Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden
Theme Cancer, Karolinska University Hospital, Solna, Sweden.
Oncologist. 2019 Jun;24(6):745-e213. doi: 10.1634/theoncologist.2018-0795. Epub 2018 Dec 14.
First trial to report safety and activity of the microtubule inhibitor vinflunine plus the tyrosine kinase inhibitor sorafenib in post-platinum metastatic urothelial cancer (mUC) patients.A recommended phase II dose was identified for the treatment combination of vinflunine plus sorafenib, with main adverse events including fatigue, febrile neutropenia, neutropenia, hypertension, and hyponatremia.An overall response rate of 41% to second-line vinflunine plus sorafenib treatment in patients with platinum-resistant mUC was confirmed.
Platinum-progressive metastatic urothelial carcinoma (mUC) is a clinical challenge. The tyrosine kinase inhibitor sorafenib has demonstrated varied activity in mUC. This trial was designed to examine safety and activity of vinflunine plus sorafenib in mUC.
In addition to standard dose of vinflunine (320 or 280 mg/m), patients received sorafenib (400, 600, or 800 mg/day), in a 3 + 3 dose-escalation phase I design.
Twenty-two patients (median age 62.5 years) were included. Five patients received vinflunine 320 mg/m and 17 received 280 mg/m. The maximum tolerated dose (MTD) of sorafenib with vinflunine 280 mg/m was 600 mg, and with vinflunine 320 mg/m it was not determined, owing to toxicity. Adverse events (AEs) grades 3 + 4 consisted of neutropenia (6 patients), febrile neutropenia (5), and hyponatremia (5). The overall response rate (ORR) in the efficacy-evaluable patients was 41% (7 of 17), all partial responses evaluated by RECIST version 1.1. Median overall survival (OS) was 7.0 months (1.8-41.7).
The defined recommended phase II dose (RPTD) was vinflunine 280 mg/m plus sorafenib 400 mg. Sorafenib was too toxic in combination with vinflunine 320 mg/m. The ORR of 41% to this second-line combination treatment of mUC is noteworthy and supports further trials.
首次报道微管抑制剂vinflunine 联合酪氨酸激酶抑制剂 sorafenib 治疗铂类耐药转移性尿路上皮癌（mUC）患者的安全性和疗效。确定了 vinflunine 联合 sorafenib 的治疗组合的推荐 II 期剂量，主要不良反应包括乏力、发热性中性粒细胞减少症、中性粒细胞减少症、高血压和低钠血症。在铂类耐药 mUC 患者中，二线 vinflunine 联合 sorafenib 治疗的总缓解率为 41%。
铂类进展性转移性尿路上皮癌（mUC）是一个临床挑战。酪氨酸激酶抑制剂 sorafenib 在 mUC 中显示出不同的活性。该试验旨在研究 vinflunine 联合 sorafenib 在 mUC 中的安全性和疗效。
除了标准剂量的 vinflunine（320 或 280 mg/m）外，患者还接受 sorafenib（400、600 或 800 mg/天）治疗，采用 3+3 剂量递增设计。
共纳入 22 例患者（中位年龄 62.5 岁）。5 例患者接受 vinflunine 320 mg/m，17 例患者接受 280 mg/m。vinflunine 280 mg/m 联合 sorafenib 的最大耐受剂量（MTD）为 600 mg，而 vinflunine 320 mg/m 的 MTD 尚未确定，因为毒性。3+4 级不良事件（AE）包括中性粒细胞减少症（6 例）、发热性中性粒细胞减少症（5 例）和低钠血症（5 例）。疗效可评估患者的总缓解率（ORR）为 41%（17 例中的 7 例），所有完全缓解均由 RECIST 版本 1.1 评估。中位总生存期（OS）为 7.0 个月（1.8-41.7）。
确定的推荐 II 期剂量（RPTD）为 vinflunine 280 mg/m 联合 sorafenib 400 mg。vinflunine 320 mg/m 联合 sorafenib 毒性太大。二线组合治疗 mUC 的缓解率为 41%，这值得进一步研究。
