Bellesoeur Audrey, Carton Edith, Mir Olivier, Groussin Lionel, Blanchet Benoit, Billemont Bertrand, Clerc Jérôme, Goldwasser François
CERIA, Centre for Research on Angiogenesis Inhibitors, Department of Medical Oncology, Cochin Teaching Hospital, AP-HP, Université Paris Descartes, 27, rue du faubourg Saint Jacques, 75014, Paris, France,
Invest New Drugs. 2014 Jun;32(3):569-72. doi: 10.1007/s10637-013-0052-7. Epub 2014 Jan 8.
Sorafenib, a multi-kinase inhibitor that targets the VEGF, PDGF and BRAF pathways, has demonstrated significant clinical activity in metastatic differentiated thyroid cancer. However, all patients eventually experience disease progression with a median progression-free survival close to 10 months. Since sorafenib exposure is known to decrease over time, we hypothesized that dose adjustments aiming to restore adequate exposure could lead to further clinical activity. We report, as a proof of concept on a patient with radio-iodine resistant metastatic thyroid cancer, who experienced disease progression after an initial response to sorafenib (400 mg twice daily). Whereas the thyroglobulin-progression-free survival at standard doses was 6 months, iterative dose optimization led to a prolonged progression-free survival up to 41 months. Sorafenib doses were increased up to 1600 mg bid, in order to maintain clinical activity, and to restore active plasma concentration, since sorafenib exposure had decreased over the time. Toxicity was mild and manageable for more than 2 years. However, the patient eventually experienced grade 3 proteinuria leading to treatment discontinuation. This observation opens up new horizons for daily management of radioactive iodine-refractory differentiated thyroid cancer patients progressing under standard doses of sorafenib, and stress the need to monitor its plasma concentration.
索拉非尼是一种靶向VEGF、PDGF和BRAF通路的多激酶抑制剂，已在转移性分化型甲状腺癌中显示出显著的临床活性。然而，所有患者最终都会出现疾病进展，无进展生存期的中位数接近10个月。由于已知索拉非尼的暴露量会随着时间的推移而减少，我们推测旨在恢复足够暴露量的剂量调整可能会带来进一步的临床活性。我们报告了一例放射性碘难治性转移性甲状腺癌患者的概念验证情况，该患者在对索拉非尼（每日两次，每次400mg）初始反应后出现疾病进展。标准剂量下无甲状腺球蛋白进展生存期为6个月，而迭代剂量优化使无进展生存期延长至41个月。由于索拉非尼的暴露量随时间减少，为了维持临床活性并恢复活性血浆浓度，索拉非尼剂量增加至每日两次，每次1600mg。毒性轻微，在两年多的时间里可控。然而，患者最终出现3级蛋白尿，导致治疗中断。这一观察结果为在标准剂量索拉非尼治疗下进展的放射性碘难治性分化型甲状腺癌患者的日常管理开辟了新的前景，并强调了监测其血浆浓度的必要性。
