Gefitinib in colorectal cancer: if wishes were horses.

It has been a wild ride for gefitinib. . .in lung cancer. Gefitinib, a synthetic inhibitor of the epidermal growth factor receptor (EGFR), was heralded as a breakthrough in non–small-cell lung cancer (NSCLC) after it demonstrated activity in phase I testing and when the two Iressa Dose Evaluation in Advanced Lung Cancer phase II trials supplied additional evidence that it could induce objective responses and improve tumor-related symptoms in patients who had experienced treatment failure after chemotherapy. Gefitinib received accelerated US Food and Drug Administration approval for single-agent use in NSCLC in 2003 on the strength of these clinical trials, but its acceptance was also bolstered by the enthusiasm of the lung cancer community (researchers and patient advocates alike), eager to have available an effective, nontoxic, targeted agent. There was little doubt that full approval would be tendered pending demonstration of an expected survival benefit in large-scale randomized trials; unfortunately, that survival advantage never materialized. Indeed, single-agent gefitinib was no better than placebo in the Iressa Survival Evaluation in Lung Cancer study, and gefitinib plus chemotherapy demonstrated no improvements in survival, time to progression, or response rate over chemotherapy alone in the two Iressa NSCLC Trial Assessing Combination Treatment trials. Making things more difficult for gefitinib, erlotinib, another small-molecule tyrosine kinase EGFR inhibitor, did improve survival in NSCLC, and received full regulatory approval in advanced disease. Gefitinib has again recently regained some glory as a legitimate targeted lung cancer therapy, when the presence of EGFR somatic gene mutations correlated with high response rates and improved survival in treated NSCLC patients. The clinical development of gefitinib has taken a different route in colorectal cancer. There is theoretical rationale for its use in patients with large bowel malignancies. The EGFR is expressed in most colorectal tumors, and its presence is associated with a worse prognosis. Monoclonal antibody EGFR inhibitors, such as cetuximab and panitumumab, can induce objective responses as single agents in advanced disease, although their effect on survival is unclear. Unlike NSCLC, gefitinib use in colorectal cancer patients treated in phase I trials was associated with prolonged stable disease but no objective responses, even when patients were treated at doses of 300 mg/d or higher (250/d is the recommended dose in lung cancer). Until recently, only one objective response has been reported from dedicated phase II efficacy studies using either gefitinib or erlotinib as a single agent. Given these data, is there any potential role for gefitinib in the treatment of colorectal cancer? Maybe. In this issue of the Journal of Clinical Oncology, Kuo et al report that adding gefitinib to standard chemotherapy leads to a high level of activity in advanced colorectal cancer patients. Kuo et al performed a phase II study of gefitinib plus fluorouracil (FU), leucovorin, and oxaliplatin (IFOX) in 27 patients with documented progressive colorectal cancer after at least one chemotherapeutic regimen (usually irinotecan based). EGFR positivity was not required for trial entry. Patients received one cycle of infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) chemotherapy, and then additional cycles of FOLFOX-4 with 500 mg/d of gefitinib. The primary objective of the trial was to determine tumor response, although safety, event-free, and overall survival were also assessed. The study aimed to accrue 35 patients and was powered to detect a 30% response rate (20% better than the 10% response rate seen with FOLFOX-4 after failure of irinotecan-based therapy), but the trial was closed early, at least partly because of the increasingly popular use of oxaliplatin as first-line therapy. Toxicities were worse in cycles that included gefitinib compared with the first cycle, in which patients received treatment with FOLFOX-4 alone. Overall, 48% of patients JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 24 AUGUST 2