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Journal of Clinical Oncology, Vol 24, No 15 (May 20), 2006: pp. 2252-2260 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.8960 Phase I Study of EKB-569, an Irreversible Inhibitor of the Epidermal Growth Factor Receptor, in Patients With Advanced Solid TumorsFrom the Mayo Clinic, Rochester, MN; Cancer Therapy and Research Institute, University of Texas Health Science Center, San Antonio, TX; and Wyeth Research, Collegeville, PA, Cambridge, MA, and Pearl River, NY Address reprint requests to Charles Erlichman, MD, Department of Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55902; e-mail: erlichman.charles{at}mayo.edu
PURPOSE: The maximum tolerated dose (MTD) and the dose-limiting toxicities of EKB-569, a selective, irreversible inhibitor of the epidermal growth factor receptor (EGFR), when administered orally once daily on an intermittent-dose schedule (14 days of a 28-day cycle) or on a continuous-dose schedule (each day of a 28-day cycle), were determined in patients with advanced solid tumors. PATIENTS AND METHODS: Planned dose escalation was 25, 50, 75, 125, 175, and 225 mg. Pharmacokinetic sampling was performed on days 1 and 14 for the intermittent-dose cohort and on days 1 and 15 for the continuous-dose cohort. RESULTS: Thirty patients received a median of two cycles (range, one to 10 cycles) in the intermittent-dose cohort; 29 patients received a median of three cycles (range, one to eight cycles) in the continuous-dose cohort. Dose-limiting toxicity was grade 3 diarrhea, and the MTD was 75 mg EKB-569 per day for both cohorts. Other common toxicities included rash, nausea, and asthenia. Exposure to EKB-569 was dose proportional. At the MTD, the mean ± standard deviation terminal half-life was 21.7 ± 4.2 hours and peak concentration increased 1.2-fold from day 1 to day 14/15. No major antitumor responses were observed. However, one patient with non–small-cell lung cancer and one with cutaneous squamous cell carcinoma had stable disease for 33 and 24 weeks, respectively. CONCLUSION: The MTD of once-daily oral EKB-569 is 75 mg. The tolerable toxicity profile and long half-life of this irreversible EGFR inhibitor warrant its further evaluation as a single agent and in combination with other drugs.
ErbB receptor tyrosine kinase family members are targets for cancer drug development.1-3 Trastuzumab and cetuximab, humanized monoclonal antibodies that bind to the extracellular domain of erbB-2 (HER-2) and erbB-1 (epidermal growth factor receptor [EGFR]), respectively, are approved for the treatment of patients with cancer.2,4 Gefitinib and erlotinib are reversible inhibitors of the EGFR tyrosine kinase that are approved for the treatment of patients with metastatic non–small-cell lung cancer.2,5 Overall response rates for these agents are only 9% to 18%.2,6 EKB-569 (Fig 1) is a potent, irreversible inhibitor of the EGFR tyrosine kinase (concentration inhibiting 50% [IC50] = 39 nmol/L).7 It inhibits the growth of human tumor cell lines that overexpress EGFR (IC50 = 80 nmol/L for A431 cells) and the growth of A431 tumors in a mouse xenograft model (effective dose range, 3.5 to 10 mg/kg/d).8 The inhibition of cell growth by EKB-569 can be correlated with the inhibition of autophosphorylation of EGFR and the subsequent inhibition of phosphorylation of proteins, such as AKT, ERK1/2, and STAT3, which are downstream in signaling pathways.9
In cancer therapy, the irreversible inhibition of the EGFR kinase by EKB-569 may be beneficial because such inhibition can occur in the presence of mM adenosine triphosphate levels within the cell and can only be overcome by new synthesis of EGFR to produce a sustained effect. Inhibition of EGFR phosphorylation is prolonged despite rapid plasma clearance of the drug, as demonstrated in a mouse xenograft model.7 After oral administration of 10 mg/kg EKB-569 to A431 tumor-bearing mice, inhibition of phosphorylation of EGFR was sustained for more than 24 hours, while the half-life of the drug in plasma was approximately 2 hours. Toxicology studies indicated that EKB-569 was well tolerated, with gastrointestinal toxicity being the dose-limiting toxicity (DLT) in mice, rats, and dogs (EKB-569 investigator's brochure). Based on preclinical data, a phase I dose-escalation study was performed in patients with advanced solid tumors known to overexpress EGFR to determine safety, pharmacokinetics, and preliminary antitumor activity.
Trial Design This phase I, open-label study was divided into two sequential parts. In part 1 (intermittent dose), oral EKB-569 (Wyeth Pharmaceuticals, Collegeville, PA) was administered once daily for 14 days of a 28-day cycle. In part 2 (continuous dose), oral EKB-569 was administered each day of a 28-day cycle. Patients continued treatment at the same dose level as long as EKB-569 was tolerated and there was no evidence of disease progression.
Patients Patients were excluded if they could not swallow the EKB-569 capsule or had prior treatment with EGFR inhibitors. Prior trastuzumab treatment was allowed. Patients also were excluded if they had chemotherapy, radiotherapy, or treatment with investigational agents within 4 weeks before study entry; surgery within 2 weeks before study entry; active CNS metastases; cerebral edema; significant gastrointestinal disorder; significant skin conditions; serious active infection; significant medical illness; or a medically significant abnormal laboratory finding. The study protocol was approved by the institutional review boards of the participating institutions, and all patients gave written informed consent. The study was conducted according to the Declaration of Helsinki and its amendments.
Dose Escalation Toxicities observed by the end of the cycle 1 evaluation period (day 22 of the first treatment cycle in the intermittent-dose schedule or day 28 of the first treatment cycle in the continuous-dose schedule) determined when dose-escalation occurred. Evaluation periods of different lengths were chosen for the two schedules based on previous experience with other EGFR tyrosine kinase inhibitors. Toxicities were graded based on the National Cancer Institute Common Toxicity Criteria, version 2.0. A DLT was defined as any possibly, probably, or definitely EKB-569-related grade 3 or 4 nonhematologic toxicity, excluding alopecia and nausea, vomiting, constipation, or diarrhea, unless the patient was receiving optimal medical therapy, or grade 4 hematologic toxicity. If at least two of three to six assessable patients had a DLT, the dose escalation was stopped, and the prior dose level was the maximum-tolerated dose (MTD).
Evaluation of Patients Tumor evaluations were performed after every two cycles. Patients were considered assessable for tumor response if tumor measurements were performed before treatment and at least after two cycles of treatment or if disease progression occurred at any time. Response was defined using WHO guidelines for complete response, partial response, stable disease, and progressive disease.10 Duration of stable disease was measured from the first date of treatment to the date of the last assessment showing stable disease. Time to tumor progression was measured from the first date of treatment to the date of documented progressive disease. Archived tumor specimens previously obtained from patients before the start of the study were evaluated for EGFR expression using an immunohistochemical assay (IMPATH Inc, Los Angeles, CA).11
Pharmacokinetic Analysis Plasma concentrations of EKB-569 were measured using a validated liquid chromatography/tandem mass spectrometry method.12 Curves of concentration of EKB-569 versus time in plasma were constructed for each patient and analyzed by a noncompartmental analysis technique.13 Peak concentration (Cmax), time to maximum concentration (tmax), area under the concentration-versus-time curve through 24 hours (AUC0-24), terminal half-life (t1/2), oral clearance (CL/F), oral steady-state volume of distribution (Vss/F), and accumulation ratio of multiple- to single-dose exposures (R) were calculated.
Patients Thirty and 29 patients were enrolled to receive the intermittent- and continuous-dose schedules, respectively, from September 2000 through February 2002. The last patient completed the study in August 2002. At least 50% of the patients in each dose group had been diagnosed with colorectal or non–small-cell lung cancer (Table 1). Patients were heavily pretreated; at least 57% in each dose group had received three or more prior chemotherapy regimens. Archived tumor specimens taken before the start of the study were analyzed for EGFR expression; 18 (78%) of the patients in the intermittent-dose group and 19 (95%) in the continuous-dose group had tumors that were positive for EGFR expression.
Summary of EKB-569 Treatment For the dose-escalation portion of the study, patients in the intermittent-dose group received 25, 50, 75, or 125 mg/d EKB-569. Two patients who received 125 mg/d EKB-569 had DLTs of grade 3 diarrhea. Diarrhea started on day 11 for both patients and lasted 3 and 4 days. Thus, the MTD for the intermittent-dose group was 75 mg/d EKB-569. Based on these results, patients in the continuous-dose group received 25, 50, 75, or 100 mg/d EKB-569. Three patients who received 100 mg EKB-569 in the continuous-dose group had DLTs of grade 3 diarrhea. For one patient, the diarrhea started on day 3 and lasted 8 days; for two, it started on day 11 and lasted 8 and 19 days, respectively. Thus, the MTD for the continuous-dose group was also 75 mg EKB-569 per day. The MTD cohorts for both the intermittent- and continuous-dose groups were expanded to include 10 additional patients. Patients in the intermittent-dose group were treated with EKB-569 for a median of two cycles (range, one to 10 cycles). Patients in the continuous-dose group were treated for a median of three cycles (range, one to eight cycles). Table 2 summarizes the number of cycles of treatment at each dose level for each dose group.
Safety Table 3 summarizes the cycle 1 EKB-569–related adverse events by dose level for each schedule. Diarrhea, rash, and asthenia occurred with the highest incidence. Table 4 summarizes the EKB-569–related adverse events of any grade that occurred in any cycle in at least 10% of the patients in the intermittent-dose group. The three with the highest incidence were diarrhea (70%), rash (60%), and nausea (30%). None of these TRAEs were grade 4. Grade 3 TRAEs, which occurred in two or more patients, included diarrhea (eight patients), rash (two patients), nausea (two patients), and vomiting (two patients). Table 5 summarizes the EKB-569–related adverse events of any grade that occurred in any cycle in at least 10% of the patients in the continuous-dose group. The three with the highest incidence were diarrhea (93%), rash (83%), and asthenia (66%). None of these TRAEs were grade 4. Grade 3 TRAEs that occurred in two or more patients included diarrhea (eight patients), nausea (five patients), vomiting (four patients), dehydration (three patients), and stomatitis (two patients). For both dose groups, these TRAEs occurred in a similar percentage of the subgroup of patients who received the MTD of 75 mg/d EKB-569.
In the intermittent-dose group, five patients had dose reductions, all of which were single-dose reductions. Three patients initially received 75 mg EKB-569 and two initially received 125 mg. All had dose reductions because of EKB-569–related gastrointestinal toxicities, which occurred in cycle 1 for three patients, in cycle 4 for one patient, and in cycle 7 for the other. One patient who received 125 mg EKB-569 had concomitant drug-related skin toxicity and stomatitis. In the continuous-dose group, seven patients had dose reductions. Six patients had single-dose reductions; one initially received 50 mg EKB-569, two initially received 75 mg, and three initially received 100 mg. One patient who initially received 100 mg had two dose reductions. All seven patients had dose reductions because of EKB-569–related gastrointestinal toxicities, which occurred in cycle 1 for six patients and in cycle 2 for the other patient. Three of these patients had one or more concomitant drug-related toxicities, which included asthenia, lethargy, skin toxicity, stomatitis, or conjunctivitis. Two patients in the intermittent-dose group and three in the continuous-dose group were removed from treatment because of adverse events. Both patients in the intermittent-dose group received 25 mg EKB-569 and discontinued in cycle 1; one patient had drug-related diarrhea and the other had fever and infection, which was unrelated to EKB-569 treatment. The three patients in the continuous-dose group received 75 mg EKB-569: one discontinued in cycle 1, one in cycle 2, and one in cycle 3. These patients had one or more EKB-569–related toxicities, which included gastrointestinal toxicities, asthenia, or stomatitis. One patient in the intermittent-dose group withdrew consent and discontinued treatment. Twenty-five of 30 patients in the intermittent-dose group and 23 of 29 patients in the continuous-dose group discontinued treatment because of disease progression. Six patients died because of disease progression. Three died within 30 days after the last dose of EKB-569. They were in the intermittent-dose group; one received 25 mg and two received 75 mg. Three patients died more than 30 days after the last dose of EKB-569. Two were in the intermittent-dose group and received 50 mg or 125 mg. The other was in the continuous-dose group and received 100 mg. No deaths were considered to be related to EKB-569 treatment.
Pharmacokinetics
An exploratory analysis of the relationships between drug exposure and toxicity grade was performed. Due to the heterogeneity of the patient population and the small number of events at each grade, no significant associations were observed. Nevertheless, there appeared to be a trend of increased toxicity grade with increased AUC0-24 and Cmax for the toxicities depicted in Figures 3 and 4. Associations were suggested between steady-state AUC0-24 and asthenia, diarrhea, rash, dry skin, stomatitis, and vomiting (Fig 3). In addition, associations were observed between Cmax and asthenia, dehydration, diarrhea, and stomatitis (Fig 4).
Antitumor Activity No patients in either dose group had complete or partial responses. Eleven patients in the intermittent-dose group had stable disease for at least 8 weeks; six received the MTD dose, 75 mg EKB-569 per day. One patient, who had non–small-cell lung carcinoma (NSCLC) and received 75 mg EKB-569, had stable disease for 33 weeks. Thirteen patients in the continuous-dose group had stable disease for at least 8 weeks; six received the MTD dose. One patient, who had cutaneous squamous cell carcinoma and received 25 mg EKB-569, had stable disease for 24 weeks. Exploratory analyses were performed to determine if EGFR expression in archived tumor specimens taken before study start or steady-state EKB-569 exposure in plasma was related to time to last stable disease or time to tumor progression, and no clinically relevant relationships were found. Similarly, no relationship between the presence or absence of rash and time to tumor progression was discerned.
In this phase I study, EKB-569 was administered to patients with advanced-stage solid tumors. EKB-569 was found to have a generally acceptable safety profile. No grade 4 related adverse events occurred when EKB-569 was administered daily for 14 days of a 28-day cycle or daily in a 28-day cycle. Diarrhea and rash were the TRAEs of highest incidence for both schedules. These also occurred with high incidence after treatment of patients with advanced solid tumors with gefitinib or erlotinib.1,14-16 The incidence of TRAEs and dose reductions and discontinuations were slightly greater for the continuous-dose schedule than for the intermittent-dose schedule. Pharmacokinetic analysis indicates that exposure to EKB-569 following oral treatment seems to be dose proportional. Absorption is modestly delayed, which may be attributable to decreased solubility of EKB-569 at a higher pH. The apparent volume of distribution is large and suggests that distribution is extensive, but the variability in drug bioavailability does not make a definitive conclusion possible. Steady-state EKB-569 concentrations are approximately two-fold higher than those following single-dose treatment, and the mean terminal half-life at steady-state is approximately 22 hours; these are properties that support a chronic, once-daily treatment schedule. Pharmacodynamic relationships between drug exposure and severity of adverse events were examined. The findings suggest that both steady-state AUC0-24 and Cmax appear to be related to the occurrence of asthenia, diarrhea, and stomatitis. The observation for dehydration, while limited to four patients with severities of grades 1 to 3, appeared unique to Cmax. These findings are consistent with these toxicities being related to dose. The less than robust relationship between EKB-569 pharmacokinetics and clinical toxicity may be due to the large interpatient variability, the heterogeneity of the cancers treated, and the small number of events. Also, drug clearance in plasma may not reflect the prolonged inhibition of the target in the case of an irreversible inhibitor. Based on these generally tolerable toxicities and the fact that two patients in this study had stable disease for 24 and 33 weeks, two phase II, modified Simon two-stage,17 open-label, single-agent studies with EKB-569 are being conducted in patients with advanced colorectal cancer or NSCLC. A dose of 50 mg/d EKB-569 was chosen for daily, oral administration because it was associated with fewer drug-related severe toxicities than 75 mg/d EKB-569, the MTD in this study. Furthermore, data from the mouse xenograft model with A431 cells suggests that, in humans, the dose of 50 mg EKB-569 per day produces biologically relevant concentrations in plasma.8,18 The primary end point of these phase II studies is the evaluation of clinical activity based on the number of complete and partial responses. In addition, secondary end points of progression-free survival, time to treatment failure, and duration of response will be measured. Phase I studies with EKB-569 in combination therapy also are being conducted in patients with advanced pancreatic or colorectal cancer.19-22 In this phase I study, 63% of patients had tumors that were positive for EGFR expression, but no complete or partial responses were observed. The lack of association of EGFR expression and clinical outcome is not unexpected. Others have shown that protein expression is a poor predictor for response, time to progression, or overall survival.23-25 Studies with gefitinib and erlotinib have indicated that clinical response in NSCLC patients is correlated with specific somatic mutations in the tyrosine kinase domain of the EGFR gene.26-28 However, disease progression occurred with the acquisition of resistance to gefitinib or erlotinib.28-30 In NSCLC patients who progressed, a secondary mutation in the EGFR gene, which leads to substitution of methionine for threonine at position 790 of the kinase domain (T790M), was identified. In studies with NSCLC cell lines, acquisition of gefitinib resistance was shown to be associated with the T790M mutation or an unidentified mutation that resulted in increased EGFR internalization. The irreversible inhibitor EKB-569 was a potent inhibitor of these gefitinib-resistant cell lines.30,31 Thus, an irreversible inhibitor seems to have a unique efficacy potential in NSCLC. Based on these results, in future phase II studies with EKB-569 in NSCLC, EGFR gene sequences will be characterized. Patients who have not been previously treated with gefitinib or erlotinib and those who have become refractory to these drugs will be evaluated. DNA sequencing of pretreatment tumor biopsy samples will be performed to correlate specific EGFR mutations with response and survival. These studies will indicate whether the irreversible inhibitor EKB-569 has a role in prolonging the survival of specific NSCLC patients.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
We thank all of the patients and clinical personnel who participated in these studies, Patricia Ofori for data management, Yan Zhang and Paul Bukowiec for clinical programming, Joyce Chen for biostatistical analysis, and Susan Leinbach for manuscript preparation.
1. Grünwald V, Hidalgo M: Developing inhibitors of the epidermal growth factor receptor for cancer treatment. J Natl Cancer Inst 95:851-867, 2003 2. Hamid O: Emerging treatments in oncology: Focus on tyrosine kinase (erbB) receptor inhibitors. J Am Pharm Assoc (Wash DC) 44:52-58, 2004 3. Rowinsky EK: Signal events: Cell signal transduction and its inhibition in cancer. Oncologist 8:5-17, 2003 4. Mitchell P: Erbitux diagnostic latest adjunct to cancer therapy. Nat Biotechnol 22:363-364, 2004[Medline] 5. Dowell J, Minna JD, Kirkpatrick P: Erlotinib hydrochloride. Nat Rev Drug Discov 4:13-14, 2005[CrossRef][Medline] 6. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123-132, 2005 7. Torrance CJ, Jackson PE, Montgomery E, et al: Combinatorial chemoprevention of intestinal neoplasia. Nat Med 6:1024-1028, 2000[CrossRef][Medline] 8. Wissner A, Overbeek E, Reich MF, et al: Synthesis and structure-activity relationships of 6,7-disubstituted 4-anilinoquinoline-3-carbonitriles: The design of an orally active, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor-2 (HER-2). J Med Chem 46:49-63, 2003[CrossRef][Medline] 9. Nunes M, Shi C, Greenberger LM: Phosphorylation of extracellular signal-regulated kinase 1 and 2, protein kinase B, and signal transducer and activator of transcription 3 are differently inhibited by an epidermal growth factor receptor inhibitor, EKB-569, in tumor cells and normal human keratinocytes. Mol Cancer Ther 3:21-27, 2004 10. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 11. Goldstein NS, Armin M: Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarcinoma: Implications for a standardized scoring system. Cancer 92:1331-1346, 2001[CrossRef][Medline] 12. Amorusi P: EKB-569: Validation of an LC/MS/MS bioanalytical method for the quantitation of EKB-569 in human plasma. Wyeth-Ayerst Research RPT-40374, Pearl River, NY, 2001 13. Jusko WJ: Guidelines for collection and analysis of pharmacokinetic data, in Evans WE, Schentag JJ, Jusko WJ (eds): Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. Vancouver, WA, Applied Thrapeutics Inc, 1992, pp 1-43 13. Camp RL, Rimm EB, Rimm DL: Met expression is associated with poor outcome in patients with axillary lymph node negative breast carcinoma. Cancer 86:2259-2265, 1999[CrossRef][Medline] 14. Hidalgo M, Siu LL, Nemunaitis J, et al: Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19:3267-3279, 2001 15. Ranson M, Hammond LA, Ferry D, et al: ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: Results of a phase I trial. J Clin Oncol 20:2240-2250, 2002 16. Herbst RS, Maddox AM, Rothenberg ML, et al: Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: Results of a phase I trial. J Clin Oncol 20:3815-3825, 2002 17. Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-10, 1989[Medline] 18. Discafani C: EKB-569, an inhibitor of EGF-R tyrosine kinase: In vivo pharmacology—Tumors overexpressing EGF-R. Wyeth-Ayerst Research: RPT 39171. Pearl River, NY, 2000 19. Morgan JA, Bukowski RM, Xiong H, et al: Preliminary report of a phase 1 study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor (EGFR), given in combination with gemcitabine to patients with advanced pancreatic cancer. Proc Am Soc Clin Oncol 22:197, 2003 (abstr 788) 20. Laheru D, Croghan G, Bukowski R, et al: A phase 1 study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor, in combination with capecitabine in patients with advanced colorectal cancer: Preliminary report. Clin Cancer Res 9:6091S-6092S, 2003 (abstr A93) 21. Salazar R, Koehne C-H, Cortes-Funes H, et al: Preliminary report of a phase 1/2A open-label study of EKB-569 in combination with 5-fluorouracil, leucovorin, and irinotecan in patients with advanced colorectal cancer. Clin Cancer Res 9:6099-6100, 2003 (abstr A125) 22. Tejpar S, Van Cutsem E, Gamelin E, et al: Phase 1/2a study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor, in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) in patients with advanced colorectal cancer. J Clin Oncol 23:264s, 2004 (abstr 3579) 23. Cortes-Funes H, Soto Parra H: Extensive experience of disease control with gefitinib and the role of prognostic markers. Br J Cancer 89:S3-S8, 2003 (suppl 2) 24. Bailey LR, Kris M, Wolf M, et al: Tumor EGFR membrane staining is not clinically relevant for predicting response in patients receiving gefitinib ('Iressa', ZD1839) monotherapy for pretreated advanced nonsmall-cell lung cancer: IDEAL 1 and 2. Proc Am Assoc Cancer Res 44:1362, 2003 (abstr LB-170) 25. Santoro A, Cavina R, Latteri F, et al: Activity of a specific inhibitor, gefitinib (Iressa, ZD1839), of epidermal growth factor receptor in refractory non-small-cell lung cancer. Ann Oncol 15:33-37, 2004 26. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004 27. Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004 28. Pao W, Miller VA, Politi KA, et al: Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73, 2005 29. Kobayashi S, Boggon TJ, Dayaram T, et al: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786-792, 2005 30. Kwak EL, Sordella R, Bell DW, et al: Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A 102:7665-7670, 2005 31. Carter TA, Wodicka LM, Shah NP, et al: Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci U S A 102:11011-11016, 2005 Submitted March 18, 2005; accepted December 20, 2005. Related Editorial
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
3x the institutional upper limit of normal [ULN] or 
60 mL/min; hemoglobin 
) and women (•), day 14 intermittent-dose schedule. AUC0-24 = 3.8955 x dose1.2389 (exponent 95% CI, 0.592 to 1.886). (B) Mean EKB-569 concentration-versus-time in patients after administration of 75 mg as a single dose (
) or steady-state dose (•), intermittent-dose schedule.
