Efficacy and Safety of Trastuzumab Emtansine Plus Capecitabine vs Trastuzumab Emtansine Alone in Patients With Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Phase 1 and Randomized Phase 2 Trial | Breast Cancer | JAMA Oncology | JAMA Network
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    Original Investigation
    June 25, 2020

    Efficacy and Safety of Trastuzumab Emtansine Plus Capecitabine vs Trastuzumab Emtansine Alone in Patients With Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Phase 1 and Randomized Phase 2 Trial

    Author Affiliations
    • 1Quirónsalud Group, IOB Institute of Oncology, Madrid, Spain
    • 2Quirónsalud Group, IOB Institute of Oncology, Barcelona, Spain
    • 3Vall d’Hebron Institute of Oncology, Barcelona, Spain
    • 4Centre Eugène Marquis, Rennes, France
    • 5Institut Curie, Paris, France
    • 6Hematology/Medical Oncology, 3rd Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
    • 7Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
    • 8Klinik für Hämatologie, Onkologie und Immunologie, Universitätsklinikum Gießen und Marburg, Standort Marburg, Philipps-Universität Marburg, Baldingerstraße, Marburg, Germany
    • 9Department of Haematology, Oncology and Tumorimmunology, Campus Virchow-Klinikum, Charité–University Medicine Berlin, Berlin, Germany
    • 10Division of Medical Oncology, Department of Oncology, Pontedera Hospital, Azienda L Toscana Nord Ovest, Pisa, Italy
    • 11Division of Breast Medical Oncology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Napoli, Italy
    • 12BC Cancer, Vancouver Cancer Centre, Vancouver, British Columbia, Canada
    • 132nd Department of Oncology, Faculty of Medicine, Comenius University, Bratislava, Slovak Republic
    • 14Department of Chemotherapy, Republican Clinical Oncology Center, Ufa, Russia
    • 15National Cancer Institute, Bratislava, Slovak Republic
    • 16Translational Genomics and Targeted Therapeutics in Solid Tumors Group, IDIBAPS, Barcelona, Spain
    • 17F. Hoffmann-La Roche Ltd, Basel, Switzerland
    • 18Now with Novartis, Basel, Switzerland
    • 19University of British Columbia, Vancouver, British Columbia, Canada
    JAMA Oncol. 2020;6(8):1203-1209. doi:10.1001/jamaoncol.2020.1796
    Visual Abstract. Efficacy of Trastuzumab Emtansine (T-DM1) Plus Capecitabine vs Trastuzumab Emtansine Alone in Patients With ERBB2-Positive Metastatic Breast Cancer
    Efficacy of Trastuzumab Emtansine (T-DM1) Plus Capecitabine vs Trastuzumab Emtansine Alone in Patients With ERBB2-Positive Metastatic Breast Cancer
    Key Points

    Question  What is the effect of adding capecitabine to trastuzumab emtansine (T-DM1) treatment in patients with previously treated ERBB2 (HER2)-positive metastatic breast cancer?

    Findings  In this phase 1/2 randomized clinical trial of 161 patients with previously treated ERBB2-positive metastatic breast cancer, the overall response rate was 44% and 36% in the combination and single-agent T-DM1 arms, respectively; median overall survival was not estimable and 24.7 months. Adverse events occurred in 95% (grade 3-4: 44%) and 89% (grade 3-4: 41%) of patients in each arm, respectively.

    Meaning  Adding capecitabine to T-DM1 increases toxic effects and does not improve clinical outcomes vs T-DM1 alone for previously treated ERBB2-positive metastatic breast cancer.


    Importance  ERBB2 (HER2)-targeted therapy provides benefits in metastatic breast cancer (mBC) and gastric cancer, but additional treatments are needed to maximize efficacy and quality of life.

    Objective  To determine maximum tolerated doses (MTDs) of trastuzumab emtansine (T-DM1) plus capecitabine in patients with previously treated ERBB2-positive mBC and locally advanced/metastatic gastric cancer (LA/mGC) (phase 1) and the efficacy and safety of this combination vs T-DM1 alone in patients with mBC (phase 2).

    Design, Setting, and Participants  The MTD in phase 1 was assessed using a 3 + 3 design with capecitabine dose modification. Phase 2 was an open-label, randomized, international multicenter study of patients with mBC treated with T-DM1 plus capecitabine or T-DM1 alone. Eligible patients had previously treated ERBB2-positive mBC or LA/mGC with no prior chemotherapy treatment for advanced disease.

    Interventions  Patients in the phase 1 mBC cohort received capecitabine (750 mg/m2, 700 mg/m2, or 650 mg/m2 twice daily, days 1-14 of a 3-week cycle) plus T-DM1 3.6 mg/kg every 3 weeks. Patients with LA/mGC received capecitabine at the mBC phase 1 MTD, de-escalating as needed, plus T-DM1 2.4 mg/kg weekly. In phase 2, patients with mBC were randomized (1:1) to receive capecitabine (at the phase 1 MTD) plus T-DM1 or T-DM1 alone.

    Main Outcomes and Measures  The phase 1 primary objective was to identify the MTD of capecitabine plus T-DM1. The phase 2 primary outcome was investigator-assessed overall response rate (ORR).

    Results  In phase 1, the median (range) age was 54.0 (37-71) and 57.5 (53-70) years for patients with mBC and patients with LA/mGC, respectively. The capecitabine MTD was identified as 700 mg/m2 in 11 patients with mBC and 6 patients with LA/mGC evaluable for dose-limiting toxic effects. In phase 2, between October 2014 and April 2016, patients with mBC (median [range] age, 52.0 [28-80] years) were randomized to receive combination therapy (n = 81) or T-DM1 (n = 80). The ORR was 44% (36 of 81 patients) and 36% (29 of 80 patients) in the combination and T-DM1 groups, respectively (difference, 8.2%; 90% CI, −4.5 to 20.9; P = .34; clinical cutoff, May 31, 2017). Adverse events (AEs) were reported in 78 of 82 patients (95%) in the combination group, with 36 (44%) experiencing grade 3-4 AEs, and 69 of 78 patients (88%) in the T-DM1 group, with 32 (41%) experiencing grade 3-4 AEs. No grade 5 AEs were reported.

    Conclusions and Relevance  Adding capecitabine to T-DM1 did not statistically increase ORR associated with T-DM1 in patients with previously treated ERBB2-positive mBC. The combination group reported more AEs, but with no unexpected toxic effects.

    Trial Registration  ClinicalTrials.gov Identifier: NCT01702558