zanidatamab 治疗人表皮生长因子受体 2（HER2）扩增型、不可切除的局部晚期或转移性胆道癌（HERIZON-BTC-01）：一项多中心、单臂、2b 期研究。

Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study.

机构信息

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Zhongshan Hospital of Fudan University, Shanghai, China.

出版信息

Lancet Oncol. 2023 Jul;24(7):772-782. doi: 10.1016/S1470-2045(23)00242-5. Epub 2023 Jun 2.

DOI:10.1016/S1470-2045(23)00242-5

PMID:37276871

Abstract

BACKGROUND

HER2 is overexpressed or amplified in a subset of biliary tract cancer. Zanidatamab, a bispecific antibody targeting two distinct HER2 epitopes, exhibited tolerability and preliminary anti-tumour activity in HER2-expressing or HER2 (also known as ERBB2)-amplified treatment-refractory biliary tract cancer.

METHODS

HERIZON-BTC-01 is a global, multicentre, single-arm, phase 2b trial of zanidatamab in patients with HER2-amplified, unresectable, locally advanced, or metastatic biliary tract cancer with disease progression on previous gemcitabine-based therapy, recruited at 32 clinical trial sites in nine countries in North America, South America, Asia, and Europe. Eligible patients were aged 18 years or older with HER2-amplified biliary tract cancer confirmed by in-situ hybridisation per central testing, at least one measurable target lesion per Response Evaluation Criteria in Solid Tumours (version 1.1), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were assigned into cohorts based on HER2 immunohistochemistry (IHC) score: cohort 1 (IHC 2+ or 3+; HER2-positive) and cohort 2 (IHC 0 or 1+). Patients received zanidatamab 20 mg/kg intravenously every 2 weeks. The primary endpoint was confirmed objective response rate in cohort 1 as assessed by independent central review. Anti-tumour activity and safety were assessed in all participants who received any dose of zanidatamab. This trial is registered with ClinicalTrials.gov, NCT04466891, is ongoing, and is closed to recruitment.

FINDINGS

Between Sept 15, 2020, and March 16, 2022, 87 patients were enrolled in HERIZON-BTC-01: 80 in cohort 1 (45 [56%] were female and 35 [44%] were male; 52 [65%] were Asian; median age was 64 years [IQR 58-70]) and seven in cohort 2 (five [71%] were male and two [29%] were female; five [71%] were Asian; median age was 62 years [IQR 58-77]). At the time of the data cutoff (Oct 10, 2022), 18 (21%) patients (17 in cohort 1 and one in cohort 2) were continuing to receive zanidatamab; 69 (79%) discontinued treatment (radiographic progression in 64 [74%] patients). The median duration of follow-up was 12·4 months (IQR 9·4-17·2). Confirmed objective responses by independent central review were observed in 33 patients in cohort 1 (41·3% [95% CI 30·4-52·8]). 16 (18%) patients had grade 3 treatment-related adverse events; the most common were diarrhoea (four [5%] patients) and decreased ejection fraction (three [3%] patients). There were no grade 4 treatment-related adverse events and no treatment-related deaths.

INTERPRETATION

Zanidatamab demonstrated meaningful clinical benefit with a manageable safety profile in patients with treatment-refractory, HER2-positive biliary tract cancer. These results support the potential of zanidatamab as a future treatment option in HER2-positive biliary tract cancer.

FUNDING

Zymeworks, Jazz, and BeiGene.

摘要

背景

HER2 在一部分胆管癌中过度表达或扩增。Zanidatamab 是一种靶向两个不同 HER2 表位的双特异性抗体，在 HER2 表达或 HER2（也称为 ERBB2）扩增的治疗耐药性胆管癌患者中表现出可耐受性和初步的抗肿瘤活性。

方法

HERIZON-BTC-01 是一项全球性、多中心、单臂、2b 期临床试验，评估 zanidatamab 在 HER2 扩增、不可切除、局部晚期或转移性胆管癌患者中的疗效，这些患者在先前基于吉西他滨的治疗中疾病进展，在北美、南美、亚洲和欧洲的 32 个临床试验地点招募。符合条件的患者年龄在 18 岁或以上，HER2 扩增经中心检测的原位杂交证实，根据实体瘤反应评估标准（第 1.1 版）至少有一个可测量的靶病灶，东部合作肿瘤学组体能状态为 0 或 1。根据 HER2 免疫组织化学（IHC）评分，患者被分为两个队列：队列 1（IHC 2+或 3+；HER2 阳性）和队列 2（IHC 0 或 1+）。患者每 2 周接受 20mg/kg 静脉注射 zanidatamab。主要终点是独立中心评估的队列 1 中确认的客观缓解率。所有接受任何剂量 zanidatamab 的患者均评估抗肿瘤活性和安全性。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT04466891，正在进行中，已关闭招募。

结果

2020 年 9 月 15 日至 2022 年 3 月 16 日期间，HERIZON-BTC-01 共纳入 87 例患者：80 例在队列 1 中（45 [56%] 为女性，35 [44%] 为男性；52 [65%] 为亚洲人；中位年龄为 64 岁[IQR 58-70]），7 例在队列 2 中（5 [71%] 为男性，2 [29%] 为女性；5 [71%] 为亚洲人；中位年龄为 62 岁[IQR 58-77]）。在数据截止日期（2022 年 10 月 10 日）时，18 例（21%）患者（队列 1 中有 17 例，队列 2 中有 1 例）仍在接受 zanidatamab 治疗；69 例（79%）停止治疗（64 例[74%]患者出现影像学进展）。中位随访时间为 12.4 个月（IQR 9.4-17.2）。队列 1 中独立中心评估确认的客观缓解率为 33 例（41.3%[95%CI 30.4-52.8]）。16 例（18%）患者出现 3 级治疗相关不良事件；最常见的是腹泻（4 例[5%]）和射血分数降低（3 例[3%]）。没有 4 级治疗相关不良事件，也没有治疗相关死亡。