title: A phase 1 study of cetuximab and lapatinib in patients with advanced solid tumor malignancies.
abstract: BACKGROUND
  Acquired resistance to antiepidermal growth factor receptor (anti-EGFR) therapy may be caused by EGFR-v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ErbB2) heterodimerization and pathway reactivation. In preclinical studies, inhibiting ErbB2 blocked this resistance mechanism and resensitized cells to anti-EGFR therapy. Cetuximab targets EGFR, whereas lapatinib inhibits both EGFR and ErbB2. The objective of this phase 1 trial was to assess the safety, dose-limiting toxicities (DLTs), and maximum tolerated doses (MTDs) of cetuximab and lapatinib in patients with solid tumors.
  
  
  METHODS
  Patients received standard weekly cetuximab with escalating lapatinib doses of 750 mg, 1000 mg, or 1250 mg daily in 3-week cycles. DLTs were monitored through the end of cycle 2. Pretreatment and post-treatment tumor biopsies and germline DNA samples were obtained for correlative studies.
  
  
  RESULTS
  Twenty-two patients were enrolled, and 18 patients each were evaluable for toxicity and response. Fifty-nine percent of patients had received prior anti-EGFR therapy. Common toxicities included rash and diarrhea. No patient experienced a DLT at the highest dose level, and no grade 4 toxicity was observed. Response included no complete responses, 3 partial responses, 9 patients with stable disease, and 6 patients with disease progression, for an overall response rate of 17% and a clinical benefit rate of 67%. The clinical benefit rate in patients who had previously received anti-EGFR therapy was 70%. The mean treatment duration was 4.7 cycles (range, 1-14 cycles). Decreased expression of EGFR/ErbB2 pathway components after treatment was correlated with response, whereas increased expression in the PI3K, Jak/Stat, and MAPK pathways occurred in nonresponders.
  
  
  CONCLUSIONS
  The combination of cetuximab and lapatinib was well tolerated, had the expected toxicities, and exhibited notable clinical activity, including in patients who had received previous anti-EGFR therapy. Further clinical study of this combination is warranted.
authors: Inova Comprehensive Cancer and Research Institute, Falls Church, Virginia.
authors: John F
authors: JF
authors: Deeken
authors: Hongkun
authors: H
authors: Wang
authors: Deepa
authors: D
authors: Subramaniam
authors: Aiwu Ruth
authors: AR
authors: He
authors: Jimmy
authors: J
authors: Hwang
authors: John L
authors: JL
authors: Marshall
authors: Christina E
authors: CE
authors: Urso
authors: Yiru
authors: Y
authors: Wang
authors: Corinne
authors: C
authors: Ramos
authors: Kenneth
authors: K
authors: Steadman
authors: Michael J
authors: MJ
authors: Pishvaian
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001005:Anus Neoplasms / Q000188:drug therapy; D001706:Biopsy; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D003875:Drug Eruptions / Q000209:etiology; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000188:drug therapy; D006801:Humans; D000077341:Lapatinib; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D010597:Pharmacogenetics; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D066246:ErbB Receptors; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: cetuximab; clinical trial; epidermal growth factor receptor; lapatinib; phase 1; solid tumors; v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2
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