Uncommon EGFR Compound Mutations in Non-Small Cell Lung Cancer (NSCLC): A Systematic Review of Available Evidence

Compound epidermal growth factor receptor (EGFR) mutations represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) patients with uncommon EGFR mutations. We conducted a systematic review to investigate the available data on this patients’ subgroup. Overall, we found a high heterogeneity in the incidence of compound mutations (4–26% of total EGFR mutant cases), which is dependent on the different testing methods adopted and the specific mutations considered. In addition, the relative incidence of distinct compound subclasses identified is reported with extreme variability in different studies. Preclinical and clinical data, excluding de novo EGFR exon 20 p.T790M compound mutations, show good responses with EGFR tyrosine kinase inhibitors (TKIs) (combined common mutations: response rate (RR) ≥ 75% with either first- or second-generation TKIs; combined common plus uncommon: RR 40–80% and 100% with first-generation TKIs and afatinib, respectively; combined uncommon: RR 20–70%, ~80% and ~75% with first-generation TKIs, afatinib and osimertinib, respectively). Overall, data are consistent in supporting the use of EGFR TKIs in treating compound EGFR mutations, taking into account different sensitivity profile of accompanying EGFR mutations for selecting the most adequate EGFR TKI for individual patients.     

Liquid Biopsy Testing for the Management of Patient with Non-Small Cell Lung Cancer Carrying a Rare Exon-20 EGFR Insertion

Increasing evidence suggests that liquid biopsy might play a relevant role in the management of metastatic non-small cell lung cancer (NSCLC) patients. Here, we show how the Molecular Tumor Board (MTB) in our cancer center employed liquid biopsy to support therapeutic decisions in a patient with NSCLC carrying a rare EGFR mutation. A 44-year-old woman, never-smoker with an EGFR, ALK, and ROS1-negative lung adenocarcinoma and multiple brain metastases received systemic therapy and surgery before being referred to our Institute. The MTB suggested NGS testing of tumor biopsy that revealed a rare exon-20 EGFR insertion (p.His773dup; c.2315_2316insCCA) and EGFR amplification. The MTB recommended treatment with erlotinib and follow-up with liquid biopsy, by using both cell-free DNA (cfDNA) and circulating tumor cells (CTCs). An increase of EGFR mutation levels in cfDNA revealed resistance to treatment about 6 months before clinical progression. Extremely low levels of EGFR p.T790M were detected at progression. Based on preclinical data suggesting activity of osimertinib against EGFR exon-20 insertions, the MTB recommended treatment with brain and bone radiotherapy and osimertinib. A dramatic reduction of EGFR mutation levels in the cfDNA was observed after 4 weeks of treatment. The PET scan demonstrated a metabolic partial remission that was maintained for 9 months. This case supports the evidence that liquid biopsy can aid in the management of metastatic NSCLC. It also suggests that treatment with osimertinib might be a therapeutic option in patients with EGFR exon-20 insertions when a clinical trial is not available.     

Hsa_circ_0005576 promotes osimertinib resistance through the miR‐512‐5p/IGF1R axis in lung adenocarcinoma cells

Osimertinib is a third‐generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) for lung adenocarcinoma (LUAD) harboring activating mutations, but patients ultimately develop acquired resistance. Circular RNAs are involved in EGFR‐TKI resistance, while the role of hsa_circ_0005576 in the osimertinib resistance of LUAD remains unknown. In this study, we demonstrated that hsa_circ_0005576 could facilitate osimertinib‐resistant LUAD cells. Briefly, knockdown of hsa_circ_0005576 not only suppressed the proliferation and promoted the apoptosis of resistant LUAD cells, but also increased their sensitivity to osimertinib. Mechanistically, hsa_circ_0005576, serving as an miRNA sponge, could directly interact with miR‐512‐5p and subsequently upregulate the miR‐512‐5p‐targeted insulin‐like growth factor 1 receptor. Rescue assays indicated that miR‐512‐5p inhibition could reverse the effects of hsa_circ_0005576 knockdown in LUAD cells resistant to osimertinib. Overall, our study revealed that hsa_circ_0005576 regulates proliferation and apoptosis through miR‐512‐5p/IGF1R signaling, which contributes further to the resistance of LUAD cells to osimertinib. In addition, this study provides a novel insight into the mechanisms underlying osimertinib resistance of LUAD.     

Reoccurrence of takotsubo cardiomyopathy induced by osimertinib: A case report

A patient with lung cancer was administrated osimertinib. She developed symptomatic heart failure due to Takotsubo cardiomyopathy (TC). As her condition improved after discontinuing osimertinib, TC was thought to be caused by osimertinib. Reoccurrence of TC was seen after readministrating half dose of osimertinib.     

Monitoring epidermal growth factor receptor C797S mutation in Japanese non–small cell lung cancer patients with serial cell-free DNA evaluation using digital droplet PCR

Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is effective in treating both naïve and T790M-mutated EGFR-TKI-resistant non–small cell lung cancer patients. The EGFR C797S mutation is the major osimertinib resistance mechanism. The present study monitored the EGFR C797S mutation during osimertinib treatment in Japanese patients using droplet digital PCR (ddPCR). In our first cohort, C797S detection was validated with tumor specimens and/or plasma samples from 26 patients using ddPCR with custom-designed probes detecting and discriminating T790M and C797S in cis and trans positions. In our second cohort, 18 patients with EGFR-T790M who were going to start osimertinib were analyzed using ddPCR by collecting the plasma samples every month from the beginning of the course of osimertinib. In the first cohort, C797S was detected in 15.4% of patients. C797S and T790M in cis and trans positions were distinguished using ddPCR. In the second cohort, serial cfDNA evaluation revealed that the rate of EGFR mutation changes with disease state. Increases of EGFR mutation were detected, including C797S several months before the diagnosis of disease progression. As with the first cohort, C797S and T790M in cis and trans position were distinguished by ddPCR at disease progression. Coincidentally, in the first cohort, next generation sequencing detected NRAS Q61K mutation and the resistance with NRAS Q61K mutation was overcome by trametinib. In the second cohort, serial cfDNA analysis was useful for evaluating bone oligo-progression and local radiation therapy.     

奥希替尼治疗非小细胞肺癌的研究进展

表皮生长因子受体(EGFR)突变的发现以及EGFR酪氨酸激酶抑制剂(TKI)疗效的证明，标志着非小细胞肺癌(NSCLC)精准药物使用时代的到来。奥希替尼是针对EGFR TKI敏感突变和野生型EGFR T790M突变，同时保留野生型EGFR的第三代TKI。因其在临床试验中表现出的显著临床有效性和良好安全性，2015年及2016年初，美国及欧洲首次批准了奥希替尼用于接受EGFR TKI治疗后进展的EGFR T790M突变阳性的NSCLC患者的治疗，2017年3月奥西替尼正式在我国获批上市。本文主要就奥希替尼在NSCLC治疗中的研究进展进行综述。     

T790M基因突变阳性的肺腺癌并骨转移患者个体化治疗远期疗效及预后的相关因素分析

[摘要] 目的：探讨T790M突变的肺腺癌骨转移患者接受个体化综合治疗的疗效及预后的相关因素。方法：回顾性分析68例经个体化综合治疗的T790M突变的肺腺癌骨转移患者的临床资料,采取化疗、放疗、靶向分子药物、单抗类药物、双磷酸盐等综合治疗,观察疗效及预后,分析相关因素。结果：个体化综合治疗有效率为60.3%(41/68),中位生存期为23 个月。无放疗、T790M耐药基因突变无合并KRAS耐药基因突变、既往化疗类型为辅助化疗、N1 期、孤立的骨转移灶、化疗交替奥希替尼治疗、转移器官个数少、以及ECOG评分<2 分对远期疗效有显著影响（P<0.05）。多因素分析显示,T790M耐药基因突变无合并KRAS耐药基因突变（P=0.012）、转移器官个数0 或1 个（P=0.000）、化疗有无交替奥希替尼（P=0.020）及孤立的骨转移灶为影响T790M突变的肺腺癌骨转移患者联合治疗后远期疗效的保护因素。结论：T790M耐药基因突变无合并KRAS耐药基因突变肺癌患者经化疗、靶向分子药物等综合治疗获得了较长的生存时间,化疗联合靶向分子药物、双磷酸盐类药物等综合治疗为T790M突变的肺腺癌骨转移患者提供了有潜力的治疗模式。     

Can Quantitative Measures of T790M Allelic Fraction Predict Survival Outcomes in Patients Receiving Osimertinib? Observations From an Early Access Programme

AimsMultiple studies have shown conflicting results on the correlation between the EGFR T790M quantitative level and survival outcomes in osimertinib-treated patients. We sought to validate such correlations using data from an osimertinib early access programme (EAP) providing access for metastatic non-small cell lung cancer patients with limited treatment options.Patients and methodsThis observational, multicentre, retrospective analysis included EAP participants who received osimertinib until disease progression, intolerable toxicities or death. Digital droplet polymerase chain reaction-based quantitative plasma genotyping was carried out upon disease progression and data were analysed to explore the relationships between T790M mutant allele fraction (MAF), T790M copy number, MAF ratio and post-osimertinib overall survival. Real-world treatment outcomes and safety were also evaluated.ResultsData from 156 EAP participants were analysed (median follow-up 37.7 months). The median age was 62 years, 62.2% were women, 79.5% were never-smokers, 60.9% had Eastern Cooperative Oncology Group performance status 0/1. In patients with available plasma data (n = 114), T790M MAF (%) showed no significant relationships with overall survival (hazard ratio 1.02; 95% confidence interval 0.99–1.04) or time to treatment discontinuation (TTD) (hazard ratio 1.01; 95% confidence interval 0.98–1.04). Absolute T790M copy number and T790M to activating EGFR mutation MAF ratio also showed no prognostic value. The investigator-assessed response rate was 42.3% and the disease control rate was 85.5%. The median TTD was 15.8 (95% confidence interval 12.5–18.5) months and the median overall survival was 22.3 (95% confidence interval 18.6–26.1) months.ConclusionT790M MAF did not correlate with TTD or overall survival in this EAP cohort but limitations should not be overlooked. Observed survival outcomes and the toxicity profile were consistent with data from other real-world series.     

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.