Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study

Abstract

BackgroundThe phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo + FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes.Patients and methodsPlasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1 : 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1 : 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment.ResultsBiomarker results were available from >80% (n = 894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME + MC populations found that the median OS in the ramucirumab + FOLFIRI arm compared with placebo + FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95% CI 12.5–15.6) versus 11.5 months (95% CI 10.1–12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95% CI 10.7–14.0) versus 13.1 months (95% CI 11.8–17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers.ConclusionsThe RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing.Clinical trials registrationNCT01183780.

The Role of Angiogenesis in Hepatocellular Carcinoma

“…Identifying tumors most sensitive to antiangiogenic therapy could improve therapeutic approaches. The search for potential predictive markers has emphasized the target or target receptors, with the VEGF pathway components being the primary focus (25); yet this search has yielded little success (50)(51)(52)(53).…”

Syntaxin binding protein 4 as a novel therapeutic target and an effective biomarker for better treatment selection in lung squamous cell carcinoma: A theranostic study

“…The use of the immune-checkpoint inhibitor (Pembrolizumab) for metastatic LSCC patients with tumors showing 50% or greater PD-L1 (CD274) is now widely recognized as a standard rst-line therapy (1)(2)(3)20). The putative predictive markers of Ramucirumab-based regimens remain unclear (21), but high-level STMN1 expression was demonstrated as a potent determinant of chemo-resistance and, thus, a poor prognosis in LSCC patients (13). The AKT/FOXM1/STMN1 pathway was indicated to drive resistance to tyrosine kinase inhibitors in advanced non-small cell lung cancer including LSCC (22).…”

Current and New Predictors for Treatment Response in Metastatic Colorectal Cancer. The Role of Circulating miRNAs as Biomarkers

“…Ramucirumab is a VEGFR2 -binding monoclonal antibody used in second-line treatment of mCRC that improves both PFS and OS, in combination with FOLFIRI. Data related to biomarker results in the RAISE study were available for 894 patients and showed that a high plasma level of VEGFD (>115 pg/mL) is a potential predictive biomarker for treatment response [45].…”