Pharmacokinetic drug evaluation of osimertinib for the treatment of non-small cell lung cancer

Introduction: First- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, erlotinib, icotinib, and afatinib are the standard-of-care for first-line therapy of non-small-cell lung cancer (NSCLC) harboring activating EGFR mutations. Unfortunately, after initial activity of an average 9–13 months, disease progression has been reported in the majority of patients. In about 50% of cases the progression is due to the onset of the T790M mutation in exon 20 of the EGFR gene. Third-generation EGFR-TKIs targeting this mutation were investigated, with osimertinib the only reaching clinical practice.

Areas covered: A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question addressing osimertinib, was undertaken.

Expert opinion: Osimertinib is the standard-of-care for EGFR-mutated patients progressing to first-line EGFR-TKIs due to the acquired EGFR T790M mutation. Results from the head-to-head first-line trial comparing osimertinib versus gefitinib or erlotinib in activating EGFR mutations might change the front-line approach. Osimertinib in combination regimens, such as immunotherapy, and in adjuvant setting are ongoing. Thus, the strategic approach for the management of EGFR-mutated NSCLC patients will change further in the next few years.     

奥希替尼治疗晚期肺腺癌1例并文献复习

分析1例晚期肺腺癌患者应用第1代表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitors,EGFR-TKIs)(吉非替尼)治疗耐药后的应用奥希替尼治疗的临床疗效及不良反应。患者应用吉非替尼治疗11个月出现耐药,后给予奥希替尼治疗28个月病情进展,期间未出现严重不良反应。奥希替尼治疗第1代EGFR-TKIs耐药后的晚期肺腺癌患者,临床疗效较好,不良反应少。     

奥希替尼治疗获得性表皮生长因子受体-酪氨酸激酶抑制剂耐药T790M突变肺腺癌晚期1例

报告1例使用奥西替尼治疗表皮生长因子受体(epithelial growth factor receptor,EGFR)基因19外显子缺失突变耐药后T790M突变肺腺癌晚期患者。患者,女,72岁,无明显诱因出现左侧胸闷、气喘5 d于当地医院治疗,查胸部CT示双侧胸腔积液,右肺中叶占位,并纵隔淋巴结肿大。为求进一步治疗遂来郑州大学第一附属医院,入院完善相关检查,PET-CT示右肺中叶软组织肿块代谢较活跃,考虑肺癌,建议结合病理诊断;双侧锁骨上区、纵隔及右肺门多发淋巴结肿大,代谢活跃,考虑转移。不符合手术指征,未进行手术治疗,第1次CT引导下经皮肺穿刺活检确诊肺腺癌,基因检测示EGFR基因第19外显子缺失突变,于2017年11月29日开始服用吉非替尼,至2018年12月4日停止服用。期间复查CT发现右上肺结节较前增大,第2次CT引导下经皮肺穿刺活检结果示肺腺癌,基因检测示EGFR基因18外显子缺失突变,合并EGFR基因第20外显子T790M突变,于2018年12月4日开始服用奥希替尼至今,复查未见异常。     

Predicting osimertinib‐treatment outcomes through EGFR mutant‐fraction monitoring in the circulating tumor DNA of EGFR T790M‐positive patients with non‐small cell lung cancer (WJOG8815L)

The WJOG8815L phase II clinical study involves patients with non‐small cell lung cancer (NSCLC) that harbored the EGFR T790M mutation, which confers resistance to EGFR tyrosine kinase inhibitors (TKIs). The purpose of this study was to assess the predictive value of monitoring EGFR genomic alterations in circulating tumor DNA (ctDNA) from patients with NSCLC that undergo treatment with the third‐generation EGFR‐TKI osimertinib. Plasma samples of 52 patients harboring the EGFR T790M mutation were obtained pretreatment (Pre), on day 1 of treatment cycle 4 (C4) or cycle 9 (C9), and at diagnosis of disease progression or treatment discontinuation (PD/stop). CtDNA was screened for EGFR‐TKI‐sensitizing mutations, the EGFR T790M mutation, and other genomic alterations using the cobas EGFR Mutation Test v2 (cobas), droplet digital PCR (ddPCR), and targeted deep sequencing. Analysis of the sensitizing—and T790M—EGFR mutant fractions (MFs) was used to determine tumor mutational burden. Both MFs were found to decrease during treatment, whereas rebound of the sensitizing EGFR MF was observed at PD/stop, suggesting that osimertinib targeted both T790M mutation‐positive tumors and tumors with sensitizing EGFR mutations. Significant differences in the response rates and progression‐free survival were observed between the sensitizing EGFR MF‐high and sensitizing EGFR MF‐low groups (cutoff: median) at C4. In conclusion, ctDNA monitoring for sensitizing EGFR mutations at C4 is suitable for predicting the treatment outcomes in NSCLC patients receiving osimertinib (Clinical Trial Registration No.: UMIN000022076).

Abbreviations

CIs

confidence intervals

ctDNA

circulating tumor DNA

ddPCR

droplet digital PCR

EGFR

epidermal growth factor receptor

MFs

mutant fractions

NGS

next‐generation sequencing

NSCLC

non‐small cell lung cancer

ORR

overall response rate

OS

overall survival

PD

progressive disease

PFS

progression‐free survival

PR

partial response

SD

stable disease

TKI

tyrosine kinase inhibitor

     

Cost-effectiveness of Osimertinib as a Second-line Treatment in Patients With EGFR-mutated Advanced Non–Small Cell Lung Cancer in China

PurposeTo assess the cost-effectiveness of osimertinib used as a second-line treatment after failure of epidermal growth factor receptor tyrosine kinase inhibitor therapy for advanced non–small cell lung cancer (NSCLC) in China.MethodsFrom the perspective of China's health care system, a Markov model was used for estimating the costs and health outcomes of osimertinib and 4 platinum-based chemotherapies, including pemetrexed + platinum (PP), gemcitabine + platinum (GP), docetaxel + platinum (DP), and paclitaxel + platinum (TP). Two scenarios were considered, one in all confirmed patients with T790M-positive disease (scenario 1) and the other in all patients whose disease progressed after epidermal growth factor receptor tyrosine kinase inhibitor therapy, which consisted of patients with T790M-positive or T790M-negative NSCLC (scenario 2). Clinical data for transition probabilities and treatment effects were obtained from published clinical trials. Health care resource utilization and costs were derived from local administrative databases and published literature. Deterministic and probabilistic sensitivity analyses were conducted to assess the uncertainty of the results.FindingsIn the base-case analysis, compared with the 4 platinum-based chemotherapies, osimertinib yielded an additional 0.671 to 0.846 quality-adjusted life-year (QALY), with incremental costs of 15,943 to 20,299 USD in scenario 1, and an additional 0.376 to 0.808 QALY with incremental costs of 9710 to 15,407 USD in scenario 2. In the probabilistic sensitivity analysis, the probabilities that osimertinib would be cost-effective were 57.7% in scenario 1 and 58.4% in scenario 2 if the willingness-to-pay threshold were 30,000 USD/QALY, and probabilities would be more than 75 % in both scenarios if the willingness-to-pay threshold were 50,000 USD/QALY.ImplicationsOsimertinib is likely to be cost-effective when used as a second-line treatment of advanced NSCLC in China based on the latest reimbursement price of osimertinib through National Reimbursement Drug List negotiation.     

Therapeutic approaches for T790M mutation positive non-small-cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC) is a subset of lung cancer with demonstrated response to targeted therapies. However, resistance to the first targeted approach usually occurs within the first year, and it is associated in 50–60% of cases to the T790M resistance mutation.

Areas covered: The review provides an overview on the significance of the presence of the T790M mutation, its detection, treatment options and subsequent mechanisms of resistance.

Expert commentary: Osimertinib is the current treatment option for T790M mutation positive NSCLC after progression to first or second-generation EGFR TKIs, with activity also on brain metastasis. However, the scenario is in continuous evolution and results from clinical trials are awaited in first-line setting and in combination strategies.