P Schöffski1, A Wozniak2, B Kasper3, S Aamdal4, M G Leahy5, P Rutkowski6, S Bauer7, H Gelderblom8, A Italiano9, L H Lindner10, I Hennig11, S Strauss12, B Zakotnik13, A Anthoney14, L Albiges15, J-Y Blay16, P Reichardt17, J Sufliarsky18, W T A van der Graaf19, M Debiec-Rychter20, R Sciot21, T Van Cann22, S Marréaud23, T Raveloarivahy23, S Collette23, S Stacchiotti24. 1. Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium; Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium. Electronic address: patrick.schoffski@uzleuven.be. 2. Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium. 3. Sarcoma Unit, Interdisciplinary Tumor Center, Mannheim University Medical Center, Mannheim, Germany. 4. Department of Oncology, Oslo University Hospital, Oslo, Norway. 5. The Christie NHS Foundation Trust, Manchester, UK. 6. Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland. 7. Department of Internal Medicine, West German Cancer Center, University Hospital, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany. 8. Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. 9. Sarcoma Unit, Institut Bergonié, Bordeaux, France. 10. Medical Clinic III, University Hospital of Munich, Munich, Germany. 11. Department of Clinical Oncology, Nottingham University Hospitals NHS Trust, Nottingham, UK. 12. Department of Oncology, University College Hospital, London, UK. 13. Department of Medical Oncology, The Institute of Oncology, Ljubljana, Slovenia. 14. Institute of Oncology, Leeds Teaching Hospitals National Health Service Trust, St. James's University Hospital, Leeds, UK. 15. Department of Medical Oncology, Gustave Roussy, Villejuif. 16. Department of Medical Oncology, Centre Léon Bérard, Lyon, France; Université Claude Bernard Lyon I, Lyon, France. 17. Department of Interdisciplinary Oncology, HELIOS Klinikum Berlin-Buch, Berlin, Germany. 18. National Cancer Institute, Bratislava, Slovakia. 19. Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands. 20. Department of Human Genetics, KU Leuven, Leuven, Belgium; University Hospitals Leuven, Leuven, Belgium. 21. University Hospitals Leuven, Leuven, Belgium; Department of Pathology, KU Leuven; Leuven, Belgium. 22. Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium; Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium. 23. European Organization for Research and Treatment of Cancer, Brussels, Belgium. 24. Department of Medical Oncology, IRCCS Fondazione Istituto Nazionale Tumori, Milano, Italy.
Abstract
Background: Alveolar soft part sarcoma (ASPS) is an orphan malignancy associated with a rearrangement of transcription factor E3 (TFE3), leading to abnormal MET gene expression. We prospectively assessed the efficacy and safety of the MET tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic ASPS. Patients and methods: Eligible patients with reference pathology-confirmed ASPS received oral crizotinib 250 mg bd. By assessing the presence or absence of a TFE3 rearrangement, patients were attributed to MET+ and MET- sub-cohorts. The primary end point was the objective response rate (ORR) according to local investigator. Secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate, overall survival (OS) and safety. Results: Among 53 consenting patients, all had a centrally confirmed ASPS and 48 were treated. A total of 45 were eligible, treated and assessable. Among 40 MET+ patients, 1 achieved a confirmed partial response (PR) that lasted 215 days and 35 had stable disease (SD) as best response (ORR: 2.5%, 95% CI 0.6% to 80.6%). Further efficacy end points in MET+ cases were DCR: 90.0% (95% CI 76.3% to 97.2%), 1-year PFS rate: 37.5% (95% CI 22.9% to 52.1%) and 1-year OS rate: 97.4% (95% CI 82.8% to 99.6%). Among 4 MET- patients, 1 achieved a PR that lasted 801 days and 3 had SD (ORR: 25.0%, 95% CI 0.6% to 80.6%) for a DCR of 100% (95% CI 39.8% to 100.0%). The 1-year PFS rate in MET- cases was 50% (95% CI 5.8% to 84.5%) and the 1-year OS rate was 75% (95% CI 12.8% to 96.1%). One patient with unknown MET status due to technical failure achieved SD but stopped treatment due to progression after 17 cycles. The most common crizotinib-related adverse events were nausea [34/48 (70.8%)], vomiting [22/48 (45.8%)], blurred vision [22/48 (45.8%)], diarrhoea (20/48 (41.7%)] and fatigue [19/48 (39.6%)]. Conclusion: According to European Organization for Research and Treatment of Cancer (EORTC) efficacy criteria for soft tissue sarcoma, our study demonstrated that crizotinib has activity in TFE3 rearranged ASPS MET+ patients. Clinical trial number: EORTC 90101, NCT01524926.
Background: Alveolar soft part sarcoma (ASPS) is an orphan malignancy associated with a rearrangement of transcription factor E3 (TFE3), leading to abnormal MET gene expression. We prospectively assessed the efficacy and safety of the MET tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic ASPS. Patients and methods: Eligible patients with reference pathology-confirmed ASPS received oral crizotinib 250 mg bd. By assessing the presence or absence of a TFE3 rearrangement, patients were attributed to MET+ and MET- sub-cohorts. The primary end point was the objective response rate (ORR) according to local investigator. Secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate, overall survival (OS) and safety. Results: Among 53 consenting patients, all had a centrally confirmed ASPS and 48 were treated. A total of 45 were eligible, treated and assessable. Among 40 MET+ patients, 1 achieved a confirmed partial response (PR) that lasted 215 days and 35 had stable disease (SD) as best response (ORR: 2.5%, 95% CI 0.6% to 80.6%). Further efficacy end points in MET+ cases were DCR: 90.0% (95% CI 76.3% to 97.2%), 1-year PFS rate: 37.5% (95% CI 22.9% to 52.1%) and 1-year OS rate: 97.4% (95% CI 82.8% to 99.6%). Among 4 MET- patients, 1 achieved a PR that lasted 801 days and 3 had SD (ORR: 25.0%, 95% CI 0.6% to 80.6%) for a DCR of 100% (95% CI 39.8% to 100.0%). The 1-year PFS rate in MET- cases was 50% (95% CI 5.8% to 84.5%) and the 1-year OS rate was 75% (95% CI 12.8% to 96.1%). One patient with unknown MET status due to technical failure achieved SD but stopped treatment due to progression after 17 cycles. The most common crizotinib-related adverse events were nausea [34/48 (70.8%)], vomiting [22/48 (45.8%)], blurred vision [22/48 (45.8%)], diarrhoea (20/48 (41.7%)] and fatigue [19/48 (39.6%)]. Conclusion: According to European Organization for Research and Treatment of Cancer (EORTC) efficacy criteria for soft tissue sarcoma, our study demonstrated that crizotinib has activity in TFE3 rearranged ASPS MET+ patients. Clinical trial number: EORTC 90101, NCT01524926.
Authors: Geraldine O'Sullivan Coyne; Shivaani Kummar; James Hu; Kristen Ganjoo; Warren A Chow; Khanh T Do; Jennifer Zlott; Ashley Bruns; Lawrence Rubinstein; Jared C Foster; Lamin Juwara; Robert Meehan; Richard Piekarz; Howard Streicher; Elad Sharon; Naoko Takebe; Andrea Regier Voth; Donald Bottaro; Rene Costello; John J Wright; James H Doroshow; Alice P Chen Journal: Clin Cancer Res Date: 2021-10-29 Impact factor: 13.801
Authors: Ian Judson; James P Morden; Lucy Kilburn; Michael Leahy; Charlotte Benson; Vivek Bhadri; Quentin Campbell-Hewson; Ricardo Cubedo; Adam Dangoor; Lisa Fox; Ivo Hennig; Katy Jarman; Warren Joubert; Sarah Kernaghan; Antonio López Pousa; Catriona McNeil; Beatrice Seddon; Claire Snowdon; Martin Tattersall; Christy Toms; Javier Martinez Trufero; Judith M Bliss Journal: Lancet Oncol Date: 2019-05-31 Impact factor: 41.316