Abstract CT006: Crizotinib achieves objective responses and long-lasting disease control in patients (pts) with metastatic papillary renal cell carcinoma type 1 (PRCC1) with somatic MET mutations. EORTC phase II trial 90101 “CREATE”
Authors: Schoffski Patrick , Wozniak Agnieszka , Escudier Bernard , Rutkowski Piotr , Anthoney Alan , Bauer Sebastian , Sufliarsky Jozef , van Herpen Carla , Lindner Lars , Grünwald Viktor , Zakotnik Branko , Lerut Evelyne , Marréaud Sandrine , Lia Michela , Raveloarivahy Tiana , Collette Sandra , Albiges Laurence 
Published: July 2016

Background: EORTC 90101 prospectively assesses the activity and safety of the ALK/ROS/MET inhibitor Crizotinib in 6 independent tumor types including advanced PRCC1, an orphan, treatment-refractory malignancy. PRCC1 is associated with mutations of the MET gene encoding the MET tyrosine kinase receptor, which leads to activation of the pathway and induces tumor cell proliferation, survival, migration, invasion, and angiogenesis. Methods: Pts with local diagnosis of advanced/metastatic PRCC1 consented for shipment of tumor tissue and trial participation and were screened for active treatment after central confirmation of the diagnosis by a reference pathologist. Eligible pts received oral Crizotinib at a starting dose of 250 mg twice daily in 3-weekly cycles. Direct bi-directional Sanger sequencing of MET exons 16-19 of archival tumor tissue was used to assign pts to MET+ and MET-PRCC1 sub-cohorts. A Simon's optimal two stage design was implemented independently in each disease-specific sub-cohort. If at least 2 out of the first 12 eligible and evaluable PRCC1 MET+ pts achieved a confirmed partial (PR) or complete response (RECIST 1.1), a maximum of 35 pts were to be enrolled and

treated to assess the activity of Crizotinib. Results: Between 12/2012 - 01/2016, 13 high-volume sites in 8 European countries recruited 41 pts with local diagnosis of PRCC1, of whom only 23 had a centrally confirmed diagnosis of PRCC1 and were treated. This abstract summarizes preliminary efficacy results; more mature data will be presented at the meeting. Among 4 pts with MET+ disease, 2 achieved a confirmed PR and one had stable disease (SD); all 3 had long lasting disease control (? 14 treatment cycles). Among 13 pts with MET- disease, none achieved a response and treatment duration was short except for one who achieved long term SD and was found to have MET amplification. Among 6 pts with “unknown” mutational status (technical failure, insufficient material), 2 achieved long term SD (? 20 cycles), suggesting the presence of other MET activating alterations. The safety analysis is pending. Conclusions: EORTC is able to perform molecularly driven screening phase II trials in rare cancers with mandatory collection of tissue blocks, real time reference pathology and genetic profiling. PRCC1 is very rare and frequently misdiagnosed. With 2 out of 4 MET+ PRCC1 patients achieving a PR, Crizotinib did meet the stage 1 success criteria of the study design. The low incidence of reference-pathology proven MET+ PRCC1, with an accrual rate of only 0.1 MET+ PRCC1 per month in our multinational network, will preclude completion of stage 2. Innovative trial methodology and new regulatory mechanisms are required to provide pts with orphan diseases with active drugs such as Crizotinib. Clinical trial information: NCT01524926.

Citation Format: Patrick Schoffski, Agnieszka Wozniak, Bernard Escudier, Piotr Rutkowski, Alan Anthoney, Sebastian Bauer, Jozef Sufliarsky, Carla van Herpen, Lars Lindner, Viktor Grünwald, Branko Zakotnik, Evelyne Lerut, Sandrine Marréaud, Michela Lia, Tiana Raveloarivahy, Sandra Collette, Laurence Albiges. Crizotinib achieves objective responses and long-lasting disease control in patients (pts) with metastatic papillary renal cell carcinoma type 1 (PRCC1) with somatic MET mutations. EORTC phase II trial 90101 “CREATE”. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT006.