title: Meta-analysis comparing the efficacy of anti-EGFR monoclonal antibody therapy between KRAS G13D and other KRAS mutant metastatic colorectal cancer tumours.
abstract: BACKGROUND
  Metastatic colorectal cancer (mCRC) tumours harbouring a RAS mutation are associated with a lack of treatment benefit from anti-EGFR monoclonal antibodies (mAbs). However, observational evidence has led to speculation that mCRC patients with KRAS G13D mutant (MT) tumours may derive a benefit from treatment with anti-EGFR mAbs.
  
  
  METHODS
  We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate whether the efficacy of anti-EGFR mAbs for mCRC differs between tumours harbouring a KRAS G13D mutation (KRAS G13D) and KRAS mutations other than G13D (other KRAS MT).
  
  
  RESULTS
  Eight RCTs (n = 5967) met the inclusion criteria for assessment of both overall survival (OS) and progression-free survival (PFS). For other KRAS MT the hazard ratio for OS benefit with addition of anti-EGFR mAb therapy was 1.06 (95% confidence interval [CI]; 0.96, 1.17), compared to 1.08 (95% CI; 0.73, 1.60) for KRAS G13D [test for interaction p=0.99]. In contrast, the hazard ratio for KRAS wild-type (WT) tumours was 0.85 (95% CI; 0.76, 0.95). Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 1.07 (95% CI; 0.92, 1.26) for other KRAS MT, 0.96 (95% CI; 0.73, 1.27) for KRAS G13D, and 0.68 (95% CI; 0.54, 0.85) for KRAS WT. Again, the test for interaction (p=0.46) demonstrated no significant difference in PFS benefit for anti-EGFR mAb therapy between KRAS G13D and other KRAS MT.
  
  
  CONCLUSIONS
  This meta-analysis demonstrates no significant difference between KRAS G13D and other KRAS MT tumours in terms of treatment benefit from anti-EGFR mAbs for mCRC.
authors.affiliation: Department of Clinical Pharmacology, School of Medicine, Flinders University, Adelaide, 5042, Australia; Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, 5042, Australia. Electronic address: andrew.rowland@flinders.edu.au.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rowland
authors.affiliation: Department of Clinical Pharmacology, School of Medicine, Flinders University, Adelaide, 5042, Australia; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, 5000, Australia.
authors.forename: Mafalda M
authors.initials: MM
authors.lastname: Dias
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, 5000, Australia.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wiese
authors.affiliation: Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, 5042, Australia.
authors.forename: Ganessan
authors.initials: G
authors.lastname: Kichenadasse
authors.affiliation: Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, 5042, Australia.
authors.forename: Ross A
authors.initials: RA
authors.lastname: McKinnon
authors.affiliation: Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, 5042, Australia.
authors.forename: Christos S
authors.initials: CS
authors.lastname: Karapetis
authors.affiliation: Department of Clinical Pharmacology, School of Medicine, Flinders University, Adelaide, 5042, Australia; Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, 5042, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sorich
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009362:Neoplasm Metastasis; D010641:Phenotype; D016016:Proportional Hazards Models; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRAS G13D mutation; anti-EGFR monoclonal antibodies; metastatic colorectal cancer; predictive biomarkers.