Kloos Richard T, Ringel Matthew D, Knopp Michael V, Hall Nathan C, King Mark, Stevens Robert, Liang Jiachao, Wakely Paul E, Vasko Vasyl V, Saji Motoyasu, Rittenberry Jennifer, Wei Lai, Arbogast Daria, Collamore Minden, Wright John J, Grever Michael, Shah Manisha H
Ohio State University, Department of Internal Medicine, Molecular Virology, Immunology, and Genetics, Pathology, Radiology, Center for Biostatistics, Ohio State University, Columbus, OH 43210, USA.
J Clin Oncol. 2009 Apr 1;27(10):1675-84. doi: 10.1200/JCO.2008.18.2717. Epub 2009 Mar 2.
Based on the pivotal role of Ras-Raf-MAP-ERK signaling and vascular endothelial growth factor (VEGF) in papillary thyroid cancer (PTC), we conducted a phase II clinical trial of sorafenib targeting RAF and VEGF receptor kinases in PTC.
The primary end point was the objective response rate. Secondary end points included response correlation with serum thyroglobulin (Tg); functional imaging; tumor genotype; and signaling inhibition in tumor biopsies. Using a Simon minimax two-stage design, 16 or 25 chemotherapy-naïve metastatic PTC patients were to be enrolled in arm A (accessible tumor for biopsy). Arm B patients had other subtypes of thyroid carcinoma or prior chemotherapy, and did not require tumor biopsies. Patients received 400 mg orally twice per day of sorafenib. Response was assessed every 2 months using RECIST (Response Evaluation Criteria in Solid Tumors).
Of 41 PTC patients, six patients had a partial response (PR; 15%; 95% CI, 6 to 29) and 23 patients (56%; 95% CI, 40 to 72) had stable disease longer than 6 months. Median duration of PR was 7.5 months (range, 6 to 14). Median progression-free survival was 15 months (95% CI, 10 to 27.5). In 14 (78%) of 18 Tg-assessable PTC patients, Tg declined more than 25%. Common grade 3 adverse events included hand-foot skin reaction, musculoskeletal pain, and fatigue. BRAF mutation was detected in 17 (77%) of 22 PTCs analyzed. Four of 10 paired tumor biopsies from PTC patients showed a reduction in levels of vascular endothelial growth factor receptor phosphorylation, ERK phosphorylation, and in VEGF expression during sorafenib therapy. No PRs were noted among non-PTC patients.
Sorafenib is reasonably well-tolerated therapy with clinical and biologic antitumor activity in metastatic PTC.
基于Ras-Raf-MAP-ERK信号传导和血管内皮生长因子（VEGF）在甲状腺乳头状癌（PTC）中的关键作用，我们开展了一项索拉非尼针对PTC中RAF和VEGF受体激酶的II期临床试验。
主要终点为客观缓解率。次要终点包括缓解与血清甲状腺球蛋白（Tg）的相关性；功能成像；肿瘤基因型；以及肿瘤活检中的信号传导抑制。采用西蒙极小极大两阶段设计，16例或25例未经化疗的转移性PTC患者将被纳入A组（可进行活检的可及肿瘤）。B组患者患有其他甲状腺癌亚型或曾接受过化疗，且不需要进行肿瘤活检。患者口服索拉非尼，每日两次，每次400mg。每2个月使用实体瘤疗效评价标准（RECIST）评估缓解情况。
41例PTC患者中，6例患者出现部分缓解（PR；15%；95%CI，6%至29%），23例患者（56%；95%CI，40%至72%）疾病稳定超过6个月。PR的中位持续时间为7.5个月（范围，6至14个月）。中位无进展生存期为15个月（95%CI，10至27.5个月）。在18例可评估Tg的PTC患者中，14例（78%）的Tg下降超过25%。常见的3级不良事件包括手足皮肤反应、肌肉骨骼疼痛和疲劳。在分析的22例PTC中，17例（77%）检测到BRAF突变。10例PTC患者的配对肿瘤活检中有4例显示，索拉非尼治疗期间血管内皮生长因子受体磷酸化、ERK磷酸化水平以及VEGF表达降低。非PTC患者中未观察到PR。
索拉非尼耐受性良好，对转移性PTC具有临床和生物学抗肿瘤活性。
