塞尔帕替尼治疗晚期突变型甲状腺髓样癌的 3 期临床试验。

Phase 3 Trial of Selpercatinib in Advanced -Mutant Medullary Thyroid Cancer.

机构信息

From the Service d'oncologie endocrinienne, département d'imagerie, Gustave Roussy and ENDOCAN-TUTHYREF Network, Villejuif (J.H.), and the Nuclear Medicine Department and Thyroid Unit, Centre François Baclesse, Caen (S.B.) - both in France; the Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy (R.E.); the Department of Medical Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia (M.S.B.); the Department of Endocrinology, Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, and Instituto D'Or de Pesquisa e Ensino - both in São Paulo (A.O.H.); Sydney Medical School, University of Sydney, Sydney (B.G.R.); the Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China (M.G.); the Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska Curie National Research Institute of Oncology, Gliwice Branch, Poland (B.J.); Federal State Institution Medical Radiology Research Center, Obninsk, Russia (P.I.); the Department of Oncology, 2nd Faculty of Medicine of Charles University and Motol University Hospital, Prague, Czech Republic (K.K.); the Clinical Oncology Department, Weston Park Cancer Center, NHS Foundation Trust, Sheffield, United Kingdom (J.W.); the Department of Endocrinology Diabetology and Metabolism, Endocrine Tumour Center at West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany (D.F.); the Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea (B.K.); the Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York (E.J.S.); the Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan (M.T.); the Endocrine Neoplasia and Hormonal Disorders Department, University of Texas M.D. Anderson Cancer Center, Houston (M.I.H.); Eli Lilly, Indianapolis (R.S., Y.L., V.S., J.W., B.L., P.M.); the Medical Oncology Department, Vall d'Hebron Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona (J.C.); and the Cancer Center, Massachusetts General Hospital, Boston (L.J.W.).

出版信息

N Engl J Med. 2023 Nov 16;389(20):1851-1861. doi: 10.1056/NEJMoa2309719. Epub 2023 Oct 21.

DOI:10.1056/NEJMoa2309719

PMID:37870969

Abstract

BACKGROUND

Selpercatinib, a highly selective, potent RET inhibitor, has shown efficacy in advanced -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 -mutant medullary thyroid cancer. (Funded by Loxo Oncology, a subsidiary of Eli Lilly; LIBRETTO-531 ClinicalTrials.gov number, NCT04211337.).

摘要

背景

Selpercatinib 是一种高度选择性、强效的 RET 抑制剂，在一项 1-2 期临床试验中显示出对晚期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。

方法

我们进行了一项 3 期随机试验，比较了 Selpercatinib 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的记录。方案规定的中期疗效分析的主要终点是盲法独立中心评估的无进展生存期。在疾病进展后，对照组的患者可以交叉使用 Selpercatinib。如果无进展生存期有显著差异，治疗失败无进展生存期（盲法独立中心评估）将作为次要的、alpha 控制的终点进行测试。其他次要终点包括总缓解率和安全性。

结果

共有 291 名患者接受了随机分组。在中位随访 12 个月时，Selpercatinib 组的盲法独立中心评估的中位无进展生存期未达到，为 16.8 个月（95%置信区间[CI]，12.2 至 25.1），对照组为 16.8 个月（95%CI，12.2 至 25.1）（疾病进展或死亡的风险比，0.28；95%CI，0.16 至 0.48；P<0.001）。Selpercatinib 组 12 个月时的无进展生存率为 86.8%（95%CI，79.8%至 91.6%），对照组为 65.7%（95%CI，51.9%至 76.4%）。Selpercatinib 组的盲法独立中心评估的中位治疗失败无进展生存期未达到，对照组为 13.9 个月（疾病进展、因治疗相关不良事件停药或死亡的风险比，0.25；95%CI，0.15 至 0.42；P<0.001）。Selpercatinib 组 12 个月时的治疗失败无进展生存率为 86.2%（95%CI，79.1%至 91.0%），对照组为 62.1%（95%CI，48.9%至 72.8%）。总缓解率为 69.4%（95%CI，62.4%至 75.8%），对照组为 38.8%（95%CI，29.1%至 49.2%）。Selpercatinib 组有 38.9%的患者因不良反应而减少剂量，而对照组为 77.3%，分别有 4.7%和 26.8%的患者因不良反应而停止治疗。