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
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 35.173.234.169. Please contact the publisher to request reinstatement.
1.
Slamon  DJ, Clark  GM, Wong  SG, Levin  WJ, Ullrich  A, McGuire  WL.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.   Science. 1987;235(4785):177-182. doi:10.1126/science.3798106PubMedGoogle ScholarCrossref
2.
Ross  JS, McKenna  BJ.  The HER-2/neu oncogene in tumors of the gastrointestinal tract.   Cancer Invest. 2001;19(5):554-568. doi:10.1081/CNV-100103852PubMedGoogle ScholarCrossref
3.
Cardoso  F, Costa  A, Senkus  E,  et al.  3rd ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 3).   Ann Oncol. 2017;28(12):3111. doi:10.1093/annonc/mdx036PubMedGoogle ScholarCrossref
4.
National Comprehensive Cancer Network. Breast cancer. Version 2.2020. Accessed February 19, 2020. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
5.
Smyth  EC, Verheij  M, Allum  W, Cunningham  D, Cervantes  A, Arnold  D; ESMO Guidelines Committee.  Gastric cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.   Ann Oncol. 2016;27(suppl 5):v38-v49. doi:10.1093/annonc/mdw350PubMedGoogle ScholarCrossref
6.
National Comprehensive Cancer Network. Gastric cancer. Version 4.2019. Accessed February 19, 2020. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf
7.
Swain  SM, Kim  SB, Cortés  J,  et al.  Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study.   Lancet Oncol. 2013;14(6):461-471. doi:10.1016/S1470-2045(13)70130-XPubMedGoogle ScholarCrossref
8.
Verma  S, Miles  D, Gianni  L,  et al; EMILIA Study Group.  Trastuzumab emtansine for HER2-positive advanced breast cancer.   N Engl J Med. 2012;367(19):1783-1791. doi:10.1056/NEJMoa1209124PubMedGoogle ScholarCrossref
9.
Krop  IE, Kim  SB, Martin  AG,  et al.  Trastuzumab emtansine versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial.   Lancet Oncol. 2017;18(6):743-754. doi:10.1016/S1470-2045(17)30313-3PubMedGoogle ScholarCrossref
10.
Lewis Phillips  GD, Li  G, Dugger  DL,  et al.  Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate.   Cancer Res. 2008;68(22):9280-9290. doi:10.1158/0008-5472.CAN-08-1776PubMedGoogle ScholarCrossref
11.
Thuss-Patience  PC, Shah  MA, Ohtsu  A,  et al.  Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study.   Lancet Oncol. 2017;18(5):640-653. doi:10.1016/S1470-2045(17)30111-0PubMedGoogle ScholarCrossref
12.
von Minckwitz  G, du Bois  A, Schmidt  M,  et al.  Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 study.   J Clin Oncol. 2009;27(12):1999-2006. doi:10.1200/JCO.2008.19.6618PubMedGoogle ScholarCrossref
13.
Schaller  G, Fuchs  I, Gonsch  T,  et al.  Phase II study of capecitabine plus trastuzumab in human epidermal growth factor receptor 2 overexpressing metastatic breast cancer pretreated with anthracyclines or taxanes.   J Clin Oncol. 2007;25(22):3246-3250. doi:10.1200/JCO.2006.09.6826PubMedGoogle ScholarCrossref
14.
Ishida  T, Kiba  T, Takeda  M,  et al.  Phase II study of capecitabine and trastuzumab combination chemotherapy in patients with HER2 overexpressing metastatic breast cancers resistant to both anthracyclines and taxanes.   Cancer Chemother Pharmacol. 2009;64(2):361-369. doi:10.1007/s00280-008-0882-8PubMedGoogle ScholarCrossref
15.
Bang  YJ, Van Cutsem  E, Feyereislova  A,  et al; ToGA Trial Investigators.  Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.   Lancet. 2010;376(9742):687-697. doi:10.1016/S0140-6736(10)61121-XPubMedGoogle ScholarCrossref
16.
Lewis Phillips  G, Fields  CT, Crocker  L,  et al.  Potent anti-tumor activity of trastuzumab-DM1 antibody conjugate in combination with cytotoxic chemotherapeutic agents, antibodies or small molecule kinase inhibitors  [abstract].  Cancer Res. 2008;68(suppl):2133.Google ScholarCrossref
17.
Diéras  V, Harbeck  N, Budd  GT,  et al.  Trastuzumab emtansine in human epidermal growth factor receptor 2-positive metastatic breast cancer: an integrated safety analysis.   J Clin Oncol. 2014;32(25):2750-2757. doi:10.1200/JCO.2013.54.4999PubMedGoogle ScholarCrossref
18.
Diéras  V, Miles  D, Verma  S,  et al.  Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial.   Lancet Oncol. 2017;18(6):732-742. doi:10.1016/S1470-2045(17)30312-1PubMedGoogle ScholarCrossref
19.
Montemurro  F, Ellis  P, Anton  A,  et al.  Safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive advanced breast cancer: primary results from the KAMILLA study cohort 1.   Eur J Cancer. 2019;109:92-102. doi:10.1016/j.ejca.2018.12.022PubMedGoogle ScholarCrossref
20.
Martin  M, Fumoleau  P, Dewar  JA,  et al.  Trastuzumab emtansine (T-DM1) plus docetaxel with or without pertuzumab in patients with HER2-positive locally advanced or metastatic breast cancer: results from a phase Ib/IIa study.   Ann Oncol. 2016;27(7):1249-1256. doi:10.1093/annonc/mdw157PubMedGoogle ScholarCrossref
21.
Krop  IE, Modi  S, LoRusso  PM,  et al.  Phase 1b/2a study of trastuzumab emtansine (T-DM1), paclitaxel, and pertuzumab in HER2-positive metastatic breast cancer.   Breast Cancer Res. 2016;18(1):34. doi:10.1186/s13058-016-0691-7PubMedGoogle ScholarCrossref
22.
López-Miranda  E, Brain  E, Saura  C,  et al.  Phase I multicenter clinical trial evaluating the combination of trastuzumab emtansine (T-DM1) and non-pegylated liposomal doxorubicin (NPLD) in HER2-positive metastatic breast cancer (MBC) (MEDOPP038 study)  [abstract No. OT1-02-03].  Cancer Res. 2017;77(suppl 4). doi:10.1158/1538-7445.SABCS16-OT1-02-03Google Scholar
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    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.

    Abstract

    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

    ×