第一代表皮生长因子受体酪氨酸激酶抑制剂在无T790M患者再治疗中的疗效与安全性
Efficacy and safety of first-generation epidermal growth factor receptor tyrosine kinase inhibitors in retreatment of patients without T790M.
作者信息
Choi Juwhan, Lee Jae Cheol, Kim In Ae, Lee Kye Young, Lee Jeong Eun, Jang Seung Hun, Yoon Seong Hoon, Oh In-Jae, Lee Sang Hoon, Kim Eun Young, Lee Sung Yong
机构信息
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
Division of Oncology, Department of Internal Medicine, Ulsan University Asan Medical Center, Seoul, Republic of Korea.
出版信息
Transl Lung Cancer Res. 2025 Jul 31;14(7):2483-2493. doi: 10.21037/tlcr-2025-36. Epub 2025 Jul 28.
BACKGROUND
Patients receiving first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) and undergoing second and/or third-line cytotoxic chemotherapy may experience regrowth of EGFR (+) clones. Retreatment with EGFR TKIs can provide antitumor effects and potentially induce T790M-positive conversion. This study evaluated the efficacy, safety, and T790M (+) conversion rates in patients without T790M mutation at the second biopsy retreated with first-generation EGFR TKIs as third-line or subsequent therapy.
METHODS
This open-label, multi-center, prospective phase II trial (NCT03382795) enrolled patients with non-small cell lung cancer (NSCLC) previously treated with first- or second-generation EGFR TKIs and cytotoxic chemotherapy They were retreated with gefitinib or erlotinib. Key endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety.
RESULTS
Among 63 patients (34 on gefitinib, 29 on erlotinib), ORR was 14.3%. Median PFS was 2.2 months, and median OS was 8.6 months. Adverse events occurred in 82.5% of patients, primarily grade ≤2. The T790M conversion rate was 31.7% and was significantly associated with prior EGFR TKI exposure duration (P=0.047). Patients with T790M conversion had a median OS of 29.3 months, significantly (P<0.001) longer than the median OS of 6.0 months for non-converters. Next-generation sequencing (NGS) of pre-retreatment blood samples identified additional T790M mutations (20.8%) undetected by conventional testing. Low TP53 expression showed a non-significant trend toward higher tendency T790M conversion (66.7% 30.8%, P=0.32).
CONCLUSIONS
EGFR retreatment induced T790M conversion in 32% of cases, enabling third-generation EGFR TKIs, leading to a substantial improvement in median OS. Blood-based NGS identified additional T790M mutations, undetected by routine polymerase chain reaction (PCR). EGFR TKI retreatment with blood-based NGS may enhance patient prognosis by identifying additional T790M positive mutations.
背景
接受一线表皮生长因子受体酪氨酸激酶抑制剂（EGFR TKI）治疗并接受二线和/或三线细胞毒性化疗的患者可能会出现EGFR（+）克隆的再生。用EGFR TKIs进行再治疗可提供抗肿瘤作用，并可能诱导T790M阳性转化。本研究评估了在第二次活检时无T790M突变的患者中，使用第一代EGFR TKIs作为三线或后续治疗进行再治疗后的疗效、安全性和T790M（+）转化率。
方法
这项开放标签、多中心、前瞻性II期试验（NCT03382795）纳入了先前接受过第一代或第二代EGFR TKIs和细胞毒性化疗的非小细胞肺癌（NSCLC）患者。他们接受了吉非替尼或厄洛替尼的再治疗。主要终点包括客观缓解率（ORR）、无进展生存期（PFS）、总生存期（OS）和安全性。
结果
在63例患者中（34例接受吉非替尼治疗，29例接受厄洛替尼治疗），ORR为14.3%。中位PFS为2.2个月，中位OS为8.6个月。82.5%的患者发生了不良事件，主要为≤2级。T790M转化率为31.7%，与先前EGFR TKI暴露持续时间显著相关（P=0.047）。T790M转化的患者中位OS为29.3个月，显著长于未转化患者（P<0.001）的中位OS 6.0个月。治疗前血样的下一代测序（NGS）发现了常规检测未检测到的额外T790M突变（20.8%）。低TP53表达显示T790M转化趋势较高，但无显著差异（66.7%对30.8%，P=0.32）。
结论
EGFR再治疗在32%的病例中诱导了T790M转化，使得能够使用第三代EGFR TKIs，从而使中位OS有了实质性改善。基于血液的NGS发现了常规聚合酶链反应（PCR）未检测到的额外T790M突变。基于血液的NGS进行EGFR TKI再治疗可能通过识别额外的T790M阳性突变来改善患者预后。
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