A prospective translational study investigating molecular predictors of resistance and response to regorafenib (REG) monotherapy in RAS mutant (mt) metastatic colorectal cancer (mCRC): Initial magnetic resonance imaging (MRI) sub-study result.

Abstract

580 Background: REG that has single agent efficacy in patients (pts) with refractory mCRC, is known to have anti-angiogenic activities. The benefit of REG in unselected pts is modest. Thus, the identification of predictive biomarkers is critical for treatment stratification. PROSPECT-R study aims to identify genetic and radiological mechanisms of primary and acquired REG resistance in RAS mt mCRC patients. Methods: Multiparametric MRI studies including dynamic contrast enhancement (DCE)-MRI and diffusion weighted imaging (DWI) were acquired pre- and at day 15 post-treatment on a 1.5T Siemens Avanto MR scanner. Regions of interest of the entire chosen target metastatic lesion were drawn by a senior radiologist and the following imaging parameters were generated: volume transfer constant (Ktrans) derived from a pharmacokinetic analysis based on the extended Kety model and apparent diffusion coefficient (ADC) calculated using a mono-exponential fitting algorithm; median values of ADC and Ktrans were reported. Results: The first seven enrolled pts were analysed; a single target lesion per patient was chosen (5 liver and 2 pelvic metastases). At day 15 post treatment, a marked decrease (68-81%) of median tumour Ktrans was observed in 4 out of 7 pts; the remaining 3 patients showed no significant median Ktrans change (-36 to + 17%). Overall, the cohort average Ktrans decreased from 0.17 to 0.07 min-1(58%). No significant ADC changes were observed at day 15. Of the 4 pts with Ktrans reduction on day 15, 1 achieved RECIST 1.1 partial response (38% reduction in target lesions), 2 had stable disease and 1 progressed, based on CT assessments performed at 8 weeks of REG therapy; 3/7 pts with no Ktrans change progressed within 2 months of initiating REG. When modified Choi criteria were applied, 3/4 pts with Ktrans reduction were classified as responders. Conclusions: REG may have early anti-angiogenic affects; DCE-MRI could be a potential predicting biomarker in pts treated with REG. Further analysis within PROSPECT-R may elucidate genetic biomarkers to validate these findings. Clinical trial information: EUDRACT No: 2014- 003579-51.