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Considerations in Maximizing Outcomes in HER2-Positive Breast Cancer

  • Authors: Sara A. Hurvitz, MD; Hope S Rugo, MD
  • CME / ABIM MOC Released: 12/21/2016
  • Valid for credit through: 12/21/2017
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Target Audience and Goal Statement

This activity is intended for oncologists and other healthcare professionals who care for patients with breast cancer.

The goal of this activity is to increase understanding about the role of biologic therapies, and the potential role of novel biosimilars, in the care for patients with human epidermal growth factor receptor 2 (HER2)+ breast cancer across the disease spectrum.

Upon completion of this activity, learners will have:

  1. Increased knowledge regarding the clinical trial evidence of biologics and biosimilars in the management of HER2-positive breast cancer across the continuum of disease
  2. Greater competence related to the selection of evidence-based regimens for patients with HER2- positive breast cancer


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  • Sara A. Hurvitz, MD, FACP

    Director, Breast Cancer Clinical Research Program, Associate Professor of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California


    Disclosure: Sara A. Hurvitz, MD, FACP, has disclosed the following relevant financial relationships:
    Received grants for clinical research from: Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Cascadian, Genentech, Inc., GlaxoSmithKline, Lilly, Mediavation Inc., Merrimack, PUMA,

    Dr Hurvitz does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Hurvitz does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

  • Hope S. Rugo, MD

    Professor of Medicine, Director of Breast Oncology and Clinical Trials Education, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California


    Disclosure: Hope S. Rugo, MD, has disclosed the following relevant financial relationships:
    Served as a speaker or a member of a speakers bureau for: Genomic Health
    Received grants for clinical research from: Amgen Inc., BioMarin Inc., Eisai Inc., Genentech, Inc., GlaxoSmithKline, Lilly, Macrogenics, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, OBI, Pfizer Inc., Plexxikon

    Dr Rugo does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Rugo does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.


  • Roderick A Smith, MS

    Scientific Director, Medscape, LLC


    Disclosure: Roderick A Smith, MS, has disclosed no relevant financial relationships.

CME Reviewer(s)

  • Amy H. Seung, PharmD, BCOP


    Disclosure: Amy H. Seung, PharmD, BCOP, has disclosed no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.

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Considerations in Maximizing Outcomes in HER2-Positive Breast Cancer


  • Recommendations for First-Line Treatment of HER2+ MBC[4,5]

    • For the case patient, a CLEOPATRA-like regimen is recommended, with the chemotherapy dropped after the patient has had a good response -- usually at least 6 cycles, but somewhere between 6 and 8 cycles
    • Dr. Rugo: Something I would do differently from CLEOPATRA is add back hormone therapy in the maintenance side:
      • There is heterogeneity in the cancer cell population and some cells may be more responsive to hormone therapy whereas other are more responsive to chemotherapy and antibodies
    • Dr Hurvitz: I agree completely; although this was not in the CLEOPATRA study design, it makes sense that when the chemotherapy stops, hormonal therapy is initiated

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  • CLEOPATRA: Phase 3 Trial of Trastuzumab, Docetaxel, and Pertuzumab in HER2+ MBC[6,7]

    • Patients in the CLEOPATRA trial could have either de novo or previously diagnosed human epidermal growth factor receptor 2 (HER2)-positive breast cancer
    • At least 12 months since last exposure to taxanes was required
    • Approximately 10% of patients in CLEOPATRA received trastuzumab in the adjuvant setting
    • The trial also included patients with de novo metastatic breast cancer (MBC) who had not received prior trastuzumab

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  • CLEOPATRA: OS and PFS Results[7]

    • There is not yet an explanation for the greater improvement observed in overall survival (OS) than in progression-free survival (PFS), despite pertuzumab not being continued after progression
      • There may be a biological change in the disease due to therapy
    • Clinicians should keep in mind toxicities that can be associated with adding pertuzumab to trastuzumab:
      • Pertuzumab is associated with diarrhea that may be exacerbated with chemotherapy
      • Rash can be significant in a small percentage of patients, perhaps due to targeting of epidermal growth factor receptor (EGFR) signaling
      • There is an increased rate of febrile neutropenia with the addition of pertuzumab to trastuzumab

  • Slide 7.

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  • Definition of Biosimilarity[8]

    • Biosimilars are biologic products that are complex chemicals, as opposed to generic drugs that are simple chemicals
    • Biosimilars require biologic testing to show that they are equivalent to the reference product and do not have anything other than mild impurities in the preclinical setting
    • Because of their complexity, biosimilars must be tested definitively in the clinical setting with a short-term endpoint to show that they have the same clinical effectiveness as the reference product; chemical tests alone are insufficient to demonstrate this

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  • HERITAGE: Phase 3 Trial of Proposed Trastuzumab Biosimilar (MYL-1401O) vs Trastuzumab[9]

    • The HERITAGE trial was undertaken to assess the efficacy and safety of a trastuzumab biosimilar (MYL-14010)
    • A study sample of 410 patients was required to show that the proposed trastuzumab biosimilar had an identical ORR to the reference trastuzumab with at least an 80% power
    • Although 500 patients enrolled, the evaluable sample size was approximately 450
      • Some patients enrolled prior to a study amendment that specified that patients could not have received any treatment for metastatic HER2-positive breast cancer, including chemotherapy
    • The primary endpoint was Week 24 ORR; after that point, patients could drop the chemotherapy and continue with the antibody alone

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  • HERITAGE: Primary Efficacy Results[9]

    • The ORR was essentially identical between the 2 arms; the ratio of ORR and the difference in ORR both fell within a predefined equivalence margin
    • Response rates were similar to previously published studies and to the control arm of the CLEOPATRA trial

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  • HERITAGE: Secondary Outcomes[9]

    • At Week 48, no significant differences were observed in PFS; less than half of the patient population had progression
    • Almost 90% of patients in both arms still survived at Week 48

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  • HERITAGE: Serious Adverse Events[9]

    • No differences in safety between the 2 arms were observed
    • Serious adverse event (AE) rates were as expected, as were rates of anti-drug antibodies and cardiac events
    • Dr Hurvitz: These are the type of data that are likely to make clinicians feel comfortable with the use of biosimilars

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  • Phase 3 Trial of Proposed Biosimilar (BCD-022) vs Trastuzumab[10]

    • Another trastuzumab biosimilar, BCD-022, was compared with trastuzumab in a smaller randomized, double-blind, phase 3 noninferiority trial
    • Patients received paclitaxel every 3 weeks, a regimen used less often in the United States; this schedule may have been used for dosing reasons

  • Slide 13.

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  • Phase 3 Trial of Proposed Biosimilar (BCD-022) vs Trastuzumab: Results[10]

    • The study showed noninferiority, with small differences in terms of ORR
    • Dr Rugo: This was a smaller trial; 126 patients is probably not sufficient to show similarity for regulatory requirements
      • The data are less definitive, but similarity was shown
    • The HERITAGE data have been submitted to the European Medicines Agency (EMA); the patent for the branded trastuzumab has already expired
    • In the United States, a trastuzumab biosimilar could not be considered for market approval until 2019, when the reference trastuzumab patent expires

  • Slide 14.

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  • Role of Biologics in Earlier-Stage HER2+ Breast Cancer

  • Slide 15.

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  • Why Use Neoadjuvant Systemic Therapy?[11-14]

    • Neoadjuvant systemic therapy has become a standard of care in HER2-positive breast cancer at large academic centers
    • Emerging data suggest that, particularly in HER2-positive disease, pathologic complete response (pCR), defined in the lymph nodes and breast at the time of surgery, is predictive of more favorable long-term outcomes as assessed by disease-free survival (DFS) and, possibly, OS
      • This surrogate earlier endpoint gives us an opportunity to evaluate new drugs in a shorter period of time with fewer patients

  • Slide 16.

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  • NeoSphere Study: pCR Rates with Neoadjuvant Pertuzumab, Trastuzumab, Docetaxel[15]

    • Two studies led to the 2013 US Food and Drug Administration (FDA) approval of dual HER2-targeted therapy combined with chemotherapy in the neoadjuvant setting
    • NeoSphere was a randomized phase 2 trial that evaluated trastuzumab, pertuzumab, and docetaxel, trastuzumab or pertuzumab plus docetaxel, and a relatively novel combination of just the dual HER2-targeted antibodies alone without chemotherapy prior to surgery
    • The pCR rate was higher in patients who received chemotherapy plus the two HER2-targeted agents, particularly in patients testing node-negative and breast-negative for residual disease
      • In these patients, the pCR rate with the combination was 39%, superior to either single biologic agent with chemotherapy

  • Slide 17.

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  • Neoadjuvant Pertuzumab- and Trastuzumab-Based Therapy[15,16]

    • The TRYPHAENA study evaluated the cardiac safety of 3 different regimens:
      • Two were based on fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by docetaxel, trastuzumab, and pertuzumab, including one that used trastuzumab and pertuzumab concurrently with FEC, which is not something that we traditionally use
      • One involved the docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) regimen, a non-anthracycline-based regimen that was administered for 6 cycles
    • All 3 regimens have shown high pCR rates; these are the 3 regimens FDA-approved for the neoadjuvant treatment of HER2+ breast cancer

  • Slide 18.

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  • LILAC: Phase 3 Trial of Proposed Trastuzumab Biosimilar (ABP 980) vs Trastuzumab in HER2+ Early Breast Cancer[17]

    • The phase 3 LILAC trial is evaluating a trastuzumab biosimilar in the neoadjuvant setting:
      • Patients are receiving epirubicin and cyclophosphamide for 4 cycles every 3 weeks, then paclitaxel every 3 weeks with either trastuzumab or the proposed biosimilar
      • Dr Rugo: This use of anthracyclines differs from clinical trials of pertuzumab, in which anthracyclines were given after surgery or not at all
    • In addition to assessing pCR, investigators are assessing long-term efficacy and safety
    • The trastuzumab arm is re-randomized after surgery to either ABP 980 or continued trastuzumab to allow for additional patients to be exposed to the biosimilar

  • Slide 19.

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  • APHINITY: Phase 3 Trial of Adjuvant Pertuzumab and Trastuzumab + Chemotherapy[18]

    • The APHINITY trial is evaluating whether pertuzumab given in early-stage breast cancer improves DFS and OS, in addition to pCR rate
      • Dr Rugo: Pertuzumab is currently approved in the neoadjuvant setting; patients who miss pertuzumab in this setting because they proceed directly to surgery may receive pertuzumab with chemotherapy, but it is stopped at the end of chemotherapy, per National Comprehensive Cancer Network (NCCN) Guidelines®
    • Dr Rugo: The trial was skewed somewhat towards higher-risk patients, in which a benefit of pertuzumab may be more evident

  • Slide 20.

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  • Studies Evaluating T-DM1 in Early-Stage HER2+ Breast Cancer[19-21]

    • A German group showed higher pCR rate with trastuzumab emtansine (T-DM1) with only 4 doses vs trastuzumab plus anastrozole in ER-positive disease
    • The ongoing phase 2 ATEMPT trial involves 3:1 randomization to T-DM1 alone for 1 year vs paclitaxel plus trastuzumab (APT regimen)

  • Slide 21.

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This content has been condensed for improved clarity.


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