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

Abstract

◥Regorafenib is a tyrosine kinase inhibitor approved by the FDA for the treatment of patients with chemotherapy refractory metastatic colorectal cancer (mCRC). 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 AE regorafenib in patients with second-line mCRC. 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, IL6, PlGF, VEGF-R1, OPN, and IL6R) were found to be prognostic for PFS. Nine markers (IL6, TIMP-1, PlGF, VCAM-1, ICAM-1, OPN, TSP-2, HGF, and VEGF-R1) were prognostic for OS. Higher baseline levels of OPN (P intx ¼ 0.0167), VCAM-1 (P intx ¼ 0.0216), and PDGF-AA (P intx ¼ 0.0435) appeared to predict for PFS benefit from regorafenib compared with placebo. VCAM-1 was also potentially predictive of OS benefit from regorafenib compared with placebo (P intx ¼ 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 patients with late-stage mCRC 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 patients with mCRC.

Clinical Impact of Primary Tumor Location in Metastatic Colorectal Cancer Patients Under Later-Line Regorafenib or Trifluridine/Tipiracil Treatment

“…Small studies suggest that APC mutations or FGFR1 amplification in tumor tissue were more enriched in REG patients with a clinical benefit than those without, ( 28 ) and plasma VCAM-1 was potentially predictive of OS benefit in REG treatment. ( 29 ) A survival benefit of FTD/TPI was observed regardless of KRAS status. ( 11 , 12 ) High thymidine kinase 1 (TK1) expression level correlated with a larger survival benefit in FTD/TPI treatment, ( 30 ) although no significant difference in TKI expression according to PTL was reported.…”

Endoglin Targeting: Lessons Learned and Questions That Remain

“…To enrich patients most likely to benefit, as well as to investigate the molecular impact of the drug, blood-based biomarkers were analyzed using multiplex ELISA to quantitatively assess circulating proteins related to angiogenesis, inflammation and immunity. This panel, termed the angiome [ 52 ], is a protein multiplex array that was consistently applied to several TRC105 clinical trials in order to explore potential prognostic, predictive and pharmacodynamic biomarkers. A list of all the clinical trials testing TRC105 is shown in Table 1 .…”

Angiokines Associated with Targeted Therapy Outcomes in Patients with Non–Clear Cell Renal Cell Carcinoma

“…Patients who progressed at or before cycle 3 had only two collections. Angiokines were measured as previously described and validated (14,15). All samples underwent one freeze-thaw cycle prior to analysis.…”