title: A phase 2 study of the insulin-like growth factor-1 receptor inhibitor MK-0646 in patients with metastatic, well-differentiated neuroendocrine tumors.
abstract: BACKGROUND
  Neuroendocrine tumor (NET) cell lines frequently express both insulin-like growth factor (IGF) ligand and the cognate IGF-1 receptor (IGF-1R) and, as such, potentially depend on the activation of IGF-1R and its downstream effectors for growth and survival. Preclinical studies suggest that somatostatin analogs and mammalian target of rapamycin (mTOR) inhibitors exhibit antitumor activity against NETs through inhibition of IGF-1-dependent signaling, suggesting that IGF-1R inhibition may be a promising therapeutic approach to NETs. Therefore, the authors of this report evaluated the safety and efficacy of MK-0646, a fully human monoclonal antibody (MoAb) that binds to the IGF-1R, as monotherapy in patients with metastatic, well-differentiated NETs.
  
  
  METHODS
  A phase 2 study was performed in which patients received intravenous MK-0646 10 mg/kg once weekly over 1 hour. Archived pretreatment tumor tissue was obtained and genotyped for v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositol-3-kinase, catalytic, alpha polypeptide (PIK3CA); and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations, and immunohistochemistry was performed to measure the expression IGF-1R.
  
  
  RESULTS
  Twenty-five patients received treatment (40% women; median age, 61 years; age range, 37-83 years), including 15 patients with carcinoid tumors and 10 patients with pancreatic NETs. No partial or complete responses were observed. The median progression-free survival was 4.2 months in the pancreatic NET cohort (range, 0.7-6.7 months) and 2.7 months in the carcinoid cohort (range, 2-3 months). Serious adverse events that were potentially related to MK-0646 included grade 3/4 hyperglycemia in 8 of 25 patients (32%), grade 2 hypersensitivity reaction in 1 of 24 patients (4%), and grade 3 lipase elevation in 1 of 25 patients (4%).
  
  
  CONCLUSIONS
  Despite a compelling preclinical rationale, MK-0646 was inactive as a single agent in well-differentiated NETs. Further studies of MK-0646 as a monotherapy in unselected NETs are unwarranted.
authors.affiliation: Department of Medicine, Division of Solid Tumors, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. reidy@mskcc.org
authors.forename: Diane L
authors.initials: DL
authors.lastname: Reidy-Lagunes
authors.forename: Efsevia
authors.initials: E
authors.lastname: Vakiani
authors.forename: Michal F
authors.initials: MF
authors.lastname: Segal
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Hollywood
authors.forename: Laura H
authors.initials: LH
authors.lastname: Tang
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.forename: M Catherine
authors.initials: MC
authors.lastname: Pietanza
authors.forename: Marinela
authors.initials: M
authors.lastname: Capanu
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Saltz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002276:Carcinoid Tumor / Q000188:drug therapy; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017211:Treatment Failure
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C569480:dalotuzumab; D017526:Receptor, IGF Type 1