Alexander Drilon, Memorial Sloan Kettering Cancer Center
Theodore W. Laetsch, University of Texas Southwestern Medical Center
Shivaani Kummar, Stanford University
Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center
Ulrik N. Lassen, Copenhagen University Hospital
George D. Demetri, Dana-Farber Cancer Institute
Michael Nathenson, Dana-Farber Cancer Institute
Robert C. Doebele, University of Colorado
Anna F. Farago, Massachusetts General Hospital
Alberto S. Pappo, St. Jude Children's Research Hospital
Brian Turpin, Cincinnati Children's Hospital Medical Center
Afshin Dowlati, University Hospitals Cleveland Medical Center
Marcia S. Brose, University of Pennsylvania
Leo Mascarenhas, University of Southern California
Noah Federman, University of California, Los Angeles
Jordan Berlin, Vanderbilt University
Wafik S. El-Deiry, Fox Chase Cancer Center
Christina Baik, University of Washington - Seattle Campus
John Deeken, Inova Schar Cancer Institute
Valentina Boni, Centro Integral Oncológico Clara Campal
Ramamoorthy Nagasubramanian, Nemours Children's Hospital
Matthew Taylor, Oregon Health and Science University
Erin R. Rudzinski, Seattle Children's Hospital
Funda Meric-Bernstam, The University of Texas MD Anderson Cancer Center
Davendra P. S. Sohal, Cleveland Clinic Taussig Cancer Institute
Patrick C. Ma, West Virginia University
Luis E. Raez, Florida International University
Jaclyn F. Hechtman, Memorial Sloan Kettering Cancer Center
Ryma Benayed, Memorial Sloan Kettering Cancer Center
Marc Ladanyi, Memorial Sloan Kettering Cancer Center
Brian B. Tuch, Loxo Oncology, Inc.
Kevin Ebata, Loxo Oncology, Inc.
Scott Cruickshank, Loxo Oncology, Inc.
Nora C. Ku, Loxo Oncology, Inc.
Michael C. Cox, Loxo Oncology, Inc.
Douglas S. Hawkins, University of Washington - Seattle Campus
David S. Hong, The University of Texas MD Anderson Cancer Center
David M. Hyman, Memorial Sloan Kettering Cancer Center

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BACKGROUND—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. METHODS—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. RESULTS—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 progressionfree 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. CONCLUSIONS—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.)

Source Citation

Drilon A, Laetsch TW, Kummar S, et al. Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children. New England Journal of Medicine. 2018;378(8):731-739. doi:10.1056/nejmoa1714448