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Title: Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials.
Austin Authors: Doebele, Robert C;Drilon, Alexander;Paz-Ares, Luis;Siena, Salvatore;Shaw, Alice T;Farago, Anna F;Blakely, Collin M;Seto, Takashi;Cho, Byung Chul;Tosi, Diego;Besse, Benjamin;Chawla, Sant P;Bazhenova, Lyudmila;Krauss, John C;Chae, Young Kwang;Barve, Minal;Garrido-Laguna, Ignacio;Liu, Stephen V;Conkling, Paul;John, Thomas ;Fakih, Marwan;Sigal, Darren;Loong, Herbert H;Buchschacher, Gary L;Garrido, Pilar;Nieva, Jorge;Steuer, Conor;Overbeck, Tobias R;Bowles, Daniel W;Fox, Elizabeth;Riehl, Todd;Chow-Maneval, Edna;Simmons, Brian;Cui, Na;Johnson, Ann;Eng, Susan;Wilson, Timothy R;Demetri, George D
Affiliation: Austin Health, Heidelberg, Victoria, Australia
Department of Medical Oncology, Universidad de Alcalá and Ciberonc, Madrid, Spain; Ramón y Cajal Health Research Institute, Madrid, Spain
Norris Cancer Center, University of Southern California, Los Angeles, CA, USA
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain
Division of Medical Oncology, University of Colorado, Aurora, CO, USA
Department of Oncology and Medical Radiotherapy, Massachusetts General Hospital, Boston, MA, USA
Sarcoma Oncology Center, Santa Monica, CA, USA
University of California San Diego, Moores Cancer Center, La Jolla, CA, USA
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
Department of Medicine, Northwestern University, Chicago, IL, USA
Mary Crowley Cancer Center, Dallas, TX, USA
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
US Oncology Research, Virginia Oncology Associates, Norfolk, VA, USA
City of Hope Comprehensive Cancer Center, Duarte, CA, USA
Scripps Clinic and Scripps MD Anderson Cancer Center, La Jolla, CA, USA
Southern California Permanente Medical Group, Los Angeles, CA, USA
Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
School of Medicine, University of Colorado, Aurora, CO, USA
Department of Developmental Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Genentech, South San Francisco, CA, USA
Ignyta, San Diego, CA, USA
Dana-Farber Cancer Institute and Ludwig Center, Harvard Medical School, Boston, MA, USA
Institut Régional Du Cancer de Montpellier, Montpellier, France
Gustave Roussy Cancer Campus, Villejuif Cedex, Paris, France
Weill Cornell Medical College, New York, NY, USA
Memorial Sloan Kettering Cancer Center, New York, NY, USA
Yonsei Cancer Center, Seoul, South Korea
Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
Hospital Universitario 12 de Octubre, H120H120-CNIO Lung Cancer Clinical Research Unit, Universidad Complutense & Ciberonc, Madrid, Spain
National Kyushu Cancer Center, Fukuoka, Japan
The Chinese University of Hong Kong, Sha Tin, Hong Kong
Department of Hematology and Oncology, University of Göttingen, Göttingen, Germany
Issue Date: Feb-2020 2019-12-11
Publication information: The Lancet. Oncology 2020; 21(2): 271-282
Abstract: Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood-brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials. An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0-2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001). Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77-18·76). 31 (57%; 95% CI 43·2-70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred. Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours. Ignyta/F Hoffmann-La Roche.
DOI: 10.1016/S1470-2045(19)30691-6
ORCID: 0000-0003-3399-5342
PubMed URL: 31838007
Type: Journal Article
Appears in Collections:Journal articles

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