A Randomized Phase 2 Study of Gefitinib With or Without Pemetrexed as First-line Treatment in Nonsquamous NSCLC With EGFR Mutation: Final Overall Survival and Biomarker Analysis

IntroductionClinical studies have shown that a combination of a tyrosine kinase inhibitor (TKI) and pemetrexed overcame acquired resistance to epidermal growth factor receptor (EGFR) TKI in NSCLC. Previously, pemetrexed+gefintib (P+G) had improved progression-free survival (PFS) compared with gefitinib. We present OS, updated PFS, biomarker analysis, and safety of P+G versus gefitinib.MethodsThis was a phase 2, multicenter, randomized study conducted in East Asian patients with advanced nonsquamous NSCLC with EGFR mutations. Patients were randomized (2:1) to receive P+G (500 mg/m² intravenously 3-weekly + 250 mg/day orally) or gefitinib.ResultsIn total, 191 patients (P+G, n=126; gefitinib, n=65) comprised the intent-to-treat and safety populations. Median OS was 43.4 months in P+G versus 36.8 months in gefitinib arm; adjusted HR 0.77 (95% CI, 0.5-1.2); one-sided P=0.105. Median PFS was significantly longer in the P+G (16.2 months) versus gefitinib arm (11.1 months); adjusted HR 0.67 (95% CI, 0.5-0.9); one-sided P=0.009. In the P+G and gefitinib arms, median PFS was 22.6 and 11.0 months, respectively, in patients with low thymidylate synthase (TS) expression, and 12.6 and 9.9 months, respectively, in patients with high TS expression. Common second-line post-discontinuation systemic therapies were EGFR-TKIs and chemotherapy. Most patients experienced at least one adverse event.ConclusionsAddition of pemetrexed to EGFR TKI gefitinib resulted in significantly improved PFS and numerically longer OS compared with gefitinib in treatment-naïve patients with EGFR-mutated advanced nonsquamous NSCLC. Low TS expression appeared to be a good predictor for treatment outcomes.     

培美曲塞与雷替曲塞联合顺铂治疗恶性胸膜间皮瘤的疗效与安全性

目的：探讨培美曲塞联合顺铂与雷替曲塞联合顺铂治疗恶性胸膜间皮瘤的疗效和安全性。方法回顾性分析64例恶性胸膜间皮瘤患者的临床资料,采用培美曲塞联合顺铂化疗的纳入PP组（32例）,采用雷替曲塞联合顺铂方案的为RP 组（32例）,比较两组不同化疗方案的疗效及不良反应。结果两组患者客观有效率、疾病控制率比较,差异均无统计学意义（χ2分别=2.35、3.76,P均＞0.05）。PP组患者中位总生存期为11.62个月,中位无疾病进展生存期为5.61个月;RP组患者中位总生存期为11.33个月,中位无疾病进展生存期为4.93个月,两组患者在中位总生存期、中位无疾病进展生存期之间的差异均无统计学意义（t分别=1.06、2.08,P均＞0.05）。两组患者不良反应均以骨髓抑制和胃肠道反应为主,两组之间不良反应比较,差异无统计学意义（χ2=2.82,P＞0.05）。结论培美曲塞或雷替曲塞联合顺铂用于MPM的临床疗效相当,对于经济条件较差的MPM患者来说,选用雷替曲塞联合顺铂治疗也可以作为MPM的一线方案。     

培美曲塞与顺铂化疗联合苦参治疗胸膜间皮瘤18例报道

目的:评价培美曲塞与顺铂静脉化疗同时联合苦参注射液胸腔灌注治疗恶性胸膜间皮瘤(MPM)合并胸腔积液的疗效与安全性。方法:回顾性分析18例经胸腔镜确诊MPM合并胸腔积液患者,使用培美曲塞500mg/m2,d1;顺铂75mg/m2,d1-3;每21天重复。同时胸腔闭式引流术引流尽胸腔积液,苦参注射液40ml胸腔注入,每隔4天重复注射。结果:18例患者中,CR 4例,PR 8例,SD 4例,PD 2例。总有效率为66.67%,疾病控制率为88.89%,肿瘤进展时间为7.2个月,中位生存期为12.3个月,1年生存率为43.85%。16例(88.89%)胸腔积液得到控制。主要毒副反应为骨髓抑制、胃肠道反应、发热、胸痛及皮疹等,对症支持处理后均可恢复。结论:培美曲塞与顺铂静脉化疗同时苦参注射液胸腔灌注治疗MPM合并胸腔积液有较好的疗效,毒副反应轻,值得临床推广应用。     

Inhibition of autophagy potentiates pemetrexed and simvastatin-induced apoptotic cell death in malignant mesothelioma and non-small cell lung cancer cells

Pemetrexed, a multitarget antifolate used to treat malignant mesothelioma and non-small cell lung cancer (NSCLC), has been shown to stimulate autophagy. In this study, we determined whether autophagy could be induced by pemetrexed and simvastatin cotreatment in malignant mesothelioma and NSCLC cells. Furthermore, we determined whether inhibition of autophagy drives apoptosis in malignant mesothelioma and NSCLC cells. Malignant mesothelioma MSTO-211H and A549 NSCLC cells were treated with pemetrexed and simvastatin alone and in combination to evaluate their effect on autophagy and apoptosis. Cotreatment with pemetrexed and simvastatin induced greater caspase-dependent apoptosis and autophagy than either drug alone in malignant mesothelioma and NSCLC cells. 3-Methyladenine (3-MA), ATG5 siRNA, bafilomycin A, and E64D/pepstatin A enhanced the apoptotic potential of pemetrexed and simvastatin, whereas rapamycin and {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 attenuated their induction of caspase-dependent apoptosis. Our data indicate that pemetrexed and simvastatin cotreatment augmented apoptosis and autophagy in malignant mesothelioma and NSCLC cells. Inhibition of pemetrexed and simvastatin-induced autophagy was shown to enhance apoptosis, suggesting that this could be a novel therapeutic strategy against malignant mesothelioma and NSCLC.     

培美曲塞联合顺铂通过TRAIL诱导非小细胞肺癌A549细胞凋亡发挥抗癌效果的研究

目的：初步探讨培美曲塞联合顺铂通过TRAIL诱导非小细胞肺癌A549细胞凋亡发挥的抗癌效果。方法：将肺癌细胞株A549做4种处理并分为4组：空白组（Blank组）、顺铂处理组（CDPP组）、培美曲塞处理组（MTA组）、培美曲塞联合顺铂处理组（MTA+CDPP组），应用CCK-8和流式细胞术检测4种处理细胞的细胞活性和细胞凋亡变化；qPCR检测顺铂单药治疗组和培美曲塞联合顺铂治疗组的细胞肿瘤坏死因子相关凋亡诱导配体（TRAIL）表达差异；干扰TRAIL后再次检测各处理组细胞的细胞活性和细胞凋亡变化；qPCR和WB检测干扰TRAIL后BCL-2转录水平和蛋白表达。结果：培美曲塞联合顺铂（CDDP）在非小细胞肺癌细胞中起到降低细胞活性和诱导细胞凋亡的作用，二者协同发挥抗肿瘤效果；培美曲塞联合顺铂治疗组TRAIL转录表达显著高于顺铂处理组；干扰TRAIL后，顺铂与培美曲塞联合诱导的细胞活力的降低作用被抑制，并逆转了顺铂与培美曲塞联合对细胞凋亡的促进作用；培美曲塞联合顺铂通过TRAIL降低Bcl-2的转录水平和蛋白表达来发挥促进肿瘤细胞凋亡的作用。结论：培美曲塞可联合顺铂（CDDP）在非小细胞肺癌细胞中发挥抗肿瘤效果，其通过TRAIL降低Bcl-2的表达来诱导肿瘤细胞凋亡，从而发挥抗肿瘤作用。     

A phase II randomized trial evaluating gefitinib intercalated with pemetrexed/platinum chemotherapy or pemetrexed/platinum chemotherapy alone in unselected patients with advanced non-squamous non-small cell lung cancer

Current pemetrexed/platinum chemotherapy does not produce a satisfactory therapeutic response in advanced lung cancer patients. The aim of this study was to determine whether the administration of gefitinib, a tyrosine kinase inhibitor (TKI), intercalated with pemetrexed/platinum could improve the efficacy in chemotherapy-naïve patients with advanced non-squamous NSCLC without subsequent gefitinib maintenance therapy. Treatment-naïve patients with stage IIIB or IV NSCLC were randomly assigned to receive pemetrexed (500 mg/m² d1) and either cisplatin (75 mg/m² d1) or carboplatin (AUC = 5 d1) plus gefitinib (250 mg/d on days 3 to 16 of a 3-week cycle) (PC-G) or pemetrexed–platinum (PC) alone. Randomization was stratified according to the tobacco smoking status and EGFR mutational status of the patients. The primary endpoint was the non-progression rate (NPR) at 12 weeks. Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and biosafety. The NPR at 12 weeks was 84.5% for the PC-G treatment arm and 83.1% for the PC treatment arm (P = 0.87). Median PFS was 7.9 months for the PC-G arm and 7.0 months for the PC arm (P = 0.57). The ORR was 50.0% for the PC-G arm and 47.4% for the PC arm (P = 0.78). Median survival was 25.4 mo for the PC-G arm and 20.8 mo for the PC arm (P = 0.54). The incidence of adverse events was similar between the two treatment arms, except for a higher incidence of skin rash with PC-G. Predefined subgroup analyses demonstrated that PC-G significantly increased the PFS compared with the PC regimen in patients with EGFR mutations (P = 0.017). Although gefitinib intercalated with pemetrexed/platinum chemotherapy did not improve the NPR at 12 weeks compared with chemotherapy, an improvement in the PFS for the intercalated treatment arm was seen in the subgroup of patients with EGFR mutations.     

克唑替尼联合PC方案治疗非小细胞肺癌的临床研究

目的 探讨克唑替尼联合PC方案治疗非小细胞肺癌的临床疗效。方法 选择2016年1月—2018年12月新疆喀什地区第二人民医院治疗的64例非小细胞肺癌患者作为研究对象。用抽签法随机将患者分为对照组和观察组,每组各32例。对照组每天静脉滴入注射用培美曲塞二钠,500 mg/m²,静滴时间超过10 min,并静脉滴入卡铂注射液,AUC5静滴时间超过30 min。观察组在对照组的基础上口服克唑替尼胶囊,250 mg/次,2次/d。1个周期为21 d,两组共治疗2个周期。观察两组患者的临床疗效,同时比较两组患者治疗前后的血清癌胚抗原（CEA）、神经元特异性烯醇化酶（NSE）、人鳞状细胞癌相关抗原（SCCAg）以及细胞角蛋白19片段（Cyfra21-1）水平和Karnofsky功能状态评分量表（KPS）评分情况。结果 治疗后,观察组总有效率为81.25%,明显高于对照组的59.37%（P<0.05）。两组治疗后的NSE、CEA、SCCAg和CYFRA21-1水平均明显降低（P<0.05）,且观察组上述肿瘤标志物水平明显低于对照组（P<0.05）。治疗后,观察组的生活质量好转率明显高于对照组,恶化率明显低于对照组（P<0.05）。结论 克唑替尼联合PC方案治疗非小细胞肺癌患者的疗效显著,能明显降低肿瘤标志物水平,提高生活质量。     

多西他赛与培美曲塞治疗晚期肺腺癌的临床疗效研究简

目的 本研究旨在对比分析多西他赛与培美曲塞治疗晚期肺腺癌的临床疗效,为临床科学用药提供依据.方法 将在我院接受治疗的120例病晚期肺腺癌患者随机分为培美曲塞组60例和多西他赛组60例.培美曲塞组进行培美曲塞化疗,疗程为2周;多西他赛组进行多西他赛化疗,疗程为2周.治疗结束后对两种治疗方法的临床疗效进分析对比研究.结果培美曲塞组的临床总有效率明显高于多西他赛组,其临床总有效率可高达41.7%,具有显著性差异P〈0.05.结论 在治疗晚期肺腺癌的临床疗效上,培美曲塞疗效显著,是一种值得在临床上大力推广的化疗药品.     

A pathological complete response after preoperative chemotherapy with carboplatin and pemetrexed in malignant pleural mesothelioma: A case report.

Malignant pleural mesothelioma is an aggressive tumour with poor prognosis and short duration of response probably due to the high chemo-refractoriness. Multimodality treatment based on preoperative chemotherapy, surgery and adjuvant radiotherapy seems to be a feasible and effective therapeutic option in selected patients.We report on a case of pathological complete response in a patient affected by malignant pleural mesothelioma who was treated with four cycles of preoperative chemotherapy based on carboplatin plus pemetrexed followed by parietal pleurectomy and lung decortication. Carboplatin plus pemetrexed was a well tolerated regimen without grade 3-4 haematological toxicity, and this confirm the feasibility of such a treatment as an alternative to the current golden standard based on cisplatin plus pemetrexed.Complete resection allows the pathologist to better describe biological markers of mesothelioma cells, in order to select patients with different treatment outcome and prognosis.