Lessons learned: The combination of pexidartinib and binimetinib was safe and tolerable and demonstrated encouraging signs of efficacy in two patients with advanced gastrointestinal stromal tumor (GIST) refractory to tyrosine kinase inhibitors (TKIs).Molecular profiling of GISTs at diagnosis and upon progression may provide insight into the mechanisms of response or resistance to targeted therapies.Additional trials are needed to further explore combined KIT and MEK inhibition in treatment-naïve and TKI-refractory patients with advanced GIST.
Background: Nearly all patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Dual inhibition of KIT and MAPK pathways has synergistic antitumor activity in preclinical GIST models.
Methods: This was an investigator-initiated, phase I, dose escalation study of the MEK inhibitor binimetinib combined with pexidartinib, a potent inhibitor of CSF1R, KIT, and FLT3, in patients with advanced or metastatic GIST who progressed on imatinib. The primary endpoint was phase II dose determination; secondary endpoints included safety, tolerability, and efficacy. An expansion cohort to further evaluate safety and efficacy was planned.
Results: Two patients were treated at dose level one (binimetinib 30 mg b.i.d. and pexidartinib 400 mg every morning and 200 mg every evening), after which the study was terminated by the manufacturer. No dose-limiting toxicities (DLTs) were reported, and treatment was well tolerated. The only grade ≥3 treatment-emergent adverse event (TEAE) was asymptomatic elevated creatine phosphokinase (CPK). Both patients had a best response of stable disease (SD) by RECIST. Progression-free survival (PFS) and overall survival (OS) were 6.1 and 14.6 months, respectively, in one patient with five prior lines of therapy. The second patient with NF1-mutant GIST had a 27% decrease in tumor burden by RECIST and remains on study after 19 months of treatment.
Conclusion: Pexidartinib combined with binimetinib was tolerable, and meaningful clinical activity was observed in two imatinib-refractory patients.
经验总结
• 在两名对酪氨酸激酶抑制剂 (TKI) 不敏感的晚期胃肠道间质瘤 (GIST) 患者中，pexidartinib联合binimetinib用药具有安全性和可耐受性，并显现出具有一定疗效的迹象，令人振奋。
• 在诊断时及病情进展后对GIST的分子分析可能会就对靶向治疗的反应或抵抗机理提供宝贵意见。
• 还需开展其他试验以进一步研究抑制 KIT 和 MEK 的联合疗法对于从未接受治疗且酪氨酸激酶抑制剂难以控制的晚期GIST患者是否有效。
摘要
背景。几乎所有晚期胃肠道间质瘤 (GIST) 患者均对伊马替尼产生耐药性，而且随后的治疗效果有限。在临床前GIST模型中，对 KIT 和 MAPK 通路的双重抑制表现出协同抗肿瘤活性。
方法。这是一项由研究者发起的 I 期剂量递增研究，旨在评估 MEK 抑制剂binimetinib联合pexidartinib(一种针对 CSF1R、KIT 及 FLT3 蛋白的强效抑制剂)对经伊马替尼治疗后病情进展的晚期或转移性GIST患者是否有效。主要终点是第 II 阶段剂量测定；次要终点包括安全性、耐受性和疗效。计划扩增队列，以进一步评估疗效和安全性。
结果。两名患者接受了一级剂量治疗(binimetinib 30 mg，每日两次，pexidartinib每天早上 400 mg，每天晚上 200 mg)，之后，制造商终止了研究。无剂量限制性毒性 (DLT) 报告，治疗耐受性良好。唯一≥ 3 级的需紧急治疗的不良事件 (TEAE) 是无症状性肌酸磷酸激酶 (CPK) 升高。根据实体瘤疗效评定标准 (RECIST)，两名患者均出现了疾病稳定 (SD) 的最佳缓解。无进展生存期 (PFS) 和总生存期 (OS) 分别为 6.1 个月和 14.6 个月，其中一名患者既往接受了五线治疗。根据RECIST，另一名具有 NF1 突变的GIST患者肿瘤负荷降低了 27%，在接受治疗 19 个月后仍在参与研究。
结论。在采用伊马替尼难以控制的两名患者中，pexidartinib联合binimetinib呈现良好的耐受性，并观察到具有意义的临床活性。
Trial registration: ClinicalTrials.gov NCT03158103.
© AlphaMed Press; the data published online to support this summary are the property of the authors.