Tsao Anne S, Harun Nusrat, Lee J Jack, Heymach John, Pisters Katherine, Hong Waun Ki, Fujimoto Junya, Wistuba Ignacio
Department of Thoracic, Head, and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Clin Lung Cancer. 2014 May;15(3):197-201. doi: 10.1016/j.cllc.2013.12.008. Epub 2013 Dec 27.
We conducted a phase I trial of cisplatin/pemetrexed/imatinib mesylate, an oral platelet-derived growth factor receptor (PDGFR) inhibitor, in chemonaive patients with malignant pleural mesothelioma (MPM).
A standard 3 + 3 dose-escalating trial was used with the end points of maximum tolerated dose (MTD), response rate, survival, safety/toxicity, and tumor PDGFR levels.
Seventeen patients with MPM were enrolled. The most common (any grade) side effects were nausea, fatigue, hypomagnesemia, and anemia. The MTD was established at dose level 3 (imatinib 600 mg) with a dose-limiting toxicity (DLT) of nausea and vomiting. The median progression-free survival (PFS) was 7.9 months and the median overall survival (OS) was 8.8 months. Patients with a sarcomatoid subtype had worse PFS (P = .01) and OS (P = .009), whereas they had a better Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 predicted for improved OS (P = .001) and PFS (P = .013). The 6 patients who completed all 6 treatment cycles had better OS (P = .006); the median PFS was 9.6 months and the OS was 22.4 months. In the translational studies, 14 patients had adequate tumor tissue that could be assessed for immunohistochemical (IHC) analysis and fluorescence in situ hybridization (FISH). Patients with higher than median p-PDGFRα IHC expression had a better OS (P = .013). When assessed as a continuous variable, higher p-PDGFRα in tumor cells correlated with an improved OS (P = .045). None of the other 4 IHC biomarkers were predictive or prognostic for survival. Twelve patients had successful PDGFRB FISH results, but none met the criteria of ≥ 4 copies of the PDGFRB gene; thus a correlation with clinical outcomes could not be done.
The cisplatin/pemetrexed/imatinib mesylate combination had clinical benefit in some patients with MPM but was not well tolerated. Further investigation into alternative antiangiogenic agents, including PDGFRα inhibitors, is warranted.
我们对顺铂/培美曲塞/甲磺酸伊马替尼（一种口服血小板衍生生长因子受体（PDGFR）抑制剂）进行了I期试验，受试对象为未经化疗的恶性胸膜间皮瘤（MPM）患者。
采用标准的3 + 3剂量递增试验，终点指标为最大耐受剂量（MTD）、缓解率、生存率、安全性/毒性以及肿瘤PDGFR水平。
17例MPM患者入组。最常见的（任何级别）副作用为恶心、疲劳、低镁血症和贫血。MTD确定为剂量水平3（伊马替尼600 mg），剂量限制性毒性（DLT）为恶心和呕吐。中位无进展生存期（PFS）为7.9个月，中位总生存期（OS）为8.8个月。肉瘤样亚型患者的PFS（P = 0.01）和OS（P = 0.009）较差，而其东部肿瘤协作组体能状态（ECOG PS）为0 - 1，提示OS（P = 0.001）和PFS（P = 0.013）可能改善。完成所有6个治疗周期的6例患者的OS较好（P = 0.006）；中位PFS为9.6个月，OS为22.4个月。在转化研究中，14例患者有足够的肿瘤组织可进行免疫组织化学（IHC）分析和荧光原位杂交（FISH）。p - PDGFRα IHC表达高于中位数的患者的OS较好（P = 0.013）。当作为连续变量评估时，肿瘤细胞中较高的p - PDGFRα与改善的OS相关（P = 0.045）。其他4种IHC生物标志物均不能预测或预后生存情况。12例患者的PDGFRB FISH结果成功，但均未达到PDGFRB基因≥4拷贝的标准；因此无法进行与临床结局的相关性分析。
顺铂/培美曲塞/甲磺酸伊马替尼联合方案对部分MPM患者有临床获益，但耐受性不佳。有必要进一步研究包括PDGFRα抑制剂在内的其他抗血管生成药物。
