Clinical outcomes of EGFR-TKI treatment and genetic heterogeneity in lung adenocarcinoma patients with EGFR mutations on exons 19 and 21

Background: Epidermal growth factor receptor (EGFR) mutations, including a known exon 19 deletion (19 del) and exon 21 L858R point mutation (L858R mutation), are strong predictors of the response to EGFR tyrosine kinase inhibi?tor (EGFR?TKI) treatment in lung adenocarcinoma. However, whether patients carrying EGFR 19 del and L858R muta?tions exhibit different responsiveness to EGFR?TKIs and what are the potential mechanism for this difference remain controversial. This study aimed to investigate the clinical outcomes of EGFR?TKI treatment in patients with EGFR 19 del and L858R mutations and explore the genetic heterogeneity of tumors with the two mutation subtypes. Methods: Of 1127 patients with advanced lung adenocarcinoma harboring EGFR 19 del or L858R mutations, 532 received EGFR?TKI treatment and were included in this study. EGFR 19 del and L858R mutations were detected by using denaturing high?performance liquid chromatography (DHPLC). T790M mutation, which is a common resistant mutation on exon 20 of EGFR, was detected by amplification refractory mutation system (ARMS). Next?generation sequencing (NGS) was used to explore the genetic heterogeneity of tumors with EGFR 19 del and L858R mutations. Results: Of the 532 patients, 319 (60.0%) had EGFR 19 del, and 213 (40.0%) had L858R mutations. The patients with EGFR 19 del presented a significantly higher overall response rate (ORR) for EGFR?TKI treatment (55.2% vs. 43.7%, P = 0.017) and had a longer progression?free survival (PFS) after first?line EGFR?TKI treatment (14.4 vs. 11.4 months,P= 0.034) compared with those with L858R mutations. However, no statistically significant difference in overall survival (OS) was observed between the two groups of patients. T790M mutation status was analyzed in 88 patients before EGFR?TKI treatment and 134 after EGFR?TKI treatment, and there was no significant difference in the co?exist?ence of T790M mutation with EGFR 19 del and L858R mutations before EGFR?TKI treatment (5.6% vs. 8.8%, P = 0.554)or after treatment (24.4% vs. 35.4%, P= 0.176). In addition, 24 patients with EGFR 19 del and 19 with L858R mutations were analyzed by NGS, and no significant difference in the presence of multiple somatic mutations was observed between the two genotypes. Conclusions: Patients with EGFR 19 del exhibit longer PFS and higher ORR compared with those with L858R muta?tions. Whether the heterogeneity of tumors with EGFR 19 del and L858R mutations contribute to a therapeutic response difference needs further investigation.     

EGFR复合少见突变阳性的非小细胞肺癌患者的临床特征及疗效分析

目的:分析非小细胞肺癌患者中表皮生长因子受体(EGFR)突变为包含少见突变的复合突变患者的临床特征与治疗效果，为EGFR复合少见突变阳性的非小细胞肺癌患者的治疗提供依据。方法:回顾性分析22例EGFR复合少见突变阳性的非小细胞肺癌患者的病历资料及治疗经过。比较患者EGFR基因突变类型、临床资料特征及治疗效果。结果:在我院2014年-2018年病理科检测的EGFR突变阳性的3 224名患者当中，EGFR复合突变共147例，占比为4.56%，而复合少见突变患者共27例，占比0.84%。晚期复合少见突变患者中有11名使用EGFR酪氨酸激酶抑制剂（TKI）治疗，对这些患者的治疗用药及疗效分析后，使用一代 TKI治疗患者6人，中位无进展生存时间（PFS）为8.4个月，二代TKI治疗患者5人，中位PFS为7.2月，两组之间无明显统计学差别。结论:EGFR复合少见突变的患者使用一代或二代EGFR-TKI治疗疗效无明显差别。     

EGFR-TKI获得性耐药晚期肺腺癌的临床特点分析

目的探讨携带表皮生长因子受体(EGFR)敏感基因突变的晚期肺腺癌患者经过一线EGFR酪氨酸激酶抑制剂(EGFR-TKI)治疗出现获得性耐药的临床特点。方法收集2011年1月至2015年12月携带EGFR敏感基因突变的193例患者,其中一线给予吉非替尼或埃克替尼治疗120例,分析EGFR-TKI治疗过程中疗效及EGFR突变类型与出现获得性耐药时临床进展特点的关系。结果一线行EGFR-TKI治疗的120例患者中无1例获完全缓解,获部分缓解(PR)80例(66.7%),中位无进展生存时间(PFS)为12.1个月;获稳定(SD)36例(30.0%),中位PFS为6.1个月,两者PFS的差异有统计学意义(P<0.05)。获PR和SD的116例患者中,EGFR 19号外显子缺失64例(55.2%),中位PFS为11.0个月;21号外显子L858R点突变52例(44.8%),中位PFS为8.6个月,两者PFS的差异有统计学意义(P<0.05)。出现获得性耐药时50例(43.1%)仅有原发病灶进展,66例(56.9%)出现了新的转移病灶。出现获得性耐药时肺部病灶进展最多(37.9%),其次是颅内转移(26.7%)。疗效评价为PR和SD及EGFR外显子19缺失和L858R突变的患者出现获得性耐药与转移部位无关,与新发或原发病灶亦无关(P>0.05)。结论携带EGFR敏感基因突变患者经EGFR-TKI治疗后出现获得性耐药的患者,肺部病灶进展最多,其次是颅内转移。转移部位与治疗疗效及EGFR突变基因型无明显关系。     

EML4-ALK Rearrangement and Its Clinical Significance in Chinese Patients with Advanced Non-Small Cell Lung Cancer

Objective: To identify the clinicopathological characteristics and clinical outcomes of Chinese patients with non-small cell lung cancer (NSCLC) and to investigate possible associations of NSCLC with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) mutations. Methods: Patients with stage IV NSCLC were screened for EML4-ALK rearrangement and EGFR mutations at the Peking University Cancer Hospital. EML4-ALK was identified using fluorescent in situ hybridization and confirmed by immunohistochemistry. EGFR mutations were determined using denaturing high-performance liquid chromatography. Results: The incidence of EML4-ALK was 9.7% (11/113). Patients with EML4-ALK were more likely to present the EGFR wild type (WT; p = 0.033). Response to EGFR-tyrosine kinase inhibitor (TKI) was similar between patients with EML4-ALK rearrangement and EGFR mutation (33.3 vs. 46.9%, p = 0.451), but progression-free survival (PFS) was inferior compared to those with EGFR mutation (2.1 vs. 8.8 months, p = 0.032), and similar to patients with WT/nonrearrangement (2.1 vs. 2.2 months, p = 0.696; and general p = 0.023 between the three cohorts). Moreover, 2 patients with concurrent EML4-ALK and EGFR mutations had superior PFS after EGFR-TKI compared to patients with single EML4-ALK rearrangement. Conclusions: Patients with EML4-ALK conferred similar objective response rates after EGFR-TKI although inferior PFS compared to those with EGFR mutation. Coexistence of EML4-ALK and EGFR mutation might represent a separate NSCLC genotype.     

Analysis of EGFR Mutation Status in Algerian Patients with Non-Small Cell Lung Cancer

Background and objective: Epidermal growth factor receptor (EGFR) mutation status is used as a predictive biomarker for the tyrosine kinase inhibitors therapy in non-small cell lung cancer (NSCLC). The incidence of EGFR mutations appears to vary according to ethnic and geographical backgrounds. This retrospective study aimed to investigate the EGFR mutation status in Algerian NSCLC patients and its association with clinicopathological features. Methods: We examined the presence of EGFR mutations (Exons 19-21) in 58 unselected  NSCLC samples using PCR followed by direct sequencing. Results: The present study included 53 (91.4%) men and 5 (8.6%) women, with a median age of 59 (ranging from 44 to 94 years old). EGFR mutations were detected in 23 patients, with an overall rate of 39.6%. There were 21 (91.3%) cases with the exon-21 L585R single mutation and two (8.7%) with dual mutations of exon-19 deletions and L585R. EGFR mutations were more frequently found in patients with confirmed adenocarcinoma (14/27, 51.8%) than in non-adenomatous NCSCL subtypes (3/14, 21.4%; p=0.03). Furthermore, early stages of the disease were significantly associated with a higher rate of EGFR mutations (14/27, 51.8%) compared with those at  advanced stage (5/21, 23.8%; p=0.02). There were no significant differences in EGFR mutation frequency by age, gender, or smoking status. Conclusion: We found that Algerian NSCLC patients exhibited a high rate of EGFR mutations, which was quite similar to that in Asians population rather than Caucasian patients. Thus, TKI-based treatments may be more beneficial for Algerian patients with NSCLC. Further studies using a large number of patients are required to confirm our preliminary findings.     

The Frequency of EGFR Mutation in Lung Adenocarcinoma and the Efficacy of Tyrosine Kinase Inhibitor Therapy in a Hungarian Cohort of Patients

In the last decades new therapeutic drugs have been developed for the treatment of non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs) significantly increase the progression free survival (PFS) of patients with NSCLC carrying epidermal growth factor receptor (EGFR) mutations. This type of lung cancer occurs mainly among non-smoking women and Asian origin. However, the new ESMO guideline recommends EGFR mutation analysis in every patient with NSCLC, because in patients with activating EGFR mutation, TKIs should be considered as first line therapy. In our recent work, we analyzed data of patients with EGFR-mutant adenocarcinoma from January 2009. The number of patients investigated was 446, among them 44 cases were positive for EGFR mutation. The ratio of positive cases was 9.86 % that is lower than the average mutation rate in Europe and much lower than that found in Asia. The exon 19 deletion was detected in 61.4 % of the patients, while L858R point mutation in exon 21 was observed in 34.1 % of them. In one subject, both exon 19 and 21 mutations were present simultaneously. A rare mutation located in exon 21 was found in another patient. TKI therapy was conducted in 38 patients. The disease control rate by TKI therapy was 85.7 %; primary resistance was documented in five subjects. Non-smoking patients with EGFR mutant adenocarcinoma had the highest benefit from TKI treatment. Our data support the recommendation that EGFR mutation status should be defined in all cases of locally advanced or metastatic lung adenocarcinoma.     

肺腺癌患者EGFR和KRAS基因突变与预后的相关性研究

目的 探讨肺腺癌患者表皮生长因子受体(EGFR)和KRAS基因突变与预后的相关性.方法 选取134例肺腺癌患者的肺腺癌组织标本,应用探针扩增阻滞突变系统在PCR仪上进行EGFR和KRAS基因突变检测,分析EGFR和KRAS基因突变与肺腺癌患者临床病理特征及预后的关系.结果 134例患者中,EGFR基因突变53例,突变率为39.55%,KRAS基因突变6例,突变率为4.48%.肺腺癌患者EGFR基因突变率与年龄、吸烟史有关(P﹤0.01).EGFR基因突变型患者的KRAS基因突变率低于EGFR基因野生型患者(P﹤0.05).EGFR基因突变型患者的无进展生存期(PFS)长于EGFR基因野生型患者(P﹤0.05),KRAS基因野生型患者的PFS长于KRAS基因突变型患者(P﹤0.05).结论 EGFR基因突变的肺腺癌患者KRAS基因更倾向于野生型,EGFR基因突变型或KRAS基因野生型的肺腺癌患者PFS更长.     

Clinical predictors of response to EGFR-tyrosine kinase inhibitors in EGFR-mutated non-small cell lung cancer: A real-world multicentric cohort analysis from India

Background: The development of various targeted therapies against Epidermal Growth Factor Receptor (EGFR) has been a major step in therapeutic advancements in lung cancer. However, the response to tyrosine kinase inhibitors (TKI) therapy in a real-world setting has not been well elucidated.Methods: As part of a retrospective analysis, patients with EGFR mutated non-small cell lung cancer at 4 tertiary care Institutions in North India between December 2007 and August 2018 were evaluated. The overall response rate, disease control rate, progression-free survival (PFS) and factors affecting PFS were analyzed.Results: A total of 483 patients were included, including 52.4% males, with mean (±SD) age of 56.7 (±12.4) years. Majority (63.8%) had good performance status (Eastern Cooperative Oncology Group 0 or 1) and 77.4% were nonsmokers. Among the EGFR mutations, exon 19 deletion was the most common mutation detected (68.1%), followed by L858R mutation in exon 21 (26.9%). Extra-thoracic metastasis was present in 69.5% patients and majority of them had ≤ 2 metastatic sites (85.1%). TKIs were used as the first-line therapy in 64.8% patients, and gefitinib was the most frequently used TKI (67.3%), followed by erlotinib (26.7%). The overall response rate and disease control rate were 65.9% and 90.7% respectively. The median PFS was 9.3 months and brain was the exclusive site of progression in 18.0% patients. On univariate analysis, the factors that significantly affected PFS were, the number of metastatic sites and the type of EGFR mutation. On multivariate analysis, the number of metastatic sites was the only factor that affected the PFS [HR (95% CI): 2.5 (1.7-3.6); Pvalue <0.001]. Skin toxicity was the most common adverse event (32.3%), followed by involvement of the gastro-intestinal tract (22.5%). Conclusion: In this one of the largest multicentric Indian study of treatment outcomes in EGFR-mutated non-small cell lung cancer in a real-world setting, we found that increased tumor burden (number of metastatic sites > 2) was the only significant factor associated with a worse PFS.     

Osimertinib in Japanese patients with EGFR T790M mutation‐positive advanced non‐small‐cell lung cancer: AURA3 trial

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the first‐line treatment for patients with EGFR mutant non‐small‐cell lung cancer (NSCLC). However, most patients become resistant to these drugs, so their disease progresses. Osimertinib, a third‐generation EGFR‐TKI that can inhibit the kinase even when the common resistance‐conferring Thr790Met (T790M) mutation is present, is a promising therapeutic option for patients whose disease has progressed after first‐line EGFR‐TKI treatment. AURA3 was a randomized (2:1), open‐label, phase III study comparing the efficacy of osimertinib (80 mg/d) with platinum‐based therapy plus pemetrexed (500 mg/m²) in 419 patients with advanced NSCLC with the EGFR T790M mutation in whom disease had progressed after first‐line EGFR‐TKI treatment. This subanalysis evaluated the safety and efficacy of osimertinib specifically in 63 Japanese patients enrolled in AURA3. The primary end‐point was progression‐free survival (PFS) based on investigator assessment. Improvement in PFS was clinically meaningful in the osimertinib group (n = 41) vs the platinum‐pemetrexed group (n = 22; hazard ratio 0.27; 95% confidence interval, 0.13‐0.56). The median PFS was 12.5 and 4.3 months in the osimertinib and platinum‐pemetrexed groups, respectively. Grade ≥3 adverse events determined to be related to treatment occurred in 5 patients (12.2%) treated with osimertinib and 12 patients (54.5%) treated with platinum‐pemetrexed. The safety and efficacy results in this subanalysis are consistent with the results of the overall AURA3 study, and support the use of osimertinib in Japanese patients with EGFR T790M mutation‐positive NSCLC whose disease has progressed following first‐line EGFR‐TKI treatment. (ClinicalTrials.gov trial registration no. NCT02151981.)     

盐酸埃克替尼治疗晚期非小细胞肺癌的临床观察

目的:观察盐酸埃克替尼治疗晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）的疗效、安全性及其影响因素。方法:回顾性分析云南省肿瘤医院2013年11月-2016年2月收治的接受盐酸埃克替尼治疗的晚期NSCLC患者56例,对患者疗效、生存期及毒副反应进行评价。结果:56例患者均可评价疗效,客观有效率（objective response rate,ORR）为30.4%,疾病控制率（disease control rate,DCR）为83.9%,中位无进展生存期（progression free survival,PFS）为9个月。腺癌患者的DCR、PFS均优于鳞癌患者（P＜0.05）。12例患者进行EGFR基因检测,均为突变阳性,EGFR突变患者的ORR为58.3%,DCR为100%,PFS为9个月。EGFR突变患者的ORR优于EGFR状态未知患者（P＜0.05）。毒副反应主要为轻度的皮肤毒性和腹泻。结论:盐酸埃克替尼是治疗晚期NSCLC的有效药物,毒副反应较轻,腺癌患者能获得较好的疗效,EGFR突变患者的疗效更好。     

Epidermal growth factor receptor mutation analysis in cytological specimens and responsiveness to gefitinib in advanced non-small cell lung cancer patients

Background

Epidermal growth factor receptor (EGFR) mutation is the key predictor of EGFR tyrosine kinase inhibitors (TKIs) efficacy in non-small cell lung cancer (NSCLC). We conducted this study to verify the feasibility of EGFR mutation analysis in cytological specimens and investigate the responsiveness to gefitinib treatment in patients carrying EGFR mutations.

Methods

A total of 210 cytological specimens were collected for EGFR mutation detection by both direct sequencing and amplification refractory mutation system (ARMS). We analyzed EGFR mutation status by both methods and evaluated the responsiveness to gefitinib treatment in patients harboring EGFR mutations by overall response rate (ORR), disease control rate (DCR) and progression free survival (PFS).

Results

Of all patients, EGFR mutation rate was 28.6% (60/210) by direct sequencing and 45.2% (95/210) by ARMS (P<0.001) respectively. Among the EGFR wild type patients tested by direct sequencing, 26.7% of them were positive by ARMS. For the 72 EGFR mutation positive patients treated with gefitinib, the ORR, DCR and median PFS were 69.4%, 90.2% and 9.3 months respectively. The patients whose EGFR mutation status was negative by direct sequencing but positive by ARMS had lower ORR (48.0% vs. 80.9%, P=0.004) and shorter median PFS (7.4 vs. 10.5 months, P=0.009) as compared with that of EGFR mutation positive patients by both detection methods.

Conclusions

Our study verified the feasibility of EGFR analysis in cytological specimens in advanced NSCLC. ARMS is more sensitive than direct sequencing in EGFR mutation detection. EGFR Mutation status tested on cytological samples is applicable for predicting the response to gefitinib. Abundance of EGFR mutations might have an influence on TKIs efficacy.     

EGFR突变IIIa期肺腺癌术后靶向治疗疗效分析

目的:探索第一代EGFR酪氨酸激酶抑制剂用于EGFR突变IIIa期肺腺癌患者术后辅助治疗的疗效。方法:回顾性纳入2014年1月至2018年7月期间本中心符合纳入标准的、接受第一代EGFR-TKI治疗的IIIa期肺腺癌患者，获取其一般临床数据、无病生存期（disease-free survival，DFS）和不良事件等信息，分析其对预后的影响。结果:研究纳入了80例IIIa期EGFR敏感突变患者，其中以T3N1分期（43/80）和19外显子缺失突变（49/80）患者为主。EGFR-TKI平均治疗时间为18.7月。全部患者总体DFS为26.8（24.5~29.1）月，不同的TNM分期之间无统计学差异（P=0.74）。总体III-IV级不良事件发生率为11.25%。结论:IIIa期EGFR突变阳性的患者术后采用EGFR-TKI辅助治疗可显著延长DFS，该治疗安全可靠。     

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。     

NTRK突变肺癌患者的临床特征和预后分析

  目的  探讨NTRK基因突变肺癌患者的临床特征、治疗情况以及与预后的关系。  方法  回顾性分析2016年10月至2019年11月就诊于华中科技大学同济医学院附属同济医院胸部肿瘤科且NGS检测伴有NTRK突变的原发性肺癌患者的临床资料，应用Kaplan-Meier法和Log-rank检验进行单因素生存分析。  结果  研究共纳入28例患者，27例为Ⅳ期，基因检测结果均为NTRK点突变或拷贝数扩增；1例为ⅢC期，基因检测结果为AEN-NTRK3（A1:N18）融合。单因素分析结果显示，接受一线治疗的NTRK突变患者无进展生存期（progression-free survival，PFS）与肿瘤组织病理类型相关（腺癌vs.鳞癌:9.4个月vs.2.5个月，P < 0.05），而与年龄、性别、吸烟史、NTRK突变位点、突变类型、是否合并经典突变无关（均P>0.05）。一线接受表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）治疗的NTRK1突变合并EGFR突变患者PFS明显长于NTRK3突变合并EGFR突变患者，中位PFS分别为12.4个月和3.0个月，差异具有统计学意义（P < 0.05）。  结论  接受一线治疗的NTRK突变肺腺癌患者PFS较鳞癌患者长。EGFR突变合并NTRK3突变肺癌患者接受EGFR-TKIs治疗的预后较差，合并NTRK3突变可能是EGFR突变肺癌预后不良的因素之一。      

Osimertinib for Japanese patients with T790M‐positive advanced non‐small‐cell lung cancer: A pooled subgroup analysis

Epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) are the standard of care for non‐small‐cell lung cancer (NSCLC) patients harboring EGFR mutations. However, almost all patients develop resistance after approximately 1 y of treatment, with >50% of cases due to the T790M secondary mutation of the EGFR gene. A large global Phase III study (AURA3) demonstrated that osimertinib significantly prolonged progression‐free survival (PFS) over platinum‐doublet chemotherapy in patients with T790M‐positive NSCLC who had progressed on previous EGFR‐TKI therapy. However, it is not clear whether efficacy or safety of osimertinib in Japanese patients is similar to the overall population. We report a pre‐planned subgroup analysis of pooled Phase II data from the AURA Extension and AURA2 trials to investigate the efficacy and safety of osimertinib in Japanese patients. This study included 81 Japanese patients. Patients were administered 80 mg osimertinib orally once daily until disease progression. The main endpoints were objective response rate (ORR), PFS, and safety. The ORR was 63.6% and median PFS was 13.8 mo. Overall survival rate at 36 mo was 54.0%. The most common all‐cause adverse events (AEs) were rash (grouped term; 65.4%), diarrhea (51.9%), paronychia (grouped term; 49.4%), and dry skin (grouped term; 39.5%). Most AEs were grade 1‐2. Five patients (6.2%) developed interstitial lung disease, resulting in two deaths (2.5%). Osimertinib demonstrated favorable ORR and PFS in Japanese patients, similar to the overall population. Additionally, osimertinib has good efficacy and a manageable safety profile in Japanese patients with NSCLC who had acquired resistance due to the T790M mutation.     

EGFR-TKI一线治疗EGFR基因突变的晚期非小细胞肺癌临床观察

背景与目的研究表明,一线表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptortyrosine kinase inhibitor,EGFR-TKI)治疗晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的客观缓解率及无进展生存期明显优于铂二联的化疗,且耐受性更好。本研究旨在分析EGFR-TKI一线治疗晚期EGFR突变阳性的NSCLC患者的疗效与耐受性。方法 54例晚期NSCLC患者肿瘤标本采用直接测序法证实EGFR活化突变(外显子19缺失或外显子21点突变),一线给予EGFR-TKI口服治疗直至疾病进展,观察疗效及不良反应,并进行生存随访。结果 54例患者外显子19缺失33例(61%),外显子21点突变21例(39%)。均一线接受EGFR-TKI治疗,总体缓解率为90%,中位无进展生存期(progression free survival,PFS)为8.3个月,中位生存期为19.5个月;外显子19缺失患者的中位PFS(9.0个月)较21点突变(7.0个月)时间长(P=0.002)。外显子19缺失患者的中位总生存期(overall survival,OS)(25.0个月)较21点突变(16.0个月)时间长(P=0.001);吉非替尼与厄洛替尼疗效相当,但吉非替尼组安全性更好;最常见的不良事件为皮疹和腹泻,有2例患者(4%)出现了3度皮肤毒性反应,2例患者(4%)出现了3度的转氨酶升高,1例患者(1%)出现了3度口腔炎。结论存在EGFR基因突变的晚期NSCLC患者一线接受EGFR-TKI治疗安全有效,且外显子19缺失比L858R突变疗效更优。     

晚期非小细胞肺癌表皮生长因子受体基因突变情况和其对吉非替尼疗效的影响

背景与目的 研究晚期非小细胞肺癌( non-small cell lung cancer,NSCLC)表皮生长因子受体(epidermal growth factor receptor,EGFR)基因突变情况和该基因突变状态对吉非替尼疗效的影响.方法 于2007年1月-2009年12月对160例晚期非鳞癌NSCLC患者进行了EGFR基因检测,EGFR基因外显子19和外显子21突变检测采用突变富集PCR法.其中111例接受了吉非替尼治疗.中位生存期(overall survival,OS)和无疾病进展生存时间(progression free survival,PFS)的比较采用Kaplan-Meier方法计算.结果 晚期非鳞癌NSCLC患者EGFR基因突变率为55％,多因素分析显示只有病理类型与是否突变明显相关.EGFR基因突变型患者的OS为29.0个月(95％CI:24.2-33.8),野生型为21.0个月( 95％CI:14.7-27.3),两者差别无统计学差异.EGFR基因突变患者的PFS为17.0个月(95％CI:5.6-17.6),而野生型为11.6个月(95％CI:8.6-25.4),两者有明显性差别(P=0.022).OS的多因素分析结果显示,OS与ECOG评分、病理类型、EGFR基因突变状态明显相关.PFS多因素分析结果显示,PFS与ECOG评分、既往化疗方案数和EGFR基因突变明显相关.EGFR基因外显子19突变与外显子21突变的OS和PFS无明显差别,客观疗效也无差别.结论 晚期非鳞癌NSCLC EGFR基因突变患者的PFS明显优于野生型患者,OS有延长趋势.EGFR基因不同突变类型的PFS和OS均无差别.     

Epidermal growth factor receptor mutation, but not sex and smoking, is independently associated with favorable prognosis of gefitinib-treated patients with lung adenocarcinoma

Epidermal growth factor receptor ( EGFR ) mutations have been reported as a predictive factor for favorable prognosis of gefitinib-treated patients with lung adenocarcinoma. However, its confounding with sex and smoking makes it unclear whether the EGFR mutation is independently associated with prolonged patient survival. In this study, we analyzed a large-scale database to discriminate the survival impact of EGFR mutations against those of sex and smoking after gefitinib therapy. EGFR mutations in exon19 and exon21 named drug-sensitive EGFR mutations were examined to investigate the impact of EGFR mutation, sex, and smoking status on survival of 362 gefitinib-treated patients with lung adenocarcinoma. Drug-sensitive EGFR mutations were detected in 169 patients (46.7%). The multivariate analysis including EGFR , sex, and smoking status showed that drug-sensitive EGFR mutations were significantly related to longer overall survival (OS) ( P <  0.001) and progression-free survival (PFS) ( P <  0.001). In addition, we investigated the impact of sex and smoking status according to EGFR mutation status, and the impact of EGFR mutation status according to sex and smoking status on survival. Sex and smoking status were not significantly associated with longer OS and PFS according to EGFR mutation status. Drug-sensitive EGFR mutations were significantly associated with longer OS and PFS according to sex or smoking status. Our results indicated that drug-sensitive EGFR mutations were the only independent factor for longer survival of patients treated with gefitinib, suggesting that patient selection based on EGFR mutation status for gefitinib therapy will lead to a better outcome for patients with lung adenocarcinoma. ( Cancer Sci 2008; 99: 303–308)     

Phosphorylated EGFR expression may predicts outcome of EGFR-TKIs therapy for the advanced NSCLC patients with wild-type EGFR

ABSTRACT: BACKGROUND: EGFR mutation is a strong predictive factor of EGFR-TKIs therapy. However, at least 10% of patients with EGFR wild-type are responsive to TKIs, suggesting that other determinants of outcome besides EGFR mutation might exist. We hypothesized that activation of phosphorylated EGFR could be a potential predictive biomarker to EGFR-TKIs treatment among patients in wild-type EGFR. METHOD: Total of 205 stage IIIb and IV NSCLC patients, tissue samples of whom were available for molecular analysis, were enrolled in this study. The phosphorylation of EGFR at tyrosine 1068 (pTyr1068) and 1173 (pTyr1173) were assessed by immunohistochemistry, and EGFR mutations were detected by denaturing high performance liquid chromatograph (DHPLC). RESULTS: Among 205 patients assessable for EGFR mutation and phosphorylation analysis, 92 (44.9%) were EGFR mutant and 165 patients (57.6%) had pTyr1173 expression. Superior progression-free survival (PFS) was seen after EGFR-TKIs therapy in patients with pTyr1068 expression compared to pTyr1068 negative ones (median PFS 7.0 months vs. 1.2 months, P<0.001). Inversely, patients with pTyr1173 had a shorter PFS (4.8 months VS. 7.7 months, P=0.016). In subgroup of patients with wild-type EGFR, pTyr1068 expression positive ones had a significantly prolonged PFS (4.2 months vs.1.2 months P<0.001) compared with those without pTyr1068 expression.Sixteen patients with both wild-type EGFR and pTyr1068 who responded to EGFR-TKIs had median PFS of 15.6 months (95%CI: 7.28-23.9). CONCLUSION: pTyr1068 may be a predictive biomarker for screening the population for clinical response to EGFR-TKIs treatment; especially for patients with wild-type EGFR.     

Clinicopathologic and Molecular Features of Epidermal Growth Factor Receptor T790M Mutation and c-MET Amplification in Tyrosine Kinase Inhibitor-resistant Chinese Non-small Cell Lung Cancer

To investigate the clinicopathologic and molecular features of the T790M mutation and c-MET amplification in a cohort of Chinese non-small cell lung cancer (NSCLC) patients resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). EGFR TKI-resistant NSCLC patients (n?=?29) and corresponding tumor specimens, and 53 samples of postoperative TKI-naïve NSCLC patients were collected. EGFR exon 19, 20, and 21 mutations were analyzed. And c-MET gene copy number was determined. The EGFR T790M mutation in exon 20 was not detected in the population of 53 TKI-naïve patients, but found in 48.3% (14/29) of the enrolled TKI-resistant patients. c-MET was amplified in 3.8% (2/53) of the TKI-naïve NSCLC patients and highly amplified in 17.2% (5/29) of the cohort. Most of T790M mutations were frequently associated with non-smoker, adenocarcinoma and EGFR activating mutations. Three male patients with T790M mutation occurred with wild-type EGFR, and were resistant to the treatments following TKI resistance. Features of c-MET amplification in TKI-naïve patients were indistinguishable from TKI-resistant patients. In the group of wild-type EGFR, patients with T790M mutation had median progression free survival (PFS) and overall survival (OS) as 9.6 months and 12.6 months, respectively; whereas the median PFS and OS of c-MET amplified patients was 4.1 months and 8.0 months, respectively. These results suggest that EGFR T790M mutation and c-MET amplification can occur in TKI-resistant NSCLC with wild-type EGFR, and these genetic defects might be related to different survival outcome. c-MET amplification in TKI-naïve or -resistant patients might share similarities in clinicopathologic features.