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Lancet Oncol. 2015 May;16(5):499-508. doi: 10.1016/S1470-2045(15)70127-0. Epub 2015 Apr 12.

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.

Collaborators (277)

Fein L, Kotliar M, Palazzo F, O'Connor J, Perez JE, Kowalyszyn R, Pavlakis N, Goldstein D, Karapetis C, Clingan P, Ng W, Atkinson V, Underhill C, Price T, Ulsperger E, Scheithauer W, Dittrich C, Van Cutsem E, Van Laethem JL, Hendlisz A, Peeters M, Polus M, Van Den Eynde M, Humblet Y, Moons V, Delaunoit T, Carrasco J, Borges G, Franke F, Silva MJ, Ganzl R, Coutinho A, Stahalova V, Prausova J, Obermannova R, Vanasek J, Pribylova J, Pfeiffer P, Petersen L, Salminen T, Osterlund P, Rougier P, Ramee JF, Achille E, Fonck M, Ferru A, Dupuis O, Laplaige P, Heinemann V, Schepp W, Kisro J, Kullmann F, Bolling C, Heinrich B, Graeven U, Folprecht G, Hegewisch-Becker S, Büchner-Steudel P, Suefferlein T, Karthaus M, Whitlock B, März W, Al-batran SE, Patila E, Pavlidis N, Varthalitis I, Kosmas C, Bodoky G, Pajkos G, Nagy Z, Gangadharan V, Goswami C, Patil S, Geva R, Hubert A, Man S, Brenner B, Beny A, Golan T, Sobrero A, Boni C, Barone C, Zagonel V, Lonardi S, Latini L, Cappuzzo F, Yukisawa S, Warita E, Kato T, Komatsu Y, Fujii H, Nagase M, Nagashima F, Segawa Y, Shimada K, Sasaki Y, Yamaguchi K, Yamazaki K, Yoshino T, Esaki T, Muro K, Nishina T, Tamura T, Nishina S, Okamoto W, Sato T, Sugimoto N, Goto M, Takiuchi H, Morita S, Tsuji A, Yoshida K, Denda T, Ohtsu S, Shimada Y, Hamaguchi T, Sato T, Tsuji A, Boku N, Nakajima T, Park YS, Kim TW, Ahn JB, Kim SY, Kim BS, Han B, Shin DB, Kang SY, Erdkamp F, Kuenen B, De Jong R, Loosveld O, Creemers GJ, Vervenne W, Sa A, Fragoso R, Volovat C, Ciuleanu T, Croitoru A, Mihutiu S, Garcia Carbonero R, Vieitez De Prado JM, Dotor Navarro E, Garcia Alfonso P, Macarulla Mercada T, Tabernero J, Lema Roso L, Gravalos Castro C, Guillen Ponce C, Grande Pulido E, Safont Aguilera MJ, Teijeira L, Viudez Berral A, Berglund A, Glimelius B, Karlberg M, Liang JY, Yang TS, Spahr J, Goel S, Tan B, Beck J, Kozloff M, Chaves J, Yee L, Knost J, Jujjavarapu S, Eisenberg P, Wertheim M, Wong L, Pennington K, Ayers J, Horvath L, Malhotra D, Reid T, Thomas J, Ritch P, Santala R, Andrews W, Azad N, Hansen V, Keiser W, Niederman T, May AS, Kirkel D, Shankaran V, Hunter-Mellado R, Chao J, Shibata S, Wu D, Makhoul I, Polikoff J, Panwalkar A, Badarinath S, Holcombe R, Goel S, Kemeny M, Rado T, Kendall S, Carney J, Jennis A, Portnoy D, Schwartzberg L, Nikolinakos P, Khan D, Sabbath K, Greenberg R, Hermann R, Hartner L, Patterson S, Pascuzzo J, Cole S, Townsend D, Knapp M, Damsker J, Modiano M, Encarnacion C, Chakmakjian C, Anderson T, Fleischauer S, Awasthi S, Berry W, Brooks D, McCollum A, Chittoor S, Cohn A, Chang D, Cox J, Solanki D, Mizrachi A, Santos E, Flynn P, Demarco L, Guzley G, Cline-Burkhardt V, Jain S, Ucar A, Khandelwal P, Martincic D, Lindquist D, Marek B, Calomeni C, McKenney S, Melnyk A, Muscato J, Papish S, Nguyen D, Park M, Prakash S, Cartwright T, Richards D, Roque T, Ruxer R, Saidman B, Shao S, Rodney A, Spira A, Wadlow R, Ulrich B, Braiteh F, Vogelzang N, Harroff A, Wilks S, Tin-u C, Kosmo M, Gupta M, Karimi M, Ebrahimi B, Houck W, Levine R, Rubenstein S, Firdaus I, Acs P, Reeves J, Voelzke W, Xiong H, Bendell J.

Author information

1
Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain. Electronic address: jtabernero@vhio.net.
2
Department of Gastroenterology, National Cancer Centre Hospital East, Chiba, Japan.
3
Rocky Mountain Cancer Center/US Oncology, Denver, CO, USA.
4
Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
5
Department of Oncology, Szent László Hospital, Budapest, Hungary.
6
Hospital Universitario Virgen del Rocio, Instituto de Biomedicina de Sevilla, RTICC, Instituto Carlos III, Spanish Ministry of Science and Innovation, Seville, Spain.
7
Prof Dr Ion Chiricuta Institute of Oncology and UMF Iuliu Hatieganu, Cluj-Napoca, Romania.
8
West Clinic, Memphis, TN, USA.
9
University Hospitals Gasthuisberg, Leuven, Belgium.
10
Department of Oncology, Mayo Clinic, Rochester, MN, USA.
11
University Hospital Motol, Prague, Czech Republic.
12
Hospital General Universitario Gregorio Marañón, Madrid, Spain.
13
Shizuoka Cancer Centre, Shizuoka, Japan.
14
Southern Medical Day Care Centre, Wollongong, NSW, Australia.
15
Medical Oncology 1, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy.
16
Department of Oncology, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, South Korea.
17
Eli Lilly Canada, Toronto, ON, Canada.
18
Eli Lilly, Indianapolis, IN, USA.
19
Eli Lilly and Company, Bridgewater, NJ, USA.

Abstract

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.

PMID:
25877855
DOI:
10.1016/S1470-2045(15)70127-0
[Indexed for MEDLINE]
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