Prognostic and Predictive Biomarkers in Metastatic Colorectal Cancer Patients Receiving Regorafenib.

Regorafenib is a tyrosine kinase inhibitor approved by the Food and Drug Administration (FDA) for the treatment of chemotherapy-refractory metastatic colorectal cancer (mCRC) patients. Regorafenib inhibits signaling through multiple receptors associated with angiogenesis, metastasis, and tumor immunity. Here we report biomarker results from LCCC1029, a randomized, placebo controlled, phase II trial of chemotherapy ± regorafenib in second-line mCRC patients. A panel of 20 soluble protein biomarkers (termed the Angiome) was assessed in the plasma of 149 patients from the LCCC1029 trial both at baseline and along the treatment continuum. Baseline protein levels were analyzed for prognostic and predictive value for progression-free survival (PFS) and overall survival (OS). Changes in protein levels during treatment were analyzed for potential pharmacodynamic effects. Six markers (HGF, IL-6, PlGF, VEGF-R1, OPN, and IL-6R) were found to be prognostic for PFS. Nine markers (IL-6, TIMP-1, PlGF, VCAM-1, ICAM-1, OPN, TSP-2, HGF, and VEGF-R1) were prognostic for OS. Higher baseline levels of OPN (Pintx=0.0167), VCAM-1 (Pintx=0.0216), and PDGF-AA (Pintx=0.0435) appeared to predict for PFS benefit from regorafenib compared to placebo. VCAM-1 was also potentially predictive of OS benefit from regorafenib compared to placebo (Pintx=0.0124). On-treatment changes of six markers reflected potential on-target effect of regorafenib. Consistent results were observed in an Italian cohort where 105 late-stage mCRC patients received regorafenib monotherapy. The key findings of this study suggest that VCAM-1 may be a predictive biomarker for regorafenib benefit while multiple protein markers may be prognostic of outcome in mCRC patients.