Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study
Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study
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DOI：
10.1016/s1470-2045(21)00247-3
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发表时间：
2021-06-28
期刊：
影响因子：
51.1
通讯作者：
Subbiah, Vivek
中科院分区：
文献类型：
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作者：
Gainor, Justin F.;Curigliano, Giuseppe;Subbiah, Vivek
RET的致癌性改变已在多种肿瘤类型中被确定，包括1-2%的非小细胞肺癌（NSCLC）。我们的目的是评估pralsetinib（一种高效、口服、选择性RET抑制剂）在RET融合阳性NSCLC患者中的安全性、耐受性和抗肿瘤活性。方法ARROW是一项多队列、开放标签、I/II期研究，在13个国家（比利时、中国、法国、德国、香港、意大利、荷兰、新加坡、韩国、西班牙、中国台湾、英国和美国）的71个研究中心（社区和学术癌症中心）进行。入组年龄≥ 18岁的局部晚期或转移性实体瘤（包括RET融合阳性NSCLC）患者，东部肿瘤协作组体能状态评分为0-2（后来在方案修订中限制为0-1）。在第2阶段，患者接受400 mg每日一次口服pralsetinib，并可继续治疗，直至疾病进展、不耐受、撤回知情同意或研究者决定。II期主要终点为总缓解率（根据实体瘤缓解评价标准第1.1版，并通过设盲独立中心审查进行评估）和安全性。在中心裁定的基线可测量疾病的RET融合阳性NSCLC患者中评估肿瘤缓解，这些患者接受过含铂化疗或因不适合标准治疗而未接受过治疗。这项正在进行的研究在ClinicalTrials.gov注册，NCT 03037385，在本次中期分析时，初治RET融合阳性NSCLC患者的入组正在进行中。2017年3月17日至2020年5月22日期间入组的233例RET融合阳性NSCLC患者的结果（数据截止日期），92例既往接受过含铂化疗的患者和29例初治患者在2019年7月11日之前接受了普拉司替尼治疗（疗效入组截止值）; 87例既往接受过治疗的患者和27例初治患者具有中心裁定的基线可测量疾病。87例既往接受过铂类化疗的患者中有53例（61%; 95% CI 50-71）记录到总体缓解，包括5例（6%）完全缓解患者; 27例初治患者中有19例（70%; 50-86），包括3例（11%）完全缓解患者。在233例RET融合阳性NSCLC患者中，常见的3级或更严重治疗相关不良事件为中性粒细胞减少（43例患者[18%]）、高血压（26例[11%]）和贫血（24例[10%]）;该人群中无治疗相关死亡。普拉塞替尼是一种新的、耐受性良好的、有前途的、每日一次口服治疗RET融合阳性NSCLC患者的选择。版权所有（c）2021 Elsevier Ltd.保留所有权利。
Background Oncogenic alterations in RET have been identified in multiple tumour types, including 1-2% of non-small-cell lung cancers (NSCLCs). We aimed to assess the safety, tolerability, and antitumour activity of pralsetinib, a highly potent, oral, selective RET inhibitor, in patients with RET fusion-positive NSCLC. Methods ARROW is a multi-cohort, open-label, phase 1/2 study done at 71 sites (community and academic cancer centres) in 13 countries (Belgium, China, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan, the UK, and the USA). Patients aged 18 years or older with locally advanced or metastatic solid tumours, including RET fusion-positive NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment) were enrolled. In phase 2, patients received 400 mg once-daily oral pralsetinib, and could continue treatment until disease progression, intolerance, withdrawal of consent, or investigator decision. Phase 2 primary endpoints were overall response rate (according to Response Evaluation Criteria in Solid Tumours version 1.1 and assessed by blinded independent central review) and safety. Tumour response was assessed in patients with RET fusion-positive NSCLC and centrally adjudicated baseline measurable disease who had received platinum-based chemotherapy or were treatment-naive because they were ineligible for standard therapy. This ongoing study is registered with ClinicalTrials.gov, NCT03037385, and enrolment of patients with treatment-naive RET fusion-positive NSCLC was ongoing at the time of this interim analysis. Findings Of 233 patients with RET fusion-positive NSCLC enrolled between March 17, 2017, and May 22, 2020 (data cutoff), 92 with previous platinum-based chemotherapy and 29 who were treatment-naive received pralsetinib before July 11, 2019 (efficacy enrolment cutoff); 87 previously treated patients and 27 treatment-naive patients had centrally adjudicated baseline measurable disease. Overall responses were recorded in 53 (61%; 95% CI 50-71) of 87 patients with previous platinum-based chemotherapy, including five (6%) patients with a complete response; and 19 (70%; 50-86) of 27 treatment-naive patients, including three (11%) with a complete response. In 233 patients with RET fusion-positive NSCLC, common grade 3 or worse treatment-related adverse events were neutropenia (43 patients [18%]), hypertension (26 [11%]), and anaemia (24 [10%]); there were no treatment-related deaths in this population. Interpretation Pralsetinib is a new, well-tolerated, promising, once-daily oral treatment option for patients with RET fusion-positive NSCLC. Copyright (c) 2021 Elsevier Ltd. All rights reserved.