Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer

First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer (NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Second-generation EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs.     

Phase II Study of the EGFR-TKI Rechallenge With Afatinib in Patients With Advanced NSCLC Harboring Sensitive EGFR Mutation Without T790M: Okayama Lung Cancer Study Group Trial OLCSG 1403

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as first-line therapy for patients with EGFR-mutated non–small-cell lung cancer (NSCLC) have shown a significantly better objective response rate and progression-free survival than platinum doublet therapy. However, acquired resistance often occurs within 12 months. One of the potential strategies for treating acquired resistance in NSCLC is the readministration of EGFR-TKIs, a strategy that has mainly been evaluated using gefitinib or erlotinib. The aim of the present study is to investigate the efficacy and safety of EGFR-TKI readministration with afatinib in patients with advanced NSCLC harboring activating EGFR mutations without T790M. The primary endpoint is progression-free survival. The secondary endpoints include the objective response rate, disease control rate, overall survival, toxicity, and quality of life. A total of 12 patients will be enrolled in this trial.     

Comparative Efficacy and Safety of TKIs Alone or in Combination With Antiangiogenic Agents in Advanced EGFR-Mutated NSCLC as the First-Line Treatment: A Systematic Review and Meta-Analysis

BackgroundSeveral studies have suggested that patients with epidermal growth factor receptor (EGFR)-mutated non–small-cell lung cancer (NSCLC) might benefit from the use of tyrosine kinase inhibitors (TKIs) in combination with antiangiogenic agents. This study aimed to comprehensively review the available evidence regarding the efficacy and safety of first-line TKI plus antiangiogenic agents versus TKIs alone in EGFR-mutated advanced NSCLC.Materials and MethodsA literature search was performed using PubMed to identify studies published up to Feb. 2020. Abstracts from major international conferences reported over the last 5 years were searched. The primary outcome was progression-free survival (PFS), and the secondary outcomes included overall survival (OS), the objective response rate (ORR), and toxicity.ResultsIn total, 7 relevant trials comprising 1612 patients were identified. TKIs plus antiangiogenic agents led to significant improvements in PFS regardless of the EGFR mutation subtype and presence of brain metastasis. In particular, in the subgroup with the L858R mutation, the hazard ratio (HR) of PFS was 0.58 (95% confidence interval [CI], 0.48-0.71, P < .001). The OS following combined treatment was similar to that following TKI monotherapy. The ORR was increased with the use of TKIs plus antiangiogenic agents (HR 1.10, 95% CI, 1.01-1.20, P = .029). In the safety analyses, TKIs plus antiangiogenic agents exhibited a significantly increased incidence of adverse events of grade 3 or higher.ConclusionThe use of TKIs plus antiangiogenic agents is associated with significantly improved PFS and ORR compared with TKIs alone in untreated EGFR-mutated NSCLC. The toxicities of combination therapy should be considered when making treatment choices.     

表皮生长因子受体酪氨酸激酶抑制剂用于非小细胞肺癌术后辅助治疗的研究进展

表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKI）在晚期EGFR突变阳性的非小细胞肺癌（non-small cell lung cancer, NSCLC）患者中的疗效肯定,但EGFR-TKI能否提高完全切除的NSCLC术后辅助治疗疗效不确切。部分研究发现在可切除的Ⅰ~Ⅲ期EGFR敏感突变肺腺癌患者中,辅助TKI治疗有使无疾病生存（disease free survival,DFS）获益的趋势,另一部分临床研究未能证实EGFR-TKI在术后辅助治疗有获益。造成各研究结果不一的原因很多,如人群选择、EGFR-TKI使用时长、耐药等。国内外目前一些设计比较合理的,对比EGFR-TKI化疗辅助治疗Ⅱ~ⅢA期EGFR敏感突变的NSCLC临床研究正在进行,值得期待。目前,早期NSCLC术后TKI辅助治疗仅限于临床试验,不建议作为临床常规治疗。     

Nationwide Real-world Cohort Study of First-line Tyrosine Kinase Inhibitor Treatment in Epidermal Growth Factor Receptor-mutated Non–small-cell Lung Cancer

BackgroundOnly a few randomized trials directly compared the relative efficacy of tyrosine kinase inhibitors (TKIs) in patients with advanced epidermal growth factor receptor (EGFR)-mutated non–small-cell lung cancer (NSCLC), and most trials comprised selected series from Asian populations. Therefore, the aim of this study was to assess the overall survival (OS) of advanced EGFR-mutated NSCLC in a large white population and to evaluate variation between different TKIs and identify predictors of survival.Patients and MethodsInformation about clinical characteristics, treatment, and survival for 873 patients with stage IV EGFR + NSCLC, diagnosed from 2015 through 2017, was derived from the Netherlands Cancer Registry. OS was evaluated by actuarial analysis and multivariable Cox regression. Prognostic factors are reported as hazard ratios and 95% confidence intervals.ResultsA total of 596 (68%) patients received first-line treatment with regular TKIs, providing a median survival of 20.2 months. Forty-five percent of patients were 70 years and older, and 54% of patients had distant metastasis in multiple organs. In the multivariate analysis, survival was significantly worse for men, and patients with higher age, poorer performance, and ≥ 3 organs with metastasis. Compared with erlotinib, OS was worse for gefitinib users (adjusted hazard ratio, 1.30; 95% confidence interval, 1.02-1.64), predominantly in patients with brain metastasis.ConclusionDutch patients with EGFR-mutated NSCLC who received first-line treatment with regular TKIs have a median OS of 20.2 months in a nationwide real-world cohort. In patients with brain metastasis, erlotinib showed superior results compared with gefitinib and was similar to afatinib.     

EGFR敏感突变非小细胞肺癌脑转移患者临床特征综述

晚期非小细胞肺癌(NSCLC)常常合并脑转移,预后和生活质量较差。表皮生长因子受体(EGFR)是常见NSCLC的敏感基因突变类型,与其他分子类型相比,具有不同的分子生物学特征。随着靶向药物的广泛使用,EGFR敏感突变NSCLC脑转移的预后及颅内外控制有很大提高。为了更好地认识EGFR敏感突变NSCLC脑实质转移的特点,本文从脑转移的发病率、发病时间、发病部位、病灶数目及大小、发病症状、靶向治疗疗效和疾病转归等方面综述了EGFR突变阳性NSCLC脑实质转移的临床特征及治疗,为脑实质转移局部治疗的介入时机以及局部治疗技术选择提供参考。     

EGFR低表达、COX-2高表达和MVD高表达的早期非小细胞肺癌的辅助化疗探索

目的探索表皮生长因子受体（EGFR）低表达、环氧合酶-2（COX-2）高表达和微血管密度（MVD）高表达的分期为T1N0M0的非小细胞肺癌（NSCLC）是否需要接受术后辅助化疗。方法通过非随机对照临床研究的方法,收集早期NSCLC（分期为T1N0M0）,并经过免疫组化证实为EGFR低表达、COX-2高表达和MVD高表达的患者为试验组,接受顺铂（DDP）联合诺维本（NVB）化疗;对照组为既往分期相同且免疫组化状态相同的早期NSCLC患者,术后没有接受任何抗肿瘤治疗。结果试验组10例,对照组13例。试验组的中位无病生存期为40个月,而对照组为25个月,但差异无显著性（P=0.079）。结论高危的早期NSCLC（分期为T1N0M0）患者接受化疗后有望取得更好的生存获益,有必要开展大规模的随机对照研究去证实。     

EGFR突变丰度的检测及其临床意义

具有表皮生长因子受体(epidermal growth factor receptor,EGFR)敏感突变的非小细胞肺癌患者对酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)具有良好反应,但是即使存在相同突变,不同患者对TKIs的反应也不一致.推测突变分子含量的不同是TKIs反应不一的部分原因,具有更高EGFR突变"丰度"的肿瘤患者可能从TKIs中获益更多.EGFR突变可根据检测方法敏感性的不同,定量检测突变分子比例以及突变蛋白表达等进行半定量或定量检测.EGFR突变丰度可能有助于反映肿瘤异质性,评估疾病进程,预测TKIs药物敏感性,早期发现耐药,具有重要的临床意义.     

术后放疗在Ⅲ(pN2)期EGFR基因野生型肺腺癌辅助化疗患者中价值

目的:探讨Ⅲ(pN 2)期表皮生长因子受体(EGFR)基因野生型肺腺癌完全切除并辅助化疗患者术后放疗(PORT)的价值及预后影响因素。 方法:回顾性分析2009—2016年间郑州大学附属肿瘤医院完全切除的Ⅲ(pN 2)期EGFR基因野生型肺腺癌患者172例,均接受>4个周期含铂两药联合...     

Epidermal Growth Factor Receptor Inhibition in Lung Cancer: Status 2012

Lung cancer is the most common cause of cancer deaths. Most patients present with advanced-stage disease, and the prognosis is generally poor. However, with the understanding of lung cancer biology, and development of molecular targeted agents, there have been improvements in treatment outcomes for selected subsets of patients with non–small-cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated significantly improved tumor responses and progression-free survival in subsets of patients with advanced NSCLC, particularly those with tumors harboring activating EGFR mutations. Testing for EGFR mutations is a standard procedure for identification of patients who will benefit from first-line EGFR TKIs. For patients with advanced NSCLC and no activating EGFR mutations (EGFR wild-type) or no other driving oncogenes such as ALK-gene rearrangement, chemotherapy is still the standard of care. A new generation of EGFR TKIs, targeting multiple receptors and with irreversible bindings to the receptors, are in clinical trials and have shown encouraging effects. Research on primary and acquired resistant mechanisms to EGFR TKIs are ongoing. Monoclonal antibodies (e.g. cetuximab), in combination with chemotherapy, have demonstrated improved outcomes, particularly for subsets of NSCLC patients, but further validations are needed. Novel monoclonal antibodies are combined with chemotherapy, and randomized comparative studies are ongoing. This review summarizes the current status of EGFR inhibitors in NSCLC in 2012 and some of the major challenges we are facing.     

Afatinib in the treatment of EGFR mutation-positive NSCLC – A network meta-analysis

Objectives

Epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) is a specific lung cancer subtype characterized by sensitivity to treatment with EGFR tyrosine kinase inhibitors (TKIs). Two reversible EGFR TKIs (gefitinib, erlotinib) and the irreversible ErbB family blocker afatinib are currently approved for treatment of EGFR mutation-positive NSCLC, but no head-to-head trials have been reported to date. We aimed to assess the relative efficacy of the three drugs by conducting a network meta-analysis (NMA).

Materials and methods

A systematic literature review was conducted to identify all the available evidence. Outcomes of interest were progression-free survival (PFS) and overall survival. For PFS, results by investigator review were considered as not all trials assessed PFS independently. Results were analyzed using Bayesian methods.

Results

The literature search identified 246 articles that were assessed for eligibility, of which 21 studies were included in the NMA, including eight trials performed in an EGFR mutation-positive population. The estimated PFS HR (95% credible interval, CrI) for afatinib compared with gefitinib was 0.70 (0.40–1.16) and compared with erlotinib was 0.86 (0.50–1.50) in the total population. The estimated probability of being best for afatinib over all other treatments for PFS was 70% versus 27% for erlotinib and 3% for gefitinib; the estimated probability of chemotherapy being the best treatment was 0%. Estimated HR (95% CrI) in patients with common mutations was 0.73 (0.42–1.24) for afatinib compared with erlotinib and 0.60 (0.34–0.99) for afatinib compared with gefitinib. OS findings were not significantly different between treatments.

Conclusions

In the absence of direct head-to-head trial data comparing efficacy between the three EGFR TKIs, our analysis suggests that afatinib is a viable treatment alternative to erlotinib or gefitinib in terms of PFS. A direct trial-based comparison of the efficacy of these agents is warranted to clarify their relative benefits.     

Immune Checkpoint Inhibitors in EGFR-Mutated NSCLC: Dusk or Dawn?

Although immune checkpoint inhibitors (ICIs) that target programmed cell death protein-1/programmed cell death ligand-1 axis have significantly shifted the treatment paradigm in advanced NSCLC, clinical benefits of these agents are limited in patients with EGFR-mutated NSCLC. Several predictive biomarkers (e.g., programmed cell death ligand-1 expression, tumor mutation burden), which have been validated in EGFR-wild type NSCLC, however, are not efficacious in EGFR-mutated tumors, suggesting the unique characteristics of tumor microenvironment of EGFR-mutated NSCLC. Here, we first summarized the clinical evidence on the efficacy of ICIs in patients with EGFR-mutated NSCLC. Then, the cancer immunogram features of EGFR-mutated NSCLC was depicted to visualize the state of cancer-immune system interactions, including tumor foreignness, tumor sensitivity to immune effectors, metabolism, general immune status, immune cell infiltration, cytokines, and soluble molecules. We further discussed the potential subpopulations with EGFR mutations that could benefit from ICI treatment. Lastly, we put forward future strategies to adequately maximize the efficacy of ICI treatment in patients with EGFR-mutated NSCLC in the upcoming era of combination immunotherapies.     

Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small-cell lung cancer: a meta-analysis of 13 randomized trials

Advanced non-small-cell lung cancer (NSCLC) harboring activating mutations of epidermal growth factor receptor (EGFR) are particularly sensitive to tyrosine kinase inhibitors (TKIs), namely erlotinib and gefitinib. The purpose of this meta-analysis was to evaluate the benefit of EGFR TKIs in EGFR-mutated NSCLCs. Eligible studies included published randomized controlled trials in which erlotinib or gefitinib (alone or with chemotherapy) were compared with standard therapy in 1260 patients with EGFR-mutated NSCLCs who were included in 13 trials. The mutational status was obtained through a retrospective or prospective analysis. Relative risk (RR) was calculated for response rate, and hazard ratios (HRs) were calculated for progression-free and overall survival. EGFR TKIs increase the chance of obtaining an objective response almost 2-fold when compared with chemotherapy (RR, 2.06; 2p < .00001). The response rate was 70% vs. 33.2% in first-line trials. In 3 second-line trials, response rates were 47.4% vs. 28.5%, with a benefit similar to first-line trials (RR, 1.79; 2p = .04). EGFR TKIs reduced the hazard of progression by 70% in all trials (HR, 0.30; 2p < .00001) and by 65% in first-line trials only (HR, 0.35; 2p < .00001). Overall, however, they do not improve survival (HR, 0.96; 2p = .71). NSCLCs harboring EGFR mutations derive greater benefit from erlotinib or gefitinib than from chemotherapy. All patients affected by NSCLC with an EGFR-positive mutation test result must be offered the opportunity to be treated with an EGFR TKI upfront or during the natural course of the disease if not previously exposed.     

EGFR-TKI治疗非小细胞肺癌中枢神经系统转移的进展

约50%的非小细胞肺癌会出现中枢神经系统转移,从而导致不良预后。非小细胞肺癌患者中存在表皮生长因子受体（epidermal growth factor receptor,EGFR）突变,这部分患者对EGFR酪氨酸激酶抑制剂（EGFR- tyrosine kinase inhibitors, EGFR-TKI）的治疗显示出了良好的耐受性及疗效。EGFR-TKI对非小细胞肺癌中枢神经系统转移也显示出了一定的疗效。本文针对EGFR-TKI药物对于非小细胞肺癌中枢神经系统转移的治疗进展进行综述。     

Genotype-driven therapies for non-small cell lung cancer: focus on EGFR, KRAS and ALK gene abnormalities

Non-small cell lung cancers (NSCLCs) are heterogeneous cancers. In 2004, the identification of epidermal growth factor receptor (EGFR) somatic mutations provided the first glimpse of a clinically relevant NSCLC oncogene. Approximately 70% of NSCLCs with EGFR mutations (exon 19 deletions or the exon 21 L858R) attain responses to EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, with improved response rate (RR), progression-free survival (PFS) and in some reports overall survival (OS) when compared with EGFR wildtype (WT) cases. Three randomized trials of gefitinib versus chemotherapy (IPASS, WJTOG3405, NEJ002) in stage IV NSCLC have consistently demonstrated better RR and PFS (hazard ratios of 0.48 [IPASS], 0.49 [WJTOG3405] and 0.30 [NEJ002]) for EGFR-mutated NSCLCs treated with gefitinib. Novel irreversible EGFR TKIs (afatinib, XL647, PF00299804) show similar activity in EGFR-mutated patients. A translocation involving the anaplastic lymphoma kinase (ALK) gene with EML4, identified in 2007, is the most recent oncogene found in NSCLC. Crizotinib (PF02341066), an ALK TKI, has shown impressive activity against ALK translocated NSCLC in an expanded cohort of a phase I trial (NCT00585195). Over 80 patients have been treated and the RR is ～60% with the 6-month PFS rate exceeding 70%. A registration phase III trial of crizotinib versus second-line chemotherapy (pemetrexed/docetaxel) is underway (PROFILE 1007, NCT00932893). KRAS, EGFR mutations and ALK translocations are mutually exclusive and few EGFR WT NSCLCs respond to EGFR TKIs. The promising results of EGFR and ALK TKIs in molecular subgroups of NSCLCs herald a new age of drug and clinical trial development for patients with NSCLC.     

Epidermal Growth Factor Receptor Inhibition in the Management of Squamous Cell Carcinoma of the Lung

Molecular therapies targeting epidermal growth factor receptor (EGFR) have had a profound impact on the management of advanced non-small cell lung cancer (NSCLC). EGFR inhibition with EGFR tyrosine kinase inhibitors (EGFR-TKIs) and anti-EGFR monoclonal antibodies (mAbs) in squamous NSCLC (sqNSCLC) remains controversial in patients whose tumors are not known to harbor EGFR mutations. Recent meta-analyses of EGFR-inhibition randomized trials that are adequately powered for histological subgroup analysis and anti-EGFR trials limited to patients with squamous histology afford the opportunity to revisit EGFR treatment in sqNSCLC. In unselected patients with sqNSCLC who are not eligible for chemotherapy, EGFR-TKI therapy is a valid treatment option over placebo or best supportive care, with improved progression-free survival noted in randomized controlled trials in both the first- and second-line setting and improved overall survival (OS) in the second-line setting. In patients eligible for chemotherapy, first-line combination regimens with anti-EGFR mAbs have been shown to improve OS over chemotherapy alone in patients with squamous histology in meta-analysis and more recently in the SQUIRE sqNSCLC trial (chemotherapy with and without necitumumab). In sqNSCLC patients who respond to induction chemotherapy, maintenance therapy with erlotinib delays disease progression and may improve the survival of patients with stable disease. In the second-line setting, survival outcomes are comparable between chemotherapy and EGFR-TKIs in meta-analysis, with the latter being more tolerable as a second-line therapy. Newer-generation EGFR-TKI therapies may further benefit patients with sqNSCLC who have failed first-line chemotherapy, given the positive trial results from LUX-Lung 8 (afatinib vs. erlotinib). EGFR is a valid therapeutic target in unselected/EGFR wild-type patients with squamous cell carcinoma of the lung. With the recent approval of immune checkpoint inhibitors in the second-line management of advanced sqNSCLC and their adoption as a new standard of care, there exists an opportunity for novel combination therapies to increase therapeutic efficacy and durable tumor control. As more targeted agents are approved, combination regimens that include an anti-EGFR agent should be evaluated, and the optimal sequencing of targeted therapies should be defined.

Implications for Practice:

Anti-epidermal growth factor receptor (EGFR) therapies remain controversial in unselected/wild-type EGFR squamous non-small cell lung cancer (NSCLC). Recent meta-analyses and squamous-only NSCLC EGFR-inhibition trials have overcome the power limitations of early trials and can now inform the management of squamous NSCLC with anti-EGFR therapies. With the approval of immunotherapeutics in the second-line management of squamous NSCLC, there exists an opportunity for novel combination therapies to improve efficacy and durable tumor control. The optimal timing and sequencing of available second-line targeted therapies, however, have yet to be defined. This review analyzes randomized clinical trials of EGFR inhibition in NSCLC and meta-analyses of these trials, with a focus on patients with squamous histology.     

非小细胞肺癌分子靶向治疗中EGFR-TKI的耐药机制研究进展

随着分子靶向治疗药物的发展,以吉非替尼(gefitinib,iressa)和厄洛替尼(erlotinib,tarceva)为代表的表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinases inhibitors,EGFR-TKIs)在治疗非小细胞肺癌中发挥了重要作用。然而在临床前和临床研究中发现许多患者对此药物存在原发性耐药或获得性耐药,使该类药物的使用受到一定限制。本文就近年来对EGFR-TKIs耐药机制的研究进展进行综述。     

MiR-200c overexpression is associated with better efficacy of EGFR-TKIs in non-small cell lung cancer patients with EGFR wild-type

Several randomized trials have demonstrated non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations can achieve favorable clinical outcomes on treatment with EGFR tyrosine kinase inhibitors (TKIs). EGFR mutation is considered as a predictive marker for efficacy of EGFR-TKIs in NSCLC. Here we show miR-200c overexpression was correlated with the epithelial phenotype and sensitivity to gefitinib in EGFR wild-type NSCLC cell lines. Up-regulated miR-200c could regain the sensitivity to gefitinib in the EGFR wild-type cell lines and miR-200c could regulate epithelial to mesenchymal transition through PI3K/AKT and MEK/ERK pathways. NSCLC patients at advanced stage (N=150) who received EGFR-TKIs (gefitinib or erlotinib) as second- or third-line therapy from September 2008 to December 2012 were included in the study. In 66 NSCLC patients with wild-type EGFR, high levels of miR-200c expression was associated with higher disease control rate (DCR), longer progression-free survival (PFS) and longer overall survival (OS) compared with low miR-200c expression subgroup. In the subgroup with EGFR mutation, the trend remained the same but not statistically significant. Overall, these findings indicated that miR-200c might be a predictive biomarker for sensitivity to EGFR-TKIs in advanced NSCLC patients with wild-type EGFR.     

EGFR突变的非小细胞肺癌脑转移的治疗策略

约10%的非小细胞肺癌(NSCLC)患者初诊时出现脑转移,而脑转移为肺癌死亡的主要原因之一.目前全脑放疗(WBRT)仍为脑转移的标准治疗方案,但其疗效已达平台期.酪氨酸激酶抑制剂(TKI)在NSCLC脑转移治疗中取得了可观的疗效.TKI联合WBRT可能成为表皮生长因子受体(EGFR)突变的肺癌脑转移的主要治疗手段.