Yan Kelvin, Bakhtiah Arizah, Hota Shweta, Evans Joanne, Mo Frankie
Department of Clinical Oncology, The Chinese University of Hong Kong, Ngan Shing Street, Shatin, Hong Kong.
Department of Clinical Oncology, Imperial College Healthcare NHS Trust, London, UK.
Target Oncol. 2025 Sep 2. doi: 10.1007/s11523-025-01173-1.
BACKGROUND: Epidermal growth factor receptor (EGFR)-driven non-small cell lung cancer (eLC) is a leading cause of death. The FLAURA study showed that upfront osimertinib (U-OSI) led to better overall survival (OS) than gefitinib or erlotinib, regardless of T790M status in advanced disease. However, if sequenced optimally, sequential OSI (S-OSI) in T790M-positive patients after first- or second-generation EGFR-tyrosine kinase inhibitors (F-S-EGFR-TKI) should theoretically lead to better OS than U-OSI. OBJECTIVE: To identify the best sequencing strategy in this group of patients. PATIENTS AND METHODS: A multicentre retrospective study was conducted on treatment-naive eLC patients who had received an F-S- EGFR-TKI between 1 January 2016 and 31 December 2020 in three tertiary NHS hospitals in the UK. Compliance to national recommendation of T790M testing was analysed. Survival outcomes of T790M testing and S-OSI were estimated with the Kaplan-Meier and Cox Proportional Hazard models. RESULTS: In 84/122 evaluable patients, after F-S-EGFR-TKI, only 50% of the patients were offered a T790M biopsy, owing to rapid progression and reduced fitness. Of which, 59.5% of the patients tested positive and had S-OSI. Median OS for the T790M-tested cohort, regardless of positivity and S-OSI, was 54.0 months vs 8.9 months in those not tested (P = < 0.001). Median OS of S-OSI in T790M-positive patients was 64.0 months vs 34.9 months in the T790M-negative cohort (P < 0.0001). On multivariable analysis, S-OSI was associated with better OS (HR 1.841; 95% CI 1.052-3.221; P = 0.0325), whereas performance status (HR 2. 256; 95% CI 1.151-4.422, P = 0.0178), presence of baseline intracranial disease (HR 2 .022; 95% CI 1.144-3.575, P = 0. 0115), the male sex (HR 2.265; 95% CI 1.302-3.939; P = 0.0038) and non-exon 19 deletion mutations (HR 1.610; 95% CI 1.112-2.331, P = 0.0116) were associated with a higher risk of death. CONCLUSIONS: High performance status and intracranial disease should be indications for U-OSI for a higher chance of response. For fitter patients, F-S-EGFR-TKI followed by T790M biopsy +/- S-OSI appears to confer better-than-expected OS in the entire cohort in the real-world setting, regardless of T790M positivity. Given the clinical benefit and potential cost-effectiveness of this approach, S-OSI should be considered a favourable option in this group of patients, especially in resource-deprived settings.
背景：表皮生长因子受体（EGFR）驱动的非小细胞肺癌（eLC）是主要的死亡原因。FLAURA研究表明，在晚期疾病中，一线使用奥希替尼（U-OSI）比吉非替尼或厄洛替尼能带来更好的总生存期（OS），无论T790M状态如何。然而，如果进行最佳排序，在第一代或第二代EGFR酪氨酸激酶抑制剂（F-S-EGFR-TKI）治疗后，T790M阳性患者序贯使用奥希替尼（S-OSI）理论上应比U-OSI带来更好的总生存期。 目的：确定该组患者的最佳排序策略。 患者与方法：对2016年1月1日至2020年12月31日期间在英国三家NHS三级医院接受F-S-EGFR-TKI治疗的初治eLC患者进行了一项多中心回顾性研究。分析了T790M检测对国家推荐的依从性。采用Kaplan-Meier法和Cox比例风险模型评估T790M检测和S-OSI的生存结局。 结果：在84/122例可评估患者中，F-S-EGFR-TKI治疗后，由于疾病快速进展和身体状况下降，仅50%的患者接受了T790M活检。其中，59.5%的患者检测呈阳性并接受了S-OSI。T790M检测队列的中位总生存期，无论阳性与否及是否接受S-OSI，为54.0个月，而未检测患者为8.9个月（P = < 0.001）。T790M阳性患者S-OSI的中位总生存期为64.0个月，而T790M阴性队列中为34.9个月（P < 0.0001）。多变量分析显示，S-OSI与更好的总生存期相关（HR 1.841；95% CI 1.052 - 3.221；P = 0.0325），而体能状态（HR 2.256；95% CI 1.151 - 4.422，P = 0.0178）、基线颅内疾病的存在（HR 2.022；95% CI 1.144 - 3.575，P = 0.0115）、男性（HR 2.265；95% CI 1.302 - 3.939；P = 0.0038）和非外显子19缺失突变（HR 1.610；95% CI 1.112 - 2.331，P = 0.0116）与更高的死亡风险相关。 结论：良好的体能状态和颅内疾病应作为U-OSI的指征，以提高缓解几率。对于身体状况较好的患者，在现实环境中，F-S-EGFR-TKI后进行T790M活检±S-OSI在整个队列中似乎能带来优于预期的总生存期，无论T790M是否阳性。鉴于这种方法的临床益处和潜在的成本效益，S-OSI应被视为该组患者的一个有利选择，尤其是在资源匮乏的环境中。
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