Abstract B049: Characterizing and targeting RET fusions-positive metastatic colorectal cancer (mCRC)
Authors: Morano Federica , Schrock Alexa , Lee Jeeyun , Nikolinakos Petros , Drilon Alexander , Christiansen Jason , Chiu Vi , Zaniboni Alberto , Rossini Daniele , Kim Seung Tae , Milione Massimo , Patel Rupal , Miller Vincet , Corallo Salvatore , Di Bartolomeo Maria , Ross Jeffrey , Bertotti Andrea , Bardelli Alberto , Di Nicolantonio Federica , Ali Siraj , Trusolino Livio , Falcone Alfredo , de Braud Filippo , Cremolini Chiara , Pietrantonio Filippo 
Published: August 2018

Abstract
Background: RET fusions occur in &lt;1% of CRCs and represent new therapeutic targets, as indicated by earlier promising case reports of patients (pts) treated with multitargeted tyrosine kinase inhibitors (TKIs). Although ALK, ROS1, and NTRK fusions identify a peculiar subtype of mCRCs that may be targeted by selective inhibitors such as entrectinib, the clinical, molecular, and therapeutic landscape of RET rearranged mCRC still needs to be unveiled. Methods: Pts with mCRC harboring RET fusions were identified worldwide taking advantage of 1) previously published molecular case reports; 2) Italian and Korean screening collaboration; 3) Ignyta’s phase 1/1b trial of RXDX-105, a novel selective and potent RET-inhibitor with VEGFR-sparing activity; and 4) Foundation Medicine Database. Clinical and molecular characteristics of RET-rearranged cases were compared with nonrearranged ones screened at 3 referral centers in Milan, Pisa, and Seoul. Results: 24 RET rearranged (12 NCOA4-RET, 8 CCDC6-RET, 2 TRIM24-RET, 1 novel TNIP1-RET, and 1 novel SNRNP70-RET) and 236 not rearranged mCRCs pts were included. Rearrangements were more frequent in older pts (p=0.027), with right-sided primary tumors (p&lt;0.028), RAS wild-type (p&lt;0.001), BRAF wild-type (p&lt;0.001), and MSI-high (p&lt;0.001). All RET fusions were found in RAS and BRAF wild-type tumors, whereas MSI-high status and right-sided primary tumor were found in the 47% and 55% of RET-positive cases, respectively. At a median follow-up of 31.5 months, pts bearing RET-rearranged tumors had a shorter overall survival (OS) when compared to nonrearranged (HR: 16.4, 95%CI: 5.64-47.39; p&lt;0.001). In the multivariable model including other significant variables (primary tumor resection and location, RAS, BRAF, and MMR status), RET rearrangements retained significant association with shorter OS (HR: 3,69, 95% CI 1.62 - 8.44; p=0.002), as well as primary tumor resection (p=0.036). Primary-tumor location and MSI status were not independent prognostic factors, instead. While multitargeted TKIs (i.e., regorafenib/sunitinib) conferred only short-lasting clinical benefit, a patient achieved a long-lasting and ongoing (16+ months) complete response to RXDX-105. NGS molecular data and preclinical experiments with unselective/selective inhibitors in RET fusion positive PDX will be presented. Conclusions: RET rearrangements define a new and rare molecular subtype of mCRCs associated with unfavorable prognosis and specific clinicopathologic and molecular features. The present findings in RET-rearranged mCRC resemble those previously reported for ALK, ROS1, and NTRK positive ones. Above all, since sensitivity to available treatment options including anti-EGFRs may be very limited, RET fusions should be regarded as novel therapeutic targets, particularly regarding the development of specific inhibitors, such as RXDX-105.
Citation Format: Federica Morano, Alexa Schrock, Jeeyun Lee, Petros Nikolinakos, Alexander Drilon, Jason Christiansen, Vi Chiu, Alberto Zaniboni, Daniele Rossini, Seung Tae Kim, Massimo Milione, Rupal Patel, Vincet Miller, Salvatore Corallo, Maria Di Bartolomeo, Jeffrey Ross, Andrea Bertotti, Alberto Bardelli, Federica Di Nicolantonio, Siraj Ali, Livio Trusolino, Alfredo Falcone, Filippo de Braud, Chiara Cremolini, Filippo Pietrantonio. Characterizing and targeting RET fusions-positive metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B049.