Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
J Thorac Oncol. 2018 Feb;13(2):246-257. doi: 10.1016/j.jtho.2017.10.033. Epub 2017 Dec 5.
Window of opportunity trials in malignant pleural mesothelioma (MPM) are challenging but can yield important translational information about a novel agent.
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) Src.
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-Src 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-Src levels after dasatinib correlated with improved median PFS (6.9 months versus 0.94 months [p = 0.03]), suggesting that p-Src 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.
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.
恶性胸膜间皮瘤（MPM）的治疗窗口试验极具挑战性，但可以为新型药物提供重要的转化信息。
我们对 24 例 MPM 患者进行了 4 周的口服达沙替尼治疗，随后进行手术，可选择加用或不加用放疗，然后进行可选的 2 年达沙替尼维持治疗。主要终点是磷酸化（p）Src 的生物标志物调节。
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。在达沙替尼治疗 4 周后，未见明显缓解；然而，pSrc 免疫组织化学（IHC）评分的调节是可见的：中位预处理评分 70（四分位距 37.5-110），中位治疗后评分 41.9（四分位距 4.2-60）（p=0.004）。达沙替尼治疗后 pSrc 水平下降与中位 PFS 延长相关（6.9 个月比 0.94 个月，p=0.03），表明 pSrc 是 MPM 中达沙替尼的可行药效学生物标志物。血小板衍生生长因子受体（PDGFR）通路分析显示高 PDGFRB 水平（细胞质[危险比]（HR）=2.54，p=0.05）、基质（HR=2.79，p=0.03）和核（HR=6.79，p=0.023）与较短的 PFS 相关。细胞质 p-PDGFRα IHC 水平低于（低于中位数）与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相关（p=0.04），而 PDGFRB（细胞质[HR=2.8，p=0.03]和核[HR=6.795，p=0.02]）的 IHC 评分高于中位数与标准摄取值水平升高相关。
总之，达沙替尼单药治疗在 MPM 中没有显著的疗效信号，也不会继续研究。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）在预后和对抗血管生成酪氨酸激酶抑制剂的耐药性方面可能具有不同的作用，是需要进一步研究的重要潜在治疗靶点。
