Efficacy of chemotherapy in epidermal growth factor receptor (EGFR) mutated metastatic pulmonary adenocarcinoma patients who had acquired resistance to first-line EGFR tyrosine kinase inhibitor (TKI)

Introduction: Salvage chemotherapy is frequently used when tumour epidermal growth factor receptor (EGFR) mutated patients experience disease progression with first-line EGFR-tyrosine kinase inhibitor (TKI) treatment. However, the efficacy of salvage chemotherapy is still unknown.

Methods: We retrospectively reviewed the chart records of our pulmonary adenocarcinoma patients between 2010 and 2013.

Results: Five hundred and six of the 1240 stage IV adenocarcinoma patients had an EGFR mutation and 338 received first-line EGFR-TKI treatment. In all, 169 patients in this group received salvage chemotherapy after failure of EGFR-TKI, and 102 patients were eligible for this study. The chemotherapy response rate of these 102 patients was 24.5%, with a median progression-free survival (PFS) of 4.5?months, and median survival time was 14.6?months. Patients who received pemetrexed-based chemotherapy had longer PFS and overall survival (OS), although the extent was statistically insignificant. Progression-free survival and OS were longer for patients who received combination chemotherapy than single-agent chemotherapy.

Conclusions: Pemetrexed-based combination chemotherapy is preferred before a more efficient treatment strategy is found.     

Strategies for overcoming resistance to EGFR family tyrosine kinase inhibitors

The first-generation epidermal growth factor receptor tyrosine kinase inhibitors erlotinib and gefitinib have been incorporated into treatment paradigms for patients with advanced non-small cell lung cancer. These agents are particularly effective in a subset of patients whose tumors harbor activating epidermal growth factor receptor mutations. However, most patients do not respond to these tyrosine kinase inhibitors, and those who do will eventually acquire resistance that typically results from a secondary epidermal growth factor receptor mutation (e.g., T790M), mesenchymal-epithelial transition factor amplification, or activation of other signaling pathways. For patients whose tumors have wild-type epidermal growth factor receptor, there are several known mechanisms of initial resistance (e.g., Kirsten rat sarcoma viral oncogene homolog mutations) but these do not account for all cases, suggesting that unknown mechanisms also contribute. To potentially overcome the issue of resistance, next-generation tyrosine kinase inhibitors are being developed, which irreversibly block multiple epidermal growth factor receptor family members (e.g., afatinib [BIBW 2992] and PF-00299804) and/or vascular endothelial growth factor receptor pathways (e.g., BMS-690514 and XL647). In addition, drugs that block parallel signaling pathways or signaling molecules downstream of the epidermal growth factor receptor, such as the insulin-like growth factor-1 receptor and the mammalian target of rapamycin, are undergoing clinical evaluation. As drug resistance appears to be pleomorphic, combinations of drugs or drugs with multiple targets may be more effective in circumventing resistance.     

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.     

Management of tyrosine kinase inhibitor resistance in lung cancer with EGFR mutation

The identification of driver mutations and drugs that inhibit their activity has been a major therapeutic advance for patients with advanced lung adenocarcinoma. Unfortunately, the success of these drugs is limited by the universal development of resistance. Treatment failure can result from inadequate drug exposure or selection of resistant malignant clones. Clinically distinct mechanisms of disease progression have been identified and can inform treatment decisions. Investigations into the biochemical mechanisms of tyrosine kinase inhibitor resistance may provide additional therapeutic targets by which the efficacy of targeted therapy can be improved.     

Reduced chemotherapy sensitivity in EGFR-mutant lung cancer patient with frontline EGFR tyrosine kinase inhibitor

Objectives

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a standard first-line treatment for EGFR-mutant patients with non-small cell lung cancer (NSCLC). However, it remains unclear whether frontline EGFR TKIs affect subsequent chemo-sensitivity in EGFR-mutant patients. This study compared chemo-sensitivity in patients treated with post-TKI chemotherapy and first-line chemotherapy controls.

Materials and methods

This study included 203 EGFR-mutant patients. The study group contained 68 patients treated with chemotherapy after first-line EGFR-TKI and the control group contained 135 patients who received first-line chemotherapy. The response rate (RR), progression-free survival (PFS) and overall survival (OS) were assessed.

Results

In study group, the RR of chemotherapy was 13.2% compared with 34.1% in the control group (P = 0.002). The median PFS of chemotherapy in the control group was significantly longer than in the study group (6.9 vs. 3.9 months, P < 0.001), while the RR (76.5% vs. 68.9%, P = 0.259) and PFS (11.0 vs. 10.2 months) of EGFR-TKI were similar between first- and second-line treatment. Cox regression analyses indicated that prior EGFR-TKI treatment had a higher risk for disease progression during chemotherapy treatment [hazard ratio (HR) = 3.06; 95% CI = 2.12–4.42, P < 0.001]. Median overall survival was 31.7 months in the control group and 23.5 months in the study group (P < 0.001). The adjusted HR for death in the study group was 1.91 (95% CI = 1.33–2.76; P < 0.001).

Conclusion

In EGFR-mutant patients, frontline EGFR-TKI significantly reduced the sensitivity of subsequent chemotherapy compared with that of TKI-naïve frontline chemotherapy. These findings need to be validated in further randomized trials.     

Breast cancer cells with acquired resistance to the EGFR tyrosine kinase inhibitor gefitinib show persistent activation of MAPK signaling

Although the epidermal growth factor receptor (EGFR) is frequently expressed in human primary breast carcinoma, the majority of breast cancer patients do not respond to treatment with EGFR tyrosine-kinase inhibitors such as gefitinib. We isolated through a stepwise dose escalation of the drug two gefitinib-resistant SK-Br-3 clones, ZD6 and ZD10 (ZD) cells, which showed, respectively, a three- to five-fold increase in the IC₅₀ for gefitinib as compared with parental cells. The levels of expression of EGFR were increased in ZD cells as compared with wild-type SK-Br-3 cells. The phosphorylation of EGFR, ErbB-2, ErbB-3 and Akt was significantly reduced in gefitinib-resistant cells. In contrast, ZD cells showed levels of MAPK phosphorylation similar to untreated wild-type cells when cultured in presence of gefitinib. Persistent activation of MAPK was also observed in gefitinib-resistant clones isolated from MDA-MB-175 and MDA-MB-361 breast cancer cell lines. ZD cells showed an increased sensitivity to the MEK inhibitor PD98059 as compared with SK-Br-3 cells, and a synergistic anti-tumor effect was observed when ZD cells were treated with a combination of gefitinib and PD98059. Overexpression of a constitutively activated form of p42-MAPK in SK-Br-3 cells resulted in an approximately 50% increase in the IC₅₀ to gefitinib. Finally, culture of ZD10 resistant cells in absence of gefitinib led to reversion of the resistant phenotype. These observations suggest that MAPK signaling might play a role in the resistance that develops in breast cancer cells after long-term exposure to gefitinib. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Clinical implications of T790M mutation in patients with acquired resistance to EGFR tyrosine kinase inhibitors

Objectives

Although T790M mutation is considered to be the major mechanism of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC), its clinical implication remains undetermined.

Methods

Post-progression tumor specimens were prospectively collected for T790M mutation analysis in NSCLC patients with acquired resistance to initial EGFR TKIs. Clinical features were compared between patients with and without T790M.

Results

Out of 70 cases, 36 (51%) were identified to have T790M mutation in the rebiopsy specimen. There was no difference in the pattern of disease progression, progression-free survival for initial TKIs (12.8 and 11.3 months), post-progression survival (14.7 and 14.1 months), or overall survival (43.5 and 36.8 months) in patients with and without T790M. In total, 34 patients received afatinib after post-progression biopsy as a subsequent treatment, and the response rate was 18%. The median progression-free survival for afatinib was 3.7 months for the entire group, and 3.2 and 4.6 months for the groups with and without T790M, respectively (P = 0.33).

Conclusions

The identification of T790M as acquired resistance mechanism was clinically feasible. Although T790M had no prognostic or predictive role in the present study, further research is necessary to identify patients with T790M-mutant tumors who might benefit from newly developed T790M-specific TKIs.     

ＥＧＦＲ-ＴＫＩｓ获得性耐药及耐药后治疗的进展

表皮生长因子受体酪氨酸激酶抑制剂（ＥＧＦＲ-ＴＫＩｓ）吉非替尼和厄洛替尼是用于化疗后失败或复发的晚期非小细胞肺癌的常用药物,随着对它们的深入研究,发现ＥＧＦＲ-ＴＫＩｓ的疗效与ＥＧＦＲ突变相关。然而,几乎所有接受ＥＧＦＲ-ＴＫＩｓ治疗的患者都会出现耐药,而获得性耐药后目前没有标准治疗方案。本文主要探讨ＥＧＦＲ-ＴＫＩｓ获得性耐药的定义,并对目前克服获得性耐药的临床研究作一综述。     

Screening for EGFR mutations in lung cancer, a report from India

Epidermal growth factor receptor (EGFR) is one of the targeted molecular markers in many cancers including the lung malignancy. Genetic modifications such as deletions, insertions and Single Nucleotide Polymorphisms in the tyrosine kinase (TK) domain of EGFR is a common feature observed in most lung cancers. Gefitinib and erlotinib are commonly available therapeutic drugs which act as specific inhibitors for the tyrosine kinase domain of EGFR and associated with EGFR mutations in exons 18-21. However the prevalence of mutation varies among ethnicity, grade, age and gender. This is the first report on the prevalence of EGFR mutation in non-small cell lung cancer patients using DNA obtained from samples such as biopsy/cytology/pleural fluid and Fine Needle Aspiration (FNA), across India. We have screened for 29 somatic mutations which span exons 18, 19, 20 and 21 of EGFR gene using Scorpion probe based ARMS-PCR technique. DNA from 220 NSCLC tissue samples were analyzed for EGFR mutations and mutations were detected in 51.8% of the study population. Among the mutant positive cases, the deletions in exon 19 (52%) and a missense mutation L858R in exon 21 (26%) were most predominant. There was a significant increase in overall mutations (p = 0.01) as a function of age, mutation in exons 19 and 21 together (p = 0.003), mutations in exons 18, 19 and 21 (p = 0.04) and mutations in exons 18 and 19 (p = 0.03) in females. Mutations did not seem to significantly correlate metastases or disease progression. Mutations in exons [19] and 21 together were significant in non-smokers compared to smokers (p = 0.01) using Mann-Whitney tests. The study suggests high prevalence of EGFR positivity in NSCLC in Indian sub-population and provides opportunities for targeted therapies for this group.     

血清CEA对EGFR突变晚期肺腺癌TKIs治疗疗效及生存的预测意义

目的 探讨治疗前血清癌胚抗原（CEA）对表皮生长因子受体（EGFR）突变的晚期肺腺癌患者接受酪氨酸激酶抑制剂（TKIs）治疗疗效及生存的影响。方法 回顾性分析首都医科大学附属北京胸科医院肿瘤内科2005年12月至2013年4月接受吉非替尼、厄洛替尼或盐酸埃克替尼治疗的120例EGFR突变晚期肺腺癌患者的临床资料,评价TKIs治疗疗效并分析影响患者预后的因素。根据实体瘤疗效评价标准11版（RECIST 1.1）评价近期疗效,Kaplan-Meier法进行生存分析,Cox风险比例模型分析影响预后的因素。结果 全组患者接受EGFR-TKIs治疗的有效率（RR）为57.5％,疾病控制率（DCR）为94.2％。全组患者的中位无进展生存期（PFS）为 9.0个月（95％ CI：7.91～10.09个月）,中位生存时间（OS）为23.5个月（95％ CI：17.89～29.11个月）。治疗前血清CEA≥5 ng／ml者（n=53）和CEA＜5 ng／ml者（n=67）的RR分别为60.4％、55.2％（P＞0.05）;两组患者的中位PFS分别为8.0个月、10.0个月（P＞005）,中位OS分别为 17.2个月、30.0个月（P=0.022）。Cox多因素分析显示,吸烟状况、血清CEA水平及PS评分是影响肺腺癌OS的独立因素。结论 EGFR突变的肺腺癌患者中,治疗前血清CEA水平不影响TKIs治疗的疗效,但CEA＜5 ng／ml者的预后更好,尚有待前瞻性研究进一步证实。     

Dual ALK and EGFR inhibition targets a mechanism of acquired resistance to the tyrosine kinase inhibitor crizotinib in ALK rearranged lung cancer

Introduction

The multitargeted tyrosine kinase inhibitor (TKI) crizotinib is active against ALK translocated non-small-cell lung cancer (NSCLC); however acquired resistance invariably develops over time. ALK mutations have previously been implicated in only a third of resistant tumors. We sought to evaluate alternative mechanisms of resistance and preclinical strategies to overcome these in a cell line driven by EML4-ALK.

Methods

We selected the NSCLC cell line NCI-H3122 (H3122: EML4-ALK E13;A20) and derived resistant variants that were able to grow in the presence of 1 μM crizotinib. These were analyzed for ALK mutations, sensitivity to crizotinib in combination with other TKIs, and for activation of alternative tyrosine kinases.

Results

All H3122 crizotinib resistant (CR) clones lacked amplification or mutations in the kinase domain of ALK. To evaluate if possible alternative kinases functioned as “bypass” tracks for downstream signaling activation in these resistance cells, we performed of phosho-receptor tyrosine kinase array that demonstrated that CR clones had higher phospho-EGFR signals than H3122 cells before and after exposure to crizotinib. A functional approach of dual ALK TKI (with crizotinib) with combinatory TKI inhibition was used as a secondary screen for possible targets. Crizotinib + erlotinib (reversible EGFR TKI) and crizotinib + afatinib (irreversible EGFR/ERBB2 TKI) were able to inhibit the growth of H3122 CR clones, confirming EGFR activation as a mechanism of resistance. The removal of crizotinib from the culture media re-sensitized CR cells to crizotinib.

Conclusions

We identified activation of EGFR as a mechanism of resistance to crizotinib in preclinical models of ALK translocated NSCLC. If EGFR activation is confirmed as a predominant mechanism of ALK TKI-induced resistance in patient-derived tumors, the use of ALK plus EGFR TKIs could be explored for this important cohort of NSCLCs.     

Combined epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor and chemotherapy in non-small-cell lung cancer: Chemo-refractoriness of cells harboring sensitizing-EGFR mutations in the presence of gefitinib

Background

Combined epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) with chemotherapy is believed to be more effective in treating non-small-cell lung cancer (NSCLC) with sensitizing-EGFR mutation (SEM). This hypothesis failed to be realized clinically and needs to be examined in vitro.

Materials and methods

Using the tetrazolium colorimetric assay and classical isobole method, we investigated the combination effects of 6 gefitinib-chemotherapeutic doublets (gefitinib/cisplatin, gemcitabine, pemetrexed, paclitaxel, docetaxel, or vinorelbine) in a panel of 15 NSCLC cell lines.

Results

Upon treatment with the 6 gefitinib-chemotherapeutic doublets, the 12 cell lines that did not harbor SEM displayed a broad spectrum of group results, from obvious synergism to robust antagonism. The values of group mean combination index (mCIs) ranged from 0.769 to 1.201. In contrast, the 3 cell lines with SEM showed a tendency toward consistent antagonism to the tested doublets, impressively, with a narrow range of higher group mCIs (0.993–1.141). In the presence of gefitinib, the SEM or gefitinib-sensitive group was more chemo-refractory than the non-SEM (index of chemo-refractoriness (RI): 69.33 versus 42.67; P = 0.036) or gefitinib-resistant group (68.25 versus 40.64, P = 0.0108), respectively. The results of using the gefitinib/drug combinations with the gefitinib-sensitive non-SEM cell line H322 and the gefitinib-resistant EGFR mutant H820 shared patterns similar to those with the SEM and non-SEM cell lines, respectively.

Conclusion

Gefitinib-treated EGFR-TKI-sensitive NSCLC cells showed a wide spectrum of chemo-refractoriness, suggesting that concomitantly combined EGFR-TKI-chemotherapy might not be a good treatment strategy for NSCLC harboring SEM.     

The small GTPase ADP-Ribosylation Factor 1 mediates the sensitivity of triple negative breast cancer cells to EGFR tyrosine kinase inhibitors

The clinical use of EGFR-targeted therapy, in triple negative breast cancer patients, has been limited by the development of resistance to these drugs. Although activated signaling molecules contribute to this process, the molecular mechanisms remain relatively unknown. We have previously reported that the small GTPase ADP-Ribosylation Factor 1 (ARF1) is highly expressed in invasive breast cancer cells and acts as a molecular switch to activate EGF-mediated responses. In this study, we aimed at defining whether the high expression of ARF1 limits sensitivity of these tumor cells to EGFR inhibitors, such as gefitinib. Here, we show that the knock down of ARF1 expression or activity decreased the dose and latency time required by tyrosine kinase inhibitors to induce cell death. This may be explained by the observation that the depletion of ARF1 suppressed gefitinib-mediated activation of key mediators of survival such as ERK1/2, AKT and Src, while enhancing cascades leading to apoptosis such as the p38MAPK and JNK pathways, modifying the Bax/Bcl2 ratio and cytochrome c release. In addition, inhibiting ARF1 expression and activation also results in an increase in gefitinib-mediated EGFR internalization and degradation further limiting the ability of this receptor to promote its effects. Interestingly, we observed that gefitinib treatment resulted in the enhanced activation of ARF1 by promoting its recruitment to the receptor AXL, an important mediator of EGFR inhibition suggesting that ARF1 may promote its pro-survival effects by coupling to alternative mitogenic receptors in conditions where the EGFR is inhibited. Together our results uncover a new role for ARF1 in mediating the sensitivity to EGFR inhibition and thus suggest that limiting the activation of this GTPase could improve the therapeutic efficacy of EGFR inhibitors.     

Continuation of epidermal growth factor receptor tyrosine kinase inhibitor treatment prolongs disease control in non-small-cell lung cancers with acquired resistance to EGFR tyrosine kinase inhibitors

Objectives

Patients with non-small-cell lung cancer (NSCLC) develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) after tumor regression. No approved targeted therapies are currently available after initial EGFR TKI treatment. This study investigated the efficacy of continuing EGFR TKI therapy with local treatments for patients with NSCLC and local progression or minimal/slow progression on TKI therapy.

Materials and Methods

Fifty-five patients with NSCLC treated with EGFR TKIs and developed acquired resistance to the drug were included. Initial response to target therapy, median progression free survival (PFS1), progression pattern, and first progression site were assessed. Median progression free survival to physician assessment progression (PFS2) and difference between PFS1 and PFS2 (PFS difference) were also recorded.

Results and Conclusion

PFS1 was 11.2 months, PFS2 was 20.3 months, and PFS difference was 8.3 months. Nineteen patients (34.5%) who manifested progression received local therapy, and 16 (28.6%) underwent rebiopsy after progression with six positive EGFR T790M mutations detected. Cox proportional hazards regression model showed that only the first line of treatment was significantly correlated with PFS difference. NSCLC patients with acquired resistance to EGFR TKIs could benefit from the same TKI therapy through months to years of disease control.     

伴脑转移的非小细胞肺癌EGFR突变率较高

目的:探讨表皮生长因子受体(epidermal growth factor receptor,EGFR)突变与非小细胞肺癌(non-small cell lung cancer,NSCLC)脑转移的相关性.方法:收集复旦大学附属华山医院胸外科及肿瘤科于2008年1月1日至2013年10月31日手术切除并经病理确诊的NSCLC患者肺癌组织标本90例.其中脑转移患者30例为观察组,无脑转移患者60例为对照组,采用直接测序法对所有标本进行EGFR基因突变检测.结果:无论腺癌还是鳞癌,脑转移NSCLC患者中EGFR基因突变明显高于无脑转移患者(46.7％vs 15.0％,P＜0.01).结论:EGFR基因突变增加可能与NSCLC脑转移相关.     

培美曲塞单药或联合吉非替尼治疗EGFR-TKI耐药后晚期非小细胞肺癌临床观察

背景与目的:生长因子受体-酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI)治疗晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)获得性耐药后尚无标准的治疗方案,亟待探寻有效的后续治疗方法.为临床应用提供指导,该研究旨在比较后续治疗采用培美曲塞单药或联合吉非替尼治疗EGFR-TKI获得性耐药的晚期NSCLC的临床疗效及安全性.方法:入组既往接受过EGFR-TKI治疗后进展的晚期NSCLC患者62例.其中32接受培美曲塞联合吉非替尼治疗,设为联合组;30例单用培美曲塞治疗,设为化疗组.评价临床疗效及不良反应.结果:联合组客观有效率(objective response rate,ORR)为46.9%,高于化疗组的20%,差异有统计学意义(χ2=4.933,P<0.05);两组疾病控制率(disease control rate,DCR)差异无统计学意义(P>0.05);联合组的中位无病生存期(progression-free survival,PFS)为8.0个月,化疗组中位PFS为6.3个月,差异有统计学意义(χ2=8.063,P<0.05),两组总生存期(overall survival,OS)差异无统计学意义(P>0.05).联合组中性粒细胞减少、皮疹的发生率高于化疗组,差异有统计学意义(P<0.05),Ⅲ~Ⅳ不良反应两组差异无统计学意义(P>0.05).结论:晚期NSCLC患者EGFR-TKI获得性耐药后,采用培美曲塞联合吉非替尼较单用培美曲塞显示出更优势临床有效率和中位PFS,不良反应可耐受,值得临床推广运用.     

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.     

Integration of EGFR inhibitors and conventional chemotherapy in the treatment of non-small-cell lung cancer

Introduction/Background

Given the limited gains of traditional chemotherapy in improving outcomes in patients with advanced non–small-cell lung cancer (NSCLC), recent research efforts have investigated the integration of targeted agents into the treatment algorithm.

Materials and Methods

Searches of PubMed and of recent results from key oncology congresses were performed to identify relevant articles and abstracts. Initial phase III trials combining the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib with platinum-based doublets as first-line therapy failed to demonstrate an overall survival advantage in unselected patients with NSCLC. However, in recent years, there has been substantial progress in understanding the determinants of response to EGFR TKI therapy, including the presence of activating EGFR mutations, which has been reflected in clinical trials specifically evaluating these patient populations. In addition, evidence suggesting potential mechanistic interference between concurrent EGFR TKIs and chemotherapy has also been observed, fueling interest in sequential or intermittent dosing. EGFR-targeted agents such as the multitargeted TKI vandetanib and the next-generation EGFR TKIs afatinib (BIBW 2992) and PF00299804 are also under clinical investigation for the treatment of NSCLC, both alone and in combination with chemotherapy.

Conclusions

Trials evaluating various regimens of EGFR-targeted agents and chemotherapy are planned and/or underway and will hopefully define the role of integrated therapy in NSCLC.     

晚期非小细胞肺癌EGFR蛋白磷酸化、基因突变与EGFR-TKI疗效相关性的研究

背景与目的：近年来以吉非替尼和厄洛替尼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 kinase inhibitors,EGFR-TKI),因其在晚期非小细胞肺癌(advanced non-small cell lung cancer,NSCLC)治疗中独特的临床疗效和较低的不良反应而备受关注。尽管EGFR基因突变是目前认为最确切的预测EGFR-TKI疗效的指标,但与临床疗效间并非“全或无”的关系,提示仍有其他机制参与其中。本研究旨在探讨晚期NSCLC组织标本中EGFR磷酸化酪氨酸1068(EGFR-pTyr1068)、1173(EGFR-pTyr1173)表达与EGFR基因突变的关系,及其在EGFR-TKI治疗中的疗效预测价值。方法：采用变性高效液相色谱法(denaturing high performance liquid chromatography,DHPLC)检测205例晚期NSCLC患者组织中EGFR基因突变(19、21外显子突变)情况;并采用免疫组化方法检测其EGFR-pTyr1068、EGFRpTyr1173表达。结果：晚期NSCLC患者组织中EGFR-pTyr1068和1173表达阳性率分别为80.0%(164/205)、57.6%(95/165);其表达与临床病理特征(年龄、性别、病理类型、吸烟状态、疾病分期)无相关性。全组EGFR基因突变率为44.9%(92/205),与吸烟状态有关(P=0.024),而与其他临床病理特征(性别、年龄、病理类型、疾病分期)无关。EGFR基因突变与EGFR-pTyr1068表达呈弱相关性(P<0.001),与EGFR-pTyr1173无相关性(P=0.297)。EGFR基因突变型患者EGFR-TKI治疗的客观缓解率(objective response rate,ORR)、疾病控制率(disease control rate,DCR)和中位无进展生存期(progress free survival,PFS)分别为48.3%(43/89)、80.9%(72/89)和8.8个月(95%CI：6.11~11.42),均明显高于EGFR基因野生型患者［16.2%(17/105)、56.2%(59/105)和2.1个月,95%CI：0.89~3.24］,差异有统计学意义(P<0.001,P<0.001,P=0.024);EGFR-pTyr1068表达阳性患者ORR和DCR分别为37.7%(58/154)和74.7%(115/154),均明显高于表达阴性患者［5.0%(2/40)和40.0%(16/40)］,差异有统计学意义(P<0.001)。EGFR-pTyr1068表达阳性患者中位PFS为7.0个月,较表达阴性患者(1.2个月)明显延长,差异有统计学意义(P<0.001)。而EGFR-pTyr1173表达与EGFR-TKI疗效呈负相关性,EGFR-pTyr1173阳性者ORR、DCR和PFS分别为27.8%(25/90)、64.4%(58/90)和4.8个月,显著低于阴性患者［37.9%(25/66)、83.3%(55/66)和7.7个月,P=0.123,P=0.007,P=0.016］。以EGFR基因突变状态分层进行亚组分析显示,在EGFR基因野生型患者中,EGFR-pTyr1068表达阳性率为69.0%(69/100),EGFR-pTyr1068表达阳性和阴性患者ORR分别为23.2%(16/69)和3.2%(1/31),DCR分别为69.6%(48/69)和35.5%(11/31),差异均有统计学意义(P=0.010,P=0.001);EGFR-pTyr1068表达阳性患者中位PFS为3.6个月,较表达阴性患者(1.2个月)明显延长,差异有统计学意义(P<0.001)。16例EGFR-pTyr1068阳性表达且对EGFRTKI有效患者,中位PFS为15.6个月(95%CI：7.28~23.9)。多因素分析显示,EGFR-pTyr1068是EGFR基因野生型患者EGFR-TKI治疗的独立疗效预测因子(OR=0.24,95%CI：0.16~0.37,P<0.001)。结论：EGFR-pTyr1068可作为晚期NSCLC患者接受EGFR-TKI治疗的有效预测因子,尤其对从EGFR基因野生型患者中筛选EGFR-TKI治疗有效者具有重要作用。