奥西替尼治疗EGFR T790M突变的老年晚期肺腺癌患者1例

1例表皮生长因子受体(epithelial growth factor receptor,EGFR)基因第19外显子突变阳性肺腺癌患者接受第一代EGFR抑制剂(tyrosine kinase inhibitors,TKIs)治疗后,无进展生存期(progression-free survival,PFS)达31个月,此后病情进展,患者肺内病灶增大,行血液标本基因检测,提示T790M突变,予以奥希替尼靶向治疗19个月,2019年9月患者仍未达到PFS。奥希替尼治疗T790M突变老年肺腺癌,疗效确切,安全性较好,该例患者主要不良反应为腹泻。     

2020—2022年辽宁省肿瘤医院小分子酪氨酸激酶抑制剂的使用情况分析

目的 分析辽宁省肿瘤医院2020-2022年小分子酪氨酸激酶抑制剂的使用情况以及变化趋势,为临床安全合理经济用药提供参考依据。方法 收集2020-2022年辽宁省肿瘤医院小分子酪氨酸激酶抑制剂使用数据,分析销售金额、用药频度（DDDs）、限定日费用（DDC）以及排序比（B/A）。结果 2020-2022年小分子酪氨酸激酶抑制剂销售金额逐年增长。奥希替尼连续3年销售金额稳居第1位。仑伐替尼销售金额大幅增长,而吉非替尼销售金额大幅下降。奥希替尼、埃克替尼、吉非替尼的DDDs近3年稳居前3位。仑伐替尼DDDs大幅上升,而索拉非尼DDDs大幅下降。普拉替尼、赛沃替尼和洛拉替尼的DDC值偏高。埃克替尼、吉非替尼、厄洛替尼、索拉非尼和达可替尼DDC值较低。从B/A可以看出,2022年埃克替尼和吉非替尼的B/A>1,赛沃替尼、培唑帕尼和阿来替尼的排序比<1。结论 2020-2022年辽宁省肿瘤医院小分子酪氨酸激酶抑制剂的使用总体上较为合理,但仍需进一步加强监管力度,保障患者用药的安全、有效和经济。     

Cost-effectiveness of Osimertinib as First-line Treatment and Sequential Therapy for EGFR Mutation-positive Non-small Cell Lung Cancer in China

Purpose

This study aimed to evaluate the cost-effectiveness of osimertinib with gefitinib or erlotinib as first-line and sequential therapy for epidermal growth factor receptor (EGFR) mutation–positive non–small cell lung cancer (NSCLC) in China.

Trametinib overcomes KRAS-G12V–induced osimertinib resistance in a leptomeningeal carcinomatosis model of EGFR-mutant lung cancer

Leptomeningeal carcinomatosis (LMC) occurs frequently in non–small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations and is associated with acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, the mechanism by which LMC acquires resistance to osimertinib, a third-generation EGFR-TKI, is unclear. In this study, we elucidated the resistance mechanism and searched for a novel therapeutic strategy. We induced osimertinib resistance in a mouse model of LMC using an EGFR-mutant NSCLC cell line (PC9) via continuous oral osimertinib treatment and administration of established resistant cells and examined the resistance mechanism using next-generation sequencing. We detected the Kirsten rat sarcoma (KRAS)-G12V mutation in resistant cells, which retained the EGFR exon 19 deletion. Experiments involving KRAS knockdown in resistant cells and KRAS-G12V overexpression in parental cells revealed the involvement of KRAS-G12V in osimertinib resistance. Cotreatment with trametinib (a MEK inhibitor) and osimertinib resensitized the cells to osimertinib. Furthermore, in the mouse model of LMC with resistant cells, combined osimertinib and trametinib treatment successfully controlled LMC progression. These findings suggest a potential novel therapy against KRAS-G12V–harboring osimertinib-resistant LMC in EGFR-mutant NSCLC.     

1例EGFR T790M突变阳性晚期肺腺癌的治疗策略及文献复习

回顾性分析中南大学湘雅医学院附属株洲医院1例晚期肺腺癌患者的临床资料,并进行相关文献复习。该患者经胸腔穿刺术及左侧淋巴结活检确诊为肺腺癌,头部MRI及上腹部增强CT示头、肝、脾、胰腺及左侧肾上腺多发转移,表皮生长因子受体扩增阻滞突变系统(epidermal growth factor receptor-amplification refractory mutation system,EGFR-ARMS)检测提示EGFR 21外显子突变(L858R),给予第1代EGFR抑制剂(tyrosine kinase inhibitors,TKIs;吉非替尼)治疗11个月后,病情出现进展,再次基因检测EGFR T790M突变为阳性,二线给予第3代EGFR-TKIs(奥西替尼)治疗,病情得到缓解。说明初次EGFR-TKIs治疗后,部分晚期肺腺癌患者耐药后仍然可在EGFR-TKIs治疗中受益。以奥西替尼为代表的第3代EGFR-TKIs治疗耐药后出现T790M突变的患者疗效显著,给晚期肺癌患者带来更多的生存获益。     

Erlotinib combined with bevacizumab and chemotherapy in first line osimertinib-resistant NSCLC patient with leptomeningeal metastasis: A case report

Rationale:Leptomeningeal metastasis (LM) is a fatal complication of advanced non-small cell lung cancer (NSCLC) with a poor prognosis. Osimertinib is a promising option for NSCLC with LM harboring epidermal growth factor receptor (EGFR) mutation. However, therapeutic approaches remain a challenge for osimertinib resistant NSCLCs with LM. Although studies have reported that the first/second-generation EGFR-tyrosine kinase inhibitors were active against osimertinib-resistant NSCLC with EGFR C797S and sensitive mutation (SM), the resistance inevitably occurred due to the development of the EGFR SM/C797S/T790M triple mutations.Patient concerns:A 48-year-old woman was diagnosed with stage IV lung adenocarcinoma harboring the EGFR mutation in the combination of chest computed tomography, biopsy and amplification refractory mutation system-polymerase chain. One year and a half after oral administration of osimertinib, the patient progressed to extensive LM.Diagnoses:Magnetic resonance images of the brain showed extensive LM. Exfoliated tumor cells from cerebrospinal fluid (CSF) were positive detected by lumbar puncture and the cytology examination. EGFR mutations (exon19 E746_T751delinsI and exon20 C797S) in CSF circulating tumor DNA were detected by next-generation sequencing (NGS).Interventions:Pemetrexed (800 mg day 1), cis-platinum (40 mg day 1-3) combined with bevacizumab (400 mg day 1) every 3 weeks were administered to the patient. After 1 cycle, due to optic nerve invasion, erlotinib was applied 150 mg/d combined with previous regimen. The patient continued erlotinib monotherapy after 6 cycles.Outcomes:After LM, erlotinib combined with pemetrexed, cis-platinum and bevacizumab were administered to the patient for 4.25 months based on the CSF NGS. Then, the patient continued erlotinib monotherapy and appeared disease progression after 10 months. The overall survival is 35 months.Lessons:LM is a fatal complication of advanced NSCLC with a poor prognosis. NGS profiling of CSF circulating tumor DNA is important in NSCLC patients with LM and erotinib plus bevacizumab and chemotherapy is a promising option for patients with LM harboring EGFR C797S/SM.