Introduction: Window of opportunity trials in malignant pleural mesothelioma (MPM) are challenging but can yield important translational information about a novel agent. Methods: We treated patients with MPM (N = 24) with 4 weeks of oral dasatinib followed by surgery with or without radiotherapy and then an optional 2 years of maintenance dasatinib. The primary end point was biomarker modulation of phosphorylated (p) SrcTyr419. Results: For all patients, the median progression‐free survival (PFS) was 7.5 months and the median overall survival was 19.1 months. No significant responses were seen after 4 weeks of dasatinib therapy; however, modulation of median p‐SrcTyr419 immunohistochemistry (IHC) scores was seen: the median pretreatment score was 70 (interquartile range 37.5–110), and the median posttreatment score was 41.9 (interquartile range 4.2–60) (p = 0.004). A decrease in p‐SrcTyr419 levels after dasatinib correlated with improved median PFS (6.9 months versus 0.94 months [p = 0.03]), suggesting that p‐SrcTyr419 is a viable pharmacodynamic biomarker for dasatinib in MPM. Platelet‐derived growth factor receptor (PDGFR) pathway analysis correlated high PDGFR beta [PDGFRB) level (in the cytoplasm [hazard ratio] (HR) = 2.54, p = 0.05], stroma [HR = 2.79, p = 0.03], and nucleus [HR = 6.79, p = 0.023]) with a shorter PFS. Low (less than the median) cytoplasmic p‐PDGFR alpha IHC levels were predictive of a decrease in positron emission tomography/computed tomography standard uptake values levels after dasatinib therapy (p = 0.04), whereas higher‐than‐median IHC scores of PDGFRB (cytoplasmic [HR = 2.8, p = 0.03] and nuclear [HR = 6.795, p = 0.02]) were correlated with rising standard uptake values levels. Conclusions: In conclusion, there was no significant efficacy signal, and dasatinib monotherapy will not continue to be studied in MPM. However, our study demonstrated that PDGFR subtypes (platelet‐derived growth factor receptor alpha and PDGFRB) may have differential roles in prognosis and resistance to antiangiogenic tyrosine kinase inhibitors and are important potential therapeutic targets that require further investigation.

中文翻译：

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生物标志物整合新辅助达沙替尼在可切除恶性胸膜间皮瘤中的试验

简介：恶性胸膜间皮瘤 (MPM) 的机会之窗试验具有挑战性，但可以产生有关新型药物的重要转化信息。方法：我们对 MPM 患者（N = 24）进行了 4 周的口服达沙替尼治疗，随后进行了有或没有放疗的手术，然后是可选的 2 年达沙替尼维持治疗。主要终点是磷酸化 (p) SrcTyr419 的生物标志物调节。结果：所有患者的中位无进展生存期 (PFS) 为 7.5 个月，中位总生存期为 19.1 个月。达沙替尼治疗 4 周后未见显着反应；然而，观察到 p-SrcTyr419 免疫组织化学 (IHC) 评分中位数的调节：治疗前评分中位数为 70（四分位距为 37.5-110），治疗后评分中位数为 41.9（四分位距为 4。2–60) (p = 0.004)。达沙替尼后 p-SrcTyr419 水平的降低与中位 PFS 的改善相关（6.9 个月对 0.94 个月 [p = 0.03]），表明 p-SrcTyr419 是 MPM 中达沙替尼的可行药效生物标志物。血小板衍生生长因子受体 (PDGFR) 通路分析与高 PDGFR β [PDGFRB) 水平相关（在细胞质中 [风险比] (HR) = 2.54，p = 0.05]，基质 [HR = 2.79，p = 0.03]，和核 [HR = 6.79, p = 0.023]) 具有较短的 PFS。低（低于中位数）细胞质 p​​-PDGFR α IHC 水平可预测达沙替尼治疗后正电子发射断层扫描/计算机断层扫描标准摄取值水平降低（p = 0.04），而高于中位数的 PDGFRB IHC 评分（细胞质 [HR = 2.8, p = 0.03] 和核 [HR = 6.795, p = 0。02]) 与标准摄取值水平的上升相关。结论：总之，没有显着的疗效信号，达沙替尼单药治疗不会继续在 MPM 中进行研究。然而，我们的研究表明，PDGFR 亚型（血小板衍生生长因子受体 α 和 PDGFRB）可能在预后和对抗血管生成酪氨酸激酶抑制剂的抵抗中具有不同的作用，并且是需要进一步研究的重要潜在治疗靶点。