美国马萨诸塞州总医院Lori J. Wirth团队研究了塞尔帕替尼治疗晚期RET突变型甲状腺髓样癌患者的疗效与安全性。2023年10月21日，《新英格兰医学杂志》发表了这一成果。

塞尔帕替尼是一种高选择性、有效的RET抑制剂，在1-2期临床试验中显示出对晚期RET突变型甲状腺髓样癌的疗效，但与已批准的多激酶抑制剂相比，其疗效尚不清楚。

研究组进行了一项3期随机临床试验，比较了塞尔帕替尼作为一线治疗与医生选择的卡博替尼或凡德他尼（对照组）。符合条件的患者在入组前14个月内有进展性疾病记录。方案指定的中期疗效分析的主要终点是无进展生存期，通过盲法独立中心评价进行评估。在疾病进展后，对照组患者中允许交叉使用塞尔帕替尼。无治疗失败生存期通过盲法独立中心来评价，是一个次要、α控制的终点，只有在无进展生存率显著时才进行测试。其他次要终点包括总体缓解和安全性。

共有291例患者接受随机分组。在中位随访12个月时，经盲法独立中心评价，塞尔帕替尼组未到达中位无进展生存期，而对照组为16.8个月（疾病进展或死亡的风险比为0.28）。塞尔帕替尼组12个月无进展生存率为86.8% ，对照组为65.7%。经盲法独立中心评价，塞尔帕替尼组未到达中位无治疗失败生存期，对照组为13.9个月（疾病进展、因治疗相关不良事件而停药或死亡的风险比为0.25）。塞尔帕替尼组12个月无治疗失败生存率为86.2%，对照组为62.1% 。塞尔帕替尼组总体缓解率为69.4%，对照组为38.8%。不良事件导致塞尔帕替尼组38.9%的患者剂量减少，而对照组为77.3%，两组分别有4.7%和26.8%的患者停止治疗。

研究结果表明，塞尔帕替尼治疗RET突变型甲状腺髓样癌患者的无进展生存期和无治疗失败生存期优于卡博替尼或凡德他尼。

附：英文原文

Title: Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer | NEJM

Author: anonymous

Issue&Volume: 2023-10-21

Abstract:

Background

Selpercatinib, a highly selective, potent RET inhibitor, has shown efficacy in advanced RET-mutant medullary thyroid cancer in a phase 1–2 trial, but its efficacy as compared with approved multikinase inhibitors is unclear.

Methods

We conducted a phase 3, randomized trial comparing selpercatinib as first-line therapy with the physician’s choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease documented within 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was progression-free survival, assessed by blinded independent central review. Crossover to selpercatinib was permitted among patients in the control group after disease progression. Treatment failure–free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if progression-free survival was significant. Among the other secondary end points were overall response and safety.

Results

A total of 291 patients underwent randomization. At a median follow-up of 12 months, median progression-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 16.8 months (95% confidence interval [CI], 12.2 to 25.1) in the control group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.16 to 0.48; P<0.001). Progression-free survival at 12 months was 86.8% (95% CI, 79.8 to 91.6) in the selpercatinib group and 65.7% (95% CI, 51.9 to 76.4) in the control group. Median treatment failure–free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 13.9 months in the control group (hazard ratio for disease progression, discontinuation due to treatment-related adverse events, or death, 0.25; 95% CI, 0.15 to 0.42; P<0.001). Treatment failure–free survival at 12 months was 86.2% (95% CI, 79.1 to 91.0) in the selpercatinib group and 62.1% (95% CI, 48.9 to 72.8) in the control group. The overall response was 69.4% (95% CI, 62.4 to 75.8) in the selpercatinib group and 38.8% (95% CI, 29.1 to 49.2) in the control group. Adverse events led to a dose reduction in 38.9% of the patients in the selpercatinib group, as compared with 77.3% in the control group, and to treatment discontinuation in 4.7% and 26.8%, respectively.

Conclusions

Selpercatinib treatment resulted in superior progression-free survival and treatment failure–free survival as compared with cabozantinib or vandetanib in patients with RET-mutant medullary thyroid cancer.

DOI: 10.1056/NEJMoa2309719

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2309719