Papillary renal-cell carcinoma type 1 (PRCC1) is associated with MET gene alterations. Our phase II trial prospectively assessed the efficacy and safety of crizotinib in patients with advanced/metastatic PRCC1 with or without MET mutations (MET+ and MET-).
Eligible patients with reference pathology-confirmed PRCC1 received 250 mg oral crizotinib twice daily. Patients were attributed to MET+/MET- sub-cohorts by the sequencing of exons 16-19 of the MET gene in tumour tissue. The primary end-point was objective response rate (ORR). If at least two of the first 12 eligible and evaluable MET+ patients achieved a confirmed partial response (PR) or complete response (CR) (in accordance with the Response Evaluation Criteria in Solid Tumours, version 1.1), a maximum of 35 patients were enrolled. Secondary end-points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), PFS rate (PFSR), overall survival (OS) and safety.
Forty-one patients provided consent, of whom 23 were eligible, treated and evaluable. In four MET+ patients, two achieved PR and one had stable disease (SD) (ORR 50%; 95% confidence interval [CI]: 6.8-93.2), DOR was 21.8 and 37.3 months, 1-year PFSR: 75.0% (95% CI: 12.8-96.1) and 1-year OS: 75.0% (95% CI: 12.8-96.1). Among 16 MET- patients, one achieved a PR lasting more than 9.9 months and 11 had SD (ORR: 6.3%; 95% CI: 0.2-30.2), 1-year PFSR: 27.3% (95% CI: 8.5-50.4) and 1-year OS: 71.8% (95% CI: 41.1-88.4). Among three patients with unknown MET status (MET?) due to technical failure, one achieved PR lasting more than 6.9 months, and one had SD (ORR 33.3%, 95% CI: 0.8-90.6), 1-year PFSR: 66.7% (95% CI: 5.4-94.5) and 1-year OS: 100%. MET amplification was found post hoc in one MET+ patient (PR, DOR: 37.3 months), and one MET- case who had SD. Common treatment-related adverse events were oedema (47.8%), fatigue (47.8%), nausea (39.1%), diarrhoea (39.1%) and blurred vision (34.8%).
Crizotinib is active and well tolerated in advanced, metastatic PRCC1, achieving objective responses and long-lasting disease control in patients with MET mutations or amplification. Sporadic, durable responses are also seen in MET- and MET? cases, suggesting the presence of other alterations of MET or alternative pathways.
European journal of cancer (Oxford, England : 1990). 2017 Nov 14 [Epub ahead of print]
Patrick Schöffski, Agnieszka Wozniak, Bernard Escudier, Piotr Rutkowski, Alan Anthoney, Sebastian Bauer, Jozef Sufliarsky, Carla van Herpen, Lars H Lindner, Viktor Grünwald, Branko Zakotnik, Evelyne Lerut, Maria Debiec-Rychter, Sandrine Marréaud, Michela Lia, Tiana Raveloarivahy, Sandra Collette, Laurence Albiges
University Hospitals Leuven, Department of General Medical Oncology, Leuven Cancer Institute, Leuven, Belgium; KU Leuven, Laboratory of Experimental Oncology, Department of Oncology, Leuven, Belgium. Electronic address: ., KU Leuven, Laboratory of Experimental Oncology, Department of Oncology, Leuven, Belgium., Gustave Roussy, Department of Medical Oncology, Villejuif, France., Maria Sklodowska-Curie Institute-Oncology Center, Department of Soft Tissue/Bone Sarcoma and Melanoma, Warsaw, Poland., Leeds Teaching Hospitals National Health Service Trust, Institute of Oncology, St. James's University Hospital, Leeds, United Kingdom., West German Cancer Center, University Hospital, Department of Internal Medicine, University of Duisburg-Essen, Germany and German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany., National Cancer Institute, Bratislava, Slovakia., Radboud University Medical Center, Department of Medical Oncology, Nijmegen, The Netherlands., Klinikum der Universität München, Medizinische Klinik III, Campus Grosshadern, München, Germany., Hannover Medical School, Department of Haematology, Haemostasis and Oncology, and Stem Cell Transplantation, Hannover, Germany., The Institute of Oncology, Department of Medical Oncology, Ljubljana, Slovenia., University Hospitals Leuven, Department of Pathology, Leuven, Belgium., KU Leuven, Department of Human Genetics, Leuven, Belgium., European Organization for Research and Treatment of Cancer, Brussels, Belgium.