EGFR-Mutated Lung Cancers Resistant to Osimertinib through EGFR C797S Respond to First-Generation Reversible EGFR Inhibitors but Eventually Acquire EGFR T790M/C797S in Preclinical Models and Clinical Samples

IntroductionOsimertinib is approved for advanced EGFR-mutated NSCLC, and identification of on-target mechanisms of resistance (i.e., EGFR C797S) to this third-generation EGFR inhibitor are evolving. Whether durable control of subsequently osimertinib-resistant NSCLC with the EGFR-sensitizing mutation (SM)/C797S is possible with first-generation EGFR inhibitors (such as gefitinib or erlotinib) remains underreported, as does the resultant acquired resistance profile.MethodsWe used N-ethyl-N-nitrosourea mutagenesis to determine the profile of EGFR SM/C797S preclinical models exposed to reversible EGFR inhibitors. In addition, we retrospectively probed a case of EGFR SM lung adenocarcinoma treated with first-line osimertinib, followed by second-line erlotinib in the setting of EGFR SM/C797S.ResultsUse of N-ethyl-N-nitrosourea mutagenesis against the background of EGFR L858R/C797S in conjunction with administration of gefitinib revealed preferential outgrowth of cells with EGFR L858R/T790M/C797S. A patient with EGFR delE746_T751insV NSCLC was treated with osimertinib with sustained response for 10 months before acquiring EGFR C797S. The patient was subsequently treated with erlotinib, with response for a period of 4 months, but disease progression ensued. Liquid biopsy disclosed EGFR delE746_T751insV with T790M and C797S present in cis.ConclusionEGFR SM NSCLC can acquire resistance to osimertinib through development of the EGFR C797S mutation. In this clinical scenario, the tumor may respond transiently to reversible first-generation EGFR inhibitors (gefitinib or erlotinib), but evolving mechanisms of on-target resistance—in clinical specimens and preclinical systems—indicate that EGFR C797S along with EGFR T790M can evolve. This report adds to the growing understanding of tumor evolution or adaptability to sequential EGFR inhibition and augments support for exploring combination therapies to delay or prevent on-target resistance.     

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.     

奥希替尼治疗晚期非小细胞肺癌的药物经济学系统评价

目的:系统评价奥希替尼治疗晚期非小细胞肺癌(NSCLC)的经济性,为临床应用及卫生和医保决策者提供参考.方法:计算机检索PubMed、Embase、Cochrane图书馆、Health Technology Assessment、中国知网、万方数据、维普网和中国生物医学文献数据库等数据库,查询自建库至2020年4月公开...     

T790M mutation positive squamous cell carcinoma transformation from EGFR-mutated lung adenocarcinoma after low dose erlotinib: A case report and literature review

Rationale:Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are widely used for the treatment of EGFR mutation positive advanced nonsmall cell lung cancer (NSCLC); however, acquired resistance is known to develop during these treatments. Among these mechanisms, histological transformation is seldom encountered. Although platinum based chemotherapy has been reported to be effective in the treatment of patients with small cell lung cancer transformation, there is a lack of information on the treatment of patients with squamous cell carcinoma (SQ) transformation.Patient Concerns and Diagnosis:An 80-year-old nonsmoking woman was referred to our hospital because of an abnormal shadow on her chest radiograph. Diagnostic bronchoscopy was performed and pathological examination revealed adenocarcinoma. Mutation analysis of the EGFR gene revealed deletion of E746-A750 in exon 19. She refused both surgical treatment and radiation therapy, and preferred periodic radiologic follow-up. Unfortunately, approximately a year and a half after the initial diagnosis, the primary lesion enlarged, and many pleural nodules were newly detected (clinically T4N2M1a, stage IVA).Interventions and Outcomes:Based on EGFR mutation analysis, a reduced dose of daily erlotinib was prescribed, which achieved a partial response and 34 months of progression-free survival (PFS). A repeated biopsy with an endobronchial cryoprobe was performed on the enlarged primary lesion. Pathological examination revealed SQ harboring an identical EGFR mutation with a secondary EGFR T790M mutation. Osimertinib 80 mg once a day was started as second line therapy, which resulted in 8 months of PFS and 15 months of survival.Lesson:The literature review and our report suggest that osimertinib is a promising treatment for NSCLC regardless of histology if T790M is present as an acquired mutation.     

手术治疗T790M基因突变阳性肺腺癌并四肢长骨骨转移患者的临床疗效

目的 比较手术和非手术治疗肺腺癌并四肢长骨转移T790M基因突变阳性患者的临床疗效。方法 选择 2016年7月—2018年12月在海南省东方市东方医院、海南省第三人民医院、海南省人民医院以及海南医学院第一附属医院就诊的肺腺癌并四肢长骨转移T790M基因突变阳性患者36例。根据治疗方式分为手术组（n=17）和非手术组（n=19）,手术组行肿瘤切除+肢体功能重建术,非手术组行微创（含介入）治疗或放疗,比较两组患者的临床疗效。结果 手术组视觉模拟疼痛评分法（visual analogue scale,VAS）评分下降比例、Ennecking评分增加比例、Kanofsky评分增加比例均高于非手术组（88.2% vs 52.6%,χ²=5.360,P=0.021;82.4% vs 47.4%, χ²=4.760,P=0.029; 70.6%  vs 36.8%,χ²=4.100,P=0.043）;手术组和非手术组有效率和疾病控制率差异无统计学意义（52.9% vs 47.4%,χ²=0.111,P=0.738;76.5% vs 78.9%,χ2=0.032,P=0.858）;生存分析结果显示,手术组中位生存期高于非手术组（12.0个月vs 9.0个月,χ²=5.009,P=0.024）。结论 手术治疗可缓解T790M基因突变阳性肺腺癌并四肢长骨转移患者的疼痛,改善肢体功能,延长生存期。     

Durvalumab for Stage III EGFR-Mutated NSCLC After Definitive Chemoradiotherapy

IntroductionIn 2018, durvalumab was approved by the U.S. Food and Drug Administration as consolidation immunotherapy for patients with stage III NSCLC after definitive chemoradiotherapy (CRT). However, whether durvalumab benefits patients with EGFR-mutated NSCLC remains unknown.MethodsWe conducted a multi-institutional retrospective analysis of patients with unresectable stage III EGFR-mutated NSCLC who completed concurrent CRT. Kaplan-Meier analyses evaluated progression-free survival (PFS) between patients who completed CRT with or without durvalumab.ResultsAmong 37 patients, 13 initiated durvalumab a median of 20 days after CRT completion. Two patients completed 12 months of treatment, with five patients discontinuing durvalumab owing to progression and five owing to immune-related adverse events (irAEs). Of 24 patients who completed CRT without durvalumab, 16 completed CRT alone and eight completed CRT with induction or consolidation EGFR tyrosine kinase inhibitors (TKIs). Median PFS was 10.3 months in patients who received CRT and durvalumab versus 6.9 months with CRT alone (log-rank p = 0.993). CRT and EGFR TKI was associated with a significantly longer median PFS (26.1 mo) compared with CRT and durvalumab or CRT alone (log-rank p = 0.023). Six patients treated with durvalumab initiated EGFR TKIs after recurrence, with one developing grade 4 pneumonitis on osimertinib.ConclusionsIn this study, patients with EGFR-mutated NSCLC did not benefit with consolidation durvalumab and experienced a high frequency of irAEs. Patients who initiate osimertinib after durvalumab may be susceptible to incident irAEs. Consolidation durvalumab should be approached with caution in this setting and concurrent CRT with induction or consolidation EGFR TKIs further investigated as definitive treatment.     

奥希替尼一线治疗EGFR突变型非小细胞肺癌脑转移患者的临床疗效

目的 探讨奥希替尼一线治疗表皮生长因子受体（EGFR）突变敏感的非小细胞肺癌（NSCLC）脑转移患者的临床疗效。方法 选取2018年1月至2021年8月在中南大学湘雅医院就诊的EGFR突变并接受奥希替尼一线治疗的NSCLC脑转移患者为研究对象。观察治疗3个月后所有患者的颅内客观缓解率（iORR）、颅内疾病控制率（iDCR）,比较不同临床特征患者iORR和iDCR的差异;记录治疗期间不良反应发生率;随访所有患者治疗后疾病进展和死亡情况,并采用COX回归模型分析奥希替尼一线治疗的预后影响因素。结果 本研究共纳入82例NSCLC脑转移患者,接受奥希替尼一线治疗3个月后iORR为69.5%,iDCR为96.3%;不同年龄、性别、是否吸烟、PS评分、EGFR突变类型、脑转移部位、是否有其他部位转移、是否有中枢神经症状的NSCLC脑转移患者iORR和iDCR比较,差异均无统计学意义（P>0.05）;治疗期间不良反应总发生率为50.0%;总生存率为73.2%,无进展生存率为78.0%;COX回归分析结果显示,EFGR突变类型为L858R的NSCLC脑转移患者发生死亡的风险是19del突变患者的2.793倍（95% CI： 0.134~0.956, P=0.040）,年龄>60岁的NSCLC脑转移患者发生死亡的风险是年龄≤60岁患者的4.385倍（95% CI： 1.267~15.175, P=0.020）。结论 奥希替尼一线治疗EGFR突变型NSCLC脑转移患者可获得良好的iORR和iDCR,且安全性较好。EGFR突变类型为L858R和年龄>60岁是NSCLC脑转移患者奥希替尼一线治疗的预后危险因素。