Journal Article

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

Van Cutsem, Eric, Nasroulah, Federico, Garcia-Carbonero, Rocio, Cohn, Allen Lee, Simms, Lorinda, Tabernero, Josep, Garcia-Alfonso, Pilar, Grothey, Axel, Yamazaki, Kentaro, Lonardi, Sara, Yoshino, Takayuki, Bodoky, Gyorgy, Clingan, Philip R, Chang, Shao-Chun, Portnoy, David C, Ciuleanu, Tudor-Eliade, Prausová, Jana, Kim, Tae Won, Obermannova, Radka

2015

Overview

Angiogenesis is an important therapeutic target in colorectal carcinoma. Ramucirumab is a human IgG-1 monoclonal antibody that targets the extracellular domain of VEGF receptor 2. We assessed the efficacy and safety of ramucirumab versus placebo in combination with second-line FOLFIRI (leucovorin, fluorouracil, and irinotecan) for metastatic colorectal cancer in patients with disease progression during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Between Dec 14, 2010, and Aug 23, 2013, we enrolled patients into the multicentre, randomised, double-blind, phase 3 RAISE trial. Eligible patients had disease progression during or within 6 months of the last dose of first-line therapy. Patients were randomised (1:1) via a centralised, interactive voice-response system to receive 8 mg/kg intravenous ramucirumab plus FOLFIRI or matching placebo plus FOLFIRI every 2 weeks until disease progression, unacceptable toxic effects, or death. Randomisation 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. This study is registered with ClinicalTrials.gov, number NCT01183780.ld We enrolled 1072 patients (536 in each group). Median overall survival was 13·3 months (95% CI 12·4–14·5) for patients in the ramucirumab group versus 11·7 months (10·8–12·7) for the placebo group (hazard ratio 0·844 95% CI 0·730–0·976; log-rank p=0·0219). Survival benefit was consistent across subgroups of patients who received ramucirumab plus FOLFIRI. Grade 3 or worse adverse events seen in more than 5% of patients were neutropenia (203 [38%] of 529 patients in the ramucirumab group vs 123 [23%] of 528 in the placebo group, with febrile neutropenia incidence of 18 [3%] vs 13 [2%]), hypertension (59 [11%] vs 15 [3%]), diarrhoea (57 [11%] vs 51 [10%]), and fatigue (61 [12%] vs 41 [8%]). Ramucirumab plus FOLFIRI significantly improved overall survival compared with placebo plus FOLFIRI as second-line treatment for patients with metastatic colorectal carcinoma. No unexpected adverse events were identified and toxic effects were manageable. Eli Lilly.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Adult / Aged / Aged, 80 and over / Angiogenesis / Antibodies, Monoclonal - administration & dosage / Antibodies, Monoclonal, Humanized - administration & dosage / Antineoplastic Combined Chemotherapy Protocols - administration & dosage / Bevacizumab / Camptothecin - administration & dosage / Camptothecin - analogs & derivatives / Cancer therapies / Chemotherapy / Colorectal cancer / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - pathology / Disease-Free Survival / Female / Fluorouracil - administration & dosage / Hematology, Oncology and Palliative Medicine / Humans / Leucovorin - administration & dosage / Ligands / Male / Medical prognosis / Medical treatment / Metastasis / Middle Aged / Neoplasm Metastasis / Neoplasm Staging / Organoplatinum Compounds - administration & dosage / Oxaliplatin / Ramucirumab / Studies / Tumors