Key Words. Epidermal growth factor receptor EGFR Tyrosine kinase inhibitor TKI Erlotinib Non-small cell lung cancer NSCLC Second-line therapy

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1 The Oncologist Lung Cancer Gefitinib in Advanced Non-Small Cell Lung Cancer: Does It Deserve a Second Chance? THOMAS E. STINCHCOMBE,MARK A. SOCINSKI Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA Key Words. Epidermal growth factor receptor EGFR Tyrosine kinase inhibitor TKI Erlotinib Non-small cell lung cancer NSCLC Second-line therapy Disclosure: Employment/leadership position: None; Intellectual property rights/inventor/patent holder: None; Consultant/advisory role: None; Honoraria: None; Research funding: Mark A. Socinski, AstraZeneca. Genentech; Ownership interest: None; Expert testimony: None; Other: Speakers bureau: Thomas E. Stinchcombe, Genentech; Speakers bureau: Mark A. Socinski. Genentech. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers. LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Discuss the data on the patient populations enrolled and the efficacy of erlotinib and gefitinib in the BR.21 and ISEL trials, respectively, and the potential reasons for the differing results of the two trials. 2. Assess the results of recent phase III trials that have compared EGFR TKI therapy with cytotoxic chemotherapy. 3. Describe the data to date from phase II clinical trials of EGFR TKI therapy in clinically or molecularly enriched patient populations. CME This article is available for continuing medical education credit at CME.TheOncologist.com. ABSTRACT There has been intense investigation into the epidermal growth factor receptor (EGFR) as a therapeutic target in the treatment of non-small cell lung cancer (NSCLC). Currently there are two EGFR tyrosine kinase inhibitors, erlotinib and gefitinib, approved for the treatment of advanced NSCLC. In a phase III trial (BR.21), treatment with erlotinib resulted in a statistically significant improvement in overall survival in patients who had experienced progression after one or two previous chemotherapy treatments in comparison with best supportive care (BSC). In contrast, in the Iressa Survival Evaluation in Lung Cancer (ISEL) trial, treatment with gefitinib did not result in a statistically significant improvement in overall survival time in comparison with BSC in patients who had received one or two previous chemotherapy treatments and were refractory to or intolerant of the previous chemotherapy. After the results of the ISEL trial, the U.S. Food and Drug Administration restricted the use of gefitinib, and gefitinib was effectively removed from routine clinical Correspondence: Thomas E. Stinchcombe, M.D., Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, 3009 Old Clinic Building, Cb 7305, Chapel Hill, North Carolina , USA. Telephone: ; Fax: ; Thomas_Stinchcombe@med.unc.edu Received January 25, 2008; accepted for publication April 6, 2008; first published online in THE ONCOLOGIST Express on September 10, AlphaMed Press /2008/$30.00/0 doi: /theoncologist The Oncologist 2008;13:

2 934 Gefitinib in Advanced NSCLC practice within the U.S. However, gefitinib was approved in other countries and clinical trials investigating gefitinib continued. Recently the Iressa Nonsmall cell lung cancer Trial Evaluating REsponse and Survival against Taxotere (INTEREST) trial met the primary endpoint of demonstrating noninferiority in terms of overall survival for gefitinib (250 mg daily) in comparison with docetaxel (75 mg/m 2 every 3 weeks). Patients treated with gefitinib experienced a lower rate of treatment-related toxicity and higher rate of improvement in quality of life. Results of recent gefitinib trials have been provocative, and suggest a role for gefitinib in the treatment of advanced NSCLC. The Oncologist 2008;13: INTRODUCTION Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality in the U.S., and in 2008 it was estimated that more patients would die from lung cancer than colorectal, breast, and prostate cancer combined [1]. Non-small cell histology is responsible for 85% of cases of lung cancer, and approximately 65% of patients present with advanced stage disease [2 4]. In addition to the patients who present with advanced stage disease, a significant percentage of patients who present with early-stage disease subsequently relapse with metastatic disease [5]. For patients with a preserved functional status, treatment with doubleagent chemotherapy has been shown to modestly improve survival, reduce disease-related symptoms, and improve quality of life [6]. However, we have reached a therapeutic plateau with standard chemotherapy agents [7 9]. Targeting the epidermal growth factor receptor (EGFR) has been an area of intense investigation over the last several years. NSCLC is associated with a high rate of EGFR expression [10, 11], and EGFR expression has been associated with a poor prognosis [12 14]. Activation of the EGFR pathway initiates a process that promotes tumor cell proliferation, angiogenesis, decreased apoptosis, and the development of metastasis [15]. There are currently two EGFR tyrosine kinase inhibitors (TKIs) approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced NSCLC: gefitinib (Iressa ; AstraZeneca, Wilmington, DE) and erlotinib (Tarceva ; Genentech, South San Francisco, CA, and OSI Pharmaceuticals, Melville, NY). Gefitinib initially received accelerated FDA approval in May 2003 for patients with locally advanced or metastatic NSCLC who had progressed after platinum-based and docetaxel (Taxotere ; Sanofi-Aventis, Bridgewater, NJ) chemotherapy based on the data from two phase II trials [16 18]. Erlotinib was approved by the FDA in November 2004 for patients who had progressed after one or two previous chemotherapy treatments based on the results of a phase III trial that compared erlotinib with best supportive care (BSC) [19, 20]. A phase III trial that compared gefitinib with BSC in patients who had progressed after one or two previous chemotherapy treatments did not reveal a statistically significant difference in overall survival [21]. In response to the results of that trial, in June 2005 the FDA restricted the use of gefitinib to patients enrolled in clinical trials or deriving clinical benefit from ongoing treatment. This effectively removed gefitinib from routine clinical practice within the U.S. However, gefitinib was approved in other countries, and clinical trials investigating the role of gefitinib continued. The results of several of these clinical trials have been very provocative, and suggest a role for gefitinib in advanced NSCLC. GEFITINIB PHASE I AND II TRIALS More than 250 patients were enrolled in phase I studies of gefitinib, and of these, 100 had NSCLC [22 24]. In these trials, responses in NSCLC were observed at doses of mg daily, but doses 600 mg daily required more dose reductions or interruptions [17]. As a result of these data, two doses were selected for investigation in phase II and III trials: 250 mg daily and 500 mg daily. Two randomized phase II trials investigating the activity of gefitinib in advanced NSCLC, the Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL)-I and IDEAL-II trials, were performed. The IDEAL-I trial was performed in 43 centers in Europe, Australia, South Africa, and Japan, whereas the IDEAL-II trial was performed in 30 centers within the U.S. [17, 18]. The IDEAL-I trial enrolled patients who had progressed after one or two previous chemotherapy regimens (at least one containing platinum), whereas patients in the IDEAL II trial were required to have received two or more previous treatments containing a platinum and docetaxel given concurrently or as separate regimens. These differences in the eligibility criteria and trial location led to differences in the patient demographics, and approximately 50% of the patients in the IDEAL-I trial were Japanese. The response rates and progression-free and median overall survival times in the 250-mg and 500-mg daily treatment arms were similar for the two doses in the IDEAL-I trial (Table 1) [18]. Drug-related toxicities were more frequent in the higher dose group, and the rates of withdrawal because of drug-related adverse events were 1.9% and 9.4% for patients receiving gefitinib at doses of 250 mg and 500 mg daily, respectively [18]. In the IDEAL-II trial, there

3 Stinchcombe, Socinski 935 Table 1. Efficacy of gefitinib in the IDEAL-I and IDEAL-II trials IDEAL-I trial [18] IDEAL-II trial [17] Gefitinib dose 250 mg 500 mg 250 mg 500 mg n Response rate (95% CI) a 18.4% (11.5% 27.3%) 19% (12.1% 27.9%) 12% (6% 20%) 10% (4% 16%) Disease control rate (95% CI) 54.4% (44.3% 64.2%) 51.4% (41.5% 61.3%) NR NR Progression-free survival (95% CI) 2.7 mos ( ) 2.8 mos ( ) NR NR Median overall survival (95% CI) 7.6 mos ( ) 8.0 mos ( ) 7 mos b 6 mos b 1-year overall survival 35% 29% 27% c 24% c a Response defined as a 50% decrease in tumor size on radiological imaging. b 95% CI not reported. c Projected 1-year survival rate. Abbreviations: CI, confidence interval; IDEAL, Iressa Dose Evaluation in Advanced Lung Cancer; NR, not reported. were no significant differences in the radiographic response rates, and the 1-year survival rates were similar in the two treatment arms (Table 1) [17]. A primary endpoint of the IDEAL-II trial was an improvement in NSCLC symptoms measured using the Functional Assessment of Cancer Therapy Lung (FACT-L), and there were no significant differences between the 250- and 500-mg doses in the rates of symptom improvement. In the IDEAL-II trial, the 500-mg dose was associated more frequently with transient acnelike rash (p.04) and diarrhea (p.006). Higher response rates were observed in women, never-smokers, patients with adenocarcinoma with any bronchioalveolar features, and Japanese patients treated with gefitinib [17, 18, 25]. At the same time that the phase I and II trials of gefitinib were ongoing, phase I and II trials with a second EGFR TKI, erlotinib, were ongoing as well. The maximum-tolerated dose (MTD) at which biologically significant plasma levels were achieved was determined to be 150 mg daily [26]. A phase II trial of erlotinib, 150 mg daily, revealed similar efficacy to gefitinib with a response rate of 12.3% (95% confidence interval [CI], 5.1% 23.7%), median survival time of 8.4 months (95% CI, months), and 1-year survival rate of 40% (95% CI, 28% 54%) [27]. The drug was well tolerated, and rash and diarrhea were observed in 75% and 56% of patients, respectively. On multivariate analysis, rash was the most significant predictor of survival: National Cancer Institute Common Toxicity Criteria rash grade 1 versus no rash (hazard ratio [HR], 0.13; 95% CI, ; p.0001) and grade 2 or 3 versus no rash (HR, 0.05; 95% CI, ; p.0001). PHASE III TRIALS WITH ERLOTINIB AND GEFITINIB Erlotinib was investigated in a phase III, double-blind, placebo-controlled trial coordinated by the National Cancer Institute of Canada (NCIC), BR.21, that compared erlotinib with BSC in patients who had progressed after first- or second-line chemotherapy [20]. Patients with an Eastern Cooperative Oncology Group performance status score of 0 3 were eligible, and patients had to not be eligible for further chemotherapy. At the time this trial was being performed, treatment with docetaxel in the second-line setting had a demonstrated survival benefit over BSC or older chemotherapy agents and was a therapeutic option [28, 29]. Of the patients enrolled, 93% had received platinum-based chemotherapy, 51% had received one prior therapy and 49% had received two prior therapies (Table 2). Patients treated with erlotinib experienced a higher response rate, longer progression-free survival time, and longer overall survival time than patients receiving placebo (Table 3 and Fig. 1). A subset univariate analysis revealed a consistent survival benefit across multiple subtypes. In the analysis of response to prior therapy, patients who experienced a complete or partial response to previous therapy (n 292) had a significant survival benefit with erlotinib (HR, 0.7; 95% CI, ; p.004), whereas patients who experienced stable (n 287) or progressive (n 152) disease did not have a statistically significant difference in survival with erlotinib (HR, 0.8; 95% CI, ; p.18 and HR, 0.9; 95% CI, ; p.34, respectively). On univariate analysis, EGFR expression by immunohistochemistry (HR, 0.68; 95% CI, ; p.02) and a high number of copies of EGFR by fluorescence in situ hybridization (FISH) (HR, 0.44; 95% CI, ; p.008) were significantly associated with longer survival among patients treated with erlotinib, compared with patients treated with placebo [30]. However, on multivariate analysis, survival after treatment with erlotinib was not influenced by the status of EGFR expression, number of EGFR copies, or presence of EGFR mutations. The Iressa Survival Evaluation in Lung Cancer (ISEL)

4 936 Gefitinib in Advanced NSCLC Table 2. Select patient characteristics of the BR.21 and ISEL trials BR.21 trial [20] ISEL trial [21] n 731 1,692 Treatment Erlotinib (n 488) Placebo (n 243) Gefitinib (n 1,129) Placebo (n 563) Median age in years (range) 62 (34 87) 59 (32 89) 62 (28 90) 61 (31 87) Sex (%) Male Female Placebo or ethnic group (%) Asian Other Performance status score (%) n of previous chemotherapy regimens (%) Response to previous chemotherapy (%) Complete or partial Stable disease Progressive disease Not evaluable Pathological subtype (%) Adenocarcinoma Squamous Other Smoking status (%) Current or ever smoker Never smoker Unknown Abbreviation: ISEL, Iressa Evaluation in Lung Cancer. trial was a phase III trial that compared gefitinib (250 mg daily) with BSC in 1,692 patients [21]. Patients were required to have received one or two previous therapies and to have refractory disease, which was defined as recurrent or progressive disease during treatment or within 90 days of the latest chemotherapy dose or intolerance to their previous chemotherapy treatment. Patients who had a performance status score of 0 2 were eligible, and those who had a performance status score of 3 were eligible if the investigator believed that the performance status was not predominantly related to the presence of comorbidities (Table 2). Of the patients enrolled, 96% had received platinum-based therapy, and 90% were determined to be refractory to the previous therapy. Patients treated with gefitinib, in comparison with patients treated with placebo, experienced a significantly higher response rate and longer time to treatment failure (HR, 0.82; 95% CI, ; p.0006) and a nonstatistically significant difference in overall survival time (5.6 months for gefitinib and 5.1 months for placebo; HR, 0.89; 95% CI, ; p.087) (Table 3 and Fig. 1). On preplanned subgroup analyses, a longer survival time was observed for patients treated with gefitinib who were never-smokers and who were of Asian origin, but not for patients with adenocarcinoma histology. An evaluation of potential biomarkers in the ISEL trial revealed that high EGFR gene copy number was a predictor of a

5 Stinchcombe, Socinski 937 Table 3. Efficacy of erlotinib and gefitinib in the BR.21 and ISEL trials Erlotinib [20] Gefitinib [21] Overall study population n Objective response (%) Stable disease (%) Progressive disease (%) Nonevaluable (%) 17 a 23 Overall survival HR, 0.70; 95% CI, ; p.001 HR, 0.89; 95% CI, ; p year survival rate 31% 27% Subset analyses Adenocarcinoma HR, 0.70; 95% CI, ; p.008 (n 365) Never smokers HR, 0.4; 95% CI, ; p.001 (n 146) Asian ethnicity HR, 0.6; 95% CI, ; p.06 (n 91) a Includes patients whose disease progression could not be confirmed. Abbreviations: CI, confidence interval; HR, hazard ratio; ISEL, Iressa Evaluation in Lung Cancer. gefitinib-related effect on survival in comparison with placebo [31]. POTENTIAL REASONS FOR THE DIFFERENT RESULTS After the completion of the phase II trials, the common perception was that erlotinib and gefitinib were similar therapies, thus the discordant results of the phase III trials were unexpected. A number of different explanations have been considered for the different results of the two trials. Different patient populations were seemingly enrolled in the two trials because of differences in the eligibility criteria between the two trials. The ISEL trial required patients to have progressed on the previous line of chemotherapy within 90 days while the BR.21 trial did not. This may have unintentionally selected for a patient population in the ISEL trial that was more refractory to treatment and less likely to benefit from additional treatment. In the ISEL trial, 18% of patients had responded to their previous chemotherapy whereas 38% had responded in the BR.21 trial, and in the ISEL trial 45% had experienced progressive disease or were nonevaluable in comparison with 28% in the BR.21 trial. Despite this difference in the selection criterion, the response and stable disease rates were similar in the two trials. The percentages of patients who had a performance status score of 0 1, had adenocarcinoma histology, and were never-smokers were similar in the two trials. A larger percentage of patients in the ISEL trial (approximately 20%) than in the BR.21 trial (approximately 12%) were Asian. HR, 0.84; 95% CI, ; p.089 (n 812) HR, 0.67; 95% CI, ; p.012 (n 375) HR, 0.66; 95% CI, ; p.01 (n 342) Another potential explanation is that a suboptimal dose of gefitinib was investigated in the ISEL trial. The decision to proceed with the 250-mg daily dose was based on a higher rate of toxicity with the 500-mg daily dose and the fact the response rates were similar for the two doses. This decision was made before the existence of the activating EGFR mutations was known. In contrast, the BR.21 trial investigated erlotinib at the MTD. Cases of NSCLC that were dependent on activation of the EGFR pathway and extremely sensitive to EGFR TKI therapy would respond equally well to gefitinib at a dose of 250 mg daily and erlotinib at a dose of 150 mg daily (i.e., cases of NSCLC with an activating EGFR mutation), but it is possible that cases that had limited sensitivity or were partially dependent on the EGFR pathway may have had a greater clinical benefit from the MTD dose of erlotinib than gefitinib, which was given at approximately 40% of the MTD. The development of rash has been observed to correlate with clinical benefit from treatment with erlotinib and gefitinib [27, 32, 33], and this led to the hypothesis that the development of a rash may be a surrogate marker of clinical benefit to EGFR TKI treatment. In a multivariate analysis of patients who received erlotinib in the BR.21 trial, there was a strong correlation between rash and the progression-free survival time (HR, 0.51 for grade 1 in comparison with grade 0; p.001; HR, 0.35 for grade 2 in comparison with grade 0; p.001) and between rash grade and the survival time (HR, 0.51 for grade 1 in comparison with

6 938 Gefitinib in Advanced NSCLC Figure 1. Overall survival in the BR.21 and ISEL trials. (A): Overall survival observed in the BR.21 trial. From Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al., Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353: Copyright 2005 Massachusetts Medical Society. All rights reserved. (B): Overall survival observed in the ISEL trial. Reprinted from The Lancet, Vol. 366, Thatcher N, Chang A, Parikh P et al., Gefitinib plus best supportive care in previously treated patients with refractory advanced nonsmall-cell lung cancer: Results from a randomised, placebocontrolled, multicentre study (Iressa Survival Evaluation in Lung Cancer), , Copyright 2005, with permission from Elsevier. Abbreviations: CI, confidence interval; ISEL, Iressa Evaluation in Lung Cancer. grade 0; p.001; HR, 0.34 for grade 2 in comparison with grade 0; p.001) [34]. In the ISEL trial, the rates of all grades of rash and grade 3 4 rash were 37% and 2%, respectively. In contrast, in the BR.21 trial, the rate of all grades of rash and grade 3 5 rash were 76% and 9%, respectively. In the IDEAL-II trial, the rate of all grades of rash was significantly higher with gefitinib at a dose of 500 mg daily than with 250-mg daily gefitinib (75% versus 62%, respectively; p.04). Thus, the lower incidence of rash observed in the ISEL trial may be a surrogate marker for a lower rate of efficacy related to the dose of gefitinib used. There has also been extensive investigation into clinical and molecular markers that explain the significant difference in clinical outcomes associated with EGFR TKI therapy. While there is an association between activating EGFR mutations and response, the association between activating EGFR mutations and survival is less clear as a result of the fact that patients who have activating EGFR mutations may have a better prognosis and these analyses were performed on a relatively small number of patients [30, 31, 35]. Investigation into the prognostic and predictive value of the mutations is further complicated by the fact that different mutations may be associated with different response and overall survival rates [36, 37]. A higher EGFR gene copy number detected by FISH may also be associated with superior response and survival with gefitinib in comparison with placebo [31, 38]. There is evidence that KRAS mutations are associated with resistance to EGFR TKIs [35, 39]. A difference in the prevalence of one or more of the biomarkers associated with response or resistance to EGFR TKI therapy between the two trials may have contributed to the difference in the trial results. TRIALS COMPARING GEFITINIB WITH CHEMOTHERAPY Several trials have compared gefitinib treatment with chemotherapy (Table 4). The Second-line Indication of Gefitinib in Non-small cell lung cancer (SIGN) study was a randomized phase II trial comparing docetaxel (75 mg/m 2 every 3 weeks) with gefitinib (250 mg daily) in patients who had progressed after one chemotherapy regimen (n 141) [40]. The trial was not designed to test for a statistical difference between treatments on any endpoint, and the primary objective was symptom improvement using the FACT-L. The rates of symptom improvement were similar in the gefitinib and docetaxel groups, 36.8% and 26%, respectively. The response rates, median progression-free survival times, and median survival times were similar in the two treatment arms (Table 4). Patients in the gefitinib arm experienced fewer drug-related adverse events (51.5% versus 78.9%, respectively) and fewer grade 3 or 4 drugrelated adverse events (8.8% versus 25.4%, respectively). A phase III trial, labeled V-15 32, investigated gefitinib (250 mg daily) versus docetaxel (60 mg/m 2 every 3 weeks) in Japanese patients who had progressed after one or two previous chemotherapy regimens (at least one had to contain a platinum agent) [41]. Of the 489 patients enrolled, approximately 78% had adenocarcinoma histology, 38% were female, and 32% were never-smokers. The primary

7 Stinchcombe, Socinski 939 Table 4. Trials comparing gefitinib with chemotherapy Trial Phase (n) Treatments endpoint was the noninferiority of gefitinib in comparison with docetaxel in overall survival, and the upper limit of the CI was required to be 1.25 in order to demonstrate noninferiority. This trial demonstrated similar activity between gefitinib and docetaxel; however, the trial did not meet the primary endpoint of demonstrating noninferiority (HR, 1.01; 95% CI, ; p.94). The response rate observed in this trial for gefitinib (22.5%) was similar to the response rate observed in the IDEAL-I trial. The rate of grade 3 or 4 treatment-related adverse events was lower in the gefitinib arm than in the docetaxel arm, 24.2% versus 79.5%, respectively. The quality of life assessment using the FACT-L and Trial Outcome Index (TOI) significantly favored treatment with gefitinib, but the rates of symptom relief as measured by the lung cancer subscale (LCS) were similar (p.562). When the poststudy treatments were assessed, 40% of patients in the gefitinib arm continued on gefitinib or received BSC, whereas in the docetaxel arm, 26% continued on docetaxel or received BSC. In the gefitinib arm, 36% of patients received docetaxel or other chemotherapy, whereas in the docetaxel arm, 53% of patients received gefitinib and 20% received additional chemotherapy. Thus, the poststudy treatments potentially may have impacted the assessment of overall survival. The Iressa Non-small cell lung cancer Trial Evaluating REsponse and Survival against Taxotere (INTEREST) compared gefitinib (250 mg daily) with docetaxel (75 mg/m 2 every 3 weeks) in 1,466 patients in 149 centers in 24 Response (%) Median PFS (mos) Median OS (mos) SIGN [40] II (141) Gefitinib, 250 mg daily Docetaxel, 75 mg/m 2 every 3 weeks V [41] III (489) a Gefitinib, 250 mg daily 22.5 b 2.0 b 11.5 b Docetaxel, 60 mg/m 2 every 3 weeks INTEREST [42] III (1,466) a Gefitinib, 250 mg daily 9.1 c 2.2 c 7.6 c Docetaxel, 75 mg/m 2 every 3 weeks INVITE [44] II (196) Gefitinib, 250 mg daily 3.1 NR d NR d Vinorelbine, 30 mg/m 2 days 1 and 8 every 3 weeks 5.1 NR NR a Noninferiority trial design. b Difference in response statistically significant (p.009). For gefitinib in comparison with docetaxel for PFS, HR, 0.81 (95% CI, ; p.077); for overall survival, HR, 1.01 (95% CI, ; p.914). c For gefitinib in comparison with docetaxel: response rate odds ratio, 1.22 (95% CI, ; p.3257); for PFS, HR, 1.04 (95% CI, ; p.4658), for overall survival, HR, (96% CI, ). d PFS reported as HR of gefitinib in comparison with docetaxel; HR, 1.19 (95% CI, ; p.310); for OS, HR, 0.98 (95% CI, ); median progression-free survival and overall survival times not reported. Abbreviations: INTEREST, Iressa Non-small cell lung cancer Trial Evaluating REsponse and Survival against Taxotere; INVITE, Iressa versus vinorelbine in chemotherapy-naïve elderly patients with advanced non-small cell lung cancer; NR, not reported; OS, overall survival; PFS, progression-free survival; SIGN, Second-line Indication of Gefitinib in Non-small cell lung cancer. countries worldwide [42]. Of the patients enrolled in the trial, approximately 20% were never-smokers, 55% had adenocarcinoma histology, 20% were of Asian ethnicity, and 34% were female. The primary endpoints were the noninferiority of gefitinib in comparison with docetaxel in overall survival in all patients and the superiority in terms of overall survival of gefitinib in patients with high EGFR gene copy number as assessed by FISH. The trial did meet the overall endpoint of demonstrating the noninferiority of gefitinib in comparison with docetaxel (HR, 1.020; 96% CI, ). The median survival times observed with gefitinib and docetaxel in this trial, 7.6 and 8.0 months, respectively, were similar to the median survival times observed in other phase III trials of second-line docetaxel [28, 43]. The INTEREST trial is also significant because it is the largest phase III trial that compared an EGFR TKI therapy with a standard chemotherapy, and it provides additional validation for the role of EGFR TKI therapy in the treatment of NSCLC. In a preplanned subgroup analysis, the treatment by subgroup interaction test was statistically insignificant in all groups except for the patients that received two prior regimens. In this subgroup, docetaxel was favored (p.0311). In patients with a high EGFR gene copy number (n 174), gefitinib did not demonstrate statistical superiority over docetaxel (HR, 1.09; 95% CI, ; p.6199). The result in patients with a high EGFR gene copy number was quite provocative and has raised questions about the predic-

8 940 Gefitinib in Advanced NSCLC Table 5. Trials of EGFR TKI therapy in patients with EGFR mutations n of patients Study Treatment Analyzed detected Mutations tive value of a high gene copy number. Based on previous retrospective data, it was thought that this patient population would be more likely to derive clinical benefit from EGFR TKI therapy, but previous comparisons were performed between patients receiving EGFR TKI therapy and those receiving placebo, rather than chemotherapy. This result emphasizes the need to prospectively collect and validate biomarkers, and to integrate the investigation of biomarkers into clinical trial design. In the secondary analyses, the objective response rates and progression-free survival times were similar with gefitinib and docetaxel (Table 4). When the quality of life and symptom improvements rates are compared, the patients who received gefitinib experienced a statistically significant higher rate of improvement in quality life according to the FACT-L and TOI assessments. In the safety analyses, the percentage of patients who experienced a grade 3 or 4 treatment-related adverse event was lower in the gefitinib arm than in the docetaxel arm, 8.5% versus 40.7%, respectively, and for treatment-related serious adverse events, the corresponding values were 3.8% and 18.2%, respectively. Thus, the quality of life and toxicity data favor gefitinib. The Iressa versus vinorelbine in chemotherapy-naïve elderly patients with advanced non-small cell lung cancer (INVITE) study was a randomized phase II trial with the primary endpoint of progression-free survival [44]. That trial assumed a median progression-free survival time of 3 months for the vinorelbine treatment arm, and was designed to investigate the superiority of gefitinib with a detection HR of 0.67 with 80% power and a two-sided level of 10%. The trial was performed in 41 centers in 10 countries in Europe, Asia, and South America, and 196 patients were enrolled. Patients were required to be aged 70 years and stage IIIB/IV, and tissue collection was mandatory. Patients received either gefitinib at a dose of 250 mg daily or vinorelbine at 30 mg/m 2 on days 1 and 8 every 3 weeks. Of the Received treatment RR (95% CI), % PFS (95% CI), mos Asahina et al. [48] Gefitinib, 250 mg daily (48 93) 8.9 ( ) Inoue et al. [49] Gefitinib, 250 mg daily (54 96) 9.7 ( ) Sequist et al. [51] a Gefitinib, 250 mg daily (36 73) 11.4 (NR) Paz-Ares et al. [50] b Erlotinib, 150 mg daily (66 92) 13.3 (NR) a Patients selected based on the presence of one or more clinical characteristics associated with EGFR mutations: low or never-smoking history, adenocarcinoma histology, female gender, and East Asian ethnicity. b Patients were required to be chemotherapy-naïve and not candidates for chemotherapy. Abbreviations: CI, confidence interval; EGFR, epidermal growth factor receptor; NR, not reported; PFS, progression-free survival; RR, response rate; TKI, tyrosine kinase inhibitor. patients enrolled, approximately 23% were women, 15% were of Asian ethnicity, 14% were never-smokers, and 40% had adenocarcinoma histology. The progression-free survival times for gefitinib in comparison with vinorelbine were similar (HR, 1.19; 95% CI, ; p.310), and the trial did not meet the primary endpoint of demonstrating superiority in terms of the progression-free survival time with the gefitinib. The overall survival times were similar as well (HR, 0.98; 95% CI, ). In an exploratory analysis, patients who were EGFR positive by FISH (n 54) had a significantly shorter progression-free survival interval with gefitinib than with vinorelbine (HR, 3.13; 95% CI, ), and patients who were EGFR negative by FISH (n 104) had similar progression-free survival times with gefitinib and with vinorelbine (HR, 0.93; 95% CI, ). The quality of life data using the FACT-L and TOI favored gefitinib, and the assessments of symptom improvement using the FACT-L LCS and the pulmonary symptom index were similar in the two treatment arms. The rate of treatment-related adverse events favored gefitinib (57.4% versus 75%, respectively), and the rate of treatment-related serious adverse events favored gefitinib as well (3.2% versus 17.7%, respectively). The subgroup of patients who were EGFR positive by FISH was relatively small, but this analysis raises additional questions about whether the EGFR-positive by FISH patient population will derive greater clinical benefit from EGFR TKI therapy than from chemotherapy. ROLE OF GEFITINIB IN SELECTED PATIENT POPULATIONS Early investigations detected EGFR activating mutations in patients who demonstrated significant responses to EGFR TKIs, and the prevalence of these mutations appeared to correlate with the clinical features that have been associated with higher response rates (never smoking, Asian ethnicity,

9 Stinchcombe, Socinski 941 female gender, adenocarcinoma histology) [45 47]. While treatment with gefitinib did not provide a statistically significant survival benefit in all patients in the ISEL trial, a significant survival benefit was observed among neversmokers and among patients of Asian ethnicity, but not among patients with adenocarcinoma histology. These subset analyses suggest that gefitinib may provide significant benefit in selected patients. Several phase II trials have investigated the efficacy of gefitinib in highly selected patient populations based on the presence of an activating EGFR mutation (Table 5) [48 51]. These activating mutations are most frequently detected in the exon region [52]. Sequist et al. [51] selected chemotherapy-naïve patients with nonsquamous histology who had one or more clinical characteristics associated with activating EGFR mutations (low or never smoking history, adenocarcinoma histology, female gender, and East Asian ethnicity). In this clinically enriched patient population, mutations were identified in 35% of patients, which is higher than the rate of 10% 15% seen in previous studies in Western populations [53]. Paz-Ares et al. [50] investigated the activity of erlotinib (150 mg daily) in chemotherapy naïve NSCLC patients who were determined not to be candidates for chemotherapy. Those trials demonstrated response rates of 55% 80% and median progression-free survival times of 9 13 months, which are higher than the response rates and median progression-free survival times observed with chemotherapy. However, the selection of patients with EGFR mutations may have identified a unique subset of patients with advanced NSCLC with a different prognosis and response to therapy. Several mechanisms of primary and secondary EGFR TKI resistance have been identified [54 58], and it is unclear what impact these differences in tumor biology may have on the behavior of the disease and response to subsequent therapies. The Spanish Lung Cancer Group is currently performing a phase III trial comparing erlotinib with platinum-based chemotherapy in chemotherapy-naïve patients with activating EGFR mutations, and that trial may validate the promising phase II data on initial therapy with an EGFR TKI in this patient population [50]. Additional trials have selected patients based on a combination of clinical, pathological, or molecular features. The ONCOBELL trial selected for patients who were never smokers or who had evidence of a high gene copy on FISH and were phospho-akt (P-Akt) positive, and patients received gefitinib at a dose of 250 mg daily [59]. Of the 183 patients who were evaluated, 42 patients were enrolled in the trial. The main reasons patients were not eligible for the trial were: smoking history unknown (n 14), negative EGFR by FISH (n 114), and negative P-Akt (n 13). The response rate observed was 47.6% (95% CI, 32.5% %), the median time to tumor progression was 6.4 months, and the 1-year survival rate was 64.3%. EGFR mutations were detected in 24 patients (66.8%), and the response rate observed in those patients was 62.5%. A phase II trial performed by the Southwest Oncology Group selected for patients with bronchioalveolar carcinoma [33]. That trial included previously treated (n 22) and untreated (n 69) patients, and patients received gefitinib at a dose of 500 mg daily. The response rates observed in the trial in the previously treated and untreated patients were 9% and 17%, respectively, and the progression-free survival times were 3 months (95% CI, 2 5) and 4 months (95% CI, 3 6), respectively. Another area of investigation is the selection of patients based on the clinical history of never having smoked. A phase II trial investigated the activity of gefitinib (250 mg daily) in 37 chemotherapy-naïve Korean patients with adenocarcinoma histology and a never smoking history [60]. The observed objective response rate was 69% (95% CI, 52% 84%), and the disease control rate was 81%. The median progression-free survival time and 1-year survival rate observed were 33 weeks and 73%, respectively. Patients were not assessed for the presence or absence of activating EGFR mutations. Retrospective data from a phase III trial that compared carboplatin and paclitaxel with and without erlotinib revealed that patients with a history of never smoking had a longer survival time with the addition of erlotinib (n 72) than with placebo (n 44) (22.5 months versus 10.1 months; HR, 0.49; 95% CI, ) [61]. The Cancer and Leukemia Group B is currently performing a randomized phase II trial of single-agent erlotinib and erlotinib in combination with carboplatin and paclitaxel in chemotherapy-naïve patients with adenocarcinoma and a never (defined as 100 cigarettes) or light (defined as 10 years and quit 1 year ago) smoking history [62]. Tissue collection is mandatory for enrollment in the trial. That trial will provide valuable prospective data about the activity of these two treatments in this patient population within the U.S. DOES GEFITINIB DESERVE A SECOND CHANCE? Currently, two chemotherapy agents, docetaxel and pemetrexed (Alimta ; Eli Lilly and Company, Indianapolis, IN), are approved by the U.S. FDA for second-line treatment of advanced NSCLC. The approval of docetaxel in the second-line setting was based on two phase III trials. One trial by Shepherd et al. [28] compared docetaxel (75 mg/m 2 every 3 weeks, n 55) with BSC (n 100), which revealed greater median and 1-year survival rates with docetaxel. A second trial by Fossella et al. [29] compared docetaxel at either 75 mg/m 2 (n 125) or 100 mg/m 2 (n 125) every 3

10 942 Gefitinib in Advanced NSCLC weeks with a control treatment, vinorelbine or ifosfamide (n 123). The median survival times were not significantly different among the three treatment groups, but the 1-year survival rate with docetaxel at 75 mg/m 2 was significantly greater than with the control treatment. Pemetrexed was subsequently approved based on a phase III trial that compared pemetrexed at 500 mg/m 2 (n 265) with docetaxel at 75 mg/m 2 (n 276) every 3 weeks. That trial did not demonstrate noninferiority in terms of survival for pemetrexed in comparison with docetaxel because a reliable and consistent survival effect of docetaxel could not be estimated from the small number of patients treated in previous docetaxel second-line trials, and a significant number of patients received docetaxel upon disease progression [63]. The comparable response rates, progression-free survival times, and overall survival times supported the conclusion that these two therapies had similar efficacies. The rates of grade 3 or 4 nonhematologic toxicities were similar in the two treatment arms. Patients who received pemetrexed were significantly less likely to experience grade 3 or 4 neutropenia (5.3% versus 40.2%; p.001), febrile neutropenia (1.9% versus 12.7%; p.001), and neutropenia with infections (0% versus 3.3%; p.004). The results of that trial were sufficient for approval of pemetrexed by the FDA. In comparison with other second-line trials, the INTEREST trial is substantially larger (n 1,466), and it met the primary endpoint of demonstrating the noninferiority of gefitinib in terms of overall survival in comparison with docetaxel. The response rates and progression-free survival times were similar as well. Patients who were treated with gefitinib experienced a lower rate of grade 3 or 4 treatmentrelated adverse events and treatment-related serious adverse events than patients treated with docetaxel. Patients who were treated with gefitinib also experienced a numerically lower rate of grade 3 or 4 neutropenia (2.2% versus 58.2%) and febrile neutropenia (1.2% versus 10.1%). Significantly more gefitinib-treated patients experienced clinically relevant improvements in quality of life. Thus, gefitinib has clearly demonstrated noninferiority to a currently approved standard therapy, a greater clinically relevant improvement in quality of life compared with docetaxel, and numerically lower toxicity. The SIGN, V-15-32, and INVITE trials provide further supporting evidence that gefitinib has efficacy similar to current standard therapies. The only fly in the ointment for gefitinib is the result of the ISEL trial, which can potentially be explained by a combination of the trial eligibility criteria and the patient population enrolled in the trial. Importantly, 90% of the patients who were enrolled in the ISEL trial were determined to have refractory disease. While the data on the efficacy of gefitinib are compelling and comparable with those of other agents currently available in the refractory setting, the approval and widespread acceptance of erlotinib will most likely impact the decision about whether or not gefitinib will receive a second chance. The approval of gefitinib by the U.S. FDA would not provide a new agent with a novel therapeutic target or a treatment for a patient population with an unmet need, but would expand the options available for patients and create a competitive landscape within the EGFR TKI marketplace. 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