目的:多靶向酪氨酸激酶抑制剂(TKIs)已被批准为难治性肉瘤的二线治疗,延长无进展生存期(PFS),但疾病控制持续时间短。Fruquintinib是一种TKI,可特异性抑制血管内皮生长因子受体-1,2,3,而不会被肝酶代谢。在这项回顾性研究中,我们评估了以氟喹替尼为基础的治疗在出现多系TKI耐药后的难治性肉瘤患者中的疗效和安全性.
方法:我们回顾性分析了在2021年11月至2023年8月对TKIs产生数种耐药并接受基于氟喹替尼的治疗的难治性肉瘤患者的临床资料。主要终点是4个月时的无进展生存率(4m-PFSR)。次要终点是中位PFS,总生存期(OS),客观反应率,疾病控制率,和不良反应(AE)。使用Kaplan-Meier方法估计PFS和OS。使用对数秩检验比较不同临床和病理因素之间的生存曲线。进行Cox比例风险分析以确定PFS相关的预后因素。
结果:我们纳入了124例患者:56例(45.2%)骨肉瘤,28例(22.6%)尤因肉瘤,7人(5.6%)患有软骨肉瘤,33例(26.6%)伴有软组织肉瘤(STS)。只有18例(14.5%)患者接受了氟喹替尼的单药治疗。中位随访时间为6.8(四分位数间距[IQR],4.6-9.4)个月,22例(17.7%)患者部分缓解,78例(62.9%)患者病情稳定。4m-PFSR为58.4%(95%置信区间[CI],49.6%-67.1%)。中位PFS和OS分别为4.4(95%CI,3.9-5.0)个月和11.4(95%CI,10.3-12.5)个月。在多变量分析中,进展的高风险比与位于肺和骨外的靶病变相关,为1.79(95%CI,1.10~2.93;p=0.020).在47例(37.9%)患者中记录了88例不良事件;最常见的是气胸(18/124,14.5%),腹泻(8/124,6.5%),口腔黏膜炎(7/124,5.6%),和血小板减少(7/124,5.6%)。
结论:Fruquintinib可能是难治性肉瘤患者出现多系TKI耐药后的潜在选择,在联合治疗中具有令人满意的疗效和安全性。然而,与其他有效物质联用时,氟喹替尼对结果的贡献程度尚不清楚.应该进行更多的氟喹替尼的前瞻性试验,特别是涉及不同的病理类型和联合治疗方案。
OBJECTIVE: Multitargeted tyrosine kinase inhibitors (TKIs) have been approved as second-line therapy in refractory sarcoma, prolonging progression-free survival (PFS) but with short-lived duration of disease control.
Fruquintinib is a TKI that specifically inhibits vascular endothelial growth factor receptor-1,2,3 with no metabolism by liver enzymes. In this retrospective study, we assessed the efficacy and safety of
fruquintinib-based treatment in patients with refractory sarcoma after developing several lines of TKI resistance.
METHODS: We retrospectively analyzed the clinical data of patients with refractory sarcoma after they had developed several lines of resistance to TKIs and who received fruquintinib-based treatment from November 2021 to August 2023. The primary endpoint was the progression-free survival rate at 4 months (4m-PFSR). Secondary endpoints were the median PFS, overall survival (OS), objective response rate, disease control rate, and adverse effects (AEs). PFS and OS were estimated using the Kaplan-Meier method. A log-rank test was used to compare survival curves between different clinical and pathological factors. Cox proportional hazards analysis was performed to identify PFS-related prognostic factors.
RESULTS: We included 124 patients: 56 (45.2%) with osteosarcoma, 28 (22.6%) with Ewing sarcoma, seven (5.6%) with chondrosarcoma, and 33 (26.6%) with soft tissue sarcomas (STS). Only 18 (14.5%) patients received monotherapy with
fruquintinib. With a median follow-up time of 6.8 (interquartile range [IQR], 4.6-9.4) months, 22 (17.7%) patients had partial response and 78 (62.9%) had stable disease. The 4m-PFSR was 58.4% (95% confidence interval [CI], 49.6%-67.1%). The median PFS and OS were 4.4 (95% CI, 3.9-5.0) months and 11.4 (95% CI, 10.3-12.5) months. In multivariate analysis, a high hazard ratio for progression was associated with target lesions located outside the lung and bone with 1.79 (95% CI, 1.10-2.93; p = 0.020). Eighty-eight AEs were recorded in 47 (37.9%) patients; the most common were pneumothorax (18/124, 14.5%), diarrhea (8/124, 6.5%), oral mucositis (7/124, 5.6%), and thrombocytopenia (7/124, 5.6%).
CONCLUSIONS: Fruquintinib may be a potential option for patients with refractory sarcoma after developing several lines of TKI resistance, with a satisfactory efficacy and safety profile in combination therapy. However, the degree of contribution of
fruquintinib to results is unclear when combined with other effective substances. Additional prospective trials of fruquintinib should be conducted, especially involving different pathological types and combination regimens.