Effect of Early Adverse Events on Survival Outcomes of Patients with Metastatic Colorectal Cancer Treated with Ramucirumab

Abstract

Background: Studies of patients treated with bevacizumab and other vascular epithelial growth factor (VEGF) inhibitors have reported that hypertension adverse events (AEs) are associated with improved overall survival (OS) or progression-free survival (PFS). Objective: Our objective was to evaluate the association between early AEs and survival outcomes for patients treated with ramucirumab, an antibody targeting the VEGF receptor-2 (VEGFR-2), plus FOLFIRI for metastatic colorectal cancer (mCRC). Methods: Data from 529 patients treated with ramucirumab plus FOLFIRI for mCRC in the RAISE clinical trial (NCT01183780) were evaluated to see whether early (first 6 weeks of therapy) AEs predicted subsequent OS and PFS. A Cox proportional hazard approach was used to evaluate associations between early AEs and survival outcomes. A secondary analysis between FOLFIRI and placebo was conducted as a sensitivity analysis. Results: Of 529 patients treated with ramucirumab plus FOLFIRI, 479 were alive and progression free at 6 weeks after commencing therapy. No significant association was identified between hypertension occurring within the first 42 days of ramucirumab plus FOLFIRI therapy and OS (grade 1–2, hazard ratio [HR] 0.90 [95% confidence interval (CI) 0.66–1.24]; grade 3+, HR 1.02 [95% CI 0.67–1.55]; P = 0.803) or PFS (grade 1–2, HR 0.98 [95% CI 0.74–1.28]; grade 3+, HR 0.93 [95% CI 0.64–1.37]; P = 0.93). However, there was a significant association between diarrhea occurring within the first 42 days of ramucirumab plus FOLFIRI therapy and worse OS (grade 1–2, HR 0.96 [95% CI 0.76–1.20]; grade 3+, HR 2.72 [95% CI 1.67–4.44]; P = 0.001) and PFS (grade 1–2, HR 1.01 [95% CI 0.83–1.23]; grade 3+, HR 2.22 [95% CI 1.43–3.45]; P = 0.005). No other AEs were significantly associated with OS or PFS. Conclusions: Ramucirumab-induced hypertension was not associated with improved OS and PFS in patients with mCRC treated with ramucirumab and FOLFIRI, but severe diarrhea was associated with poorer OS and PFS. Clinical trial registration: No. NCT01183780.