Patrick Schöffski1, Agnieszka Wozniak2, Michael G Leahy3, Steinar Aamdal4, Piotr Rutkowski5, Sebastian Bauer6, Stephan Richter7, Viktor Grünwald8, Maria Debiec-Rychter9, Raf Sciot10, Birgit Geoerger11, Sandrine Marréaud12, Sandra Collette12, Axelle Nzokirantevye12, Sandra J Strauss13. 1. Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium; Department of Oncology, Laboratory of Experimental Oncology, KU Leuven, Leuven, Belgium. Electronic address: patrick.schoffski@uzleuven.be. 2. Department of Oncology, Laboratory of Experimental Oncology, KU Leuven, Leuven, Belgium. 3. The Christie NHS Foundation Trust, Manchester, UK. 4. Department of Oncology, Oslo University Hospital, Oslo, Norway. 5. Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland. 6. Department of Internal Medicine, West German Cancer Center, University Hospital, University of Duisburg-Essen, Germany and German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany. 7. University Hospital Carl Gustav Carus, University Cancer Center/Medical Dpt. I, Dresden, Germany. 8. Clinic for Haematology, Haemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany. 9. Department of Human Genetics, KU Leuven and University Hospitals Leuven, Leuven, Belgium. 10. Department of Pathology, University Hospitals Leuven, Leuven, Belgium. 11. Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France. 12. European Organization for Research and Treatment of Cancer, Brussels, Belgium. 13. Department of Oncology, University College London Hospitals NHS Trust, London, UK.
Abstract
BACKGROUND: Alveolar rhabdomyosarcomas (ARMSs) can harbour MET and anaplastic lymphoma kinase (ALK) alterations. We prospectively assessed crizotinib in patients with advanced/metastatic ARMS. METHODS: Eligible patients with a central diagnosis of ARMS received oral crizotinib 250 mg twice daily. Patients were attributed to MET/ALK+ or MET/ALK- subcohorts by assessing the presence or absence of the forkhead box O1 (FOXO1; a marker of MET upregulation) and/or ALK gene rearrangement. The primary end-point was the objective response rate (ORR). Secondary end-points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS) and safety. FINDINGS: Nineteen of 20 consenting patients had centrally confirmed ARMS. Molecular assessment revealed rearrangement of FOXO1 in 17 tumours and ALK in none. Thirteen eligible patients were treated, but only eight were evaluable for the primary end-point because of the observed aggressiveness of the disease. Among seven evaluable MET+/ALK- patients, only one achieved a confirmed partial response (ORR: 14.3%; 95% confidence interval [CI]: 0.3-57.8) with a DOR of 52 d. Further MET+/ALK- efficacy end-points were DCR: 14.3% (95% CI: 0.3-57.8), median PFS: 1.3 months (95% CI: 0.5-1.5) and median OS: 5.6 months (95% CI: 0.7-7.0). The remaining MET+/ALK- and MET-/ALK- patients had early progression as best response. Common treatment-related adverse events were fatigue (5/13 [38.5%]), nausea (4/13 [30.8%]), anorexia (4/13 [30.8%]), vomiting (2/13 [15.4%]) and constipation (2/13 [15.4%]). All 13 treated patients died early because of progressive disease. INTERPRETATION: Crizotinib is well tolerated but lacks clinically meaningful activity as a single agent in patients with advanced metastatic ARMS. Assessing single agents in aggressive, chemotherapy-refractory ARMS is challenging, and future trials should explore established chemotherapy ± investigational compounds in earlier lines of treatment. CLINICAL TRIAL NUMBER: EORTC 90101, ClinicalTrials.gov NCT01524926.
BACKGROUND:Alveolar rhabdomyosarcomas (ARMSs) can harbour MET and anaplastic lymphoma kinase (ALK) alterations. We prospectively assessed crizotinib in patients with advanced/metastatic ARMS. METHODS: Eligible patients with a central diagnosis of ARMS received oral crizotinib 250 mg twice daily. Patients were attributed to MET/ALK+ or MET/ALK- subcohorts by assessing the presence or absence of the forkhead box O1 (FOXO1; a marker of MET upregulation) and/or ALK gene rearrangement. The primary end-point was the objective response rate (ORR). Secondary end-points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS) and safety. FINDINGS: Nineteen of 20 consenting patients had centrally confirmed ARMS. Molecular assessment revealed rearrangement of FOXO1 in 17 tumours and ALK in none. Thirteen eligible patients were treated, but only eight were evaluable for the primary end-point because of the observed aggressiveness of the disease. Among seven evaluable MET+/ALK- patients, only one achieved a confirmed partial response (ORR: 14.3%; 95% confidence interval [CI]: 0.3-57.8) with a DOR of 52 d. Further MET+/ALK- efficacy end-points were DCR: 14.3% (95% CI: 0.3-57.8), median PFS: 1.3 months (95% CI: 0.5-1.5) and median OS: 5.6 months (95% CI: 0.7-7.0). The remaining MET+/ALK- and MET-/ALK- patients had early progression as best response. Common treatment-related adverse events were fatigue (5/13 [38.5%]), nausea (4/13 [30.8%]), anorexia (4/13 [30.8%]), vomiting (2/13 [15.4%]) and constipation (2/13 [15.4%]). All 13 treated patients died early because of progressive disease. INTERPRETATION:Crizotinib is well tolerated but lacks clinically meaningful activity as a single agent in patients with advanced metastatic ARMS. Assessing single agents in aggressive, chemotherapy-refractory ARMS is challenging, and future trials should explore established chemotherapy ± investigational compounds in earlier lines of treatment. CLINICAL TRIAL NUMBER: EORTC 90101, ClinicalTrials.gov NCT01524926.
Authors: Josephine H Haduong; Christine M Heske; Wendy Allen-Rhoades; Wei Xue; Lisa A Teot; David A Rodeberg; Sarah S Donaldson; Aaron Weiss; Douglas S Hawkins; Rajkumar Venkatramani Journal: Pediatr Blood Cancer Date: 2022-02-07 Impact factor: 3.167
Authors: David Milewski; Samriddhi Shukla; Berkley E Gryder; Arun Pradhan; Johnny Donovan; Parvathi Sudha; Sushmitha Vallabh; Athena Pyros; Yan Xu; Artem Barski; Sara Szabo; Brian Turpin; Joseph G Pressey; Douglas P Millay; Javed Khan; Vladimir V Kalinichenko; Tanya V Kalin Journal: Oncogene Date: 2021-02-24 Impact factor: 9.867