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.

Funding

Blueprint Medicines.

中文翻译：

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Pralsetinib 用于晚期或转移性 RET 改变的甲状腺癌 (ARROW) 患者：一项多队列、开放标签、注册、1/2 期研究

背景

RET 的致癌改变代表了甲状腺癌的重要治疗靶点。我们旨在评估 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 71 个社区和医院环境中进行，招募了 18 岁或以上患有RET改变的局部晚期或转移性实体瘤的患者，包括RET突变的甲状腺髓样和RET融合阳性甲状腺癌，东部肿瘤合作组的体能状态为 0-2（后来在协议修正案中限制为 0-1）。对接受 400 mg 每日一次口服 pralsetinib 直至疾病进展、不耐受、撤销同意或研究者决定的患者进行评估的 2 期主要终点是总体反应率（实体瘤反应评估标准 1.1 版；隐蔽独立中央审查）和安全。对既往接受过卡博替尼或凡德他尼或两者，或不适合标准治疗的RET突变甲状腺髓样癌患者和先前接受过治疗的RET融合阳性甲状腺癌患者的肿瘤反应进行评估；对所有RET患者进行了安全性评估- 改变的甲状腺癌。这项正在进行的研究在clinicaltrials.gov注册，NCT03037385，并且在本中期分析时正在招募RET融合阳性甲状腺癌患者。

发现

2017 年 3 月 17 日至 2020 年 5 月 22 日期间，招募了122 名RET突变髓样癌患者和 20 名RET融合阳性甲状腺癌患者。在 2019 年 7 月 11 日（疗效分析的入组截止）之前接受帕拉替尼治疗的基线可测量疾病患者中，未接受治疗的RET突变患者的总体缓解率为 15 (71%) of 21 (95% CI 48–89)甲状腺髓样癌和 55 名患者中的 33 名 (60%) (95% CI 46-73) 在先前接受过卡博替尼或凡德他尼或两者的患者中，以及 9 名患者中的 8 名 (89%) (95% CI 52-100)用RET融合阳性甲状腺癌（所有响应确认为每个组）。常见 (≥10%) 3 级及以上与治疗相关的不良事件截至 2020 年 5 月 22 日登记的RET改变的甲状腺癌是高血压（142 名患者中的 24 名 [17%]）、中性粒细胞减少（19 [13%]）、淋巴细胞减少（17 [12%]）和贫血（14 [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（≥2%）是肺炎（5 名患者 [4%]）。五名患者 [4%] 由于治疗相关事件而停药。一名 (1%) 患者因治疗相关的不良事件死亡。

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。

资金

蓝图药物。