BACKGROUND: 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. METHODS: 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 FINDINGS: 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%]). INTERPRETATION: 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. FUNDING: Eli Lilly.

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Gastroenterology National Cancer Centre Hospital East Chiba Japan

Department of Oncology Asan Medical Centre University of Ulsan College of Medicine Seoul South Korea

Department of Oncology Mayo Clinic Rochester MN USA

Department of Oncology Szent László Hospital Budapest Hungary

Eli Lilly and Company Bridgewater NJ USA

Eli Lilly Canada Toronto ON Canada

Eli Lilly Indianapolis IN USA

Hospital General Universitario Gregorio Marañón Madrid Spain

Hospital Universitario Virgen del Rocio Instituto de Biomedicina de Sevilla RTICC Instituto Carlos 3 Spanish Ministry of Science and Innovation Seville Spain

Medical Oncology 1 Istituto Oncologico Veneto IOV IRCCS Padova Italy

Medical Oncology Department Vall d'Hebron University Hospital and Institute of Oncology Universitat Autònoma de Barcelona Barcelona Spain

Prof Dr Ion Chiricuta Institute of Oncology and UMF Iuliu Hatieganu Cluj Napoca Romania

Rocky Mountain Cancer Center US Oncology Denver CO USA

Shizuoka Cancer Centre Shizuoka Japan

Southern Medical Day Care Centre Wollongong NSW Australia

University Hospital Motol Prague Czech Republic

University Hospitals Gasthuisberg Leuven Belgium

West Clinic Memphis TN USA

Komentář v

Lancet Oncol. 2015 May;16(5):476-7. doi: 10.1016/S1470-2045(15)70169-5. PubMed

Komentář v

Nat Rev Clin Oncol. 2015 Jul;12(7):373. doi: 10.1038/nrclinonc.2015.80. PubMed

Erratum v

Lancet Oncol. 2015 Jun;16(6):e262. doi: 10.1016/S1470-2045(15)70273-1. PubMed

Citace poskytuje Crossref.org

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Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study

Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study

Exposure-response relationship of ramucirumab in patients with advanced second-line colorectal cancer: exploratory analysis of the RAISE trial

Subgroup analysis in RAISE: a randomized, double-blind phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab or placebo in patients with metastatic colorectal carcinoma progression

Aflibercept Plus FOLFIRI vs. Placebo Plus FOLFIRI in Second-Line Metastatic Colorectal Cancer: a Post Hoc Analysis of Survival from the Phase III VELOUR Study Subsequent to Exclusion of Patients who had Recurrence During or Within 6 Months of Completing Adjuvant Oxaliplatin-Based Therapy

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ClinicalTrials.gov
NCT01183780