Phase II Trial of Sorafenib in Metastatic Thyroid Cancer
Phase II Trial of Sorafenib in Metastatic Thyroid Cancer
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DOI：
10.1200/jco.2008.18.2717
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发表时间：
2009-04-01
影响因子：
45.3
通讯作者：
Shah, Manisha H.
中科院分区：
文献类型：
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作者：
Kloos, Richard T.;Ringel, Matthew D.;Shah, Manisha H.
目的基于Ras-Raf-MAP-ERK信号通路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，我们进行了一项针对RAF和VEGF受体激酶的索拉非尼在PTC中的II期临床试验。次要终点包括与血清甲状腺球蛋白（Tg）的反应相关性;功能成像;肿瘤基因型;和肿瘤活检中的信号抑制。采用Simon最小最大两阶段设计，16或25例未经化疗的转移性PTC患者入组A组（可触及肿瘤进行活检）。B组患者有其他亚型的甲状腺癌或既往化疗，不需要肿瘤活检。患者每天口服两次索拉非尼，每次400 mg。结果41例PTC患者中，6例部分缓解（PR; 15%，95%CI，6 ~ 29），23例稳定期超过6个月（56%，95%CI，40 ~ 72）。PR的中位持续时间为7.5个月（范围，6至14）。中位无进展生存期为15个月（95% CI，10 - 27.5）。在18例Tg可评估的PTC患者中，有14例（78%）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个PTC中的17个（77%）中检测到BRAF突变。在索拉非尼治疗过程中，10例PTC患者的配对肿瘤活检中有4例显示血管内皮生长因子受体磷酸化、ERK磷酸化和VEGF表达水平降低。在非PTC patients.ConclusionSorafenib是合理的耐受性良好的治疗转移性PTC的临床和生物学抗肿瘤活性。
PurposeBased 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.Patients and MethodsThe 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 chemotherapynaive 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).ResultsOf 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.ConclusionSorafenib is reasonably well-tolerated therapy with clinical and biologic antitumor activity in metastatic PTC.