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)

Thatcher, Nick; Chang, Alex; Parikh, Purvish; Rodrigues Pereira, José; Ciuleanu, Tudor; von Pawel, Joachim; Thongprasert, Sumitra; Tan, Eng Huat; Pemberton, Kristine; Archer, Venice; Carroll, Kevin

doi:10.1016/s0140-6736(05)67625-8

Cited by 2,079Lung Cancer Treatments and MutationsLung Cancer Diagnosis and TreatmentLung Cancer Research Studies

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)

Thatcher, Nick, Chang, Alex, Parikh, Purvish, Rodrigues Pereira, José, Ciuleanu, Tudor, von Pawel, Joachim, Thongprasert, Sumitra, Tan, Eng Huat +3 more·2005·The Lancet

DOI 10.1016/s0140-6736(05)67625-8

Open this paper in CoChat — free account

Abstract

Background This placebo-controlled phase III study investigated the effect on survival of gefitinib as second-line or third-line treatment for patients with locally advanced or metastatic non-small-cell lung cancer.Methods 1692 patients who were refractory to or intolerant of their latest chemotherapy regimen were randomly assigned in a ratio of two to one either gefitinib (250 mg/day) or placebo, plus best supportive care. The primary endpoint was survival in the overall population of patients and those with adenocarcinoma. The primary analysis of the population for survival was by intention to treat. This study has been submitted for registration with ClinicalTrials.gov, number 1839IL/709.Findings 1129 patients were assigned gefitinib and 563 placebo. At median follow-up of 7.2 months, median survival did not differ significantly between the groups in the overall population (5.6 months for gefitinib and 5.1 months for placebo; hazard ratio 0.89 [95% CI 0.77-1.02], p=0.087) or among the 812 patients with adenocarcinoma (6.3 months vs 5.4 months; 0.84 [0.68-1.03], p=0.089). Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than the placebo group for never-smokers (n=375; 0.67 [0.49-0.92], p=0.012; median survival 8.9 vs 6.1 months) and patients of Asian origin (n=342; 0.66 [0.48-0.91], p=0.01; median survival 9.5 vs 5.5 months). Gefitinib was well tolerated, as in previous studies.Interpretation Treatment with gefitinib was not associated with significant improvement in survival in either coprimary population. There was pronounced heterogeneity in survival outcomes between groups of patients, with some evidence of benefit among never-smokers and patients of Asian origin.

Integrity signals

Registry

Crossref · 10.1016/s0140-6736(05)67625-8

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

The clinical development of EGFR inhibitors in NSCLC started before the discovery of EGFR mutations, with initial studies of Gefitinib and Erlotinib conducted in unselected patients in both pretreated and treatment-naïve settings in combination with standard chemotherapy.
“The clinical development of EGFR inhibitors in NSCLC started before the discovery of EGFR mutations, therefore initial studies with Gefitinib and Erlotinib were conducted in unselected patients in both pretreated [52–54] and in treatment-naïve patients in combination with standard chemotherapy [55–58].”
From A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives (2015) · cites this paper as [53]

Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib
Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Haserlat, S. M., Supko, J. G., Haluska, F. G., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040938 · Cited by 11,486 · see citing works
EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
Paez, J. G., Jänne, P. A., Lee, J. C., Tracy, S., Greulich, H., Gabriel, S., Herman, P., Kaye, F. J., Lindeman, N., Boggon, T. J., et al. (2004) · Science · doi:10.1126/science.1099314 · Cited by 9,368 · see citing works
World Medical Association Declaration of Helsinki: Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects
(1997) · JAMA · doi:10.1001/jama.1997.03540350075038 · Cited by 1,023 · see citing works

Flagged first, then by citations

Sorted by citations

Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma
Mok, T. S., Wu, Y.-L., Thongprasert, S., Yang, C.-H., Chu, D.-T., Saijo, N., Sunpaweravong, P., Han, B., Margono, B., Ichinose, Y., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810699 · Cited by 8,261 · see citing works
Self-citation
Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations
Sequist, L. V., Yang, J. C.-H., Yamamoto, N., O'Byrne, K., Hirsh, V., Mok, T., Geater, S. L., Orlov, S., Tsai, C.-M., Boyer, M., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.44.2806 · Cited by 3,228 · see citing works
Epidermal growth factor receptor mutations in lung cancer
Sharma, S. V., Bell, D. W., Settleman, J., & Haber, D. A. (2007) · Nature Reviews Cancer · doi:10.1038/nrc2088 · Cited by 3,170 · see citing works
Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers
Shigematsu, H., Lin, L., Takahashi, T., Nomura, M., Suzuki, M., Wistuba, I. I., Fong, K. M., Lee, H., Toyooka, S., Shimizu, N., et al. (2005) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dji055 · Cited by 2,377 · see citing works
Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs
Kris, M. G., Johnson, B. E., Berry, L. D., Kwiatkowski, D. J., Iafrate, A. J., Wistuba, I. I., Varella-Garcia, M., Franklin, W. A., Aronson, S. L., Su, P.-F., et al. (2014) · JAMA · doi:10.1001/jama.2014.3741 · Cited by 1,724 · see citing works
Organoid Cultures Derived from Patients with Advanced Prostate Cancer
Gao, D., Vela, I., Sboner, A., Iaquinta, P. J., Karthaus, W. R., Gopalan, A., Dowling, C., Wanjala, J. N., Undvall, E. A., Arora, V. K., et al. (2014) · Cell · doi:10.1016/j.cell.2014.08.016 · Cited by 1,559 · see citing works
Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology
Lindeman, N. I., Cagle, P. T., Beasley, M. B., Chitale, D. A., Dacic, S., Giaccone, G., Jenkins, R. B., Kwiatkowski, D. J., Saldivar, J.-S., Squire, J., et al. (2013) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e318290868f · Cited by 1,280 · see citing works
Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer
Pao, W., & Chmielecki, J. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2947 · Cited by 1,083 · see citing works
Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors
Gazdar, A. F. (2009) · Oncogene · doi:10.1038/onc.2009.198 · Cited by 991 · see citing works
American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non–Small-Cell Lung Cancer
Azzoli, C. G., Baker, S., Temin, S., Pao, W., Aliff, T., Brahmer, J., Johnson, D. H., Laskin, J. L., Masters, G., Milton, D., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.23.5622 · Cited by 915 · see citing works
First-Line Gefitinib in Patients With Advanced Non–Small-Cell Lung Cancer Harboring Somatic EGFR Mutations
Sequist, L. V., Martins, R. G., Spigel, D., Grunberg, S. M., Spira, A., Jänne, P. A., Joshi, V. A., McCollum, D., Evans, T. L., Muzikansky, A., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.8494 · Cited by 820 · see citing works
Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses
Sun, X., Briel, M., Walter, S. D., & Guyatt, G. H. (2010) · BMJ · doi:10.1136/bmj.c117 · Cited by 808 · see citing works
Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer
Hirsch, F. R., Varella-Garcia, M., Bunn, P. A., Franklin, W. A., Dziadziuszko, R., Thatcher, N., Chang, A., Parikh, P., Pereira, J. R., Ciuleanu, T., et al. (2006) · Journal of Clinical Oncology · doi:10.1200/jco.2006.06.3958 · Cited by 703 · see citing works
Self-citation
The Differential Efficacy of Pemetrexed According to NSCLC Histology: A Review of Two Phase III Studies
Scagliotti, G., Hanna, N., Fossella, F., Sugarman, K., Blatter, J., Peterson, P., Simms, L., & Shepherd, F. A. (2009) · The Oncologist · doi:10.1634/theoncologist.2008-0232 · Cited by 690 · see citing works
Understanding resistance to EGFR inhibitors—impact on future treatment strategies
Wheeler, D. L., Dunn, E. F., & Harari, P. M. (2010) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2010.97 · Cited by 683 · see citing works
Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023
Kelly, K., Chansky, K., Gaspar, L. E., Albain, K. S., Jett, J., Ung, Y. C., Lau, D. H. M., Crowley, J. J., & Gandara, D. R. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.4824 · Cited by 573 · see citing works
Epidermal growth factor receptor targeting in cancer: a review of trends and strategies
Yewale, C., Baradia, D., Vhora, I., Patil, S., & Misra, A. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.07.100 · Cited by 533 · see citing works
Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial
Douillard, J.-Y., Shepherd, F. A., Hirsh, V., Mok, T., Socinski, M. A., Gervais, R., Liao, M.-L., Bischoff, H., Reck, M., Sellers, M. V., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.24.3030 · Cited by 492 · see citing works
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor–Resistant Disease
Ohashi, K., Maruvka, Y. E., Michor, F., & Pao, W. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.43.3912 · Cited by 467 · see citing works
Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancers Dependent on the Epidermal Growth Factor Receptor Pathway
Nguyen, K.-S. H., Kobayashi, S., & Costa, D. B. (2009) · Clinical Lung Cancer · doi:10.3816/clc.2009.n.039 · Cited by 437 · see citing works
Xenograft and organoid model systems in cancer research
Bleijs, M., van de Wetering, M., Clevers, H., & Drost, J. (2019) · The EMBO Journal · doi:10.15252/embj.2019101654 · Cited by 400 · see citing works
Racial/ethnic disparities in genomic sequencing
Spratt, D. E., Chan, T., Waldron, L., Speers, C., Feng, F. Y., Ogunwobi, O. O., & Osborne, J. R. (2016) · JAMA Oncology · doi:10.1001/jamaoncol.2016.1854 · Cited by 375 · see citing works
Phase III Study, V-15-32, of Gefitinib Versus Docetaxel in Previously Treated Japanese Patients With Non–Small-Cell Lung Cancer
Maruyama, R., Nishiwaki, Y., Tamura, T., Yamamoto, N., Tsuboi, M., Nakagawa, K., Shinkai, T., Negoro, S., Imamura, F., Eguchi, K., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.15.0185 · Cited by 367 · see citing works
Phase I Trial of the Irreversible EGFR and HER2 Kinase Inhibitor BIBW 2992 in Patients With Advanced Solid Tumors
Yap, T. A., Vidal, L., Adam, J., Stephens, P., Spicer, J., Shaw, H., Ang, J., Temple, G., Bell, S., Shahidi, M., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.26.7278 · Cited by 349 · see citing works
Smoking at diagnosis and survival in cancer patients
Warren, G. W., Kasza, K. A., Reid, M. E., Cummings, K. M., & Marshall, J. R. (2013) · International Journal of Cancer · doi:10.1002/ijc.27617 · Cited by 265 · see citing works
EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients
Cappuzzo, F., Finocchiaro, G., Rossi, E., Jänne, P. A., Carnaghi, C., Calandri, C., Bencardino, K., Ligorio, C., Ciardiello, F., Pressiani, T., et al. (2008) · Annals of Oncology · doi:10.1093/annonc/mdm492 · Cited by 267 · see citing works
Influence of Chemotherapy on EGFR Mutation Status Among Patients With Non–Small-Cell Lung Cancer
Bai, H., Wang, Z., Chen, K., Zhao, J., Lee, J. J., Wang, S., Zhou, Q., Zhuo, M., Mao, L., An, T., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2011.39.3744 · Cited by 199 · see citing works
EGFR-mutated lung cancer: a paradigm of molecular oncology
Zhang, Z., Stiegler, A. L., Boggon, T. J., Kobayashi, S., & Halmos, B. (2010) · Oncotarget · doi:10.18632/oncotarget.186 · Cited by 197 · see citing works
Randomized Phase III Trial of Gefitinib versus Docetaxel in Non–Small Cell Lung Cancer Patients Who Have Previously Received Platinum-Based Chemotherapy
Lee, D. H., Park, K., Kim, J. H., Lee, J.-S., Shin, S. W., Kang, J.-H., Ahn, M.-J., Ahn, J. S., Suh, C., & Kim, S.-W. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-1903 · Cited by 179 · see citing works
Second-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): A better mousetrap? A review of the clinical evidence
Ou, S.-H. I. (2012) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2011.11.010 · Cited by 182 · see citing works
A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives
Russo, A., Franchina, T., Rita Ricciardi, G. R., Picone, A., Ferraro, G., Zanghì, M., Toscano, G., Giordano, A., & Adamo, V. (2015) · Oncotarget · doi:10.18632/oncotarget.4254 · Cited by 173 · see citing works
Effects of Erlotinib in EGFR Mutated Non-Small Cell Lung Cancers with Resistance to Gefitinib
Costa, D. B., Nguyen, K.-S. H., Cho, B. C., Sequist, L. V., Jackman, D. M., Riely, G. J., Yeap, B. Y., Halmos, B., Kim, J. H., Jänne, P. A., et al. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-1455 · Cited by 171 · see citing works
Gefitinib for non-small-cell lung cancer patients with epidermal growth factor receptor gene mutations screened by peptide nucleic acid-locked nucleic acid PCR clamp
Sutani, A., Nagai, Y., Udagawa, K., Uchida, Y., Koyama, N., Murayama, Y., Tanaka, T., Miyazawa, H., Nagata, M., Kanazawa, M., et al. (2006) · British Journal of Cancer · doi:10.1038/sj.bjc.6603466 · Cited by 167 · see citing works
Pooled analysis of the prospective trials of gefitinib monotherapy for EGFR-mutant non-small cell lung cancers
Costa, D. B., Kobayashi, S., Tenen, D. G., & Huberman, M. S. (2007) · Lung Cancer · doi:10.1016/j.lungcan.2007.05.017 · Cited by 160 · see citing works
Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: Comparative pharmacokinetics and drug–drug interactions
Peters, S., Zimmermann, S., & Adjei, A. A. (2014) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2014.06.010 · Cited by 155 · see citing works
Effect of epidermal growth factor receptor tyrosine kinase domain mutations on the outcome of patients with non-small cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors
Jänne, P. A., & Johnson, B. E. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-0555 · Cited by 147 · see citing works
A phase 2 trial of dacomitinib (PF-00299804), an oral, irreversible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non–small cell lung cancer after failure of prior chemotherapy and erlotinib
Reckamp, K. L., Giaccone, G., Camidge, D. R., Gadgeel, S. M., Khuri, F. R., Engelman, J. A., Koczywas, M., Rajan, A., Campbell, A. K., Gernhardt, D., et al. (2014) · Cancer · doi:10.1002/cncr.28561 · Cited by 144 · see citing works
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors vs Conventional Chemotherapy in Non–Small Cell Lung Cancer Harboring Wild-Type Epidermal Growth Factor Receptor: A Meta-analysis
Lee, J.-K., Hahn, S., Kim, D.-W., Suh, K. J., Keam, B., Kim, T. M., Lee, S.-H., & Heo, D. S. (2014) · JAMA · doi:10.1001/jama.2014.3314 · Cited by 141 · see citing works
Targeting EGFR in Lung Cancer: Current Standards and Developments
Díaz-Serrano, A., Gella, P., Jiménez, E., Zugazagoitia, J., & Paz-Ares Rodríguez, L. (2018) · Drugs · doi:10.1007/s40265-018-0916-4 · Cited by 108 · see citing works
Treatment with HIF-1α Antagonist PX-478 Inhibits Progression and Spread of Orthotopic Human Small Cell Lung Cancer and Lung Adenocarcinoma in Mice
Jacoby, J. J., Erez, B., Korshunova, M. V., Williams, R. R., Furutani, K., Takahashi, O., Kirkpatrick, L., Lippman, S. M., Powis, G., O'Reilly, M. S., et al. (2010) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e3181dc211f · Cited by 84 · see citing works
Genome Sequencing during a Patient’s Journey through Cancer
Nangalia, J., & Campbell, P. J. (2019) · New England Journal of Medicine · doi:10.1056/nejmra1910138 · Cited by 66 · see citing works
United States Food and Drug Administration approved oral kinase inhibitors for the treatment of malignancies
Jeong, W., Doroshow, J. H., & Kummar, S. (2013) · Current Problems in Cancer · doi:10.1016/j.currproblcancer.2013.06.001 · Cited by 59 · see citing works
Dacomitinib in lung cancer: a &ldquo;lost generation&rdquo; EGFR tyrosine-kinase inhibitor from a bygone era?
Ou, S.-H., & Soo, R. (2015) · Drug Design, Development and Therapy · doi:10.2147/dddt.s52787 · Cited by 28 · see citing works

Authors: Thatcher, N., Chang, A., Parikh, P., Rodrigues Pereira, J., Ciuleanu, T., von Pawel, J., Thongprasert, S., Tan, E. H., Pemberton, K., Archer, V., & Carroll, K.
Affiliations: The Christie Hospital (GB)
Johns Hopkins University (US)
Tata Memorial Hospital (IN)
Institute of Oncology Prof. Dr. Ion Chiricuta (RO)
Maharaj Nakorn Chiang Mai Hospital (TH)
National Cancer Centre Singapore (SG)
Corresponding author: Thatcher, Nick
ORCID: Chang, Alex
Parikh, Purvish
Ciuleanu, Tudor
Carroll, Kevin
Venue: The Lancet
Publisher: Elsevier BV
Published: 2005-10
Volume: 366
Issue: 9496
Pages: 1527-1537
ISSN: 0099-5355 (ISSN-L)
0140-6736
DOI: 10.1016/s0140-6736(05)67625-8
OpenAlex: W2153477391
Cited by: 2,079
References: 3
Citations by year: 2026: 11 · 2025: 10 · 2024: 21 · 2023: 19 · 2022: 18 · 2021: 42 · 2020: 48 · 2019: 33 · 2018: 51 · 2017: 82 · 2016: 96 · 2015: 126 · 2014: 126 · 2013: 163 · 2012: 167
FWCI: 133.68
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: The Lancet (publishedVersion)
PubMed (publishedVersion)
Research Explorer (The University of Manchester) (submittedVersion)
Funders: AstraZeneca
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
Keywords: gefitinib, non-small cell lung cancer, second-line therapy, third-line therapy, best supportive care, overall survival, never smokers, Asian patients, EGFR tyrosine kinase inhibitors, subgroup heterogeneity
MeSH terms: Gefitinib, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Quinazolines, Survival Rate

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

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)

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Record

About these checks