Introduction: In ret proto‐oncogene (RET)–rearranged lung cancers, data on the frequency of brain metastases and, in particular, the outcomes of multikinase inhibitor therapy in patients with intracranial disease are not well characterized. Methods: A global, multi‐institutional registry (cohort A, n = 114) and a bi‐institutional data set (cohort B, n = 71) of RET‐rearranged lung cancer patients were analyzed. Patients were eligible if they had stage IV lung cancers harboring a RET rearrangement by local testing. The incidence of brain metastases and outcomes with multikinase inhibitor therapy were determined. Results: The frequency of brain metastases at the time of diagnosis of stage IV disease was 25% (95% confidence interval [CI]: 18%–32%) in all patients from both cohorts. The lifetime prevalence of brain metastasis in stage IV disease was 46% (95% CI: 34%–58%) in patients for whom longitudinal data was available. The cumulative incidence of brain metastases was significantly different (p = 0.0039) between RET‐, ROS1‐, and ALK receptor tyrosine kinase (ALK)–rearranged lung cancers, with RET intermediate between the other two groups. Although intracranial response data was not available in cohort A, the median progression‐free survival of multikinase inhibitor therapy (cabozantinib, vandetanib, or sunitinib) in patients with brain metastases was 2.1 months (95% CI: 1.3–2.9 months, n = 10). In cohort B, an intracranial response was observed in 2 of 11 patients (18%) treated with cabozantinib, vandetanib (± everolimus), ponatinib, or alectinib; the median overall progression‐free survival (intracranial and extracranial) was 3.9 months (95% CI: 2.0–4.9 months). Conclusions: Brain metastases occur frequently in RET‐rearranged lung cancers, and outcomes with multikinase inhibitor therapy in general are suboptimal. Novel RET‐directed targeted therapy strategies are needed.

中文翻译：

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简要报告：RET 重排肺癌患者的脑转移频率和多激酶抑制剂结果

简介：在 ret 原癌基因 (RET) 重排肺癌中，关于脑转移频率的数据，特别是颅内疾病患者的多激酶抑制剂治疗的结果尚未得到很好的表征。方法：对 RET 重排肺癌患者的全球多机构登记（队列 A，n = 114）和双机构数据集（队列 B，n = 71）进行了分析。如果患者患有 IV 期肺癌，且经当地检测发现存在 RET 重排，则符合资格。确定了脑转移的发生率和多激酶抑制剂治疗的结果。结果：在两个队列的所有患者中，诊断为 IV 期疾病时脑转移的发生率为 25%（95% 置信区间 [CI]：18%–32%）。在可获得纵向数据的患者中，IV 期疾病的终生脑转移患病率为 46%（95% CI：34%–58%）。RET-、ROS1-和 ALK 受体酪氨酸激酶 (ALK) 重排肺癌之间的脑转移累积发生率显着不同 (p = 0.0039)，RET 介于其他两组之间。虽然队列 A 中没有颅内缓解数据，但多激酶抑制剂治疗（卡博替尼、凡德他尼或舒尼替尼）治疗脑转移患者的中位无进展生存期为 2.1 个月（95% CI：1.3-2.9 个月，n = 10） ）。在队列 B 中，接受卡博替尼、凡德他尼（±依维莫司）、普纳替尼或艾来替尼治疗的 11 名患者中有 2 名（18%）观察到颅内反应；中位总体无进展生存期（颅内和颅外）为 3.9 个月（95% CI：2.0-4.9 个月）。结论：RET 重排肺癌中经常发生脑转移，并且多激酶抑制剂治疗的结果总体上不理想。需要新的 RET 靶向治疗策略。