Analysis of plasma protein biomarkers from the phase 3 CONCUR study of regorafenib in Asian patients with metastatic colorectal cancer (mCRC).

Abstract

672 Background: In the randomized phase 3 CONCUR trial (NCT01584830), regorafenib significantly improved overall survival (OS) and progression-free survival (PFS) vs placebo (PBO) in Asian patients (n = 136 regorafenib; n = 68 PBO) with treatment-refractory mCRC (HR [95% CI]: OS 0.55 [0.40‒0.77]; PFS 0.31 (0.22‒0.44]). Protein biomarker data from the phase 3 CORRECT trial of mostly Western patients with mCRC identified TIE-1 as a potential predictor of clinical response to regorafenib; however, this association was not significant in multivariable analyses. We present an exploratory protein biomarker analysis of patients in CONCUR. Methods: Sixteen proteins of interest, many of which are involved in angiogenesis, were quantified by multiplex immunoassay or ELISA in plasma samples collected at study entry from 121/204 (59%) patients (n = 83 regorafenib; n = 38 PBO). Potential predictive and prognostic effects were evaluated. Results: The biomarker cohort was representative of the overall study population in major baseline demographic factors, OS (HR 0.61; 95% CI 0.40‒0.93), and PFS (HR 0.25; 95% CI 0.16‒0.39). Elevated levels of ANG-2 (HR 2.46; p = 0.0016) and VEGF-A (HR 1.38; p = 0.03) were associated with poor OS prognosis; however, no significant association with treatment OS benefit for regorafenib vs PBO was observed for either marker (ANG-2: HR 0.76; p = 0.3307; VEGF-A: HR 0.83; p = 0.20). Elevated levels of five plasma proteins were associated with poor PFS prognosis: ANG-2 (HR 1.73; p = 0.0085), VEGF-A (HR 1.30; p = 0.0308), IL-8 (HR 1.67; p = 0.0014), VWF (HR 2.39; p = 0.0029), and IGF-BP2 (HR 1.71; p = 0.0384). Elevated levels of IL-8 (HR 0.70; p = 0.019), VWF (HR 0.53; p = 0.0312), and IGF-BP2 (HR 0.60; p = 0.0336) showed a modest interaction with regorafenib PFS; however, these results did not reach statistical significance after adjustment for multiple testing (p = 0.0045). Conclusions: None of the plasma proteins analyzed were predictive of regorafenib clinical benefit as measured by both OS and PFS in Asian patients with mCRC. These results, as well as those in CORRECT, suggest that rationally selected protein markers are not suitable to predict treatment benefit of regorafenib. Clinical trial information: NCT01584830.

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

“…Multiple potential prognostic markers were identified in LCCC1029 trial and the Italian cohort with a high degree of consistency. Our finding that PlGF is a negative prognostic marker in LCCC1029 is consistent with the CORRECT report (15), while the finding that Ang-2 is a negative prognostic marker in the Italian cohort is consistent with the CONCUR report (16).…”

“…However, to the best of our knowledge, circulating protein biomarkers have not been well-studied in patients receiving regorafenib in later-line settings. While a few prognostic markers were suggested in CORRECT (15) and CONCUR trials (16), no predictive biomarkers have been reported.…”

Prognostic factors for regorafenib treatment in patients with refractory metastatic colorectal cancer: A real-life retrospective multi-center study

“…Another subgroup analysis of the CORRECT study revealed that K-RAS and PIK3CA mutations were favorable prognostic factors for survival [ 20 ]. In addition, other subgroup analyses identified several prognostic biomarkers [ 21 ]. In real-world experiences, the potential prognostic factors were poor ECOG PS, a short time from the initial diagnosis of metastases to the start of regorafenib treatment (<160 mg), >3 metastatic sites, the presence of liver metastases, and the presence of K-RAS mutations [ 11 , 14 , 18 ].…”

Development and Validation of a Novel Serum Prognostic Marker for Patients with Metastatic Colorectal Cancer on Regorafenib Treatment

“…CEA has been routinely employed as a surrogate marker to detect early recurrence for patients with localized CRC who underwent surgical resection [22]. For advanced mCRC, the level of CEA has shown an inverse correlation with poor survival despite patients receiving therapy aggressively [23][24][25].…”