Continued HER2 Suppression With Lapatinib Plus Trastuzumab Versus Trastuzumab Alone
Condition: Cancer
Intervention: Lapatinib; Trastuzumab
Intervention description: Oral Lapatinib 1000 mg once daily. Lapatinib was a small molecule, reversible inhibitor targeting HER2 tyrosine kinase receptor.; IV Trastuzumab 6 mg/kg every three weeks. Trastuzumab was a humanized, monoclonal antibody directed against the extracellular domain of the HER2 tyrosine kinase receptor.
Intervention MeSH terms: Trastuzumab; Lapatinib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Masking: None (Open Label)
Enrollment: 37.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: carcinoma, breast lump, Pagets disease, breast cancer positive for human epidermal growth factor receptor 2, breast cancer progression, estrogen-receptor

Summary:

      This was a randomized, open-label, multi-center Phase III study evaluating the efficacy and
      safety of lapatinib in combination with trastuzumab versus trastuzumab alone as continued
      HER2 suppression therapy in women with HER2-positive metastatic breast cancer (MBC). Eligible
      subjects should have completed 12 to 24 weeks of first- or second-line treatment with
      trastuzumab plus chemotherapy, experienced either complete disappearance of all metastatic
      lesions, or persistence of metastatic disease (stable disease) without unequivocal
      progression or the occurrence of new lesions, and been indicated to continue to receive
      trastuzumab alone as maintenance therapy. Eligible subjects who entered the LPT112515 study
      on first-line treatment should not have known history of central nervous system (CNS)
      metastases; subjects who entered the study on second-line treatment should not have known
      history of CNS metastases or have stable (asymptomatic and off steroids ≥3 months) CNS
      metastases. The primary objective of this study was to compare progression-free survival
      (PFS) in subjects with HER2-positive MBC randomized to receive treatment with lapatinib plus
      trastuzumab versus those randomized to receive trastuzumab alone. The secondary objectives
      included overall survival, clinical benefit response rate (CR, PR or SD ≥24 weeks) and the
      qualitative and quantitative adverse event profile of the 2 treatment arms. It was estimated
      that 280 subjects (140 per group) would be required to observe 193 PFS events.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Signed the informed consent form (ICF)

          -  Female, ≥18 years of age

          -  Histologically verified breast cancer with distant metastases (metastatic breast
             cancer)

          -  Documentation of HER2 overexpression or gene amplification in the invasive component
             of either the primary tumor or metastatic disease site defined as:

          -  3+ by IHC and/or

          -  HER2/neu gene amplification by fluorescence, chromogenic or silver in situ
             hybridization [FISH, CISH or SISH; >6 HER2/neu gene copies per nucleus or a FISH, CISH
             or SISH HER2 gene copies to chromosome 17 signal ratio of ≥2.0]

          -  Completed 12 to 24 weeks of first- or second-line treatment with trastuzumab in
             combination with chemotherapy

          -  Either complete disappearance of all lesions, or persistence of metastatic disease
             (stable disease) without unequivocal progression or the occurrence of new lesions

          -  Documentation of lesion response during the course of therapy received prior to
             randomization (i.e., improvement or no worsening of tumor burden; the absence of new
             lesions)

          -  Measurable disease is not required for study participation

          -  No known or suspected (associated neurological signs and symptoms) brain metastases
             (including leptomeningeal involvement)

          -  Stable brain metastasis (defined as asymptomatic and off steroids ≥3 months) are
             permitted in subjects on second-line treatment (completed 12-24 weeks of second-line
             treatment with trastuzumab plus chemotherapy)

          -  Baseline of Left Ventricular Ejection Fraction (LVEF) ≥50% measured by
             echocardiography (ECHO) or multi-gated acquisition scan (MUGA)

          -  Completion of screening assessments

          -  Have adequate marrow and organ function

        Exclusion Criteria:

          -  History of other malignancy. Subjects who have been disease-free for 5 years or
             subjects with a history of completely resected non-melanoma skin cancer (basal or
             squamous) are eligible

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status >2

          -  Concurrent anti-cancer treatment, except anti-hormonal therapy for subjects with
             hormone receptor positive breast cancer

          -  Concurrent treatment with an investigational agent

          -  Prior treatment with anti-HER2 therapy, except trastuzumab or lapatinib

          -  Concurrent treatment with protocol-defined prohibited medications (refer to protocol
             for details)

          -  Serious cardiac illness or medical condition including but not confined to:

          -  Uncontrolled arrhythmias

          -  Uncontrolled or symptomatic angina

          -  History of congestive heart failure (CHF)

          -  Myocardial infarction <6 months from study entry

          -  Acute or current active (requiring anti-viral therapy) hepatic or biliary disease
             (with the exception of subjects with Gilbert's syndrome, asymptomatic gallstones,
             liver metastases or stable chronic liver disease per investigator assessment)

          -  Concurrent disease or condition that may interfere with study participation, or any
             serious medical disorder that would interfere with the subject's safety (for example,
             active or uncontrolled infection or any psychiatric condition prohibiting
             understanding or rendering of informed consent)

          -  Women of childbearing potential, including women whose last menstrual period was <12
             months ago (unless surgically sterile) who are unable or unwilling to use adequate
             contraceptive measures during the study treatment period. Adequate contraception
             includes intra-uterine device, barrier methods with spermicide, or oral contraceptives
             (unless clinically contraindicated for the subject population or per local practice,
             refer to protocol for further details)

          -  Pregnant or lactating females

          -  Any clinically significant gastrointestinal abnormalities that may alter absorption
             such as malabsorption syndrome or major resection of the stomach or bowels.

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to any of the study agents or their excipients that, in the opinion
             of the Investigator or GSK medical monitor , contra-indicates participation