A phase 2 study of the insulin-like growth factor-1 receptor inhibitor MK-0646 in patients with metastatic, well-differentiated neuroendocrine tumors Journal Article
| Authors: | Reidy-Lagunes, D. L. ; Vakiani, E.; Segal, M. F.; Hollywood, E. M.; Tang, L. H.; Solit, D. B.; Pietanza, M. C.; Capanu, M.; Saltz, L. B. |
| Article 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. © 2012 American Cancer Society. |
| Keywords: | immunohistochemistry; adult; cancer survival; treatment response; aged; aged, 80 and over; disease-free survival; middle aged; treatment failure; cancer growth; drug dose reduction; drug efficacy; drug safety; patient selection; side effect; antineoplastic agents; pancreatic neoplasms; metastasis; progression free survival; multiple cycle treatment; phase 2 clinical trial; genotype; continuous infusion; phosphatidylinositol 3 kinase; somatomedin c receptor; hyperglycemia; neuroendocrine tumor; receptor, igf type 1; gene expression regulation, neoplastic; antibodies, monoclonal; mammalian target of rapamycin; carcinoid; b raf kinase; carcinoid tumor; allergic reaction; neuroendocrine tumors; diphenhydramine; kaplan-meier estimate; dalotuzumab; insulin-like growth factor; igf-1 |
| Journal Title: | Cancer |
| Volume: | 118 |
| Issue: | 19 |
| ISSN: | 0008-543X |
| Publisher: | Wiley Blackwell |
| Date Published: | 2012-10-01 |
| Start Page: | 4795 |
| End Page: | 4800 |
| Language: | English |
| DOI: | 10.1002/cncr.27459 |
| PROVIDER: | scopus |
| PUBMED: | 22437754 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 1 October 2012" - "CODEN: CANCA" - "Source: Scopus" |
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