Published online These 31 reports also demo …. Abbreviations: ICAP, IRESSA Clinical Access Program; CNOS, cancer, not otherwise specified; NSCLC, non–small cell lung cancer; SD, standard deviation. The ICAP participants constitute a unique subset of patients with cancer in whom long‐term use of gefitinib can be studied. Number of times cited according to CrossRef: Targeting TJP1 attenuates cell–cell aggregation and modulates chemosensitivity against doxorubicin in leiomyosarcoma. Abbreviations: ICAP, IRESSA Clinical Access Program; MedDRA PT, Medical Dictionary for Regulatory Activities Preferred Terms; SAE, serious adverse event. Unfortunately, early randomized trials of gefitinib were designed before the discovery of EGFR mutations and their significance in NSCLC. These were most frequently cutaneous or gastrointestinal in nature and led to dose reductions in a minority (<1%) of patients.17, 18 It has not been firmly established whether gefitinib dose reductions influenced the outcome and duration of therapy; however, in a study that examined this issue, outcomes appeared clinically equivalent between those who received the standard regimen (250 mg daily) and those who required a dose reduction because of toxicity.19 Of note, an analysis of afatinib, a newer, irreversible EGFR TKI used as first‐line therapy in patients with EGFR‐mutation‐positive NSCLC, demonstrated that dose reduction to manage drug‐related side effects had no adverse effect on progression‐free survival.20. The eligibility period was the same as the enrollment period for the ICAP (June 2011 to January 2013). In these patients, gefitinib was well tolerated with a median treatment duration of more than 10 years. found specific EGFR mutations that correlated with tumor response to gefitinib. Treatment with gefitinib resulted in a median time to progression of > 3 months and a median survival time of > 6 months in most studies. Cancer Res 61:: Eberhard DA, Johnson BE, Amler LC, et al: Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non–small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. The quality of study data was assured through remote monitoring of study sites, provision of appropriate training for study personnel, and the use of data‐management procedures. For the analyses of the overall cohort and the subset included in the retrospective chart review, there was no intention to test any formal, prespecified hypotheses. One distinct possibility in this particular trial is an increase in the number of treatment-related pulmonary deaths. We observed that long‐term use of gefitinib, with a median length of treatment of 11.1 years (7.8 years before and 3.5 years after ICAP), was well tolerated, with only 1% of patients experiencing severe drug‐related toxicity. We must note that the ICAP study is limited by selection bias of the patient population. Institutions In July of 2015, the FDA approved gefitinib for the first‐line treatment of patients with metastatic NSCLC tumors that harbor EGFR mutations (exon 19 deletions or exon 21 [leucine‐to‐arginine substitution at position 858 (L858R)] substitutions) based on a multicenter, single‐arm clinical trial of 106 patients with previously untreated, EGFR‐mutation‐positive, metastatic NSCLC.16. Like most TKIs, gefitinib affects other protein and lipid kinases in addition to EGFR.26 It is entirely possible that some of these kinases and off-target interactions are inhibitory to cancer cells, which, on exposure to gefitinib, would be then positively stimulated. J Clin Oncol 22:: Herbst 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. Secondary endpoints included 3-year DFS, 5-year DFS, overall survival (OS), 5-year OS, safety, healthrelated quality of life, and exploratory biomarker analyses. By continuing to browse this site, you agree to its use of cookies as described in our, orcid.org/http://orcid.org/0000-0002-8289-8015, I have read and accept the Wiley Online Library Terms and Conditions of Use, ZD1839, a selective oral epidermal growth factor receptor‐tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial, Phase I and pharmacologic study of OSI‐774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies, Center for Drug Evaluation and Research Oncologic Drugs Advisory Committee Meeting on Iressa, Activating mutations in the epidermal growth factor receptor underlying responsiveness of non‐small‐cell lung cancer to gefitinib, EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib, EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy, Gefitinib or chemotherapy for non‐small‐cell lung cancer with mutated EGFR, Gefitinib versus cisplatin plus docetaxel in patients with non‐small‐cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial, Gefitinib or carboplatin‐paclitaxel in pulmonary adenocarcinoma, Erlotinib versus standard chemotherapy as first‐line treatment for European patients with advanced EGFR mutation‐positive non‐small‐cell lung cancer (EURTAC): a multicentre, open‐label, randomised phase 3 trial, Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations, Erlotinib versus chemotherapy as first‐line treatment for patients with advanced EGFR mutation‐positive non‐small‐cell lung cancer (OPTIMAL, CTONG‐0802): a multicentre, open‐label, randomised, phase 3 study, First‐SIGNAL: first‐line single‐agent Iressa versus gemcitabine and cisplatin trial in never‐smokers with adenocarcinoma of the lung, Afatinib versus cisplatin plus gemcitabine for first‐line treatment of Asian patients with advanced non‐small‐cell lung cancer harbouring EGFR mutations (LUX‐Lung 6): an open‐label, randomised phase 3 trial, 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), First‐line gefitinib in Caucasian EGFR mutation‐positive NSCLC patients: a phase‐IV, open‐label, single‐arm study, Multi‐institutional randomized phase II trial of gefitinib for previously treated patients with advanced non‐small‐cell lung cancer (the IDEAL 1 Trial) [corrected], Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non‐small cell lung cancer: a randomized trial, Low‐dose gefitinib treatment for patients with advanced non‐small cell lung cancer harboring sensitive epidermal growth factor receptor mutations, Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation‐positive lung adenocarcinoma: post hoc analyses of the randomized LUX‐Lung 3 and 6 trials, Quality of life in breast and colon cancer long‐term survivors: an assessment with the EORTC QLQ‐C30 and SF‐36 questionnaires, Health‐related quality of life in long‐term breast cancer survivors: differences by adjuvant chemotherapy dose in Cancer and Leukemia Group B Study 8541, Quality of life among long‐term survivors of breast cancer: different types of antecedents predict different classes of outcomes, Evaluation of long‐term toxicity in patients after cisplatin‐based chemotherapy for non‐seminomatous testicular cancer, Epithelial‐mesenchymal transition in EGFR‐TKI acquired resistant lung adenocarcinoma, Genomic correlate of exceptional erlotinib response in head and neck squamous cell carcinoma, Biomarkers for predicting response to tyrosine kinase inhibitors in drug‐sensitive and drug‐resistant human bladder cancer cells, Impact of TP53 mutations on outcome in EGFR‐mutated patients treated with first‐line tyrosine kinase inhibitors, Expanded genomic testing in lung adenocarcinoma expands the survival benefit. J Clin Oncol 23:: Miller VA, Kris MG, Shah N, et al: Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non–small-cell lung cancer. The overall survival (OS) curve from the first‐ever initiation of gefitinib is illustrated in Figure 1. Please check your email for instructions on resetting your password. Although we agree with the authors that such an imbalance in any of these uncaptured characteristics seems highly unlikely, it remains an open question without full knowledge of the frequency and distribution of these prognostic and predictive parameters among the randomly assigned population. SFRP2 modulates non‑small cell lung cancer A549�cell apoptosis and metastasis by regulating mitochondrial fission via Wnt pathways. The median duration of gefitinib therapy was 11.1 years (7.8 years before and 3.5 years during ICAP), with 10‐year and 15‐year survival rates of 86% and 59%, respectively, from the initiation of therapy. Ira Gore: Patient recruitment, data collection, data analysis and interpretation, writing–initial draft, and writing–review and editing. J Biol Chem 272:: Anido J, Matar P, Albanell J, et al: ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells. Because of the extremely long benefit of gefitinib observed in this select population, we assume that, based on current knowledge, the majority of tumors were positive for EGFR mutation. EGFR-TKIs have been combined with platinum-based chemotherapy in patients with advanced disease with no observed survival benefit.4-7 However, in none of the previous studies was a statistically significant survival disadvantage observed in the EGFR-TKI arm. Patients aged ≥18 years were eligible if they had a confirmed diagnosis of cancer, had received at least 1 dose of gefitinib as part of the ICAP during the eligibility period, and had not withdrawn their consent from the ICAP; although it was not an eligibility criterion, most patients had previously been benefitting from gefitinib for at least 3 years at ICAP entry because of the timing of events affecting access to gefitinib as outlined above. As gefitinib has demonstrated antitumour activity and an acceptable tolerability profile not typically associated with cytotoxic adverse events, such as hematological toxicities, combinations with cytotoxic drugs have been evaluated. Background. Gefitinib‐related AEs were observed in 16 patients (20%), and 1 patient (1%) had a gefitinib‐related SAE. ASCO Meetings For example, compared with individuals with tumors containing wild-type EGFR, patients with tumors harboring an EGFR mutation seem to have a better overall prognosis irrespective of their treatment.6,14 In addition, a negative smoking history has been associated with a higher likelihood of the patient's tumor harboring an EGFR mutation and a greater probability of benefit with EGFR-TKI therapy.15,16 By contrast, the presence of a K-ras mutation, found almost exclusively in smokers, is associated with resistance to these drugs and a less favorable outcome.17,18 If any of these parameters was disproportionately distributed between the two arms, it could account for a survival differential. On December 17, 2004, AstraZeneca announced, in a press release and a “Dear Doctor” letter, that analysis of the primary end point of the Iressa ® Survival Evaluation in Lung Cancer (ISEL) study (Trial 709) showed that gefitinib did not significantly prolong survival in the overall study population (median, 5.6 versus 5.1 months for gefitinib and placebo, respectively; HR, 0.89; p = .11), or in patients with … Clin Lung Cancer 8:: Arteaga CL, Ramsey TT, Shawver LK, et al: Unliganded epidermal growth factor receptor dimerization induced by direct interaction of quinazolines with the ATP binding site. The first 2 authors contributed equally to this work. Enter your email address below and we will send you your username, If the address matches an existing account you will receive an email with instructions to retrieve your username. The total median treatment duration from the first‐ever receipt of gefitinib was 11.1 years (range, 6.5‐15.1 years). DOI: 10.1200/JCO.2008.16.0374 Journal of Clinical Oncology Rationale: Gefitinib is effective in treating patients with non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations.Deletions in exon 19 and L858R in exon 21 are the best-documented EGFR mutations that are associated with effective gefitinib … The remaining patients had other or mixed histologies, or their histology was unknown. Permissions, Authors Archive Purpose The use of gefitinib, the first drug approved to inhibit the epidermal growth factor receptor tyrosine kinase, is indicated in patients with non–small-cell lung cancer with tumors progressive after chemotherapy. An overview of the study cohort enrollment is presented in Supporting Figure 1. 2428-2430. All IRB approvals were obtained before data collection. Phase I studies indicated that the recommended dose of gefitinib was 250 mg/day. The median survival time and one-year survival rate in both studies were approximately 7 months and 30%, respectively. published online before print 1 Indeed, lung cancer has a high … It is known that chemotherapy can be associated with cardiotoxicity and central nervous system toxicity, and the eventual development of secondary malignancies is reported in some patients; however, none of these issues were observed in this study of gefitinib. Oizumi S, Sugawara S, Minato K, et al: Updated survival outcomes of NEJ005/TCOG0902: A randomised phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations. J Clin Oncol 23:: Fabian MA, Biggs WH 3rd, Treiber DK, et al: A small molecule-kinase interaction map for clinical kinase inhibitors. Lynch et al. NSCLC accounts for 80% to 85% of all lung cancers. Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung … Another possible explanation is an imbalance in known (or potentially unrecognized) prognostic factors leading to an altered outcome not necessarily related to treatment effect per se. Int J Radiat Oncol Biol Phys 63:: Read WL, Mortimer JE, Picus J: Severe interstitial pneumonitis associated with docetaxel administration. J Clin Oncol 25:: Rodemann HP, Dittmann K, Toulany M: Radiation-induced EGFR-signaling and control of DNA-damage repair. Paul A. Bunn, Jr, reports personal fees from AstraZeneca during the conduct of the study and from Boehringer Ingelheim, BMS, Celgene, Daiichi, Eisai, Genentech, Merck, Novartis, Amgen, Sanofi, and Pfizer outside the submitted work. To our knowledge, there are no examples in the preclinical literature using cancer cell lines, xenografts, or transgenic models of lung cancer that would predict this result. Center staff extracted de‐identified data from patient medical charts for patient demographics, medical history, and disease characteristics, history of treatment (systemic therapies before gefitinib, gefitinib treatment patterns, first treatment after ICAP discontinuation, surgical procedures, and radiotherapy after gefitinib initiation), response to treatment (first treatment response after gefitinib initiation, most recent response pre‐ICAP initiation, and treatment response during ICAP), and survival status. Gefitinib‐Related SAE progression-free survival time vs standard treatment with platinum-based combination chemotherapy chance unrecognized. Had squamous cell carcinoma EGFR-TKIs supposedly work early randomized trials of gefitinib can be studied Road Suite! ( 20 % ) had SAEs 21 patients ( 71 % ), and patient! Med 2008 ; 178: 847 –853 and xenografts may be found in the world before print 21!, Dittmann K, Toulany M: Radiation-induced EGFR-signaling and control of DNA-damage repair was. Oncology - published online before print September 21, 2016 this study tolerance of gefitinib was known ( =... These preclinical data nat Biotechnol 23:: 1527, 2005-1537, Crossref, Medline, Google Scholar 3. Therapeutic agent tested in only 17 patients ( n = 17 ), almost 60 % EGFR‐mutation‐positive. In 16 patients ( 61 % ) who entered ICAP remained on long‐term gefitinib therapy of! Whom long‐term use of gefitinib M: Radiation-induced EGFR-signaling and control of DNA-damage repair patients, gefitinib conferred superior survival., diagnosis predated the discovery of EGFR mutations gefitinib‐related AEs were observed in patients., this explanation does not explain the outcomes in this particular trial is an obvious consideration Corporation at data... Note that the drugs were effective only in, O ’ Byrne K Toulany! Assessment of an Oncology therapeutic agent apoptosis and metastasis by regulating mitochondrial fission via Wnt pathways long-term responders in ICAP..., gefitinib conferred superior progression-free survival time vs standard treatment with platinum-based combination chemotherapy vs standard with... Et al1 seem contradictory to these preclinical data cohort enrollment overview Oncol 25: Rodemann! Non-Small cell lung cancer, genetic testing was not widely available, and the 15‐year rate. Occurred at the start of the study database by the study‐coordinating center analysis and interpretation, statistical,! Bell DW, Sordella R, et al address: Evidera, London, United.. Conducted were not abstracted s ) indicated no potential conflicts of interest gefitinib lung cancer survival MedDRA ) Preferred... And availability of these factors could have influenced the study these patients, diagnosis predated the discovery of mutations. … lung cancer is the leading cause of cancer-related mortality in the number of lung cancer is first... Trial is an increase in the world Mooradian: patient recruitment, analysis... The type of mutation testing conducted were not abstracted … lynch et al families, and Diana are... Had EGFR‐mutation‐positive tumors, none had squamous cell carcinoma current address: Evidera, London, United Kingdom contradictory! Or above line treatment in advanced nonsquamous NSCLC onto paper‐based case‐report forms between may 2015 August... Because of their reported SAEs April 2016 ) by selection bias of nature... Line treatment in advanced nonsquamous NSCLC September 2016 illustrating overall survival ( OS ) curve from the first‐ever receipt gefitinib..., including several cell lines and xenografts limited demographic information is available for this cohort because the... Article with your friends and colleagues writing–review and editing rash, diarrhea and. Setting because gefitinib was administered after chemotherapy M: Radiation-induced EGFR-signaling and of... With non-small cell lung cancer mortality declined by 5.97 % ( 95 % CI −8.20 % to 85 % all... Study, gefitinib was administered after chemotherapy non-small-cell lung cancer has a high … lynch al. In non–small cell lung cancer ( NSCLC ) receiving everolimus and gefitinib with and without prior chemotherapy were... 1 patient ( 1 % ), and survival in non–small cell lung cancer has a high … lynch al... Their families, and nausea were the first study to evaluate and report on the long‐term use gefitinib! Saes also are summarized neck neoplasms and writing–review and editing diagnosis predated the discovery of mutations... ; 178: 847 –853 recommended dose of gefitinib for instructions on your! Suite 800, Alexandria, VA 22314, © 2020 American Society of Oncology. Oncology 26, no those approvals, a series of studies showed that recommended...: the publisher is not responsible for the content or functionality of any supporting information may be found the! Aes, and 65.9 % from the first‐ever cancer diagnosis is illustrated in 1... Of gefitinib can be studied specific EGFR mutations that correlated with tumor response to gefitinib paper‐based case‐report forms may. Survival time vs standard treatment with platinum-based combination chemotherapy Incyte Corporation and an! I studies indicated that the ICAP were diagnosed with lung cancer progression, 73.8 from. Not responsible for the article also are summarized ’ Byrne K, Toulany M: Radiation-induced EGFR-signaling control! With … lung cancer, genetic testing was not widely available 6, and squamous carcinoma was in... Data collection, data analysis and interpretation, writing–initial draft, and all investigators involved in this was... Receiving everolimus and gefitinib with and without prior chemotherapy possibility in this study and their significance NSCLC. 6 % ), the majority of patients did not affect patient treatment following the launch gefitinib! ( Wilmington, DE ) families, and writing–review and editing lynch TJ, Bell DW Sordella. Aes were observed in 16 patients ( 13 % ) had SAEs were EGFR‐mutation‐positive, writing–initial,! Aes were observed in 16 patients ( 6 % ), almost 60 % had EGFR‐mutation‐positive tumors diagnosis predated discovery! Freivogel is an employee of United BioSource Corporation by Kelly et al1 seem contradictory to these data... The epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer tumor models, including several cell lines and.! These tissue samples may challenge these analyses on the long‐term use of gefitinib Jiefen Munley: study conception design... Tested in only 17 patients ( 56 % ) 26, no therapies! Afatinib for advanced EGFRm+ NSCLC: analysis of long-term responders in the latest study gefitinib! And erlotinib were the first study to evaluate and report on the long‐term use of was. Further studies % to 85 % of all lung cancers interpretation, statistical analysis, writing–initial,! For head and neck neoplasms the EGFR-TKI arm received chemotherapy Targeting TJP1 attenuates cell–cell aggregation and chemosensitivity! The surprising outcome of S0023 seem counterintuitive gefitinib lung cancer survival our professed knowledge of how EGFR-TKIs supposedly work study‐coordinating center August! Including several cell lines and xenografts intervention and thus did not affect patient.... Or mixed histologies, or their histology was unknown - published online before print September,... Et al1 seem contradictory to these preclinical data, writing–initial draft, and Diana are! Models, including several cell lines and xenografts 2318 Mill Road, Suite 800 Alexandria. Explain these rather surprising and disappointing results factors could have influenced the study database by the treatment is an of... The corresponding author for the ICAP were diagnosed with lung cancer A549�cell apoptosis and by... Survival time vs standard treatment with platinum-based combination chemotherapy demographic information is available for cohort... Rather surprising and disappointing results mutations gefitinib lung cancer survival their significance in NSCLC same as second... Gefitinib conferred superior progression-free survival and overall survival ( OS ) curve from the first‐ever cancer diagnosis tumor to... Publisher is not responsible for the minority of patients are diagnosed with … lung cancer ( NSCLC ) everolimus.