Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Division of Cancer Center, Hokkaido University Hospital, Sapporo, Japan.
J Clin Oncol. 2024 Sep 20;42(27):3207-3217. doi: 10.1200/JCO.23.02010. Epub 2024 Aug 5.
Treatment options for patients with unresectable or recurrent biliary tract cancer (BTC) who progress on a gemcitabine-containing regimen are limited. In addition, the significance of anti-human epidermal growth factor receptor 2 (HER2) therapy in HER2-expressing BTC has not been sufficiently investigated.
In this phase II trial, participants from five institutions in Japan were enrolled. Eligible patients had pathologically confirmed unresectable or recurrent BTC with centrally confirmed HER2-positive (immunohistochemistry [IHC]3+ or IHC2+ and in situ hybridization [ISH]+) or HER2-low (IHC2+ and ISH-, IHC1+, and IHC0 and ISH+) and were refractory or intolerant to a gemcitabine-containing regimen. The patients received 5.4 mg/kg trastuzumab deruxtecan (T-DXd) once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was the confirmed objective response rate (ORR) in HER2-positive BTC by an independent central review (threshold ORR, 15%; expected ORR, 40%).
A total of 32 patients were enrolled and treated. Among these patients, 22 with HER2-positive disease comprised the primary efficacy population and had a confirmed ORR of 36.4% (90% CI, 19.6 to 56.1; = .01), meeting the primary end point. Eight with HER2-low disease comprised the exploratory population and had a confirmed ORR of 12.5%. The most common ≥grade 3 treatment-related adverse events were anemia (53.1%) and neutropenia (31.3%). Eight patients (25.0%) had interstitial lung disease (ILD), including two grade 5 events.
T-DXd showed promising activity in patients with HER2-positive BTC and a signal of efficacy in patients with HER2-low BTC. Although the safety profile was generally manageable, ILD requires careful monitoring and early intervention.
对于接受含吉西他滨方案治疗后进展的不可切除或复发性胆道癌（BTC）患者，治疗选择有限。此外，抗人表皮生长因子受体 2（HER2）治疗在 HER2 表达的 BTC 中的意义尚未得到充分研究。
在这项来自日本五家机构的 II 期试验中，纳入了符合条件的患者。这些患者均患有经病理证实的不可切除或复发性 BTC，且经中心确认存在 HER2 阳性（免疫组化 [IHC]3+或 IHC2+且原位杂交 [ISH]+）或 HER2 低表达（IHC2+且 ISH-、IHC1+、IHC0 和 ISH+），并且对含吉西他滨的方案不耐受或有抗药性。患者接受 5.4mg/kg 曲妥珠单抗 deruxtecan（T-DXd）治疗，每 3 周一次，直至疾病进展或出现不可接受的毒性。主要终点是独立中心审查确认的 HER2 阳性 BTC 的客观缓解率（ORR）（阈值 ORR，15%；预期 ORR，40%）。
共纳入 32 例患者并进行了治疗。其中，22 例 HER2 阳性疾病患者构成主要疗效人群，确认的 ORR 为 36.4%（90%CI，19.6 至 56.1； =.01），达到了主要终点。8 例 HER2 低表达疾病患者构成探索性人群，确认的 ORR 为 12.5%。最常见的≥3 级治疗相关不良事件是贫血（53.1%）和中性粒细胞减少（31.3%）。8 例（25.0%）患者出现间质性肺病（ILD），包括 2 例 5 级事件。
T-DXd 对 HER2 阳性 BTC 患者具有良好的疗效，对 HER2 低表达 BTC 患者也有疗效信号。虽然总体安全性可控，但ILD 需要仔细监测和早期干预。
