Clinical and pre-clinical biomarkers of Regorafenib (REG) efficacy in metastatic colorectal cancer (mCRC) in a phase II trial

Abstract

Background: REG demonstrated efficacy in pre-treated mCRC pts. Lack of predictive biomarkers, potential toxicities and cost/effectiveness concerns highlight the unmet need for better patient selection. Method(s): RAS mutant mCRC pts with biopsiable metastatic deposits were enrolled in this phase II trial. Tissue biopsies (6-12 cores) were obtained at baseline (BL), after 2 months if stable disease (SD) and at disease progression (PD). Dynamic contrast enhanced (DCE) MRI was acquired pre and at day 15 post-treatment. Median values of volume transfer constant (Ktrans), enhancing fraction (EF) and their product, KEF [Ktrans*EF/100] were generated. Circulating tumour (ct) DNA was collected monthly until PD and tested for clonal RAS mutations by digital droplet PCR. PDOs derived from responders and non-responders pts were implanted orthotopically in the liver of mice and treated with REG for 5 days. Changes in tumour and fractional blood volume (fBV) were monitored by oxygen-enhanced MRI. Result(s): mCRC pts (n=27) with paired MRI scans were analysed; a single target lesion per pt was chosen (25 liver and 2 pelvic metastases). Median KEF decrease was 58.2%. In the 23 analysable pts (4 received 70% drop in KEF(8/27) was associated with higher disease control rate (DCR) measured by RECIST 1.1 at 2 months (m) (p=0.05), progression free survival (PFS) [HR=0.24 (0.07-0.86), p=0.03], 6-m PFS (43.8% VS 0%) and overall survival (OS) [HR 0.08 (0.01-0.63), p=0.02]. In all pts with DCR, PFS was found to be 5.6 vs. 4.2m[HR 0.30 (95% CI 0.06-1.49), p=0.140) and OS was 15.2 vs. 5.8m[HR 0.11 (95% CI 0.01-1.06), p=0.057]. KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS [HR 0.21 (0.06 - 0.71), p=0.01] and OS [HR 0.28 (0.07 - 1.04), p=0.06]. PDOs xeno-transplants treated with REG compared to controls had significant lower tumour fBV (4.5 VS 10.6, p=0.03) and lower microvascular density measured by CD31 staining (4.3 VS 8.9, p=0.02). Conclusion(s): Combining DCE-MRI and ctDNA predicts depth and duration of antiangiogenic response to REG with potential health economic implications.