Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA.
UPMC Hillman Cancer Center and Magee-Womens Research Institute and Foundation, Pittsburgh, PA.
J Clin Oncol. 2024 Jul 20;42(21):2537-2545. doi: 10.1200/JCO.23.02076. Epub 2024 May 22.
The interleukin-6/Janus kinase (JAK)/signal transducers and activators of transcription 3 axis is a reported driver of chemotherapy resistance. We hypothesized that adding the JAK1/2 inhibitor ruxolitinib to standard chemotherapy would be tolerable and improve progression-free survival (PFS) in patients with ovarian cancer in the upfront setting.
Patients with ovarian/fallopian tube/primary peritoneal carcinoma recommended for neoadjuvant chemotherapy were eligible. In phase I, treatment was initiated with dose-dense paclitaxel (P) 70 mg/m once daily on days 1, 8, and 15; carboplatin AUC 5 intravenously day 1; and ruxolitinib 15 mg orally (PO) twice a day, every 21 days (dose level 1). Interval debulking surgery (IDS) was required after cycle 3. Patients then received three additional cycles of chemotherapy/ruxolitinib, followed by maintenance ruxolitinib. In the randomized phase II, patients were randomly assigned to paclitaxel/carboplatin with or without ruxolitinib at 15 mg PO twice a day for three cycles, IDS, followed by another three cycles of chemotherapy/ruxolitinib, without further maintenance ruxolitinib. The primary phase II end point was PFS.
Seventeen patients were enrolled in phase I. The maximum tolerated dose and recommended phase II dose were established to be dose level 1. One hundred thirty patients were enrolled in phase II with a median follow-up of 24 months. The regimen was well tolerated, with a trend toward higher grade 3 to 4 anemia (64% 27%), grade 3 to 4 neutropenia (53% 37%), and thromboembolic events (12.6% 2.4%) in the experimental arm. In the randomized phase II, the median PFS in the reference arm was 11.6 versus 14.6 in the experimental, hazard ratio (HR) for PFS was 0.702 (log-rank = .059). The overall survival HR was 0.785 ( = .24).
Ruxolitinib 15 mg PO twice a day was well tolerated with acceptable toxicity in combination with paclitaxel/carboplatin chemotherapy. The primary end point of prolongation of PFS was achieved in the experimental arm, warranting further investigation.
白细胞介素-6/Janus 激酶（JAK）/信号转导和转录激活因子 3 轴是报道的化疗耐药驱动因素。我们假设在新辅助化疗中将 JAK1/2 抑制剂芦可替尼（ruxolitinib）加入标准化疗中是可以耐受的，并能改善卵巢癌患者的无进展生存期（progression-free survival，PFS）。
适合新辅助化疗的卵巢/输卵管/原发性腹膜癌患者有资格入组。在 I 期，治疗起始时给予剂量密集型紫杉醇（paclitaxel，P）70mg/m 静脉推注，每日一次，第 1、8 和 15 天；卡铂 AUC 5 静脉滴注，第 1 天；芦可替尼 15mg 口服，每日两次，每 21 天一个周期（剂量水平 1）。第 3 个周期后需要进行间隔性肿瘤减灭术（interval debulking surgery，IDS）。患者随后接受三个周期的化疗/芦可替尼治疗，随后进行维持性芦可替尼治疗。在随机 II 期，患者随机分为接受紫杉醇/卡铂联合或不联合芦可替尼（po 15mg，每日两次）治疗三个周期，IDS，随后再进行三个周期的化疗/芦可替尼治疗，不再进行维持性芦可替尼治疗。主要的 II 期终点是 PFS。
17 例患者入组 I 期。确定最大耐受剂量和推荐的 II 期剂量为剂量水平 1。130 例患者入组 II 期，中位随访时间为 24 个月。该方案耐受性良好，实验组中 3 级至 4 级贫血（64% 27%）、3 级至 4 级中性粒细胞减少症（53% 37%）和血栓栓塞事件（12.6% 2.4%）的发生率呈上升趋势。在随机 II 期，参照组的中位 PFS 为 11.6 个月，实验组为 14.6 个月，PFS 的风险比（hazard ratio，HR）为 0.702（log-rank =.059）。总生存 HR 为 0.785（=.24）。
芦可替尼 15mg，po，每日两次，与紫杉醇/卡铂化疗联合应用耐受性良好，毒性可接受。实验组延长 PFS 的主要终点达到，需要进一步研究。
