P-309 PROSPECT-R: A PROSPECTive translational study investigating molecular predictors of resistance and response to Regorafenib (REG) monotherapy in RAS mutant (mt) metastatic colorectal cancer (CRC)

Abstract

Introduction: Background: CRC is the third commonest cancer worldwide and is associated with a high morbidity and mortality. REG, a multi-kinase inhibitor with anti-angiogenic (VEGFR 2/3, TIE-2), anti-stromal (PDGFR-β, FGFR) and anti-oncogenic (KIT, RET and B-RAF) activities has single agent efficacy in patients (pts) with refractory metastatic CRCs (R-CRC). The benefit of REG in unselected pts is modest. Thus, the identification of predictive molecular biomarkers is critical for treatment stratification. The PROSPECT-R study aims to identify genetic and non-genetic mechanisms of primary and acquired REG resistance in RAS mt R-CRC patients, for whom other treatment options are highly limited Methods: PROSPECT-R is a single-centre phase II translational study in R-CRC pts previously treated with standard chemotherapy drugs (fluoropyrimidine, oxaliplatin, irinotecan) and at least one anti-angiogenic antibody. Whole exome sequencing (WES) is performed on archival diagnostic specimens and on fresh biopsies collected immediately before REG treatment, at the time of response or stable disease (8 weeks) and at progression (PD). Live cells are isolated from biopsies and cultured in vitro or in mice to allow functional validation of putative REG resistance drivers and the development of rational combination therapies to overcome resistance. Blood samples are collected every 4 weeks for analysis of candidate circulating makers (tumour DNA and micro-RNA). Additionally, dynamic contrast enhanced and diffusion weighted magnetic resonance imaging are performed pre-treatment and on day 15 for imaging biomarker development. Treatment efficacy is measured by regular computed tomography scans and serum tumour markers. The identification of genetic biomarkers of REG resistance by WES is the primary endpoint, while secondary outcomes include identification of response and resistance biomarkers by proteomic, epigenetic, radiological and ex-vivo studies. The study aims to recruit 20-30 pts with paired biopsies (pre-treatment and PD). Recruitment started in January 2015 and to date 4 pts have started treatment on the study.