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

被引:64
|
作者
Hadoux, J. [1 ,2 ]
Elisei, R. [5 ]
Brose, M. S. [6 ]
Hoff, A. O. [7 ,8 ]
Robinson, B. G. [9 ]
Gao, M. [10 ]
Jarzab, B. [11 ]
Isaev, P. [12 ]
Kopeckova, K. [13 ,14 ]
Wadsley, J. [15 ]
Fuehrer, D. [16 ]
Keam, B. [17 ]
Bardet, S. [3 ,4 ]
Sherman, E. J. [18 ]
Tahara, M. [19 ]
Hu, M. I. [20 ]
Singh, R. [21 ]
Lin, Y. [21 ]
Soldatenkova, V [21 ]
Wright, J. [21 ]
Lin, B. [21 ]
Maeda, P. [21 ]
Capdevila, J. [22 ]
Wirth, L. J. [23 ]
机构
[1] Gustave Roussy, Dept Imagerie, Serv Oncol Endocrinienne, Villejuif, France
[2] ENDOCAN TUTHYREF Network, Villejuif, France
[3] Ctr Francois Baclesse, Nucl Med Dept, Caen, France
[4] Ctr Francois Baclesse, Thyroid Unit, Caen, France
[5] Univ Pisa, Dept Clin & Expt Med, Endocrine Unit, Pisa, Italy
[6] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Dept Med Oncol, Philadelphia, PA USA
[7] Univ Sao Paulo, Dept Endocrinol, Inst Canc Estado Sao Paulo, Sao Paulo, Brazil
[8] Inst Dor Pesquisa & Ensino, Sao Paulo, Brazil
[9] Univ Sydney, Sydney Med Sch, Sydney, Australia
[10] Tianjin Med Univ Canc Inst & Hosp, Dept Thyroid & Neck Tumor, Tianjin, Peoples R China
[11] Maria Sklodowska Curie Natl Res Inst Oncol, Dept Nucl Med & Endocrine Oncol, Gliwice Branch, Gliwice, Poland
[12] Fed State Inst, Med Radiol Res Ctr, Obninsk, Russia
[13] Charles Univ Prague, Dept Oncol, Fac Med 2, Prague, Czech Republic
[14] Motol Univ Hosp, Prague, Czech Republic
[15] NHS Fdn Trust, Weston Pk Canc Ctr, Clin Oncol Dept, Sheffield, England
[16] Univ Duisburg Essen, Univ Hosp Essen, Dept Endocrinol Diabetol & Metab, Endocrine Tumour Ctr,West German Canc Ctr, Essen, Germany
[17] Seoul Natl Univ Hosp, Dept Internal Med, Seoul, South Korea
[18] Mem Sloan Kettering Canc Ctr, Dept Med Oncol, New York, NY USA
[19] Natl Canc Ctr Hosp East, Dept Head & Neck Med Oncol, Kashiwa, Japan
[20] Univ Texas MD Anderson Canc Ctr, Endocrine Neoplasia & Hormonal Disorders Dept, Houston, TX USA
[21] Eli Lilly, Indianapolis, IN USA
[22] Univ Autonoma Barcelona, Vall dHebron Inst Oncol, Med Oncol Dept, Barcelona, Spain
[23] Massachusetts Gen Hosp, Canc Ctr, Boston, MA USA
来源
NEW ENGLAND JOURNAL OF MEDICINE | 2023年 / 389卷 / 20期
关键词
MUTATIONS; CARCINOMA; PROTOONCOGENE; CABOZANTINIB; DISEASE; MODEL;
D O I
10.1056/NEJMoa2309719
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. (Funded by Loxo Oncology, a subsidiary of Eli Lilly; LIBRETTO-531 ClinicalTrials.gov number, NCT04211337.)
引用
收藏
页码:1851 / 1861
页数:11
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