ASCO Connection 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. To review the pharmacology, pharmacokinetics, clinical efficacy, and toxicity of gefitinib in non-small-cell lung cancer (NSCLC). The 10‐year survival rate from first‐ever initiation of gefitinib was 86%, and the 15‐year survival rate was 59%. 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. Baseline characteristics were similar in both treatment groups. Lecia V. Sequist reports personal fees from AstraZenaca during the conduct of the study and from Ariad, Boehringer Ingelheim, Clovis, Genentech, Merrimack, Taiho, and Novartis outside the submitted work. The ICAP participants constitute a unique subset of patients with cancer in whom long‐term use of gefitinib can be studied. Gefitinib was the first targeted agent to be approved for the treatment of patients with advanced nonsmall cell lung cancer (NSCLC) who failed on previous chemotherapy. Additional supporting information may be found in the online version of this article. Lynch TJ, Bell DW, Sordella R, et al. In addition, the study population in the retrospective chart review was relatively small (n = 79), and the data collected were limited (patient demographics, medical history and disease characteristics, treatment regimen, response, survival, and safety). 26, no. Newest Articles This is the first report of long‐term (>10 years) safety, tolerability, and survival data on patients with non–small cell lung cancer (NSCLC) who received treatment with gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. J Clin Oncol 23:: Fabian MA, Biggs WH 3rd, Treiber DK, et al: A small molecule-kinase interaction map for clinical kinase inhibitors. In addition, there is a suggestion that NSCLCs with K-ras mutations do worse when treated with the EGFR-TKI erlotinib.25 This again raises the question of the K-ras gene status of the tumors in the SWOG study. 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. Working off-campus? Collection and assembly of data: Vicki L. Keedy, Carlos L. Arteaga, David H. Johnson, Manuscript writing: Vicki L. Keedy, Carlos L. Arteaga, David H. Johnson, Final approval of manuscript: Vicki L. Keedy, Carlos L. Arteaga, David H. Johnson. Before ICAP initiation, patients received gefitinib predominantly as monotherapy (84%). Klaus Freivogel: Study conception and design, data analysis and interpretation, statistical analysis, writing–initial draft, and writing–review and editing. 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. Clin Cancer Res 13:: Douillard J-Y, 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). AstraZeneca made provisions for gefitinib to remain available to this limited group of patients in the United States under the IRESSA Clinical Access Program (ICAP) in June 2011. However, this explanation does not explain the outcomes in this particular setting because gefitinib was administered after chemotherapy. JCO OP DAiS, ASCO eLearning First-line afatinib treatment significantly reduced the risk of lung cancer progression by 27% versus gefitinib. Efficacy and safety of apatinib plus docetaxel as the second or above line treatment in advanced nonsquamous NSCLC. The majority of patients are diagnosed with … 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. Meghan Mooradian reports personal fees from Boehringer Ingelheim outside the submitted work. Dara Stein's current address: Evidera, London, United Kingdom. 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. Time‐to‐event analyses were assessed using Kaplan–Meier estimates. Thatcher 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). 2428-2430. This is the first study to evaluate and report on the long‐term use of gefitinib. DOI: 10.1200/JCO.2008.16.0374 Journal of Clinical Oncology - Number of times cited according to CrossRef: Targeting TJP1 attenuates cell–cell aggregation and modulates chemosensitivity against doxorubicin in leiomyosarcoma. Overall survival of patients with non-small cell lung cancer (NSCLC) receiving everolimus and gefitinib with and without prior chemotherapy. Diana DeVincenzo: Data analysis and interpretation, statistical analysis, writing–initial draft, and writing–review and editing. IRESSA Clinical Access Program (ICAP) study cohort enrollment overview. Data from the paper case‐report forms were entered by double data entry into the study database by the study‐coordinating center. 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. ASCO Daily News When an investigational treatment yields an unexpected detrimental outcome, the prospect of excessive toxicity caused by the treatment is an obvious consideration. Supporting Figure 1. We thank the patients, their families, and all investigators involved in this study. —Keunchil Park, MD, PhD A total of 319 patients were randomized to receive 40 mg daily afatinib (n = 160) or 250 mg daily gefitinib (n = 159). We must note that the ICAP study is limited by selection bias of the patient population. Advertisers, Journal of Clinical Oncology J Thorac Oncol 2:: Gandara DR, Gumerlock PH: Epidermal growth factor receptor tyrosine kinase inhibitors plus chemotherapy: Case closed or is the jury still out? Treatment with gefitinib resulted in a median time to progression of > 3 months and a median survival time of > 6 months in most studies. A subset of patients (n = 79) underwent retrospective chart review to capture demographic, safety, and survival data. 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. Causes of death other than SAEs also are summarized. Unfortunately, early randomized trials of gefitinib were designed before the discovery of EGFR mutations and their significance in NSCLC. Introduction. ASCO Meetings 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. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. 2006; 24:2549–56. Jiefen Munley: Study conception and design, data analysis and interpretation, statistical analysis, writing–initial draft, and writing–review and editing. Patients with advanced NSCLC (N = 191) who entered the IRESSA Clinical Access Program (ICAP) (June 2011 to January 2013) and had previously obtained a clinical benefit from gefitinib therapy (including patients who had received gefitinib since 2001) were analyzed for adverse events (AEs). Gefitinib can bring significantly improved therapeutic efficacy, lower expression levels of EGFR and CYFRA21-1, and longer survival time for patients with advanced NSCLC. Gefitinib is a treatment for non small cell lung cancer (NSCLC) that has spread into the surrounding tissues (locally advanced) or to other parts of the body. 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. There were 23 deaths, of which none were related to gefitinib‐related SAEs; 9 were from lung cancer, 5 were from other nongefitinib‐related causes, 5 were from SAEs not related to gefitinib, and 4 were from unknown causes. Lung cancer is the leading cause of cancer-related death worldwide; it is responsible for over a million deaths per year and over 400,000 in Eastern Asia alone. Patients who had never previously received gefitinib were not eligible for enrollment in this program. The unique mechanism of action of this agent leads to distinctive patterns of response and toxicity in persons with lung cancer… Of the 7 patients who had EGFR‐mutation‐negative tumors, 6 were receiving treatment for ≤2.7 years and 1 was receiving treatment for >5 years. As mentioned previously, several trials have evaluated EGFR inhibitors in combination with chemotherapy with negative results.4-7 In a subset analysis of one of these trials,6 patients with wild-type EGFR seemed to have a worse survival when treated with an EGFR-TKI plus chemotherapy compared with chemotherapy alone. Phase I studies indicated that the recommended dose of gefitinib was 250 mg/day. Dose modifications because of gefitinib‐related AEs occurred in 4 patients (5%) before ICAP, and dose interruptions because of gefitinib‐related AEs occurred in 13 patients (17%) before ICAP and in 1 patient during ICAP. Improvements in survival are being seen across the spectrum of EGFR -mutant non–small cell lung cancer (NSCLC) in patients with resectable, oligometastatic, and metastatic disease with … However, gefitinib and related quinazolines have been shown to induce EGFR homodimers and EGFR–HER-2 and EGFR–HER-3 heterodimers.22-24 Although these dimers are inactive under the experimental conditions shown in these studies, this property raises the possibility that gefitinib can stabilize ErbB receptor oligomers and indirectly enhance EGFR-independent signaling by kinases present in those protein complexes. Shortly after those approvals, a series of studies showed that the drugs were effective only in … It is now standard of care across the country — and probably the world — to screen … 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. Gandara et al21 also reported that lung cancer cell lines possessing wild-type EGFR with K-ras mutations demonstrated significantly increased apoptosis when treated with docetaxel followed by gefitinib. Seventy‐five of 191 patients (39%) remained on long‐term gefitinib therapy as of September 2016. How then do we explain these rather surprising and disappointing results? No patient‐identification information was collected. Lung cancer is the second most-diagnosed type of cancer in American men and women. The SAEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) into Preferred Terms. In both studies, the two doses of gefitinib produced similar results in terms of objective responses (approximately 20% in IDEAL-1 and 10% in IDEAL-2), disease control rate (about 50% in IDEAL 1 and 40% in IDEAL 2), and overall survival (about 8 months in IDEAL 1 and 7 months in IDEAL 2). Potentially, a chance and unrecognized imbalance in one of these factors could have influenced the study's outcome. Is it possible that chemoradiotherapy selected for an enriched K-ras mutant tumor cell population that did less well when subsequently treated with gefitinib? Data were collected by local center staff from the patient medical charts and recorded onto paper‐based case‐report forms between May 2015 and August 2016. Frontline treatment with apatinib in combination with gefitinib (Iressa) demonstrated superior progression-free survival (PFS) in patients with advanced EGFR- mutant non–small cell lung cancer … We should point out, however, that the lung cancer cell lines and models used in preclinical studies with EGFR antagonists such as gefitinib may not mirror the lung cancers in this study because they had been modified by the primary therapy. The way history unfolded in the case of gefitinib, with a period of regulatory approval but subsequent limitation of access, allowed for the ICAP program to serve as a complete registry of all US patients who were receiving gefitinib from 2011 to 2015. The clinical courses and survival of patients with lung cancer, who have EGFR mutations as deletions in exon 19 or L858R, can be changed with gefitinib treatment. Adenocarcinoma was diagnosed in 44 patients (56%), and squamous carcinoma was diagnosed in 10 patients (13%). Published online In addition to the SAEs reported for all patients in the overall ICAP populations, other safety information and adverse events (AEs) were extracted during ICAP. Klaus Freivogel is an employee of United BioSource Corporation. Overall, serious AEs (SAEs) were reported in 64 patients (34%), the majority of which were attributed to underlying disease or comorbidities; only 3 patients (1.6%) had SAEs that were considered as possibly gefitinib‐related. Outside the submitted work. We have examined the impact of gefitinib on progression-free survival and overall survival in patients with EGFR mutation–positive non–small cell lung cancer. Multiple randomized controlled trials (RCTs) have demonstrated improvement in progression-free survival (PFS) when comparing EGFR-TKI against platinum-based chemotherapy in this genetically distinct subset of NSCLC (1–8). Med Oncol 23:: Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. However, EGFR-TKI statistically significantly prolonged progression-free survival (PFS) overall (HR = 0.37, 95% CI = 0.32 to 0.42, P <.001) and in all subgroups. The 2-year lung cancer survival increased by 19.81% (95% CI 14.90% to 24.71%) 3 years following the launch of gefitinib. Lancet 366:: 1527, 2005-1537, Crossref, Medline, Google Scholar: 3. 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. Jason Hoffman, PharmD, RPh No significant difference in overall survival between afatinib and gefitinib among patients with EGFR-mutant advanced non-small cell lung cancer. First-line afatinib for advanced EGFRm+ NSCLC: Analysis of long-term responders in the LUX-Lung 3, 6, and 7 trials. Gefitinib is also used in clinical trials for other … September 21, 2016. Should Crizotinib Take It All in ROS1-Positive Non–Small-Cell Lung Cancer?, http://www.fda.gov/ohrms/dockets/ac/05/questions/2005‐4095Q1_02_Iressa‐Questions.pdf, Dermatitis acneiform, pruritus, rash pustular, diarrhea, Lung infection, chronic obstructive pulmonary disease, Acute respiratory failure, pulmonary alveolar hemorrhage, acute kidney injury, interstitial lung disease, Gefitinib treatment duration: Median [range], y, Dose changes because of gefitinib‐related AEs, Dose reduction because of gefitinib‐related AEs, Dose interruption because of gefitinib‐related AEs, Discontinuation because of gefitinib‐related AEs, Discontinuation because of progressive disease. In the initial gefitinib clinical trials, the majority of toxicities occurred early in the course of therapy, at about the time steady‐state serum levels were reached. Finally, the surprising outcome of S0023 also raises the disquieting possibility that gefitinib somehow stimulated tumor growth either directly or indirectly. Seventy‐five of the 191 patients (39%) who entered ICAP remained on active treatment as of September 2016. Gefitinib‐related AEs were observed in 16 patients (20%), and 1 patient (1%) had a gefitinib‐related SAE. The results of S0023 seem counterintuitive to our professed knowledge of how EGFR-TKIs supposedly work. Of note, patients with a history of prior thoracic radiotherapy seem to be less responsive to gefitinib,11 and perhaps the prior exposure to irradiation renders these preclinical data irrelevant in this setting. Medical writing support, which was in accordance with Good Publication Practice (PPP3) guidelines, was provided by Meredith Rogers, MS, CMPP, and Marissa Nolan, PhD, of The Lockwood Group (Stamford, CT) and was funded by AstraZeneca. Those who discontinued (n = 116) did so because of disease progression (n = 42; 36%), death (n = 39; 34%), AEs (n = 15; 13%), or other reasons, such as patient or physician decisions (n = 20; 17%). Although this is the first study reporting on long‐term tolerance to gefitinib, comparable studies are currently ongoing in Asia and Europe based on similar patient populations. Lynch et al. Conclusions: Gefitinib monotherapy confers substantial clinical benefit in terms of progression-free survival and overall survival in non–small cell lung cancer patients with EGFR … JCO Oncology Practice Frontline treatment with apatinib in combination with gefitinib (Iressa) demonstrated superior progression-free survival (PFS) in patients with advanced EGFR-mutant non–small cell lung cancer (NSCLC), according to results from the phase 3 ACTIVE trial (NCT02824458).1. For patients in whom the initial dose of gefitinib was known (n = 67), the starting dose was 250 mg daily. Clinical and genetic features associated with such long‐term benefit warrant further studies. Ando M, Okamoto I, Yamamoto N, Takeda K, Tamura K, Seto T, et al. Although it is assumed that most of these patients' tumors harbor EGFR mutations, molecular studies of available tumor specimens are planned to uncover the features that predict long‐term survival. George Simon reports grants from Boehringer Ingelheim and Merck outside the submitted work and personal fees from Celgene, Genentech, Lilly, Ariad, Genprex Inc, and RefleXion Medical. N Engl J Med 354:: Bell DW, Lynch TJ, Haserlat SM, et al: Epidermal growth factor receptor mutations and gene amplification in non–small-cell lung cancer: Molecular analysis of the IDEAL/INTACT gefitinib trials. The results of the trial by Kelly et al1 seem contradictory to these preclinical data. Secondary endpoints included 3-year DFS, 5-year DFS, overall survival (OS), 5-year OS, safety, healthrelated quality of life, and exploratory biomarker analyses. The ASCO Post 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. The 2-year lung cancer survival increased by 19.81% (95% CI 14.90% to 24.71%) 3 years following the launch of gefitinib. Gefitinib is an oral, reversible, tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) that plays a key role in the biology of non small cell lung cancer (NSCLC). The overall survival (OS) curve from the first‐ever initiation of gefitinib is illustrated in Figure 1. The majority of the reported SAEs (152; 94%) were considered to be unrelated to gefitinib treatment and consistent with underlying disease conditions or comorbidities. Contact Us Abbreviations: ICAP, IRESSA Clinical Access Program; MedDRA PT, Medical Dictionary for Regulatory Activities Preferred Terms; SAE, serious adverse event. ISEL (Iressa Survival Evaluation in Lung Cancer) was a double-blind, placebo-controlled, parallel-group, multicenter, randomized, Phase III study to assess the survival advantage of gefitinib (250 mg/day) as second- or third-line treatment for patients with locally advanced or metastatic NSCLC . J Clin Oncol 22:: Herbst RS, Giaccone G, Schiller JH, et al: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 2. Gefitinib has shown potent activity in a number of lung cancer tumor models, including several cell lines and xenografts. found specific EGFR mutations that correlated with tumor response to gefitinib. As a single agent and in combination with various chemotherapy agents, gefitinib has been shown to exert antitumor activity, including effects on cell proliferation, apoptosis, and angiogenesis, in a variety of human cancer cell lines known to express EGFR (12, 13, 14). The third patient remained on gefitinib after the onset of the SAEs (lung infection and chronic obstructive pulmonary disease exacerbations) and died of exacerbation of chronic obstructive pulmonary disease 11 weeks later. Your friends and colleagues 1 % ), almost 60 % had gefitinib lung cancer survival tumors was... Of all lung cancers the paper case‐report forms were entered by double entry... Toxicity compared with chemotherapy FDA to treat lung cancer patients treated with gefitinib the starting dose was 250.... Because gefitinib was 11.1 years ( range, 6.5‐15.1 years ) however, this does! Survival rates, and writing–review and editing learn more about types of cancer. 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