Lung cancer is the leading cause of cancer death both in the. EGFR Inhibitors as First-Line Therapy in Advanced Non-small Cell Lung Cancer

STATE OF THE ART: CONCISE REVIEW EGFR Inhibitors as First-Line Therapy in Advanced Non-small Cell Lung Cancer Thomas Fong, MD,* Daniel Morgensztern, MD,* and Ramaswamy Govindan, MD* Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), erlotinib and gefitinib, are active agents in the treatment of advanced non-small cell lung cancer (NSCLC). Although platinum-based doublet chemotherapy remains the cornerstone for the first-line treatment of metastatic NSCLC, several phase II and III trials have been conducted utilizing EGFR TKIs in this setting. Patients with advanced NSCLC who are life long never-smokers, those with EGFR TK mutations, and those with bronchioloalveolar cell carcinoma histology seem to have promising efficacy with first-line therapy with EGFR TKIs compared with unselected groups of patients receiving the same agents. Phase III trials have clearly demonstrated no improvement in survival when EGFR TKIs were combined with conventional platinum-based doublets, with the exception of subset analysis in nonsmokers. This review will summarize the results of clinical trials on erlotinib or gefitinib in the first-line treatment of select and unselected patients with NSCLC and describe ongoing studies with these agents in NSCLC. Key Words: EGFR TK Inhibitors, First-line Therapy, NSCLC. (J Thorac Oncol. 2008;3: 303 310) Lung cancer is the leading cause of cancer death both in the United States 1 and worldwide, 2 with non-small cell lung cancer (NSCLC) accounting for approximately 87% of the newly diagnosed cases. 3 The majority of patients present with unresectable disease, and relapses are common even in those treated with curative intent. 4 The outcomes for patients with advanced stage is universally poor, with median survival typically below 10 months in randomized trials with platinum-based doublets and patients rarely surviving beyond 2 years. 5 7 Despite multiple studies involving different chemotherapy combinations, the benefit from systemic cytotoxic treatment seems to have reached a plateau, where intensification of the regimens leads to increased toxicity and no From the *Department of Medicine, Washington University School of Medicine, St. Louis, Missouri; Alvin J. Siteman Cancer Center at Washington University School of Medicine, St. Louis, Missouri; and St. Louis Veterans Affairs Medical Center, St. Louis, Missouri. Address for correspondence: Ramaswamy Govindan, MD, Division of Oncology, 660 S Euclid Box 8056, St Louis, MO 63110. E-mail: rgovinda@im.wustl.edu Copyright 2008 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/08/0303-0303 meaningful improvement in the outcomes. 8 Therefore, there is a great need for the development of novel approaches. One of the most commonly studied approaches is the targeting of the epidermal growth factor receptor (EGFR) pathway, which may be inhibited by either a monoclonal antibody against the EGFR receptor or by EGFR tyrosine kinase inhibitors (TKIs). This review will summarize the available data from clinical trials evaluating the role of EGFR TKIs as the first-line treatment for NSCLC. EGFR is a member of the HER/ErbB family of transmembrane receptors that forms dimers upon ligand binding, activating the intracellular TK domain, and triggering downstream effector pathways leading to cellular proliferation, angiogenesis, and metastasis. 9 The two classes of agents targeted at EGFR include monoclonal antibodies directed at the extracellular domain of the EGFR and low molecular weight TKIs that inhibit the TK activity of EGFR. Cetuximab (Erbitux; ImClone, Branchburg, NJ) is a high-affinity antibody against the extracellular domain of EGFR that inhibits tumor growth through EGFR blockade and possibly also through the induction of immune effector cells. This agent has an established role in the treatment of colorectal cancer and head and neck malignancies, but there is little evidence to support its role in patients with metastatic NSCLC. 10 There are two low molecular weight EGFR TKIs currently used in the treatment of advanced NSCLC. Gefitinib (Iressa; Astra- Zeneca, Wilmington, DE) was the first agent of this class approved by the U.S. Food and Drug Administration (FDA) in May 2003 for third-line therapy in NSCLC, 11 but is currently no longer available in the United States outside of clinical trials. Erlotinib (Tarceva; Genentech, San Francisco, CA) was approved by the FDA in November 2004 for advanced NSCLC that had progressed through at least one prior chemotherapy regimen. 12 Given the efficacy of EGFR TKIs in advanced NSCLC in the salvage setting, along with their favorable toxicity profile compared with conventional chemotherapy, there is considerable interest in evaluating their efficacy in the firstline treatment for NSCLC. Overview of EGFR Agents in Advanced NSCLC Clinical efficacy of EGFR TKIs in advanced NSCLC has been observed in several trials. In BR.21, the Canadian phase III trial that led to FDA approval for erlotinib, 731 patients with NSCLC previously treated with one or two chemotherapy regimens were randomized to receive erlotinib or placebo. 13 Erlotinib was shown to be superior to placebo in Journal of Thoracic Oncology Volume 3, Number 3, March 2008 303

Fong et al. Journal of Thoracic Oncology Volume 3, Number 3, March 2008 terms of response rates (RRs) (9% to 1%), progression-free survival (PFS) (2.2 months versus 1.8 months), and overall survival (OS) (6.7 months versus 4.7 months, all p-values 0.001). Gefitinib was noted to have clinically meaningful antitumor activity in the multinational IDEAL-1 trial. In this phase II study of 210 patients with advanced NSCLC, gefitinib led to objective response in 19% and median survival of 8 months. 14 Disappointingly, however, gefitinib was not superior to best supportive care in previously treated NSCLC patients in the placebo-controlled, phase III Iressa Survival Evaluation in Lung Cancer (ISEL) trial. 15 In this study of 1692 patients randomized in a 2:1 fashion to receive gefitinib or placebo, median survival was 5.6 months and 5.1 months, respectively (p 0.08). Although gefitinib failed to improve survival in patients with previously treated NSCLC and is no longer prescribed in the United States, 15 this agent continues to be used in several other countries. Subset analyses from multiple studies involving EGFR TKIs identified subgroups of patients with clinical and molecular features associated with increased probability of benefit to this therapy. In the BR.21 trial, 13 erlotinib responses were significantly more common in never-smokers than ever smokers, women than men, Asians than other races, and adenocarcinoma versus other histologies. Furthermore, despite the negative overall results in the ISEL study of gefitinib, 15 preplanned subgroup analysis showed significantly longer survival in never-smokers and in Asians. In addition to adenocarcinoma histology, bronchioloalveolar cell carcinoma (BAC) has been described to be particularly sensitive to gefitinib. 16 Skin rash also correlates with increased likelihood of response to EGFR TKIs in NSCLC. 17 Still, despite differing response rates observed in certain patient subgroups, no clear survival advantage in regards to patient characteristics could be demonstrated in these trials. The prognostic importance of these features is still under discussion, and clinical response may be seen outside these well-known subgroups. The EGFR monoclonal antibody cetuximab has been evaluated in patients with advanced NSCLC to a limited extent. In a randomized phase II trial of first-line cisplatin/ vinorelbine with or without cetuximab, higher response rates (35% and 28%, respectively) and improved PFS (4.8 months and 4.2 months) favored addition of cetuximab to chemotherapy. 18 A phase II trial conducted by the Southwest Oncology Group (SWOG) randomized previously untreated patients with advanced NSCLC to receive carboplatin/paclitaxel with concurrent cetuximab followed by maintenance cetuximab, or the same chemotherapy with sequential cetuximab. 19 Of the 195 evaluable patients, similar response rates (34% and 31%, respectively), PFS (4 months, both arms), and OS (11 and 10 months, respectively) were observed. A randomized phase II trial of gemcitabine/platinum with or without cetuximab as first-line treatment for advanced NSCLC was recently reported. 20 Trends suggesting benefit were observed with higher response rates (28% versus 18%), PFS (5.1 month versus 4.2 months), and OS (12.0 months versus 9.3 months) in the cetuximab arm. A randomized multicenter phase III study of first-line taxane/carboplatin with or without cetuximab enrolled 676 advanced NSCLC patients at 97 U.S. centers. 21 There was no difference in the primary end point of PFS (hazard ratio 0.90, 95% confidence interval, 0.76 1.07), though response rates were higher in the cetuximab arm (26% versus 17%). The phase III multinational First-Line Treatment for Patients with EGFR-Expressing Advanced NSCLC (FLEX) trial randomized over a thousand patients to receive cisplatin/vinorelbine with or without cetuximab. 22 Although details have not yet been published, the study was positive for its primary end point of OS according to recent press release. Until the FLEX trial, results with first-line chemotherapy and the EGFR monoclonal antibody cetuximab have been modest, and the rest of this review will focus on first-line EGFR TKIs alone or in combination with chemotherapy in select and unselected patients with advanced NSCLC. Molecular Predictors of Response to EGFR TKI Therapy One of the molecular predictors associated with response to TKIs in NSCLC is the presence of specific activating EGFR mutations. Lynch et al. reported the presence of EGFR mutations in eight of nine patients treated with gefitinib who were known to have clinical response, whereas none of seven patients who failed to respond to gefitinib had mutations. 23 All detected mutations were small in-frame deletions or amino acid substitutions clustered within the TK domain of EGFR. In a similar study of patients with NSCLC, EGFR TK mutations were found in 15 of 58 tumor samples from Japan and 1 of 16 from the United States. 24 Mutations were correlated with known clinical predictors of response to EGFR TKIs, as they were detected more commonly in women, Japanese, and patients with adenocarcinoma. High EGFR gene copy number may be identified by fluorescence in situ hybridization (FISH) analysis in approximately 25% to 35% of NSCLC patients. 25 In a correlative study to ISEL, FISH-positivity was predictive of a survival benefit from gefitinib. 26 FISH-positive patients also had improved survival with erlotinib in univariate analysis in the BR.21 trial. 27 Nevertheless, in multivariate analysis, neither EGFR expression by immunohistochemistry, high EGFR copy number by FISH, or EGFR mutation status were significantly predictive for survival after treatment with erlotinib. In the INVITE study of previously untreated elderly patients with advanced NSCLC, FISH-positive patients had improved survival when treated with gefitinib compared with vinorelbine (hazard ratio 2.88, 95% confidence interval, 1.21, 6.83). 28 In the INTEREST trial of gefitinib versus docetaxel in previously treated NSCLC patients, though, EGFR FISH status had no impact on survival. 29 EGFR expression detected by immunohistochemistry was also found to correlate with response to erlotinib and survival in subset analysis of the BR.21 trial, though the survival benefit did not persist in multivariate analysis. 27 K-ras mutations, frequently detected in heavy smokers, have been found to be associated with resistance to EGFR TKIs in NSCLC. Mutations in K-ras exon 2 (amino acid substitutions in codons 12 or 13 in each case) were found in 24% of refractory tumors, but in none of the tumors sensitive to EGFR TKIs (p 0.02) in one study. 30 K-ras mutations seem to be strong predictors for lack of response to EGFR TKIs. 304 Copyright 2008 by the International Association for the Study of Lung Cancer

Journal of Thoracic Oncology Volume 3, Number 3, March 2008 EGFR Inhibitors as the First-line Therapy of Advanced NSCLC First-Line EGFR TKI Therapy in Clinical Trials in Select Populations Never-smokers In a phase II trial, gefitinib 250 mg daily was given as initial therapy for 54 patients with advanced NSCLC, all never-smokers with adenocarcinoma histology. 31 All but four patients enrolled in this Korean study were female. The overall response rate was 61% with median PFS of 26 weeks (6 months) and 1-year survival of 79%. The median duration of response in the 33 responders was 30 weeks (7 months). Although it is difficult to interpret an uncontrolled small phase II study, the response rates and 1-year survival are far better than what is commonly reported with platinum-based doublet therapy (Table 1). First-line gefitinib was also given in a prospective multicenter phase II trial (ONCOBELL) of advanced NSCLC patients who were EGFR FISH-positive, phospho-akt positive and/or never-smokers. 32 The rationale for the molecular selection criteria was previous work by the authors suggesting increased sensitivity to EGFR TKIs in patients positive both for EGFR by FISH and for the antiapoptotic protein phospho-akt. 33 Both chemotherapy-naive and previously treated patients were included in this study, and gefitinib was the first-line therapy in 16 of the 42 patients (38%). Overall response was 48%, with a RR of 50% in untreated and 46% in previously treated patients. The median time to disease progression was 6.4 months, and 1-year survival was 64%. Both of these phase II studies suggest promising efficacy of first-line EGFR TKI monotherapy in never-smokers. Subset analyses from two large randomized, placebocontrolled, phase III trials also suggest that never-smokers with advanced NSCLC may derive benefit from first-line EGFR TKIs in combination with chemotherapy. 34,35 In TRIBUTE, 34 never-smokers treated with erlotinib combined with chemotherapy had significantly better survival than those receiving chemotherapy alone, 22.5 months versus 10.1 months. These patients also had superior time to progression (TTP) and objective RR (Table 1). In the Tarceva Lung Cancer Investigation Trial, 35 erlotinib was also superior in never-smokers in terms of PFS (7.9 months versus 5.4 months, p 0.02) and median survival (not reached versus 11.4 months) (Table 1). These results suggest the possible role of EGFR TKIs alone or in combination with conventional chemotherapy in the first-line treatment of NSCLC in never-smokers. There is an ongoing phase II study designed to confirm the benefit of erlotinib with or without chemotherapy in never-smokers in the first-line setting (CALGB 30406). Of note, clinical characteristics such as female gen- TABLE 1. Trials of First-Line EGFR TKIs in Selected Patients with NSCLC First Author Regimen No. pts RR (%) TTP/PFS (mo) MST (mo) 1-yr Survival (%) Never-smokers Lee 31 G 55 61 6.5 mo NR 79 Cappuzzo 32 (ONCOBELL) G 42 48 6.4 mo NR 64 Herbst 34 (TRIBUTE subset) E CbP 72 30 6.0 mo 22.5 mo NR Gatzemeier 35 (TALENT subset) E CsGem 8 NR 7.9 mo NR NR EGFR-selected Asahina 38 G 16 75 8.9 mo NR 88 Cappuzzo 32 (ONCOBELL) G 42 48 6.4 mo NR 64 Paz-Ares 39 E 21 90 NR NR NR Sequist 40 (itarget) G 31 55 11.4 mo 20.8 mo NR BAC Miller 50 E 33 27 NR NR NR West 51 G 101 17 4 mo 13 mo 51 Bearz 52 E or G 16 44 NR NR NR Cadranel 53 G 88 13 2.5 mo NR NR Elderly Jackman 42 E 80 10 3.5 mo 10.9 mo 46 Swinson 45 G 41 10 1 mo 2.7 mo NR Crino 28 (INVITE) G 97 3 NR NR NR V 99 5 NR NR NR Poor PS Lilenbaum 46 E 46 2 2.5 mo NR NR CbP 42 10 4.0 mo NR NR Hesketh 47 E 72 8 2.1 mo 5.0 mo 22 Spigel 48 G 70 4 3.7 mo 6.3 mo 24 G, gefitinib; E, erlotinib; Cb, carboplatin; P, paclitaxel; Cs, cisplatin; Gem, gemcitabine; V, vinorelbine; RR, response rate; TTP, time to progression; PFS, progression-free survival; MST, median survival time; NR, not reported; pts, patients; mo, months. Copyright 2008 by the International Association for the Study of Lung Cancer 305

Fong et al. Journal of Thoracic Oncology Volume 3, Number 3, March 2008 der, Asian ethnicity, and adenocarcinoma histology were not predictors for benefit from erlotinib or gefitinib in any of the four phase III, randomized trials assessing EGFR TKIs in combination with chemotherapy as first-line treatment of advanced NSCLC. 34 37 EGFR TK Mutations NSCLC patients with EGFR TK mutations were treated with first-line gefitinib in a phase II study conducted in northeastern Japan. 38 In this trial, 82 patients were screened for known activating EGFR TK mutations in exons 18 21, which were found in 20 patients (24%). Genomic DNA was isolated from tumor specimens, sequenced, and detected mutations confirmed by PCR amplification and repeat sequencing. Sixteen patients, predominantly female and neversmokers, were enrolled and treated with gefitinib. Objective response was seen in 75%, and all but two patients were alive at 1 year (88%). In a Spanish trial of erlotinib for previously untreated patients with advanced NSCLC with EGFR TK mutations, 37 of 297 tumors screened were found to have mutations. 39 Preliminary data shows that for 21 evaluable patients, response was observed in 90% (6 CR, 13 PR). A U.S. trial of first-line gefitinib in patients with advanced NSCLC and EGFR mutations, itarget, found mutations in 34 of the 98 patients screened. 40 Gefinitib was given to 31 patients, with response observed in 55%, PFS of 11 months, and OS of 21 months (Table 1). Although these are small and limited studies, these results compare favorably to conventional chemotherapy in this select patient group. A phase III trial is currently being conducted by the Spanish Lung Cancer Group in which previously untreated patients with EGFR TK mutations are being randomized to receive erlotinib or four cycles of platinum-based chemotherapy, with PFS as the primary end point. 41 This study will likely further clarify the role of EGFR TKIs in the first-line treatment of patients with advanced NSCLC and mutations in the TK domain of EGFR. Elderly Patients Elderly patients have also been evaluated for first-line EGFR TKI therapy given the concern for treatment-related toxicities with conventional chemotherapy (Table 1). In a phase II study of patients aged 70 or older with advanced NSCLC and no prior chemotherapy, 80 patients were treated with erlotinib monotherapy. 42 Partial response was seen in 10%, and an additional 41% achieved stable disease for at least 2 months. The median survival, 1-year survival, and 2-year survival were 11 months, 46%, and 19%, respectively. These are favorable results when compared with trials evaluating first-line chemotherapy in elderly patients with advanced NSCLC. 43,44 Crino et al. recently reported on gefitinib versus vinorelbine in previously untreated elderly patients with advanced NSCLC in the randomized phase II INVITE trial. 28 Although the primary end point of superior PFS for gefitinib was not met in this trial of 196 patients, gefitinib was similar to vinorelbine in terms of PFS, RR, and OS, and was better tolerated and associated with higher quality of life improvement compared with vinorelbine. In another phase II trial of patients over 70 years of age with advanced NSCLC unfit or unwilling for chemotherapy, gefitinib was given as first-line therapy with predictably modest results. 45 Of 41 evaluable patients, 10% achieved PR. Nevertheless, PFS was only 32 days, with median survival of 82 days. Despite these results, it is fair to state that elderly patients (not otherwise selected by EGFR TK mutations or smoking status) seem to tolerate EGFR TK inhibitors reasonably well. Even though the primary end point was not met, the results from the INVITE study suggest at least in certain elderly patients that EGFR TK inhibitors may produce outcomes similar to single agent chemotherapy. This issue needs to be studied further in prospective trials. Performance Status First-line EGFR TKI therapy has been evaluated in advanced NSCLC patients with poor performance status (PS). In a randomized phase II trial, erlotinib monotherapy was compared with conventional platinum-based doublet chemotherapy (carboplatin and paclitaxel) in patients with advanced NSCLC and PS of 2. In preliminary results, RR (10% versus 2%) and PFS (4.0 months versus 2.5 months) are significantly better with chemotherapy than erlotinib. 46 Erlotinib as first-line therapy for patients with advanced NSCLC and PS of 2 was also given in a SWOG phase II trial (S0341). 47 In a preliminary report of 72 evaluable patients, 8% had response and median OS was 5 months. In a phase II nonrandomized trial, gefitinib monotherapy was given as first-line therapy in patients with advanced NSCLC and PS 2 or 3. Of 70 patients, partial response was seen in 4%, with median OS of 6.3 months. 48 These data do not support the use of EGFR TKIs in the first-line setting solely based on PS alone. An ongoing phase III trial in the United Kingdom (TOPICAL) in patients with PS 2 or 3 or with renal insufficiency will likely provide further insight regarding the use of EGFR TKIs in this patient population. 41 BAC Patients with BAC, a histologic subtype of adenocarcinoma, have been shown to be particularly responsive to EGFR TKIs in phase II trials. Although the pathophysiology is not clear at this time, the postulated mechanisms include the possibility of more common EGFR mutations and EGFR amplification in patients with pure BAC, BAC with focal invasion, or adenocarcinoma with BAC features. 49 In a retrospective review of 139 patients treated with gefitinib at Memorial Sloan- Kettering Cancer Center, higher response rates were noted in adenocarcinoma versus other NSCLC (19% versus 0%). 16 Additionally, adenocarcinoma with BAC features or pure BAC was associated with higher response compared with other adenocarcinomas (38% versus 14%, p 0.001). When tested in multivariate analysis, bronchioloalveolar features remained significant as an independent predictor of response. In a phase II trial of erlotinib for first-line treatment in unselected patients with advanced NSCLC, BAC was found to be associated with longer OS in subset analysis. 17 Six patients with BAC had a median survival longer than 607 days, a statistically significant increase compared with adenocarcinoma, squamous, or other histology. A prospective 306 Copyright 2008 by the International Association for the Study of Lung Cancer

Journal of Thoracic Oncology Volume 3, Number 3, March 2008 EGFR Inhibitors as the First-line Therapy of Advanced NSCLC phase II trial of 33 patients with BAC (adenocarcinoma with BAC features, pure BAC or BAC with focal invasion) reported a 27% objective response to first-line therapy with erlotinib. 50 In the SWOG phase II trial S0126, 136 patients (101 chemotherapy-naive) with advanced BAC were treated with gefitinib, leading to objective responses in 17% and median survival of 13 months. 51 Subset analysis revealed improved survival in women, never-smokers, patients with good PS, and patients who developed a rash. In another trial of 16 patients with BAC, 52 in which all patients were Caucasian, female, and never-smokers, first-line erlotinib or gefitinib resulted in objective response in 44%. This report also noted the interesting finding that all responders had normal CA 15-3 levels before treatment, whereas all nonresponders had abnormal CA 15-3 levels. A French phase II study administered gefitinib as first-line treatment in advanced adenocarcinoma with BAC features, 53 with partial responses noted in 13% and median PFS of 3 months. Phase III trials of EGFR TKIs in this limited patient subgroup have not been conducted. Nevertheless, based on the available evidence, patients with BAC may be reasonable candidates for first-line therapy with EGFR TKIs. First-Line EGFR TKI Therapy in Clinical Trials: Unselected Patients Single-agent Given the plateau in benefits achieved with platinumbased doublet chemotherapy, the toxicities associated with these regimens, and the promising results with EGFR TKIs in the salvage setting, there has been understandable enthusiasm in evaluating EGFR TKIs for first-line therapy in all patients with advanced NSCLC (Table 2). In a phase II trial of 53 chemotherapy-naive patients receiving erlotinib for the treatment of advanced NSCLC, objective response was seen in 23%, median TTP was 84 days, and median OS was 391 days. 17 Patients were not selected by any known clinical predictors in this study, and treatment was well-tolerated. Results were more modest in a phase II trial of first-line gefitinib in unselected patients with advanced NSCLC. 54 Of 58 evaluable patients in this multicenter study, objective response was observed in 5%, and stable disease in an additional 40%. Median PFS was 7 weeks, and median survival was 29 weeks. In an earlier prospective phase II trial of chemotherapy-naive patients with advanced NSCLC, 40 patients treated with first-line gefitinib were evaluated for response. 55 PR was seen in 12 (30%) patients. Nevertheless, 4 (10%) patients died of interstitial lung disease. The authors acknowledged that this severe toxicity was not acceptable for first-line therapy. This incidence of death from interstitial lung disease has not been observed in other trials with gefitinib, perhaps due in part from greater investigator awareness of this potential toxicity and earlier discontinuation of therapy when appropriate. Further, this latter trial was conducted in an Asian population, whereas the former two trials described were conducted in a Caucasian population, likely contributing to differences in the response rates and toxicities. The recently reported phase III INTEREST 29 trial confirmed the efficacy of EGFR TKIs in the salvage setting, as gefitinib monotherapy led to noninferior survival, along with more favorable toxicity profile and superior quality of life measurements when compared with docetaxel. There have been no published randomized phase III trials utilizing first-line erlotinib or gefitinib monotherapy to date, though first-line erlotinib monotherapy is a treatment arm in the TOPICAL and TORCH trials that are currently accruing patients (Table 3). Combination with Chemotherapy The combination of EGFR TKIs with first-line chemotherapy for advanced NSCLC has failed to show benefit compared with chemotherapy alone in four large randomized, phase III trials. 34 37 In the TRIBUTE trial of over 1000 patients, those treated with erlotinib in combination with carboplatin and paclitaxel fared no better than placebo in terms of RR, TTP, or OS. 34 Patients in this trial were not selected based on known prognostic factors. Whereas the subgroup of never-smokers had improved outcomes, erlotinib TABLE 2. Trials of First-Line EGFR TKIs in Unselected Patients with NSCLC First Author Regimen No. pts RR (%) TTP/PFS (mo) MST (mo) 1-yr Survival (%) Phase II unselected patients Giaccone 17 E 53 23 3 mo 13 mo 54 Reck 54 G 58 5 1.7 mo 6.7 mo NR Niho 55 G 40 30 NR 13.9 mo 55 Phase III Herbst 34 (TRIBUTE) E CbP 526 22 5.1 mo 10.6 mo 22 CbP 533 19 4.9 mo 10.5 mo 19 Gatzemeier 35 (TALENT) E CsGem 580 32 7.9 mo 10.0 mo 41 CsGem 579 30 5.4 mo 10.2 mo 42 Giaccone 36 (INTACT-1) G CsGem 730 51 5.7 mo 9.9 mo 42 CsGem 365 47 6.0 mo 10.9 mo 44 Herbst 37 (INTACT-2) G CbP 692 30 5.0 mo 9.3 mo 39 CbP 345 29 5.0 mo 9.9 mo 42 E, erlotinib; G, gefitinib; Cb, carboplatin; P, paclitaxel; Cs, cisplatin; Gem, gemcitabine; RR, response rate; TTP, time to progression; PFS, progression-free survival; MST, median survival time; NR, not reported; pts, patients; mo, months. Copyright 2008 by the International Association for the Study of Lung Cancer 307

Fong et al. Journal of Thoracic Oncology Volume 3, Number 3, March 2008 TABLE 3. Select Ongoing Trials of First-Line EGFR TKIs in Patients with Advanced NSCLC Regimen Site Notes Phase II unselected patients Erlotinib/gemcitabine Australia Erlotinib vs. platinum-based chemotherapy New Mexico (US) Phase II select patients EGFR Status Gefitinib Korea EGFR mutations Erlotinib with or without carboplatin/paclitaxel Multicenter (US) EGFR overexpression and/or EGFR amplification Never-smokers Erlotinib with or without carboplatin/paclitaxel Multicenter (US) Never-smokers and adenocarcinoma Adenocarcinoma Erlotinib Multicenter (US) Adenocarcinoma and women Elderly ( 70 yr) Erlotinib and/or gemcitabine NCI (US) Erlotinib/pemetrexed/bevacizumab Moffitt (US) Performance status Erlotinib Multicenter (US) PS 0 1 and less than 10% weight loss Erlotinib/bevacizumab Multicenter (US) PS 2 Gefitinib vs. carboplatin/gemcitabine Multicenter (Canada) PS 2 Phase III unselected patients Erlotinib, then 2nd line cisplatin/gemcitabine vs. Multicenter Cisplatin/gemcitabine, then 2nd line erlotinib (TORCH) (Italy, Canada) Phase III select patients EGFR Status Erlotinib vs. chemotherapy Multicenter (Spain) EGFR mutations Never smokers Gefitinib vs. cisplatin/gemcitabine Multicenter (Korea) Never-smokers and adenocarcinoma Gefitinib vs. carboplatin/paclitaxel Multicenter (Asia) Unsuitable for chemotherapy Erlotinib vs. placebo (TOPICAL) United Kingdom PS 2 3 or renal insufficiency NCI, National Cancer Institute. with concurrent chemotherapy did not confer a survival advantage over chemotherapy alone in the overall patient population. In the Tarceva Lung Cancer Investigation Trial (TALENT), 1172 patients received either erlotinib or placebo in combination with up to six cycles of cisplatin and gemicitabine, followed by maintenance erlotinib or placebo. 35 This was also performed in unselected patients with advanced NSCLC, and likewise failed to demonstrate benefit for erlotinib in the specified primary end point of OS or secondary endpoints of RR, TTP, duration of response, or quality of life. Gefitinib in combination with chemotherapy was likewise not shown to have improved efficacy over chemotherapy alone in unselected patients with advanced NSCLC in phase III trials. This was evaluated in two trials of identical design using different chemotherapy regimens. The Iressa NSCLC Trial Assessing Combination Treatment (INTACT) 1 (enrolling mostly European patients) used cisplatin and gemcitabine, whereas INTACT 2 (predominantly American patients) used the combination of carboplatin and paclitaxel. 36,37 In both of these trials, chemotherapy was combined with one of three treatment arms: placebo, gefitinib 250 mg/d, or gefitinib 500 mg/d. Over 1000 previously untreated patients were recruited for each of these trials, with primary end points including OS, TTP, RR, and safety evaluations. Median survival times for gefitinib 500 mg/d, gefitinib 250 mg/d, and placebo were 9.9, 9.9, and 10.9 months, respectively, in INTACT 1, and 8.7, 9.8, and 9.9 months, respectively, in INTACT 2. No difference in any of the efficacy end points between the treatment groups was observed in either of these trials. Proposed reasons for lack of efficacy in these phase III trials include mechanistic interactions between chemotherapy and EGFR TKIs. The effects of EGFR TKIs in regards to antiproliferation and cell-cycle arrest were speculated to possibly render tumor cells less sensitive to cytotoxic agents. 35 Based on the results of the above trials, EGFR TKIs as monotherapy or in combination with conventional chemotherapy cannot be recommended as first-line therapy in unselected patients with advanced NSCLC. Comparison with Standard Chemotherapy Although the response rates from single-agent EGFR TKIs in the first-line setting of unselected patients are typically lower than combination chemotherapy, disease-free survival is comparable, particularly in elderly patients treated with single agent. The efficacy of first-line EGFR TKIs in 308 Copyright 2008 by the International Association for the Study of Lung Cancer

Journal of Thoracic Oncology Volume 3, Number 3, March 2008 EGFR Inhibitors as the First-line Therapy of Advanced NSCLC comparison with standard chemotherapy is being investigated in a number of ongoing trials (Table 3). 41 Comments Despite the negative overall findings of four randomized, phase III trials evaluating first-line EGFR TKIs with chemotherapy in unselected patients with advanced NSCLC, there is strong evidence that certain subsets of patients may be appropriate candidates for first-line EGFR-targeted therapies. In particular, never-smokers seem to have promising overall and PFS benefit from first-line EGFR TKI therapy alone or in combination with chemotherapy. Impressive results have been observed in EGFR TKI first-line therapy in the never-smoker population in phase II and subset analyses of phase III studies. Patients with EGFR TK mutations have been shown to have significant response to EGFR TKIs; however, these mutations are present only in a small percentage of patients in the Western hemisphere. Finally, patients with BAC histology have been shown to have promising efficacy with first-line EGFR TKI therapy in small studies. Patients with NSCLC who are never-smokers and those who have EGFR mutations and/or BAC histology seem to respond to first-line single-agent EGFR TKIs with results comparable to conventional chemotherapy. Nevertheless, whether these clinical or molecular features are valid prognostic or predictive markers can only be definitively ascertained through prospective randomized phase III studies. Until then, the use of erlotinib or gefitinib as first-line therapy for advanced NSCLC remains investigational. REFERENCES 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin 2006;56:106 130. 2. Parkin DM, Bray F, Ferlay J, et al. 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