Analysis of Angiogenesis Biomarkers for Ramucirumab Efficacy in Patients with Metastatic Colorectal Cancer from RAISE, a Global, Randomized, Double-Blind, Phase III Study

Abstract

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 performed 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 performed 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