Efficacy of Selpercatinib in RET-Altered Thyroid Cancers
Efficacy of Selpercatinib in RET-Altered Thyroid Cancers
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DOI：
10.1056/nejmoa2005651
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发表时间：
2020-08-27
影响因子：
158.5
通讯作者：
Cabanillas, M. E.
中科院分区：
文献类型：
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作者：
Wirth, L. J.;Sherman, E.;Cabanillas, M. E.
背景：70%的甲状腺髓样癌发生RET突变，RET融合在其他甲状腺癌中很少发生。在RET改变的甲状腺癌患者中，选择性RET抑制的有效性和安全性尚不清楚。方法：我们在selpercatinib的1-2期试验中招募了RET突变型甲状腺髓样癌患者，这些患者既往接受过或未接受过vandetanib或cabozantinib治疗，以及既往接受过RET融合阳性甲状腺癌治疗的患者。主要终点是客观反应（完全或部分反应），由独立审查委员会确定。次要终点包括反应持续时间、无进展生存期和安全性。结果：在前55名连续入组的ret突变型甲状腺髓样癌患者中，先前接受过万德替尼、卡博赞替尼或两者同时接受治疗的患者中，有应答的百分比为69%(95%可信区间[CI]， 55至81)，1年无进展生存率为82% （95% CI， 69至90）。88例ret突变型甲状腺髓样癌患者此前未接受万德替尼或卡博赞替尼治疗，缓解率为73% (95% CI, 62 - 82)， 1年无进展生存率为92% （95% CI, 82 - 97）。在19例先前接受过RET融合阳性甲状腺癌治疗的患者中，有应答的百分比为79% (95% CI, 54 - 94)， 1年无进展生存率为64% （95% CI, 37 - 82）。3级及以上最常见的不良事件是高血压（21%）、谷丙转氨酶升高（11%）、天冬氨酸转氨酶升高（9%）、低钠血症（8%）和腹泻（6%）。在所有接受治疗的531例患者中，12例（2%）由于药物相关不良事件而停用自泊卡替尼。结论：在这项1-2期试验中，selpercatinib对既往接受过或未接受过vandetanib或cabozantinib治疗的甲状腺髓样癌患者显示出持久的疗效，主要是低度毒性作用。
BACKGROUND RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown.METHODS We enrolled patients with RET-mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated RET fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.RESULTS In the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events.CONCLUSIONS In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly lowgrade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment.