Manji Gulam A, Stanton Liam J, Hirbe Angela C, Ge Liner, Sta Ana Sarah, Titus Shiny, Labadie Brian W, May Michael S, Lyu Yang, Chrisinger John S A, Sender Naomi, Monga Varun, Milhem Mohammed, Chugh Rashmi, Sims Peter, Tan Aik Choon, Lee Shing, Van Tine Brian A, Schwartz Gary K
Columbia University Irving Medical Center, New York, NY.
Herbert Irving Herbert Irving Comprehensive Cancer Center, New York, NY.
JCO Oncol Adv. 2025 Apr 25;2(1):e2400083. doi: 10.1200/OA-24-00083. eCollection 2025.
To evaluate the preliminary efficacy and safety of the combination of pexidartinib, an inhibitor of colony-stimulating factor-1 receptor (CSF1R), and sirolimus, a mammalian target of rapamycin inhibitor, to target infiltrating M2 macrophages in malignant peripheral nerve sheath tumors (MPNSTs).
This investigator-initiated, phase II, multicenter, single-arm trial enrolled patients with unresectable MPNSTs. Patients were treated with pexidartinib 1000 mg and sirolimus 2 mg orally daily. The primary end point was progression-free survival (PFS). Secondary end points included objective response, safety profile, and overall survival (OS). Pretreatment and on-treatment tumor biopsies were obtained to evaluate changes in the tumor microenvironment (TME) using multiplex immunofluorescence and differential transcriptional profiling.
Fifteen patients with MPNSTs were enrolled and 14 initiated therapy. Eight had neurofibromatosis type 1, five were sporadic, and one was undetermined. Although the target sample size was 25, because of the lower-than-expected accrual during the COVID-19 pandemic, enrollment was halted on April 12, 2023. The median PFS and median OS were 6 weeks (95% CI, 6 to 19.1) and 17.9 weeks (95% CI, 13.7 to not applicable), respectively. One patient achieved confirmed stable disease. Three patients experienced PFS ≥12 weeks. Grade 3 treatment-related toxicities (rash and leukopenia) occurred in four (28.6%) patients. Although the study did not meet its primary end point, correlative analysis demonstrated that four of the five long-term survivors had an immune-rich pretreatment TME, three of whom had a reduction in M2-tumor-associated macrophage signal with treatment.
Further studies of combination of pexidartinib and sirolimus and/or immunotherapy should be performed in the subset of patients with advanced MPNST with an immune-rich TME.
评估集落刺激因子-1受体（CSF1R）抑制剂培西达替尼与雷帕霉素靶蛋白抑制剂西罗莫司联合应用，以靶向恶性外周神经鞘瘤（MPNSTs）中浸润的M2巨噬细胞的初步疗效和安全性。
本由研究者发起的II期多中心单臂试验纳入了不可切除MPNSTs患者。患者接受每日口服培西达替尼1000 mg和西罗莫司2 mg治疗。主要终点为无进展生存期（PFS）。次要终点包括客观缓解、安全性概况和总生存期（OS）。获取治疗前和治疗期间的肿瘤活检样本，采用多重免疫荧光和差异转录谱分析评估肿瘤微环境（TME）的变化。
15例MPNSTs患者入组，14例开始治疗。8例患有1型神经纤维瘤病，5例为散发性，1例未确定。尽管目标样本量为25例，但由于在2019冠状病毒病大流行期间入组人数低于预期，于2023年4月12日停止入组。中位PFS和中位OS分别为6周（95%CI，6至19.1）和17.9周（95%CI，13.7至不适用）。1例患者达到确认的疾病稳定。3例患者的PFS≥12周。4例（28.6%）患者发生3级治疗相关毒性（皮疹和白细胞减少）。尽管该研究未达到其主要终点，但相关性分析表明，5例长期存活者中有4例在治疗前TME富含免疫细胞，其中3例在治疗后M2肿瘤相关巨噬细胞信号减少。
对于晚期MPNST且TME富含免疫细胞的患者亚组，应进一步开展培西达替尼与西罗莫司联合和/或免疫治疗的研究。
