Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials.

Autor:	Hong DS; University of Texas MD Anderson Cancer Center, Houston, TX, USA., DuBois SG; Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA, USA., Kummar S; Stanford University School of Medicine, Stanford University, Palo Alto, CA, USA., Farago AF; Massachusetts General Hospital, Boston, MA, USA., Albert CM; Seattle Children's Hospital, University of Washington, Seattle, WA, USA., Rohrberg KS; Rigshospitalet, Copenhagen University, Copenhagen, Denmark., van Tilburg CM; Hopp Children's Cancer Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany; German Cancer Research Center, Heidelberg, Germany., Nagasubramanian R; Nemours Children's Hospital, Orlando, FL, USA., Berlin JD; Vanderbilt University Medical Center, Nashville, TN, USA., Federman N; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA., Mascarenhas L; Saban Research Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Geoerger B; Gustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Université Paris-Saclay, Villejuif, France., Dowlati A; University Hospitals Cleveland Medical Center, Cleveland, OH, USA., Pappo AS; St Jude Children's Research Hospital, Memphis, TN, USA., Bielack S; Klinikum Stuttgart-Olgahospital, Stuttgart Cancer Center, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany., Doz F; SIREDO Center Care, Innovation, Research In Pediatric, Adolescent and Young Adult Oncology, Institut Curie and Paris Descartes University, Paris, France., McDermott R; St Vincent's University Hospital and Cancer Trials Ireland, Dublin, Ireland., Patel JD; University of Chicago, Chicago, IL, USA., Schilder RJ; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA., Tahara M; National Cancer Center Hospital East, Kashiwa, Japan., Pfister SM; Hopp Children's Cancer Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany; German Cancer Research Center, Heidelberg, Germany; German Cancer Network, Heidelberg, Germany., Witt O; Hopp Children's Cancer Center Heidelberg, Heidelberg University Hospital, Heidelberg, Germany; German Cancer Research Center, Heidelberg, Germany., Ladanyi M; Memorial Sloan Kettering Cancer Center, New York, NY, USA., Rudzinski ER; Seattle Children's Hospital, Seattle, WA, USA., Nanda S; Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA., Childs BH; Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA., Laetsch TW; University of Texas Southwestern Medical Center/Children's Health, Dallas, TX, USA., Hyman DM; Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA., Drilon A; Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. Electronic address: drilona@mskcc.org.
Jazyk:	angličtina
Zdroj:	The Lancet. Oncology [Lancet Oncol] 2020 Apr; Vol. 21 (4), pp. 531-540. Date of Electronic Publication: 2020 Feb 24.
DOI:	10.1016/S1470-2045(19)30856-3
Abstrakt:	Background: The selective TRK inhibitor larotrectinib was approved for paediatric and adult patients with advanced TRK fusion-positive solid tumours based on a primary analysis set of 55 patients. The aim of our analysis was to explore the efficacy and long-term safety of larotrectinib in a larger population of patients with TRK fusion-positive solid tumours. Methods: Patients were enrolled and treated in a phase 1 adult, a phase 1/2 paediatric, or a phase 2 adolescent and adult trial. Some eligibility criteria differed between these studies. For this pooled analysis, eligible patients were aged 1 month or older, with a locally advanced or metastatic non-CNS primary, TRK fusion-positive solid tumour, who had received standard therapy previously if available. This analysis set includes the 55 patients on which approval of larotrectinib was based. Larotrectinib was administered orally (capsule or liquid formulation), on a continuous 28-day schedule, to adults mostly at a dose of 100 mg twice daily, and to paediatric patients mostly at a dose of 100 mg/m 2 (maximum of 100 mg) twice daily. The primary endpoint was objective response as assessed by local investigators in an intention-to-treat analysis. Contributing trials are registered with ClinicalTrials.gov, NCT02122913 (active not recruiting), NCT02637687 (recruiting), and NCT02576431 (recruiting). Findings: Between May 1, 2014, and Feb 19, 2019, 159 patients with TRK fusion-positive cancer were enrolled and treated with larotrectinib. Ages ranged from less than 1 month to 84 years. The proportion of patients with an objective response according to investigator assessment was 121 (79%, 95% CI 72-85) of 153 evaluable patients, with 24 (16%) having complete responses. In a safety population of 260 patients treated regardless of TRK fusion status, the most common grade 3 or 4 larotrectinib-related adverse events were increased alanine aminotransferase (eight [3%] of 260 patients), anaemia (six, 2%), and decreased neutrophil count (five [2%]). The most common larotrectinib-related serious adverse events were increased alanine aminotransferase (two [<1%] of 260 patients), increased aspartate aminotransferase (two [<1%]), and nausea (two [<1%]). No treatment-related deaths occurred. Interpretation: These data confirm that TRK fusions define a unique molecular subgroup of advanced solid tumours for which larotrectinib is highly active. Safety data indicate that long-term administration of larotrectinib is feasible. Funding: Bayer and Loxo Oncology. (Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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