Addition of Ramucirumab to Second-Line FOLFIRI Improves Overall Survival in Metastatic Colorectal Cancer


Key Points

  • The addition of ramucirumab to FOLFIRI in second-line treatment increased overall survival in patients with metastatic colorectal cancer.
  • No unexpected adverse events were observed, and toxicities were manageable.

In the phase III RAISE trial reported in The Lancet Oncology, Tabernero et al found that the addition of the antiangiogenic anti-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 (Avastin), oxaliplatin, and fluoropyrimidine treatment.

Study Details

In this double-blind trial, 1,072 patients from 24 countries were randomly assigned between December 2010 and August 2013 to receive ramucirumab 8 mg/kg plus FOLFIRI (n = 536) or FOLFIRI plus placebo (n = 536) every 2 weeks until disease progression or unacceptable toxicity after disease 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 disease 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 (one in 32% and 29%, two in 33% and 36%, three or more 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).

Adverse Events

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 adverse events 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 hemorrhage in three in the ramucirumab group and one in the control group; liver injury/failure in one patient in each group; gastrointestinal perforation in four patients in the ramucirumab group and none in the control group; arterial thromboembolic event in one in the ramucirumab group and five in the control group; and congestive heart failure in one in the ramucirumab group and two in the control group.

Serious adverse events occurred in 36% vs 31% of patients. Adverse events led to dose modification in 83% vs 75% and discontinuation of treatment 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.”

Josep Tabernero, MD, of Vall d’Hebron Institute of Oncology, Barcelona, is the corresponding author of The Lancet Oncology article.

The study was funded by Eli Lilly. For full disclosures of the study authors, visit

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