title: Phase 1 study of lenvatinib combined with carboplatin and paclitaxel in patients with non-small-cell lung cancer.
abstract: BACKGROUND
  This dose-finding study evaluated lenvatinib, an oral multitargeted receptor tyrosine kinase inhibitor, in combination with carboplatin/paclitaxel in chemotherapy-naïve non-small-cell lung cancer (NSCLC) patients.
  
  
  METHODS
  Patients received lenvatinib twice daily (BID) with carboplatin (area under the curve 6 mg ml(-1) min(-1), day 1)/paclitaxel (200 mg m(-2), day 1) every 3 weeks. The initial dose of lenvatinib was 6 mg BID. The primary end point was maximum tolerated dose (MTD) of lenvatinib. At the MTD, the cohort was expanded by 16 patients. Safety, pharmacokinetics, pharmacodynamics, and antitumor effects were evaluated.
  
  
  RESULTS
  Twenty-eight patients were treated. At 6 mg BID, dose-limiting toxicities (DLTs) included febrile neutropenia/gingival infection (n=2). No DLTs occurred with 4 mg BID, the recommended MTD for the expansion. Common grade 3/4 toxicities included neutropenia, leukopenia, hypertension, and thrombocytopenia. The combination had no significant impact on individual drug pharmacokinetics. Response rate and median progression-free survival were 68% and 9.0 months, respectively, with 4 mg BID. In the plasma biomarker analysis, stromal cell-derived factor 1α, stem cell factor, and granulocyte colony-stimulating factor correlated with antitumor activity.
  
  
  CONCLUSIONS
  The MTD for lenvatinib with carboplatin/paclitaxel is 4 mg BID in advanced NSCLC patients. This regimen demonstrated manageable tolerability and encouraging antitumor activity.
authors.affiliation: Department of Thoracic Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Japan. mnishio@jfcr.or.jp
authors.forename: M
authors.initials: M
authors.lastname: Nishio
authors.forename: T
authors.initials: T
authors.lastname: Horai
authors.forename: A
authors.initials: A
authors.lastname: Horiike
authors.forename: H
authors.initials: H
authors.lastname: Nokihara
authors.forename: N
authors.initials: N
authors.lastname: Yamamoto
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.forename: H
authors.initials: H
authors.lastname: Murakami
authors.forename: N
authors.initials: N
authors.lastname: Yamamoto
authors.forename: F
authors.initials: F
authors.lastname: Koizumi
authors.forename: K
authors.initials: K
authors.lastname: Nishio
authors.forename: W
authors.initials: W
authors.lastname: Yusa
authors.forename: N
authors.initials: N
authors.lastname: Koyama
authors.forename: T
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D010671:Phenylurea Compounds; D011804:Quinolines; D016190:Carboplatin; C531958:lenvatinib; D017239:Paclitaxel