Xing Ligang, Pan Yueyin, Shi Yuankai, Shu Yongqian, Feng Jifeng, Li Wei, Cao Lejie, Wang Lifeng, Gu Wei, Song Yong, Xing Puyuan, Liu Yutao, Gao Wen, Cui Jiuwei, Hu Nana, Li Rutian, Bao Hua, Shao Yang, Yu Jinming
Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, Shandong, China.
Department of Medical Oncology, First Affiliated Hospital, University Science and Technology of China, Hefei, Anhui, China.
Clin Cancer Res. 2020 Dec 1;26(23):6168-6175. doi: 10.1158/1078-0432.CCR-20-2081. Epub 2020 Aug 17.
Dynamic biomarker monitoring may inform pathways for treating -T790M-positive non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases with osimertinib. This study aimed to determine the efficacy and safety of osimertinib for real-world patients with -T790M NSCLC and CNS metastases and to explore potential circulating biomarkers of therapeutic response.
APOLLO (ClinicalTrials.gov registration: NCT02972333) was a prospective, single-arm, open-label trial which ran from January 2017 to April 2019. Eligible patients had confirmed -T790M-positive NSCLC, prior treatment with an EGFR-tyrosine kinase inhibitor, and CNS metastases. All enrolled patients received oral osimertinib 80 mg once daily until disease progression or intolerable toxicity. Primary outcome was overall progression-free survival (PFSo) and secondary outcomes included objective response rate (ORR) and adverse events (AE). Exploratory biomarker analysis involved collection of plasma and cerebrospinal fluid (CSF) samples for next-generation sequencing and drug penetration analysis.
From January to September 2017, 38 patients were enrolled. After a median follow-up of 8.2 months (range, 0.07-15.6), 23 (60.5%) of 38 patients had disease progression or death. Median PFSo was 8.4 months [95% confidence interval (CI), 5.8-10.9]. Overall ORR was 39.4%. Twelve (31.6%) of 38 patients had ≥1 grade 3-4 AE. Median osimertinib CSF penetration rate was 31.7%. Patients with undetectable plasma mutations at week 6 had improved PFSo compared with those with detectable mutations (not reached vs. 4.5 months; 95% CI, 0.0-1.1; < 0.05).
Osimertinib had potent activity against -T790M-positive NSCLC with CNS metastases. Dynamic monitoring of plasma may suffice for predicting clinical responses, mitigating the need for repeat CSF biopsy..
动态生物标志物监测可为使用奥希替尼治疗T790M阳性非小细胞肺癌（NSCLC）及中枢神经系统（CNS）转移瘤提供治疗途径。本研究旨在确定奥希替尼对真实世界中T790M NSCLC及CNS转移瘤患者的疗效和安全性，并探索治疗反应的潜在循环生物标志物。
APOLLO（ClinicalTrials.gov注册号：NCT02972333）是一项前瞻性、单臂、开放标签试验，于2017年1月至2019年4月进行。符合条件的患者确诊为T790M阳性NSCLC，既往接受过EGFR酪氨酸激酶抑制剂治疗，且有CNS转移瘤。所有入组患者每日口服一次80mg奥希替尼，直至疾病进展或出现无法耐受的毒性。主要结局为总无进展生存期（PFSo），次要结局包括客观缓解率（ORR）和不良事件（AE）。探索性生物标志物分析包括采集血浆和脑脊液（CSF）样本进行二代测序和药物渗透分析。
2017年1月至9月，共入组38例患者。中位随访8.2个月（范围0.07 - 15.6个月）后，38例患者中有23例（60.5%）出现疾病进展或死亡。中位PFSo为8.4个月[95%置信区间（CI），5.8 - 10.9]。总体ORR为39.4%。38例患者中有12例（31.6%）发生≥1次3 - 4级AE。奥希替尼的脑脊液中位渗透率为31.7%。与血浆中可检测到突变的患者相比，第6周血浆中未检测到突变的患者PFSo有所改善（未达到对比4.5个月；95% CI，0.0 - 1.1；P < 0.05）。
奥希替尼对伴有CNS转移瘤的T790M阳性NSCLC具有显著活性。动态监测血浆可能足以预测临床反应，从而减少重复脑脊液活检的必要性。
