER2/EGFR in Cancer Research
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