PHASE II RANDOMIZED STUDY OF TRASTUZUMAB EMTANSINE VERSUS TRASTUZUMAB PLUS DOCETAXEL IN PATIENTS WITH HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 – POSITIVE METASTATIC BREAST CANCER R2 김형오 J Clin Oncol 31: © 2013 by American Society of Clinical Oncology

Introduction  HER-2 overexpression in 20% of breast cancers  Increased mortality in early stage disease  Decreased time to relapse  Increased incidence of metastases  Trastuzumab + taxane based chemotherapy demonstrated significantly improved overall survival and progression free survival  Trastuzumab containing regimen : 1 st line therapy for HER2 (+) metastatic breast cancer(MBC)

Introduction  MBC will eventrually progress in most patients  Chemotherapy associated toxicity  Source of morbidity  Severe myelosuppression in docetaxel Tx  Trastuzumab emtansine(T-DM1)  Cytotoxic microtubule polymerization inhibitor DM1 conjugated to the humanized monoclonal Ab trastuzumab  Ab-drug conjugate by stable thioether linker  Selectively delivers a cytotoxic agent to tumor cells

Purpose  To compare T-DM1’s(DM1 conjugated trastuzumab) effects / side effects with HT’s (Trastuzumab + docetaxel) in HER2(+) MBC patients

Patients and Methods  Patients  18 years of age or more  Hitologically or cytologically confirmed  HER2(+) immunohistochemistry 3+, >10% cell staining Fluorescent in situ hybridization (+)  Unresectable  Locally advanced breast cancer or MBC w/o prior chemotherapy or trastuzumab for metastatic disease

Patients and Methods  Exclusion criteria  Less than 6 months from completion of CTx  Untreated / symptomatic brain metastases  Treatment for brain metastases ≤ 60 days  Cumulative anthracycline dose equivalent to doxorubicin more than 500mg/m2  History of significant cardiovascular or other severe uncontrolled systemic disease

Patients and Methods  Study design  Patients randomly assigned 1:1 T-DM1 3.6mg/kg IV q3wks Trastuzumab 8mg/kg IV loading dose followed by 6mg/kg q3wks and docetaxel 75 or 100mg/m2 (HT)  Progression free survival  Adverse events  Objective Response rate  QOL

Efficacy ORR in HT : 58.0% ORR in T-DM1 : 64.2%

Safety

T-DM1HT Grade ≥ 346.4%90.9% Grade 45.8%57.6% Treatment stopped d/t adverse event 7.2%40.9% Decreased LVEF Grade 1 : 2 Grade 3 : 1 Grade 2 : 2 Grade 3 : 1

QOL

Discussion  T-DM 1 and HT  Median PFS 14.2 months and 9.2 months  Grade 4 AE 5.8% and 57.6%  Adverse event Headache, thrombocytopenia, AST, ALT elevation in T-DM 1, and alopecia, neutropenia, peripheral edema, diarrhea in HT group  AE leading to treatment discontinuation 7.2% and 40.9%

Discussion  QOL  FACT-B  Favorable safety profile in T-DM1

Conclussion  In this study, T-DM1 was superior to 1 st line HT therapy in terms of PFS, safety and QOL in HER2(+), metastatic breast cancer patients