title: A phase I trial of gefitinib and nimotuzumab in patients with advanced non-small cell lung cancer (NSCLC).
abstract: BACKGROUND
  Nimotuzumab (TheraCIM®) is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) with minimal skin toxicity. Combining a different class of anti-EGFR drug with gefitinib is a new strategy to overcome intrinsic and acquired resistance to gefitinib. The aim of this phase I trial was to determine recommended phase II dose (RPIID) and the safety of gefitinib and nimotuzumab combination treatment.
  
  
  METHODS
  Patients with advanced/metastatic NSCLC were treated with escalating doses of weekly nimotuzumab (100mg or 200mg, IV) and fixed doses of daily gefitinib (250 mg/day, PO) until disease progression or unacceptable toxicity. We planned to enroll 10 additional patients at RPIID to ascertain the safety of treatment. EGFR mutations and KRAS mutations were analyzed from available tumor samples.
  
  
  RESULTS
  A total of 16 patients were enrolled (3 in 100mg cohort, 13 in 200mg cohort). Six patients (37.5%) were female, and 5 (31.3%) were never smokers. Adenocarcinoma was the major histologic type (13 patients, 81.3%). Treatment was well-tolerated without dose-limiting toxicity (DLT). Four patients (25.0%) experienced grade 2 skin toxicity (1 in 100mg cohorts, 3 in 200mg cohort). Other common grade 1/2 toxicities were fatigue (37.5%) and diarrhea (25.0%). Among 16 evaluable patients, four patients (25.0%) achieved partial response and 7 patients (43.8%) had stable disease. Two of 4 responders had EGFR mutation (exon 19 deletion).
  
  
  CONCLUSIONS
  Dual agent molecular targeting of EGFR with nimotuzumab and gefitinib in patients with advanced NSCLC is well-tolerated. The RPIID for nimotuzumab is 200mg weekly IV and for gefitinib 250 mg/day PO. Based upon this phase I trial, we are planning to conduct a randomized phase II trial comparing gefitinib and nimotuzumab with gefitinib alone in patients with advanced NSCLC.
authors.affiliation: Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Se Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Hyo Sup
authors.initials: HS
authors.lastname: Shim
authors.forename: Jaeho
authors.initials: J
authors.lastname: Cho
authors.forename: Jae Heon
authors.initials: JH
authors.lastname: Jeong
authors.forename: Sun Mi
authors.initials: SM
authors.lastname: Kim
authors.forename: Yun Kyoung
authors.initials: YK
authors.lastname: Hong
authors.forename: Ji Hee
authors.initials: JH
authors.lastname: Sung
authors.forename: Sang-Jun
authors.initials: SJ
authors.lastname: Ha
authors.forename: Hye Ryun
authors.initials: HR
authors.lastname: Kim
authors.forename: Hyun
authors.initials: H
authors.lastname: Chang
authors.forename: Joo Hang
authors.initials: JH
authors.lastname: Kim
authors.forename: Crombet
authors.initials: C
authors.lastname: Tania
authors.forename: Byoung Chul
authors.initials: BC
authors.lastname: Cho
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics / Q000276:immunology; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D012871:Skin Diseases / Q000209:etiology; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; C501466:nimotuzumab; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000077156:Gefitinib