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• W2017389411 abstract "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. 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. Lung cancer is the leading cause of cancer death both in the United States1Jemal A Siegel R Ward E et al.Cancer statistics, 2006.CA Cancer J Clin. 2006; 56: 106-130Crossref PubMed Scopus (5368) Google Scholar and worldwide,2Parkin DM Bray F Ferlay J et al.Global cancer statistics, 2002.CA Cancer J Clin. 2005; 55: 74-108Crossref PubMed Scopus (16858) Google Scholar with non-small cell lung cancer (NSCLC) accounting for approximately 87% of the newly diagnosed cases.3Govindan R Page N Morgensztern D et al.Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database.J Clin Oncol. 2006; 24: 4539-4544Crossref PubMed Scopus (1296) Google Scholar The majority of patients present with unresectable disease, and relapses are common even in those treated with curative intent.4Spira A Ettinger DS Multidisciplinary management of lung cancer.N Engl J Med. 2004; 350: 379-392Crossref PubMed Scopus (775) Google Scholar 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.5Schiller JH Harrington D Belani CP et al.Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.N Engl J Med. 2002; 346: 92-98Crossref PubMed Scopus (4594) Google Scholar, 6Fossella F Pereira JR von Pawel J et al.Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group.J Clin Oncol. 2003; 21: 3016-3024Crossref PubMed Scopus (845) Google Scholar, 7Kelly K Crowley J Bunn Jr, PA et al.Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non–small-cell lung cancer: a Southwest Oncology Group trial.J Clin Oncol. 2001; 19: 3210-3218Crossref PubMed Scopus (1022) Google Scholar 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 meaningful improvement in the outcomes.8Figlin RA Crowley JJ Jacobs EL et al.Evaluation of cisplatin, carboplatin, and etoposide in metastatic nonsmall cell lung carcinoma. A phase II study of the Southwest Oncology Group.Cancer. 1996; 78: 998-1003Crossref PubMed Scopus (2) Google Scholar 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.9Schlessinger J Ligand-induced, receptor-mediated dimerization and activation of EGF receptor.Cell. 2002; 110: 669-672Abstract Full Text Full Text PDF PubMed Scopus (754) Google Scholar 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.10Morgensztern D Govindan R Is there a role for cetuximab in non small cell lung cancer?.Clin Cancer Res. 2007; 13: 4602s-4605sCrossref PubMed Scopus (14) Google Scholar There are two low molecular weight EGFR TKIs currently used in the treatment of advanced NSCLC. Gefitinib (Iressa; AstraZeneca, 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,11Cohen MH Williams GA Sridhara R et al.United States Food and Drug Administration Drug Approval summary: Gefitinib (ZD1839; Iressa) tablets.Clin Cancer Res. 2004; 10: 1212-1218Crossref PubMed Scopus (431) Google Scholar 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.12Johnson JR Cohen M Sridhara R et al.Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen.Clin Cancer Res. 2005; 11: 6414-6421Crossref PubMed Scopus (193) Google Scholar 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 first-line treatment for 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.13Shepherd FA Rodrigues Pereira J Ciuleanu T et al.Erlotinib in previously treated non-small-cell lung cancer.N Engl J Med. 2005; 353: 123-132Crossref PubMed Scopus (4902) Google Scholar Erlotinib was shown to be superior to placebo in 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.14Fukuoka M Yano S Giaccone G et al.Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected].J Clin Oncol. 2003; 21: 2237-2246Crossref PubMed Scopus (2779) Google Scholar 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.15Thatcher N Chang A Parikh P et al.Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer).Lancet. 2005; 366: 1527-1537Abstract Full Text Full Text PDF PubMed Scopus (1938) Google Scholar 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,15Thatcher N Chang A Parikh P et al.Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer).Lancet. 2005; 366: 1527-1537Abstract Full Text Full Text PDF PubMed Scopus (1938) Google Scholar 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,13Shepherd FA Rodrigues Pereira J Ciuleanu T et al.Erlotinib in previously treated non-small-cell lung cancer.N Engl J Med. 2005; 353: 123-132Crossref PubMed Scopus (4902) Google Scholar 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,15Thatcher N Chang A Parikh P et al.Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer).Lancet. 2005; 366: 1527-1537Abstract Full Text Full Text PDF PubMed Scopus (1938) Google Scholar 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.16Miller VA Kris MG Shah N et al.Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer.J Clin Oncol. 2004; 22: 1103-1109Crossref PubMed Scopus (710) Google Scholar Skin rash also correlates with increased likelihood of response to EGFR TKIs in NSCLC.17Giaccone G Gallegos Ruiz M Le Chevalier T et al.Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study.Clin Cancer Res. 2006; 12: 6049-6055Crossref PubMed Scopus (188) Google Scholar 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.18Rosell R Daniel C Ramlau R et al.Randomized phase II study of cetuximab in combination with cisplatin (C) and vinorelbine (V) vs. CV alone in the first-line treatment of patients (pts) with epidermal growth factor receptor (EGFR)-expressing advanced non-small-cell lung cancer (NSCLC).J Clin Oncol. 2004; 22 (Abstract 7012.)Crossref Scopus (19) Google Scholar 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.19Herbst RS Chansky K Kelly K et al.A phase II randomized selection trial evaluating concurrent chemotherapy plus cetuximab or chemotherapy followed by cetuximab in patients with advanced non-small cell lung cancer (NSCLC): Final report of SWOG 0342.J Clin Oncol. 2007; 25 (Abstract 7545.)Crossref Scopus (363) Google Scholar 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.20Butts CA Bodkin D Middleman EL et al.Gemcitabine/platinum alone or in combination with cetuximab as first-line treatment for advanced non-small cell lung cancer (NSCLC).J Clin Oncol. 2007; 25 (Abstract 7539.)Crossref Scopus (196) Google Scholar 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.21Lynch TJ Patel T Dreisbach L et al.A randomized multicenter phase III study of cetuximab (Erbitux) in combination with Taxane/Carboplatin versus Taxane/Carboplatin alone as first-line treatment for patients with advanced/metastatic Non-small cell lung cancer (NSCLC).J Thorac Oncol. 2007; 2: S340-S341Crossref Google Scholar 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.22von Pawel J Park K Pereira JR et al.Phase III study comparing cisplatin/vinorelbine plus cetuximab versus cisplatin/vinorelbine as first-line treatment for patients with epidermal growth factor (EGFR)-expressing advanced non-small cell lung cancer (NSCLC) (FLEX).J Clin Oncol. 2006; 24 (Abstract 7109.)Google Scholar 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. 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.23Lynch 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. 2004; 350: 2129-2139Crossref PubMed Scopus (9490) Google Scholar 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.24Paez JG Janne PA Lee JC et al.EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.Science. 2004; 304: 1497-1500Crossref PubMed Scopus (8027) Google Scholar 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.25Gridelli C Bareschino MA Schettino C et al.Erlotinib in non-small cell lung cancer treatment: current status and future development.Oncologist. 2007; 12: 840-849Crossref PubMed Scopus (87) Google Scholar In a correlative study to ISEL, FISH-positivity was predictive of a survival benefit from gefitinib.26Hirsch FR Varella-Garcia M Bunn Jr, PA et al.Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer.J Clin Oncol. 2006; 24: 5034-5042Crossref PubMed Scopus (662) Google Scholar FISH-positive patients also had improved survival with erlotinib in univariate analysis in the BR.21 trial.27Tsao MS Sakurada A Cutz JC et al.Erlotinib in lung cancer - molecular and clinical predictors of outcome.N Engl J Med. 2005; 353: 133-144Crossref PubMed Scopus (1666) Google Scholar 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).28Crino L Zatloukal P Reck M et al.Gefitinib (IRESSA) versus vinorelbine in chemonaive elderly patients with advanced non-small-cell lung cancer (INVITE): a randomized Phase II study.J Thorac Oncol. 2007; 2: S341Crossref Google Scholar In the INTEREST trial of gefitinib versus docetaxel in previously treated NSCLC patients, though, EGFR FISH status had no impact on survival.29Douillard JY Kim E Hirsh V et al.Gefitinib (IRESSA) versus docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer pre-treated with platinum-based chemotherapy: a randomized, open-label Phase III study (INTEREST): PRS-02.J Thorac Oncol. 2007; 2: S305-S306Crossref Google Scholar 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.27Tsao MS Sakurada A Cutz JC et al.Erlotinib in lung cancer - molecular and clinical predictors of outcome.N Engl J Med. 2005; 353: 133-144Crossref PubMed Scopus (1666) Google Scholar 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.30Pao W Wang TY Riely GJ et al.KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib.PLoS Med. 2005; 2: e17Crossref PubMed Scopus (1304) Google Scholar K-ras mutations seem to be strong predictors for lack of response to EGFR TKIs. 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.31Lee DH Han JY Lee HG et al.A phase II study of gefitinib as a first-line therapy of advanced or metastatic adenocarcinoma of the lung in lifetime non-smokers.J Clin Oncol. 2005; 23 (Abstract 7072.)Google Scholar 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).TABLE 1Trials of First-Line EGFR TKIs in Selected Patients with NSCLCFirst AuthorRegimenNo. ptsRR (%)TTP/PFS (mo)MST (mo)1-yr Survival (%)Never-smokers Lee31Lee DH Han JY Lee HG et al.A phase II study of gefitinib as a first-line therapy of advanced or metastatic adenocarcinoma of the lung in lifetime non-smokers.J Clin Oncol. 2005; 23 (Abstract 7072.)Google ScholarG55616.5 moNR79 Cappuzzo32Cappuzzo F Ligorio C Janne PA et al.Prospective study of gefitinib in epidermal growth factor receptor fluorescence in situ hybridization-positive/phospho-Akt-positive or never smoker patients with advanced non-small-cell lung cancer: the ONCOBELL trial.J Clin Oncol. 2007; 25: 2248-2255Crossref PubMed Scopus (191) Google Scholar (ONCOBELL)G42486.4 moNR64 Herbst34Herbst RS Prager D Hermann R et al.TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer.J Clin Oncol. 2005; 23: 5892-5899Crossref PubMed Scopus (1360) Google Scholar (TRIBUTE subset)E + CbP72306.0 mo22.5 moNR Gatzemeier35Gatzemeier U Pluzanska A Szczesna A et al.Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial.J Clin Oncol. 2007; 25: 1545-1552Crossref PubMed Scopus (836) Google Scholar (TALENT subset)E + CsGem8NR7.9 moNRNREGFR-selected Asahina38Asahina H Yamazaki K Kinoshita I et al.A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations.Br J Cancer. 2006; 95: 998-1004Crossref PubMed Scopus (259) Google ScholarG16758.9 moNR88 Cappuzzo32Cappuzzo F Ligorio C Janne PA et al.Prospective study of gefitinib in epidermal growth factor receptor fluorescence in situ hybridization-positive/phospho-Akt-positive or never smoker patients with advanced non-small-cell lung cancer: the ONCOBELL trial.J Clin Oncol. 2007; 25: 2248-2255Crossref PubMed Scopus (191) Google Scholar (ONCOBELL)G42486.4 moNR64 Paz-Ares39Paz-Ares L Sanchez JM Garcia-Velasco A et al.A prospective phase II trial of erlotinib in advanced non-small cell lung cancer (NSCLC) patients (p) with mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor.J Clin Oncol. 2006; 24 (Abstract 7020.)Crossref PubMed Scopus (110) Google ScholarE2190NRNRNR Sequist40Sequist LV Martins RG Spigel D et al.iTarget: a phase II trial to assess the response to gefitinib in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) tumors.J Clin Oncol. 2007; 15 (Abstract 7504.)Google Scholar (iTARGET)G315511.4 mo20.8 moNRBAC Miller50Miller VA Patel J Shah N et al.The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (OSI-774) shows promising activity in patients with bronchioloalveolar cell carcinoma (BAC): preliminary results of a phase II trial.Proc Am Soc Clin Oncol. 2003; 22 (Abstract 2491.)Google ScholarE3327NRNRNR West51West HL Franklin WA McCoy J et al.Gefitinib therapy in advanced bronchioloalveolar carcinoma: Southwest Oncology Group Study S0126.J Clin Oncol. 2006; 24: 1807-1813Crossref PubMed Scopus (138) Google ScholarG101174 mo13 mo51 Bearz52Bearz A Talamini R Vaccher E et al.Ca-15. 3 antigen as predictor of response to EGFR inhibitors in patients with bronchio-alveolar carcinoma.J Clin Oncol. 2007; 25 (Abstract 18151.)PubMed Google ScholarE or G1644NRNRNR Cadranel53Cadranel J Quoix E Debove P et al.IFCT0401 trial: Phase II study of gefitinib administered as first line treatment in non-resectable pneumonic-type adenocarcinoma (P-ADC).J Clin Oncol. 2006; 24 (Abstract 7186.)Google ScholarG88132.5 moNRNRElderly Jackman42Jackman DM Yeap BY Lindeman NI et al.Phase II clinical trial of chemotherapy-naive patients > or = 70 years of age treated with erlotinib for advanced non-small-cell lung cancer.J Clin Oncol. 2007; 25: 760-766Crossref PubMed Scopus (307) Google ScholarE80103.5 mo10.9 mo46 Swinson45Swinson D Williams S Beddard K et al.Phase II trial of first-line gefitinib in patients unsuitable for chemotherapy with stage III/IV non-small-cell lung cancer.J Clin Oncol. 2005; 23 (Abstract 7256.)Google ScholarG41101 mo2.7 moNR Crino28Crino L Zatloukal P Reck M et al.Gefitinib (IRESSA) versus vinorelbine in chemonaive elderly patients with advanced non-small-cell lung cancer (INVITE): a randomized Phase II study.J Thorac Oncol. 2007; 2: S341Crossref Google Scholar (INVITE)G973NRNRNRV995NRNRNRPoor PS Lilenbaum46Lilenbaum R Axerold R Thomas S et al.Randomized phase II trial of single agent erlotinib vs. standard chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and performance status (PS) of 2.J Clin Oncol. 2006; 24 (Abstract 7022.)Google ScholarE4622.5 moNRNRCbP42104.0 moNRNR Hesketh47Hesketh PJ Chanksy K Wozniak AJ et al.Erlotinib as initial therapy in patients with advanced non-small cell lung cancer (NSCLC) and a performance status (PS) of 2: A SWOG phase II trial (S0341).J Clin Oncol. 2007; 25 (Abstract 7536.)Google ScholarE7282.1 mo5.0 mo22 Spigel48Spigel DR Hainsworth JD Burkett ER et al.Single-agent gefitinib in patients with untreated advanced non-small-cell lung cancer and poor performance status: a Minnie Pearl Cancer Research Network Phase II Trial.Clin Lung Cancer. 2005; 7: 127-132Abstract Full Text PDF PubMed Scopus (32) Google ScholarG7043.7 mo6.3 mo24G, 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. Open table in a new tab 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. 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.32Cappuzzo F Ligorio C Janne PA et al.Prospective study of gefitinib in epidermal growth factor receptor fluorescence in situ hybridization-positive/phospho-Akt-positive or never smoker patients with advanced non-small-cell lung cancer: the ONCOBELL trial.J Clin Oncol. 2007; 25: 2248-2255Crossref PubMed Scopus (191) Google Scholar 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.33Cappuzzo F Magrini E Ceresoli GL et al.Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer.J Natl Cancer Inst. 2004; 96: 1133-1141Crossref PubMed Scopus (360) Google Scholar 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, placebo-controlled, phase III trials also suggest that never-smokers with advanced NSCLC may derive benefit from first-line EGFR TKIs in combination with chemotherapy.34Herbst RS Prager D Hermann R et al.TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer.J Clin Oncol. 2005; 23: 5892-5899Crossref PubMed Scopus (1360) Google Scholar, 35Gatzemeier U Pluzanska A Szczesna A et al.Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial.J Clin Oncol. 2007; 25: 1545-1552Crossref PubMed Scopus (836) Google Scholar In TRIBUTE,34Herbst RS Prager D Hermann R et al.TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer.J Clin Oncol. 2005; 23: 5892-5899Crossref PubMed Scopus (1360) Google Scholar 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" @default.
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• W2017389411 title "EGFR Inhibitors as First-Line Therapy in Advanced Non-small Cell Lung Cancer" @default.
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