• Lori J Wirth, Eric Sherman, Bruce Robinson, Benjamin Solomon, Hyunseok Kang, Jochen Lorch, Francis Worden, Marcia Brose, Jyoti Patel, Sophie Leboulleux, Yann Godbert, Fabrice Barlesi, John C Morris, Taofeek K Owonikoko, TanDaniel S WDSWFrom Massachusetts General Hospital (L.J.W.) and Dana-Farber Cancer Institute (J. Lorch), Boston; Memorial Sloan Kettering Cancer Center, New York (E.S., A.D.); Royal North Shore Hospital, St. Leonards, NSW (B.R.), and Peter MacCallum Canc, Oliver Gautschi, Jared Weiss, Christelle de la Fouchardière, Mark E Burkard, Janessa Laskin, Matthew H Taylor, Matthias Kroiss, Jacques Medioni, Jonathan W Goldman, Todd M Bauer, Benjamin Levy, Viola W Zhu, Nehal Lakhani, Victor Moreno, Kevin Ebata, Michele Nguyen, Dana Heirich, Edward Y Zhu, Xin Huang, Luxi Yang, Jennifer Kherani, S Michael Rothenberg, Alexander Drilon, Vivek Subbiah, Manisha H Shah, and Maria E Cabanillas.
• From Massachusetts General Hospital (L.J.W.) and Dana-Farber Cancer Institute (J. Lorch), Boston; Memorial Sloan Kettering Cancer Center, New York (E.S., A.D.); Royal North Shore Hospital, St. Leonards, NSW (B.R.), and Peter MacCallum Cancer Institute, Melbourne, VIC (B.S.) - both in Australia; University of California, San Francisco-Helen Diller Family Comprehensive Cancer Center, San Francisco (H.K.), David Geffen School of Medicine at UCLA, Los Angeles (J.W.G.), and Chao Family Comprehensive Cancer Center, University of California Irvine, Orange (V.W.Z.) - all in California; University of Michigan, Ann Arbor (F.W.), and START Midwest, Grand Rapids (N.L.) - both in Michigan; University of Pennsylvania, Philadelphia (M.B.); University of Chicago, Chicago (J.P.); Gustave Roussy, Villejuif (S.L.), Institut Bergonié, Bordeaux (Y.G.), Aix Marseille University, Centre National de la Recherche Scientifique, INSERM, Centre de Recherche en Cancérologie de Marseille, Assistance Publique-Hôpitaux de Marseille, Early Phase Cancer Trial Center CLIP2, Hospital La Timone, Marseille (F.B.), Centre Léon Bérard, Lyon (C.D.L.F.), and Hôpital Européen Georges-Pompidou, Faculté de Médecine Paris-Descartes, Paris (J.M.) - all in France; Mayo Clinic-Rochester, Rochester, MN (J.C.M.); Winship Cancer Institute of Emory University, Atlanta (T.K.O.); National Cancer Center Singapore, Singapore (D.S.W.T.); University of Bern, Bern, and Cantonal Hospital of Lucerne, Lucerne - both in Switzerland (O.G.); University of North Carolina-Chapel Hill, Chapel Hill (J.W.); University of Wisconsin-Carbone Cancer Center, Madison (M.E.B.); British Columbia Cancer Agency, Vancouver, Canada (J. Laskin); Oregon Health and Science University, Portland (M.H.T.); Universitätsklinikum Würzburg, Department of Internal Medicine I, Division of Endocrinology and Diabetology, Würzburg, Germany (M.K.); Sarah Cannon Research Institute-Tennessee Oncology, Nashville (T.M.B.); Johns Hopkins Kimmel Cancer Center, Washington, DC (B.L.); Fundación Jimenez Diaz, START-Madrid, Madrid (V.M.); Loxo Oncology, Stamford, CT (K.E., M.N., D.H., E.Y.Z., X.H., L.Y., J.K., S.M.R.); University of Texas M.D. Anderson Cancer Center, Houston (V.S., M.E.C.); and Ohio State University Comprehensive Cancer Center, Columbus (M.H.S.).
• N. Engl. J. Med. 2020 Aug 27; 383 (9): 825835825-835.

BackgroundRET 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.MethodsWe 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.ResultsIn 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.ConclusionsIn this phase 1-2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).Copyright © 2020 Massachusetts Medical Society.

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