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A phase 2 study of the insulin‐like growth factor‐1 receptor inhibitor MK‐0646 in patients with metastatic, well‐differentiated neuroendocrine tumors
Author(s) -
ReidyLagunes Diane L.,
Vakiani Efsevia,
Segal Michal F.,
Hollywood Ellen M.,
Tang Laura H.,
Solit David B.,
Pietanza M. Catherine,
Capanu Marinela,
Saltz Leonard B.
Publication year - 2012
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.27459
Subject(s) - kras , medicine , cancer research , neuroendocrine tumors , insulin like growth factor , cancer , oncogene , sarcoma , endocrinology , oncology , receptor , colorectal cancer , growth factor , pathology , cell cycle
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. Cancer 2012. © 2012 American Cancer Society.