曲妥珠单抗德鲁司坦治疗 HER2 阳性晚期结直肠癌患者(DESTINY-CRC02):一项多中心、随机、2 期试验的初步结果。

IF 41.6 1区 医学 Q1 ONCOLOGY
Lancet Oncology Pub Date : 2024-09-01 Epub Date: 2024-08-05 DOI:10.1016/S1470-2045(24)00380-2
Kanwal Raghav, Salvatore Siena, Atsuo Takashima, Takeshi Kato, Marc Van den Eynde, Filippo Pietrantonio, Yoshito Komatsu, Hisato Kawakami, Marc Peeters, Thierry Andre, Sara Lonardi, Kensei Yamaguchi, Jeanne Tie, Cristina Gravalos Castro, Hung-Chih Hsu, John H Strickler, Tae-You Kim, Yongjun Cha, Daniel Barrios, Qi Yan, Takahiro Kamio, Kojiro Kobayashi, Aislyn Boran, Makito Koga, John D Allard, Takayuki Yoshino
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In stage 1, patients were randomly assigned (1:1), via a secure interactive response technology system, to receive 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan administered intravenously every 21 days. Stratification factors were ECOG performance status, HER2 status, and RAS status. In stage 2, patients were assigned into the 5·4 mg/kg treatment group only. The primary endpoint was confirmed objective response rate by blinded independent central review, assessed in all patients for whom treatment was assigned (full analysis set). Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04744831, and is ongoing (not recruiting).</p><p><strong>Findings: </strong>Between March 5, 2021, and March 29, 2022, 135 patients were centrally screened, 122 of whom were enrolled. In stage 1, 40 patients each were randomly assigned to receive trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg. In stage 2, an additional 42 patients were enrolled in the 5·4 mg/kg group. 64 (52%) participants were male and 58 (48%) were female. The median duration of follow-up was 8·9 months (IQR 6·7-10·5) in the 5·4 mg/kg group and 10·3 months (5·9-12·7) in the 6·4 mg/kg group. The confirmed objective response rate by blinded independent central review was 37·8% (31/82 [95% CI 27·3-49·2]) in the 5·4 mg/kg group and 27·5% (11/40 [14·6-43·9]) in the 6·4 mg/kg group. 34 (41%) of 83 patients in the 5·4 mg/kg group and 19 (49%) of 39 in the 6·4 mg/kg group had grade 3 or worse drug-related treatment-emergent adverse events. 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引用次数: 0

摘要

背景:曲妥珠单抗德鲁司坦在治疗难治性 HER2 阳性、RAS 野生型和 BRAF 野生型转移性结直肠癌患者中显示出令人鼓舞的活性。有必要对RAS突变患者和既往接受过抗HER2治疗的患者进行剂量优化和进一步的抗肿瘤评估。我们旨在评估两种剂量的曲妥珠单抗德鲁司坦(5-4 mg/kg和6-4 mg/kg),以确定HER2阳性、RAS野生型或突变型转移性结直肠癌患者的推荐剂量:DESTINY-CRC02是一项多中心、随机、两阶段、两臂、二期研究,在澳大利亚、比利时、法国、意大利、日本、韩国、西班牙、台湾、英国和美国的53家研究医院和医疗中心进行。符合条件的患者年龄在 18 岁及以上或 20 岁及以上(视地区而定),病理记录显示为不可切除、复发或转移性 HER2 阳性、RAS 野生型或突变型结直肠癌。患者的东部合作肿瘤学组(ECOG)表现为 0 或 1,既往接受过化疗,并在有临床指征的情况下接受过抗 EGFR、抗 VEGF 或抗 PD-L1 治疗。在第一阶段,患者通过安全互动反应技术系统随机分配(1:1)接受每21天静脉注射5-4 mg/kg或6-4 mg/kg曲妥珠单抗。分层因素包括 ECOG 表现状态、HER2 状态和 RAS 状态。在第二阶段,患者仅被分配到5-4 mg/kg治疗组。主要终点是通过盲法独立中央审查确认的客观反应率,评估对象是所有接受治疗的患者(完整分析集)。对所有至少接受过一次治疗的患者进行了安全性评估。该试验已在 ClinicalTrials.gov 注册,编号为 NCT04744831,目前正在进行中(未招募):2021年3月5日至2022年3月29日期间,集中筛选了135名患者,其中122人被纳入。在第一阶段,随机分配40名患者分别接受5-4毫克/千克和6-4毫克/千克的曲妥珠单抗德鲁司坦治疗。在第二阶段,又有42名患者被纳入5-4毫克/千克组。64名参与者(52%)为男性,58名参与者(48%)为女性。5-4 mg/kg组的中位随访时间为8-9个月(IQR为6-7-10-5),6-4 mg/kg组为10-3个月(5-9-12-7)。经盲法独立中央审查确认的客观反应率为:5-4 mg/kg组37-8%(31/82 [95% CI 27-3-49-2]),6-4 mg/kg组27-5%(11/40 [14-6-43-9])。5-4 mg/kg组83名患者中有34名(41%)和6-4 mg/kg组39名患者中有19名(49%)出现了3级或更严重的药物相关治疗突发不良事件。在5-4毫克/千克组中,最常见的3级或更严重的药物相关治疗突发不良事件是中性粒细胞计数减少(83名患者中有13人[16%])、贫血(6人[7%])、恶心(6人[7%])和白细胞计数减少(5人[6%]);中性粒细胞计数减少(39 名患者中有 10 人[26%])、贫血(8 人[21%])、血小板计数减少(4 人[10%])和白细胞计数减少(4 人[10%])。在5-4毫克/千克组的83名患者中,有11人(13%)发生了与药物相关的严重不良事件;在6-4毫克/千克组的39名患者中,有6人(15%)发生了与药物相关的严重不良事件;在5-4毫克/千克组,最常见的不良事件是恶心(3人[4%]),在6-4毫克/千克组,最常见的不良事件是疲劳(2人[5%])、中性粒细胞减少(2人[5%])和血小板减少(2人[5%])。5-4毫克/千克组有一名(1%)患者发生了与药物相关的治疗突发不良事件,导致死亡(肝功能衰竭)。5-4毫克/千克组有7名患者(8%)发生了与药物相关的间质性肺病或肺炎事件(均为1级或2级),6-4毫克/千克组有5名患者(13%)发生了与药物相关的间质性肺病或肺炎事件(4例为1级或2级,1例为5级):曲妥珠单抗德鲁司坦5-4毫克/千克的抗肿瘤活性和良好的安全性支持将其作为HER2阳性转移性结直肠癌预处理患者的最佳单药剂量,包括RAS突变、既往接受过抗HER2治疗或两者兼有的患者:资金来源:第一三共公司和阿斯利康公司。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Trastuzumab deruxtecan in patients with HER2-positive advanced colorectal cancer (DESTINY-CRC02): primary results from a multicentre, randomised, phase 2 trial.

Background: Trastuzumab deruxtecan has shown encouraging activity in patients with treatment-refractory HER2-positive, RAS wild-type and BRAF wild-type metastatic colorectal cancer. Dose optimisation and further antitumour assessments in patients with RAS mutations and those with previous anti-HER2 therapy are warranted. We aimed to evaluate two doses of trastuzumab deruxtecan (5·4 mg/kg and 6·4 mg/kg) to establish the recommended dose in patients with pretreated HER2-positive, RAS wild-type or mutant metastatic colorectal cancer.

Methods: DESTINY-CRC02 was a multicentre, randomised, two-stage, two-arm, phase 2 study done in 53 research hospitals and medical centres in Australia, Belgium, France, Italy, Japan, South Korea, Spain, Taiwan, the UK, and the USA. Eligible patients were aged 18 years and older or 20 years and older (depending on region) with pretreated pathologically documented, unresectable, recurrent, or metastatic HER2-positive, and RAS wild-type or mutant colorectal cancer. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and have received previous chemotherapy, and anti-EGFR, anti-VEGF, or anti-PD-L1 therapy, if clinically indicated. In stage 1, patients were randomly assigned (1:1), via a secure interactive response technology system, to receive 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan administered intravenously every 21 days. Stratification factors were ECOG performance status, HER2 status, and RAS status. In stage 2, patients were assigned into the 5·4 mg/kg treatment group only. The primary endpoint was confirmed objective response rate by blinded independent central review, assessed in all patients for whom treatment was assigned (full analysis set). Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04744831, and is ongoing (not recruiting).

Findings: Between March 5, 2021, and March 29, 2022, 135 patients were centrally screened, 122 of whom were enrolled. In stage 1, 40 patients each were randomly assigned to receive trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg. In stage 2, an additional 42 patients were enrolled in the 5·4 mg/kg group. 64 (52%) participants were male and 58 (48%) were female. The median duration of follow-up was 8·9 months (IQR 6·7-10·5) in the 5·4 mg/kg group and 10·3 months (5·9-12·7) in the 6·4 mg/kg group. The confirmed objective response rate by blinded independent central review was 37·8% (31/82 [95% CI 27·3-49·2]) in the 5·4 mg/kg group and 27·5% (11/40 [14·6-43·9]) in the 6·4 mg/kg group. 34 (41%) of 83 patients in the 5·4 mg/kg group and 19 (49%) of 39 in the 6·4 mg/kg group had grade 3 or worse drug-related treatment-emergent adverse events. The most common grade 3 or worse drug-related treatment-emergent adverse events were neutrophil count decreased (13 [16%] of 83 patients), anaemia (six [7%]), nausea (six [7%]), and white blood cell count decreased (five [6%]) in the 5·4 mg/kg group; and were neutrophil count decreased (10 [26%] of 39 patients), anaemia (eight [21%]), platelet count decreased (four [10%]), and white blood cell count decreased (four [10%]) in the 6·4 mg/kg group. Drug-related serious adverse events occurred in 11 (13%) of 83 patients in the 5·4 mg/kg group and six (15%) of 39 patients in the 6·4 mg/kg group; the most common in the 5·4 mg/kg group was nausea (three [4%] patients) and the most common in the 6·4 mg/kg group were fatigue (two [5%] patients), neutropenia (two [5%]), and thrombocytopenia (two [5%]). A drug-related treatment-emergent adverse event related to death occurred in one (1%) patient in the 5·4 mg/kg group (due to hepatic failure). Adjudicated drug-related interstitial lung disease or pneumonitis events were observed in seven (8%) patients in the 5·4 mg/kg group (all grade 1 or 2) and in five (13%) patients in the 6·4 mg/kg group (four grade 1 or 2; one grade 5).

Interpretation: The promising antitumour activity and favourable safety profile support trastuzumab deruxtecan 5·4 mg/kg as the optimal single-agent dose for patients with pretreated HER2-positive metastatic colorectal cancer, including those with RAS mutations, previous anti-HER2 therapy, or both.

Funding: Daiichi Sankyo and AstraZeneca.

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来源期刊
Lancet Oncology
Lancet Oncology 医学-肿瘤学
CiteScore
62.10
自引率
1.00%
发文量
913
审稿时长
3-8 weeks
期刊介绍: The Lancet Oncology is a trusted international journal that addresses various topics in clinical practice, health policy, and global oncology. It covers a wide range of cancer types, including breast, endocrine system, gastrointestinal, genitourinary, gynaecological, haematological, head and neck, neurooncology, paediatric, thoracic, sarcoma, and skin cancers. Additionally, it includes articles on epidemiology, cancer prevention and control, supportive care, imaging, and health-care systems. The journal has an Impact Factor of 51.1, making it the leading clinical oncology research journal worldwide. It publishes different types of articles, such as Articles, Reviews, Policy Reviews, Personal Views, Clinical Pictures, Comments, Correspondence, News, and Perspectives. The Lancet Oncology also collaborates with societies, governments, NGOs, and academic centers to publish Series and Commissions that aim to drive positive changes in clinical practice and health policy in areas of global oncology that require attention.
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