title: Phase I Study of Lapatinib and Pemetrexed in the Second-Line Treatment of Advanced or Metastatic Non-Small-Cell Lung Cancer With Assessment of Circulating Cell Free Thymidylate Synthase RNA as a Potential Biomarker.
abstract: BACKGROUND
  Lapatinib is a dual tyrosine kinase inhibitor that targets epidermal growth factor receptor and HER2. We report on a dose-escalation study of lapatinib combined with pemetrexed in second-line treatment to evaluate the safety and efficacy in advanced or metastatic non-small-cell lung cancer (NSCLC) and an exploratory study in which circulating cell-free thymidylate synthase ribonucleic acid (cfTSmRNA) was measured in all patients and compared with clinical benefit.
  
  
  METHODS
  Eligible patients had stage IIIB or IV NSCLC after 1 previous line of chemotherapy and an Eastern Cooperative Oncology Group performance status of 0 to 2. Three dose levels (DLs) of lapatinib (daily)/pemetrexed (every 21 days) were evaluated: DL0, 1250 mg/400 mg; DL1, 1250 mg/500 mg; and DL2, 1500 mg/500 mg, respectively. The primary outcome was identification of the optimal treatment regimen.
  
  
  RESULTS
  Eighteen patients were treated (DL0: n = 4; DL1: n = 8; DL2: n = 6). The most common adverse events (any grade) were diarrhea (61%), rash (44%), nausea (33%), anemia, and fatigue (both 28%). DL1 was determined as optimal after 3 dose-limiting toxicities (DLTs) during the first cycle of DL2 (Grade 3 diarrhea and mucositis, Grade 4 lymphocytopenia); no other DLTs were observed. Partial response was detected in 4 patients. cfTSmRNA was at the limit of detection and was not measurable in all patients. Nonsignificant trends were observed, suggesting that higher levels of cfTSmRNA are associated with poorer outcome. Confirmatory studies are required.
  
  
  CONCLUSIONS
  Lapatinib and pemetrexed was well tolerated, and data suggest a similar response rate to pemetrexed monotherapy.
authors.affiliation: Department of Oncology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Rodryg
authors.initials: R
authors.lastname: Ramlau
authors.affiliation: Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitatsklinikum Heidelberg, Translational Lung Research Centre Heidelberg (TLRC-H), Member of the German Centre for Lung Research (DZL), Department of Internal Oncology, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Thomas
authors.affiliation: University of Turin, Thoracic Oncology Unit, Turin, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Novello
authors.affiliation: Northern Institute for Cancer Research, School of Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Plummer
authors.affiliation: Krankenhaus Grosshansdorf, Department of Thoracic Surgery, Grosshansdorf, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
authors.affiliation: GlaxoSmithKline Oncology, Uxbridge, UK.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kaneko
authors.affiliation: GlaxoSmithKline Oncology, Uxbridge, UK.
authors.forename: Mike R
authors.initials: MR
authors.lastname: Lau
authors.affiliation: Northern Institute for Cancer Research, School of Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Margetts
authors.affiliation: Northern Institute for Cancer Research, School of Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: John
authors.initials: J
authors.lastname: Lunec
authors.affiliation: Northern Institute for Cancer Research, School of Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Joyce
authors.initials: J
authors.lastname: Nutt
authors.affiliation: University of Turin, Thoracic Oncology Unit, Turin, Italy. Electronic address: giorgio.scagliotti@unito.it.
authors.forename: Giorgio V
authors.initials: GV
authors.lastname: Scagliotti
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000068437:Pemetrexed / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D013940:Thymidylate Synthase / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D011799:Quinazolines; D000068437:Pemetrexed; D000077341:Lapatinib; D013940:Thymidylate Synthase
keywords: Epidermal growth factor receptor; Optimal treatment regimen; Tyrosine kinase inhibitor