Effect of crizotinib on disease control in patient with advanced papillary renal cell carcinoma type 1 with MET mutations or amplification: Final results of EORTC 90101 CREATE.
580 Background: Papillary renal cell carcinoma type 1(PRCC1) is associated with MET alterations. Our phase II trial assessed the efficacy and safety of crizotinib in patients (pts) with advanced/metastatic PRCC1 with/without MET mutations( MET+, MET-). Methods: Eligible pts with reference pathology-confirmed PRCC1 received oral crizotinib 250mg twice-daily. Pts were attributed to MET+/ MET- sub-cohorts by sequencing of MET exons 16-19 in tumour tissue. Primary endpoint was objective response rate (ORR). If at least 2 of the first 12 eligible/evaluable MET+ pts achieved a confirmed partial (PR) or complete response (RECIST 1.1), a maximum of 35 pts were enrolled. Other endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS) and rate (PFSR), overall survival (OS) and safety. Results: 23 of 41 pts consenting were eligible, treated and evaluable. In 4 MET+ pts, 2 achieved a PR and 1 had stable disease (SD) (ORR 50%; 95% CI: 6.8-93.7%), DOR was 666 and 1138 days, 1-year PFSR was 75.0% (12.8-96.1%), 1-year OS: 75.0% (12.8-96.1%). Among 16 MET- pts, 1 achieved a PR lasting 302+ days and 11 had SD (ORR: 6.3%; 0.2-30.2%), 1-year PFSR: 27.3% (8.5-50.4%), 1-year OS: 71.8% (41.1-88.4%). Among 3 pts with unknown MET status ( MET?) due to technical failure, 1 achieved a PR lasting 211+ days and 1 had SD (ORR 33.3%, 0.8%-90.6%), 1-year PFSR: 66.7% (5.4-94.5%), 1-year OS: 100%. MET amplification was found post hoc in 1 MET+ (PR, DOR: 1138 days) and 1 MET- case (SD). Common treatment-related AEs were oedema (47.8%), fatigue (47.8%), nausea (39.1%), diarrhoea (39.1%), and blurred vision (34.8%). Conclusions: Crizotinib is active and well tolerated in advanced, metastatic PRCC1, achieving objective responses and long-lasting disease control in pts with MET mutations or amplification. Sporadic, durable responses are also seen in MET-/ MET? cases, suggesting the presence of other alterations of MET or alternative pathways. Clinical trial information: NCT01524926.