Ramucirumab With FOLFIRI in Metastatic Colorectal Cancer

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In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On April 24, the monoclonal antibody ramucirumab ­(Cyramza) was approved for use in combination with FOLFIRI (leucovorin, fluorouracil, irinotecan) for treatment of patients with metastatic colorectal cancer with disease progression on a first-line line regimen including bevacizumab (Avastin), oxaliplatin, and a fluoropyrimidine.1,2  The drug was initially approved to treat patients with gastric cancer and, subsequently, to treat non–small cell lung cancer.

Supporting Trial

Approval was based on results of the phase III RAISE trial showing significantly increased overall survival with ramucirumab treatment in this setting.2,3 In the trial, 1,072 patients were randomly assigned to FOLFIRI plus ramucirumab (n = 536) or FOLFIRI plus placebo (n = 536) given in 2-week cycles. Ramucirumab was given every 2 weeks at 8 mg/kg via intravenous infusion until disease progression or unacceptable toxicity.

Patients had a median age of 62 years, 57% were male, 76% were white and 20% were Asian, 49% had Eastern Cooperative Oncology Group (ECOG) performance status of 0, 49% had KRAS-mutant tumors, and time to disease progression after beginning first-line treatment was < 6 months in 24%.

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 placebo group (hazard ratio [HR] = 0.85, P = .023). Progression-free survival was also significantly prolonged in the ramucirumab group (median, 5.7 vs 4.5 months, HR = 0.79, P < .001).

How It Works 

Ramucirumab is a recombinant human IgG1 monoclonal antibody that acts as a vascular endothelial growth factor receptor 2 (VEGFR2) antagonist. It specifically binds VEGFR2 and blocks binding of the VEGFR ligands VEGF-A, VEGF-C, and VEGF-D.

As a result of receptor blockade, ramucirumab inhibits ligand-stimulated activation of VEGFR2, thus inhibiting ligand-induced proliferation and migration of endothelial cells. Ramucirumab inhibited angiogenesis in animal models.

How It Is Given

The recommended dose of ramucirumab in metastatic colorectal cancer is 8 mg/kg every 2 weeks via intravenous infusion over 60 minutes prior to FOLFIRI administration. Ramucirumab should be continued until disease progression or unacceptable toxicity. All patients should be premedicated with an intravenous histamine H1 antagonist (eg, diphenhydramine hydrochloride) prior to each infusion; patients who have a grade 1 or 2 infusion reaction should also be premedicated with dexamethasone (or equivalent) and acetaminophen.

The infusion rate should be reduced by 50% for grade 1 or 2 infusion-related reactions, and treatment should be permanently discontinued for grade 3 or 4 infusion-related reactions. Treatment should be interrupted in patients with severe hypertension and prior to surgery until wounds are fully healed. Treatment should be interrupted in patients with urine protein levels ≥ 2 g/24 hours and restarted after improvement to < 2 g/24 hours at 6 mg/kg upon first occurrence and at 5 mg/kg upon second occurrence. Ramucirumab should be permanently discontinued in patients with severe hypertension that cannot be managed with antihypertensive therapy, proteinuria of > 3 g/24 hours or nephrotic syndrome, arterial thromboembolic events, gastrointestinal perforation, grade 3 or 4 bleeding, or reversible posterior leukoencephalopathy syndrome.

Safety Profile

In the phase III trial, patients received a median of 8 doses (range, 1–68) of ramucirumab. Median duration of exposure was 4.4 months, with 32% of patients receiving ramucirumab for ≥ 6 months. Safety data were generally consistent with the safety profile of ramucirumab in other approved indications. An exception is thyroid dysfunction (hypothyroidism), which was reported in 2.6% of patients based on thyroid monitoring in patients with metastatic colorectal cancer.

The most common adverse events of any grade in patients receiving ramucirumab-FOLFIRI that occurred with an incidence ≥ 2% higher vs the placebo-FOLFIRI group were diarrhea (60% vs 51%), neutropenia (59% vs 46%), decreased appetite (37% vs 27%), epistaxis (33% vs 15%), and stomatitis (31% vs 21%). The most common grade ≥ 3 adverse events were neutropenia (38% vs 33%), diarrhea (11% vs 10%), and hypertension (11% vs 3%). Granulocyte colony-stimulating factor treatment was required in 20% of patients in the ramucirumab group. Adverse events led to discontinuation of any study drug in 29% vs 13% of patients, with the most common being neutropenia (12.5% vs 5.3%) and thrombocytopenia (4.2% vs 0.8%); the most common events leading to discontinuation of ramucirumab were proteinuria (1.5%) and gastrointestinal perforation (1.7%). The most common serious adverse events in the ramucirumab group were diarrhea (3.6%), intestinal obstruction (3.0%), and febrile neutropenia (2.8%).

Ramucirumab carries boxed warnings for hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events, gastrointestinal perforation, and impaired wound healing. It also has warnings/precautions for arterial thromboembolic events (sometimes fatal), hypertension, infusion-related reactions, clinical deterioration in patients with cirrhosis (including new onset or worsening encephalopathy, ascites, or hepatorenal syndrome), reversible posterior leukoencephalopathy syndrome, proteinuria, thyroid dysfunction, and embryofetal risk. Patients should be monitored for hypertension, proteinuria, and thyroid function during treatment and for infusion-related reactions. ■


1. U.S. Food and Drug Administration: Ramucirumab mCRC. Available at Accessed May 4, 2015.

2. Cyramza® (ramucirumab) injection prescribing information, Eli Lilly and Company, April 2015. Available at Accessed May 4, 2015.

3. 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 2015 5:499-508, 2015.