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 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.

Figure 1.

Overall survival in patients receiving ramucirumab + FOLFIRI compared with that in patients receiving placebo + FOLFIRI in patients with (A) high VEGF-D expression levels (≥115 pg/ml) and (B) low VEGF-D expression levels (<115 pg/ml). CI, confidence interval; FOLFIRI, 5-fluororuracil, leucovorin, and irinotecan; HR, hazard ratio; VEGF-D, vascular endothelial growth factor D.

Figure 2.

Progression-free survival in patients receiving ramucirumab + FOLFIRI compared with that in patients receiving placebo + FOLFIRI in patients with (A) high VEGF-D expression levels (≥115 pg/ml) and (B) low VEGF-D expression levels (<115 pg/ml). CI, confidence interval; FOLFIRI, 5-fluororuracil, leucovorin, and irinotecan; HR, hazard ratio; VEGF-D, vascular endothelial growth factor D.

Figure 3.

VEGF-D (N = 884) subpopulation treatment effect pattern plot (STEPP) with sliding windows of size 200 with the largest overlap between windows of size 160 for (A) overall survival and (B) progression-free survival. VEGF-D, vascular endothelial growth factor D.