Crizotinib achieves long-lasting disease control in advanced papillary renal-cell carcinoma type 1 patients with MET mutations or amplification. EORTC 90101 CREATE trial

Autor: Maria Debiec-Rychter, Agnieszka Wozniak, Patrick Schöffski, Sebastian Bauer, Piotr Rutkowski, Alan Anthoney, Michela Lia, Branko Zakotnik, Jozef Sufliarsky, Evelyne Lerut, Laurence Albiges, Sandrine Marreaud, Bernard Escudier, Viktor Grünwald, Sandra Collette, Lars H. Lindner, Tiana Raveloarivahy, Carla M.L. van Herpen
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
Oncology
Cancer Research
Time Factors
Pyridines
Medizin
Kaplan-Meier Estimate
Gastroenterology
0302 clinical medicine
Stable Disease
Prospective Studies
Aged
80 and over
Papillary renal cell carcinomas
Middle Aged
Proto-Oncogene Proteins c-met
Disease control
Kidney Neoplasms
Europe
Phenotype
Treatment Outcome
030220 oncology & carcinogenesis
Female
medicine.symptom
Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
medicine.drug
medicine.medical_specialty
Nausea
Antineoplastic Agents
Disease-Free Survival
03 medical and health sciences
All institutes and research themes of the Radboud University Medical Center
Crizotinib
Internal medicine
Biomarkers
Tumor
medicine
Carcinoma
Humans
Genetic Predisposition to Disease
Adverse effect
Carcinoma
Renal Cell
Protein Kinase Inhibitors
Aged
business.industry
Gene Amplification
medicine.disease
Confidence interval
030104 developmental biology
Mutation
Pyrazoles
business
Zdroj: European Journal of Cancer, 87, 147-163
European Journal of Cancer, 87, pp. 147-163
ISSN: 0959-8049
Popis: Purpose 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−). Experimental design 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. Results 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%). Conclusion 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.
Databáze: OpenAIRE
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