Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial
Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial
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DOI：
10.1016/s1470-2045(21)00086-3
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发表时间：
2021-06-01
期刊：
影响因子：
51.1
通讯作者：
Yoshino, Takayuki
中科院分区：
文献类型：
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作者：
Siena, Salvatore;Di Bartolomeo, Maria;Yoshino, Takayuki
背景 HER2 扩增已在 2-3% 的结直肠癌患者中被发现，尽管目前还没有批准的结直肠癌 HER2 靶向疗法。我们的目的是研究 tra stuzurnab deruxtecan（一种人源化抗 H ER2 抗体与拓扑异构酶 I 抑制剂有效负载的抗体药物偶联物）对表达 HER2 的转移性结直肠癌患者的抗肿瘤活性和安全性。 方法 DESTINY-CRCO1 是一项开放标签的 2 期研究，招募了来自意大利、日本、西班牙、英国和美国的 25 家诊所和医院的患者。符合条件的患者集中确诊为表达 HER2 的非转移性结直肠癌，且在两种或多种既往治疗方案（允许使用曲妥珠单抗 Denixtecan 以外的 HER2 靶向治疗）后病情进展，年龄为 18 岁或以上（日本≥ 20 岁），东部肿瘤合作组评分为 0 或 1，并且患有 RAS 和 BRAF (V600E) 野生型肿瘤。根据 HER2 表达水平将患者纳入三个队列之一：队列 A（HER2 阳性，免疫组织化学 [IHCJ 3+ 或 IHC2+ 和原位杂交 [ISH1 阳性）]、队列 B（IHC2+ 和 ISH 阴性）或队列 C (IHC1+)。患者每 3 周静脉注射 6.4 mg/kg 曲妥珠单抗 deruxtecan，直至疾病进展、不可接受的不良事件、撤回同意或死亡。主要终点是通过独立中央审查确认的队列 A 的客观缓解率，该审查在完整分析集中进行评估，并在安全分析集中评估安全性。完整分析集和安全性分析集均包括接受一剂或多剂曲妥珠单抗地尼替康的所有患者。这项正在进行的试验已在 ClinicalTrials.gov 注册，注册号为 NCT03384940。 结果 2018 年 2 月 23 日至 2019 年 7 月 3 日期间，共有 78 名患者入组该研究（A 组 53 例，B 组 7 例，C 组 18 例），所有患者均接受了至少一剂研究药物。对于 53 名 (68%) HER2 阳性肿瘤患者（A 组），中位随访 27.1 周（IQR 19.3-40.1）后，24 名患者（45.3%，95% CI 31.6-59.6）报告出现确认的客观缓解。至少 10% 的所有参与者发生 3 级或更严重的治疗相关不良事件，包括中性粒细胞计数减少（78 人中的 17 人 [22%]）和贫血（11 人 [14%]）。 5 名患者 (6%) 被判定患有间质性肺疾病或肺炎（两名 2 级；一名 3 级；两名 5 级，唯一与治疗相关的死亡）。 解释 Trastuzumab deruxtecan 在标准治疗难治性 HER2 阳性转移性结直肠癌中显示出有前景且持久的活性，其安全性与之前 trastuzumab deruxtecan 试验中报告的安全性一致。间质性肺病和肺炎是重要的风险，需要仔细监测和及时干预。版权所有 (C) 2021 由 Elsevier Ltd 出版。保留所有权利。
Background HER2 amplification has been identified in 2-3% of patients with colorectal cancer, although there are currently no approved HER2-targeted therapies for colorectal cancer. We aimed to study the antitumour activity and safety of tra stuzurnab deruxtecan (an antibody-drug conjugate of humanised a nti-H ER2 antibody with topoisoinerase I inhibitor payloads) in patients with HER2-expressing metastatic colorectal cancer.Methods DESTINY-CRCO1 is an open-label, phase 2 study that recruited patients from 25 clinics and hospitals in Italy, Japan, Spain, the UK, and the USA. Eligible patients had centrally confirmed HER2-expressing inetastatic colorectal cancer that had progressed on two or more previous regimens (HER2-targeted therapies other than trastuzumab denixtecan permitted), were aged 18 years or older (>= 20 years in Japan), had an Eastern Cooperative Oncology Group score of 0 or 1, and had RAS and BRAF(V600E) wild-type tumours. Patients were enrolled into one of three cohorts by HER2 expression level: cohort A (HER2-positive, immunohistochemistry [IHCJ 3+ or IHC2+ and in-situ hybridisation [ISH1-positive), cohort B (IHC2+ and ISH-negative), or cohort C (IHC1+). Patients received 6.4 mg/kg trastuzumab deruxtecan intravenously every 3 weeks until disease progression, unacceptable adverse events, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate in cohort A by independent central review which was assessed in the full analysis set and safety was assessed in the safety analysis set. Both the full analysis set and the safety analysis set included all patients who received one or more doses of trastuzumab denixtecan. This ongoing trial is registered with ClinicalTrials.gov, number NCT03384940.Findings Between Feb 23, 2018, and July 3, 2019, 78 patients were enrolled in the study (53 in cohort A, seven in cohort B, and 18 in cohort C), all of whom received at least one dose of study drug. For the 53 (68%) patients with HER2-positive tumours (cohort A), a confirmed objective response was reported in 24 (45.3%, 95% CI 31.6-59.6) patients after a median follow-up of 27.1 weeks (IQR 19.3-40.1). Grade 3 or worse treatment-emergent adverse events that occurred in at least 10% of all participants were decreased neutrophil count (17 [22%] of 78) and anaemia (11 [14%]). Five patients (6%) had adjudicated interstitial lung disease or pneumonitis (two grade 2; one grade 3; two grade 5, the only treatment-related deaths).Interpretation Trastuzumab deruxtecan showed promising and durable activity in HER2-positive metastatic colorectal cancer refractory to standard treatment, with a safety profile consistent with that reported in previous trastuzumab deruxtecan trials. Interstitial lung disease and prieuinonitis are important risks requiring careful monitoring and prompt intervention. Copyright (C) 2021 Published by Elsevier Ltd. All rights reserved.