Predictive biomarkers to identify patients with tumors most sensitive to antiangiogenic agents would probably further improve the efficacy outcomes of trials of these drugs. Such improvements might be a necessity owing to increasing scrutiny of cost-to-benefit ratios for treatments.
—Josep Tabernero, MD, PhD
In the phase III RAISE trial reported in The Lancet Oncology, Josep Tabernero, MD, PhD, Head of Medical Oncology at Vall d’Hebron Institute of Oncology, Barcelona, and colleagues found that the addition of the antiangiogenic anti–vascular endothelial growth factor receptor 2 (VEGFR2) antibody ramucirumab (Cyramza) to second-line FOLFIRI (leucovorin, fluorouracil, irinotecan) improved overall survival in patients with metastatic colorectal cancer that had progressed on first-line bevacizumab, oxaliplatin, and fluoropyrimidine treatment.1
In this double-blind trial, 1,072 patients from 24 countries were randomly assigned between December 2010 and August 2013 to receive ramucirumab at 8 mg/kg plus FOLFIRI (n = 536) or FOLFIRI plus placebo (n = 536) every 2 weeks until disease progression or unacceptable toxicity after progression on first-line therapy. Randomization was stratified by region, KRAS mutation status, and time to disease progression after starting first-line treatment. The primary endpoint was overall survival in the intention-to-treat population.
The ramucirumab and control groups were generally balanced for age (mean, 62 years in both, 40% ≥ 65 years in both), sex (54% and 61% male), ethnicity (76% and 77% white, 21% and 19% Asian), region (Europe for 44% in both, North America for 27% in both), Eastern Cooperative Oncology Group performance status (0 for 49% and 48%, 1 for 50% and 51%), time to progression after start of first-line treatment (≥ 6 months for 77% and 76%), KRAS mutation status (mutant in 50% and 49%), carcinoembryonic antigen level (< 200/µg/L in 73% in both), number of metastatic sites (1 in 32% and 29%, 2 in 33% and 36%, ≥ 3 in 29% and 34%), and site of primary tumor (colon in 67% in both, rectum in 33% and 32%).
Improved Overall Survival
After study medication, subsequent systemic anticancer therapy was received by 54% of the ramucirumab group and 56% of the control group. Median follow-up was 21.7 months.
Median overall survival was 13.3 months (95% confidence interval [CI] = 12.4–14.5 months) in the ramucirumab group vs 11.7 months (95% CI = 10.8–12.7 months) in the control group (hazard ratio [HR] = 0.844, P = .0219). Hazard ratios favored the ramucirumab group in all evaluated subgroups, including KRAS status, time to disease progression, and region subgroups.
Median progression-free survival was 5.7 months (95% CI = 5.5–6.2 months) vs 4.5 months (95% CI = 4.2–5.4 months; HR = 0.793, P < .0005), with hazard ratios favoring ramucirumab in all evaluated subgroups. Objective response rates were 13.4% vs 12.5%, (P = .63).
Grade ≥ 3 adverse events occurred in 79% of the ramucirumab group (grade 4 in 17%) vs 62% of the control group (grade 4 in 14%). The most common were neutropenia (38% vs 23%), hypertension (11% vs 3%), diarrhea (11% vs 10%), and fatigue (12% vs 8%). Febrile neutropenia occurred in 3% vs 2%.
Grade 5 adverse events consisted of bleeding/hemorrhagic events in three patients in the ramucirumab group and one in the control group, gastrointestinal (GI) hemorrhage in three and one, liver injury/failure in one and one, GI perforation in four and zero , arterial thromboembolic event in one and five, and congestive heart failure in one and two.
Serious adverse events occurred in 36% vs 31% of patients. Adverse events led to dose modification in 83% vs 75% and discontinuation in 11% vs 4%. Ramucirumab dose omission, dose reduction, and discontinuation occurred in 8%, 6%, and 4%, respectively.
The investigators concluded:
In view of our results, the combination of ramucirumab with FOLFIRI is an effective second-line treatment for patients with metastatic colorectal carcinoma. Predictive biomarkers to identify patients with tumors most sensitive to antiangiogenic agents would probably further improve the efficacy outcomes of trials of these drugs. Such improvements might be a necessity owing to increasing scrutiny of cost-to-benefit ratios for treatments. We have begun translational research of prespecified potential biomarkers to assist in selection of patients. ■
Disclosure: The study was funded by Eli Lilly. For full disclosures of the study authors, visit www.thelancet.com.
1. Tabernero J, Yoshino T, Cohn AL, et al: Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): A randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16:499-508, 2015.
Weijing Sun, MD, FACP, of the UPMC GI Cancer Center of Excellence at the University of Pittsburgh, discusses angiogenesis inhibitors in metastatic colorectal cancer.
The phase III RAISE trial—reported by Tabernero and colleagues in The Lancet Oncology1 and reviewed in this issue of The ASCO Post—demonstrated that ramucirumab (Cyramza), a fully human IgG1 monoclonal antibody to the vascular endothelial growth factor receptor 2 (VEGFR2) extracellular domain, in...