A phase II trial of ZD1839 (Iressa™) 750 mg per day, an oral epidermal growth factor receptor-tyrosine kinase inhibitor, in patients with metastatic colorectal cancer

MacKenzie, Mary J.; Hirte, H.; Glenwood, Goss; Maroun, J.; Goel, Rakesh; Major, Pierre; Miller, Wilson H.; Panasci, Lawrence; Lorimer, Ian A. J.; Batist, Gerald; Matthews, Sarah; Douglas, L.; Seymour, Lesley

doi:10.1007/s10637-005-5862-9

Cited by 58 publications

(28 citation statements)

References 15 publications

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“…Cetuximab (IMC-C225, Erbitux), a monoclonal antibody targeted to EGFR, has shown antitumor activity in a wide variety of tumor types, including colon cancer (44,45). Gefitinib (ZD1839, Iressa) and erlotinib (Tarceva) are small molecular EGFR inhibitors that have been intensively studied in advanced NSCLC and colon cancer patients (46)(47)(48)(49). Our current study not only implicates GPI transamidase subunits as novel oncogenes but also adds credence to the notion that the GPI anchoring process is a new and common pathway inducing tumor formation and contributing to tumor invasion.…”

Section: Discussionsupporting

confidence: 57%

Overexpression of Glycosylphosphatidylinositol (GPI) Transamidase Subunits Phosphatidylinositol Glycan Class T and/or GPI Anchor Attachment 1 Induces Tumorigenesis and Contributes to Invasion in Human Breast Cancer

Guo²,

Chatterjee³

et al. 2006

Cancer Research

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Based on the oncogenic role of phosphatidylinositol glycan (PIG) class U in human tumors, we explored the role of two additional subunits of the glycosylphosphatidylinositol (GPI) transamidase complex in human breast cancer. We found that PIG class T (PIG-T) and GPI anchor attachment 1 (GPAA1) were overexpressed in breast cancer cell lines and primary tumors. Forced expression of PIG-T and GPAA1 transformed NIH3T3 cells in vitro and increased tumorigenicity and invasion of these cells in vivo. Suppression of PIG-T expression in breast cancer cell lines led to inhibition of anchorage-independent growth. Moreover, we found that PIG-T and GPAA1 expression levels positively correlated with paxillin phosphorylation in invasive breast cancer cell lines. Furthermore, suppression of PIG-T and GPAA1 expression led to a decrease in paxillin phosphorylation with a concomitant decrease in invasion ability. These results suggest that the GPI transamidase complex is composed of a group of proto-oncogenes that individually or as a group contribute to breast cancer growth. This aberrant growth is mediated, at least partially, by phosphorylation of paxillin, contributing to invasion and progression of breast cancer. (Cancer Res 2006; 66(20): 9829-36)

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Section: Discussionsupporting

confidence: 57%

Overexpression of Glycosylphosphatidylinositol (GPI) Transamidase Subunits Phosphatidylinositol Glycan Class T and/or GPI Anchor Attachment 1 Induces Tumorigenesis and Contributes to Invasion in Human Breast Cancer

Guo²,

Chatterjee³

et al. 2006

Cancer Research

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“…In contrast to non -small cell lung carcinoma (NSCLC), the efficacy of EGFR TKIs as single agents in mCRC is limited. In mCRC, gefitinib at doses of 250 to 750 mg and erlotinib at 150 mg resulted in objective response rates of <1% (18,19) and 4% (20), respectively. This low single agent activity in mCRC does not preclude activity of these classes of compounds when given in combination with other agents.…”

Section: Discussionmentioning

confidence: 99%

Phase I Pharmacokinetic/Pharmacodynamic Study of EKB-569, an Irreversible Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase, in Combination with Irinotecan, 5-Fluorouracil, and Leucovorin (FOLFIRI) in First-Line Treatment of Patients with Metastatic Colorectal Cancer

Folprecht

Tabernero

Köhne

et al. 2008

Clinical Cancer Research

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Purpose: To determine the recommended dose (RD) of EKB-569, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with FOLFIRI chemotherapy in patients with metastatic colorectal cancer (mCRC). Methods: Patients with previously untreated mCRC received FOLFIRI and EKB-569 at doses of 10, 25, 50, and 75 mg/day (EKB started on day 3).Three sequential skin biopsies were obtained in selected patients to assess the pharmacodynamic effects on EGFR signaling of FOLFIRI alone and with EKB-569. Complete pharmacokinetic sampling and tumor biopsies, when feasible, were conducted. Results: Forty-seven patients were enrolled. Dose-limiting toxicities (grade 3 diarrhea or asthenia) were observed in 1/7 patients at 50 mg EKB-569 and in 2/3 at 75 mg. Two additional dose levels (35 mg EKB-569/day and 50 mg EKB-569/day plus modified FOLFIRI) were evaluated. The RD was 25 mg EKB-569/full dose FOLFIRI. Grades 3 to 4 toxicities in >10% of patients were diarrhea (30%), neutropenia (21%), and asthenia (17%). Twenty-one patients had an objective response [48%; 95% confidence interval (95% CI), 32-65%]. The median time to tumor progression was 7.7 months. At the RD, EKB-569 resulted in complete inhibition of phosphorylated EGFR (pEGFR) and downstream receptor signaling in skin and tumor samples. FOLFIRI alone did not affect pEGFR, but inhibited epidermal proliferation and activated mitogenactivated protein kinase (MAPK) and induced p27 expression in the skin. Conclusion: The RD of EKB-569 is 25 mg/day when combined with FOLFIRI and results in complete EGFR inhibition. Chemotherapy alone interferes with pharmacodynamic markers, an observation to be taken into account in future studies of targeted agents with chemotherapy.Colorectal cancer is the second most frequent cause of cancerrelated death worldwide, and patients with metastatic colorectal cancer (mCRC) have a median survival of 8.5 months without chemotherapy (1). Current standard chemotherapy regimens such as FOLFIRI [irinotecan/5-fluorouracil (5-FU)/ leucovorin (LV)] or FOLFOX (oxaliplatin/5-FU/LV) induce response rates of about 50%, prolong progression-free survival to about 8 months, and increase the median overall survival to 20 months (2 -5). Despite these advances, the long-term prognosis of patients with mCRC remains poor, with <5% surviving 5 years. Therefore, new treatment strategies have to be explored to improve the prognosis of this disease.The epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target in a variety of cancers including mCRC. Two different approaches have been clinically developed to target the EGFR: monoclonal antibodies (i.e., cetuximab and panitumumab) directed to the ectodomain of the receptor that have shown meaningful clinical activity in patients with mCRC refractory to standard chemotherapy (6); and small-molecule tyrosine kinase inhibitors (TKI).

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“…Gefitinib monotherapy also failed to show evidence of clinical activity, as defined by objective tumor response, in two different phase II trials in patients with metastatic colorectal cancer (143,144). However, preliminary results from two phase II studies of gefitinib plus FOLFOX in metastatic colorectal cancer suggest the addition of gefitinib to standard chemotherapy has some beneficial effects (123,145).…”

Section: Egfr Inhibitionmentioning

confidence: 99%

“…Evidence suggests that development of rash (skin toxicity) or diarrhea may be associated with statistically significant improvements in response, overall survival, and patient outcomes (139,140). Nausea has also been reported in some patients receiving gefitinib (143).…”

Section: Mol Cancer Res 2007;5(3) March 2007mentioning

confidence: 99%

The Role of VEGF and EGFR Inhibition: Implications for Combining Anti–VEGF and Anti–EGFR Agents

Tabernero

2007

Molecular Cancer Research

383

266

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A phase II trial of ZD1839 (Iressa™) 750 mg per day, an oral epidermal growth factor receptor-tyrosine kinase inhibitor, in patients with metastatic colorectal cancer

Abstract: ZD1839, when given at 750 mg/day to patients with pre-treated metastatic colorectal cancer, does not result in significant tumor regression.

Cited by 58 publications

References 15 publications

Overexpression of Glycosylphosphatidylinositol (GPI) Transamidase Subunits Phosphatidylinositol Glycan Class T and/or GPI Anchor Attachment 1 Induces Tumorigenesis and Contributes to Invasion in Human Breast Cancer

Overexpression of Glycosylphosphatidylinositol (GPI) Transamidase Subunits Phosphatidylinositol Glycan Class T and/or GPI Anchor Attachment 1 Induces Tumorigenesis and Contributes to Invasion in Human Breast Cancer

Phase I Pharmacokinetic/Pharmacodynamic Study of EKB-569, an Irreversible Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase, in Combination with Irinotecan, 5-Fluorouracil, and Leucovorin (FOLFIRI) in First-Line Treatment of Patients with Metastatic Colorectal Cancer

The Role of VEGF and EGFR Inhibition: Implications for Combining Anti–VEGF and Anti–EGFR Agents

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