• Julien Hadoux, Rossella Elisei, Marcia S Brose, Ana O Hoff, Bruce G Robinson, Ming Gao, Barbara Jarzab, Pavel Isaev, Katerina Kopeckova, Jonathan Wadsley, Dagmar Führer, Bhumsuk Keam, Stéphane Bardet, Eric J Sherman, Makoto Tahara, Mimi I Hu, Ravinder Singh, Yan Lin, Victoria Soldatenkova, Jennifer Wright, Boris Lin, Patricia Maeda, Jaume Capdevila, Lori J Wirth, and LIBRETTO-531 Trial Investigators.
• 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.).
• N. Engl. J. Med. 2023 Nov 16; 389 (20): 185118611851-1861.

BackgroundSelpercatinib, 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.MethodsWe 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.ResultsA 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.ConclusionsSelpercatinib 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.).Copyright © 2023 Massachusetts Medical Society.

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