2017—2019年苏州九龙医院抗肿瘤靶向药物使用情况分析

目的 统计上海交通大学医学院附属苏州九龙医院（简称苏州九龙医院）近3年抗肿瘤靶向药物的使用情况,分析用药趋势,为抗肿瘤靶向药物的合理使用提供参考。方法 采用限定日剂量（DDD）,对2017—2019年苏州九龙医院抗肿瘤靶向药物的品种、规格、销售数量、销售金额、用药频度（DDDs）、日均费用（DDC）和排序比（B/A）等进行统计分析。结果 苏州九龙医院近3年抗肿瘤靶向药物使用数量和使用金额逐年增长,奥希替尼在所有抗肿瘤靶向药物中增长最为迅速,DDDs已升至第一位。大分子抗体药物增速较快,DDC也普遍偏高,销售金额将赶超小分子激酶抑制剂。埃克替尼的B/A连续3年≥2.00,利妥昔单抗的B/A综合最低。结论 随着医疗政策的倾斜、药品降价,抗肿瘤靶向药物将使更多的患者获益。     

High levels of AXL expression in untreated EGFR-mutated non-small cell lung cancer negatively impacts the use of osimertinib

For non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, the initial therapeutic interventions will have crucial impacts on their clinical outcomes. Drug tolerant factors reportedly have an impact on EGFR-tyrosine kinase inhibitor sensitivity. This prospective study investigated the impacts of drug tolerant-related protein expression in tumors based on the efficacy of osimertinib in the first-setting of EGFR-mutated advanced NSCLC patients. A total of 92 patients with EGFR-mutated advanced or postoperative recurrent NSCLC were analyzed and treated with osimertinib at 14 institutions in Japan. AXL, p53, and programmed death-ligand 1 (PD-L1) expression in patient tumors was determined using immunohistochemistry. The AXL signaling pathway was investigated using a cell line-based assay and AXL-related gene expression in The Cancer Genome Atlas (TCGA) database. High levels of AXL and positive-p53 expression were detected in 26.1% and 53.3% of the pretreatment EGFR-mutated NSCLC tumors, respectively. High AXL expression levels were significantly associated with a shorter progression-free survival compared with low AXL expression levels, irrespective of the EGFR activating mutation status (p = 0.026). Cell line-based assays indicated that the overexpression of AXL protein accelerated PD-L1 expression, which induced insensitivity to osimertinib. In the TCGA database, AXL RNA levels were positively correlated with PD-L1 expression in the lung adenocarcinoma cohort. The results show that high AXL expression levels in tumors impact clinical predictions when using osimertinib to treat EGFR-mutated NSCLC patients. Trial Registration: UMIN000043942.     

HPLC法测定甲磺酸奥希替尼的含量

为了建立一种检测甲磺酸奥希替尼含量的HPLC法,使用Agilent ZORBAX Eclipse Plus C₁₈色谱柱(4.6 mm×250 mm,5 μm),流动相为甲醇-磷酸二氢钠缓冲液(pH 3.0)(50∶50),检测波长210 nm,柱温35 ℃,流速1.0 mL/min进行检测。甲磺酸奥希替尼浓度在分析物正常浓度的50%~150%(0.201 1~0.603 2 mg/mL)范围内与峰面积呈良好线性关系(r=0.999 9),最低检测限为0.08 μg/mL,定量限为0.32 μg/mL。3批样品的含量(%)分别为100.1、99.5和99.7。在所建立的色谱条件下,甲磺酸奥希替尼与各有关物质分离良好,包括部分工艺杂质及降解杂质。结果表明,所建立的方法专属、准确、简单、耐用,可用于奥希替尼原料的含量测定。     

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.     

Targeting DNA-PK overcomes acquired resistance to third-generation EGFR-TKI osimertinib in non-small-cell lung cancer

The third-generation of epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),represented by osimertinib,has achieved remarkable clinical outcomes in the treatment of non-small-cell lung cancer(NSCLC)with EGFR mutation.However,resistance eventually emerges in most patients and the underlying molecular mechanisms remain to be fully understood.In this study,we generated an osimertinib-acquired resistant lung cancer model from a NSCLC cell line H1975 harboring EGFR L858R and T790M mutations.We found that the capacity of DNA damage repair was compromised in the osimertinib resistant cells,evidenced by increased levels ofγH2AX and higher intensity of the comet tail after withdrawal from cisplatin.Pharmacological inhibiting the activity or genetic knockdown the expression of DNA-PK,a key kinase in DNA damage response(DDR),sensitized the resistant cells to osimertinib.Combination of osimertinib with the DNA-PK inhibitor,PI-103,or NU7441,synergistically suppressed the proliferation of the resistant cells.Mechanistically,we revealed that DNA-PK inhibitor in combination with osimertinib resulted in prolonged DNA damage and cell cycle arrest.These findings shed new light on the mechanisms of osimertinib resistance in the aspect of DNA repair,and provide a rationale for targeting DNA-PK as a therapeutic strategy to overcome osimertinib-acquired resistance in NSCLC.     

奥希替尼治疗EGFR突变的晚期非小细胞肺癌疗效与安全性的Meta分析

目的系统评价奥希替尼治疗非小细胞肺癌(NSCLC)的疗效和安全性。方法计算机检索The Cochrane Library、EMbase、PubMed、中国知网、维普网、万方数据建库至2019年12月31日,查找奥希替尼治疗NSCLC的随机对照试验(RCTs),并进行质量评价和资料提取,用Stata 12.0进行Meta分析。结果纳入8篇RCTs研究,共涉及1795例患者。Meta分析结果显示,在疗效上奥希替尼组的无进展生存期(PFS)、客观缓解率(ORR)、疾病控制率(DCR)均优于对照组,差异均有统计学意义(均P<0.05)。在亚组分析中,对于Ex19del/L858R突变的患者,1线治疗使用奥希替尼所达到的PFS、ORR、DCR均优于第一代EGFR-TKIs(吉非替尼/厄洛替尼),除ORR外在差异上均有统计学意义(均P<0.05);对于出现T790M突变的患者,≥2线治疗使用奥希替尼所达到的PFS、ORR、DCR均优于化疗,且差异均有统计学意义(均P<0.05);在安全性上奥希替尼组的药品不良反应(ADR)与≥3级ADR发生率均低于对照组,但在ADR发生率的差异上没有统计学意义(P>0.05);此外奥希替尼组中腹泻、间质性肺炎、QT间期延长、皮疹/痤疮样皮炎的发生率均高于对照组,差异均有统计学意义(均P<0.05)。结论对于表皮生长因子受体(EGFR)突变的NSCLC患者,无论是1线用药还是出现T790M突变后的≥2线用药,奥希替尼在疗效上均具有优势,且能降低≥3级ADR的发生,但也存在一定的安全性风险,需要对用药患者进行密切关注。     

Marginal Zone Lymphoma and Lung Adenocarcinoma with an EGFR Exon 19 E746-S752del Mutation in a Patient with IgG4-related Disease

A 68-year-old man presented with a solid mass at the left renal pelvis and ureter with multiple systemic lymphadenopathies and a mass with a cavity in the right lower lobe of the lung. While a transbronchial lung biopsy revealed no malignancy, a biopsy of the renal pelvis showed marginal zone lymphoma with polyclonal IgG4-positive cells. The serum IgG4 level and presence of a bilateral orbital mass suggested Mikulicz disease. The lesions shrank following the administration of steroids. A rebiopsy confirmed lung adenocarcinoma, and its background showed IgG4-positive cells a year later. IgG4-related diseases require careful follow-up because they can be complicated by malignancy.     

2020—2023年宜昌市中心人民医院新型抗肿瘤药物使用情况分析

目的 分析2020—2023年宜昌市中心人民医院新型抗肿瘤药物的使用情况和发展趋势,为该类药物的临床合理使用和规范化管理提供参考。方法 收集宜昌市中心人民医院2020年1月1日—2023年12月31日新型抗肿瘤药物的相关用药信息,对品种数、销售金额、用药频度（DDDs）、限定日费用（DDC）、药品排序比（B/A）等指标进行回顾性统计分析。结果 2020—2023年新型抗肿瘤药物的品种数呈波动态势,总销售金额和总DDDs逐年增长,30种药物的DDC下降。贝伐珠单抗、奥希替尼和曲妥珠单抗的销售金额均位居前3位。信迪利单抗的DDDs增长速度最快,在2023年排名升至第1位,DDC值从2020年270.76降至2023年的102.86,连续4年B/A≥1。奥希替尼和阿美替尼的临床使用频率明显增加,2023年DDDs分别排名第2、3位。伊马替尼和吉非替尼使用频率较高、DDC值低,B/A在4年内均大于2,同步性好,利用度高。结论 宜昌市中心人民医院新型抗肿瘤药物使用量逐渐增加,药品价格下降,符合国家政策要求及肿瘤治疗的发展趋势。     

Comprehensive cross‐platform comparison of methods for non‐invasive EGFR mutation testing: results of the RING observational trial

Several platforms for noninvasive EGFR testing are currently used in the clinical setting with sensitivities ranging from 30% to 100%. Prospective studies evaluating agreement and sources for discordant results remain lacking. Herein, seven methodologies including two next‐generation sequencing (NGS)‐based methods, three high‐sensitivity PCR‐based platforms, and two FDA‐approved methods were compared using 72 plasma samples, from EGFR‐mutant non‐small‐cell lung cancer (NSCLC) patients progressing on a first‐line tyrosine kinase inhibitor (TKI). NGS platforms as well as high‐sensitivity PCR‐based methodologies showed excellent agreement for EGFR‐sensitizing mutations (K = 0.80–0.89) and substantial agreement for T790M testing (K = 0.77 and 0.68, respectively). Mutant allele frequencies (MAFs) obtained by different quantitative methods showed an excellent reproducibility (intraclass correlation coefficients 0.86–0.98). Among other technical factors, discordant calls mostly occurred at mutant allele frequencies (MAFs) ≤ 0.5%. Agreement significantly improved when discarding samples with MAF ≤ 0.5%. EGFR mutations were detected at significantly lower MAFs in patients with brain metastases, suggesting that these patients risk for a false‐positive result. Our results support the use of liquid biopsies for noninvasive EGFR testing and highlight the need to systematically report MAFs.

Abbreviations

BEAMing

beads, emulsion, amplification, and magnetics

cfDNA

circulating free DNA, cell‐free DNA

cobas

cobas^® EGFR Mutation Test v2 (Roche Diagnostics)

ctDNA

circulating tumor DNA

CUSUM

cumulative sum

ddPCR

droplet digital polymerase chain reaction

dPCR

digital polymerase chain reaction

EGFR

epidermal growth factor receptor

FFPE

formalin‐fixed, paraffin‐embedded

ICC

intraclass correlation coefficient

MAF

mutant allele frequency

NGS platforms

Ion S5™ XL and GeneRead™

NGS

next‐generation sequencing

NSCLC

non‐small‐cell lung cancer

PNA‐Q‐PCR

peptic nucleic acid probe‐based real‐time polymerase chain reaction

Therascreen

Therascreen EGFR Plasma RGQ PCR Kit (QIAgen)

TKI

tyrosine kinase inhibitor