EGFR-TKIs治疗非小细胞肺癌进展

目前,肺癌依然是导致人类恶性肿瘤死亡的首位疾病。在过去10年中,EGFR-TKI药物的出现,显著改善了患者的生存,从而改变了肺癌的标准治疗模式。作为一线、二线或其他治疗,EGFR-TKI药物,包括吉非替尼和厄洛替尼,在特定人群中(腺癌、女性、非吸烟、亚裔患者)疗效显著。除上述两种药物,由浙江贝达药业有限公司研发的EGFR-TKIs埃克替尼也已经完成了其III期临床试验(ICOGEN),并取得可喜的结果。本文将对以上3种EGFR-TKI药物治疗非小细胞肺癌进展进行综述。     

Tumor gene mutations and messenger RNA expression: correlation with clinical response to icotinib hydrochloride in non-small cell lung cancer

Background  Molecular targeted drugs is now widely used in non-small cell lung cancer (NSCLC) clinical treatment. Icotinib hydrochloride is a new type of oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs). In this study, we examined the role of EGFR, K-RAS, B-RAF somatic mutations and EGFR mRNA expression in tumor specimens from advanced NSCLC patients as predicators of the efficacy of icotinib hydrochloride.

Methods  We analyzed tumor paraffin-embedded specimens, which were obtained from 14 of 40 patients with advanced NSCLC who enrolled in the stage I clinical trial of icotinib hydrochloride. Somatic mutations were evaluated by mutant-enriched liquidchip (MEL) technology, and EGFR mRNA expression was measured by branched DNA liquidchip (MBL) technology.

Results  In the 14 specimens, seven patients showed EGFR mutations, exon 19 deletion (3/7) and exon 21 point mutation (4/7); and two patients showed K-RAS mutation. No mutations in EGFR exon 20 or B-RAF were detected. In patients with EGFR mutation, one patient developed progress disease (PD), three patients had stable disease (SD), two patients had partial responses (PR) and one patient had a complete response (CR). In patients with wild-type EGFR, four patients had PD, three patients acquired SD, and none had PR/CR (P=0.0407). EGFR mutations were associated with better progress-free survival (PFS) (141 days vs. 61 days) but without a statistically significant difference (P=0.8597), and median overall survival (OS) (≥449 days vs. 140 days). EGFR mRNA expression levels were evaluated (three high, eight moderate, one low, and two that can not be measured due to insufficient tumor tissue) and no statistically significant relationships was observed with response, PFS or OS.

Conclusions  The EGFR mutation rate was consistent with that reported in the Asian population, so the MEL technology is reliable for measuring EGFR mutation with high throughput and rapidity. EGFR exon 19 deletions and exon 21 point mutation are predictive biomarkers for response to icotinib hydrochloride as second line treatment or above.

     

埃克替尼联合TP化疗治疗晚期非小细胞肺癌的疗效及对miR-204-5p、miR-1269表达的影响

目的 从miR-204-5p、miR-1269表达变化方面观察埃克替尼联合TP化疗治疗晚期非小细胞肺癌（NSCLC）的临床有效性和安全性。方法 前瞻性选取2019年2月—2020年12月河北北方学院附属第一医院胸外科NSCLC患者82例,计算机随机数字生成法分为对照组（n＝41）、试验组（n＝41）。对照组给予TP化疗,紫杉醇剂量175 mg·m^-2,第1天静脉滴注;卡铂剂量300 mg·m^-2,第2天静脉滴注。4周为1个周期,治疗4个周期。试验组在对照组TP方案治疗基础上加用埃克替尼,TP化疗方案及操作同对照组,同时口服埃克替尼,每次125 mg,每天3次,当患者出现3级及以上不良反应时,可暂停（1～2周）服用,待症状缓解或消失再次恢复每次125 mg,每天3次。4周为1个周期,治疗4个周期后进行效果评价。比较两组临床疗效、不良反应发生情况,分别于治疗前、治疗2个周期、治疗4个周期检测两组患者肺功能［第1秒呼气容积（FEV₁）、最大呼气容积（FVC）］、肿瘤标志物［糖类抗原125（CAl25）、癌胚抗原（CEA）、细胞角蛋白19片段（CYFRA21-1）］、miR-204-5p、miR-1269水平。结果 治疗4个周期后,试验组客观缓解率（ORR）为43.90%,疾病控制率（DCR）为82.93%,分别高于对照组的24.39%、63.41%（P<0.05）;治疗前两组患者FEV₁、FVC比较,差异无统计学意义（P>0.05）;治疗2个周期、4个周期后两组FEV₁、FVC均较治疗前升高,且同时间点试验组高于对照组（P<0.05）。治疗前两组患者CA125、CEA、CYFRA21-1比较,差异无统计学意义（P>0.05）;治疗2个周期、4个周期后两组CA125、CEA、CYFRA21-1较治疗前降低,且同时间点试验组低于对照组（P<0.05）;治疗前两组患者miR-204-5p、miR-1269表达水平比较,差异无统计学意义（P>0.05）;治疗2个周期、4个周期后两组miR-204-5p较治疗前升高,miR-1269较治疗前降低,且同时间点试验组miR-204-5p高于对照组,miR-1269低于对照组（P<0.05）。两组不良反应发生率比较,差异无统计学意义（P>0.05）。结论 埃克替尼联合TP化疗治疗晚期NSCLC效果显著,可有效改善患者肺功能,降低肿瘤标志物水平,调节miR-204-5p、miR-1269表达,且安全性高。     

Efficacy and safety of icotinib in Chinese patients with advanced non-small cell lung cancer after failure of chemotherapy

Background The preclinical experiments and several clinical studies showed icotinib,an oral epidermal growth factor receptor （EGFR） tyrosine kinase inhibitor,in Chinese patients with advanced non-small cell lung cancer （NSCLC） who failed previous chemotherapy.We performed a retrospective study of the efficacy and safety of icotinib monotherapy in a different and more recent sample of Chinese patients.Methods The clinical data of 149 patients with advanced NSCLC who were admitted to Zhejiang Cancer Hospital from August 1,2011 to July 31,2012 were retrospectively analyzed.All patients were given icotinib treatment after the failure of previous chemotherapy.Univariate and multivariate analyses were conducted based on the Kaplan Meier method and Cox proportional hazards model.Results The objective response rate was 33/149 and disease control rate was 105/149.No complete response occurred.Median progression free survival （PFS） with icotinib treatment was 5.03 months （95％ CI：3.51 to 6.55）.Median overall survival was 12.3 months （95％ CI：10.68 to 13.92）.Multivariate analysis showed that the mutation of EGFR and one regimen of prior chemotherapy were significantly associated with longer PFS.At least one drug related adverse event was observed in 65.8％ （98/149） of patients,but mostly grade 1 or 2 and reversible and none grade 4 toxicity.Conclusions lcotinib monotherapy is an effective and well tolerated regimen for Chinese patients with NSCLC after the failure of chemotherapy.It is a promising agent and further study with icotinib in properly conducted trials with larger patient samples and other ethnic groups is warranted.     

Icotinib Enhanced Radiosensitization of Nasopharyngeal Carcinoma by Inhibiting the Expression of Epidermal Growth Factor Receptor

Epidermal growth factor receptor (EGFR) is frequently overexpressed in multiple malignancies. Icotinib (IH), a new EGFR tyrosine kinase inhibitor, enhances radiosensitivity in various types of cancer, but its effect on nasopharyngeal carcinoma (NPC) remains unclear. Total 115 NPC tissue sections and 30 nasopharyngitis tissue sections were enrolled. The correlation of EGFR expression and clinicopathologic features of NPC was analyzed. Survival analysis was calculated by using univariate and multivariate regression analysis. A radioresistant NPC cell line, CNE-2R, was established with a gradient irradiation schedule. Cell viability, colony formation and EGFR expression of CNE-2/2R cells were examined. Significant higher expression of EGFR was observed in NPC tissues than chronic nasopharyngitis lesions. EGFR expression was significantly correlated with both tumor stage (P < 0.001) and tumor-node-metastasis stage of NPC (P = 0.006). EGFR expression was an independent prognostic factor of disease-free survival (P = 0.047) and the overall survival of NPC (P = 0.016). Cell viability was higher in CNE-2R than CNE-2 on days 1, 2, 4, and 6 after radiation of 4 Gy. The colony number of CNE-2R was significantly higher than that of CNE-2 (P < 0.05), while IH enhanced the radiosensitizing effect of CNE-2R with lower survival fraction (P < 0.05). EGFR mRNA and protein expression levels were significantly higher in CNE-2R cells compared to CNE-2 cells, but significantly decreased after IH treatment (all P < 0.05). In conclusion, high EGFR expression is a poor prognostic factor for NPC patients. IH enhances the radiosensitivity of CNE-2R cells and reduce EGFR expression.     

The short-term efficacy of icotinib on the treatment of advanced non-small-cell lung cancer简

Objective： The aim of the study was, （1） to observe the short-term efficacy and adverse reactions of icotinib hydrochloride on the treatment of advanced non-small cell lung cancer （NSCLC）; （2） to explore whether there is difference in the efficacy of icotinib hydrochloride among the subgroups of sex, age, smoking history, classification of CEA, histological type, multi-line treatment and PS score. Methods： The study was conducted to collect 138 patients taking icotinib hydrochloride with advanced non-small cell lung cancer in hospitals of Dalian （China） from September 1st 2011 to June 14th 2012. All patients had taken icotinib hydrochloride （125 mg three times a day） until the disease was progressed or the adverse reactions could not be tolerated. During the period of taking it, other anti-tumor treatments were forbidden. We observed the symptoms, such as cough, short breath, hemoptysis, pain. The objective efficacy was evaluated by RECIST criteria, and the adverse reactions related to the treatment was assessed on the basis of NCl-CTC 3.0. Results： Of all patients, CR was 1 （0.7%）, PR was 59 （42.8%）, SD was 37 （26.8%）, PD was 41 （29.7%）. And ORR was 43.5% （60/138）, DCR 70.3% （97/138）. The DCR of females was 83.5% （71/85） versus 49.1% （26/53） of males. The difference of ORR and DCR between the two subgroups had statistical significance （X2 = 8.065, P = 0.05; X2 = 18.577, P = 0.000）. The difference of ORR and DCR between the subgroups of patients after or before 70 years old had no statistical significance. The difference of ORR and DCR between the subgroups of smoking and non-smoking had statistical significance （X2 = 8.492; X2 = 13.602）. The difference of ORR and DCR between the CEA subgroups had statistical significance （X2 = 14.141; X2 = 14.160）, showed 81 patients with abnormal CEA before the treatment with ORR 56.8.0% （46/81）, DCR 81.5% （66/81）; 57 patients of normal CEA before the treatment with ORR 24.6% （14/57）, DCR 52.6% （30/57）. The 36 patients （26.1%） using icotinib hydrochloride as the first-line treatment, 78 patients （56.5%） using icotinib hydrochloride as the second-line, 20 patients （14.5%） using icotinib hydrochloride as the third-line, and 4 patients （2.9%） with tyrosine kinase inhibitor （TKI） resistance, there was statistical difference of DCR among the multi-groups above （~2 = 11.734, P = 0.008）. ORR was 31.1% （14/45） versus DCR 53.3% （24/45） in 45 patients with PS 3-4 points, and ORR was 49.4% （46/93） versus DCR 78.5% （73/93） in 93 patients with PS 0-2 points, and there was statistical difference （X2 = 4.156; X2 = 9.149）. The main adverse reactions were rash （26.8%）, diarrhea （13.8%）, mild liver function abnormal （10.9%）. Conclusion： The short-term efficacy of icotinib hydrochloride on the treatment of advanced NSCLC is positive, and the relevant adverse reactions are mild. The efficacy is better when the patient is female, non-smoker, treated as first-line, with higher CEA before treatment and lower PS scores.     

Effective treatment with icotinib in advanced lung adenocarcinoma harboring rare EGFR mutation G719A/L833V: A case report

Rationale:Mutations in epidermal growth factor receptor (EGFR) play critical roles in the pathogenesis of non–small cell lung cancer (NSCLC), and they are highly associated with sensitivity to tyrosine kinase inhibitors. Targeted therapies are approved for patients with “classical” mutations and a small number of other mutations. However, patients with rare, even double EGFR mutations have different responses to EGFR tyrosine kinase inhibitor, which brings uncertainty to clinical practice.Patient concerns:A 74-year-old woman, never-smoker, was presented with chest pain. Chest computed tomography scan showed a big lesion in the right upper lobe with mediastinal lymph nodes metastases. Fine-needle biopsy and pathology suggested lung adenocarcinoma. A rare G719A/L833V double mutation of EGFR was detected in both tissue and plasma samples by next-generation sequencing.Interventions and outcomes:Icotinib was used as first-line therapy and showed good efficacy. Partial response was achieved, and the progression-free survival was 8 months.Lessons:This is the first report of the icotinib treatment achieving long-lasting and stable disease control in an NSCLC patient with EGFR G719A/L833V mutation. Icotinib could be a first-line treatment option in NSCLC patients harboring EGFR G719A/L833V mutation.     

三种EGFR-TKI药物治疗晚期肺癌疗效及预后因素的回顾性研究

目的:探讨厄洛替尼、吉非替尼、埃克替尼治疗晚期非小细胞肺癌的疗效及安全性。方法:收集从2015年12月至2017年9月被确诊为转移性非小细胞肺癌的46位患者,分析了患者接受三种TKI药物治疗后基线特征、生存期及安全性。结果:研究结果表明,三组患者接受TKI药物治疗后总PFS为9.2个月,厄洛替尼组患者平均PFS为10.8个月,接受吉非替尼及埃克替尼治疗的患者,其PFS分别为7.8 个月和6.7个月。不同EGFR突变类型的肺癌患者,其PFS相似,约9个月。接受TKI治疗前CEA及CYFRA211阳性的患者,其PFS分别为8.0个月和8.5个月。接受TKI治疗前CEA及CYFRA211阴性的患者,其PFS均约为10.8个月。研究中发现,常见的治疗相关不良反应包括乏力、皮疹及腹泻。而肝功能不全、骨髓抑制、浮肿、发热、甲沟炎和疼痛发生率较低。结论:三种TKI药物在具有EGFR敏感突变的晚期转移性肺癌患者中显示了较好的抗肿瘤作用、可耐受药物的毒性。     

埃克替尼治疗EGFR不同突变类型晚期肺腺癌的疗效分析

目的:回顾分析埃克替尼一线治疗EGFR不同突变类型肺腺癌患者的疗效是否存在差异.方法:收集福州肺科医院2016年01月至2017年12月确诊EGFR突变肺腺癌患者79例,EGFR 19外显子缺失33例,21外显子突变46例,均予口服"埃克替尼125 mg tid"治疗,进行生存期随访;应用χ2检验比较临床特征及临床疗效...     

埃克替尼对非小细胞肺癌EGFR 18外显子突变的临床疗效

目的:探讨埃克替尼对非小细胞肺癌(non-small cell lung cancer,NSCLC)EGFR 18外显子G719X/E709X/G724S的临床疗效.方法:回顾性分析24例埃克替尼治疗EGFR 18外显子少见突变的NSCLC患者,服用至病情进展或出现不可耐受的毒副作用,比较疗效.结果:24例G719X/E709X/G724S突变患者中G719X突变19例,中位无进展生存时间2.8个月,E709X突变3例,中位无进展生存时间3.1个月,G724S突变2例,中位无进展生存时间3.5个月.G724S突变患者生存时间稍长.复合突变与单纯突变相比,复合突变中位无进展生存时间更长(G719X突变3.3个月Vs.2.6个月,P=0.029;E709X突变7.2个月vs.2.7个月,P=0.225).结论:埃克替尼在EGFR基因18外显子少见突变的疗效上比传统敏感突变未见明显优势,但复合突变比单纯突变临床获益更多.