title: Randomized trial of lapatinib versus placebo added to paclitaxel in the treatment of human epidermal growth factor receptor 2-overexpressing metastatic breast cancer.
abstract: OBJECTIVE
  Lapatinib is an oral small-molecule tyrosine kinase inhibitor of both epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2). This study is designed to test whether the addition of lapatinib to paclitaxel improves overall survival (OS) compared with placebo plus paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC).
  
  
  METHODS
  This phase III, randomized, double-blind study assessed the efficacy and safety of lapatinib plus paclitaxel compared with placebo plus paclitaxel in patients with newly diagnosed HER2-positive MBC. The primary end point was OS. Secondary end points included progression-free survival (PFS), overall response rate (ORR), clinical benefit rate, and safety.
  
  
  RESULTS
  The addition of lapatinib to paclitaxel significantly improved OS versus paclitaxel (treatment hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.94; P = .0124); median OS was 27.8 versus 20.5 months, respectively. Median PFS was prolonged by 3.2 months, from 6.5 months with placebo plus paclitaxel to 9.7 months with lapatinib plus paclitaxel (HR, 0.52; 95% CI, 0.42 to 0.64; stratified log-rank P < .001). ORR was significantly higher with lapatinib plus paclitaxel compared with placebo plus paclitaxel (69% v 50%, respectively; P < .001). The incidence of grades 3 and 4 diarrhea and neutropenia was higher in the lapatinib plus paclitaxel arm. Only 4% of patients in this group reported febrile neutropenia. Cardiac events were low grade, asymptomatic, and mostly reversible. The incidence of hepatic events was similar in both arms. There were no fatal adverse events in the lapatinib plus paclitaxel arm.
  
  
  CONCLUSIONS
  This trial demonstrated that lapatinib combined with paclitaxel offers a significant and clinically meaningful survival advantage over paclitaxel alone in patients with HER2-positive MBC.
authors.affiliation: Sun Yat-Sen University Cancer Center, Guangzhou, China. guanzhzh@mail.sysu.edu.cn
authors.forename: Zhongzhen
authors.initials: Z
authors.lastname: Guan
authors.forename: Binghe
authors.initials: B
authors.lastname: Xu
authors.forename: Michelle L
authors.initials: ML
authors.lastname: DeSilvio
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Shen
authors.forename: Wichit
authors.initials: W
authors.lastname: Arpornwirat
authors.forename: Zhongsheng
authors.initials: Z
authors.lastname: Tong
authors.forename: Vicharn
authors.initials: V
authors.lastname: Lorvidhaya
authors.forename: Zefei
authors.initials: Z
authors.lastname: Jiang
authors.forename: Junlan
authors.initials: J
authors.lastname: Yang
authors.forename: Anatoly
authors.initials: A
authors.lastname: Makhson
authors.forename: Wai Lim
authors.initials: WL
authors.lastname: Leung
authors.forename: Mark W
authors.initials: MW
authors.lastname: Russo
authors.forename: Beth
authors.initials: B
authors.lastname: Newstat
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: George
authors.initials: G
authors.lastname: Chen
authors.forename: Cristina
authors.initials: C
authors.lastname: Oliva
authors.forename: Henry
authors.initials: H
authors.lastname: Gomez
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077341:Lapatinib; D008875:Middle Aged; D016017:Odds Ratio; D017239:Paclitaxel / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D000077341:Lapatinib; D017239:Paclitaxel; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human