Abstract CT045: Prospective precision medicine trial of crizotinib (C) in patients (pts) with advanced, inoperable inflammatory myofibroblastic tumor (IMFT) with and without ALK alterations: EORTC phase II study 90101 "CREATE"
Authors: Schoffski Patrick , Sufliarsky Jozef , Gelderblom Hans , Blay Jean-Yves , Strauss Sandra J. , Stacchiotti Silvia , Rutkowski Piotr , Lindner Lars H. , Leahy Michael G. , Italiano Antoine , Isambert Nicolas , Debiec-Rychter Maria , Sciot Raf , Cann Thomas Van , Marréaud Sandrine , Nzokirantevye Axelle , Collette Sandra , Wozniak Agnieszka 
Published: August 2018

Abstract
Background: The multi-tumor phase 2 trial EORTC 90101 (NCT01524926) assessed the activity and safety of the ALK/MET/ROS1 inhibitor C in IMFT, an orphan malignancy associated with ALK rearrangement or copy number changes.
Methods: Pts with local diagnosis of advanced/metastatic IMFT consented for shipment of a tumor tissue block and were screened for treatment after central confirmation of the diagnosis by reference pathology. Eligible ALK positive (+) and negative (-) pts received oral C 250 mg bid until RECIST 1.1 progression (PD). ALK+ was defined as at least 15% of tumor cells with rearrangement on FISH (Vysis LSI ALK Dual Color Break Apart Probe, Abbott Molecular) and/or immunohistochemical positivity (ALK MAb Clone CD246, DAKO). A Simon's optimal 2 stage design was implemented. If at least 2 out of the first 12 eligible and evaluable ALK+ pts achieved a confirmed RECIST 1.1 partial or complete response (PR, CR), a maximum of 35 pts were enrolled. If at least 6 had a confirmed PR/CR, the trial would be deemed successful.
Results: Between 10/2012 and 04/2017, 13 sites in 8 European countries recruited 35 pts with a local diagnosis of IMFT, of whom only 20 had centrally confirmed IMFT and were treated with C. Among 12 eligible and evaluable ALK+ pts, 6 achieved a confirmed PR or CR, 1 a non-confirmed PR and 5 had stable disease (SD) as best response (ORR 50.0%, 95% confidence interval: 21.1-78.9%). Further efficacy endpoints in ALK+ pts: disease control rate (DCR = CR/PR/SD as best response) 100.0% (73.5-100.0%), 1-year (y) progression free rate (PFR) 73.3 % (37.9-90.6%), 1-y OS rate (OSR) 81.8% (44.7-95.1%). Among 7 eligible and evaluable ALK- pts, 1 achieved a PR, 5 had SD and 1 PD (ORR 14.3%, 0.0-57.9%). Further data in ALK- cases: DCR 85.7% (59.8-100.0%), 1-y PFR 53.6 % (13.2-82.5%), 1-y OSR 83.3% (27.3-97.5%). One additional ALK- case was non evaluable (no measurable disease at baseline). Common related adverse events were nausea (11/20 [55%]), fatigue (9/20 [45%]), blurred vision (9/20 [45%]), vomiting (7/20 [35%]), diarrhea (7/20 [35%]).
Conclusions: EORTC can perform precision medicine phase II trials in ultra-rare cancers such as IMFT, with mandatory collection of tissue, real time reference pathology and genetic profiling. With an ORR of 50% and a DCR of 100% in ALK+ disease, C met pre-specified response rate criteria in this trial. The drug achieves long-lasting disease control in the vast majority of ALK+ pts. Sporadic responses and disease stabilization in ALK- cases either suggest limitations of the assays and their cut-offs for target positivity, or the presence of other oncogenic drivers/alternative fusions that may be sensitive to C. Based on the findings of this prospective trial, C should be considered as systemic treatment standard of care for this orphan disease.
Citation Format: Patrick Schoffski, Jozef Sufliarsky, Hans Gelderblom, Jean-Yves Blay, Sandra J. Strauss, Silvia Stacchiotti, Piotr Rutkowski, Lars H. Lindner, Michael G. Leahy, Antoine Italiano, Nicolas Isambert, Maria Debiec-Rychter, Raf Sciot, Thomas Van Cann, Sandrine Marréaud, Axelle Nzokirantevye, Sandra Collette, Agnieszka Wozniak. Prospective precision medicine trial of crizotinib (C) in patients (pts) with advanced, inoperable inflammatory myofibroblastic tumor (IMFT) with and without ALK alterations: EORTC phase II study 90101 "CREATE" [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT045.