EGFR T790M突变丰度对奥希替尼治疗晚期非小细胞肺癌疗效的影响

摘 要：［目的］ 分析奥希替尼治疗晚期非小细胞肺癌疗效,并探索ddPCR方法外周血检测表皮生长因子（epidermal growth factor,EGFR）T790M突变的丰度与奥希替尼疗效之间的关系。［方法］ 回顾性分析104例接受奥希替尼治疗的Ⅲb~Ⅳ期非小细胞癌肺癌患者,采用ddPCR法测定外周血T790M突变丰度,采用Kaplan-Meier法和Cox模型进行生存预后分析,并探索疗效相关T790M突变丰度的界值。［结果］ 外周血EGFR T790M突变丰度中位值为0.89%（0.02%~35.10%）。将突变丰度分为＜5.00%和≥5.00%两组,客观缓解率分别为46.5%和88.9%（P=0.001）,中位无进展生存期分别为8.80个月和21.83个月（P=0.039）。Cox回归分析显示,初治时基因类型（EGFR 19外显子缺失和21外显子L858R突变）、PS评分、外周血EGFR T790M突变丰度分组（＜5.00%和≥5.00%）是奥希替尼治疗患者PFS的独立影响因素。［结论］ EGFR T790M突变丰度可能可预测奥希替尼治疗的晚期EGFR T790M突变NSCLC患者的有效率和无进展生存期。     

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...     

非小细胞肺癌表皮生长因子受体T790M突变的研究进展

摘 要：临床工作中表皮生长因子受体—酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitor，EGFR-TKI）耐药的非小细胞肺癌（non-small cell lung cancer，NSCLC）患者须进行EGFR T790M突变的检测。由于多种原因一些患者无法通过组织再活检获得满意基因检测结果，而液体活检也存在敏感性较低等限制。探索与T790M突变状态相关的临床因素、提高T790M突变再活检的技术水平有助于实现EGFR-TKI耐药后的精准诊断。T790M突变的NSCLC患者首选三代EGFR-TKI奥希替尼，但仍会不可避免地出现耐药。该文对继发性T790M突变的发生、相关检测技术的优劣、临床因素、治疗选择、奥希替尼的耐药机制及对策等研究情况进行综述，希望为患者临床再活检策略及后续治疗的选择提供帮助。     

厄洛替尼与西妥昔单抗联合应用治疗吉非替尼耐药NSCLC的疗效

本研究通过EGFR-TKI和EGFR单克隆抗体联合应用探讨治疗EGFR突变阴性和EGFR T790M突变继发性耐药的NSCLC的疗效。方法:应用EGFR突变阴性和EGFR T790M突变继发性耐药的NSCLL细胞原代培养及药敏技术检验EGFR-TKI和EGFR单克隆抗体联合应用的疗效。结果:检测厄洛替尼和西妥昔单抗联合处理对于15例EGFR突变阴性和8例T790M突变阳性的继发性耐药的NSCLC患者原代细胞的影响,应用浓度分别为50 μg/mL西妥昔单抗和1 μM厄洛替尼作用于EGFR突变阴性的NSCLC患者原代细胞,结果显示这三组间T/C值无显著性差异（P>0.05）,对于T790M突变阳性的继发性耐药的NSCLC原代细胞这三组间T/C值有显著性差异（P<0.05）,联合用药组疗效明显高于单药组。结论:进一步验证了厄洛替尼和西妥昔单抗联合应用对于EGFR突变阴性的NSCLC患者无效,但对于T790M突变阳性的继发性耐药的NSCLC患者有效。      

非小细胞肺癌患者外周血表皮生长因子受体T790M检测与奥希替尼疗效的相关性研究

摘 要：［目的］ 评估非小细胞肺癌患者第一代表皮生长因子受体-酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI）获得性耐药后外周血EGFR T790M突变的阳性率和用外周血T790M检测结果预测奥希替尼疗效的可靠性。［方法］ 回顾性分析2017 年3月至2018年6月经第一代EGFR-TKI治疗后获得性耐药且使用超级扩增阻滞突变系统(ultra-amplification refractory mutation system,Ultra-ARMS )进行外周血EGFR T790M检测的原发性非小细胞肺癌患者。评估血T790M阳性患者使用奥希替尼的疗效。［结果］共有103例符合标准的第一代EGFR-TKI获得性耐药患者,其中28例（27.2%,28/103）血T790M阳性,75例（72.8%,75/103）血T790M阴性。血T790M阳性患者中,接受奥希替尼治疗有23例：部分缓解（partial response,PR） 15例,疾病稳定（stable disease,SD）6例,疾病进展（progression of disease,PD） 2例。疾病控制率(disease control rate,DCR) 91.3%,客观有效率（objective response rate,ORR)65.2%。奥希替尼治疗的中位无进展生存时间（progression free survival,PFS） 12.5个月（95%CI：11.2~13.8）。有9例血T790M阴性患者后续进行了组织检测,3例在组织中检测到T790M突变。有6例血T790M阴性的患者虽未再行组织检测,但要求试用奥希替尼靶向治疗,1例患者获得了PR,1例SD（PFS超过5个月）。［结论］对第一代EGFR-TKI获得性耐药后未能再次行组织活检的非小细胞肺癌患者,Ultra-ARMS方法检测血T790M阳性可预测奥希替尼疗效。血T790M检测阴性的患者建议再次取组织进行T790M检测以排除假阴性。组织检测是T790M检测的金标准,血T790M检测可作为补充。     

T790M突变的非小细胞肺癌研究现状与前景

目前,针对表皮生长因子受体(epidermal growth factor receptor,EGFR)突变的非小细胞肺癌(non-small cell lung cancer,NSCLC)公认的一线治疗方案是以EGFR酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)为主的靶向治疗,尽管一代、二代TKIs带来的靶向治疗可为患者带来更长的无进展生存(progression-free survival,PFS),及更好的耐受,但其远期治疗不可避免会出现耐药.其中,50%以上的获得性耐药与T790M突变有关,因此美国国立综合癌症网络(National Comprehensive Cancer Network,NCCN)推出的最新指南已经提出三代TKI(Osimertinib,奥西替尼)可用于一线TKI治疗进展同时检出T790M突变的患者.但就在三代TKI为我们带来令人鼓舞的可长达13个月的中位PFS及延续着后EGFR-TKIs治疗时代的同时,也面临着严峻的挑战,如怎样实现T790M的检测及动态监测、对已有三代TKI的研究进展、出现三代TKI耐药的机制及后续治疗等,本文将围绕以上各热点问题展开综述.     

奥希替尼联合抗血管生成靶向药对人肺腺癌细胞抑制作用的实验研究

目的:通过体外细胞学实验初步探究奥希替尼联合两种不同机制的抗血管靶向治疗药物（贝伐珠单抗或阿帕替尼）治疗表皮生长因子受体（EGFR）敏感突变和T790M耐药突变肺腺癌细胞的抗肿瘤活性及其作用机制。方法:培养人肺腺癌细胞PC-9（E19 del）和H1975（E21 L858R/E20 T790M）,CCK-8法检测奥希替尼及抗血管靶向治疗药物（贝伐珠单抗或阿帕替尼）单药或联合处理肺腺癌细胞48 h后的抑瘤率;蛋白质印迹法检测EGFR及其下游AKT和ERK信号通路蛋白表达情况。结果:PC-9和H1975肺腺癌细胞对奥希替尼敏感且呈剂量依赖性。奥希替尼联合抗血管生成靶向药物（贝伐珠单抗,阿帕替尼）较同等浓度的单药奥希替尼可增加对PC-9和H1975细胞株的抑瘤率（P<0.05）。低浓度奥希替尼联合高浓度阿帕替尼（1 000 nmol/L）的抑制作用与高浓度奥希替尼相当（P>0.05）。随着联合的阿帕替尼浓度的升高,对PC-9和H1975细胞抑瘤率也有一定程度的提高（P<0.05）。不同处理因素对PC-9细胞的抑制率均高于对H1975细胞（P<0.01）。随着奥希替尼浓度的上升,p-EGFR、p-AKT、p-ERK磷酸化蛋白表达逐渐降低。结论:奥希替尼联合贝伐珠单抗或阿帕替尼会进一步增强对EGFR敏感突变或T790M突变肺腺癌细胞的杀伤作用。奥希替尼与阿帕替尼联合使用具有很强的抑瘤活性,具有很好的应用前景。奥希替尼单药或与抗血管形成药联合作用可能是进一步下调EGFR及其下游AKT和ERK信号通路的活化。     

纳米递药系统负载奥希替尼抗非小细胞肺癌的研究进展

奥希替尼是不可逆的第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）,用于治疗经典EGFR突变和T790M耐药突变的非小细胞肺癌（NSCLC）。然而,与其他EGFR-TKIs一样,奥希替尼不可避免地存在获得性耐药、水溶性差、肿瘤累积率低等问题,限制了其治疗效果。纳米递药系统可增加药物的溶解度和稳定性,延长药物血液循环时间,提高细胞摄取率,增加在肿瘤组织中的聚集改善药物耐药问题,已成为解决传统靶向药物弊端的有效手段。本文综述了第三代EGFR-TKI奥希替尼的作用机制,重点阐述了奥希替尼纳米递药系统抗NSCLC的研究进展,并对该领域面临的挑战和未来发展方向进行了展望。     

第三代表皮生长因子受体酪氨酸激酶抑制剂治疗非小细胞肺癌耐药机制的研究进展

奥希替尼是一种不可逆第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）,对EGFR敏感突变和T790M突变具有高度选择性。尽管第三代EGFR-TKI治疗非小细胞肺癌（NSCLC）患者取得了良好疗效,但耐药的发生不可避免。耐药机制影响了后续治疗方案的制定,精准靶向耐药机制,实施个体化治疗方案更有助于患者临床获益。第三代EGFR-TKI获得性耐药机制主要包括EGFR依赖的耐药机制、旁路替代途径激活及表型转化。部分耐药机制已有较为明确的治疗方式,但更多耐药机制的克服策略尚在探索之中。文章旨在综述第三代EGFR-TKI治疗NSCLC后的获得性耐药机制及克服策略,发现潜在临床靶点。     

晚期肺癌奥西替尼获得性耐药进展模式及挽救治疗效果分析

目的:探讨伴有表皮生长因子受体（EGFR）敏感突变或经酪氨酸激酶抑制剂（TKI）治疗后T790M突变的肺癌晚期患者接受奥西替尼治疗后的耐药进展模式以及挽救治疗方法和效果。方法:收集2017年4月（奥西替尼在中国获批时）至2019年5月在江苏省肿瘤医院采用奥西替尼治疗的145例晚期肺癌患者资料。截至2019年12月最后一...     

Efficacy of immunotherapy targeting the neoantigen derived from epidermal growth factor receptor T790M/C797S mutation in non–small cell lung cancer

Lung cancer is the leading cause of cancer‐related deaths worldwide. Epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKI) often have good clinical activity against non–small cell lung cancer (NSCLC) with activating EGFR mutations. Osimertinib, which is a third‐generation EGFR‐TKI, has a clinical effect even on NSCLC harboring the threonine to methionine change at codon 790 of EGFR (EGFR T790M) mutation that causes TKI resistance. However, most NSCLC patients develop acquired resistance to osimertinib within approximately 1 year, and 40% of these patients have the EGFR T790M and cysteine to serine change at codon 797 (C797S) mutations. Therefore, there is an urgent need for the development of novel treatment strategies for NSCLC patients with the EGFR T790M/C797S mutation. In this study, we identified the EGFR T790M/C797S mutation‐derived peptide (790‐799) (MQLMPFGSLL) that binds the human leukocyte antigen (HLA)‐A*02:01, and successfully established EGFR T790M/C797S‐peptide‐specific CTL clones from human PBMC of HLA‐A2 healthy donors. One established CTL clone demonstrated adequate cytotoxicity against T2 cells pulsed with the EGFR T790M/C797S peptide. This CTL clone also had high reactivity against cancer cells that expressed an endogenous EGFR T790M/C797S peptide using an interferon‐γ (IFN‐γ) enzyme‐linked immunospot (ELISPOT) assay. In addition, we demonstrated using a mouse model that EGFR T790M/C797S peptide‐specific CTL were induced by EGFR T790M/C797S peptide vaccine in vivo. These findings suggest that an immunotherapy targeting a neoantigen derived from EGFR T790M/C797S mutation could be a useful novel therapeutic strategy for NSCLC patients with EGFR‐TKI resistance, especially those resistant to osimertinib.     

CD73 Inhibitor Oleclumab Plus Osimertinib in Previously Treated Patients With Advanced T790M-Negative EGFR-Mutated NSCLC: A Brief Report

IntroductionCD73 is overexpressed in EGFR-mutated NSCLC and may promote immune evasion, suggesting potential for combining CD73 blockers with EGFR tyrosine kinase inhibitors (TKIs). This phase 1b-2 study (NCT03381274) evaluated the anti-CD73 antibody oleclumab plus the third-generation EGFR TKI osimertinib in advanced EGFR-mutated NSCLC.MethodsPatients had tissue T790M-negative NSCLC with TKI-sensitive EGFR mutations after progression on a first- or second-generation EGFR TKI and were osimertinib naive. They received osimertinib 80 mg orally once daily plus oleclumab 1500 mg (dose level 1 [DL1]) or 3000 mg (DL2) intravenously every 2 weeks. Primary end points included safety and objective response rate by Response Evaluation Criteria in Solid Tumors version 1.1.ResultsBy July 9, 2021, five patients received DL1 and 21 received DL2. Of these patients, 60.0% and 85.7% had any-grade treatment-related adverse events (TRAEs) and 20.0% and 14.3% had grade 3 TRAEs, respectively. No dose-limiting toxicities, serious TRAEs, or deaths occurred. Four patients were T790M positive on retrospective circulating tumor DNA (ctDNA) testing; three had objective partial responses. In patients who were T790M negative in tumor and ctDNA, objective response rate was 25.0% at DL1 and 11.8% at DL2 (all partial responses); response durations at DL2 were 14.8 and 16.6 months. In patients receiving DL2, excluding those who were T790M positive by ctDNA, median progression-free survival was 7.4 months, and median overall survival was 24.8 months. DL2 was the recommended phase 2 dose.ConclusionsOleclumab plus osimertinib was found to have moderate activity with acceptable tolerability in previously treated patients with advanced EGFR-mutated NSCLC.     

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.)     

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.     

Different characteristics and survival in non-small cell lung cancer patients with primary and acquired EGFR T790M mutation

Primary epidermal growth factor receptor (EGFR) T790M mutation can be occasionally identified in previous untreated nonsmall cell lung cancer (NSCLC) patients. To compare clinical characteristics and outcomes in patients with primary and acquired EGFR T790M mutation, we collected the data of patients diagnosed with EGFR mutation from 2012 to 2017 in Shanghai Chest Hospital. Primary EGFR T790M mutation was identified in 61 patients (1.1%; 95% confidence interval (CI): 0.8%–1.3%) of 5685 TKI-naive EGFR mutant patients. Acquired T790M mutation was detected in 98 patients (50.3%; 95%CI: 43.2%–57.3%) of 195 TKI-treated patients. T790M mutation always coexisted with sensitizing EGFR mutations. Primary EGFR T790M always coexisted with 21L858R (46/61) whereas acquired T790M coexisted with 19del (68/98), (p < 0.001). Among them, 18 patients with primary T790M mutation received osimertinib and 72 patients with acquired T790M mutation received osimertinib. The median progression-free survival (PFS) of osimertinib was significantly longer in primary T790M group (17.0 months, 95%CI:14.0–20.0 months) compared to acquired T790M group (10.0 months, 95%CI:8.6–11.4 months, p = 0.022). However, the median overall survival (OS) of acquired T790M mutation patients was significantly longer compared to that of primary T790M mutation patients who received osimertinib (50.4 months vs. 29.9 months, p = 0.016). Our findings suggest that primary T790M mutation likely coexists with 21L858R while acquired mutation likely coexists with 19del. Both mutations showed good response to osimertinib. Patients with primary T790M mutation experienced greater benefits from osimertinib. However, patients with acquired T790M mutation had a better overall survival during the entire clinical treatment.     

<Emphasis Type="Italic">BIM</Emphasis> Deletion Polymorphism Confers Resistance to Osimertinib in <Emphasis Type="Italic">EGFR</Emphasis> T790M Lung Cancer: a Case Report and Literature Review

The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib (AZD9291) has shown significant clinical efficacy against the EGFR T790M mutation in non-small cell lung cancer (NSCLC) patients. However, resistance inevitably occurs, and the mechanisms leading to treatment failure need to be further investigated. The B-cell lymphoma 2 (BCL-2)-like 11 (BIM) deletion polymorphism, which occurs at a frequency of 21% in East Asians but is absent in African and European populations, has been associated with resistance to first-generation EGFR TKIs, such as gefitinib and erlotinib; and is a poor prognostic factor for NSCLC patients with EGFR mutations. Nevertheless, the significance of this BIM deletion polymorphism in the resistance to osimertinib has not been reported. Here, we show for the first time that a NSCLC patient harboring the EGFR L858R/T790M mutations, as well as the BIM deletion polymorphism, exhibited poor clinical outcomes with osimertinib treatment. This result suggests that the BIM deletion polymorphism might have prognostic value for determining NSCLC patient outcomes following osimertinib treatment.     

Prospective Observational Study of Treatment Resistance-related Gene Screening Using Plasma Circulating Tumor DNA in Third-generation EGFR-TKI Osimertinib Therapy (Elucidator)

BackgroundOsimertinib is a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits EGFR activating and EGFR T790M resistance mutations. Osimertinib was found to be more effective than first-generation EGFR-TKIs in patients with previously untreated advanced non–small-cell lung cancer (NSCLC) harboring EGFR-positive mutations in a prior phase III trial. Osimertinib is, therefore, one of the most important standard therapies for EGFR mutation-positive patients. However, there are few reports about osimertinib resistance mechanisms in first-line EGFR-TKI therapy. Understanding first-line osimertinib resistance mechanisms is essential for future therapeutic strategies in patients with NSCLC with EGFR-positive mutations. To clarify the resistance mechanisms of first-line osimertinib, we proposed to analyze circulating tumor (ct) deoxyribonucleic acid (DNA) by the ultra-sensitive next-generation sequencing method.Patients and MethodsWe aim to collect ctDNA samples from patients with the following key inclusion criteria: histologically or cytologically proven NSCLC, activating EGFR mutation-positive, planned treatment with first-line osimertinib, and written informed consent. Patients with comorbidities, who are deemed unsuitable for participation by an attending physician, would be excluded. We plan to enroll 180 cases and estimate a final analysis of 120 cases following registration and 2-year observation. ctDNA samples are collected at osimertinib treatment initiation, 3 and 12 months later, and disease progression. The key primary endpoint is to clarify the incidence and ratio of osimertinib resistance. The key secondary endpoint is to examine how the quantity of osimertinib resistance-associated mutations detected in ctDNA at treatment initiation influences disease progression.     

Osimertinib in patients with epidermal growth factor receptor T790M advanced non‐small cell lung cancer selected using cytology samples

Osimertinib is a potent, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for EGFR‑TKI sensitizing (EGFRm) and T790M resistance mutations. The primary objective of the cytology cohort in the AURA study was to investigate safety and efficacy of osimertinib in pretreated Japanese patients with EGFR T790M mutation‐positive non‐small cell lung cancer (NSCLC), with screening EGFR T790M mutation status determined from cytology samples. The cytology cohort was included in the Phase I dose expansion component of the AURA study. Patients were enrolled based on a positive result of T790M by using cytology samples, and received osimertinib 80 mg in tablet form once daily until disease progression or until clinical benefit was no longer observed at the discretion of the investigator. Primary endpoint for efficacy was objective response rate (ORR) by investigator assessment. Twenty‐eight Japanese patients were enrolled into the cytology cohort. At data cut‐off (February 1, 2016), 12 (43%) were on treatment. Investigator‐assessed ORR was 75% (95% confidence interval [CI] 55, 89) and median duration of response was 9.7 months (95% CI 3.8, not calculable [NC]). Median progression‐free survival was 8.3 months (95% CI 4.2, NC) and disease control rate was 96% (95% CI 82, 100). The most common all‐causality adverse events were paronychia (46%), dry skin (46%), diarrhea (36%) and rash (36%). Osimertinib provided clinical benefit with a manageable safety profile in patients with pretreated EGFR T790M mutation‐positive NSCLC whose screening EGFR T790M mutation‐positive status was determined from cytology samples. (ClinicalTrials.gov number NCT01802632).     

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.