BACKGROUND: The 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 METHODS: Plasma 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. RESULTS: Biomarker 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. CONCLUSIONS: The 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 REGISTRATION: NCT01183780.

Department of Clinical Oncology Aichi Cancer Center Hospital Nagoya Japan

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Oncology and Radiotherapy University Hospital Motol Prague Czech Republic

Digestive Oncology University Hospital Gasthuisberg Leuven Belgium; KU Leuven Leuven Belgium

Division of Gastrointestinal Oncology Digestive Endoscopy National Cancer Center Hospital East Chiba Japan

Laboratory for Experimental Medicine Eli Lilly and Company Indianapolis USA

Medical Oncology Department Hospital Universitario 12 de Octubre CNIO; CIBERONC Universidad Complutense Madrid Spain

Medical Oncology Prof Dr 1 Chiricuţă Institute of Oncology Cluj Napoca Romania

Medical Oncology Rocky Mountain Cancer Center US Oncology Denver USA

Medical Oncology Vall d'Hebron University Hospital and Institute of Oncology Barcelona Spain; CIBERONC Universitat Autònoma de Barcelona Barcelona Spain

Oncology Eli Lilly and Company Argentina

Oncology Eli Lilly and Company Indianapolis USA

Oncology Szent László Hospital Budapest Hungary

Oncology West Clinic Memphis USA

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NCT01183780