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Journal of Clinical Oncology, Vol 23, No 24 (August 20), 2005: pp. 5446-5449 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.904
Gefitinib in Colorectal Cancer: If Wishes Were HorsesOregon Health & Science University Cancer Institute, Portland, OR 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.1-3 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.4-6 Making things more difficult for gefitinib, erlotinib, another small-molecule tyrosine kinase EGFR inhibitor, did improve survival in NSCLC,7 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.8-10 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.11 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.12,13 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).1,14 Until recently, only one objective response has been reported from dedicated phase II efficacy studies using either gefitinib or erlotinib as a single agent.15,16 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 al17 report that adding gefitinib to standard chemotherapy leads to a high level of activity in advanced colorectal cancer patients. Kuo et al17 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),18 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 had severe or life-threatening neutropenia, and an equal number experienced grade 3/4 diarrhea. Eighty-eight percent of those older than age 60 years had grade 3/4 neutropenia, although their rate of diarrhea was no different from that in younger patients. One patient developed asymptomatic drug-induced interstitial pneumonitis. Thirty-three percent of patients achieved objective responses, whereas 48% had stable disease for a prolonged period. Response rates did not differ depending on number of prior regimens. Median event-free survival was 5.4 months, and overall survival was 12 months. Fifty-six percent of patients stopped the treatment because of progressive disease, 22% stopped the treatment because of toxicity, and 14% stopped the treatment for surgical resection or ablation of residual disease. The authors concluded EGFR inhibition with gefitinib may enhance the cytotoxicity of FOLFOX-4, and that inhibition generically provides "substantial benefits" to patients. Do minor flaws in the study design, conduct, or analysis call these conclusions into question? The authors state IFOX has a higher response rate than FOLFOX-4 alone, comparing their 33% response rate to the 10% seen on the trial by Rothenberg et al18 of FOLFOX-4 in patients who experienced treatment failure after irinotecan, bolus FU, and leucovorin. However, we are taught not to compare the results of different trials conducted in different populations, and for good reason. Patients who are healthier respond better to drug therapy. The patients in the study by Kuo et al17 were extraordinarily robust, particularly considering the extensive pretreatment they had received, with nearly 80% having an Eastern Cooperative Oncology Group performance status of 0. Only a small fraction on the patients in the Rothenberg study was equally fit. We cannot even be sure that the findings by Kuo et al17 are different from those of Rothenberg et al.18 Kuo et al do not supply CIs for the IFOX response rate, and it seems likely they would overlap with FOLFOX results from the trial by Rothenberg et al. Next, Kuo et al17 chose to use 500 mg/d of gefitinib, a surprising choice, given the fact that these investigators demonstrated a 67% rate of severe diarrhea on their phase I trial at the same IFOX dose level (Cho et al, submitted for publication). In addition, multiple randomized phase II trials in NSCLC showed that 250 mg/d is as effective as 500 mg/d, but the lower dose is much safer when the drug is used alone, let alone in combination with cytotoxic chemotherapy (as in the study by Kuo et al).2,3 The authors, instead of seriously entertaining the possibility that the adverse effects were related to this high gefitinib dose, at least partly blame "cumulative toxicities of oxaliplatin and FU" for the higher rates of neutropenia and diarrhea seen in cycles with gefitinib compared with the first cycle of chemotherapy alone. However, those specific cumulative toxicities do not typically occur with FOLFOX-4. In a large-scale trial of FOLFOX-4 alone in advanced colorectal cancer (N9741)19 neuropathy was worse in later cycles compared with the first cycle, but diarrhea and neutropenia were not (D. Sargent, personal communication, April 2005). Finally, in the study by Kuo et al,17 the authors did not require EGFR positivity for patients to participate, a decision which in itself is reasonable, given that expression as measured by immunohistochemistry is not required for activity in NSCLC, or for activity in colorectal cancer with other EGFR inhibitors, such as cetuximab. However, it would have been interesting to test at least the EGFR status of these colorectal cancer patients treated with gefitinib, to see if the same holds true with the small-molecule inhibitor use in this population. Fascinating questions are highlighted by this trial. What accounts for the divergent effects of small-molecule tyrosine kinase inhibitors (TKIs) within and between different diseases? Gefitinib has single-agent activity in patients with NSCLC but it does not prolong their survival. It enhances the actions of cytotoxic drugs preclinically but does not clearly add substantial clinical benefit in lung cancer patients. In colorectal cancer, however, gefitinib similarly inhibits the growth of colorectal cancer cells preclinically, but as a small-molecule TKI has no appreciable single-agent clinical activity. Gefitinib clearly potentiates the growth-inhibitory in vitro and in vivo effects of oxaliplatin and fluoropyrimidines on colorectal cancer cells, but unlike NSCLC, the study by Kuo et al17 does suggest gefitinib might potentiate the effects of chemotherapy in patients. Can gefitinib seem more or less effective based on the population-based rate of EGFR mutations in the tested tumor type? This is certainly true in lung cancer. High response rates were seen in Iressa Dose Evaluation in Advanced Lung Cancer 1, in which half the patients were Japanese, a population known to have an EGFR mutation rate approximately twice that of whites. Low EGFR mutation rates were likely present in the predominantly non-Asian, unselected populations tested in the larger-scale randomized NSCLC studies, and this may have negated any treatment benefit. An early report of colorectal cancer patients screened for EGFR mutations (demographics unknown) stated such events occur in less than 1% of patients,20 suggesting that gefitinib should be ineffective in this disease if activating mutations are its target. However, a recent article detailing the examination of 33 tumor specimens from Japanese patients reported that 12% harbor mutations in the EGFR kinase domain.21 Thus, colorectal cancer mutations appear to be more frequent in Asians, and these might be better patients in whom to test gefitinib. Mutational status was not reported in the study by Kuo et al,17 in which 26% of patients were Asian. Regardless, extrapolating from the data just discussed, only a small absolute number (fewer than five) of the patients should have had mutations, and they could only account for a small proportion of the increased number who had an objective response with the addition of gefitinib to FOLFOX. Thus, if the results from Kuo et al hold up, it appears likely that gefitinib enhances the effects of chemotherapy independently of mutational status. Why are there activity differences between small-molecule TKIs and monoclonal antibodies in advanced colorectal cancer? Gefitinib and erlotinib offer no objective standards of activity in the general colorectal cancer population, whereas the monoclonal antibodies cetuximab and panitumumab can induce objective responses.12,13,15,16 A simplistic explanation is that antibodies act through immune, or other non–EGFR-related mechanisms. Supporting this possibility is a recent report that cetuximab can induce responses in patients with tumors that lack EGFR expression by conventional immunohistochemistry staining.22 The authors suggest this class of agents acts through antibody-dependent cell-mediated cytotoxicity, leading to recruitment of cytotoxic effector cells such as monocytes and natural-killer cells. In any case, data from combination chemotherapy (plus biologic therapy) studies are more concordant for antibodies and TKIs. Cetuximab clearly at least adds to chemotherapeutic cytotoxicity and can even reverse resistance to irinotecan. If we believe the results from Kuo et al, gefitinib can itself potentiate drug activity clinically, although the mechanisms by which this occurs, and the question of whether it can salvage a specific drug to which patients are refractory, remain unanswered. Is IFOX ready for prime time? Not yet. We all want a simple, oral, relatively nontoxic targeted therapy to work in colorectal cancer. However, although the results from Kuo et al17 are encouraging, this small phase II trial, using selected patients, cannot be definitive. We must especially be vigilant given the serious toxicity seen with IFOX, as well as the positive phase II but completely negative phase III results for gefitinib in NSCLC (regardless of the possible reasons). The demonstration of high levels of activity on the study by Kuo et al may also bode well for IFOX in the first-line setting, and an up-front trial is currently being conducted by the same group. As with other biologic-containing regimens, it would be prudent to define the true molecular targets and/or mechanisms of chemotherapy potentiation for gefitinib or IFOX. As with NSCLC, we could then likely determine the small but real fraction of patients who could particularly benefit from TKI administration. Author's Disclosures of Potential Conflicts of Interest
Dollar Amount Codes (A) < $10,000 (B) $10,000–99,999 (C)
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12. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004 13. Hecht JR, Patnaik A, Malik I, et al: ABX-EGF monotherapy in patients with metastatic colorectal cancer: An updated analysis. J Clin Oncol 22:247, 2004 (suppl; abstr 3511)
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15. Rothenberg ML, Lafleur B, Washington MK, et al: Changes in epidermal growth factor receptor signaling in serum and tumor biopsies obtained from patients with progressive metastatic colorectal cancer treated with gefitinib (ZD1839): An Eastern Cooperative Oncology Group study. J Clin Oncol 22:195, 2004 (suppl; abstr 3000) 16. Oza AM, Townsley CA, Siu LL, et al: Phase II study of erlotinib in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 22:196, 2003
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18. Rothenberg ML, Oza AM, Bigelow RH, et al: Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: Interim results of a phase III trial. J Clin Oncol 21:2059-2069, 2003
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21. Nagahara H, Mimori K, Ohta M, et al: Somatic mutations of epidermal growth factor receptor in colorectal cancer. Clin Cancer Res 11:1368-1371, 2005
22. Chung KY, Shia J, Kemeny NE, et al: Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunocytochemistry. J Clin Oncol 23:1803-1810, 2005 Related Article
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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