Department of Oncology and Hemato-Oncology, Università degli Studi di Milano and Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Lancet Oncol. 2021 Jun;22(6):779-789. doi: 10.1016/S1470-2045(21)00086-3. Epub 2021 May 4.
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 trastuzumab deruxtecan (an antibody-drug conjugate of humanised anti-HER2 antibody with topoisomerase I inhibitor payloads) in patients with HER2-expressing metastatic colorectal cancer.
DESTINY-CRC01 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 metastatic colorectal cancer that had progressed on two or more previous regimens (HER2-targeted therapies other than trastuzumab deruxtecan 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 wild-type tumours. Patients were enrolled into one of three cohorts by HER2 expression level: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC2+ and in-situ hybridisation [ISH]-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 deruxtecan. This ongoing trial is registered with ClinicalTrials.gov, number NCT03384940.
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).
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 pneumonitis are important risks requiring careful monitoring and prompt intervention.
Daiichi Sankyo.
HER2 扩增已在 2-3%的结直肠癌患者中被发现，尽管目前尚无针对结直肠癌的批准的 HER2 靶向治疗方法。我们旨在研究曲妥珠单抗 deruxtecan（人源化抗 HER2 抗体与拓扑异构酶 I 抑制剂有效载荷的抗体药物偶联物）在 HER2 表达的转移性结直肠癌患者中的抗肿瘤活性和安全性。
DESTINY-CRC01 是一项开放标签、2 期研究，在意大利、日本、西班牙、英国和美国的 25 个诊所和医院招募了患者。入选的患者为经中心确认的 HER2 表达的转移性结直肠癌患者，在接受两种或两种以上先前治疗方案（允许使用除曲妥珠单抗 deruxtecan 以外的 HER2 靶向治疗）后进展，年龄在 18 岁或以上（日本≥20 岁），东部肿瘤合作组（ECOG）评分 0 或 1，且为 RAS 和 BRAF 野生型肿瘤。根据 HER2 表达水平，患者被分为三个队列之一：队列 A（HER2 阳性，免疫组化[IHC] 3+或 IHC2+且原位杂交[ISH]-阳性）、队列 B（IHC2+且 ISH-阴性）或队列 C（IHC1+）。患者每 3 周接受 6.4 mg/kg 曲妥珠单抗 deruxtecan 静脉注射，直到疾病进展、无法耐受的不良事件、患者撤回同意或死亡。主要终点是独立中心审查确认的队列 A 的客观缓解率，该终点在全分析集进行评估，安全性在安全性分析集进行评估。全分析集和安全性分析集均包括接受过一次或多次曲妥珠单抗 deruxtecan 治疗的所有患者。这项正在进行的试验在 ClinicalTrials.gov 上注册，编号为 NCT03384940。
在 2018 年 2 月 23 日至 2019 年 7 月 3 日期间，共有 78 名患者入组了该研究（队列 A 53 名，队列 B 7 名，队列 C 18 名），所有患者均至少接受过一次研究药物治疗。在 53 名（68%）HER2 阳性肿瘤患者（队列 A）中，在中位随访 27.1 周（19.3-40.1）后，24 名（45.3%，95%CI 31.6-59.6）患者报告了确认的客观缓解。至少有 10%的所有参与者出现的 3 级或更高级别的治疗相关不良事件为中性粒细胞计数减少（78 名患者中有 17 名[22%]）和贫血（78 名患者中有 11 名[14%]）。5 名患者（6%）发生了经裁决的间质性肺病或肺炎（2 级 2 例；3 级 1 例；5 级 2 例，为唯一与治疗相关的死亡）。
曲妥珠单抗 deruxtecan 在对标准治疗耐药的 HER2 阳性转移性结直肠癌中显示出有前景和持久的疗效，其安全性与先前曲妥珠单抗 deruxtecan 试验报告的一致。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。
第一三共株式会社。
