後天T790M突變非小細胞肺癌病患的預後：來自真實世界的數據

The Clinical Outcomes of Patients with Non-small Cell Lung Cancer Harboring Acquired T790M Mutation: The Real-world Data

10.6342/NTU202102347

張立群

非小細胞肺癌 ； 表皮生長因子受體基因 ； T790M突變 ； 泰格莎 ； 存活分析 ； Non-small cell lung cancer ； EGFR ； T790M ； osimertinib ； survival

臺灣大學臨床醫學研究所學位論文

2021年

碩士

施金元

英文

背景：多數具有EGFR基因突變的非小細胞肺癌(non-small cell lung cancer)患者在接受表皮生長因子受體(epidermal growth factor receptor)酪胺酸激酶抑制劑(tyrosine kinase inhibitors)治療後最終仍會產生抗藥性，抗藥性大多來自於EGFR T790M基因突變。Osimertinib(商品名 Tagrisso，泰格莎)常用於治療後天T790M基因突變的非小細胞肺癌患者，但投予osimertinib的時機與病患存活時間的相關性仍有待釐清。 研究方法：在這個回溯性的研究中，我們收集了兩家醫院具有後天T790M基因突變的非小細胞肺癌患者，檢視並分析包括病患的基本資料、EGFR基因突變類型、是否接受osimertinib治療、osimertinib投予的時機、治療成效等臨床資訊。主要結果(primary outcome)定為在從偵測到T790M突變開始計算的不同時段內，比較接受或未接受osimertinib治療病患的累計死亡率。 研究結果：本研究共紀錄了205位具有後天T790M基因突變的非小細胞肺癌患者，其中108位患者進入存活分析。從偵測到T790M突變開始13周內未使用osimertinib的非小細胞肺癌患者其累計死亡率顯著高於接受osimertinib治療的患者 (12.8%和1.7%，p = 0.023)。接受osimertinib治療的84位患者中，從偵測到T790M突變到開始給予osimertinib治療之間天數的中位數為56天，以投予osimertinib在偵測到T790M突變起56天內和56天後分組，疾病無惡化存活期(progression-free survival, PFS)的中位數分別為8.2個月和21.8個月，未達到統計學上的顯著差異(p = 0.063)；以osimertinib作為偵測到T790M後第一線或第二線以後治療分組，PFS的中位數分別為10.9個月和9.3個月，兩組相當接近(p = 0.950)。多變項分析中，從血漿循環腫瘤DNA檢驗測得T790M突變的病患，其PFS (風險比率，hazard ratio = 2.79, 95% confidence interval, 1.30-5.95)及存活時間(hazard ratio = 5.27, 95% confidence interval, 2.12-13.15)與由腫瘤組織切片測得T790M突變的病患相比與較短。 結論：對於後天T790M突變的非小細胞肺癌患者，延後投予osimertinib可能會增加患者的死亡率，但以osimertinib作為偵測到T790M突變後第一線或第二線以後的治療，PFS沒有顯著的差異，然而偵測到T790M突變的檢體來源可能是重要的預後因子。

Background: Most patients with EGFR-mutated non-small cell lung cancer (NSCLC) receiving epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) therapy would eventually encounter drug resistance, which is frequently caused by EGFR T790M mutation. Osimertinib is frequently used to treat acquired T790M-mutated NSCLC. The correlation between the timing of osimertinib use and survival benefit remains unclear. Methods: In this retrospective two-center study, we enrolled patients with EGFR-mutated NSCLC harboring acquired T790M mutation. The clinical data were collected and analyzed, including clinical characteristics, types of EGFR mutation, use of osimertinib or not, the timing of osimertinib use, and treatment outcomes. The primary outcome was defined as comparison of cumulative death rate in patients who had and hadn’t received osimertinib within different time interval since T790M mutation detected. Results: A total of 205 patients with EGFR-mutated NSCLC harboring acquired T790M mutation were identified. Among them, 108 patients were included for survival analysis. Patients who hadn’t received osimertinib within 13 weeks since T790M mutation detected had higher cumulative death rate than those who had received osimertinib (12.8% vs. 1.7%，p = 0.023). For patients received osimertinib therapy (n = 84), the median duration from detection of T790M mutation to osimertinib treatment was 56 days. The median progression-free survival (PFS) showed no significant difference between patient groups receiving osimertinib therapy within and beyond 56 days (8.2 vs. 21.8 months, p = 0.063). The median PFS in patients received osimertinib as first subsequent therapy after T790M detected was similar to those as second subsequent therapy or beyond (10.9 vs. 9.3 months, p = 0.950). In multivariate analysis, the patients with T790M mutation detected from circulating tumor DNA had a shorter PFS (hazard ratio = 2.79, 95% confidence interval, 1.30-5.95) and survival (hazard ratio = 5.27, 95% confidence interval, 2.12-13.15) as compared with those who had T790M mutation detected from tumor tissue. Conclusions: For NSCLC patients with acquired EGFR T790M mutation, delay in the administration of osimertinib might increase mortality rate. But there was no significant difference in osimertinib PFS between patients received osimertinib as first subsequent therapy or second subsequent therapy or beyond after T790M detected. The specimen from which T790M mutation detected may indicate of a prognostic value.

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