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.
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! 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