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Predictors of the Response to Gefitinib in Refractory Non-Small Cell Lung Cancer
Abstract
Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has a response rate of 10% to 20% in refractory non-small cell lung carcinoma. Although female gender, adenocarcinoma, and never having smoked are possible markers of a favorable response, mutations of the EGFR gene have also been reported to be highly significant predictors of response. Seventy patients with relapsed non-small cell lung carcinoma were enrolled in the Expanded Access Program. After the drug became available commercially, 28 more patients were treated with gefitinib. Response evaluations were feasible in 80 patients. Twenty-seven tumor specimens (8 responders and 19 nonresponders) were available for the sequence analysis of the EGFR gene. The response rate was 25% (20/80) and the disease control rate (remission + stable disease) was 47.5% (38/80). The response rate was significantly higher for adenocarcinoma (41.0%) versus non-adenocarcinoma (9.8%, P = 0.001), in those who never smoked (58.8%) versus smokers (15.9%, P < 0.001), and in females (42.1%) versus males (19.7%, P = 0.049). A deletion or mutation of the EGFR gene was found in six of eight responders. Remission was noted in all patients with a mutation, whereas the response rate was 9.5% (2/21) in patients without a mutation (P < 0.001). The predictors of response showed significant correlations with survival and time to progression. In a multivariate logistic analysis, the independent predictors of response were smoking history and adenocarcinoma. Given that 9.5% of smokers and 6.7% of those with non-adenocarcinoma showed a mutation of the EGFR gene, the genetic profile may replace those variables as an independent predictor of a response.
... Based on the IDEAL trials data and the "orphan indication" of third-line therapy for NSCLC, gefitinib (250 mg/d) obtained US Food and Drug Administration (FDA) approval in May, 2003, for use as monotherapy in advanced NSCLC patients after treatment with CT enclosing a platinum agent or docetaxel. During the period that the expanded use program was open, it was objectified by various groups that certain clinical/epidemiologic patient features (adenocarcinoma histology, East Asian ethnicity, a history of never smoking, female gender and the appearance of rash with the treatment) predisposed to better respond to the TKI (21)(22)(23)(24). ...
... Pao et al. (34) confirmed these findings in erlotinib-responsive cases. From there, retrospective series corroborated EGFR mutations as a molecular predictors of response to EGFR TKIs as well as its incidence and distribution according to clinical variables (23,(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). The more common EGFR mutations are exon 19 in-frame deletions and the single point mutation L858R in exon 21. ...
The epidermal growth factor receptor (EGFR) oncogene was positioned as an attractive target for drug development in non-small cell lung cancer (NSCLC). Gefitinib and erlotinib were the first two reversible inhibitors of the EGFR kinase. The discovery of EGFR kinase domain-activating mutations that significantly correlated with a high likelihood of response to EGFR tyrosine-kinase inhibitors (TKIs) allowed to design studies to test these drugs as potential first-line therapies. In the same way, the feasibility of personalized medicine was established in patients with advanced NSCLC. Currently in the field of NSCLC with EGFR mutation have developed second and even third generation TKIs that would be gaining the positioning in the treatment of this subset population of NSCLC. In spite of this, without the knowledge that EGFR first generation TKIs have provided, we would not have gotten so far. We will review step by step how it was forged the exciting history of the subpopulation of lung cancer with EGFR mutated, through the various clinical trials performed with first generation TKIs that changed the focus, the future of NSCLC as well as survival of these patients.
... [9][10][11][12][13][14][15][16][17][18][19][20] Testing for this ALK gene fusion has been facilitated by the commercial availability of a Abbreviations: CI, confidence interval; n, number of studies; N, number of patients; RR, relative risk; SD, standard deviation; WMD, weighted mean difference. a References 7,17,28,48,53,56,58,110,129,133,170,[191][192][193][194][195][196][197][198]202,211, References 7,17,53,56,115,129,133,191,[193][194][195]202,[250][251][252][253][254]258,259,261,266,267,[273][274][275][277][278][279] c References 17,28,53,56,58,129,170,185,191,193,195,201,211,[250][251][252]254,255,[261][262][263]266,267,[275][276][277][278] References 17,28,53,56,90,129,170,183,184,191,193,197,[253][254][255]258,259,261,262,266,267,[270][271][272][276][277][278] dual-probe ''break-apart'' fluorescence in situ hybridization (FISH) assay for ALK rearrangements that was already in clinical use to detect ALK fusions in lymphomas and certain sarcomas. 15 A recent report of a large clinical series indicated that ALK rearrangements were seen in about 5% of 1500 NSCLC patients screened. ...
... [9][10][11][12][13][14][15][16][17][18][19][20] Testing for this ALK gene fusion has been facilitated by the commercial availability of a Abbreviations: CI, confidence interval; n, number of studies; N, number of patients; RR, relative risk; SD, standard deviation; WMD, weighted mean difference. a References 7,17,28,48,53,56,58,110,129,133,170,[191][192][193][194][195][196][197][198]202,211, References 7,17,53,56,115,129,133,191,[193][194][195]202,[250][251][252][253][254]258,259,261,266,267,[273][274][275][277][278][279] c References 17,28,53,56,58,129,170,185,191,193,195,201,211,[250][251][252]254,255,[261][262][263]266,267,[275][276][277][278] References 17,28,53,56,90,129,170,183,184,191,193,197,[253][254][255]258,259,261,262,266,267,[270][271][272][276][277][278] dual-probe ''break-apart'' fluorescence in situ hybridization (FISH) assay for ALK rearrangements that was already in clinical use to detect ALK fusions in lymphomas and certain sarcomas. 15 A recent report of a large clinical series indicated that ALK rearrangements were seen in about 5% of 1500 NSCLC patients screened. ...
Objective:
To establish evidence-based recommendations for the molecular analysis of lung cancers that are that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed.
Participants:
Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies.
Evidence:
Three unbiased literature searches of electronic databases were performed to capture articles published published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation.
Consensus process:
Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4).
Conclusions:
The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines.
... The vast majority of studies showed a significant association between EGFR mutations, particularly exon 19 deletion, and response to TKIs (49,(66)(67)(68)(69)(70)(71)(72)(73)(74). Recent prospective studies confirmed that responders to gefitinib or erlotinib harbored an EGFR gene mutation (75)(76)(77)(78)(79)(80). ...
... Available data indicate that a significant fraction of patients with EGFR mutations (12-84%) do not respond to TKIs (47,60,67). Retrospective analyses of large phase III trials (60, 81) did not show any significant improvement in response rate for patients with EGFR mutations treated with a TKI. ...
The epidermal growth factor receptor (EGFR) plays a key role in cancer development and progression in several human malignancies including non-small cell lung cancer (NSCLC). Several strategies aimed at inhibiting the EGFR have been investigated in the last years, including the use of small tyrosine kinase inhibitors (TKIs) directed against the intracellular domain of the receptor and monoclonal antibodies targeting its extracellular portion. Subgroups of patients who are more likely to respond to TKIs have been identified based on both clincal and biological features. Never-smoking history has emerged as the most relevant clinical characteristic predictive of response to TKIs in NSCLC, while presence of drug-sensitive EGFR mutations and EGFR gene gain represent critical biological variables associated with an improved outcome for patients exposed to these agents. Recent studies have highlighted the existence of biological factors involved in intrinsic and acquired resistance to TKIs, including k-ras, HER-2 and EGFR exon 20 mutations. Increasing knowledge of EGFR biology and drug-receptor interactions will allow to identify individuals who are likely to derive a clinical benefit from the proposed targeted therapy, sparing refractory patients expensive and potentially toxic treatment.
... Molecularly, NSCLC cells demonstrate mutation (10-12) and amplification (13,14) of the EGFR gene. Treatment with gefitinib has demonstrated that NSCLC patients with such mutations or amplifications, as well as expression of phosphorylated Akt (15) and ErbB3 (16) are associated with an improved outcome (17)(18)(19)(20)(21)(22)(23). However, it is often difficult to obtain the tumor tissue of patients to detect gene status. ...
... In the present retrospective study, the response and disease progression of primary and metastatic lesions was analyzed in lung adenocarcinoma patients who achieved PR, CR or SD following three months of treatment with gefitinib. A more positive outcome was observed in the present study compared with previous studies (21,26,27). The CR and PR rates were 23.1% (12/52) and 57.7% (30/52), respectively. ...
Non-small cell lung cancer is a subtype of adenocarcinoma, which has previously shown positive responses to gefitinib. The aim of the current study was to determine a clinical profile of gefitinib-induced disease controls for patients with lung adenocarcinoma. Retrospective evaluation of the clinical characteristics of 52 lung adenocarcinoma patients, enrolled at the Zhejiang Cancer Hospital (Hangzhou, China) between October 2004 and August 2008, was undertaken. All patients received gefitinib (250 mg/day orally) until disease progression or until an unacceptable toxicity was observed. Of the 52 patients, complete response (CR) and partial response (PR) rates were 23.1% (12/52) and 57.7% (30/52), respectively. An additional 19.2% (10/52) of patients demonstrated stable disease (SD) after three months of treatment with gefitinib. Disease control was observed in the primary lesion, and tumor metastasis to the lungs, brain, adrenal glands, pleura, peritoneum, pericardium, bone and lymph nodes was identified. The one-year progression-free survival (PFS) and overall survival (OS) rates were 74.8 and 78.0%, respectively. Multivariate analysis revealed that female patients were associated with significantly longer survival times when compared with males (hazard ratio, 0.077; 95% confidence interval [CI], 0.007-0.083; P=0.035). One-year PFS and OS rates in CR, PR and SD patients were 77.8, 73.9 and 33.3%, and 89.2, 79.8 and 33.7%, respectively, although neither difference was identified to be statistically significant. In addition, the median OS of SD patients was 12 months (95% CI, 7.2-16.8 months). Brain metastasis was the major site of disease progression (23.1%). Gefitinib treatment for patients with lung adenocarcinoma showed a marked long-term survival benefit, even in SD patients. However, further studies are required to analyze the efficacy of gefitinib in penetrating the blood-brain barrier in order to prolong PFS in patients with lung adenocarcinoma.
... EGFR gene mutations are observed predominantly in lung cancers from nonsmokers; gain-of-function EGFR gene mutations that promote angiogenesis may facilitate cancer development from a few initial tumor cells in this particular subpopulation of patients. On the contrary, EGFR gene mutations are rarely identifi ed in lung cancers in cigarette smokers, which are usually more malignant than lung cancers in nonsmokers ( 3 ) . It has been observed that cancer patients with EGFR gene mutations have longer survival times than those without EGFR gene mutations ( 3 ) . ...
... On the contrary, EGFR gene mutations are rarely identifi ed in lung cancers in cigarette smokers, which are usually more malignant than lung cancers in nonsmokers ( 3 ) . It has been observed that cancer patients with EGFR gene mutations have longer survival times than those without EGFR gene mutations ( 3 ) . Also, the identifi cation of an EGFR gene mutation that results in a truncated protein in a lung cancer patient ( http://www.egfr.org ) argues for a causal effect in carcinogenesis in this case. ...
... Indeed, many EGFR-positive tumors do not respond to EGFR TKI therapy, while a large number of EGFR-negative tumors have been reported to respond. [8][9][10][11] Moreover, although EGFR mutation status is the best predictor of response to TKIs, many NSCLC EGFR mutated patients do not respond. 12 For this reason, a number of alternative predictive markers are currently under investigation. ...
... Several studies have reported no correlation between EGFR levels and response to gefitinib or erlotinib. [8][9][10][11] Conversely, two other studies have suggested that EGFR IHC assessment could help to identify a subset of patients achieving survival improvement. [13][14][15] In the BR21 trial, individuals with high EGFR expression were associated with response to erlotinib (P=0.03). ...
In recent years, a number of novel agents have been investigated that target specific molecular pathways in non-small cell lung cancer (NSCLC). A great deal of effort has been focused on identifying specific markers that predict treatment response, given that a tailored approach would maximize both the therapeutic index and the cost-effectiveness. The epidermal growth factor receptor (EGFR) pathway has emerged as a key regulator of cancer cell proliferation and invasion, and several specific EGFR inhibitors have been examined. Gefitinib and erlotinib are selective EGFR tyrosine kinase inhibitors (EGFR-TKIs), demonstrating good results in selected cases both in terms of objective response rate and of overall survival. At present, EGFR gene mutations are the best positive predictive factors for TKI therapy, and a number of other potential biomarkers are being investigated as additional positive or negative predictors of response. The correct selection of patients that could benefit from these innovative therapies, based on an accurate molecular characterization, is mandatory to provide the best clinical management. Currently, the main factor limiting the characterization of metastatic NSCLC patients is the small quantity of tumor cells available for molecular analysis. In this paper we provide an overview of the most important molecular predictive markers for EGFR-TKIs therapy in NSCLC patients, and focus attention on biological samples suitable for analysis and alternative sampling approaches such as plasma- or serum-derived DNA.
... The one-and two-year survival was 54.3% and 8.7%, respectively, consistent with studies in other Asian countries. 20,21 The efficacy of gefitinib mainly depends on the mutant rate of EGFR, which is higher in the Asian population. ...
Background:
In this study, positron emission tomography-computed tomography (PET-CT) was used to monitor the maximal standard uptake value (SUVmax) in advanced lung adenocarcinoma patients with epithermal growth factor receptor (EGFR) mutation to prove its role in predicting the prognosis of targeted therapy.
Methods:
A total of 46 patients with advanced lung adenocarcinoma (IIIb-IV stage) were enrolled in the current study. They were positive for EGFR mutation. All patients received gefitinib (250 mg per day, administered orally). PET-CT was conducted prior to (at baseline) and six months after gefitinib administration for the lesion size and SUVmax. The recommendations of the European Organization for Research and Treatment of Cancer criteria were chosen for PET assessment. Metabolic response (SUV decline < -25%) was compared with morphologic response evaluated by CT scan and overall survival.
Result:
Compared to patients with △SUV% ≥ 25% (progressive metabolic disease), the survival time was significantly prolonged in △SUV% < -25% (including complete metabolic response and progressive metabolic disease) (10.6/18.4, P = 0.000), but was not in -25% ≤ △SUV% < 25% (stable metabolic disease) (10.6/10.7, P = 0.088). Patients who achieved △SUV% < -25% after treatment were associated with a longer median survival, higher control rate, and better prognosis. There was a strong correlation between SUV changes (△SUV%) and CT size change (△lesion size%) (R(2) = 0.891, P = 0.000).
Conclusion:
Changes in the SUV could be used to predict the prognosis of targeted therapy in advanced lung adenocarcinoma.
... [1][2][3][4][5] The patient in this case was an East Asian female non-smoker who had an activating EGFR mutation; therefore, she was expected to have a good response to gefitinib or erlotinib. 10,11 However, as seen in this case, initially good responders to EGFR-TKIs almost always experience AR and disease progression after approximately 12 months. 12 Several mechanisms of AR have been reported, which could be grouped into four main categories: (i) the acquisition of secondary mutations in EGFR, such as the T790M mutation; (ii) parallel activation of downstream signaling pathways (by-pass track), such as MET amplification and hepatocyte growth factor overexpression; (iii) phenotypic transformation from NSCLC to small cell lung cancer; and (iv) genetic alteration in addition to EGFR mutation, for instance, HER2 amplification or BRAF mutation. ...
We report a case showing the long-term clinical benefit of the continued use of gefitinib in a patient with asymptomatic progression of lung adenocarcinoma harboring an exon 19 deletion of the EGFR gene. Although follow-up studies showed smoldering progression of metastatic lesions, continued treatment with gefitinib controlled pulmonary adenocarcinoma for more than 6 years.
... The need for routine testing for EGFR mutations and ALK rearrangements for patients with squamous histology is debated, in part due to the low prevalence of these molecular alterations. The rate of EGFR mutations in patients with squamous histology is reported to be 1-15% [Chou et al. 2005;Kim et al. 2005;Pallis et al. 2007;Park et al. 2009;Miyamae et al. 2011]. One issue with basing the decision to perform molecular testing on histology is that there can be significant interobserver variability among pathologists in the classification of squamous and nonsquamous histology when hematoxylin-eosin slides are used [Grilley-Olson et al. 2013]. ...
The identification of EGFR mutations and ALK rearrangements in nonsmall cell lung cancer (NSCLC) has led to the rapid development of targeted therapies and significant changes in the treatment paradigm. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and crizotinib are now standard therapies for patients with the appropriate molecular alteration. Current investigations are determining the mechanisms of resistance to targeted therapies and developing novel agents to combat resistance. For patients with KRAS mutant NSCLC, a phase III trial of the MEK inhibitor, selumetinib, has been initiated. For patients without a defined mutation or a mutation without a known targeted therapy, immunotherapy, ganetespib, nintedanib and MET inhibitors in combination with EGFR TKIs are in development. Preliminary results of phase III trials raise doubts about the future development of dacomitinib as a second-line agent.
... 30 Imatinib and gefitinib are the successful examples of tyrosine kinase inhibitor therapies for cancers. [31][32][33] In light of the findings above, we sought to predict potential specific tyrosine kinases using three websites: To confirm this novel target, we next undertook MTS assays in stable cell lines using a specific Tie2 kinase inhibitor. As shown in ...
Serine/arginine‐rich splicing factor 1 (SRSF1) has been linked to various human cancers including pediatric acute lymphoblastic leukemia (ALL). Our previous study has shown that SRSF1 potentially contributes to leukemogenesis, however its underlying mechanism remains unclear. In this study, leukemic cells were isolated from pediatric ALL bone marrow samples, followed by immune‐precipitation assays and mass spectrum analysis specific to SRSF1. Subcellular localization of the SRSF1 protein and its mutants were analyzed by immunofluorescence staining. Cell growth, colony formation, cell apoptosis and cell cycle were investigated using stable leukemic cell lines generated with lentivirus‐mediated overexpressed wild‐type or mutant plasmids. Cytotoxicity of the Tie2 kinase inhibitor was also evaluated. Our results showed the phosphorylation of SRSF1 at tyrosine 19 (Tyr‐19) was identified in newly diagnosed ALL samples, but not in complete remission and normal control samples. Compared to the SRSF1‐wild type cells, the missense mutants of the Tyr‐19 phosphorylation affected the subcellular localization of SRSF1. In addition, the Tyr‐19 phosphorylation of SRSF1 also led to increased cell proliferation and enhanced colony‐forming properties by promoting cell cycle. Remarkably, we further identified the kinase Tie2 as a potential therapeutic target in leukemia cells. In conclusion, we identify for the first time that the phosphorylation state of SRSF1 is linked to different phases in pediatric ALL. The Tyr‐19 phosphorylation of SRSF1 disrupts its subcellular localization and promotes proliferation in leukemia cells by driving cell‐cycle progression. Inhibitors targeting Tie2 kinase that may catalyze Tyr‐19 phosphorylation of SRSF1 offer a promising therapeutic target for treatment of pediatric ALL.
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... Among NSCLCs, lung adenocarcinoma is the most frequent, and its prognosis depends largely on the presence of mutations in the epidermal growth factor receptor (EGFR) gene. This is because for patients with EGFR mutations, there are the EGFR tyrosine kinase inhibitors (EGFR-TKIs), molecularly targeted drugs which prolong overall survival markedly [6][7][8][9]. Thus, there is a continuing need for a new therapeutic target in patients with wild-type EGFR. ...
L-type amino acid transporter 1 (LAT1) and ASC amino acid transporter 2 (ASCT2) have been associated with tumor growth and progression. However, the clinical significance of LAT1 and ASCT2 coexpression in the prognosis of patients with lung adenocarcinoma remains unclear.
In total, 222 patients with surgically resected lung adenocarcinoma were investigated retrospectively. Tumor sections were stained immunohistochemically for LAT1, ASCT2, CD98, phosphorylated mammalian target-of-rapamycin (p-mTOR), and Ki-67, and microvessel density (MVD) was determined by staining for CD34. Epidermal growth factor receptor (EGFR) mutation status was also examined.
LAT1 and ASCT2 were positively expressed in 22% and 40% of cases, respectively. Coexpression of LAT1 and ASCT2 was observed in 12% of cases and was associated significantly with disease stage, lymphatic permeation, vascular invasion, CD98, Ki-67, and p-mTOR. Only LAT1 and ASCT2 coexpression indicated a poor prognosis for lung adenocarcinoma. Furthermore, this characteristic was recognized in early-stage patients, especially those who had wild-type, rather than mutated, EGFR. Multivariate analysis confirmed that the coexpression of LAT1 and ASCT2 was an independent factor for predicting poor outcome.
LAT1 and ASCT2 coexpression is an independent prognostic factor for patients with lung adenocarcinoma, especially during the early stages, expressing wild-type EGFR.
... Interestingly, Sharma et al. point out the controversy surrounding the predictive value of EGFR mutations in non-selected patient groups where 10-20% of patients who show a partial response to the small molecule EGFR inhibitor gefitinib do not have an identifiable EGFR/ErbB1 mutation [126]. Thus EGFR/ErbB1 polymorphisms may not be solely responsible for the inhibitory effect caused by RTK-specific drugs [126,127,128]. ...
Receptor tyrosine kinases (RTKs) are membrane proteins that control the flow of information through signal transduction pathways, impacting on different aspects of cell function. RTKs are characterized by a ligand-binding ectodomain, a single transmembrane α-helix, a cytosolic region comprising juxtamembrane and kinase domains followed by a flexible C-terminal tail. Somatic and germline RTK mutations can induce aberrant signal transduction to give rise to cardiovascular, developmental and oncogenic abnormalities. RTK overexpression occurs in certain cancers, correlating signal strength and disease incidence. Diverse RTK activation and signal transduction mechanisms are employed by cells during commitment to health or disease. Small molecule inhibitors are one means to target RTK function in disease initiation and progression. This review considers RTK structure, activation, and signal transduction and evaluates biological relevance to therapeutics and clinical outcomes.
... Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) has improved the outcome of advanced non-small cell lung cancer (NSCLC). EGFR-TKIs have higher response rates in Asian patients, females, non-smokers, and those with adenocarcinoma histology [1][2][3] . The efficacy of EGFR-TKIs is associated with the activation of EGFR mutations 2,3 . ...
The presence of epidermal growth factor receptor (EGFR) mutation is a prognostic and predictive marker for EGFR-tyrosine kinase inhibitor (TKI) therapy. However, inevitably, relapse occurs due to the development of acquired resistance, such as T790M mutation. We report a case of repeated responses to EGFR-TKIs in a never-smoked woman with adenocarcinoma. After six cycles of gemcitabine and cisplatin, the patient was treated by gefitinib for 4 months until progression. Following the six cycles of third-line pemetrexed, gefitinib retreatment was initiated and continued with a partial response for 6 months. After progression, she was recruited for an irreversible EGFR inhibitor trial, and the time to progression was 11 months. Although EGFR direct sequencing on the initial diagnostic specimen revealed a wild-type, we performed a rebiopsy from the progressed subcarinal node at the end of the trial. The result of peptide nucleic acid clamping showed L858R/L861Q.
... metastasis | resistance | personalized medicine | combination therapy | phosphotyrosine M utational and copy number analyses from epithelial tumors have identified several activating tyrosine kinase mutations and amplifications, such as epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma and erythroblastic leukemia viral oncogene homolog 2 (ERBB2 or HER2/neu) gene amplification in breast cancer (1). The dependence on these tyrosine kinases for tumor growth and survival has led to successful clinical treatment with tyrosine kinase inhibitors (TKIs) (2,3). However, recent genomic analyses of prostate adenocarcinoma revealed that activating tyrosine kinase mutations or amplifications are very rare (1,(4)(5)(6). ...
In prostate cancer, multiple metastases from the same patient share similar copy number, mutational status, erythroblast transformation specific (ETS) rearrangements, and methylation patterns supporting their clonal origins. Whether actionable targets such as tyrosine kinases are also similarly expressed and activated in anatomically distinct metastatic lesions of the same patient is not known. We evaluated active kinases using phosphotyrosine peptide enrichment and quantitative mass spectrometry to identify druggable targets in metastatic castration-resistant prostate cancer obtained at rapid autopsy. We identified distinct phosphopeptide patterns in metastatic tissues compared with treatment-naive primary prostate tissue and prostate cancer cell line-derived xenografts. Evaluation of metastatic castration-resistant prostate cancer samples for tyrosine phosphorylation and upstream kinase targets revealed SRC, epidermal growth factor receptor (EGFR), rearranged during transfection (RET), anaplastic lymphoma kinase (ALK), and MAPK1/3 and other activities while exhibiting intrapatient similarity and interpatient heterogeneity. Phosphoproteomic analyses and identification of kinase activation states in metastatic castration-resistant prostate cancer patients have allowed for the prioritization of kinases for further clinical evaluation.
... Recently reports of EGFR mutations and its role in responsiveness in NSCLC patients have been reported 7,8,9,10,11 . An unprecedented long-term survival is being observed in patients harbouring EGFR mutations and treated with tirosin-kinase inhibitors. ...
... Since the beginning of use of the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) gefitinib and erlotinib for treatment of advanced non-small-cell lung cancer (NSCLC) [1], studies have shown that NSCLC patients with EGFR-activating mutations can benefit from TKI treatment [2,3]. The status of EGFR mutations has become the best predictor of the response to TKIs [4][5][6][7][8][9]. Direct sequencing is the ''gold standard'' method for the detection of EGFR mutations. ...
Epidermal growth factor receptor (EGFR) mutation status is the most valuable indicator in the screening of non-small-cell lung cancer (NSCLC) patients for tyrosine kinase inhibitor (TKI) therapy. Accurate, rapid and economical methods of detecting EGFR mutations have become important. The use of two mutation-specific antibodies targeting the delE746-A750 mutation in exon 19 and L858R mutation in exon 21 makes this task possible, but the lack of consensually acceptable criteria for positive results limits the application of this antibody based mutation detection.
We collected 399 specimens from NSCLC patients (145 resection specimens, 220 biopsy specimens, and 34 cytology specimens) whose EGFR mutation status had been detected by TaqMan PCR assay. Immunohistochemical (IHC) analyses using EGFR mutation-specific antibodies were employed for all samples. After staining and scoring, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated in accordance with different levels of positive grades in comparison with the results of PCR-based assay.
In IHC-based analyses, 144 cases were scored 0, 104 cases were scored 1+, 103 cases were scored 2+, and 48 cases were scored 3+. With the molecular-based results were set as the "gold standard", the prevalence of mutation was 6.94% (10/144), 23.08% (24/104), 67.96% (70/103) and 100% (48/48), respectively, for samples with scores 0, 1+, 2+ and 3+. When score 3+ was considered positive, the specificity and PPV were 100%; if only score 0 was considered negative, 93.06% NPV was obtained.
Patients with score 3+ have a perfect PPV (100%), and may accept TKI treatment directly without any molecular-based assays. Patients with score 0 had high NPV (93.06%), which could reach 97.22% when the detection of total EGFR was applied. However, samples with score 1+ or 2+ are unreliable and need further verification of EGFR mutation status by molecular-based assays.
... Follow-up biopsy to determine the T790M mutation status may be unnecessary if further research supports the initial finding that DNA sufficient for genotypic assessment can be isolated from blood samples [101][102][103] . A study reported a 92% sensitivity for detection of EGFR mutations in patients with metastatic NSCLC with this method (11 of 12 patients) 83 . ...
The two essential requirements for pathologic specimens in the era of personalized therapies for non-small cell lung carcinoma (NSCLC) are accurate subtyping as adenocarcinoma (ADC) versus squamous cell carcinoma (SqCC) and suitability for EGFR molecular testing, as well as for testing of other oncogenes such as EML4-ALK and KRAS. Actually, the value of EGFR expressed in patients with NSCLC in predicting a benefit in terms of survival from treatment with an epidermal growth factor receptor targeted therapy is still in debate, while there is a convincing evidence on the predictive role of the EGFR mutational status with regard to the response to tyrosine kinase inhibitors (TKIs).
This is a literature overview on the state-of-the-art of EGFR oncogenic mutation in NSCLC. It is designed to highlight the preclinical rationale driving the molecular footprint assessment, the progressive development of a specific pharmacological treatment and the best method to identify those NSCLC who would most likely benefit from treatment with EGFR-targeted therapy. This is supported by the belief that a rationale for the prioritization of specific regimens based on patient-tailored therapy could be closer than commonly expected.
... In vivo, erlotinib influences the expression of radiation response genes from several functional classes, including those involved in cell cycle arrest and DNA damage repair [26]. In a preclinical study involving three human cancer cell lines with low, moderate, or very high EGFR expression, the extent of erlotinib-induced radiosensitization was proportional to the EGFR expression level [27]. The cell line expressing very high levels of EGFR exhibited the strongest radioresistance, and treatment with erlotinib increased the extent of G1 arrest and augmented apoptosis in those cells. ...
Cisplatin-based concurrent chemoradiotherapy for patients with unresectable, locally advanced esophageal squamous cell carcinoma (ESCC) is associated with significant toxicities that are often intolerable. Prognosis for this subgroup of patients remains poor, and new therapeutic approaches are urgently needed. We investigated the efficacy and safety of paclitaxel combined with erlotinib and concurrent radiotherapy in patients with inoperable ESCC. Erlotinib (150 mg) was administered daily for 60 days beginning at the start of radiotherapy, and paclitaxel (45 mg/m²) was administered weekly along with intensity modulated conformal radiotherapy (60 Gy in 30 fractions). The median follow-up time was 21 months. The associations between EGFR and VEGF expression and treatment outcome were evaluated. Among the 21 patients treated, the overall response rate (CR + PR) was 85.6%. The median LPFS, PFS and OS were: 17.5, 14.3, and 22.9 months, respectively. Treatment-related grade 3 toxicities included esophagitis (two patients) and hypoleukemia (one patient). Grade 4 pulmonary toxicity was observed in one patient. Patients expressing EGFR had longer PFS, while those expressing VEGF or with a history of smoking had worse outcomes. Weekly paclitaxel combined with erlotinib and concurrent radiotherapy shows promise as an effective, tolerated regimen for patients with inoperable ESCC.
... In vivo, erlotinib influences the expression of radiation response genes from several functional classes, including those involved in cell cycle arrest and DNA damage repair [26]. In a preclinical study involving three human cancer cell lines with low, moderate, or very high EGFR expression, the extent of erlotinib-induced radiosensitization was proportional to the EGFR expression level [27]. The cell line expressing very high levels of EGFR exhibited the strongest radioresistance, and treatment with erlotinib increased the extent of G1 arrest and augmented apoptosis in those cells. ...
Cisplatin-based concurrent chemoradiotherapy for patients with unresectable, locally advanced esophageal squamous cell carcinoma (ESCC) is associated with significant toxicities that are often intolerable. Prognosis for this subgroup of patients remains poor, and new therapeutic approaches are urgently needed. We investigated the efficacy and safety of paclitaxel combined with erlotinib and concurrent radiotherapy in patients with inoperable ESCC. Erlotinib (150 mg) was administered daily for 60 days beginning at the start of radiotherapy, and paclitaxel (45 mg/m²) was administered weekly along with intensity modulated conformal radiotherapy (60 Gy in 30 fractions). The median follow-up time was 21 months. The associations between EGFR and VEGF expression and treatment outcome were evaluated. Among the 21 patients treated, the overall response rate (CR + PR) was 85.6%. The median LPFS, PFS and OS were: 17.5, 14.3, and 22.9 months, respectively. Treatment-related grade 3 toxicities included esophagitis (two patients) and hypoleukemia (one patient). Grade 4 pulmonary toxicity was observed in one patient. Patients expressing EGFR had longer PFS, while those expressing VEGF or with a history of smoking had worse outcomes. Weekly paclitaxel combined with erlotinib and concurrent radiotherapy shows promise as an effective, tolerated regimen for patients with inoperable ESCC.
... respectively. [32][33][34][35] Only two studies have evaluated the efficacy of gefitinib in Taiwanese patients. 36,37 In the first study, the patients had inoperable NSCLC and secondary brain metastases. ...
Background: The IRESSA Survival Evaluation in Lung cancer (ISEL) trial showed some improvement in survival which failed to reach statistical significance in the overall population and in patients with adenocarcinoma. However, gefitinib (IRESSA) treatment was associated with a significant improvement in the survival in subgroups of patients of Asian origin and never smokers. Here we review the clinical experience of gefitinib in patients of Asian origin with advanced non-small cell lung cancer (NSCLC) and discuss the evidence for the underlying biological basis for the apparent heterogeneity in clinical outcome between patients of Asian and non-Asian origin.
... The EGFR mutation is most commonly seen in East Asian patients with pulmonary adenocarcinoma. An association with high positive prediction rate (ranging between 65% and 87%) and negative prediction rate (ranging between 69% and 90%) was reported from Taiwan [12,13], Japan [14,15] and Korea [16,17]. In a prospective study, a response rate of 75% was observed in NSCLC patients with exon 19 deletion and exon 21 L858R mutation [18]. ...
Opinion statement:
Most patients with squamous cell carcinoma (SCC) present with advanced or metastatic disease at the time of diagnosis. Given the low prevalence of oncogenic driver mutations in SCC, I do not routinely perform molecular testing. The times that I perform molecular testing in SCC are for patients with SCC and a light or never smoking history, adenosquamous histology, or when the histological diagnosis is not definitive. For patients with a good performance status and adequate organ function, a platinum doublet is the standard therapy, and I generally use carboplatin and gemcitabine or carboplatin and paclitaxel. In the second-line setting for patients who are chemotherapy candidates, I will use docetaxel on a weekly or every three week schedule. Erlotinib is a treatment option in the third-line setting. My preference is for patients to participate in clinical trials because the development of novel therapies for patients with SCC has been slow compared with nonsquamous non-small cell lung cancer. Ongoing investigations into the genomics of SCC will hopefully identify driver mutations or alterations in pathways essential for oncogenesis and tumor growth and will lead to the development of targeted therapies. The complexity of the genomics of SCC will make the development of targeted therapies challenging.
The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib and the cytotoxic agent docetaxel are both
used for the second-line treatment of advanced non-small cell lung cancer (NSCLC). This study aimed to investigate the efficacy
and safety of gefitinib in combination with docetaxel within this disease setting, and to evaluate the predictive value of
assessing pre-treatment levels of soluble serum EGFR and HER2. In this open-label, non-comparative, multicenter, phase II
trial, patients with non-resectable advanced or metastatic NSCLC were treated with oral gefitinib (250mg/day) in combination
with docetaxel (75mg/m2 IV every 3weeks). Forty-eight patients were enrolled: 30 had progressed during or after platinum-based chemotherapy (Group
A) and 18 were unsuitable for platinum-based chemotherapy (Group B). Anti-tumor activity was seen with objective response
rates of 23.3% (Group A) and 11.8% (Group B). The most frequent adverse events considered to be gefitinib-related were diarrhea
(57.4%) and skin-related events (dry-skin: 31.9%; rash: 29.8%; pruritus: 12.8%), and those considered to be docetaxel-related
were alopecia (21.3%), nausea (19.1%), and diarrhea (17.0%). The addition of gefitinib did not seem to affect the hematological
toxicity seen with docetaxel. Serum biomarker investigations revealed that patients who responded had lower serum EGFR levels
than non-responders, although this association was not significant (p=0.07). In conclusion, the combination of gefitinib with docetaxel was feasible, generally well tolerated, and has activity
for the treatment of advanced NSCLC. Soluble serum EGFR (and HER2 levels) did not appear to be predictive for response. Although
this study confirms that the combination of gefinitib and docetaxel appears promisingly effective and tolerable, it should
not be recommended as a standard option for second-line therapy in non-small cell lung cancer until results from phase III
trials showing a significant superiority over docetaxel alone are available.
Histologic subtype has emerged as a potential prognostic and/or predictive factor in advanced non-small cell lung cancer (NSCLC). Several studies support the importance of differentiating between squamous and non-squamous NSCLC in terms of efficacy of chemotherapeutics (e.g. pemetrexed) or treatment-related toxicities (e.g. bevacizumab). In addition, molecular markers and gene profiles have been correlated with histologic subtype. This review examines the emerging clinical significance of histologic type in the management of NSCLC, discusses caveats in accurate histologic diagnosis, and reviews biomarkers with potential predictive value for NSCLC chemotherapeutics.
Non–small-cell lung carcinoma is a leading cause of cancer deaths in the United States and worldwide. Historically, diagnostic classification and treatment decisions were based on a simple algorithm that considered only the distinction from small cell carcinoma and tumor stage. However, we are increasingly recognizing the histologic and molecular heterogeneity of lung cancers and are developing more effective targeted therapies as a result. Use of targeted epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor therapy is one of the great successes in this regard. The presence of somatic EGFR activating mutations appears to be the best predictor of response to this targeted therapy. This review recaps the rationale behind the development of EGFR tyrosine kinase inhibitors and offers some historical perspective on the clinical experience with these drugs. Finally, we provide some guidelines to the practicing pathologist regarding currently available techniques for mutation analysis as well as a discussion of alternate modalities for assessing EGFR receptor activation in tissue samples.
Drugs that target the EGFR have a major impact on the treatment of advanced non-small-cell lung cancer (NSCLC). EGFR mutations in NSCLC are associated with a dramatic and sustained response to EGFR tyrosine kinase inhibitors (TKIs). This review summarizes the results of randomized trials using EGFR TKIs or EGFR monoclonal antibodies with chemotherapy in the first-line setting, and discusses several unresolved issues regarding the use of the EGFR TKIs as the first-line therapy in advanced NSCLC.
Non-small cell lung cancer [NSCLC] is a major cause of cancer related deaths in the world. In a significant proportion of NSCLC cases, the Epidermal Growth Factor Receptor [EGFR] is over-expressed prompting the development of anti-EGFR therapies. Clinical studies of EGFR tyrosine kinase inhibitors [TKIs] demonstrated an overall response rate of 10% in NSCLC with higher response rates in females, never smokers, adenocarcinoma histology and East Asians. Mutations in exons 18-21 of the EGFR gene appear to be the most important molecular predictors of response to TKIs with response rates of >60% reported in most studies. Consequently screening NSCLC patients for tumours harbouring EGFR mutations will assist in selecting patients for TKI therapy. The gold standard for detecting EGFR mutations has been direct DNA sequencing however the sensitivity of this molecular technique is limited by the amount of tumour DNA is time and resource consuming. Recently several highly sensitive techniques have been developed to detect EGFR mutant DNA in different biological samples. In this review we aim to provide an overview of the clinical relevance of screening for EGFR mutations in NSCLC and recent molecular tests that have been developed for this purpose to allow the reader to critically evaluate the various methodologies that are available.
The EGF receptor (EGFR) is one of the most important targets for cancer treatment implicated in the control of cell survival, proliferation and metastasis. In the last few years different EGFR molecular antagonists have been evaluated in the clinical setting and some of these drugs have demonstrated clinical efficacy in a subset of non-small cell lung cancer (NSCLC) patients. Gefitinib or erlotinib are a new class of compounds able to inhibit the tyrosine kinase domain of EGFR (EGFR TKI) and, during recent years, clinical and biologic predictors for TKI sensitivity have been identified. Among clinical features, never-smoking history has emerged as the most relevant clinical characteristic predictive of response to TKIs in NSCLC, and EGFR gene mutation or EGFR increased gene copy number represent critical biologic variables associated with an improved outcome for patients exposed to these agents. Unfortunately, cancer cells possess escape mechanisms to overcome inhibition of cell proliferation leading to drug resistance. There are several mechanisms that have been identified as responsible for intrinsic or acquired resistance. The aim of the present review is to analyze available data in order to identify an optimal paradigm for patient selection.
Background: Lung cancer has been the leading cause of cancer death in South Korea since 2000. This study examined the clinical characteristics of lung cancer patients diagnosed in a community hospital from the year 2000 to 2005, and compared these results with previously reported statistical data. Method: The lung cancer data in a form of an electronic medical record was downloaded from the hospital medical information system. The clinical characteristics of the 1,509 patients with lung cancer were analyzed retrospectively. Result: The mean age of the patients was 63.7 years. 82.5% and 74.5% of the patients were men and smokers, respectively. Squamous cell carcinoma (41.6%) was the most common pathology type followed by adenocarcinoma(32.3%) and small cell carcinoma(13.9%). When 604 patients who were diagnosed from 2000 to 2003 were compared with 905 patients diagnosed from 2004 to 2005, the age of patients increased significantly (61.5 years vs. 65.1 years; p<0.001) and the proportion of adenocarcinomas was significantly higher(29.3% vs. 34.4%; p=0.046). Conclusion: Among the major histology types of lung cancer, the incidence of adenocarcinoma has been increasing recently. The age of the lung cancer patients at diagnosis is getting older. This is despite the fact that the distributions of the initial anatomic stages have not changed significantly.
The mutations in oncogenic genes, such as EGFR, ALK, BRAF, HER2, DDR2, RET and AKT1, defined subsets of non-small cell lung cancers (NSCLC) with potential sensitivity to targeted therapies. At present, the mutational spectrum, prevalence and clinicopathologic characteristics in squamous cell carcinomas with minor (<10%) glandular component (SQCC-mGC) are not well established.
Three hundred and ten surgically resected lung squamous cell carcinoma (SQCC) specimens were collected. The histology of all cases was re-evaluated using hematoxylin-eosin (H&E) and immunohistochemistry (IHC) staining. EGFR, KRAS, HER2, BRAF, PIK3CA, AKT1 and DDR2 mutations, as well as ALK and RET rearrangements, were examined in 310 SQCCs by directed sequencing.
Ninety-five SQCC-mGCs (30.6%) and 215 pure SQCCs (69.4%) were identified. Of the 95 SQCC-mGCs, 26 (27.4%; 95%CI, 18.7%-37.4%) were found to harbor known oncogenic mutations, including 10 with EGFR, 7 with KRAS, 3 with PIK3CA, 1 with BRAF, 1 with HER2, 1 each with EGFR/PIK3CA and KRAS/PIK3CA double mutations and 2 with EML4-ALK fusions. Ten of 215 pure SQCCs (4.7%; 95%CI, 2.3%-8.4%) harbored mutations, including 7 with PIK3CA, 1 each with AKT1, DDR2, and EGFR. No RET rearrangements were detected in SQCCs. SQCC-mGCs had a significantly higher rate of mutations in known oncogenic genes than that in pure SQCCs (27.4% vs. 4.7%, p<0.001). All KRAS mutations occurred in SQCC-mGCs.
Our results demonstrated that oncogenic mutations in EGFR, KRAS, BRAF, HER2 and ALK were extremely rare or absent in patients with pure SQCC, while SQCC-mGC had relatively high frequency of EGFR, ALK or KRAS mutations. Prospective identification of these known oncogenic mutations in SQCC-mGC before the initiation of treatment is an essential step to identify which patient could benefit from targeted therapies.
Lung Cancer has been the leading cause of cancer deaths in South Korea since the year 2000, and its incidence continues to rise. Here we report the result of national survey of lung cancer conducted by Korean association for the study of lung cancer (KASLC).
Patients with non-small-cell lung cancer (NSCLC) appear to gain particular benefit from treatment with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKI) if their disease tests positive for EGFR activating mutations. Recently, several large, controlled, phase III studies have been published in NSCLC patients with EGFR mutation-positive tumours. Given the increased patient dataset now available, a comprehensive literature search for EGFR TKIs or chemotherapy in EGFR mutation-positive NSCLC was undertaken to update the results of a previously published pooled analysis. Pooling eligible progression-free survival (PFS) data from 27 erlotinib studies (n = 731), 54 gefitinib studies (n = 1802) and 20 chemotherapy studies (n = 984) provided median PFS values for each treatment. The pooled median PFS was: 12.4 months (95% accuracy intervals [AI] 11.6–13.4) for erlotinib-treated patients; 9.4 months (95% AI 9.0–9.8) for gefitinib-treated patients; and 5.6 months (95% AI 5.3–6.0) for chemotherapy. Both erlotinib and gefitinib resulted in significantly longer PFS than chemotherapy (permutation testing; P = 0.000 and P = 0.000, respectively). Data on more recent TKIs (afatinib, dacomitinib and icotinib) were insufficient at this time-point to carry out a pooled PFS analysis on these compounds. The results of this updated pooled analysis suggest a substantial clear PFS benefit of treating patients with EGFR mutation-positive NSCLC with erlotinib or gefitinib compared with chemotherapy.
Several studies have suggested that epidermal growth factor receptor (EGFR) gene mutation, EGFR gene amplification, and some other biomarkers may be predictors of gefitinib sensitivity. We analyzed EGFR mutation and EGFR copy number in 22 gefitinib-treated non-small cell lung cancer (NSCLC) cases and their relation to the survival of patients. We also studied 143 gefitinib-naive Japanese NSCLC cases. The ErbB2 copy number was also studied in 59 gefitinib-naive NSCLC cases. In gefitinib-treated patients, the presence of EGFR mutation was associated with a higher response rate to gefitinib and a longer overall survival, but the increased EGFR gene copy number was not. In gefitinib-naive cases, EGFR mutation but not EGFR gene copy number was significantly correlated with gender, pathological subtypes, and smoking status. The ErbB2 copy number was not significantly correlated with the EGFR mutation or EGFR copy number in 59 cases. In conclusion, EGFR mutation was a better predictor of clinical outcome in gefitinib-treated patients than the EGFR gene copy number.
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used for non-small cell lung cancer patients with an EGFR gene mutation. However, skin disorders are known as adverse events. In the present study, we investigated whether EGFR-TK occupancy is useful as an index for assessing clinical efficacy and adverse events for the proper use and development of EGFR-TKIs. Average binding occupancies (Φss) of EGFR-TKIs, gefitinib and erlotinib, for the EGFR-TK of cancer or skin cells were calculated. The relationships of Φss with response rate (RR) or frequency of rash were analyzed using the ternary complex model. Then, the relationships between the dose of EGFR-TKIs and RR or frequency of rash were examined. Gefitinib showed a greater difference for Φss value for both wild-type and mutant EGFR as compared to erlotinib at usual dose. The RR increased in a nonlinear manner rapidly rising when Φss exceeded 95%. It was thought that a very high Φss value might be needed to obtain the therapeutic effect of EGFR-TKIs. Meanwhile, the frequency of rash increased in a linear manner along with elevation of Φss. It was shown that the Kd ratio (Kd for mutant/Kd for wild type) was less than 0.001, when the high RR and low frequency of rash were obtained simultaneously. The results showed that the therapeutic effects and skin disorder can be assessed by using Φss. Furthermore, it is likely that a proper choice of drug and dose can be made by using Φss in EGFR-TKI therapy.
Background:
Erlotinib has been approved for the management of NSCLC patients after failure of the first or subsequent line of chemotherapy. Although the efficacy of erlotinib is clearly associated with the presence of EGFR mutations, there is a subset of patients with EGFR wild-type (EGFRwt) tumors who impressively respond.
Patients and methods:
Patients with EGFRwt NSCLC who received salvage (≥2nd line) treatment with erlotinib for a prolonged period (>6 months), were sought from the database of the Hellenic Oncology Research Group. We retrospectively analyzed the clinical, pathological and molecular characteristics of the patients with available tumor material.
Results:
Forty-four patients that received erlotinib for >6 months (median 10.1 months) were enrolled in the study. The majority of them were male, never-smokers with adenocarcinoma histology and a good performance status. KRAS and PIK3CA mutations were detected in 21% (9/42 tested) and 13% (4/30 tested) of the patients, respectively. The ALK-EML4 translocation was found in 10% (2/20 tested); there was no patient with HER2 or BRAF mutated tumor. Twelve (54.5%) tumor specimens were considered positive for EGFR-overexpression. Eleven patients experienced a partial response (objective response rate 25%; 95% CI 12-38%) and the remaining 33 had stable disease. The median progression-free survival and overall survival were 10.1 (95% CI 8.6-11.6 months) and 24.1 (95% CI 11.2-37 months), respectively.
Conclusions:
Treatment with erlotinib significantly improves the clinical outcome in a subset of NSCLC patients with EGFRwt tumors. Further molecular analysis of such tumor specimens could provide a more comprehensive characterization of this particular group of patients. Nevertheless, the presence of other mutations should not prevent the treating physician from using erlotinib at later lines of salvage therapy for NSCLC patients.
Epidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinoma (ADC) but rare in squamous cell carcinoma (SQC). The efficacy of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) for SQC with EGFR mutations is unclear. The aim of this study was to evaluate the efficacy of EGFR-TKIs for these patients. We performed a retrospective matched-pair case-control study from 3 cancer centers, including 44 SQC and 44 ADC patients with EGFR mutation who were treated with EGFR-TKI. Subsequently, we performed a pooled analysis on the efficacy of EGFR-TKIs for EGFR-mutant SQC in 115 patients, including 71 patients selected from 25 published reports. In our multicenter study, EGFR-mutant SQC and ADC patients had similar objective response rate (ORR) (43.2% vs. 54.5%, p = 0.290), but SQC patients had lower disease control rate (DCR) (71.3% vs. 100%, p = 0.001), significant shorter median progression free survival (PFS) (5.1 vs. 13.0 months, p = 0.000) and median overall survival (OS) (17.2 vs. 23.6 months, p = 0.027). In pooled analysis, the ORR, DCR, PFS and OS of SQC patients were 39.1%, 71.3%, 5.6 months and 15.0 months, respectively. Performance status was the only independent predictor of PFS and erlotinib treatment was associated with a better survival. In conclusion, EGFR-TKI was less effective in EGFR-mutant SQC than in ADC but still has clinical benefit for SQC patients. Further study is need to evaluate the using of EGFR-TKIs in these SQC patients.
Purpose:
This pooled analysis aims to evaluate the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in lung squamous cell carcinoma with EGFR mutation.
Methods:
Advanced stage (IIIB/IV) lung squamous cell carcinoma patients with EGFR mutations treated with EGFR-TKIs were extracted from the publications searched from the databases of EMBASE, Medline (Ovid SP), Web of Science, Cochrane library, PubMed Publisher, ASCO meeting abstract and Google Scholar before August 2016, or identified from the database of Shanghai Chest Hospital from July 2014 to August 2016. Pooled objective response rate, disease control rate and median progression-free survival were accessed directly or by Kaplan-Meier method and combined in different studies by Comprehensive Meta Analysis software via one-group dichotomous or continuous analysis functions.
Results:
The combined objective response rate, disease control rate and median progression-free survival were 31.6% (95%CI, 24.1%~40.2%), 72.0% (95% CI, 63.5%~79.2%) and 3.08 months (95% CI, 2.31-3.84 months) in lung squamous cell carcinoma patients with EGFR mutation.
Conclusion:
The EGFR-TKIs had a modest response for EGFR mutated lung squamous cell carcinoma patients and might be a selective option for those patients.
A 45-year-old female nonsmoker presented to her primary care physician complaining of dry cough, pleuritic pain, and headache. Chest X-ray revealed an opacity in the left lower lobe of the lung. Chest CT scan showed a 3.7-cm mass in the left lower lobe and mediastinal adenopathy. Cranial MRI demonstrated a 6.5-cm mass in the occipital lobe, with additional smaller cerebellar lesions. A brain biopsy was performed, demonstrating metastatic adenocarcinoma with TTF-1 immunoreactivity, consistent with a primary tumor in the lung. The patient was treated with platinum–taxane based chemotherapy, with radiologic progression of disease. The patient was subsequently referred to a tertiary care center for therapeutic consultation.
Introduction: The importance of non-small cell lung cancer (NSCLC) histologic subtype has increased during the last few decades because of an unprecedented shift in epidemiology and an increasing number of target-specific chemotherapeutic agents. This review examined histology as a potential prognostic and/or predictive factor of clinical outcomes in advanced NSCLC. Methods: Literature searches of articles from 1982 to 2007 were conducted. We identified publications detailing phase II or III studies, retrospective analyses, and meta-analyses that reported a statistically significant prognostic or predictive role for histology. Results: Of 408 publications identified, II reported a prognostic association between histology and clinical outcomes, and 7 suggested that histologic subtype was predictive of outcomes in patients with advanced NSCLC treated with specific cytotoxic chemotherapy regimens. Fourteen publications reported histology was prognostic and/or predictive in patients treated with epidermal growth factor receptor inhibitors. Inadequate data collection, test methodology, or Study design-including insufficient sample size, misclassified samples, and grouping of histologic subtypes for analysis-may have obscured the interpretation of the role of histology in many of the Studies. Conclusions: Although differences in Study design and analyses make definitive Conclusions difficult, evidence suggests that histology may be prognostic or predictive of clinical efficacy outcomes. To determine which patients would benefit from specific treatments and to further understand the role of histology, future studies should focus on establishing a definitive histologic diagnosis, and should include an analysis of histologic subtypes and efficacy outcomes.
Background: We and other researchers have previously reported that pulmonary adenocarcinomas with epidermal growth factor receptor (EGFR) mutations are usually sensitive to gefitinib, an EGFR-specific tyrosine kinase inhibitor, although this relationship is not complete. In this study, we searched for mutations or changes in the expression of genes downstream to EGFR and evaluated their relationship with the effectiveness of gefitinib. Methods: We studied 78 lung cancer patients who had recurrent disease after surgical resection and were treated with gefitinib. We searched for mutations occurring in the KRAS and PIK3CA gene. We also evaluated the expression level of EGFR, PIK3CA, and PTEN by real-time reverse transcriptase polymerase chain reaction. Gefitinib effectiveness was evaluated by imaging studies; a survival analysis was also done. Results: We found seven (9%) somatic mutations in KRAS and two (2%) in PIK3CA. EGFR mutations were present in 44 (56%). KRAS mutations were found only in tumors without EGFR mutations, whereas PIK3CA mutation was found in tumors with EGFR mutation. Tumor response was assessable in 52 tumors. None of the six tumors with KRAS mutations responded to gefitinib treatment; however, two tumors with PIK3CA mutations showed partial response. Survival was significantly longer in patients with EGFR mutations or in those without KRAS mutations. In tumors with EGFR mutations, survival was longer in those with high PIK3CA or PTEN expression than in those with low expression of these molecules. Conclusions: An evaluation of the KRAS mutation, as well as PIK3CA and PTEN expression, might help identify lung cancer patients who are most suitable for gefitinib treatment.
Objective
To establish evidence-based recommendations for the molecular analysis of lung cancers that are that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed.
Participants
Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies.
Evidence
Three unbiased literature searches of electronic databases were performed to capture articles published published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation.
Consensus Process
Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4).
Conclusions
The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines.
Background: Erlotinib (Tarceva, OSI Pharmaceuticals, Melville, NY) is an oral, epidermal growth factor receptor tyrosine kinase inhibitor that has antitumor activity and good tolerability in non-small cell lung cancer (NSCLC). In particular, higher response rates have been reported in Asian patients than in Western patients. The aim of this study conducted by the Korean Cancer Study Group was to evaluate the efficacy and tolerability of erlotinib monotherapy as a palliative treatment for advanced NSCLC patients in Korea. Patients and Methods: Patients with histologically or cytologically confirmed stage IIIB or IV NSCLC including recurrent or metastatic disease, with performance status from 0 to 3, were eligible either if they had received any anticancer treatment except epidermal growth factor receptor inhibitors or if they were unsuitable for chemotherapy because of poor performance status. Enrolled patients were treated with oral erlotinib at a dose of 150 mg daily until disease progression or development of intolerable toxicity. Results: A total of 120 patients were enrolled between January 2005 and May 2006. Forty-four patients (36.7%) were female and 72 patients were current or former smoker. Fifty percent of patients had received one prior palliative chemotherapy regimens and 34.2% had two or more prior palliative regimens. The overall tumor response rate was 24.2% (95% confidence interval [CI], 16.8-32.8%) with 4 complete responses and 25 partial responses, and the disease control rate was 56.7%. The favorable clinical variables for tumor response were female (P = 0.001), never smokers (P = 0.041), and adenocarcinoma (P = 0.001). The most common adverse event was skin rash (78% of which grade 3 or 4 skin rash occurred in 13.3% of the patients). With a median follow-up of 23.6 months, the median time to progression was 2.7 months (95% Cl, 2.2-3.2), and the median overall survival was 12.9 months (95% Cl, 6.9-18.8). By multivariate analysis, female and development of skin rash were significantly associated with longer time to progression and overall survival. Conclusion: Erlotinib monotherapy showed significant antitumor activity and an acceptable tolerability profile as a palliative treatment in advanced NSCLC patients in Korea, especially in females, never smokers, and patients with adenocarcinoma histology.
Advances in the understanding of non-small-cell lung cancer biology have led to the clinical development of biological therapies targeting molecular mechanisms underlying cancer growth and survival of this disease. In some cases, such strategies have significantly improved the outcome of advanced non-small-cell lung cancer in combination with platinum-based chemotherapy, as for the monoclonal antibodies cetuximab and bevacizumab directed against the EGF receptor and VEGF, respectively. In others, they have found a place in therapy in the management of pretreated patients, as for the EGF receptor tyrosine kinase inhibitors gefitnib and erlotinib. Importantly, the recognition that certain clinical or biological characteristics predict for increased sensitivity to treatment has highlighted the importance of patient selection when designing clinical trials with these agents. This review is structured in order to summarize the targeted therapies currently used for advanced non-small-cell lung cancer. In the latter part, biological agents under investigation are discussed.
L’incidence du cancer pulmonaire est incontestablement corrélée au tabagisme, qui est le facteur de risque principal de cette pathologie. Il est estimé que près de 85 % des cas sont dus à l’inhalation de la fumée de tabac, qui contient près de 80 composants potentiellement carcinogènes. Le tabac est responsable actuellement en France de plus de 1 décès sur 9 (1 décès sur 5 chez les hommes et 1 décès sur 35 chez les femmes). Cependant, un nombre important de cancers pulmonaires apparaît non lié au tabagisme. Dans le cadre de ce chapitre, nous allons nous focaliser sur cette entité particulière que constitue le cancer pulmonaire chez le non-fumeur notamment sur le plan épidémiologique, clinique, moléculaire et sur les implications thérapeutiques.
Objective To establish evidence-based recommendations for the molecular analysis of lung cancers that are that are required to guide EGFR - and ALK -directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. Participants Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies. Evidence Three unbiased literature searches of electronic databases were performed to capture articles published published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation. Consensus Process Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4). Conclusions The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines.
In this chapter we provide a survey of the state of the art in cancer biomarkers. The different roles and uses of biomarkers are introduced. Several examples are provided of biomarkers that are now used in the clinical routine, with a particular emphasis on breast cancer. Furthermore, several promising new areas for research and application are highlighted.
The challenges and difficulties involved with the development of fundamental discoveries into useful clinical biomarkers are discussed; and we describe some of the current international initiatives and guidelines that have been attempting to assist this process. We present bioinformatics, system analyses and system modelling approaches, and discuss their application and relevance for biomarker effective discovery and prioritisation.
Finally, we emphasize the need for large-scale harmonization, standardization and integration of multi-level data to ensure that the potential offered by the current unprecedented availability of data and information is fully exploited, so as to develop validated and useful biomarkers.
Anticancer cytotoxic agents go through a process by which their antitumor activity—on the basis of the amount of tumor shrinkage they could generate—has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.
We conducted a randomized study to determine whether any of three chemotherapy regimens was superior to cisplatin and paclitaxel in patients with advanced non-small-cell lung cancer.
A total of 1207 patients with advanced non-small-cell lung cancer were randomly assigned to a reference regimen of cisplatin and paclitaxel or to one of three experimental regimens: cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel.
The response rate for all 1155 eligible patients was 19 percent, with a median survival of 7.9 months (95 percent confidence interval, 7.3 to 8.5), a 1-year survival rate of 33 percent (95 percent confidence interval, 30 to 36 percent), and a 2-year survival rate of 11 percent (95 percent confidence interval, 8 to 12 percent). The response rate and survival did not differ significantly between patients assigned to receive cisplatin and paclitaxel and those assigned to receive any of the three experimental regimens. Treatment with cisplatin and gemcitabine was associated with a significantly longer time to the progression of disease than was treatment with cisplatin and paclitaxel but was more likely to cause grade 3, 4, or 5 renal toxicity (in 9 percent of patients, vs. 3 percent of those treated with cisplatin plus paclitaxel). Patients with a performance status of 2 had a significantly lower rate of survival than did those with a performance status of 0 or 1.
None of four chemotherapy regimens offered a significant advantage over the others in the treatment of advanced non-small-cell lung cancer.
The epidermal growth factor receptor (EGFR) is a promising target for anticancer therapy because of its role in tumor growth, metastasis and angiogenesis, and tumor resistance to chemotherapy and radiotherapy. We have developed a low-molecular-weight EGFR tyrosine kinase inhibitor (EGFR-TKI), ZD1839 (Iressa(2) ). ZD1839, a substituted anilinoquinazoline, is a potent EGFR-TKI (IC(50) = 0.033 micro M) that selectively inhibits EGF-stimulated tumor cell growth (IC(50) = 0.054 micro M) and that blocks EGF-stimulated EGFR autophosphorylation in tumor cells. In studies with mice bearing a range of human tumor-derived xenografts, ZD1839 given p.o. once a day inhibited tumor growth in a dose-dependent manner. The level of expression of EGFR did not determine xenograft tumor sensitivity to ZD1839. Long-term ZD1839 (>3 months) treatment of mice bearing A431 xenografts was well tolerated, and ZD1839 completely inhibited tumor growth and induced regression of established tumors. No drug-resistant tumors appeared during ZD1839 treatment, but some tumors regrew after drug withdrawal. These studies indicate the potential utility of ZD1839 in the treatment of many human tumors and indicate that continuous once-a-day p.o. dosing might be a suitable therapeutic regimen.
No chemotherapy regimen, including the widely used combination of gemcitabine/cisplatin, confers significantly improved survival over any other in metastatic non-small cell lung cancer (NSCLC); however, the selection of patients according to key genetic characteristics can help to tailor chemotherapy. Ribonucleotide reductase subunit M1 (RRM1) is involved in DNA synthesis and repair and in gemcitabine metabolism, and the excision repair cross-complementing group 1 (ERCC1) gene has been related to cisplatin activity.
Patients were part of a large randomized trial carried out from September 1998 to July 2000, comparing gemcitabine/cisplatin versus gemcitabine/cisplatin/vinorelbine versus gemcitabine/vinorelbine followed by vinorelbine/ifosfamide. We analyzed RRM1 and ERCC1 mRNA expression in paraffin-embedded samples obtained from bronchoscopy by real-time quantitative reverse transcription-PCR. Results were correlated with survival using the Kaplan-Meier method.
A total of 100 patients were assessed. There was a strong correlation between RRM1 and ERCC1 mRNA expression levels (Spearman r = 0.410; P < 0.001). In the gemcitabine/cisplatin arm, patients with low RRM1 mRNA expression levels had significantly longer median survival than those with high levels [13.7 versus 3.6 months; 95% confidence interval (CI), 9.6-17.8 months; P = 0.009]. Median survival was also significantly longer among patients with low mRNA expression levels of both RRM1 and ERCC1 (not reached), than among those with high levels of both genes (6.8 months; 95% CI, 2.6-11.1 months; P = 0.016).
RRM1 mRNA expression is a crucial predictive marker of survival in gemcitabine/cisplatin-treated patients. Genetic testing of RRM1 mRNA expression levels can and should be used to personalize chemotherapy.
On May 5, 2003, gefitinib (Iressa; ZD1839) 250-mg tablets (AstraZeneca Inc.) received accelerated approval by the United States Food and Drug Administration as monotherapy for patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Information provided in this summary includes chemistry manufacturing and controls, clinical pharmacology, and clinical trial efficacy and safety results. Gefitinib is an anilinoquinazoline compound with the chemical name 4-quinazolinamine,N-(3-chloro-4-flurophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]. It has the molecular formula C(22)H(24)ClFN(4)O(3). Gefitinib is often referred to as a "specific" or "selective" inhibitor of epidermal growth factor receptor. Studies demonstrate, however, that gefitinib inhibits the activity of other intracellular transmembrane tyrosine-specific protein kinases at concentrations similar to those at which it inhibits the epidermal growth factor signal. Maximum plasma concentrations resulting from clinically relevant doses are 0.5-1 microM or more, well within the IC(50) values of several tyrosine kinases. No clinical studies have been performed that demonstrate a correlation between epidermal growth factor receptor expression and response to gefitinib. Gefitinib is 60% available after oral administration and is widely distributed throughout the body. Gefitinib is extensively metabolized in the liver by cytochrome P450 3A4 enzyme. Over a 10-day period, approximately 86% of an orally administered radioactive dose is recovered in the feces, with <4% of the dose in the urine. After daily oral administration, steady-state plasma levels are reached in 10 days and are 2-fold higher than those achieved after single doses. Gefitinib effectiveness was demonstrated in a randomized, double-blind, Phase II, multicenter trial comparing two oral doses of gefitinib (250 versus 500 mg/day). A total of 216 patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving 250 mg/day gefitinib and in 8% (6 of 76) of patients receiving 500 mg/day gefitinib. The overall objective response rate (RR) for both doses combined was 10.6% (15 of 142 patients; 95% confidence interval, 6.0-16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range, 4.6-18.6+ months). Other submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV non-small cell lung cancer patients. Patients were randomized to receive gefitinib (250 or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin (n = 1093) or carboplatin plus paclitaxel (n = 1037). Results from this study showed no benefit (RR, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Interstitial lung disease has been observed in patients receiving gefitinib. Worldwide, the incidence of interstitial lung disease was about 1% (2% in the Japanese post-marketing experience and about 0.3% in a United States expanded access program). Approximately one-third of the cases have been fatal. Gefitinib was approved under accelerated approval regulations on the basis of a surrogate end point, RR. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in disease-related symptoms or increased survival. Accelerated approval regulations require the sponsor to conduct additional studies to verify that gefitinib therapy produces such benefit.
We describe 16 months' single-institution experience with gefitinib ("Iressa", ZD1839) used as "ultimum refugium" for pretreated non-small-cell lung cancer (NSCLC) patients.
Toxicity, response and survival data of NSCLC patients participating in a compassionate-use program with gefitinib were reviewed. Documented disease progression and confirmation of the absence of other treatment options were requested. Oral gefitinib at a dose of 250 mg/day was given until disease progression, unacceptable toxicity or death. Cox's proportional hazards model was used to analyze relationships between factors and probability of survival.
Rapid disease precluded treatment in eight cases. Of 92 evaluable patients, one-third had a baseline performance status (PS) of > or =2. The main side-effects of gefitinib were grade 1-2 diarrhea and skin rash. A disease control rate of 46% (objective response rate 8.7%) and 1-year survival of 29% were documented. Histology (adenocarcinoma) and a "never-smoking" history were predictive of response. Number of previous chemotherapy regimens, gender, time since diagnosis and time since last chemotherapy lacked such an association. Radiotherapy during gefitinib treatment was well tolerated and was associated with prolonged survival in a patient with multiple brain metastases. Multivariate analyses revealed a significant impact of PS on survival. A "never-smoking" history, adenocarcinoma/bronchoalveolar-cell carcinoma and female gender showed a trend towards better survival outcomes.
Gefitinib's single-agent activity in a group consisting of pretreated NSCLC patients is confirmed. Side-effects of gefitinib were mild. Prolonged survival was associated with good PS and less significantly with a never-smoking history, female gender and histology. Additional studies on mechanisms of tumor control and selection of target populations for this remarkable new drug are warranted.
Receptor tyrosine kinase genes were sequenced in non–small cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations
of the epidermal growth factor receptor gene EGFR were found in 15of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor
gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung
adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinib-insensitive tumors
or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib.
Gefitinib ('Iressa', ZD1839) is an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has demonstrated antitumour activity and favourable tolerability in Phase II studies. We investigated whether EGFR expression levels could predict for response to gefitinib in patients with advanced non-small-cell lung cancer (NSCLC), who received gefitinib (250 mg day(-1)) as part of a worldwide compassionate-use programme. Tissue samples were analysed by immunohistochemistry to assess membrane EGFR immunoreactivity. Of 147 patients enrolled in our institution, 50 patients were evaluable for assessment of both clinical response and EGFR expression. The objective tumour response rate was 10% and disease control was achieved in 50% of patients. Although high EGFR expression was more common in squamous-cell carcinomas than adenocarcinomas, all objective responses were observed in patients with adenocarcinoma. Response and disease control with gefitinib were not associated with high EGFR expression. Overall, median survival was 4 months, and the 1-year survival rate was 18%. Strong EGFR staining correlated with shorter survival time for all patients. Gefitinib demonstrated promising clinical activity in this group of patients with NSCLC. These results have also shown that EGFR expression is not a significant predictive factor for response to gefitinib.
More persons in the United States die from non-small cell lung cancer (NSCLC) than from breast, colorectal, and prostate cancer combined. In preclinical testing, oral gefitinib inhibited the growth of NSCLC tumors that express the epidermal growth factor receptor (EGFR), a mediator of cell signaling, and phase 1 trials have demonstrated that a fraction of patients with NSCLC progressing after chemotherapy experience both a decrease in lung cancer symptoms and radiographic tumor shrinkages with gefitinib.
To assess differences in symptomatic and radiographic response among patients with NSCLC receiving 250-mg and 500-mg daily doses of gefitinib.
Double-blind, randomized phase 2 trial conducted from November 2000 to April 2001 in 30 US academic and community oncology centers. Patients (N = 221) had either stage IIIB or IV NSCLC for which they had received at least 2 chemotherapy regimens.
Daily oral gefitinib, either 500 mg (administered as two 250-mg gefitinib tablets) or 250 mg (administered as one 250-mg gefitinib tablet and 1 matching placebo).
Improvement of NSCLC symptoms (2-point or greater increase in score on the summed lung cancer subscale of the Functional Assessment of Cancer Therapy-Lung [FACT-L] instrument) and tumor regression (>50% decrease in lesion size on imaging studies).
Of 221 patients enrolled, 216 received gefitinib as randomized. Symptoms of NSCLC improved in 43% (95% confidence interval [CI], 33%-53%) of patients receiving 250 mg of gefitinib and in 35% (95% CI, 26%-45%) of patients receiving 500 mg. These benefits were observed within 3 weeks in 75% of patients. Partial radiographic responses occurred in 12% (95% CI, 6%-20%) of individuals receiving 250 mg of gefitinib and in 9% (95% CI, 4%-16%) of those receiving 500 mg. Symptoms improved in 96% of patients with partial radiographic responses. The overall survival at 1 year was 25%. There were no significant differences between the 250-mg and 500-mg doses in rates of symptom improvement (P =.26), radiographic tumor regression (P =.51), and projected 1-year survival (P =.54). The 500-mg dose was associated more frequently with transient acne-like rash (P =.04) and diarrhea (P =.006).
Gefitinib, a well-tolerated oral EGFR-tyrosine kinase inhibitor, improved disease-related symptoms and induced radiographic tumor regressions in patients with NSCLC persisting after chemotherapy.
In situ hybridization was performed to detect rat Pneumocystis carinii in the lung sections. Rats were immunosuppressed by weekly subcutaneous injection of 10 mg/kg methylprednisolone. On the 6th, 8th and 9th week of immunosuppression, the lungs were removed and fixed in 10% neutral formalin. A 22 base oligonucleotide probe complementary to P. carinii 5S ribosomal RNA was commercially synthesized and its 3' terminal was labeled with biotin. In situ hybridization was performed utilizing manual capillary action technology on the Microprobe system. P. carinii were detected along the luminal surface of alveolar pneumocytes, in exudate of alveolar cavities, and also in secretory material of bronchioles. In the 6th week group, positive reaction was observed focally in the peripheral region of the lung sections, but the reaction was observed diffusely in the 8th or 9th week groups. In comparison with Grocott's methenamine silver stain, in situ hybridization technique can detect the organism rapidly, and can detect trophic forms very well. Furthermore, no nonspecific reaction with other pathogenic fungi and protozoa was recognized. Therefore, in situ hybridization can be a good technique to detect P. carinii in the lungs of infected rats.
Proto oncogenes represent a family of genes which when activated have been shown to play a role in the pathogenesis of a number of malignancies in vertebrate species including humans.1,2 In physiologic states these same genes are known to play a role in the normal cell growth control and differentiation. The HER2/neu gene is a member of the Type I receptor tyrosine kinase (RTK) group which is one of the subfamilies in the proto oncogene family and encodes a 185kD surface membrane receptor protein. This gene has been localized to chromosome 17q21,1 and the encoded protein is expressed in a wide variety of tissues including the skin, oral mucera, breast, ovary, endometrium, lung, liver, pancreas, small and large bowel, kidney, bladder and the central nervous system as well as some connective tissues.4–5 The exact physiological role of the HER2/neu protein in these tissues is not completely understood, but like other proto oncogenes it is believed to play an important signaling role in cellular proliferation and differentiation processes. Current data suggests that it forms hetero-dimers with other members of the RTKI family (such as HER 1, HER3 and HER4 in response to various ligands known as heregulins.6–8 Activation of HER2/neu results in an increase its kinase activity which in turn initiates signal transduction resulting in either cellular proliferation and/or differentiation, depending on the ligand as well as the conditions.9–14 In human breast cancers, a non-inherited alteration occurs in this gene in 25–30% of cases.
Increasing knowledge of the structure and function of the epidermal growth factor receptor (EGFR) subfamily of tyrosine kinases and of their role in the initiation and progression of various cancers has, in recent years, provided the impetus for a substantial research effort aimed at developing new anticancer therapies that target specific components of the EGFR signal transduction pathway. Selective compounds have been developed that target either the extracellular ligand-binding region of the EGFR or the intracellular tyrosine kinase region, resulting in interference with the signalling pathways that modulate mitogenic and other cancer-promoting responses (e.g. cell motility, cell adhesion, invasion and angiogenesis). Potential new anticancer agents that target the extracellular ligand-binding region of the receptor include a number of monoclonal antibodies, immunotoxins and ligand-binding cytotoxic agents. Agents that target the intracellular tyrosine kinase region include small molecule tyrosine kinase inhibitors (TKIs), which act by interfering with ATP binding to the receptor, and various other compounds that act at substrate-binding regions or downstream components of the signalling pathway. Currently, the most advanced of the newer therapies undergoing clinical development are antireceptor monoclonal antibodies (e.g. trastuzumab and cetuximab) and a number of small molecule EGFR-TKIs principally of the quinazoline and pyrazolo-pyrrolo-pyridopyrimidine inhibitor structural classes. The latter group of compounds offers several advantages in cancer chemotherapy, including the possibility of inhibiting specific deregulated pathways in cancer cells while having minimal effects on normal cell function. They also have favourable pharmacokinetic and pharmacodynamic properties and low toxicity, and some TKIs such as the reversible inhibitor ZD1839 ('Iressa') are now undergoing phase II to III clinical trials. In addition, the accumulation of evidence from laboratory studies strongly suggests that EGFR-selective TKIs will have synergistic effects with other antitumour agents or therapy such as cytostatic agents, conventional cytotoxic drugs and radiotherapy. As our knowledge of signal transduction pathways in cancer increases, it is hoped that further advances in this area will allow the therapeutic potential of these compounds as anticancer agents to be realised.
Non-small cell lung cancer (NSCLC) is a systemic illness. The majority of newly diagnosed patients depend on systemic chemotherapy to improve outcome. Among the new chemotherapeutic agents recently tested, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has shown convincing single-agent activity in advanced NSCLC. The two initial phase II studies using paclitaxel alone showed a 1-year survival rate of 40%, comparable to that seen with combination regimens. Paclitaxel/carboplatin is one of several standard regimens for patients with stage IIIB to IV disease. It is as effective as any other new agent/platinum combination studied to date; it is easy to administer and well tolerated. Identification of the molecular and genetic events involved in each step of tumor progression seems to be crucial both to understanding lung cancer and for the development of new pharmacologic compounds that target specific cellular processes affecting growth and proliferation. An innovative strategy is to combine established chemotherapy with these new compounds. Resistance to available chemotherapy drugs is the major obstacle to effective chemotherapy. Genetic abnormalities could play a role in outlining some patterns of chemoresistance. Acquired resistance to paclitaxel can be mediated by several mechanisms, including overexpression of p-glycoprotein, altered expression of beta-tubulin isotypes, intrinsic or acquired mutations in beta-tubulin, and expression of novel genes. Beta-tubulin mutations were recently identified in 33% of 49 NSCLC patients, none of whom had an objective response to paclitaxel treatment. Cisplatin resistance is associated with several molecular alterations, including overexpression of metallothionein and the mRNA level of the excision repair cross-complementing (ERCC1) gene. Early detection of circulating cancer cells in peripheral blood would enable more accurate lung cancer staging. Furthermore, sequential measurements of DNA concentration may be used to monitor the effects of therapy. Serum DNA can be used as a surrogate for detecting genetic abnormalities and as a potential guide for customizing treatment. We analyzed the presence of beta-tubulin mutations in serum DNA from NSCLC patients and from healthy individuals. Beta-tubulin mutations were detected in 42% of the 131 patients and in none of the control group. Several clinical studies are proposed to develop more customized approaches in lung cancer.
Overexpression of the excision repair cross-complementing 1 (ERCC1) gene, which is crucial in the repair of cisplatin (CDDP)-DNA adducts, is reported to negatively influence the effectiveness of CDDP-based therapy for gastric and ovarian cancers. Recent evidence indicates that Gemcitabine (Gem) may modulate ERCC1 nucleotide excision repair activity, and down-regulation of DNA repair activity by ERCC1 antisense RNA reportedly inhibits synergism of CDDP/Gem. We investigated whether ERCC1 mRNA expression levels were associated with clinical outcomes after treatment with a combination Gem/CDDP regimen for patients with advanced stage non-small cell lung cancer (NSCLC).
Response and survival were correlated with the level of ERCC1 expression in 56 patients with advanced (stage IIIb or IV) NSCLC treated as part of a multicenter randomized trial with Gem 1250 mg/m(2) days 1 and 8 plus CDDP 100 mg/m(2) on day 1 every 3 weeks. mRNA was isolated from paraffin-embedded pretreatment primary tumor specimens, and relative expression levels of ERCC1/beta-actin were measured using a quantitative reverse transcription-PCR (Taqman) system.
ERCC1 expression was detectable in all tumors. There were no significant differences in ERCC1 levels by gender, age, performance status, weight loss, or tumor stage. The overall response rate was 44.7%. There were no significant associations between ERCC1 expression and response. Median overall survival was significantly longer in patients with low ERCC1 expression tumors (61.6 weeks; 95% confidence interval, 42.4-80.7 weeks) compared to patients with high expression tumors (20.4 weeks, 95% confidence interval, 6.9-33.9 weeks). ERCC1 expression, Eastern Cooperative Oncology Group performance status, and presence of weight loss were significant prognostic factors for survival in a Cox proportional hazards multivariable analysis.
These data suggest that ERCC1 expression is a predictive factor for survival after CDDP/Gem therapy in advanced NSCLC. Although there was a trend toward decreased response with high ERCC1 mRNA levels, this difference failed to reach statistical significance. This result may reflect the impact of Gem and the requirement for ERCC1 expression for CDDP/Gem synergism or may be attributable to the relatively small patient sample size in this study. Prospective studies of ERCC1 as a predictive marker for activity of CDDP-based regimens in NSCLC are warranted.
Gefitinib is an oral selective inhibitor of the epidermal growth factor receptor tyrosine kinase that is an effective treatment for patients with advanced non-small cell lung cancer who do not respond to platinum-based chemotherapy. We assessed four patients who had non-small cell lung cancer causing severe acute interstitial pneumonia in association with gefitinib. Although two patients recovered after treatment with steroids, the other two died from progressive respiratory dysfunction. On the basis of autopsies and bilateral distribution of diffuse ground-glass opacities in chest CTs, we diagnosed diffuse alveolar damage, which was consistent with acute interstitial pneumonia. Patients with interstitial pneumonia also had other pulmonary disorders such as previous thoracic irradiation and poor performance status. Physicians should be aware of the alveolar damage induced by gefitinib, especially for patients with these characteristic features.
To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non-small-cell lung cancer (NSCLC).
This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomly assigned to receive either 250-mg or 500-mg oral doses of gefitinib once daily.
Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively.
Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC [corrected]
The epidermal growth factor receptor (EGFR) is an important novel target for anticancer therapy. In this study, we examined the molecular mechanisms that underlie the antitumor effects of the anti-EGFR monoclonal antibody C225 (Cetuximab) and the selective EGFR tyrosine kinase inhibitor ZD1839 (Iressa; AstraZeneca) in non-small cell lung cancer (NSCLC) cell lines. Cell growth, assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, was inhibited at low concentrations of ZD1839 and C225 in control A431 cells, whereas the NSCLC cell lines were comparatively more resistant. In A431 cells, but not in the NSCLC cells, ZD1839 treatment resulted in a modest increase in DNA fragmentation, the externalization of phosphatidyl serine, and the activation of caspase-3, known markers of apoptotic cell death. However, poly(ADP-ribose) polymerase cleavage was not detected, and caspase inhibition by carbobenzoxy-Val-Ala-Asp-fluoromethyl ketone partially reduced ZD1839-generated DNA fragmentation. Overexpression of the antiapoptotic protein Bcl-2 in A431 cells suppressed the cytotoxicity upon anti-EGFR treatment. These results thus demonstrate that the toxic effect of ZD1839 in A431 cells is caused by a form of cell death that involves a mitochondrial step and is, at least in part, dependent on caspase activation. EGFR expression levels showed no significant correlation with sensitivity to ZD1839 and C225. Evaluation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase and phosphatidylinositol 3'-kinase/Akt pathways showed considerable inhibition of these pathways by ZD1839 and C225 in A431 cells, whereas one or both of these pathways remained active upon anti-EGFR treatment in NSCLC cells. In addition, treatment with specific inhibitors of mitogen-activated protein kinase kinase or phosphatidylinositol 3'-kinase resulted in a smaller effect on proliferation than simultaneous treatment with both inhibitors, whereas induction of apoptosis was observed only when both pathways were blocked. Together, these data suggest that persistent activity of either of these signaling pathways is involved in the lack of sensitivity of NSCLC cell lines to EGFR inhibitors.
To investigate the anti-tumor activity and toxicity of the epidermal growth factor receptor (EGFR) inhibitor gefitinib (ZD1839 or Iressa; AstraZeneca Pharmaceuticals, Wilmington, DE), in patients with advanced non-small cell lung cancer (NSCLC).
This was an open label, expanded access program (EAP) of oral gefitinib administered at 250 mg per day continuously until evidence of undue toxicity or disease progression.
Two hundred consecutive patients with advanced NSCLC were enrolled in this study. The median number of prior chemotherapy regimens was 2 (range 0-6). One hundred seventy-two patients were treated with gefitinib; 23 expired from disease progression prior to treatment and 5 withdrew their consent. One hundred fifty-four patients are evaluable for toxicity; 8 (5.2%) experienced grade 3/4 toxicity; 2 patients discontinued therapy for grade 3 rash and one for grade 3 nausea. Of 172 patients evaluable for efficacy, 7 (4.1%; 95% CI; 1.7-8.2%) experienced a partial response (PR); 60 patients (34.9%) had stable disease (SD) as their best response. Median survival for all patients was 4.5 months (95% CI; 4.1-4.9 months). One-year survival was 29%. Significant independent prognostic factors associated with improved survival were female gender, good performance status (0/1), and adenocarcinoma histology.
Gefitinib has anti-tumor activity, in a heterogeneous population of NSCLC patients treated on the EAP study. Treatment with gefitinib in this population is associated with a longer survival in women, those with good performance status and in patients with adenocarcinomas. These findings need to be further validated in additional clinical studies.
Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown.
We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells.
Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib.
A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib.
ERCC1 (excision repair cross-complementation group 1) and XPD (ERCC2, excision repair cross-complementation group 2) as genes have been known to be belonged to the nucleotide excision repair pathway and therefore related to DNA repair. Polymorphisms in these genes have been rarely evaluated in terms of predicting cancer patient survival. We investigated whether these polymorphisms have an effect on response to chemotherapy and survival in 109 patients with non-small-cell lung cancer treated with cisplatin combination chemotherapy. Polymorphisms of ERCC1 Asn118Asn (C --> T), XPD Lys751Gln (A --> C) and Asp312Asn (G --> A) were evaluated using a SNaPshot kit. As for chemotherapy response, treatment response did not show statistically significant differences between the wild genotypes and the variant genotypes for the ERCC1 and XPD gene. The median survival time of all patients was 376 days (95% CI, 291-488). As for survival rate according to the polymorphism of codon 118 in ERCC1, median survival time in patients showing C/C genotype was 486 days (95% CI, 333-x), which was significantly different from the 281 days (95% CI, 214-376) of patients with the variant genotype (T/T or C/T) (P = 0.0058). Using the Cox-proportional hazards model, the polymorphism of codon 118 in ERCC1, response to chemotherapy, weight loss and performance status effected overall survival significantly (P = 0.0001, 0.0001, 0.0028 and 0.0184, respectively). However, polymorphisms of codons 751 and 312 in the XPD gene did not affect patient survival (P = 0.4711 and 0.4542, respectively). Therefore, we suggest that the C/C genotype in codon 118 of ERCC1 is a surrogate marker for predicting better survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy.
A high incidence of interstitial lung disease (ILD) has been reported in patients with non-small cell lung cancer (NSCLC) treated with gefitinib in Japan. We retrospectively analyzed 112 patients with advanced NSCLC who received gefitinib monotherapy. Univariate and multivariate analyses were used to identify risk factors for gefitinib-related ILD and predictive factors for tumor response to gefitinib. The incidence of ILD was 5.4%, and it was higher in the patients with pre-existing pulmonary fibrosis (33% versus 2%; P < 0.001). The results of a multivariate analysis showed that pulmonary fibrosis was a significant risk factor for ILD (odds ratio: 177, 95% confidence interval: 4.53-6927, P = 0.006). The response rate was 33% in the 98 evaluable patients and higher in women (53% versus 23%; P = 0.003), patients with adenocarcinoma (38% versus 6%; P = 0.010), never-smokers (63% versus 18%; P < 0.001), and the patients with no history of thoracic radiotherapy (39% versus 13%; P = 0.015). The results of a multivariate analysis showed that the predictors of tumor response were "no history of smoking" and "no history of thoracic radiotherapy". Never-smokers had a significantly longer survival time than smokers (P = 0.007). Although gefitinib therapy confers a clinical benefit on patients with advanced NSCLC, especially on women, patients with adenocarcinoma, never-smokers, and patients with no history of thoracic radiotherapy, it also poses a high risk of ILD, especially to patients with pulmonary fibrosis. The risk-benefit ratio must be carefully considered.
We describe the case of a 69-year-old woman with advanced adenocarcinoma of the lung, in whom interstitial pneumonia was induced by gefitinib. The shadow was not clear on chest radiography, but diffuse ground-glass opacity was detected on high-resolution CT. Two treatments with pulse corticosteroids improved the lung injury temporarily. However, it became worse on reduction of the steroids. The improvement and deterioration of the pneumonia had been followed in detail by 8 examinations by high-resolution CT. The ground-glass opacity seen in the CT did not completely disappear or progress rapidly under steroid therapy. The patient died 46 days after the onset of the pneumonia. Autopsy disclosed marked cancerous invasion of the lung, and diffuse alveolar damage was also recognized in parts. The cause of death was considered to be respiratory failure due mainly to cancer progression and additionally to diffuse alveolar damage induced by gefitinib.
A worldwide compassionate-use program has enabled >42,000 patients with advanced non-small cell lung cancer (NSCLC) to receive gefitinib treatment. Here we report the outcome of gefitinib therapy in patients who enrolled in the "Iressa" Expanded Access Program at the Samsung Medical Center.
Patients with advanced or metastatic NSCLC who had progressed after prior systemic chemotherapy and for whom no other treatment option was available were eligible to receive gefitinib treatment as part of the Expanded Access Program. A post hoc assessment of potential prognostic factors for response and survival was performed by multivariate analysis.
All 111 evaluable patients had stage IV disease; most patients had a baseline performance status of 2 [n = 52 (47%)] or 3 [n = 18 (16%)] and had received >/=2 prior chemotherapy regimens (56%). The objective response rate was 26%, the disease control rate (measured over >/=8 weeks) was 40%, and the 1-year survival rate was 44%. Adenocarcinoma histology was associated with better response and disease control rates, and a performance status of 0-2 was also associated with a better disease control rate. Both of these factors, as well as female gender, were significantly associated with longer survival. Gefitinib was well tolerated; the most common adverse event was grade 1 skin rash.
Gefitinib demonstrated significant antitumor activity and a favorable tolerability profile in this series of NSCLC patients with poor prognosis.
Gefitinib (Iressa, Astra Zeneca Pharmaceuticals) is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor
(EGFR) and induces dramatic clinical responses in nonsmall cell lung cancers (NSCLCs) with activating mutations within the
EGFR kinase domain. We report that these mutant EGFRs selectively activate Akt and signal transduction and activator of transcription
(STAT) signaling pathways, which promote cell survival, but have no effect on extracellular signal–regulated kinase signaling,
which induces proliferation. NSCLC cells expressing mutant EGFRs underwent extensive apoptosis after small interfering RNA–mediated
knockdown of the mutant EGFR or treatment with pharmacological inhibitors of Akt and STAT signaling and were relatively resistant to apoptosis induced
by conventional chemotherapeutic drugs. Thus, mutant EGFRs selectively transduce survival signals on which NSCLCs become dependent;
inhibition of those signals by gefitinib may contribute to the drug's efficacy.
Preclinical studies indicate that gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE), an orally active epidermal growth factor receptor tyrosine kinase inhibitor, may enhance antitumor efficacy of cytotoxics, and combination with paclitaxel and carboplatin had acceptable tolerability in a phase I trial. Gefitinib monotherapy demonstrated unparalleled antitumor activity for a biologic agent, with less toxicity than docetaxel, in phase II trials in refractory, advanced non-small-cell lung cancer (NSCLC). This phase III, randomized, placebo-controlled, double-blind trial evaluated gefitinib plus paclitaxel and carboplatin in chemotherapy-naive patients with advanced NSCLC.
Patients received paclitaxel 225 mg/m(2) and carboplatin area under concentration/time curve of 6 mg/min/mL (day 1 every 3 weeks) plus gefitinib 500 mg/d, gefitinib 250 mg/d, or placebo. After a maximum of six cycles, daily gefitinib or placebo continued until disease progression. End points included overall survival, time to progression (TTP), response rate (RR), and safety evaluation. Results A total of 1,037 patients were recruited. Baseline demographic characteristics were well balanced. There was no difference in overall survival (median, 8.7, 9.8, and 9.9 months for gefitinib 500 mg/d, 250 mg/d, and placebo, respectively; P =.64), TTP, or RR between arms. Expected dose-related diarrhea and skin toxicity were observed in gefitinib-treated patients, with no new significant/unexpected safety findings from combination with chemotherapy. Subset analysis of patients with adenocarcinoma who received > or = 90 days' chemotherapy demonstrated statistically significant prolonged survival, suggesting a gefitinib maintenance effect.
Gefitinib showed no added benefit in survival, TTP, or RR compared with standard chemotherapy alone. This large, placebo-controlled trial confirmed the favorable gefitinib safety profile observed in phase I and II monotherapy trials.
The purpose of this study was to determine whether the addition of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE) to standard first-line gemcitabine and cisplatin provides clinical benefit over gemcitabine and cisplatin alone in patients with advanced or metastatic non-small-cell lung cancer (NSCLC). Gefitinib has demonstrated encouraging efficacy in advanced NSCLC in phase II trials in pretreated patients, and a phase I trial of gefitinib in combination with gemcitabine and cisplatin showed favorable tolerability.
This was a phase III randomized, double-blind, placebo-controlled, multicenter trial in chemotherapy-naive patients with unresectable stage III or IV NSCLC. All patients received up to six cycles of chemotherapy (cisplatin 80 mg/m(2) on day 1 and gemcitabine 1,250 mg/m(2) on days 1 and 8 of the 3-week cycle) plus either gefitinib 500 mg/d, gefitinib 250 mg/d, or placebo. Daily gefitinib or placebo was continued until disease progression. End points included overall survival (primary), time to progression, response rates, and safety evaluation.
A total of 1,093 patients were enrolled. There was no difference in efficacy end points between the treatment groups: for the gefitinib 500 mg/d, gefitinib 250 mg/d, and placebo groups, respectively, median survival times were 9.9, 9.9, and 10.9 months (global ordered log-rank [GOLrank] P =.4560), median times to progression were 5.5, 5.8, and 6.0 months (GOLrank; P =.7633), and response rates were 49.7%, 50.3%, and 44.8%. No significant unexpected adverse events were seen.
Gefitinib in combination with gemcitabine and cisplatin in chemotherapy-naive patients with advanced NSCLC did not have improved efficacy over gemcitabine and cisplatin alone. The reasons for this remain obscure and require further preclinical testing.
Gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, induces radiographic regressions and symptomatic improvement in patients with non-small-cell lung cancer (NSCLC). Phase II trials suggested female sex and adenocarcinoma were associated with response. We undertook this analysis to identify additional clinical and pathologic features associated with sensitivity to gefitinib.
We reviewed medical records, pathologic material, and imaging studies of all 139 NSCLC patients treated on one of three consecutive studies of gefitinib monotherapy performed at our institution. We identified patients experiencing a major objective response and compared their clinical and pathologic features with the others. Univariate and multivariable analyses were performed on potential predictive features associated with sensitivity to gefitinib.
Of 139 patients, 21 (15%; 95% CI, 9% to 21%), experienced a partial radiographic response. Variables identified as significant in univariate analysis included adenocarcinoma versus other NSCLC (19% v 0%; P=.004), adenocarcinoma with bronchioloalveolar features versus other adenocarcinomas (38% v 14%; P<.001), never smoker status versus former/current (36% v 8%; P<.001), and Karnofsky performance status > or =80% versus < or =70% (22% v 8%; P=.03). Multivariable analysis revealed the presence of adenocarcinoma with any bronchioloalveolar features (P=.004) and being a never smoker (P=.006) were independent predictors of response.
Our data suggest that individuals in whom gefitinib is efficacious are more likely to have adenocarcinomas of the bronchioloalveolar subtype and to be never smokers. These observations may provide clues to mechanisms determining sensitivity to this agent and suggest that NSCLC has a different biology in patients who never smoked and those with bronchioloalveolar carcinoma.
Death rate statistics of Korea
- Seo Jh
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Seo JH, Jeong CS. Death rate statistics of Korea, 2003: Korea National Statistical Office; 2004.
American Society of Clinical Oncology treatment of unresectable non – small-cell lung cancer guideline: update 2003
- Dg Pfister
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Pfister DG, Johnson DH, Azzoli CG, et al. American Society of
Clinical Oncology treatment of unresectable non – small-cell lung cancer
guideline: update 2003. J Clin Oncol 2004;22:330 – 53.
Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non -small cell lung cancer
- R V Lord
- J Brabender
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Lord RV, Brabender J, Gandara D, et al. Low ERCC1 expression
correlates with prolonged survival after cisplatin plus gemcitabine
chemotherapy in non -small cell lung cancer. Clin Cancer Res 2002;8:
2286 -91.
Death rate statistics of Korea
- J H Seo
- C S Jeong
Seo JH, Jeong CS. Death rate statistics of Korea, 2003: Korea
National Statistical Office; 2004.
American Society of Clinical Oncology treatment of unresectable non -small-cell lung cancer guideline: update
- D G Pfister
- D H Johnson
- C G Azzoli
Pfister DG, Johnson DH, Azzoli CG, et al. American Society of
Clinical Oncology treatment of unresectable non -small-cell lung cancer
guideline: update 2003. J Clin Oncol 2004;22:330 -53.