Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.
Chungbuk National University College of Medicine, Cheongju, South Korea.
Gastric Cancer. 2019 Nov;22(6):1206-1214. doi: 10.1007/s10120-019-00958-4. Epub 2019 Apr 3.
Poziotinib (HM781-36B) is an irreversible pan-HER tyrosine kinase inhibitor which targets EGFR, HER2, and HER4. This prospective, multicenter, open-label, phase I/II study determined the maximum tolerated dose (MTD) and evaluated the safety and efficacy of poziotinib combined with paclitaxel and trastuzumab in patients with HER2-positive advanced gastric cancer (GC).
Patients with HER2-positive GC previously treated with one line of chemotherapy received oral poziotinib (8 mg or 12 mg) once daily for 14 days, followed by 7 days off. Paclitaxel (175 mg/m infusion) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg infusion) were administered concomitantly with poziotinib on day 1 every 3 weeks.
In the phase I part, 12 patients were enrolled (7 at dose level 1, 5 at dose level 2). One patient receiving poziotinib 8 mg and 2 receiving poziotinib 12 mg had dose-limiting toxicities (DLTs); all DLTs were grade 4 neutropenia, one with fever. The most common poziotinib-related adverse events were diarrhea, rash, stomatitis, pruritus and loss of appetite. The MTD of poziotinib was determined to be 8 mg/day and this was used in the phase II part which enrolled 32 patients. Two patients (6.3%) had complete responses and 5 (15.6%) had partial responses (objective response rate 21.9%). Median progression-free survival and overall survival were 13.0 weeks (95% CI 9.8-21.9) and 29.5 weeks (95% CI 17.9-59.2), respectively.
The MTD of poziotinib combined with paclitaxel and trastuzumab was 8 mg/day. This combination yielded promising anti-tumor efficacy with manageable toxicity in previously treated patients with HER2-positive GC.
波齐替尼（HM781-36B）是一种不可逆的泛 HER 酪氨酸激酶抑制剂，针对 EGFR、HER2 和 HER4。这项前瞻性、多中心、开放标签、I/II 期研究确定了最大耐受剂量（MTD），并评估了先前接受过一线化疗的 HER2 阳性晚期胃癌（GC）患者中波齐替尼联合紫杉醇和曲妥珠单抗的安全性和疗效。
先前接受过一线化疗的 HER2 阳性 GC 患者接受口服波齐替尼（8mg 或 12mg），每日一次，连用 14 天，然后停药 7 天。紫杉醇（175mg/m 输注）和曲妥珠单抗（8mg/kg 负荷剂量，然后 6mg/kg 输注）在每 3 周的第 1 天与波齐替尼同时给药。
在 I 期部分，入组 12 例患者（剂量水平 1 组 7 例，剂量水平 2 组 5 例）。1 例接受波齐替尼 8mg 和 2 例接受波齐替尼 12mg 的患者出现剂量限制毒性（DLT）；所有 DLT 均为 4 级中性粒细胞减少症，其中 1 例伴有发热。最常见的波齐替尼相关不良事件为腹泻、皮疹、口腔炎、瘙痒和食欲下降。波齐替尼的 MTD 确定为 8mg/天，这一剂量用于入组 32 例患者的 II 期部分。2 例患者（6.3%）完全缓解，5 例患者（15.6%）部分缓解（客观缓解率 21.9%）。中位无进展生存期和总生存期分别为 13.0 周（95%CI 9.8-21.9）和 29.5 周（95%CI 17.9-59.2）。
波齐替尼联合紫杉醇和曲妥珠单抗的 MTD 为 8mg/天。在先前接受过治疗的 HER2 阳性 GC 患者中，该联合方案具有良好的抗肿瘤疗效和可管理的毒性。
