Anampa Jesus D, Flynn Daniel L, Leary Cynthia, Oh Sun, Xue Xiaonan, Oktay Maja H, Condeelis John S, Sparano Joseph A
Department of Medical Oncology, Montefiore Einstein Comprehensive Cancer Center, Bronx, New York.
Deciphera Pharmaceuticals LLC, Waltham, Massachusetts.
Clin Cancer Res. 2025 Jan 17;31(2):266-277. doi: 10.1158/1078-0432.CCR-24-2464.
Breast cancer cells disseminate to distant sites via tumor microenvironment of metastasis (TMEM) doorways. The TIE2 inhibitor rebastinib blocks TMEM doorway function in the PyMT mouse model of breast cancer. We aimed to assess the safety and pharmacodynamics of rebastinib plus paclitaxel or eribulin in patients with HER2-negative metastatic breast cancer (MBC).
This phase Ib trial enrolled 27 patients with MBC who received 50 mg or 100 mg of rebastinib orally twice daily in combination with weekly paclitaxel 80 mg/m2 (if ≤2 prior non-taxane regimens) or eribulin 1.4 mg/m2 on days 1 and 8 (if ≥1 prior regimen). Safety, tolerability, and pharmacodynamic parameters indicating TIE2 kinase inhibition and TMEM doorway function were evaluated.
No dose-limiting toxicities in cycle 1 or 2 were observed among the first 12 patients at either rebastinib dose level. The most common treatment-emergent adverse events were anemia (85%), fatigue (78%), anorexia (67%), leukopenia (67%), increased alanine aminotransferase (59%), hyperglycemia (56%), nausea (52%), and neutropenia (52%). Adverse events attributed to rebastinib include muscular weakness and myalgias. Intraocular pressure increased at the 100-mg rebastinib dose level, whereas angiopoietin-2 levels increased at both dose levels, providing pharmacodynamic evidence for TIE2 blockade. Circulating tumor cells decreased significantly with the combined treatment. Objective response occurred in 5/23 (22%) evaluable patients.
In patients with MBC, the recommended phase II dose of rebastinib associated with pharmacodynamic evidence of TIE2 inhibition is either 50 or 100 mg orally twice daily in combination with paclitaxel or eribulin.
乳腺癌细胞通过转移瘤微环境（TMEM）通道扩散至远处部位。TIE2抑制剂瑞巴替尼可在PyMT乳腺癌小鼠模型中阻断TMEM通道功能。我们旨在评估瑞巴替尼联合紫杉醇或艾日布林用于人表皮生长因子受体2（HER2）阴性转移性乳腺癌（MBC）患者的安全性和药效学。
这项Ib期试验纳入了27例MBC患者，这些患者接受每日两次口服50mg或100mg瑞巴替尼，联合每周一次紫杉醇80mg/m²（若既往非紫杉烷类方案≤2种）或第1天和第8天静脉滴注艾日布林1.4mg/m²（若既往方案≥1种）。对表明TIE2激酶抑制和TMEM通道功能的安全性、耐受性及药效学参数进行了评估。
在前12例患者中，两个瑞巴替尼剂量水平在第1或2周期均未观察到剂量限制性毒性。最常见的治疗中出现的不良事件为贫血（85%）、疲劳（78%）、厌食（67%）、白细胞减少（67%）、丙氨酸转氨酶升高（59%）、高血糖（56%）、恶心（52%）和中性粒细胞减少（52%）。与瑞巴替尼相关的不良事件包括肌无力和肌痛。在瑞巴替尼100mg剂量水平时眼压升高，而两个剂量水平血管生成素-2水平均升高；这为TIE2阻断提供了药效学证据。联合治疗使循环肿瘤细胞显著减少。23例可评估患者中有5例（22%）出现客观缓解。
在MBC患者中，与TIE2抑制的药效学证据相关的瑞巴替尼II期推荐剂量为每日两次口服50mg或100mg，联合紫杉醇或艾日布林。
