Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Cancer. 2011 May 15;117(10):2112-9. doi: 10.1002/cncr.25769. Epub 2010 Nov 29.
Treatment options for patients with advanced head and neck squamous cell carcinoma (HNSCC) are scarce. This phase 2 study was conducted to evaluate the safety, tolerability, pharmacokinetics, and efficacy of dasatinib in this setting.
Patients with recurrent and/or metastatic HNSCC after platinum-based therapy were treated with dasatinib either orally or via percutaneous feeding gastrostomy (PFG). Primary endpoints were 12-week progression-free survival (PFS) and objective response rate with a 2-stage design and early withdrawal if the 12-week PFS rate was ≤20% and no patients had an objective response (OR). Forty-nine serum cytokines and angiogenic factors (CAFs) were analyzed from treated patients.
Of the 15 patients enrolled, 12 were evaluable for response, and all patients were evaluable for toxicity. No OR was observed and 2 patients (16.7%) had stable disease (SD) at 8 weeks. The median treatment duration was 59 days, the median time to disease progression was 3.9 weeks, and the median survival was 26 weeks. One patient required a dose reduction, 3 patients required dose interruptions, and 4 patients were hospitalized for toxicity. Dasatinib inhibited c-Src both when administered orally and via PFG. Greater mean drug exposure, decreased half-life, and greater maximum concentration were observed in patients receiving dasatinib via PFG. Eleven baseline CAFs were associated with treatment outcome and 1 CAF, macrophage migration inhibitory factor, was found to be differentially modulated in correlation with SD versus disease progression.
Single-agent dasatinib failed to demonstrate significant activity in patients with advanced HNSCC, despite c-Src inhibition. The toxicity profile was consistent with that reported in other solid tumors, and the drug can be given via PFG tube.
晚期头颈部鳞状细胞癌（HNSCC）患者的治疗选择有限。本Ⅱ期研究旨在评估达沙替尼在这种情况下的安全性、耐受性、药代动力学和疗效。
铂类治疗后复发和/或转移性 HNSCC 的患者接受达沙替尼口服或经皮胃造口管（PFG）给药。主要终点为 12 周无进展生存期（PFS）和客观缓解率（ORR），采用两阶段设计，若 12 周 PFS 率≤20%且无患者出现客观缓解（OR），则提前终止试验。对接受治疗的患者的 49 种血清细胞因子和血管生成因子（CAFs）进行了分析。
在入组的 15 例患者中，12 例可评估疗效，所有患者均可评估毒性。未观察到 OR，2 例患者（16.7%）在 8 周时疾病稳定（SD）。中位治疗持续时间为 59 天，中位疾病进展时间为 3.9 周，中位总生存期为 26 周。1 例患者需要减少剂量，3 例患者需要中断剂量，4 例患者因毒性住院。达沙替尼口服和 PFG 给药均可抑制 c-Src。接受 PFG 给药的患者药物暴露量更大、半衰期更短、最大浓度更高。11 种基线 CAFs 与治疗结果相关，1 种 CAF，即巨噬细胞移动抑制因子，与 SD 与疾病进展相关时被发现差异调节。
尽管抑制了 c-Src，但单药达沙替尼在晚期 HNSCC 患者中并未显示出显著的活性。毒性谱与其他实体瘤报道的一致，且可通过 PFG 管给药。
