Targeted therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has established the precision oncology paradigm in lung cancer. Most patients with EGFR-mutated lung cancer respond but eventually acquire resistance. Methods: Patients exhibiting the EGFR p.T790M resistance biomarker benefit from sequenced targeted therapy with osimertinib. We hypothesized that metabolic response as detected by ¹⁸F-FDG PET after short-course osimertinib identifies additional patients susceptible to sequenced therapy. Results: Fourteen patients with EGFR-mutated lung cancer and resistance to first- or second-generation EGFR TKI testing negatively for EGFR p.T790M were enrolled in a phase II study. Five patients (36%) achieved a metabolic ¹⁸F-FDG PET response and continued osimertinib. In those, the median duration of treatment was not reached (95% CI, 24 mo to not estimable), median progression-free survival was 18.7 mo (95% CI, 14.6 mo to not estimable), and median overall survival was 41.5 mo. Conclusion: Connecting theranostic osimertinib treatment with early metabolic response assessment by PET enables early identification of patients with unknown mechanisms of TKI resistance who derive dramatic clinical benefit from sequenced osimertinib. This defines a novel paradigm for personalization of targeted therapies in patients with lung cancer dependent on a tractable driver oncogene.

表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）的靶向治疗已经建立了肺癌的精准肿瘤学范例。大多数 EGFR 突变肺癌患者有反应，但最终会产生耐药性。方法：表现出 EGFR p.T790M 耐药生物标志物的患者受益于奥希替尼的测序靶向治疗。我们假设，短程奥希替尼治疗后通过 ¹⁸ F-FDG PET 检测到的代谢反应可识别出其他对序贯治疗敏感的患者。结果：14 名患有 EGFR 突变肺癌且对第一代或第二代 EGFR TKI 耐药且 EGFR p.T790M 检测呈阴性的患者被纳入 II 期研究。 5 名患者 (36%) 取得了代谢 ¹⁸ F-FDG PET 反应并继续使用奥希替尼。其中，中位治疗持续时间未达到（95% CI，24 个月至不可估计），中位无进展生存期为 18.7 个月（95% CI，14.6 个月至不可估计），中位总生存期为 41.5 个月。结论：将治疗诊断奥希替尼治疗与 PET 早期代谢反应评估相结合，能够早期识别 TKI 耐药机制未知的患者，这些患者从测序奥希替尼中获得显着的临床获益。这为依赖易处理的驱动癌基因的肺癌患者的个体化靶向治疗定义了一种新的范例。