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Randomized Phase II Trial of the Clinical and Biological Effects of Two Dose Levels of Gefitinib in Patients With Recurrent Colorectal Adenocarcinoma

From the Vanderbilt-Ingram Cancer Center, Nashville, TN; Dana-Farber Cancer Center, Boston, MA; University of Wisconsin Cancer Center, Madison, WI; University of Pittsburgh Cancer Center, Pittsburgh, PA; Northwestern University Lurie Cancer Center, Chicago, IL.

Address reprint requests to Mace L. Rothenberg, MD, Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, 777 Preston Research Building, Nashville, TN 37232-6307; e-mail: mace.rothenberg{at}vanderbilt.edu

PURPOSE: The clinical objective of this trial was to evaluate gefitinib in patients with metastatic colorectal cancer that had progressed despite prior treatment. Serial tumor biopsies were performed when possible and analyzed for activation of the epidermal growth factor receptor (EGFR) signaling pathway. Serial serum samples were measured for amphiregulin and transforming growth factor–alpha (TGF).

PATIENTS AND METHODS: One hundred fifteen patients were randomly assigned to receive gefitinib 250 or 500 mg orally once a day. One hundred ten patients were assessable for clinical efficacy. Biologic evaluation was performed on paired tumor samples from 28 patients and correlated with clinical outcome.

RESULTS: Median progression-free survival was 1.9 months (95% CI, 1.8 to 2.1 months) and 4-month progression-free survival rate was 13% ± 5%. One patient achieved a radiographic partial response (RR = 1%; 95% CI, 0.01% to 5%). Median survival was 6.3 months (95% CI, 5.1 to 8.2 months). The most common adverse events were skin rash, diarrhea, and fatigue. In the biopsy cohort, expression of total or activated EGFR, activated Akt, activated MAP-kinase, or Ki67 did not decrease following 1 week of gefitinib. However, a trend toward decreased post-treatment levels of activated Akt and Ki67 was observed in patients with a PFS higher than the median, although these did not reach the .05 level of significance.

CONCLUSION: Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.

Supported by PHS Grants No. CA23318, CA66636, CA21115, CA49957, CA21076, CA17145, and CA39229 (to Eastern Cooperative Oncology Group institutions), P50 CA95103 (Vanderbilt Specialized Program Of Research Excellence [SPORE] in Gastrointestinal Cancer grant), CA46413 (to R.J.C.), and K24 CA82301 (to M.L.R.). This study was conducted as a collaboration between the Eastern Cooperative Oncology Group (PI: Robert L. Comis, MD) and the Vanderbilt SPORE in Gastrointestinal Cancer (PI: R.J.C.).

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004, and at the 12th SPORE Investigators' Workshop, Baltimore, MD, July 10-13, 2004.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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