Second-line therapy with gefitinib in combination with docetaxel for advanced non-small cell lung cancer: a phase II randomized study

This randomized, open-label, parallel-group, phase II study evaluated the efficacy and safety of gefitinib and docetaxel in combination, as second-line therapy for advanced or metastatic non-small cell lung cancer (NSCLC). Eighty-nine patients who had failed first-line, platinum-based chemotherapy were randomly assigned to gefitinib (250 mg/day orally) in combination with docetaxel (75 mg/m² every 3 weeks) or single-agent docetaxel (75 mg/m² every 3 weeks). Objective response rates were 6.8% with gefitinib plus docetaxel and 9.1% with docetaxel alone. Disease control was experienced by a higher proportion of patients receiving gefitinib plus docetaxel (59.1%) versus docetaxel alone (34.1%). Median progression-free and overall survival appeared to be longer with gefitinib plus docetaxel (3.9 months [95% CI:2.3–5.4] and 7.6 months [95% CI:5.4–10.4], respectively) than with docetaxel alone (2.1 months [95% CI:2.1–3.7] and 6.2 months [95% CI:5.2–7.2], respectively). The most common non-hematological adverse events were diarrhea, alopecia, rash and dry skin in the combination arm, and vomiting and asthenia with docetaxel alone. Gefitinib and docetaxel combination therapy has antitumor activity and may be a feasible treatment option in patients with advanced NSCLC who have failed platinum-based chemotherapy.     

埃克替尼治疗非小细胞肺癌脑转移的回顾性研究

目的 探讨埃克替尼治疗非小细胞肺癌（NSCLC）脑转移的疗效及安全性。方法 回顾性分析31例采用埃克替尼治疗的NSCLC 脑转移患者的临床资料。所有患者均口服埃克替尼125mg,每天3次,直至疾病进展或出现不可耐受的不良反应,其中25例患者接受脑部放疗。结果 31例患者颅内病灶的有效率（RR）和疾病控制率（DCR）分别为25.8％和83.9％,全身病灶的RR和DCR分别为38.7％和87.1％。接受埃克替尼联合脑部放疗的患者在RR上优于接受埃克替尼单药治疗者,但差异无统计学意义（P＞0.05）。RR和DCR与年龄、性别、病理类型、PS评分、脑转移数目、埃克替尼治疗情况、脑部放疗及表皮生长因子受体（EGFR）突变状况均无关。全组中位无进展生存时间（PFS）为6.5个月（95％CI：4.787～8.213个月）,其中EGFR突变型为10.1个月。PFS与EGFR 基因突变状况有关,而与其他临床病理特征无关。主要不良反应为皮疹、皮肤干燥和腹泻,以1～2级为主。结论 埃克替尼对NSCLC 脑转移有一定疗效,且不良反应可耐受,值得进一步研究。     

Phase II combination of gefitinib and docetaxel for advanced or metastatic non-small cell lung cancer: clinical results and biological monitoring

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 (250 mg/day) in combination with docetaxel (75 mg/m² IV every 3 weeks). 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.     

Pharmacogenomics of EGFR-targeted therapies in non-small cell lung cancer:EGFR and beyond

Commonly observed aberrations in epidermal growth factor receptor (EGFR) signaling have led to the development of EGFR-targeted therapies for various cancers, including non–small cell lung cancer (NSCL...     

非小细胞肺癌中磷酸化Akt蛋白表达研究

背景与目的表皮生长因子受体(EGFR)信号传导通路下游分子Akt的激活在肺癌进展的过程中有重要作用,但磷酸化Akt蛋白的表达是否与EGFR表达存在相关性以及是否能提示患者的预后目前尚无定论。本研究旨在评价国人非小细胞肺癌组织中磷酸化Akt蛋白表达的意义。方法应用组织微阵列和免疫组织化学技术检测167例NSCLC手术标本中磷酸化Akt蛋白的表达。结果磷酸化Akt蛋白在NSCLC中的阳性表达率为52.1%(87/167),阳性表达率与性别、发病年龄、吸烟情况、病理类型、分化程度、病理分期及预后之间的相关性无统计学显著意义(P>0.05),并且磷酸化Akt与表皮生长因子受体蛋白表达之间的相关性亦无统计学意义(P=0.122)。结论国人非小细胞肺癌组织中磷酸化Akt阳性表达与患者临床病理特征无明显相关性,并且磷酸化Akt蛋白对患者预后无提示意义。     

吉非替尼治疗晚期复治性非小细胞肺癌的临床研究

目的探讨应用吉非替尼(IRESSA)治疗晚期非小细胞肺癌(NSCLC)患者的疗效及其对生活质量的影响。方法既往化疗失败的Ⅲb-Ⅳ期NSCLC患者41例,其中二线化疗失败者占85.4%(35/41)。IRESSA 250 mg口服,每日1次,服药至病情进展或出现不能耐受的不良反应。患者分别在治疗后1个月、2个月和以后每3个月复查。结果本组41例患者均可评价疗效,其中PR 18例,SD 14例,PD 9例,有效率为43.9%(18/41),疾病控制率(PR SD)为78.0%(32/41)。男性患者和女性患者的有效率分别为42.1%和45.5%(P>0.05)。至随访结束,41例患者中,有22例(53.7%)存活,其中位生存时间(MST)为10.1个月;19例死亡患者的疾病进展时间(TTP)为2.7个月,MST为5.0个月;PR患者的MST为13.3个月。全组患者症状改善率为78.0%。服药28 d,KPS评分提高20±5分,无Ⅲ-Ⅳ度毒性反应。结论IRESSA单药对化疗失败的晚期NSCLC疗效确切,并可用于一般状况评分较差的患者,其不良反应轻,是二三线用药的良好选择。     

老年晚期非小细胞肺癌患者ＥＧＦＲ基因的突变研究

目的　探讨老年晚期非小细胞肺癌（ＮＳＣＬＣ）患者ＥＧＦＲ基因突变情况及其与临床病理特征之间的关系。方法　采用ＰＣＲ扩增和实时荧光ＰＣＲ技术分析ＮＳＣＬＣ中ＥＧＦＲ基因第１９和２１号外显子的突变情况。结果　８６例老年ＮＳＣＬＣ酪氨酸激酶域存在体细胞突变２５例（２９.１％）,其中第１９号外显子的缺失突变为１３例（１５.１％）,第２１号外显子的替代突变为１２例（１４.０％）。肺腺癌、肺泡癌的突变率为３６.４％（２４／６６）,高于鳞癌的６.３％（１／１６）;女性患者突变率为４８.３％（１４／２９）,高于男性患者的１９.３％（１１／５７）;非吸烟患者的突变率为４３.９％（１８／４１）,高于长期吸烟者的１５.６％（７／４５）。结论 中国老年ＮＳＣＬＣ患者ＥＧＦＲ基因酪氨酸激酶区第１９和２１外显子的突变特征与肺癌总体患者类似,与年龄关系不大,突变率以腺癌、女性及非吸烟者较高。老年ＮＳＣＬＣ患者同样可以通过基因检测获得ＴＫＩ治疗预测信息。     

EGFR inhibitors with concurrent thoracic radiation therapy for locally advanced non-small cell lung cancer

Currently, a combination of chemotherapy and radiotherapy is the standard treatment approach for locally advanced non-small cell lung cancer (NSCLC). However, the clinical outcomes are still disappointing, with the 5-year survival rate being only approximately 20%. Further improvement in treatment outcome for patients with locally advanced NSCLC will require the development of more effective combined-modality therapies. Increasing attention has focused on the integration of targeted agents into current therapies. Many preclinical studies in this area have targeted the epidermal growth factor receptor (EGFR) signaling pathway to increase radiosensitivity. The in vitro rationale for targeting EGFR and concurrent ionizing radiation is well established, but to date, rare clinical data could provide proof-of-principle. In this review article, we briefly discuss pre-clinical data and the rationale and report all the different published clinical trials focusing on efficacy and toxicity in order to clarify and to summarize the present state-of-the-art of this particular combination in NSCLC.     

吉非替尼治疗晚期非小细胞肺癌的临床研究

目的:总结吉非替尼治疗晚期非小细胞肺癌的近期疗效及副作用。方法:40例经放化疗失败的非小细胞肺癌患者进入本研究,其中8例局限于胸腔内,32例已有远处转移。口服吉非替尼250mg/次,每天1次。全组服药的中位时间为5个月。按照WHO标准统一评定疗效及副反应。结果:40例可评价病例中完全缓解2例,部分缓解10例,病情稳定12例,病情进展16例。全组有效率为30%,疾病控制率为60%,症状缓解率为30%,缓解最明显的症状为咳嗽和疼痛。中位生存期5·6个月(1~20个月),中位进展时间(TTP)为(6·6±1·8)个月,1年生存率为45%。主要的毒副作用是皮疹,共发生25例,占全组的62·5%,其它副作用有腹泻、恶心、脱发,无1例因毒副反应退出。结论:吉非替尼对晚期非小细胞肺癌有明显的抗肿瘤作用,是一种有效且具有良好耐受性的治疗药物。     

突变特异性免疫组织化学法检测非小细胞肺癌EGFR基因突变

背景与目的：表皮生长因子受体(epidermal growth factor receptor,EGFR)基因的突变状态是非小细胞肺癌(non-small cell lung cancer,NSCLC)患者使用EGFR酪氨酸激酶抑制剂(tyrosine kinase inhibitors, TKIs)的重要疗效预测指标。该研究旨在探讨突变特异性免疫组织化学(immunohistochemistry,IHC)法检测NSCLC标本EGFR基因突变的临床实用价值。方法：同时采用突变特异性IHC法和扩增阻滞突变系统(amplifi-cation refractory mutation system,ARMS)法检测290例NSCLC患者的EGFR基因突变状态,计算突变特异性IHC法检测EGFR基因突变的灵敏度、特异度、阳性预测值(positive predictive value,PPV)和阴性预测值(negative predictive value,NPV);比较ARMS法和突变特异性IHC法检测EGFR突变的一致性。结果：以ARMS法检测结果为金标准,当染色评分≥1+为阳性时,突变特异性IHC法诊断EGFR基因突变的灵敏度为72.92%,特异度为95.20%,PPV为93.75%,NPV为78.08%。突变特异性IHC法诊断不同类型EGFR基因突变的准确性相差明显：诊断19外显子缺失突变的灵敏度只有55.55%,但其特异度在99%以上;当染色评分为1+时,诊断L858R突变的灵敏度为90.27%,特异度为95.86%,当染色评分为2+或3+时,其特异度则为98.63%~100%。突变特异性IHC法与ARMS法检测结果有较好的一致性(P<0.001,Kappa值：0.612~0.864)。突变特异性IHC法能直观判断EGFR基因突变细胞丰度。结论：突变特异性IHC法是EGFR突变分子检测的有效补充。     

厄洛替尼治疗中国晚期非小细胞肺癌患者的疗效和安全性

目的 观察厄洛替尼治疗中国晚期非小细胞肺癌(NSCLC)患者的疗效和安全性.方法 2005年11月至2009年3月,用厄洛替尼150 mg/d治疗519例中国晚期NSCLC患者,持续治疗至疾病进展或发生不能耐受的不良反应、或由于任何其他原因退出试验为止,评价缓解率、疾病进展时间(TTP)、总生存期(OS)和药物不良反应.结果 519例患者中,有38例未进行肿瘤评价或无肿瘤评价数据,有2例不可评价近期疗效.479例可评价近期疗效的患者中,完全缓解(CR)1例,部分缓解(PR)127例,疾病稳定(SD)263例,疾病进展(PD)88例,总缓解率为26.7%,疾病稳定率为54.9%,疾病控制率为81.6%.全组患者的中位TTP为6.44个月,中位OS为15.37个月,1年生存率为60.3%.厄洛替尼治疗过程中常见的不良反应有皮疹、瘙痒、皮肤干燥、腹泻、恶心、呕吐、口腔炎、腹痛、疲劳、呼吸困难、咳嗽、食欲减退、感染、结膜炎及干性角膜结膜炎,大部分为轻到中度,仅有3例(0.6%)患者发生与厄洛替尼治疗相关的严重不良反应,其中1例因间质性肺病并发呼吸衰竭而死亡.结论 厄洛替尼治疗中国晚期NSCLC患者的疗效明确,耐受性较好,是治疗晚期NSCLC的最佳选择之一.     

A multicenter phase II study of cetuximab in combination with chest radiotherapy and consolidation chemotherapy in patients with stage III non-small cell lung cancer

Background

Cetuximab has demonstrated improved efficacy in combination with chemotherapy and radiotherapy. We evaluated the integration of cetuximab in the combined modality treatment of stage III non-small cell lung cancer (NSCLC).

Methods

Patients with surgically unresectable stage IIIA or IIIB NSCLC were treated with chest radiotherapy, 73.5 Gy (with lung and tissue heterogeneity corrections) in 35 fractions/7 weeks, once daily (63 Gy without heterogeneity corrections). Cetuximab was given weekly during radiotherapy and continued during consolidation therapy with carboplatin and paclitaxel up to a maximum of 26 weekly doses. The primary endpoint was overall survival. Baseline tumor tissue was analyzed for EGFR by fluorescence in situ hybridization (FISH).

Results

Forty patients were enrolled in this phase II study. The median overall survival was 19.4 months and the median progression-free survival 9.3 months. The best overall response rate in 31 evaluable patients was 67%. No grade 3 or 4 esophagitis was observed. Three patients experienced grade 3 rash; 16 patients (69%) developed grade 3/4 neutropenia during consolidation therapy. One patient died of pneumonitis, possibly related to cetuximab. EGFR gene copy number on baseline tumor tissues, analyzed by FISH, was not predictive of efficacy outcomes.

Conclusions

The addition of cetuximab to chest radiotherapy and consolidation chemotherapy was tolerated well and had modest efficacy in stage III NSCLC. Taken together with the lower incidence of esophagitis, our results support evaluation of targeted agents instead of chemotherapy with concurrent radiotherapy in this setting.     

易瑞沙在24例化疗后进展的晚期非小细胞肺癌中的作用

背景与目的 易瑞沙（Iressa）是小分子表皮生长因子受体酪氨酸激酶抑制剂，主要用于治疗晚期非小细胞肺癌（NSCLC）。本研究探讨易瑞沙单药治疗化疗后进展的晚期非小细胞肺癌的疗效与不良反应。方法 24例化疗后进展的晚期NSCLC患者接受治疗，其中二线以上治疗后进展者占62．5％。易瑞沙250mg口服，每日1次，服用至疾病进展或出现不可耐受的不良反应。治疗后每4周复查一次，16周后每8周复查一次。结果本组24例患者均可评价疗效。其中完全缓解1例，部分缓解8例，无变化3例，进展12例。有效率为37．5％，稳定率为12．5％，临床获益率为50．0％，中位肿瘤进展时间为87天。随访2年，1和2年生存率分别为33．3％和12．5％。常见不良反应为Ⅰ、Ⅱ度皮肤改变和腹泻，未发生Ⅲ度以上不良反应。有2例患者因怀疑发生肺部间质性改变而结束治疗。结论 易瑞沙治疗化疗后进展的晚期NSCLC的疗效显著，不良反应轻，是晚期NSCLC患者二、三线用药的最佳选择之一。     

三维适形加量放射治疗非小细胞肺癌

目的：探讨三维适形加量放射治疗非小细胞肺癌（NSCLC）的优势。方法：21例非小细胞肺癌,CT模拟机定位,输入TPS（Pinnacle^3 7．4／7．6）,勾画GTV1,先常规或三维适形放疗30Gy／15F～50Gy／25F,第2次CT定位,勾画GTV2,予三维适形放射治疗至66Gy／33F～70Gy／35F。结果：GTV2与GTVl相比,平均缩小比例39．5％,13例大于40％。近期疗效：CR19．0％,PR71．4％,NC9．5％,总有效率（CR＋PR）90．5％,1年生存率85．7％。早期放射性肺损伤：1级13例（61．9％）,2级6例（28．6％）,3级2例（9．5％）。放射性食管炎：1级15例（71．4％）,2级6例（28．6％）。后期放射肺纤维化：0级2例（9．5％）,1级15例（71．4％）,2级4例（19．0％）。结论：三维适形加量放射治疗NSCLC过程中,肿瘤平均退缩比例为39．5％,再次重新勾画GTV并加量,可以有效地减少治疗范围,提高靶区剂量,降低放射治疗副反应。     

广西壮族非小细胞肺癌患者EGFR基因突变的研究

目的研究广西壮族非小细胞肺癌患者表皮生长因子受体（EGFR）基因突变的情况。方法收集163例广西壮族非小细胞肺癌（NSCLC）组织,采用ARMS（amplificationrefractorymutationsystem,ARMS）法PCR扩增检测EGFR基因外显子18、19、20及21的突变,进一步分析其突变与临床特征的关系,并与文献报道国内8个省、市的数据进行比较。结果163例NSCLC中共检出73例EGFR基因突变,EGFR突变阳性率为44．8％,显著高于文献报道国内8个省市的总体水平（30．0％）（P〈0．05）。其中,外显子19和21突变各占突变总数38．4％。腺癌和腺鳞癌突变发生率占突变总数的80．8％,女性EGFR基因突变率（57．7％）显著高于男性（38．7％）（P〈0．05）。结论广西壮族NSCLC患者EGFR基因突变率显著高于中国8个省、市的总体水平,其中以外显子19和21突变为多见。女性、腺癌和腺鳞癌患者是选用EGFR酪氨酸激酶抑制剂的优势人群。     

EGFR mutation frequency and effectiveness of erlotinib: A prospective observational study in Danish patients with non-small cell lung cancer

Objectives

In 2008, we initiated a prospective study to explore the frequency and predictive value of epidermal growth factor receptor (EGFR) mutations in an unselected population of Danish patients with non-small cell lung cancer offered treatment with erlotinib, mainly in second-line.

Materials and methods

Four hundred and eighty eight patients with advanced NSCLC were included. The mutation status was assessed using the cobas^® EGFR Mutation Test. Erlotinib was administrated (150 mg/d) until disease progression or unacceptable toxicities occurred. The primary endpoint was progression-free survival. Secondary endpoints were overall survival and response.

Results

Biopsies were retrieved from 467 patients, and mutation results obtained for 462. We identified 57 (12%) patients with EGFR mutations: 33 exon 19 deletions, 13 exon 21 mutations, 5 exon 18 mutations, 3 exon 20 insertions, 1 exon 20 point mutation (S768I), and two complex mutations. Seven percent of the patients were never smokers. The differences in median progression-free survival and overall survival between the mutated group and the wild-type group were 8.0 vs. 2.5 months, p < 0.001 and 12.1 vs. 3.9 months, p < 0.001. Performance status (0–1 vs. 2–3) and line of treatment (1st vs. 2nd and 3rd) had no influence on outcome in EGFR-mutated patients.

Conclusion

We found a higher frequency of EGFR mutations than expected in a cohort with less than 10% never smokers. The outcome after treatment with erlotinib was much better in patients with EGFR mutations than in patients with wild-type EGFR and was independent of performance status and treatment line in EGFR-mutated patients.     

非小细胞肺癌EGFR-TKIs耐药——小细胞肺癌转化的机制和治疗

肺癌是当前死亡率最高的恶性肿瘤之一。表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）明显提高了晚期非小细胞肺癌（NSCLC）患者的生活质量,延长了生存期。EGFR基因优势突变的NSCLC患者临床获益明显,然而由于耐药产生,患者的中位无进展生存期（PFS）仅1年左右。最近,有文献报道EGFR TKIs耐药的机制之一是NSCLC转化为小细胞肺癌（SCLC）。本文对这种现象进行了分析总结,探讨了其转化的可能机制。根据EGFR-TKIs耐药后的处理方法和病理表型转化患者的治疗报道,探讨NSCLC EGFR-TKIs耐药后转化为SCLC患者的治疗策略。     

Erlotinib usage after prior treatment with gefitinib in advanced non-small cell lung cancer: A clinical perspective and review of published literature

Erlotinib and gefitinib are among the most widely researched, used and available molecularly targeted therapies for treatment of advanced non-small cell lung cancer (NSCLC). They are both tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR). In the past decade, there have been reports on clinical benefit from use of erlotinib after gefitinib failure in NSCLC patients. A review of published literature on this focussed topic is provided herein. Pooled analysis of published literature shows that majority of patients were female (60.6%), non-smokers (64.5%), had adenocarcinoma histology (88.3%) and were of East Asian ethnicity (92.3%). Presence of sensitizing EGFR mutation was detected in 48.4% of subjects. Disease control rates with prior gefitinib therapy and with subsequent erlotinib treatment were 79.4% and 45.4% respectively. Based upon our review, the most important predictive factor for clinical benefit from erlotinib identified was previous response to gefitinib. The exact explanations for the potential benefit from erlotinib use in this patient population is still not known and further studies are required to determine the role of molecular mechanisms especially those related to resistance to initial EGFR TKI therapy.     

Phase I study of the combination of nedaplatin and weekly paclitaxel in patients with advanced non-small cell lung cancer

Purpose This trial was conducted to determine the maximum tolerated dose (MTD), principal toxicity, and recommended dose for phase II study of the combination of nedaplatin and weekly paclitaxel in patients with advanced non-small cell lung cancer (NSCLC). Methods Patients with previously untreated NSCLC, either stage IIIB with pleural effusion or stage IV, were eligible if they had a performance status of 0–2, were 75 years or younger, and had adequate organ function. The respective doses of nedaplatin (day 1) and weekly paclitaxel (days 1, 8, and 15) studied were 80/60, 80/70, 80/80, 80/90, and 100/90 (mg m⁻²), repeated every 4 weeks. Results From May 2004 through June 2005, 21 patients (18 men and 3 women; median age, 63 years; age range, 53–75 years) were enrolled. The MTD was determined to be 100 mg m⁻² of nedaplatin and 90 mg m⁻² of weekly paclitaxel. Dose-limiting toxicities at the MTD were neutropenic fever and hepatic dysfunction. We recommend doses of 80 mg m⁻² of nedaplatin and 90 mg m⁻² of weekly paclitaxel for phase II study. Grade 3–4 hematologic toxicities included neutropenia in 29% of patients, thrombocytopenia in 0%, and anemia in 5%. Although the most frequent non-hematologic toxicity was hepatic dysfunction, all cases were only mildly to moderately severe. Although two patients had grade 3 or 4 pulmonary toxicity due to Pneumocystis carinii pneumonia, these patients recovered after receiving trimetoprim-sulfamethoxazole, steroid therapy, and supplemental oxygen. There were no treatment-related deaths. The overall response rate was 19.0% (95% confidence interval, 5.4–41.9%), and all responses were in patients receiving the recommended doses. The median dose-intensities for nedaplatin and paclitaxel were 91.6 and 87.1%, respectively, of the planned doses. Conclusion This combination chemotherapy is active and well tolerated and warrants phase II study.     

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.