title: A study-level meta-analysis of efficacy data from head-to-head first-line trials of epidermal growth factor receptor inhibitors versus bevacizumab in patients with RAS wild-type metastatic colorectal cancer.
abstract: Head-to-head trials comparing first-line epidermal growth factor receptor inhibitor (EGFRI) versus vascular endothelial growth factor inhibitor (bevacizumab) therapy yielded differing results, and debate remains over optimal first-line therapy for patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC).
  
  
  
  A PubMed search identified first-line mCRC trials comparing EGFRI plus chemotherapy versus bevacizumab plus chemotherapy; data were subsequently updated using recent congress presentations. This study-level meta-analysis estimated the overall survival (OS) treatment effect of first-line chemotherapy plus EGFRIs or bevacizumab in patients with RAS WT mCRC. Secondary end-points were progression-free survival (PFS), objective response rate (ORR), resection rate and safety. Early tumour shrinkage (ETS) of ≥20% at week 8 was an exploratory end-point.
  
  
  
  Three trials comprising data from 1096 patients with RAS WT mCRC were included. OS (hazard ratio [HR]: 0.80 [95% confidence interval: 0.68-0.93]), ORR (odds ratio [OR]: 0.57) and ETS (OR: 0.48) favoured EGFRIs plus chemotherapy versus bevacizumab plus chemotherapy. PFS (HR: 0.98) and resections (OR: 0.93) were similar between treatments. For patients with KRAS exon 2 WT/'other' RAS mutant mCRC the OS HR was 0.70. A safety meta-analysis was not possible due to a lack of data; in the individual studies, skin toxicities and hypomagnesaemia were more common with EGFRIs, nausea and hypertension were more common with bevacizumab.
  
  
  
  This meta-analysis supports a potential benefit for first-line EGFRI plus chemotherapy versus bevacizumab plus chemotherapy with respect to OS, ORR and ETS in patients with RAS WT mCRC. A patient-level meta-analysis is awaited.
authors: Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, Marchioninistr. 15, D-81377, Munich, Germany. Electronic address: Volker.Heinemann@med.uni-muenchen.de.
authors: Volker
authors: V
authors: Heinemann
authors: Department of Medical Oncology, Hospital Universitario Marqués de Valdecilla, Av. de Valdecilla, 39008, Santander, Spain. Electronic address: oncrhf@humv.es.
authors: Fernando
authors: F
authors: Rivera
authors: Department of Oncology, Indiana University Simon Cancer Center, 535 Barnhill Drive, Indianapolis, IN, 46202, USA. Electronic address: bhoneil@iu.edu.
authors: Bert H
authors: BH
authors: O'Neil
authors: Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, Marchioninistr. 15, D-81377, Munich, Germany. Electronic address: Sebastian.Stintzing@med.uni-muenchen.de.
authors: Sebastian
authors: S
authors: Stintzing
authors: Biostatistics, Amgen Ltd, 1 Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex, UB8 1DH, UK. Electronic address: reijak@amgen.com.
authors: Reija
authors: R
authors: Koukakis
authors: Medical Development, Amgen Switzerland AG, Dammstrasse 23, 6301, Zug, Switzerland. Electronic address: jan-henrik.terwey@amgen.com.
authors: Jan-Henrik
authors: JH
authors: Terwey
authors: Department of Medical Oncology, Institut de Cancérologie de l'Ouest (ICO) René Gauducheau, 44805, St Herblain, France. Electronic address: jean-yves.douillard@esmo.org.
authors: Jean-Yves
authors: JY
authors: Douillard
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000627:therapeutic use*; D000068818:Cetuximab / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D003875:Drug Eruptions / Q000209:etiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D008274:Magnesium / Q000097:blood; D000077544:Panitumumab; D015996:Survival Rate; D014883:Water-Electrolyte Imbalance / Q000097:blood / Q000139:chemically induced; D018631:ras Proteins / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D000068258:Bevacizumab; D000077544:Panitumumab; C512478:EGFR protein, human; D066246:ErbB Receptors; D018631:ras Proteins; D008274:Magnesium; D000068818:Cetuximab
keywords: Bevacizumab; Cetuximab; Meta-analysis; Panitumumab; Progression-free survival; Survival