Clinical Implications of the BIM Deletion Polymorphism in Advanced Lung Adenocarcinoma Treated With Gefitinib

Background

Proapoptotic protein Bcl-2–like 11 (BIM) is a crucial tumor suppressor gene in lung cancer development. A 2903-bp genomic deletion polymorphism is present in BIM intron 2, which alters RNA splicing and impairs the generation of the death-inducing isoform of BIM and resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). In the present study, we investigated the clinical implications of this genetic polymorphism in patients with advanced lung adenocarcinoma treated with gefitinib.

晚期非小细胞肺癌EGFR-TKIs获得性耐药后治疗策略研究进展

肺癌是癌症相关死亡的首要原因。非小细胞肺癌（NSCLC）约占肺癌的85%,且患者在诊断时大多为晚期。随着表皮生长因子受体（EGFR）在肺癌中被发现,针对特定基因突变的靶向治疗成为晚期NSCLC的重要治疗方式,并显著延长了患者生存期。尽管第一、二、三代EGFR-酪氨酸激酶抑制剂（TKI）蓬勃发展,但随着治疗时间的推移,患者都可能面临耐药和进展。为克服这一难题,基于耐药机制的相关治疗策略正在研究中。本文旨在对近年来EGFR-TKIs,特别是在疗效及安全性上作为指南更优推荐的第三代EGFR-TKIs的耐药机制和治疗策略的研究进展进行综述。     

A Multicenter Double-blind Phase II Study of Metformin With Gefitinib as First-line Therapy of Locally Advanced Non–Small-cell Lung Cancer

We present the rationale and study design of the CGMT (combined gefitinib and metformin therapy) trial (www.ClinicalTrials.gov Identifier: NCT01864681), which is aimed at treating locally advanced non–small-cell lung cancer. The CGMT trial is a multicenter, phase II randomized, double-blinded, and placebo-controlled study, which is designed to evaluate the safety and efficacy of metformin in combination with gefitinib as first-line therapy in patients presenting with stage IIIb-IV non–small-cell lung cancer expressing the epidermal growth factor receptor mutant. Two therapies are proposed for this trial. The first regimen is comprised of gefitinib plus metformin. The second therapy is comprised of gefitinib plus placebo. The primary objective of this trail is to compare the progression-free survival rate at year 1 of the study. The secondary objective of this trial is to compare the 2-year overall survival, the 2-year progression-free survival, the objective response rate, and the disease-control rate, and to evaluate the relative safety of both therapies. Based on the statistical design, we plan to enroll approximately 200 patients.     

血清CEA和LDH对肺腺癌靶向治疗疗效和预后的评价作用

目的分析治疗前血清癌胚抗原(CEA)和乳酸脱氢酶(LDH)对接受酪氨酸激酶抑制剂(TKIs)靶向治疗的肺腺癌患者疗效和预后的评价作用。方法回顾性收集45例接受表皮生长因子受体(EGFR)TKIs治疗的肺腺癌患者的完整临床资料,分析CEA、LDH与EGFR-TKI治疗疗效和无进展生存期(PFS)的关系。结果以正常值为截点,治疗前血清CEA值正常9例,升高36例,两组控制率分别为44.4%、83.3%,差异有统计学意义(P=0.028)。治疗前血清LDH是否升高与治疗疗效无显著影响(P0.05)。生存分析结果显示:治疗前CEA值升高、EGFR突变患者的中位PFS显著延长(P=0.010、0.005),EGFR突变状态、治疗前LDH水平是影响患者PFS的独立因素(P=0.009、0.017)。结论治疗前血清CEA、LDH水平对肺腺癌TKIs靶向治疗患者的疗效和预后的评估有重要的参考价值。     

Targeting DNA-PK overcomes acquired resistance to third-generation EGFR-TKI osimertinib in non-small-cell lung cancer

The third-generation of epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),represented by osimertinib,has achieved remarkable clinical outcomes in the treatment of non-small-cell lung cancer(NSCLC)with EGFR mutation.However,resistance eventually emerges in most patients and the underlying molecular mechanisms remain to be fully understood.In this study,we generated an osimertinib-acquired resistant lung cancer model from a NSCLC cell line H1975 harboring EGFR L858R and T790M mutations.We found that the capacity of DNA damage repair was compromised in the osimertinib resistant cells,evidenced by increased levels ofγH2AX and higher intensity of the comet tail after withdrawal from cisplatin.Pharmacological inhibiting the activity or genetic knockdown the expression of DNA-PK,a key kinase in DNA damage response(DDR),sensitized the resistant cells to osimertinib.Combination of osimertinib with the DNA-PK inhibitor,PI-103,or NU7441,synergistically suppressed the proliferation of the resistant cells.Mechanistically,we revealed that DNA-PK inhibitor in combination with osimertinib resulted in prolonged DNA damage and cell cycle arrest.These findings shed new light on the mechanisms of osimertinib resistance in the aspect of DNA repair,and provide a rationale for targeting DNA-PK as a therapeutic strategy to overcome osimertinib-acquired resistance in NSCLC.     

阿美替尼二线治疗晚期非小细胞肺癌的疗效观察

目的:探究使用阿美替尼二线治疗驱动基因阳性非小细胞肺癌(non-small cell lung cancer, NSCLC)患者的疗效及安全性并分析影响患者疗效的相关因素。方法:共收集72例2020年03月至2021年03月于我院接受阿美替尼二线治疗的EGFR敏感突变IV期NSCLC患者的临床资料,最终回顾性分析了59例患者使用阿美替尼二线治疗的疗效、安全性及疗效的影响因素。结果:阿美替尼二线治疗IV期EGFR阳性突变NSCLC患者整体中位无进展生存期(mPFS)为12.0个月(95%CI:9.02个月～14.97个月),客观缓解率(ORR)为42.4%,疾病控制率(DCR)为94.9%,其中,T790M阳性突变的患者mPFS为16.0个月(95%CI:13.2个月～18.7个月),无突变者mPFS为8.0个月(95%CI:5.8个月～10.2个月),差异有统计学意义(P<0.001),而患者是否有T790M突变在ORR、DCR均无显著差异(P>0.05)。基因突变类型上,EGFR 19外显子缺失突变的患者mPFS为11.5个月,21外显子L858R突变患者mPFS为10....     

奥希替尼用于EGFR+晚期非小细胞肺癌患者一线治疗的药物经济学评价

目的评估奥希替尼在2020年国家谈判价格下用于有表皮生长因子受体(epidermal growth factor receptor,EGFR)阳性突变的局部晚期或转移性非小细胞肺癌(non-small cell lung cancer,NSCLC)患者一线治疗的成本效用。方法基于卫生服务支付方角度,构建包含无进展生存期(progression-free survival,PFS)和疾病进展期(progressive disease,PD)的分区生存模型,以质量调整生命年(quality-adjusted life years,QALYs)作为结果指标计算增量成本效用比(incremental cost-utility,ICER)。疗效数据来自多中心、随机、对照、双盲的FLAURA试验,成本数据来自招采挂网数据和专家咨询,不同健康状态的健康效用值源于文献。对关键参数进行敏感度分析。结果与厄洛替尼、吉非替尼、阿法替尼和埃克替尼相比,奥希替尼在国家谈判价格下终身成本更高,获得的QALYs也更高。与已过专利期的厄洛替尼和吉非替尼相比,奥希替尼ICER值分别为122 695元和117 359元,约为我国人均GDP的1.7倍;与同样仍在专利期的阿法替尼和埃克替尼相比,奥希替尼ICER值分别为16 502元和43 337元,远低于我国人均GDP。单因素敏感度分析显示,奥希替尼价格是对ICER值影响最大的因素。概率敏感度分析显示,当支付意愿为我国三倍人均GDP时,奥希替尼具有成本效果的概率为100%。结论与厄洛替尼、吉非替尼、阿法替尼和埃克替尼相比,奥希替尼用于EGFR+的局部晚期或转移性NSCLC患者一线治疗更具成本效用。     

抗非小细胞肺癌药物奥希替尼研究进展

年3月22日中国食品药品监督管理局(CFDA)批准表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)奥希替尼(Osimertinib)用于治疗EGFR T790M基因突变阳性的局部晚期或转移性非小细胞肺癌(NSCLC)。奥希替尼是第三代EGFR-TKI,治疗效果显著,副作用更小,尤其适用于对第一、二代EGFR-TKI耐药或者脑转移的病人。与含铂类治疗药物的二联化学疗法相比,奥希替尼可使NSCLC病人中位无进展生存期(PFS)延长5.7个月,疾病进展风险下降70%。该文就奥希替尼的作用机制、研究历程、药效学、药动学、不良反应,耐药机制进行综述,为临床使用提供参考。     

复治晚期非小细胞肺癌EGFR-TKI治疗失败后培美曲塞与多西他赛挽救性化疗的疗效比较

目的 比较复治晚期非小细胞肺癌（NSCLC）表皮生长因子受体 酪氨酸激酶抑制剂（EGFR TKI）治疗失败后用培美曲塞或多西他赛挽救性化疗的疗效及毒副反应。方法120例复治晚期NSCLC患者于EGFR-TKI治疗失败后分别接受培美曲塞（500mg／m2,d1）或多西他赛（75mg／m2,d1）的挽救性化疗,均21天为1周期。记录并比较两者的疗效和预后。结果培美曲塞组和多西他赛组的有效率（RR）分别为13.4％和5.3％（P=0.307）,疾病控制率（DCR）分别为58.5％和42.1％（P=0.093）,中位无进展生存期（PFS）分别为2.83个月和2.10个月（P=0.862）,中位总生存期（OS）分别为8.40个月和9.10个月（P=0.527）。EGFR-TKI治疗有效和挽救性化疗前行为状态评分（PS）≤1者的中位PFS较长。培美曲塞组1～4级中性粒细胞减少的发生率低于多西他赛组,分别为41.5％和65.8％（P=0.013）。在非血液学毒性方面两组差异均无统计学意义（P＞0.05）。结论 复治晚期NSCLC TKI治疗失败后用培美曲塞或多西他赛挽救性化疗,部分患者仍可以获益,两组疗效相当,且大部分患者能够耐受化疗的毒副反应。对于EGFR-TKI治疗有效、挽救性化疗前PS评分较好的患者,有可能从挽救性化疗中获益更大。