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N Engl J Med. 2018 Feb 22;378(8):731-739. doi: 10.1056/NEJMoa1714448.

Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children.

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From Memorial Sloan Kettering Cancer Center (A. Drilon, J.F.H., R.B., M.L., D.M.H.) and Weill Cornell Medical College (A. Drilon, D.M.H.), New York; University of Texas Southwestern Medical Center-Children's Health, Dallas (T.W.L.); Stanford Cancer Center, Stanford University, Palo Alto (S.K.), Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California (L.M.), and UCLA David Geffen School of Medicine (N.F.), Los Angeles, and Loxo Oncology, South San Francisco (B.B.T., K.E., S.C., N.C.K., M.C.C.) - all in California; Dana-Farber-Boston Children's Cancer and Blood Disorders Center (S.G.D.), Dana-Farber Cancer Institute (G.D.D., M.N.), Ludwig Center at Harvard (G.D.D.), and Massachusetts General Hospital (A.F.F.) - all in Boston; the Finsen Center, Rigshospitalet, Copenhagen (U.N.L.); University of Colorado, Aurora (R.C.D.); St. Jude Children's Research Hospital, Memphis (A.S.P.), and Vanderbilt University, Nashville (J.B.) - both in Tennessee; Cincinnati Children's Hospital Medical Center, Cincinnati (B.T.); University Hospitals of Cleveland Medical Center (A. Dowlati) and Taussig Cancer Institute, Cleveland Clinic (D.P.S.S.), Cleveland; University of Pennsylvania Perelman School of Medicine, Department of Otorhinolaryngology and Head and Neck Surgery, and the Abramson Cancer Center (M.S.B.), and Fox Chase Cancer Center (W.S.E.-D.), Philadelphia; University of Washington-Seattle Cancer Care Alliance (C.B.), Seattle Children's Hospital (E.R.R.), and Seattle Children's Hospital, University of Washington, Fred Hutchinson Cancer Research Center (D.S. Hawkins), Seattle; University of Texas M.D. Anderson Cancer Center, Houston (F.M.-B., D.S. Hong); Inova Schar Cancer Institute, Falls Church, VA (J.D.); START Madrid, Centro Integral Oncológico Clara Campal, Madrid (V.B.); Nemours Children's Hospital, Orlando (R.N.), and Memorial Cancer Institute-Florida International University, Miami (L.E.R.) - both in Florida; Oregon Health and Science University, Portland (M.T.); and WVU Cancer Institute, West Virginia University, Morgantown (P.C.M.).



Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions.


We enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety.


A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events.


Larotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; numbers, NCT02122913 , NCT02637687 , and NCT02576431 .).

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