第三代EGFR-TKI奥希替尼临床研究进展

奥希替尼是第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）,被批准用于治疗EGFR T790M突变阳性的局部晚期或转移性非小细胞肺癌（NSCLC）的抗肿瘤药物。其疗效显著,耐受性较好,副作用较第一、二代EGFR-TKI更易被接受。对已接受其他EGFR-TKI治疗且出现耐药的患者,奥希替尼可为该类患者带来新的选择。2017年3月22日国家食品药品监督管理总局（CFDA）加速批准了阿斯利康公司的甲磺酸奥希替尼片的进口申请。现就奥希替尼的作用机制、上市情况、临床实验、药动学、耐受性和安全性进行综述,为临床应用提供参考。     

非小细胞肺癌表皮生长因子受体–酪氨酸激酶抑制剂的研究进展及其耐药后治疗策略

肺癌是全球死亡率最高的癌症之一,非小细胞肺癌占肺癌总人群的85%以上。约2/3的非小细胞肺癌患者在诊断时已为晚期,内科治疗是晚期非小细胞肺癌患者的主要治疗手段。近些年随着靶向治疗药物表皮生长因子受体–酪氨酸激酶抑制剂（EGFR-TKI）分子治疗的出现,非小细胞肺癌患者的治疗取得了明显的成效。但是EGFR-TKI耐药问题也接踵而至,总结了非小细胞肺癌患者EGFR-TKI治疗进展以及耐药后的治疗策略,为临床选择适合患者个体化治疗方案提供参考。     

EGFR-TKI耐药后继续应用原TKI联合化疗与单纯化疗疗效比较

目的:研究表皮生长因子受体-酪氨酸酶抑制剂(EGFR-TKI)治疗中晚期肺癌发生耐药后行原TKI联合化疗较单纯化疗有无生存获益。方法:回顾性分析一线化疗联合第一代EGFR-TKI治疗中晚期肺癌发生耐药65例,按照后续治疗方案的不同分为单纯组(单纯培美曲塞化疗)35例和联合组(原TKI联合培美曲塞化疗)30例,比较两组疾病控制率(DCR)、无进展生存期(PFS)及和总生存期(OS)。结果:DCR单纯组51.43%,显著低于联合组的80.00%(P<0.05);中位FPS单纯组6.0个月,显著低于联合组的8.0个月(P<0.05);中位OS单纯组8.0个月,显著低于联合组的10.0个月(P<0.05)。结论:在耐药后使用原TKI联合培美曲塞化疗疗效优于单纯应用培美曲塞化疗,且在Ⅳ期肺癌患者中效果更好,而不良反应可耐受。     

艾迪注射液联合GP方案治疗EGFR-TKI获得性耐药的晚期非小细胞肺癌疗效观察

目的观察艾迪注射液联合GP化疗方案治疗表皮生长因子酪氨酸激酶抑制剂(EGFR-TKI)治疗失败后的晚期非小细胞肺癌(NSCLC)的临床疗效。方法选取2011年12月—2013年12月襄阳市中心医院接受EGFR-TKI治疗后出现获得性耐药的62例晚期NSCLC患者,分为对照组和治疗组,每组各31例。对照组给予GP方案常规化疗:注射用盐酸吉西他滨1 000 mg/m2,1次/d,持续静脉滴注3 h,第1、8天给药;顺铂注射液75 mg/m2,1次/d,静脉滴注,第1天给药。21天为1个周期,连续观察2个周期。治疗组在对照组的基础上静脉滴注艾迪注射液,50 m L溶于5%葡萄糖溶液500 m L静滴,1次/d,2周为1个疗程,连续使用3个疗程。评价两组患者的近期疗效指标客观有效率(ORR)、疾病控制率(DCR)以及远期疗效指标无进展生存期(PFS)、总生存期(OS)。患者的生活质量(KPS)以Karnofsky评分进行评定。对毒副反应进行评价。结果 62例患者均可评价疗效,其中治疗组ORR 61.29%,DCR 83.87%,对照组ORR 35.48%,DCR 70.97%,治疗组的ORR、DCR均明显高于对照组,两组比较差异具有统计学意义(P0.05、0.01)。治疗组中位PFS为6.3(1.2~20.6)个月,对照组中位PFS为3.4(0.7~10.3)个月,两组比较差异具有统计学意义(P0.05)。治疗组死亡患者的中位OS为15.1(1.4~28.2),对照组死亡患者的中位OS为8.9(1.0~17.2)个月,两组患者中位OS差异无统计学意义。治疗后,治疗组患者的KPS评分显著高于对照组,两组比较差异具有统计学意义(P0.01)。治疗组不良反应发生率为32.3%,对照组不良反应发生率为37.8%,两组不良反应发生率比较无显著性差异。治疗组胃肠道反应发生率为38.7%(12/31),对照组胃肠道反应发生率为51.6%(16/31),与对照组比较显著减少(P0.01)。结论艾迪注射液联合GP化疗方案治疗EGFR-TKI获得性耐药的晚期NSCLC的疗效较好,能延缓疾病进展,延长生存期,提高生存质量,且减轻化疗带来的胃肠道反应,值得临床进一步研究。     

非小细胞肺癌EGFR-TKI耐药后化疗序贯TKI治疗的效果

目的评价铂类化疗药物联合白蛋白结合型紫杉醇序贯酪氨酸激酶抑制剂(TKI)治疗TKI耐药后进展期非小细胞肺癌(NSCLC)患者的疗效和安全性。方法 21例晚期NSCLC患者均口服吉非替尼250mg/d或厄洛替尼150mg/d,耐药后改换铂类药物联合白蛋白结合型紫杉醇化疗序贯原TKI治疗,直到病情进展或不良反应不能耐受为止。观察临床疗效、不良反应以及疗效与临床特征之间的关系。结果 21例患者耐药后序贯治疗的有效率为14.3%,疾病控制率为66.7%,中位疾病进展时间(TTP)为155d。序贯治疗获益的14例患者TTP较未获益的7例患者增加(200d vs.101d)(P<0.01);与6例野生型患者相比,7例敏感突变患者TTP增加(234dvs.90d)(P<0.05);但二线和三线序贯治疗患者TTP比较无统计学差异(P>0.05)。序贯治疗后主要不良反应为轻度皮疹、腹泻及血液学毒性。结论铂联合白蛋白结合型紫杉醇化疗序贯TKI治疗表皮生长因子受体-TKI获得性耐药后NSCLC近期疗效较好,可作为TKI耐药后患者的选择。     

Pharmacokinetic drug evaluation of osimertinib for the treatment of non-small cell lung cancer

Introduction: First- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, erlotinib, icotinib, and afatinib are the standard-of-care for first-line therapy of non-small-cell lung cancer (NSCLC) harboring activating EGFR mutations. Unfortunately, after initial activity of an average 9–13 months, disease progression has been reported in the majority of patients. In about 50% of cases the progression is due to the onset of the T790M mutation in exon 20 of the EGFR gene. Third-generation EGFR-TKIs targeting this mutation were investigated, with osimertinib the only reaching clinical practice.

Areas covered: A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question addressing osimertinib, was undertaken.

Expert opinion: Osimertinib is the standard-of-care for EGFR-mutated patients progressing to first-line EGFR-TKIs due to the acquired EGFR T790M mutation. Results from the head-to-head first-line trial comparing osimertinib versus gefitinib or erlotinib in activating EGFR mutations might change the front-line approach. Osimertinib in combination regimens, such as immunotherapy, and in adjuvant setting are ongoing. Thus, the strategic approach for the management of EGFR-mutated NSCLC patients will change further in the next few years.     

Pharmacogenomics in non-small-cell lung cancer chemotherapy

The disappointing results in long-term survival of patients who have a resectable non-small cell lung cancer (NSCLC) may reflect the lack of knowledge on the way by which molecular abnormalities in neoplastic cells affect responsiveness to adjuvant therapy. This issue deserves intensive investigation to select methodological approaches for a new generation of chemotherapeutic strategies. Remarkable advances in the understanding of NSCLC biology have been made, including the discovery of critical mutations in oncogenes (i.e. K-Ras and c-myc), as well as the loss of tumor-suppressor genes, such as TP53, p16^INK4 or Rb. Other studies demonstrated the role of mutations or deregulation of the expression of several molecular determinants involved in cell cycle control such as epidermal growth factor receptor (EGFR). All these characteristics, as well as alterations in gene products directly related to drug activity, might contribute to the aggressive behaviour of NSCLC. The future challenge of chemotherapy of NSCLC relies on the identification of molecular markers that are predictive of drug sensitivity and are helpful in the selection of chemotherapeutic agents best suited to the individual patient. Other intriguing issues will be the identification of the optimal drug sequence in combination regimens and the pharmacogenetics of severe toxicities. Moreover, due to the developments of novel technologies to decipher genetic alterations involved in tumor progression, new agents are gaining momentum, including inhibitors of intracellular signal transduction, and a large body of research, using prospective clinical trials, should be devoted to this area.     

Targeting epidermal growth factor receptor in the treatment of non-small-cell lung cancer

Importance of the field: The management of non-small-cell lung cancer (NSCLC) has undergone a paradigm shift in the last decade, with the survival advantage demonstrated by the incorporation of anti-epidermal growth factor receptor (EGFR) agents to the standard treatment of advanced/metastatic NSCLC.

Areas covered in this review: We review the existing data regarding the distinct anti-EGFR agents in the NSCLC treatment and the potential role of the investigated biomarkers in the clinical outcome.

What the reader will gain: Tyrosine kinase inhibitors have been used in first-line, second-line and more settings with extremely good results in a subgroup of patients. Cetuximab remains the only anti-EGFR monoclonal antibody to show survival benefit when combined with a cytotoxic agent in the front-line setting. Anti-EGFR treatment is associated with a dramatic clinical benefit in a subgroup of patients, emphasizing the importance of customizing treatment. Several biomarkers have been investigated for their predictive or prognostic value. Validation of identification of biomarkers remains a focus of intense research that may ultimately guide therapeutic decision making, as none of these is considered ideal to discriminate responding from non-responding patients. However, the current evidence of the EGFR mutation analysis from a recent randomised trial suggests that EGFR mutation analysis is quite a good predictive marker for responsiveness to anti-EGFR TKIs. Moreover, the identification of surrogate markers to indicate optimal activity of the anti-EGFR agent is also needed. This review article provides data from large clinical trials using anti-EGFR agents and correlates these results with the tested biomarkers.

Take home message: EGFR inhibition has shown very encouraging results and has improved the outcome of the NSCLC treatment. However, a plateau of significant clinical benefit seems to have been reached and we believe that the time to move away from the traditional treatment approach to more individualizing therapies has come.     

Alectinib for ALK-positive non-small-cell lung cancer

Introduction: Anaplastic lymphoma kinase (ALK) rearrangements are present in about 5% of advanced non-small-cell lung cancer (NSCLC) patients. Despite the initial response, after a median of 1-2 years, ALK-positive patients developed an acquired resistance to the ALK-inhibitor crizotinib. Among the most promising second-generation ALK-inhibitors, alectinib is being investigated in crizotinib-naïve and -resistant ALK-positive NSCLC patients.

Areas covered: The current state-of-the-art of ALK-inhibitors treatment, and in particular the role of alectinib in this setting, is reviewed and discussed. A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question was undertaken.

Expert commentary: Alectinib reports promising results with a good safety profile, becoming a potentially very important option for ALK-translocated NSCLC patients. The preliminary results from the J-ALEX phase III randomized trial performed in ALK-rearranged NSCLC Japanese patients showed a better activity and tolerability of alectinib versus crizotinib.     

Erlotinib in non-small-cell lung cancer

Epidermal growth factor receptor (EGFR) plays an essential role in normal cell growth and differentiation, and is involved in tumour proliferation and survival. EGFR overexpression is a common feature in solid malignancies, including non-small-cell lung cancer (NSCLC), and is associated with poor clinical prognosis. Erlotinib is a small-molecule inhibitor of EGFR tyrosine kinase, showing a significant improvement in median survival, quality of life and related symptoms in an unselected population of advanced NSCLC patients in the second- or third-line setting. Erlotinib is well tolerated (with common toxicities including rash and diarrhoea) when administered at a standard oral daily dose of 150 mg. Further investigations are ongoing to contribute to our understanding of the role of erlotinib in NSCLC treatment.     

Protein kinase inhibitors to treat non-small-cell lung cancer

Introduction: Activating mutations of the EGFR and rearrangement of anaplastic lymphoma kinase (ALK) best illustrate the therapeutic relevance of molecular characterization in NSCLC patients.

Areas covered: For this review article, all published data on the most relevant Phase III trials with tyrosine kinase inhibitors (TKIs) for the treatment of NSCLC were collected and analyzed.

Expert opinion: Eight Phase III trials clearly established EGFR TKIs as the best therapeutic option for front-line therapy in EGFR-mutated patients. In pretreated NSCLC, EGFR TKIs are considered more effective than standard monotherapy with cytotoxics in presence of classical EGFR mutations, whereas in the EGFR wild-type population, a similar efficacy to docetaxel or pemetrexed in term of survival has been demonstrated. In ALK-translocated NSCLC, a Phase III trial demonstrated the superiority of a multi-target TKI, including ALK, in terms of progression-free survival, response rate and toxicity profile when compared to standard second-line chemotherapy. New agents targeting EGFR or ALK are under evaluation particularly in individuals with acquired resistance to EGFR TKIs or crizotinib.     

Strategies to overcome resistance to tyrosine kinase inhibitors in non-small-cell lung cancer

The use of molecularly targeted agents has dramatically improved the prognosis of defined subsets of patients with non-small-cell lung cancer harboring somatically activated oncogenes, such as mutant EGFR or rearranged ALK. However, after initial marked responses to EGFR or ALK tyrosine kinase inhibitors (TKIs), almost all patients inevitably progress due to development of acquired resistance. Multiple molecular mechanisms of resistance have been identified; the best characterized are secondary mutations in the tyrosine kinase domain of the oncogene, such as T790M in EGFR and L1196M in ALK, which prevent target inhibition by the corresponding TKI. Other mechanisms include copy number gain of the ALK fusion gene and the activation of bypass signaling pathways that can maintain downstream proliferation and survival signals despite inhibition of the original drug target. Here, the authors provide an overview of the known mechanisms of resistance to TKIs and outline the therapeutic strategies, including new investigational agents and targeted therapies combinations, that have been developed to overcome resistance.     

Ginsenoside Rg3 attenuates the osimertinib resistance by reducing the stemness of non‐small cell lung cancer cells

In the present study, we found that Ginsenoside Rg3 attenuated the stemness of non‐small cell lung cancer (NSCLC) cells, evident by decreasing spheroid formation ability, ALDH1 activity and stemness marker expression. Furthermore, osimertinib‐resistant NSCLC cells displayed a stronger stemness than the parental cells. Ginsenoside Rg3 reduced the stemness and osimertinib resistance of osimertinib‐resistant cells. RNA‐sequencing revealed that Hippo signaling was shown on the top of the most upregulated pathways regulated by Ginsenoside Rg3 in NSCLC cells, and YAP/TAZ expression was suppressed by Ginsenoside Rg3. Notably, the inhibitor of Hippo signaling attenuated the effects of Ginsenoside Rg3 on the stemness of NSCLC cells. Therefore, Ginsenoside Rg3 attenuates the osimertinib resistance of NSCLC cells via suppressing the stemness, which is dependent on Hippo pathway.     

Targeting the EGFR T790M mutation in non-small-cell lung cancer

Introduction: The presence of activating mutations of the epidermal growth factor receptor (EGFR) is predictive of response to first- and second-generation tyrosine kinase inhibitors (TKIs) in patients with advanced non-small-cell lung cancer (NSCLC). However, patients that initially respond to these drugs inexorably become resistant. The T790M mutation in the exon 20 of the EGFR is the main mechanism of resistance to EGFR TKIs occurring in over 50% of the cases. Third generation EGFR TKIs have been shown to be active in patients who progressed after TKI treatment and carry the T790M mutation.

Areas covered: This review is focused on the implications of tumor heterogeneity for targeting the T790M in patients with NSCLC.

Expert opinion: Pre-clinical and clinical data suggest that the T790M is heterogeneously expressed in tumors that become resistant to first- and second-generation EGFR TKIs. These findings have important implications for the molecular diagnostic of the T790M mutation. Indeed, the analysis of both the circulating free tumor DNA (ctDNA) isolated from plasma and the tumor tissue might provide complimentary information to identify patients carrying the T790M mutation. However, further studies are needed to better understand the influence of tumor heterogeneity on the activity of drugs targeting the T790M.     

A semisynthetic cabazitaxel analogue,C1 overcomes P-gp-meditaed multidrug resistance in non-small-cell lung cancer

OBJECTIVE To investigate the effect of C1 against P-glycoprotein(P-gp)-meditaed multidrug resistance(MDR) in non-small-cell lung cancer cells. METHODS Human non-small-cell lung cancer(NSCLC) cell lines A549, H1299, H460, normal lung cell lines MRC5,taxol-resistant daughter line A549/TR and cisplatin-resistant daughter A549/CR were used to achieve this objective. Cell proliferation was analyzed by cytotoxicity assay,P-gp ATPase activity in vitro was detected by P-gp-Glo?Assay System, P-gp activity in vivo was determined by FACS analyses of intracellular accumulation of Rh123 in A549/TR and A549/CR cells, anti-tumor effect of C1 and taxol were evaluated by parental and drug-resistant cell xenograft of nude mice. RESULTS Cytotoxicity assay results showed that C1 potently inhibits cell proliferation in NSCLC cell lines but not in normal lung cells. However,C1 was more efficacious than taxol in the A549/TR-and A549/CR-treated cells that overproduced P-gp. The drugefflux function of P-gp depends on the ATP hydrolysis that reflects ATPase activity. Taxol, the most widely used taxoid in NSCLC treatment, could inhibit P-gp ATPase activity at lower concentrations, but stimulated it at higher concentrations. In contrast, C1 could significantly inhibit P-gp ATPase activity in a concentration-dependent manner.When the drug-resistant cells were treated in the presence of C1 at 0.1, 0.2 and 0.4 μmol·L-1, the intracellular accumulation of rhodamine 123 was higher than that in A549/TR and A549/CR treated with taxol at the same concentrations, respectively. These results indicated that C1 can reduce drug efflux through inhibiting the transmembrane pumping function of P-gp but not decreasing the expression of P-gp protein. We next compared the efficacy of TM2 and taxol in vivo using A549, A549-Taxol,and A549-CDDP xenograft models. In parental and drugresistant cell xenograft, C1 could significantly inhibit tumor growth in a dose-dependent manner. The TGI for the group receiving docetaxel treatment(8.5 mg · kg~(-1)) was 46.06% and 87.88% for the C1-treated group(10 mg·kg~(-1))in A549 xenografts. The maximal TGI of C1 was 80.4% in A549/TR xenografts, and 54.5% in A549/CR xenografts. Importantly, C1 produced a significant inhibition of tumor growth in drug-resistant cell xenografts, compared with taxol at the same dosing schedule and frequency.Additionally, C1 did not cause reduced body weight of the host mice or other side effects such as hair loss, mortality,and lethargy. CONCLUSION C1 overcomes P-gp-mediated MDR by directly inhibiting its transport function.     

非小细胞肺癌中EGFR突变与EGFR-TKI临床敏感性及耐药性的研究进展

目的阐述非小细胞肺癌(NSCLC)中表皮生长因子受体(EGFR)突变与表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)临床敏感性及耐药性之间的关系。方法分析总结已经发表的国内外相关文献,对非小细胞肺癌治疗中EGFR-TKI的敏感性和耐药性进行介绍。结果在NSCLC患者中用EGFR-TKI治疗有效性和EGFR活化性突变有着紧密的联系,二者都在亚洲人种,女性,不吸烟,腺癌患者中发生率较高;患者对EGFR-TKI耐药不仅与EGFR二次突变有关,还与KRAS突变,HER2过表达,蛋白酪氨酸磷酸酶基因(PTEN)缺失,胰岛素样生长因子受体1(IGFR-1)过表达等有联系。结论EGFR突变可作为临床衡量EGFR-TKI敏感性指标;耐药机制复杂多变,目前还没有完全研究清楚。     

Targeting the eicosanoid pathway in non-small-cell lung cancer

Multiple lines of evidence suggest that cyclooxygenase-2 (COX-2) upregulation is an early event in the development of non-small-cell lung cancer. Preclinical data indicate tumors with upregulation of COX-2 synthesize high levels of prostaglandin E₂ (PGE₂), which in turn are associated with increased production of proangiogenic factors and enhanced metastatic potential. These findings indicate that an increase in COX-2 expression may play a significant role in the development and growth of lung cancers and possibly with the acquisition of an invasive and metastatic phenotype. Consequently, inhibitors of COX-2 are being studied for their chemopreventative and therapeutic effects in individuals at high risk for lung cancer and patients with established cancers.     

Salinomycin overcomes acquired tamoxifen resistance through AIB1 and inhibits cancer cell invasion in endocrine resistant breast cancer

Salinomycin is a monocarboxylic polyether ionophore isolated from Streptomyces albus. It has been widely used as an antibiotic in veterinary medicine in poultry. A recent study demonstrated that salinomycin selectively inhibits human breast cancer stem cells; one possible mechanism of tamoxifen resistance. Our results show that salinomycin is effective in inhibiting MCF‐7/LCC2 and MCF‐7/LCC9 cell lines which are well‐established endocrine resistant cells and has a synergistic effect in combination with tamoxifen using MTT proliferation assay. The inhibitory effect of salinomycin on the reduction of critical ER co‐activator; amplified breast 1 (AIB1) mRNA and protein expression is overcoming tamoxifen resistance . Moreover, salinomycin significantly inhibits cell invasion in Matrigel invasion assay. The effect was mediated at least in part by the decrease of matrix metalopeptidase 9 (MMP‐9) which is one critical enzyme facilitated in the cell invasion process. In conclusion, salinomycin should be developed as a novel agent used alone or in combination for endocrine‐resistant breast cancer.     

Advances in chemotherapy in advanced non-small-cell lung cancer

Importance of the field: Lung cancer is the most common cancer in the world today, in terms of both incidence and mortality. Non-small-cell lung cancer (NSCLC) accounts for about 85% of all lung cancers diagnosis, and the majority of people diagnosed with NSCLC have advanced disease.

Areas covered in this review: In this review the main advances achieved in the medical treatment of advanced NSCLC are discussed, regarding both targeted therapies and chemotherapy. Among targeted therapies, recent data on the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab and the epidermal growth factor receptor tyrosyne kinase inhibitors (EGFR-TKIs) gefitinib and erlotinib are described. Among chemotherapeutic agents, the role of pemetrexed is discussed.

What the reader will gain: The reader will gain up-to-date information on the main advances, achieved in the last 3 years in the medical treatment of advanced NSCLC.

Take home message: Some recent advances have changed the face of the first-line chemotherapy of advanced NSCLC, giving physicians more options to tailor choice in this challenging setting.     

抗雌激素治疗对耐酪氨酸激酶抑制剂非小细胞肺癌细胞株抗增殖作用的机制探讨

目的 探讨氟维司群逆转吉非替尼耐药非小细胞肺癌细胞株耐药性的可能性及其机制.方法 分别用不同浓度的氟维司群和吉非替尼,单药以及联合对非小细胞肺癌细胞株H1975[含表皮生长因子受体(EGFR)L858R&T790m突变]、H1650(含EGFR Del E746-A750&PTEN De突变)、PC-9(含EGFR Del E746-A750突变)细胞进行干预后,采用MTT法检测细胞增殖变化,Western blot法检测EGFR、雌激素受体(ER)、磷酸化表皮生长因子受体(p-EGFR)的蛋白表达.结果①H1975、H1650、PC-9肺癌细胞中均有EGFR及ER表达;②吉非替尼及氟维司群联合用药较单药可明显抑制H1975、H1650、PC-9肺癌细胞的增殖(P<0.001);③H1975耐药细胞株内T790m突变型EGFR的磷酸化水平可以快速地被雌激素升高或被氟维司群抑制;④ 在酪氨酸激酶抑制剂(EGFR-TKI)获得性耐药的肺癌细胞株中雌激素、表皮生长因子(EGF)分别下调EGFR、ER的水平,氟维司群、吉非替尼分别上调EGFR、ER的水平.结论 采用EGFR的靶向治疗与抗雌激素治疗相结合的治疗方案提高EGFR和ER阳性的EGFR-TKI获得性耐药的NSCLC的治疗效果在理论上是可行的.