Objectives

NTRK fusions result in constitutively active oncogenic TRK proteins responsible for ∼ 0.2 % of non-small cell lung cancer (NSCLC) cases. Approximately 40 % of patients with advanced NSCLC develop CNS metastases; therefore, treatments with intracranial (IC) efficacy are needed. In an integrated analysis of three phase I/II studies (ALKA-372–001: EudraCT 2012–000148–88; STARTRK-1: NCT02097810; STARTRK-2: NCT02568267), entrectinib, a potent, CNS-active, TRK inhibitor, demonstrated efficacy in patients with NTRK fusion-positive (fp) NSCLC (objective response rate [ORR]: 64.5 %; 2 August 2021 data cut-off). We present updated data for this cohort.

Materials and methods

Eligible patients were ≥ 18 years with locally advanced/metastatic, NTRK-fp NSCLC with ≥ 12 months of follow-up. Tumor responses were assessed by blinded independent central review (BICR) per RECIST v1.1 at Week 4 and every eight weeks thereafter. Co-primary endpoints: ORR; duration of response (DoR). Secondary endpoints included progression-free survival (PFS); overall survival (OS); IC efficacy; safety. Enrolment cut-off: 2 July 2021; data cut-off: 2 August 2022.

Results

The efficacy-evaluable population included 51 patients with NTRK-fp NSCLC. Median age was 60.0 years (range 22–88); 20 patients (39.2 %) had investigator-assessed baseline CNS metastases. Median survival follow–up was 26.3 months (95 % CI 21.0–34.1). ORR was 62.7 % (95 % CI 48.1–75.9), with six complete and 26 partial responses. Median DoR and PFS were 27.3 months (95 % CI 19.9–30.9) and 28.0 months (95 % CI 15.7–30.4), respectively. Median OS was 41.5 months. In patients with BICR-assessed baseline CNS metastases, IC-ORR was 64.3 % (n = 9/14; 95 % CI 35.1–87.2), including seven complete responders, and IC-DoR was 55.7 months. In the safety–evaluable population (n = 55), most treatment-related adverse events were grade 1/2; no treatment-related deaths were reported.

Conclusion

Entrectinib has continued to demonstrate deep and durable systemic and IC responses in patients with NTRK-fp NSCLC.

中文翻译：

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更新了恩曲替尼治疗 NTRK 融合阳性非小细胞肺癌的疗效和安全性

目标

NTRK融合产生组成型活性致癌 TRK 蛋白，导致约 0.2% 的非小细胞肺癌 (NSCLC) 病例。大约 40% 的晚期 NSCLC 患者会发生中枢神经系统转移；因此，需要具有颅内（IC）疗效的治疗。在三项 I/II 期研究（ALKA-372-001：EudraCT 2012-000148-88；STARTRK-1：NCT02097810；STARTRK-2：NCT02568267）的综合分析中，entrectinib，一种有效的 CNS 活性 TRK 抑制剂，在NTRK融合阳性 (fp) NSCLC患者中显示出疗效（客观缓解率 [ORR]：64.5%；数据截止日期为 2021 年 8 月 2 日）。我们提供该队列的最新数据。

材料和方法

符合资格的患者为≥18岁的局部晚期/转移性NTRK -fp NSCLC患者，且随访≥12个月。在第 4 周以及此后每八周，根据 RECIST v1.1 通过盲法独立中央审查 (BICR) 评估肿瘤反应。共同主要终点：ORR；响应持续时间 (DoR)。次要终点包括无进展生存期（PFS）；总生存期（OS）；IC功效；安全。报名截止日期：2021年7月2日；数据截止日期：2022 年 8 月 2 日。

结果

可评估疗效的人群包括 51 名NTRK -fp NSCLC 患者。中位年龄为 60.0 岁（范围 22-88 岁）；20 名患者 (39.2%) 有研究者评估的基线 CNS 转移。中位生存随访时间为 26.3 个月（95% CI 21.0-34.1）。ORR 为 62.7%（95% CI 48.1-75.9），其中 6 例完全缓解，26 例部分缓解。中位 DoR 和 PFS 分别为 27.3 个月（95% CI 19.9–30.9）和 28.0 个月（95% CI 15.7–30.4）。中位 OS 为 41.5 个月。在 BICR 评估的基线 CNS 转移患者中，IC-ORR 为 64.3%（n = 9/14；95% CI 35.1–87.2），其中包括 7 名完全缓解者，IC-DoR 为 55.7 个月。在安全性可评估人群 (n = 55) 中，大多数与治疗相关的不良事件为 1/2 级；没有报告与治疗相关的死亡。

结论

Entrectinib 在NTRK -fp NSCLC患者中继续表现出深度且持久的全身反应和 IC 反应。