奥希替尼联合贝伐珠单抗治疗14例EGFR突变型肺腺癌脑转移的疗效观察

目的:观察和评估奥希替尼联合贝伐珠单抗治疗14例EGFR突变型肺腺癌脑转移患者的疗效及安全性.方法:回顾性分析2017年1月至2019年12月广州市胸科医院收治的伴有EGFR突变的肺腺癌脑转移患者共14例,所有患者均给予奥希替尼及贝伐珠单抗联合治疗,每3周为1个周期,观察其脑转移病灶疗效并评估不良反应.结果:14例患者...     

奥希替尼治疗不同表皮生长因子受体基因突变型晚期肺腺癌疗效分析

目的 分析一代表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)耐药后奥希替尼治疗不同EGFR基因突变的晚期肺腺癌临床疗效.方法 回顾性分析2015年1月至2019年10月郑州大学第一附属医院收治的82例EGFR敏感突变且第1代EGFR-TKIs耐药后基因检测T790M突变的晚期肺腺癌患者的临床资料.将50例19外...     

阿美替尼联合贝伐珠单抗治疗晚期NSCLC伴原发EGFR T790M突变：3例病案报道及文献复习

随着检测技术的发展，非小细胞肺癌患者（non-small cell lung cancer, NSCLC）伴原发表皮生长因子受体（epidermal growth factor receptor, EGFR）T790M突变的检出率不断增加，而针对原发EGFR T790M突变NSCLC的一线治疗尚无标准。本文中我们报道了3例晚期NSCLC伴EGFR敏感突变及原发T790M突变的治疗经验，3例患者一线初治均为阿美替尼联合贝伐珠单抗。其中，1例在治疗3个月后因出血风险停用贝伐珠单抗并于10个月后更换为奥希替尼；1例患者在治疗13个月后更换为奥希替尼并停用贝伐珠单抗。3例患者最佳疗效均达部分缓解（partial response,PR）。随访至2022年10月，2例患者一线治疗后进展，无进展生存期（progression-free survival, PFS）分别为11个月和7个月；1例患者治疗后持续反应，治疗时间已达19个月。2例患者基线伴有多发脑转移，一线治疗后颅内病灶最佳疗效均为PR，颅内PFS分别为14个月和未达到（16+个月）。3例患者在治疗期间未见新的不良反应，未发生3级以上不良反...     

贝伐珠单抗联合奥希替尼治疗晚期肺腺癌致心力衰竭1例

<正>患者女性,67岁,2014年7月因咳嗽咳痰伴发热就诊。胸部CT检查显示右肺尖结节灶,伴右肺门、纵隔多发淋巴结转移。经肺穿刺病理检查显示非小细胞肺癌(腺癌)。2014年8月起行3个周期吉西他滨+顺铂(GP)新辅助化疗方案,化疗后出现Ⅲ度谷丙转氨酶和谷草转移氨酶升高(上限的8倍),疗效评估为部分缓解。2014年11月行肺癌根治术,术后病理     

奥希替尼治疗非小细胞肺癌的研究进展

表皮生长因子受体(EGFR)突变的发现以及EGFR酪氨酸激酶抑制剂(TKI)疗效的证明，标志着非小细胞肺癌(NSCLC)精准药物使用时代的到来。奥希替尼是针对EGFR TKI敏感突变和野生型EGFR T790M突变，同时保留野生型EGFR的第三代TKI。因其在临床试验中表现出的显著临床有效性和良好安全性，2015年及2016年初，美国及欧洲首次批准了奥希替尼用于接受EGFR TKI治疗后进展的EGFR T790M突变阳性的NSCLC患者的治疗，2017年3月奥西替尼正式在我国获批上市。本文主要就奥希替尼在NSCLC治疗中的研究进展进行综述。     

EGFR敏感突变的晚期肺腺癌一线化疗与吉非替尼联合治疗的随机对照研究

背景与目的：表皮生长因子受体(epidermal growth factor receptor,EGFR)敏感突变的晚期肺腺癌患者目前标准一线治疗方案为表皮生长因子受体-酪氨酸激酶抑制剂(epithelial growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI)单药治疗。该研究探索化疗联合吉非替尼与单用化疗、单用吉非替尼在EGFR基因敏感突变的晚期肺腺癌一线治疗中的疗效及安全性比较。方法：本研究共纳入了61例EGFR基因敏感突变(19外显子缺失突变或21外显子L858R点突变)、PS 0～1分的初治晚期肺腺癌患者,并用随机数字法随机分成3组。A组20例,给予AC方案化疗(培美曲塞500 mg/m²,第1天;卡铂AUC 5,第1天)联合口服吉非替尼(250 mg/d,第5~21天),每4周为1个周期,最多6个周期,然后每4周进行1次培美曲塞单药联合吉非替尼口服(用药方法及剂量同前)维持治疗;B组20例,给予AC方案化疗(培美曲塞500 mg/m²,第1天;卡铂AUC 5,第1天),每4周为1个周期,最多6个周期,然后每4周进行1次培美曲塞单药维持治疗;C组21例,口服吉非替尼治疗(250 mg/d)。3组的治疗均持续至患者出现疾病进展或出现无法耐受的不良反应或死亡。研究的主要终点为中位无进展生存时间(progression-free survival,PFS)和12个月PFS率,次要终点为总体缓解率、安全性/不良反应。结果：随访中A、C组各失访1例。A组患者中位PFS为20.1个月(95%CI：18.0～22.2个月),B组患者中位PFS为5.5个月(95%CI：3.9～7.2个月),C组患者中位PFS为9.8个月(95%CI：6.8～12.8个月)。A组的12个月PFS率为78.9%,B组为15.0%,C组为40.0%。总体缓解率：A组为84.2%,B组为35.0%,C组为65.0%。安全性方面,严重不良反应的发生率A组为36.8%,B组为30.0%,C组为5.0%。最常见的3～4度不良反应为中性粒细胞减少(A组3例、B组4例)、乏力(A组2例、B组2例)及肝功能损害(A组2例、C组1例)。结论：一线接受化疗与吉非替尼联合治疗的EGFR敏感突变的晚期肺腺癌患者PFS更长。长期的生存结果仍在进一步随访中。     

贝伐珠单抗联合阿来替尼治疗ALK阳性肺腺癌脑转移1例

肺癌是全球高发病率、高死亡率的恶性肿瘤,非小细胞肺癌( NSCLC )约占肺癌的 85％.其中间变性淋巴瘤激酶( ALK)融合基因阳性肺癌是NSCLC的独特分子亚型,约占3％～7％[1],棘皮动物微管相关蛋白样 4(EMLL4)-ALK 是NSCLC中的主要融合体,代表大多数ALK阳性病例[2].脑部是最常见的肺癌远处...     

The safety and efficacy of osimertinib for the treatment of EGFR T790M mutation positive non-small-cell lung cancer

First- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the evidence-based first-line treatment for metastatic non-small-cell lung cancers (NSCLCs) that harbor sensitizing EGFR mutations (i.e. exon 19 deletions or L858R). However, acquired resistance to EGFR TKI monotherapy occurs invariably within a median time frame of one year. The most common form of biological resistance is through the selection of tumor clones harboring the EGFR T790M mutation, present in >50% of repeat biopsies. The presence of the EGFR T790M mutation negates the inhibitory activity of gefitinib, erlotinib, and afatinib. A novel class of third-generation EGFR TKIs has been identified by probing a series of covalent pyrimidine EGFR inhibitors that bind to amino-acid residue C797 of EGFR and preferentially inhibit mutant forms of EGFR versus the wild-type receptor. We review the rapid clinical development and approval of the third-generation EGFR TKI osimertinib for treatment of NSCLCs with EGFR-T790M.     

Efficacy and safety of osimertinib in treating EGFR-mutated advanced NSCLC: A meta-analysis

Osimertinib is the only Food and Drug Administration-approved third-generation epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI). A meta-analysis was performed to aggregate the mixed results of published clinical trials to assess the efficacy and safety of osimertinib. A systematic search of the PubMed, Web of Science, and Cochrane Library electronic databases was performed to identify eligible literature. The primary endpoints were overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and adverse events (AEs). A total of 3,086 advanced nonsmall cell lung cancer (NSCLC) patients from 11 studies have been identified. The aggregate efficacy parameters for treatment-naïve patients with EGFR-TKI-sensitizing mutations are as follows: ORR 79% (95% CI 75–84%), DCR 97% (95% CI 95–99%), 6-month PFS 83% (95% CI 80–87%), and 12-month PFS 64% (95% CI 59–69%). The aggregate efficacy parameters for advanced NSCLC harboring T790M mutations after earlier-generation EGFR-TKI therapy are as follows: ORR 58% (95% CI 46–71%), DCR 80% (95% CI 63–98%), 6-month PFS 63% (95% CI 58–69%), and 12-month PFS 32% (95% CI 17–47%). EGFR-TKI-naïve patients with EGFR-positive mutations tend to have longer median PFS than EGFR-TKI-pretreated counterparts (19.17 vs. 10.58 months). The most common AEs were diarrhea and rash, of which the pooled incidences were 44 and 42%, respectively. Generally, osimertinib is a favorable treatment option for previously treated T790M mutation-positive advanced NSCLC as well as a preferable therapy for untreated EGFR mutation-positive advanced NSCLC. Additionally, osimertinib is well tolerated by most patients.     

Impact of bevacizumab in combination with erlotinib on EGFR‐mutated non–small cell lung cancer xenograft models with T790M mutation or MET amplification

Erlotinib (ERL), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, shows notable efficacy against non–small cell lung cancer (NSCLC) harboring EGFR mutations. Bevacizumab (BEV), a humanized monoclonal antibody to vascular endothelial cell growth factor (VEGF), in combination with ERL (BEV+ERL) significantly extended progression‐free survival in patients with EGFR‐mutated NSCLC compared with ERL alone. However, the efficacy of BEV+ERL against EGFR‐mutated NSCLC harboring T790M mutation or MET amplification, is unclear. Here, we examined the antitumor activity of BEV+ERL in four xenograft models of EGFR‐mutated NSCLC (three harboring ERL resistance mutations). In the HCC827 models (exon 19 deletion: DEL), ERL significantly inhibited tumor growth by blocking EGFR signal transduction. Although there was no difference between ERL and BEV+ERL in maximum tumor growth inhibition, BEV+ERL significantly suppressed tumor regrowth during a drug‐cessation period. In the HCC827‐EPR model (DEL+T790M) and HCC827‐vTR model (DEL+MET amplification), ERL reduced EGFR signal transduction and showed less pronounced but still significant tumor growth inhibition than in the HCC827 model. In these models, tumor growth inhibition was significantly stronger with BEV+ERL than with each single agent. In the NCI‐H1975 model (L858R+T790M), ERL did not inhibit growth or EGFR signal transduction, and BEV+ERL did not inhibit growth more than BEV. BEV alone significantly decreased microvessel density in each tumor. In conclusion, addition of BEV to ERL did not enhance antitumor activity in primarily ERL‐resistant tumors with T790M mutation; however, BEV+ERL enhanced antitumor activity in T790M mutation‐ or MET amplification‐positive tumors as long as their growth remained significantly suppressed by ERL.     

T790M基因突变阳性的肺腺癌并骨转移患者个体化治疗远期疗效及预后的相关因素分析

[摘要] 目的：探讨T790M突变的肺腺癌骨转移患者接受个体化综合治疗的疗效及预后的相关因素。方法：回顾性分析68例经个体化综合治疗的T790M突变的肺腺癌骨转移患者的临床资料,采取化疗、放疗、靶向分子药物、单抗类药物、双磷酸盐等综合治疗,观察疗效及预后,分析相关因素。结果：个体化综合治疗有效率为60.3%(41/68),中位生存期为23 个月。无放疗、T790M耐药基因突变无合并KRAS耐药基因突变、既往化疗类型为辅助化疗、N1 期、孤立的骨转移灶、化疗交替奥希替尼治疗、转移器官个数少、以及ECOG评分<2 分对远期疗效有显著影响（P<0.05）。多因素分析显示,T790M耐药基因突变无合并KRAS耐药基因突变（P=0.012）、转移器官个数0 或1 个（P=0.000）、化疗有无交替奥希替尼（P=0.020）及孤立的骨转移灶为影响T790M突变的肺腺癌骨转移患者联合治疗后远期疗效的保护因素。结论：T790M耐药基因突变无合并KRAS耐药基因突变肺癌患者经化疗、靶向分子药物等综合治疗获得了较长的生存时间,化疗联合靶向分子药物、双磷酸盐类药物等综合治疗为T790M突变的肺腺癌骨转移患者提供了有潜力的治疗模式。     

Efficacy of third-line pemetrexed monotherapy versus pemetrexed combination with bevacizumab in patients with advanced EGFR mutation-positive lung adenocarcinoma

Objective

The purposes of this study were to observe the effects of different treatment strategies, including third-line pemetrexed alone versus its combination with bevacizumab, in patients with advanced epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma, and to analyze the effects of the different medication orders of first- and second-line drugs on third-line efficacy.

Patients and methods

One hundred and sixteen cases of patients with EGFR-positive lung adenocarcinoma who had received third-line pemetrexed alone or in combination with bevacizumab between March 2010 and March 2014 at Guangzhou Institute of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University were analyzed retrospectively. Additionally, all the patients were treated with first-line gemcitabine and cisplatin (GP) chemotherapy and second-line EGFR tyrosine kinase inhibitor (TKI) or with first-line EGFR-TKI and second-line GP chemotherapy.

Results

The median survival of 61 cases with third-line pemetrexed monotherapy was 36.22 months, the median survival time of 55 cases with third-line pemetrexed plus bevacizumab was 38.76 months, and there was a significant difference in survival time between the two groups (P=0.04). Subgroup analysis revealed that among the 55 cases with third-line bevacizumab plus pemetrexed treatment, the median survival of 29 patients with first-line GP and second-line EGFR-TKI was 42.80 months, while the median survival of 26 patients with first-line EGFR-TKI and second-line GP was only 34.46 months; additionally, there was a significant difference in the survival time between the two subgroups (P=0.001). Among 61 cases with third-line pemetrexed treatment, the median survival of 34 patients with first-line GP and second-line EGFR-TKI was 38.72 months, while the median survival of 27 patients with first-line EGFR-TKI and second-line GP was only 32.94 months; the survival time of the two subgroups was significantly different (P=0.001).

Conclusions

Regardless of the order of the first- and second-line chemotherapy and TKI therapy, the pemetrexed plus bevacizumab regimen was superior to the pemetrexed monotherapy as the third-line therapy in patients with advanced EGFR-positive lung adenocarcinoma. However, this strategy is worth further investigation in prospective studies.     

High levels of AXL expression in untreated EGFR-mutated non-small cell lung cancer negatively impacts the use of osimertinib

For non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, the initial therapeutic interventions will have crucial impacts on their clinical outcomes. Drug tolerant factors reportedly have an impact on EGFR-tyrosine kinase inhibitor sensitivity. This prospective study investigated the impacts of drug tolerant-related protein expression in tumors based on the efficacy of osimertinib in the first-setting of EGFR-mutated advanced NSCLC patients. A total of 92 patients with EGFR-mutated advanced or postoperative recurrent NSCLC were analyzed and treated with osimertinib at 14 institutions in Japan. AXL, p53, and programmed death-ligand 1 (PD-L1) expression in patient tumors was determined using immunohistochemistry. The AXL signaling pathway was investigated using a cell line-based assay and AXL-related gene expression in The Cancer Genome Atlas (TCGA) database. High levels of AXL and positive-p53 expression were detected in 26.1% and 53.3% of the pretreatment EGFR-mutated NSCLC tumors, respectively. High AXL expression levels were significantly associated with a shorter progression-free survival compared with low AXL expression levels, irrespective of the EGFR activating mutation status (p = 0.026). Cell line-based assays indicated that the overexpression of AXL protein accelerated PD-L1 expression, which induced insensitivity to osimertinib. In the TCGA database, AXL RNA levels were positively correlated with PD-L1 expression in the lung adenocarcinoma cohort. The results show that high AXL expression levels in tumors impact clinical predictions when using osimertinib to treat EGFR-mutated NSCLC patients. Trial Registration: UMIN000043942.