Efficacy and safety of fruquintinib-based treatment in patients with refractory bone and soft tissue sarcomas after developing resistance to several TKIs: A multicentered retrospective study.
Authors: Li Binghao , Yang Chenchen , Xu Jie , Sun Xin , Liang Xin , Liu Kuisheng , Yang Yi , Ji Tao , Xie Lu , Ye Zhaoming , Tang Xiaodong 
Published: June 2024

11528 Background: Multi-targeted tyrosine kinase inhibitors (TKIs) have been approved as the second-line therapy for refractory bone and soft tissue sarcomas, prolonging progression-free survival (PFS) but with still limited duration of disease control. Fruquintinib is a highly selective TKI that inhibits vascular endothelial growth factor receptor (VEGFR)-1,2,3 without undergoing metabolism by liver enzymes. This retrospective study assessed the efficacy and safety of fruquintinib-based treatment in refractory bone and soft tissue sarcomas after multiple lines of TKIs. Methods: This study included patients with refractory bone and soft tissue sarcomas, who had developed several lines of resistance to TKIs and then received fruquintinib-based treatment from November 2021 to August 2023. The primary endpoint was the PFS rate at 4 months (4m-PFSR). Secondary endpoints included PFS, overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Results: We included 124 patients from two Chinese centers: 56 (45.2%) osteosarcoma, 28 (22.6%) Ewing sarcoma, 7 (5.6%) chondrosarcoma, and 33 (26.6%) soft tissue sarcomas. Among them, 72 (58.1%) patients had target lesions limited to the lung and bone. The median age was 21 (interquartile range [IQR], 12-39) years. Seventy-three (58.8%) patients previously had four or more lines of therapy. All patients had received TKI treatment, and among them, 19 (15.3%) had used more than two lines of TKIs. During fruquintinib treatment, 18 (14.5%) patients received monotherapy, 34 (27.4%) combined with albumin-bound paclitaxel, 31 (25.0%) combined with irinotecan or topotecan, and 15 (12.1%) combined with programmed cell death 1/programmed cell death-ligand 1 (PD1/PD-L1) inhibitors. With a median follow-up time of 6.8 (IQR, 4.6-9.4) months, 22 (17.7%) patients had partial response (PR) and 78 (62.9%) were in stable disease (SD). 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 (HR) of 1.79 (95% CI, 1.10-2.93; P=0.020) for progression or death was associated with target lesions located outside lung and bone. 88 AEs were recorded in 47(37.9%) patients and the most common were pneumothorax (18/124, 14.5%), diarrhea (8/124, 6.5%), mucositis oral (7/124, 5.6%), and thrombocytopenia (7/124, 5.6%). Conclusions: Fruquintinib demonstrated as an potential option for patients with refractory bone and soft tissue sarcomas after developing resistance to several TKIs, with satisfactory efficacy and safety profile when used in combination therapy. More prospective trials on fruquintinib are needed, especially on different pathological types and diverse combination regimens. Clinical trial information: NCT06202599 .