Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study
Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study
复制标题
DOI：
10.1016/s2213-8587(21)00120-0
复制
发表时间：
2021-07-21
影响因子：
44.5
通讯作者：
Taylor, Matthew H.
中科院分区：
文献类型：
--
作者：
Subbiah, Vivek;Hu, Mimi, I;Taylor, Matthew H.
背景 RET 的致癌改变是甲状腺癌的重要治疗靶点。我们的目的是评估 pralsetinib（一种高效、选择性 RET 抑制剂）在 RET 改变的甲状腺癌患者中的安全性和抗肿瘤活性。方法 ARROW 是一项 1/2 期开放标签研究，在 13 个国家的社区和医院环境中的 71 个地点进行，纳入了 18 岁或以上患有 RET 改变的局部晚期或转移性实体瘤（包括 RET 突变髓质）的患者 甲状腺癌和 RET 融合阳性甲状腺癌，东部肿瘤合作组表现状态为 0-2（后来在方案修订中限制为 0-1）。对于接受 400 mg 每日一次口服 pralsetinib 直至疾病进展、不耐受、撤回同意或研究者决定的患者，第 2 期主要终点评估为总体缓解率（实体瘤反应评估标准 1.1 版；隐蔽的独立中心审查）和安全性。对既往接受过卡博替尼或凡德他尼或两者，或不符合标准治疗资格的 RET 突变甲状腺髓样癌患者以及既往接受过 RET 融合阳性甲状腺癌患者的肿瘤反应进行评估；对所有 RET 改变的甲状腺癌患者的安全性进行了评估。这项正在进行的研究已在 ClinicalTrials.gov 注册，NCT03037385，在本中期分析时，RET 融合阳性甲状腺癌患者的入组工作正在进行中。2017 年 3 月 17 日至 2020 年 5 月 22 日期间的研究结果，入组了 122 名 RET 突变髓质患者和 20 名 RET 融合阳性甲状腺癌患者。在2019年7月11日之前接受pralsetinib治疗的基线可测量疾病的患者中（疗效分析的入组截止时间），未接受治疗的RET突变型甲状腺髓样癌患者的总体缓解率为21例患者中的15例（71%）（95% CI 48-89），之前接受过治疗的患者的总体缓解率为55例患者中的33例（95% CI 46-73）（95% CI 46-73）卡博替尼或凡德他尼， 或两者兼而有之，而 RET 融合阳性甲状腺癌患者中的 9 例 (95% CI 52-100) 中有 8 例 (89%)（每组均得到确认）。截至 2020 年 5 月 22 日入组的 RET 改变甲状腺癌患者中，常见 (>= 10%) 3 级及以上治疗相关不良事件为高血压（142 名患者中的 24 名患者 [17%]）、中性粒细胞减少症 (19 名患者 [13%])、淋巴细胞减少症 (17 名患者 [12%]) 和贫血 (14 名患者 [10%])。 21 名患者 (15%) 报告了严重的治疗相关不良事件，其中最常见的 (>= 2%) 是肺炎（5 名患者 [4%]）。五名患者 [4%] 由于治疗相关事件而停止治疗。一名 (1%) 患者因治疗相关不良事件死亡。 解释 Pralsetinib 是一种新的、耐受性良好、有效的每日一次口服治疗选择，适用于 RET 改变的甲状腺癌患者。版权所有 (C) 2021 爱思唯尔有限公司。保留所有权利。
Background Oncogenic alterations in RET represent important therapeutic targets in thyroid cancer. We aimed to assess the safety and antitumour activity of pralsetinib, a highly potent, selective RET inhibitor, in patients with RET-altered thyroid cancers.Methods ARROW, a phase 1/2, open-label study done in 13 countries across 71 sites in community and hospital settings, enrolled patients 18 years or older with RET-altered locally advanced or metastatic solid tumours, including RET-mutant medullary thyroid and RET fusion-positive thyroid cancers, and an Eastern Co-operative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment). Phase 2 primary endpoints assessed for patients who received 400 mg once-daily oral pralsetinib until disease progression, intolerance, withdrawal of consent, or investigator decision, were overall response rate (Response Evaluation Criteria in Solid Tumours version 1.1; masked independent central review) and safety. Tumour response was assessed for patients with RET-mutant medullary thyroid cancer who had received previous cabozantinib or vandetanib, or both, or were ineligible for standard therapy and patients with previously treated RET fusion-positive thyroid cancer; safety was assessed for all patients with RET-altered thyroid cancer. This ongoing study is registered with clinicaltrials.gov, NCT03037385, and enrolment of patients with RET fusion-positive thyroid cancer was ongoing at the time of this interim analysis.Findings Between Mar 17, 2017, and May 22, 2020, 122 patients with RET-mutant medullary and 20 with RET fusion- positive thyroid cancers were enrolled. Among patients with baseline measurable disease who received pralsetinib by July 11, 2019 (enrolment cutoff for efficacy analysis), overall response rates were 15 (71%) of 21 (95% CI 48-89) in patients with treatment-naive RET-mutant medullary thyroid cancer and 33 (60%) of 55 (95% CI 46-73) in patients who had previously received cabozantinib or vandetanib, or both, and eight (89%) of nine (95% CI 52-100) in patients with RET fusion-positive thyroid cancer (all responses confirmed for each group). Common (>= 10%) grade 3 and above treatment-related adverse events among patients with RET-altered thyroid cancer enrolled by May 22, 2020, were hypertension (24 patients [17%] of 142), neutropenia (19 [13%]), lymphopenia (17 [12%]), and anaemia (14 [10%]). Serious treatment-related adverse events were reported in 21 patients (15%), the most frequent (>= 2%) of which was pneumonitis (five patients [4%]). Five patients [4%] discontinued owing to treatment-related events. One (1%) patient died owing to a treatment-related adverse event.Interpretation Pralsetinib is a new, well-tolerated, potent once-daily oral treatment option for patients with RET-altered thyroid cancer. Copyright (C) 2021 Elsevier Ltd. All rights reserved.