Department of Thoracic/Head & Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
J Thorac Oncol. 2011 Dec;6(12):2104-11. doi: 10.1097/JTO.0b013e31822e7256.
Two phase II clinical trials in the aerodigestive tumors were undertaken to evaluate the efficacy of imatinib mesylate-docetaxel. We hypothesized that imatinib mesylate would inhibit platelet-derived growth factor receptor (PDGFR) on pericytes and increase docetaxel uptake into tumor cells for an additive antitumor effect. Baseline tumor specimens, serum, and perfusion computed tomography (CT) scans were obtained for supportive evaluation.
Eligible patients with metastatic non-small cell lung cancer (NSCLC) treated with 1 prior therapy and chemonaive patients with head and neck squamous cell carcinoma (HNSCC) were enrolled in separate trials, which administered both docetaxel (60 mg/m every 3 weeks) and oral imatinib mesylate (400 mg daily). Both trials used interim analyses for efficacy and safety.
Twenty-two patients with NSCLC and seven patients with HNSCC were enrolled. Both trials were closed early due to lack of efficacy, significant toxicity, and a potential antagonistic effect. In the NSCLC study, the response rate was 4.5%, median progression-free survival (PFS) 7.9 weeks, and overall survival 35.6 weeks. The HNSCC trial yielded a response rate 0%, PFS 8.8 weeks, and overall survival 34.7 weeks. Baseline NSCLC tumor immunohistochemical biomarker analyses indicated that lower expression of stromal PDGFRβ correlated with a better PFS, whereas stromal PDGFRα and tumor cell PDGFRβ were associated with a worse clinical outcome when treated with imatinib mesylate-docetaxel.
We do not recommend further investigation of this regimen in the aerodigestive tumors. Future investigations in PDGFR tyrosine kinase inhibitors should be used with caution in combination with taxanes and validation of the potential predictive or prognostic biomarkers stromal PDGFRα/β, and tumor cell PDGFRβ are needed.
在气消化道肿瘤中进行了两项 II 期临床试验，以评估甲磺酸伊马替尼联合多西紫杉醇的疗效。我们假设甲磺酸伊马替尼可以抑制周细胞上的血小板衍生生长因子受体（PDGFR），并增加肿瘤细胞内多西紫杉醇的摄取，从而产生相加的抗肿瘤作用。获得基线肿瘤标本、血清和灌注计算机断层扫描（CT）扫描以进行支持性评估。
招募了 22 名接受过 1 种治疗的转移性非小细胞肺癌（NSCLC）患者和 7 名头颈部鳞状细胞癌（HNSCC）的化疗初治患者，分别参加了两项试验，这两项试验都给予多西紫杉醇（60mg/m，每 3 周）和口服甲磺酸伊马替尼（400mg 每天）。这两项试验都进行了中期疗效和安全性分析。
共招募了 22 名 NSCLC 患者和 7 名 HNSCC 患者。由于疗效不佳、毒性显著和潜在拮抗作用，两项试验均提前关闭。在 NSCLC 研究中，反应率为 4.5%，中位无进展生存期（PFS）为 7.9 周，总生存期为 35.6 周。HNSCC 试验的反应率为 0%，PFS 为 8.8 周，总生存期为 34.7 周。基线 NSCLC 肿瘤免疫组织化学生物标志物分析表明，基质 PDGFRβ 的低表达与更好的 PFS 相关，而基质 PDGFRα 和肿瘤细胞 PDGFRβ 与接受甲磺酸伊马替尼联合多西紫杉醇治疗的不良临床结局相关。
我们不建议在气消化道肿瘤中进一步研究该方案。未来在 PDGFR 酪氨酸激酶抑制剂的研究中应谨慎使用，并需要验证潜在的预测或预后生物标志物基质 PDGFRα/β和肿瘤细胞 PDGFRβ。
