第一部分 奥希替尼治疗晚期非小细胞肺癌的疗效与安全性分析

目的：奥希替尼是一种口服、不可逆的第三代表皮生长因子受体（epidermal growth factor receptor，EGFR）酪氨酸激酶抑制剂（tyrosine kinase inhibitor，TKI）。多项前瞻性临床试验证实其对于T790M耐药突变晚期非小细胞肺癌（non-small-cell lung cancer，NSCLC）疗效显著，目前缺乏中国NSCLC人群奥希替尼治疗的真实世界数据。本研究旨在真实世界中探索奥希替尼对经治、晚期NSCLC中国患者的疗效数据。方法： 本研究回顾性收集了2017年3月1日至2018年7月1日就诊于中国医科院肿瘤医院，存在EGFR突变、既往EGFR-TKI或化疗后进展，接受奥希替尼治疗的94例晚期NSCLC患者的临床资料。主要研究目标是疾病控制率（disease control rate，DCR）和无进展生存期（progression-free survival，PFS），次要研究目标包括客观缓解率（objective response rate，ORR），缓解持续时间（duration of response，DoR）以及安全性。结果：本研究共计纳入94例患者，其中91例可评价疗效，ORR和DCR分别是47.3%和90.1%。中位缓解持续时间为12.5个月（95%可信区间[confidence interval，CI] 10.7-14.3）。总人群中位PFS为8.6个月（95% CI, 7.2-10.0），奥希替尼二线和≥三线治疗中位PFS分别为8.5个月（95% CI, 7.4-9.6）和9.1个月（95% CI, 6.6-11.6）。亚组分析显示，基线T790M突变阳性的人群DCR和中位PFS分别为91.9%和8.6个月（95% CI, 7.2-10.0），而T790M突变阴性的患者DCR和中位PFS仅分别为80.0%和3.2个月（95% CI, 0.5-5.9）。T790M突变伴随EGFR第19号外显子缺失（EGFR 19del）的患者中位PFS较T790M突变伴随EGFR第21号外显子L858R突变的患者显著延长（17.9个月vs 7.3个月，P＜0.001）。对于45例存在中枢神经系统（central nervous system，CNS）转移的患者，中位PFS为8.8个月（95% CI, 6.9-10.7），颅内疾病进展时间（intracranial time to progression，iTTP）未达到。本研究人群中，奥希替尼安全性可控，未观察到不良反应导致的死亡事件。结论：通过真实世界临床数据，本研究证实了奥希替尼对于经治、T790M突变晚期NSCLC中国人群疗效显著且安全性可控。

第二部分 奥希替尼治疗晚期非小细胞肺癌获得性耐药机制及预后分析

目的：对于第一/二代表皮生长因子受体（epidermal growth factor receptor，EGFR）酪氨酸激酶抑制剂（tyrosine kinase inhibitor，TKI）耐药，获得性T790M突变的晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）患者，第三代EGFR-TKI奥希替尼是标准后续治疗方案。然而，前瞻性临床试验结果显示奥希替尼通常于10个月左右出现耐药。本研究旨在探索奥希替尼耐药机制以及不同耐药机制与奥希替尼疗效和预后的相关性。方法：本研究回顾性收集了2017年3月1日至2018年12月31日就诊于中国医科院肿瘤医院，第一代或第二代EGFR-TKI治疗后耐药、T790M突变阳性、接受奥希替尼治疗的晚期NSCLC患者的临床资料。存在奥希替尼治疗前和耐药后分子检测配对结果、未被证实小细胞肺癌（small-cell lung cancer, SCLC）转化的患者纳入分子检测分析组。数据截止日期为2019年5月14日。结果：分子检测分析组共计纳入49例患者，其中24例奥希替尼耐药后T790M突变保留，25例T790M突变丢失。49例患者中27例耐药后检测出分子改变，包括EGFR突变（C797S, C796S, G796S, V802I, V834L, E758D 和G724S），非EGFR突变（PIK3CA, ALK, BRAF, KRAS 和TP53），EGFR扩增以及MET扩增。至随访截止，T790M突变保留人群和T790M突变丢失人群中位PFS分别为9.3个月 (95% CI, 4.9-13.7)和7.8个月 (95% CI, 5.4-10.2)（P=0.053）。检出EGFR通路相关耐药机制的患者中位PFS显著优于旁路激活的患者（13.5个月[95% CI, 5.5-21.5] vs. 8.2个月[95% CI, 3.6-12.8]; P=0.012）。结论：本研究阐述了奥希替尼治疗中国晚期NSCLC人群的获得性耐药机制，耐药后T790M突变保留或者EGFR通路相关耐药机制的患者奥希替尼治疗表现出更长时间的临床获益。

第三部分 奥希替尼治疗晚期非小细胞肺癌临床耐药模式及后续治疗分析

目的：第三代表皮生长因子受体（epidermal growth factor receptor，EGFR）酪氨酸激酶抑制剂（tyrosine kinase inhibitor，TKI）奥希替尼是EGFR突变、靶向药物治疗进展后检测出T790M突变的晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）患者的标准治疗，但奥希替尼耐药后目前仍没有一个明确的后续治疗模式。本研究旨在真实临床实践中分析奥希替尼临床耐药模式以及耐药后不同治疗模式的疗效和预后。方法：本研究回顾性收集了2017年3月1日至2018年7月1日在中国医科院肿瘤医院就诊，奥希替尼治疗后进展的NSCLC患者的临床病历资料。结果：本研究共纳入65例患者，临床耐药模式包括：15例局部进展(23.1%)，29例缓慢进展(44.6%)，21例爆发进展(32.3%)。大多数患者表现为单纯胸部进展 (40/65, 61.5%)，只有10例患者表现为单纯颅内进展(15.4%)。疾病进展后，20例患者后续应用化疗(30.8%)，后续化疗的患者相较于后续不化疗患者具有更长的中位总生存（overall survival, OS），但二者未达到统计学差异（25.0个月 vs. 11.8个月，P=0.106）。39例患者在进展后继续奥希替尼治疗，中位进展后治疗持续时间4.1个月。进展后继续奥希替尼治疗和停止奥希替尼治疗的患者中位OS没有统计学差异(18.9个月vs. 15.1个月，P=0.802)。亚组分析显示，耐药后爆发进展的患者，后续接受化疗具有更长的中位OS。但对于局部进展或者缓慢进展的患者，本研究数据仍不成熟。 结论：化疗是奥希替尼治疗进展的晚期NSCLC患者的一种有效后续治疗选择。耐药后继续奥希替尼治疗在未经选择人群中未观察到生存获益。

Part I Efficacy and safety of osimertinib in patients with pretreated advanced non-small cell lung cancer

Background: Osimertinib is an oral, irreversible third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The results of several clinical trials demonstrated its efficacy in patients with non–small-cell lung cancer (NSCLC) harboring EGFR sensitizing mutations and T790M resistance mutations, while the real-world data of osimertinib in Chinese patients was lacking. Our study aimed to assess the efficacy and safety of osimertinib in patients with pretreated NSCLC in the real-world setting. Methods: Ninety-four patients with pretreated advanced EGFR-mutated NSCLC who received osimertinib between Mar 1, 2017 and Jul 1, 2018 were retrospectively collected. Primary endpoints were disease control rate (DCR) and progression-free survival (PFS). Secondary objectives included objective response rate (ORR), duration of response (DoR), and safety. Results: A total of 94 patients were included. In evaluable for response analysis set (n=91), overall ORR was 47.3%, and DCR was 90.1%. Median DoR in responding patients was 12.5 months (95% CI, 10.7-14.3). Median PFS was 8.6 months (95% CI, 7.2-10.0) in overall population, 8.5 months (95% CI, 7.4-9.6) in 2nd line group, and 9.1 months (95% CI, 6.6-11.6) in ≥3rd line group. For subgroup analysis, DCR and median PFS were 91.9% and 8.6 months (95% CI, 7.2-10.0) in patients with detectable T790M mutation at baseline, respectively, while 80.0% and 3.2 months (95% CI, 0.5-5.9) for those without. Median PFS was significantly longer for T790M-positive patients co-occurring with exon19del than with L858R mutation (17.9 months vs. 7.3 months; P<0.001). Among 45 patients with metastases to the central nervous system (CNS), median systemic PFS was 8.8 months (95% CI, 6.9-10.7), while intracranial time to progression (iTTP) was not reached. Safety profile was acceptable in our study patients, no adverse events (AEs) related deaths was observed. Conclusions: Osimertinib was highly active in patients with pretreated advanced NSCLC who harbored EGFR T790M mutation, with manageable side-effects. 

Part II Acquired resistance to osimertinib in patients with advanced non-small cell lung cancer: Mechanisms and clinical outcomes

Background: Osimertinib, a third-generation epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI), has demonstrated substantial clinical benefit in patients with non-small cell lung cancer (NSCLC) who resistant to early-generation EGFR-TKIs and acquired T790M mutation. However, resistance to osimertinib ultimately occurs after approximately 10 months according to prospective clinical research. The aim of our study was to identify mechanism of resistance to osimertinib and correlate it with the clinical outcomes. Methods: We retrospectively analyzed patients with advanced NSCLC who received osimertinib for T790M-mutated acquired resistance to prior EGFR-TKI between Mar 1, 2017 and Dec 31, 2018. Patients with paired molecular data of pre-osimertinib and after resistance development, and was not confirmed with SCLC transformation were included in the molecular analysis set. The data cutoff was May 14, 2019. Results: Of the 49 patients evaluated in the molecular analysis set, 24 patients maintained T790M mutation, while 25 patients performed T790M-loss. Molecular modification was identified in 27 of 49 patients, including EGFR acquired mutations (C797S, C796S, G796S, V802I, V834L, E758D and G724S), non-EGFR dependent mutations (PIK3CA, ALK, BRAF, KRAS and TP53), EGFR amplification and MET amplification. At data cutoff, median progression-free survival (PFS) was 9.3 months (95% CI, 4.9, 13.7) in the T790M-retained group, compared with 7.8 months (95% CI, 5.4, 10.2) in the T790M-loss population (P=0.053). Median PFS was significantly longer in patients with EGFR-dependent resistance mechanism (13.5 months [95%CI, 9.1, 17.9]) than in those with bypass activation (8.2 months [95%CI, 3.6, 12.8]; P= 0.007). Conclusions: Our study demonstrated heterogeneous mechanisms of resistance to osimertinib in Chinese patients with advanced NSCLC. Patients who maintained T790M mutation or with EGFR-dependent resistance mechanism have a longer clinical benefit.

Part III Clinical modality of osimertinib resistance and subsequent management analysis in patients with advanced non-small cell lung cancer

Background: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib has become the standard treatment in patients with pretreated non-small cell lung cancer (NSCLC) who developed T790M resistance mutation. However, no standard treatment after osimertinib failure has been established. The aim of our study was to explore clinical resistance modality of osimertinib and assess the survival benefit of post-progression treatment in the real-world setting. Methods: Between Mar 1, 2017 and Jul 1, 2018, medical data of patients with advanced NSCLC who developed resistance to osimertinib were retrospectively collected in our cancer center. Results: A total of 65 patients were analyzed. Clinical resistance modality varied among patients: 15 (23.1%) with local progression, 29 (44.6%) with gradual progression and 21 (32.3%) with dramatic progression. As for site of osimertinib failure, most patients performed intrathoracic progression only (40/65, 61.5%), while only 10 (15.4%) cases presented intracranial failure alone. After evidence of progressive disease (PD), 20 patients (30.8%) received subsequent chemotherapy, and showed a trend of longer median overall-survival (OS) compared to those with non-chemotherapy regimen (25.0 months vs. 11.8 months, P=0.106). Thirty-nine patients (60.0%) continued osimertinib beyond progression with median post-progression treatment duration of 4.1 months. No significant difference of median OS in osimertinib-continued and osimertinib-discontinued groups (18.9 months vs. 15.1 months, P= 0.802) was found. For subgroup analysis, OS was in favor of chemotherapy in patients performed dramatic progression, but was immature in patients with local or gradual progression. Conclusions: Chemotherapy was an effective option after osimertinib failure in advance NSCLC. Continuation of osimertinib beyond progression did not provide survival benefit in non-selected patients.