First-line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Research Articles

Efficacy of platinum-based combination chemotherapy in advanced lung adenocarcinoma harboring sensitive epidermal growth factor receptor (EGFR) mutations with acquired resistance to first-line EGFR tyrosine kinase inhibitor (TKI)

BackgroundThe epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) eventually fails in treating advanced lung adenocarcinoma harboring sensitive EGFR mutations because of acquired resistance. In clinical practical setting, platinum-doublet chemotherapy has been frequently performed after failure of first-line EGFR-TKIs. The efficacy of different regimens was compared. MethodsFrom January 2012 to December 2013, 160 patients with mutated EGFR receiving first-line EGFR-TKIs and second-line chemotherapy were analyzed retrospectively. Sixty-eight patients received pemetrexed-based therapy and among them, 61 were in combination with cisplatin. Ninety-two patients received non-pemetrexed-based therapy and among them, 79 were combined with cisplatin. ResultsThe progression-free survival of first-line EGFR-KI was 9.0 and 8.6 months for pemetrexed and non-pemetrexed treatment groups respectively (HR: 0.9146, 95% CI: 0.6656 to 1.257, P=0.5818). The median progression-free survival (PFS) of second-line therapy was 8.3 and 5.6 months for pemetrexed and non-pemetrexed treatment groups respectively (HR: 0.4217, 95% CI: 0.2952 to 0.6025, P=0.0001). The median overall survival (OS) after first-line EGFR-TKIs was 16.9 and 10.3 months for pemetrexed and non-pemetrexed groups respectively (HR: 0.5160, 95% CI: 0.3381 to 0.7873, P=0.0021). For those receiving pemetrexed continuous maintenance therapy, there was 18.7 months of survival after first-line EGFR-TKI, compared to 11.1 months for those without maintenance (HR: 0.4012, 95% CI: 0.2577 to 0.6247, P <0.0001). ConclusionThe efficacy of pemetrexed was superior to other chemotherapeutic agents in second line treatment for patients with lung adenocarcinoma harboring sensitive EGFR mutations after first-line EGFR-TKI therapy. Continuous maintenance pemetrexed therapy also improved the PFS and OS.

Comparing overall survival between first generation EGFR-TKIs and chemotherapy in lung cancer patients with Del19/L858R.

ObjectiveCombined overall survival (OS) analysis of Lux-Lung 3 and Lux-Lung 6 demonstrated that patients with epidermal growth factor receptor (EGFR) exon 19 deletions (Del19) would benefit from first-line second generation EGFR tyrosine kinase inhibitors (TKIs) afatinib but not for those with L858R. This study was to investigate the survival difference between first-line first generation EGFR-TKIs and chemotherapy in patients with either Del19 or L858R, and to directly compare OS in these two mutation groups.MethodsEligibles were all prospective and retrospective studies comparing EGFR-TKIs with conventional chemotherapy or receiving single agent EGFR-TKIs and demonstrating survival analysis based on mutation types. The primary outcome was OS measured as pooled hazard ratios (HRs). All measures were pooled using randomeffects models and 95% confidential interval (95% CI) was calculated.ResultsA total of 14 studies incorporating 1,706 patients with either Del19 or L858R were included. Enrolling patients with Del19 or L858R in randomized controlled trials (RCTs), first-line first generation EGFR-TKIs were associated with no OS benefit, compared with chemotherapy (pooled HRTKI/Chemo for Del19: 0.82, 95% CI: 0.64-1.06, P = 0.14; pooled HRTKI/Chemo for L858R: 1.15, 95% CI: 0.85-1.56, P = 0.38). Direct comparison of Del19 with L858R receiving with first-line first generation EGFR-TKIs demonstrated no significant survival difference (pooled HR19/21: 0.88, 95% CI: 0.67-1.16, P = 0.37).ConclusionsAmong patients with advanced non-small cell lung cancer (NSCLC) harboring Del19 and L858R, first-line first generation EGFR-TKIs demonstrated no survival benefit comparing with chemotherapy. Direct comparison between Del19 and L858R revealed no significant survival difference after first-line first generation EGFR-TKIs.

Identification of plasma microRNA profiles for primary resistance to EGFR-TKIs in advanced non-small cell lung cancer (NSCLC) patients with EGFR activating mutation.

BackgroundEGFR mutation is a strong predictor of efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) therapy in advanced non-small cell lung cancer (NSCLC). However, around 20–30 % of EGFR-mutated cases showed no response to EGFR-TKIs, suggesting that other determinants beyond EGFR mutation likely exist. This study analyzed the role of microRNAs (miRNAs) in primary resistance to EGFR-TKIs in advanced NSCLC patients with EGFR mutation.MethodsTraining group: 20 advanced NSCLC patients with EGFR 19 deletion treated with first-line EGFR-TKIs were enrolled; half of them had dramatic responses while the other half had primary resistance. Matched plasma samples were collected for miRNA profiling using TaqMan low-density array (TLDA). Bioinformatics analyses were used to identify related miRNAs possibly accounted for resistance. Testing group: Quantitative reverse transcriptase PCR (qRT-PCR) was employed to detect the level of miRNA with significant differential expression in the training set. Validation group: Another cohort with EGFR 19 deletion mutations, who had dramatically different responses to EGFR-TKI, was used to validate the difference of miRNA expression between the sensitive and resistant groups using RT-PCR.ResultsTraining group: 153 miRNAs were found to be differentially expressed between the sensitive and resistant groups. Potential target genes were predicted with a target scan database. Twelve differentially expressed miRNAs were selected for the analysis because of their known roles in tumorigenesis of lung cancer, resistance to drugs, and regulation of EGFR pathway. Training group: three out of the 12 miRNAs (miR-21, AmiR-27a, and miR-218) were verified to have significantly higher expression (PmiR-21 = 0.004, PmiR-27a = 0.009, PmiR-218 = 0.041, respectively) in the resistant group compared to the sensitive group. Validation group: The expression levels of these three miRNAs were validated to be significantly different (P = 0.011, 0.011, 0.026, respectively) in the validation cohort (n = 34).ConclusionsHigher expression levels of miR-21, AmiR-27a, and miR-218 detected in this study suggest potential roles of these miRNAs in primary resistance to EGFR-TKI in advanced NSCLC patients with EGFR exon 19 deletion mutations. These findings need to be further confirmed in a study with a larger sample size.

Overall survival benefits of first-line EGFR tyrosine kinase inhibitors in EGFR-mutated non-small-cell lung cancers: a systematic review and meta-analysis.

Background:Accumulating data shows that exon 19 deletions and L858R, both activating epidermal growth factor receptor mutations in non-small-cell lung cancers (NSCLCs), are just two different entities in terms of prognosis and treatment response to tyrosine kinase inhibitors (TKIs).Methods:A systematic review and meta-analysis of randomized controlled trials comparing TKIs with conventional chemotherapy was performed. Eight trials of 1498 patients and five trials of 1279 patients with either exon 19 deletions or L858R were included in the meta-analysis.Results:TKI treatment demonstrated progression-free survival benefit in patients with exon 19 deletions (hazard ratio (HR): 0.27, 95% confidence interval (CI): 0.21–0.35) and L858R (HR: 0.45, 95% CI: 0.35–0.58). Patients with exon 19 deletions had significant overall survival (OS) benefit under TKI treatment (HR: 0.72, 95% CI: 0.60–0.88). Subgroup analyses showed that irreversible TKIs, but not reversible TKIs, had statistically significant OS benefit in these patients (irreversible TKIs, HR: 0.59, 95% CI: 0.47–0.73; reversible TKIs, HR: 0.84, 95% CI: 0.69–1.02). Patients with L858R demonstrated no OS benefit under first-line TKI use (HR: 1.15, 95% CI: 0.95–1.39).Conclusions:In patients with advanced NSCLC harbouring exon 19 deletions, TKIs are associated with better OS compared with conventional chemotherapy. Future clinical trials should take exon 19 deletions and L858R as distinct disease entities and evaluate the treatment efficacy separately.

Impact of Continuing First-Line EGFR Tyrosine Kinase Inhibitor Therapy Beyond RECIST Disease Progression in Patients with Advanced EGFR-Mutated Non-Small-Cell Lung Cancer (NSCLC): Retrospective GFPC 04-13 Study.

Retrospective studies suggested a benefit of first-line tyrosine kinase inhibitor (TKI) treatment continuation after response evaluation in solid tumors (RECIST) progression in epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients. The aim of this multicenter observational retrospective study was to assess the frequency of this practice and its impact on overall survival (OS). The analysis included advanced EGFR-mutated NSCLC patients treated with first-line TKI who experienced RECIST progression between June 2010 and July 2012. Among the 123 patients included (67 ± 12.7years, women: 69%, non smokers: 68%, PS 0-1: 87%), 40.6% continued TKI therapy after RECIST progression. There was no difference between the patients who did and did not continue TKI therapy with respect to progression-free survival (PFS1: 10.5 versus 9.5months, p = 0.4). Overall survival (OS) showed a non-significant trend in favor of continuing TKI therapy (33.0 vs. 21.2months, p = 0.054). Progressions were significantly less symptomatic in the TKI continuation group than in the discontinuation group (18% vs. 37%, p < 0.01). Univariate analysis showed a higher risk of death among patients with PS >1 (HR 4.33, 95 %CI: 2.21-8.47, p = 0.001), >1 one metastatic site (HR 1.96, 95 %CI: 1.06-3.61, p = 0.02), brain metastasis (HR 1.75, 95 %CI: 1.08-2.84, p = 0.02) at diagnosis, and a trend towards a higher risk of death in cases of TKI discontinuation after progression (HR 1.62, 95 %CI: 0.98-2.67, p = 0.056 ). In multivariate analysis only PS >1 (HR 6.27, 95 %CI: 2.97-13.25, p = 0.00001) and >1 metastatic site (HR 2.54, 95 %CI: 1.24-5.21, p = 0.02) at diagnosis remained significant. This study suggests that under certain circumstances, first-line TKI treatment continuation after RECIST progression is an acceptable option in EGFR-mutated NSCLC patients. NCT02293733.

AZD9291 in TKI EGFR resistance in non-small cell lung cancer and the new concept of phase I trials.

Epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs) constitute the standard of care for stage IV EGFR mutated non-small cell lung cancer (NSCLC) patients initiating first-line systemic treatment. Despite the initial remarkable activity of targeted treatment in these patients rendering objective response rates (ORR) of 50-80% and progression-free survivals (PFS) of 9-12 months, most patients present disease progression during the first 12 to 24 months. Although the activity of platinum-based doublets has been shown in EGFR mutated NSCLC patients after progression to first-line TKIs, PFS is rather short. Drug development companies have more recently focused their attention on the molecular basis of EGFR TKIs acquired resistance. Secondary resistance mutations have proven to be the most frequent cause of acquired resistance. Among them, T790M mutation in exon 20 seems to be the leading responsible for that resistance. Several agents have shown preliminary preclinical and clinical activity in overcoming acquired resistance to firstline EGFR TKIs. To date, however, only AZD9291, an oral, potent, irreversible EGFR TKI that is selective for EGFR tyrosine kinase inhibitor-sensitizing mutations and the T790M resistance mutation has shown to be not only highly active but also fairly tolerable in a large cohort of patients. Here we present a critical analysis of this trial in its clinical setting and propose some future directions.

Abstract 761: Changing the paradigm for treating drug resistance in NSCLC: Novel combinations of AZD6094, a selective MET inhibitor, and an irreversible, selective (EGFRm/T790M) EGFRTKI, AZD9291

Abstract Aberrant receptor tyrosine kinase (RTK) signaling is a well-documented driver of disease onset and progression across myriad cancer types, where the MET RTK contributes to tumor progression, maintenance and resistance to targeted therapies. Here we explore the therapeutic potential of AZD6094, a highly potent and selective MET inhibitor, in EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC). Although many EGFRm NSCLC patients receiving first-line EGFR Tyrosine Kinase Inhibitors (TKI) benefit from therapy initially, the majority of patients will acquire resistance in 9-14 months1,2. Of this patient population, ∼10-15% of patients with emerging resistance to early generation EGFRm-TKI will have MET amplification3. Using xenograft models (HCC827) of resistance to erlotinib or gefitinib, both first-generation EGFRm-TKI, we assessed the efficacy of AZD6094 in models with varying copy number gain for MET. We demonstrate that the combination of AZD6094 with gefitinib, or AZD9291, an irreversible, selective (EGFRm/T790M) EGFR TKI, results in tumor growth inhibition (TGI) of &amp;gt;100% in 3 models (HCC827-ER1, PCS030 clone 1 and 2)4, suggesting that the combination is necessary and sufficient to address acquired resistance due to MET gene amplification. Moreover, we explore efficacy of AZD6094 in models representative of resistance to first-line treatment with EGFRm-TKIs, harboring MET amplification and T790M EGFR mutations. In NCI-H820 xenografts (EGFRm/T790M/MET), we demonstrate for the first time that combining MET and EGFRm/T790M TKIs (AZD6094 with AZD9291) induces tumor regressions (TGI% &amp;gt;100%, 94% regressions) and the loss of palpable tumors in 5/7 animals as compared to AZD9291 (TGI 48%) or AZD6094 treatment alone (TGI &amp;gt;100%). Pharmacodynamic analysis of tumor lysates demonstrated potent and durable inhibition of pMET in all AZD6094 treatment groups. Due to the clinical importance of understanding acquired resistance to targeted TKIs, we then generated a model of resistance to AZD6094 in MET-amplified NSCLC NCI-H1993 cells and analyzed several resistant clones (H1993R). Interestingly, MET phosphorylation remains strongly inhibited in AZD6094-treated H1993R cells, while EGFR protein expression is upregulated and leads to co-dependency between both pathways. Enhanced expression and phosphorylation of EGFR, as well as AKT, MEK and ERK activation were commonly observed in H1993R cells. Taken together, our data support the potential of AZD6094 as a novel combination therapy for MET-driven NSCLC in the context of EGFRm TKI resistance, and highlight the clinical relevance of EGFR and MET signaling in the context of emerging TKI resistance mechanisms and coordinated pathways. 1. Mok et al. N Engl J Med 2009;361:947-957. 2. Rosell et al. Lancet Oncol 2012;13:239-246. 3. Engelman et al. Science 2007;316:1039-1043. 4. Models from Precos Ltd Citation Format: Celina D'Cruz, Evan Barry, Ryan Henry, Lillian Castriotta, Alwin Schuller, Garry Beran, Susan Ashton, Cath Eberlein, Corinne Reimer, Melanie Frigault, Michael Zinda, Darren Cross, Stephen Fawell. Changing the paradigm for treating drug resistance in NSCLC: Novel combinations of AZD6094, a selective MET inhibitor, and an irreversible, selective (EGFRm/T790M) EGFRTKI, AZD9291. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 761. doi:10.1158/1538-7445.AM2015-761

EGFR: The Paradigm of an Oncogene-Driven Lung Cancer.

Somatic, activating mutations in EGFR identify a significant minority of patients with non-small cell lung cancer (NSCLC). Although these mutations are associated with an approximately 70% response rate to some EGFR tyrosine kinase inhibitors (gefitinib, erlotinib, and afatinib), patients develop resistance (i.e., "acquired resistance") after a median of 9 to 12 months. In patients with clinical acquired resistance, repeat biopsy of tumors has identified a number of relevant mechanisms of resistance, but by far the most frequent event is the acquisition of EGFR T790M, a mutation in the "gatekeeper" residue that confers resistance to gefitinib, erlotinib, and afatinib. This emphasizes the critical dependence upon EGFR signaling for some tumors, a property that has been exploited therapeutically. Dual EGFR blockade using afatinib and cetuximab led to a 29% radiographic response rate. More recently, drugs that target EGFR T790M (e.g., rociletinib, AZD9291, and others) have entered clinical trials, with impressive results observed in phase I clinical trials. The development of these newer drugs, with efficacy after resistance to first-line EGFR tyrosine kinase inhibitor, has led to exploration of these strategies in multiple disease settings: at resistance, in the first line, and in adjuvant treatment of those with completely resected early-stage disease who would otherwise die of recurrent/metastatic disease. This example of translational research that identifies mechanisms of resistance to first-generation drugs, and then targets those mechanisms yielding clinical benefit, is a paradigm for how targeted therapies can be developed.

Effectiveness of EGFR-TKIs versus chemotherapy as first-line treatment for advanced non-small cell lung cancer: a meta-analysis

背景与目的表皮因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitor, EGFR-TKI）应用于非小细胞肺癌（non-small cell lung cancer, NSCLC）一线治疗取得较好的临床疗效，然而EGFR-TKI一线用药选择仍面临很多问题。本研究应用循证医学的方法对NSCLC患者临床特征及基因突变情况对一线EGFR-TKIs治疗及化疗获益进行分析，以便指导临床用药。方法用计算机检索Pubmed、Embase、American Society of Clinical Oncology（ASCO）、European Society for Medical Oncology（ESCO）及生物医学数据库等数据库，寻找出EGFR-TKI与化疗相比一线治疗NSCLC的疗效的随机对照研究（randomized controlled trials, RCT）。对纳入RCT进行资料提取和质量评价，采用Review Manager 5.2软件分析、对比NSCLC患者在TKI治疗中的疗效。结果纳入的14项研究，共5, 000例患者。Meta分析结果显示，EGFR基因突变的NSCLC患者，EGFR-TKIs治疗与化疗相比有较好的近期有效率（RR=2.31; 95%CI: 1.88-2.84）和延长无疾病进展时间（progression free survival, PFS）（HR=0.39; 95%CI: 0.30-0.49），总生存时间（overall survival, OS）上两者无明显差异（HR=0.99; 95%CI: 0.84-1.16）。临床选择（亚裔、腺癌、不吸烟）NSCLC患者，EGFR-TKIs一线治疗与化疗相比也有较好的近期有效率（RR=1.30; 95%CI: 1.15-1.47），PFS和OS无差异（HR=0.93; 95%CI: 0.58-1.49）（HR=0.91; 95%CI: 0.81-1.02）。未经选择的患者，一线EGFR-TKIs治疗有效率、PFS与化疗无差异，但OS劣于一线接受化疗患者。结论EGFR突变的NSCLC患者一线EGFR-TKIs获益更多；对于不能耐受化疗的亚裔、腺癌、不吸烟患者，推荐一线EGFR-TKIs治疗；未经选择的NSCLC患者一线EGFR-TKIs治疗临床无获益，而且一线EGFR-TKI治疗的OS明显低于一线化疗。

Therapeutic strategies utilized in the setting of acquired resistance to EGFR tyrosine kinase inhibitors.

Patients with EGFR-mutant lung cancer derive significant therapeutic benefit from treatment with EGFR tyrosine kinase inhibitors (TKI). Unfortunately, acquired resistance is an inevitable consequence of this treatment strategy, with a broad variety of resistance mechanisms including acquired EGFR mutations (e.g., T790M) and activation of bypass signaling pathways, such as MET and HER2. Several therapeutic strategies hypothesized to delay or overcome resistance have been tested in clinical trials, including "next-generation" EGFR TKIs and rational combinations of targeted agents. However, to date, there are no FDA-approved therapies for patients with acquired resistance to first-line EGFR TKI therapy. There remains a critical need for more effective and better tailored treatments in this setting to match treatments to the individual patient and specific resistance mechanism at hand. In this review, we discuss known mechanisms of resistance to first-line EGFR TKI therapy and describe previous and ongoing strategies to overcome resistance.

Elevated neutrophil-to-lymphocyte ratio predicts poor outcome in patients with advanced non-small-cell lung cancer receiving first-line gefitinib or erlotinib treatment.

Elevated neutrophil-to-lymphocyte ratio (NLR) has been demonstrated to be a poor prognostic factor in multiple types of malignancies, whereas the effect of NLR on the prognosis of epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) patients treated with first-line EGFR tyrosine kinase inhibitors (TKIs) is not fully addressed. 81 metastatic NSCLC patients harboring EGFR mutation treated with first-line EGFR TKIs were retrospectively included. The associations between baseline clinical characteristics, including NLR, and tumor response, progression and survival were investigated. Elevated NLR (≥3.5) was observed in 33 of 81 patients. The progression-free and overall survival of the patients with increased NLR was significantly worse than that of the patients with decreased NLR (8.20 vs 10.60 months, P < 0.001 and 17.20 vs 23.20 months, P < 0.001, respectively). Elevated NLR was confirmed to be an independent prognostic factor for worse progression-free and overall survival in Cox multivariate analysis. Elevated NLR is likely to be associated with poor outcome in EGFR-mutated advanced NSCLC patients treated with first-line EGFR TKIs.

Patients with exon 19 deletion were associated with longer progression-free survival compared to those with L858R mutation after first-line EGFR-TKIs for advanced non-small cell lung cancer: a meta-analysis.

BackgroundsIt has been extensively proved that the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is superior to that of cytotoxic chemotherapy in advanced non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. However, the question of whether the efficacy of EGFR-TKIs differs between exon 19 deletion and exon 21 L858R mutation has not been yet statistically answered.MethodsSubgroup data on hazard ratio (HR) for progression-free survival (PFS) of correlative studies were extracted and synthesized based on random-effect model. Comparison of outcomes between specific mutations was estimated through indirect and direct methods, respectively.ResultsA total of 13 studies of advanced NSCLC patients with either 19 or 21 exon alteration receiving first-line EGFR-TKIs were included. Based on the data from six clinical trials for indirect meta-analysis, the pooled HRTKI/chemotherapy for PFS were 0.28 (95% CI 0.20–0.38, P<0.001) in patients with 19 exon deletion and 0.47 (95% CI 0.35–0.64, P<0.001) in those with exon 21 L858R mutation. Indirect comparison revealed that the patients with exon 19 deletion had longer PFS than those with exon 21 L858R mutation (HR19 exon deletion/exon 21 L858R mutation = 0.59, 95% CI 0.38–0.92; P = 0.019). Additionally, direct meta-analysis showed similar result (HR19 exon deletion/exon 21 L858R mutation = 0.75, 95% CI 0.65 to 0.85; P<0.001) by incorporating another seven studies.ConclusionsFor advanced NSCLC patients, exon 19 deletion might be associated with longer PFS compared to L858 mutation at exon 21 after first-line EGFR-TKIs.

187P - Common and Rare Egfr Mutations in Non-Small Cell Lung Cancer

ABSTRACT Background: In non-small cell lung cancer (NSCLC), the association between common EGFR mutations (Del EX19/ L858R) with EGFR tyrosine kinase inhibitors (EGFR-TKIs) has been well established. Not so for rare EGFR mutations, not even their impact on treatment response to platinum-based chemotherapy. Methods: We analyzed 188 NSCLC patients’ harbouring EGFR mutations from Mexico, Colombia and Costa Rica. Patients were treated according to international guidelines for the treatment of lung cancer. As first line treatment, 64.1% receive platinum-based chemotherapy and 30.8% receive EGFR-TKIs, after chemotherapy progression. Clinical-pathological characteristics and presence of common and rare EGFR mutations regarding treatment response were analysed. Protocol is registered with ClinicalTrials.gov, number NCT01023828. Results: Of all patients, 79.5% had common and 20.5% had rare EGFR mutations. Lepidic and acinar adenocarcinoma were associated with common EGFR mutation (p = 0.010). Patients who harboured common EGFR mutations had higher response rates to EGFR-TKIs versus those who had rare EGFR mutations (63.8% cf 32.4%, p Conclusions: Our findings suggested that patients who harboured rare EGFR mutations only could receive platinum-based chemotherapy as first-line treatment and EGFR-TKIs could be reserved as second- or third-line treatment. Disclosure: All authors have declared no conflicts of interest.

Exon 19 deletion association with progression-free survival compared to L858R mutation at exon 21 in treatment with first-line EGFR-TKIs: A meta-analysis of subgroup data from eight phase III randomized controlled trials.

8107 Background: The superior efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) compared with cytotoxic chemotherapy in patients harboring sensitive EGFR mutations has been extensively proved by a well-known series of eight phase III randomized controlled trials (RCT). However, the question of whether the efficacy of EGFR-TKIs differs between EGFR exon 19 deletions and exon 21 L858R mutations has not been statistically answered. Methods: Subgroup data on hazard ratio (HR) for progression free survival (PFS) in these RCTs were extracted and were synthesized based on random-effect model. Comparison of outcomes between specific mutations was estimated through indirect methods. All calculations were performed using STATA version 11.0. Results: A total of 7 randomized RCTs (IPASS, WJTOG3405, EUTRAC, OPTIMAL, LUXLUNG3, and LUXLUNG6, as well as NEJ002 being included in sensitivity analysis) involving 1489 patients with either 19 or 21 exon alteration receiving first-line EGFR-TK...

A meta-analysis of smoking status on clinical outcomes of non-small cell lung cancer patients harboring activating epidermal growth factor receptor (EGFR) mutations receiving first-line EGFR tyrosine kinase inhibitor.

8101 Background: In several univariate analyses from randomized phase 3 trials, ever-smokers with advanced EGFR mutated (m) NSCLC did not seem to benefit from improved progression-free survival (PF...

A cautionary lesson on the use of targeted methods for EGFR mutation analysis: a case report

Epidermal growth factor receptor (EGFR) mutation analysis is recommended for lung cancer patients prior to the prescription of first-line EGFR tyrosine kinase inhibitors in order to predict response to treatment....

Prior EGFR tyrosine-kinase inhibitor therapy did not influence the efficacy of subsequent pemetrexed plus platinum in advanced chemonaïve patients with EGFR-mutant lung adenocarcinoma.

BackgroundTumor cells before and after epidermal growth-factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) therapy might display different characteristics. The aim of this study was to evaluate the influence of prior EGFR TKI therapy on the efficacy of subsequent pemetrexed plus platinum (PP) in advanced chemonaïve patients with EGFR-mutant lung adenocarcinoma.Materials and methodsAdvanced chemonaïve patients with EGFR-mutant lung adenocarcinoma receiving PP as first-line chemotherapy were enrolled retrospectively in two medical centers of Taiwan. The objective of this study was to compare objective response rate (ORR), disease-control rates (DCR), progression-free survival (PFS), and overall survival (OS) of PP in patients with and without prior EGFR TKI therapy.ResultsIn total, 105 patients were analyzed. Sixty-one patients (58.1%) had prior EGFR TKI therapy and used PP as second-line treatment. The other 44 patients (41.9%) received PP as first-line therapy. ORRs of PP in patients with and without prior EGFR TKI therapy were 24.6% and 38.6%, respectively (P=0.138). DCRs of the two groups were 62.3% and 65.9%, respectively (P=0.837). The median PFS (6.1 versus 6.1 months, P=0.639) and OS (34.4 versus 32.3 months, P=0.394) were comparable between the groups with and without prior EGFR TKI therapy. In a subgroup analysis of patients with prior EGFR TKI therapy, there was no significant association between the efficacy of first-line EGFR TKI and the outcome of subsequent PP therapy.ConclusionOur results suggested that prior EGFR TKI therapy would not influence the efficacy of subsequent PP therapy in advanced chemonaïve patients with EGFR-mutant lung adenocarcinoma.

Factor associated with failure to administer subsequent treatment after progression in the first-line chemotherapy in EGFR-mutant non-small cell lung cancer: Okayama Lung Cancer Study Group experience

Early administration of both epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy and cytotoxic chemotherapy is crucial for non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. We investigated the effect of first-line administration of these therapies on subsequent therapy in NSCLC patients. This study enrolled 63 consecutive patients with advanced EGFR-mutant NSCLC and good performance status (PS) and who underwent first-line EGFR-TKI therapy or standard cytotoxic chemotherapy and then had progressive disease, from 2007 to 2011. The ability of each patient to receive the other therapy after first-line treatment failure was assessed. In the first-line setting, 23 and 40 patients received EGFR-TKI therapy and cytotoxic chemotherapy, respectively. At relapse, the EGFR-TKI therapy group showed more frequent PS deterioration (p = 0.042) and greater likelihood of symptomatic central nervous system (CNS) relapse (p = 0.093) compared with the cytotoxic chemotherapy group. Nine (39 %) of 23 patients initially receiving EGFR-TKI therapy could not receive standard cytotoxic therapy after progression mainly due to symptomatic CNS relapse. Only one (3 %) of 40 initially treated with cytotoxic chemotherapy failed to receive subsequent EGFR-TKI therapy (p < 0.001). Multivariate analysis revealed a correlation between the first-line therapy and the failure to switch to the other therapy after disease progression (OR 48.605, p = 0.005). In this study, patients who could not receive both EGFR-TKI therapy and cytotoxic chemotherapy in the early-line setting were included more in the first-line EGFR-TKI group, suggesting a potential risk associated with missing the timing of administration of subsequent therapy. Further investigation is warranted to detect their pretreatment clinical or molecular characteristics for development of a new treatment strategy specific for such subpopulation.

Lung Cancers with Concomitant EGFR Mutations and ALK Rearrangements: Diverse Responses to EGFR-TKI and Crizotinib in Relation to Diverse Receptors Phosphorylation

We investigated the incidence of concomitant epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements in Chinese patients with non-small cell lung cancer (NSCLC), and assessed responses to EGFR tyrosine kinase inhibitors (EGFR-TKIs) and crizotinib in such tumors. We screened 977 consecutive patients with NSCLC for the presence of concomitant EGFR mutations and ALK rearrangements by rapid amplification of cDNA ends-coupled PCR sequencing and FISH. Immunohistochemistry (IHC) and Western blotting were used to correlate the activation of EGFR, ALK, and downstream proteins with responses to EGFR-TKIs and crizotinib. The overall frequency of concomitant EGFR mutations and ALK rearrangements was 1.3% (13/977). EGFR/ALK co-alterations were found in 3.9% (13/336) EGFR-mutant and 18.6% (13/70) ALK-rearranged patients. Ten tumors were treated with first-line EGFR-TKIs, with a response rate of 80% (8/10). Two tumors with high phospho-ALK levels and low phospho-EGFR levels achieved stable and progressive disease, respectively. Median progression-free survival was 11.2 months. Coexpression of mutant EGFR and ALK fusion proteins in the same tumor cell populations was detected by IHC. Two cases with high phospho-ALK levels treated with crizotinib achieved partial responses; two cases with low phospho-ALK levels had progressive or stable disease. ALK rearrangements and EGFR mutations could coexist in a small subgroup of NSCLC. Advanced pulmonary adenocarcinomas with such co-alterations could have diverse responses to EGFR-TKIs and crizotinib. Relative phospho-ALK and phospho-EGFR levels could predict the efficacy of EGFR-TKI and crizotinib.

Role of the expression level of Nrf2 in predicting response of EGFR-TKIs in lung adenocarcinoma patients with EGFR gene mutations

背景与目的表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKIs）是含有EGFR基因敏感突变肺腺癌患者一线治疗首选药物，但其疗效存在个体差异。已有研究表明核因子E2相关因子2（nuclear factor erythroid-2-related factor 2, Nrf2）在肺癌患者中存在个体表达差异，且其与化疗药物疗效相关。Nrf2激活可抑制EGFR-TKIs在EGFR基因突变细胞株中的敏感性。本研究旨在探讨Nrf2在含有EGFR基因突变肺腺癌患者中的表达及其与一线EGFR-TKIs疗效的相关性。方法应用免疫组化检测31例进展期含有EGFR基因突变的肺腺癌患者组织标本中Nrf2的表达。结果含有EGFR基因突变的进展期肺腺癌患者中Nrf2表达存在个体差异，Nrf2阳性率为77.4%，Nrf2核高表达率为38.7%；Nrf2在核内的表达水平与EGFR-TKIs缓解程度、无进展生存期（progression free survival, PFS）相关（P < 0.05），而与性别、年龄、吸烟、分化程度、EGFR基因突变状态和总生存期（Overall survival, OS）无关（P>0.05）。Nrf2阳性程度与PFS和OS显著相关（P < 0.05），Nrf2阳性组中位PFS、OS低于阴性组（P < 0.05）。多因素分析表明Nrf2在肿瘤细胞核内的表达水平是EGFR-TKIs PFS的独立预测因素，Nrf2在肿瘤细胞内的整体阳性程度是OS的独立预测因素（P < 0.05）。结论Nrf2在含有EGFR基因突变的肺腺癌患者中的表达水平与EGFR-TKIs疗效相关，Nrf2可能成为预测EGFR-TKIs疗效的一个理想指标。