Abstract：
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.
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.
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.
Entrectinib has continued to demonstrate deep and durable systemic and IC responses in patients with NTRK-fp NSCLC.
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.
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.
Entrectinib has continued to demonstrate deep and durable systemic and IC responses in patients with NTRK-fp NSCLC.
摘要：
目的：NTRK融合导致组成型活性致癌TRK蛋白，约占非小细胞肺癌（NSCLC）病例的0.2％。大约40%的晚期NSCLC患者发生CNS转移；因此，需要具有颅内（IC）疗效的治疗。在对三个I/II期研究的综合分析中（ALKA-372-001：EudraCT2012-000148-88；STARTRK-1：NCT02097810；STARTRK-2：NCT02568267），恩替尼,一个强大的，中枢神经系统活性，TRK抑制剂,NTRK融合阳性（fp）NSCLC患者的疗效（客观缓解率[ORR]：64.5％；2021年8月2日数据截止）。我们提供了该队列的最新数据。
方法：符合条件的患者为≥18岁的局部晚期/转移性患者，NTRK-fpNSCLC随访≥12个月。在第4周和此后每8周通过根据RECISTv1.1的盲法独立中央审查(BICR)评估肿瘤应答。共同主要终点：ORR；反应持续时间（DoR）。次要终点包括无进展生存期(PFS);总生存期(OS);IC疗效;安全性。入学截止日期：2021年7月2日；数据截止日期：2022年8月2日。
结果：可评价疗效的人群包括51例NTRK-fpNSCLC患者。中位年龄为60.0岁（范围22-88）；20例患者（39.2%）有研究者评估的基线CNS转移。中位生存期随访为26.3个月（95%CI21.0-34.1）。ORR为62.7%（95%CI48.1-75.9），有6个完整和26个部分响应。平均DoR和PFS分别为27.3个月（95%CI19.9-30.9）和28.0个月（95%CI15.7-30.4），分别。中位OS为41.5个月。在BICR评估基线中枢神经系统转移的患者中，IC-ORR为64.3%（n=9/14；95%CI35.1-87.2），包括七个完整的响应者，IC-DoR为55.7个月。在安全性可评估的人群中（n=55），大多数治疗相关不良事件为1/2级;未报告治疗相关死亡.
结论：Entrectinib在NTRK-fpNSCLC患者中继续表现出深度和持久的全身和IC反应。
方法：符合条件的患者为≥18岁的局部晚期/转移性患者，NTRK-fpNSCLC随访≥12个月。在第4周和此后每8周通过根据RECISTv1.1的盲法独立中央审查(BICR)评估肿瘤应答。共同主要终点：ORR；反应持续时间（DoR）。次要终点包括无进展生存期(PFS);总生存期(OS);IC疗效;安全性。入学截止日期：2021年7月2日；数据截止日期：2022年8月2日。
结果：可评价疗效的人群包括51例NTRK-fpNSCLC患者。中位年龄为60.0岁（范围22-88）；20例患者（39.2%）有研究者评估的基线CNS转移。中位生存期随访为26.3个月（95%CI21.0-34.1）。ORR为62.7%（95%CI48.1-75.9），有6个完整和26个部分响应。平均DoR和PFS分别为27.3个月（95%CI19.9-30.9）和28.0个月（95%CI15.7-30.4），分别。中位OS为41.5个月。在BICR评估基线中枢神经系统转移的患者中，IC-ORR为64.3%（n=9/14；95%CI35.1-87.2），包括七个完整的响应者，IC-DoR为55.7个月。在安全性可评估的人群中（n=55），大多数治疗相关不良事件为1/2级;未报告治疗相关死亡.
结论：Entrectinib在NTRK-fpNSCLC患者中继续表现出深度和持久的全身和IC反应。
