Andrew Rowland1, Mafalda M Dias2, Michael D Wiese3, Ganessan Kichenadasse4, Ross A McKinnon4, Christos S Karapetis4, Michael J Sorich5. 1. 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. 2. 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. 3. School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, 5000, Australia. 4. Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, 5042, Australia. 5. 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.
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. CONCLUSION: 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.
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 KRASG13D 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 KRASG13D mutation (KRASG13D) 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 KRASG13D [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 KRASG13D, 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 KRASG13D and other KRAS MT. CONCLUSION: This meta-analysis demonstrates no significant difference between KRASG13D and other KRAS MT tumours in terms of treatment benefit from anti-EGFR mAbs for mCRC.
Authors: Khurum H Khan; David Cunningham; Benjamin Werner; Georgios Vlachogiannis; Inmaculada Spiteri; Timon Heide; Javier Fernandez Mateos; Alexandra Vatsiou; Andrea Lampis; Mahnaz Darvish Damavandi; Hazel Lote; Ian Said Huntingford; Somaieh Hedayat; Ian Chau; Nina Tunariu; Giulia Mentrasti; Francesco Trevisani; Sheela Rao; Gayathri Anandappa; David Watkins; Naureen Starling; Janet Thomas; Clare Peckitt; Nasir Khan; Massimo Rugge; Ruwaida Begum; Blanka Hezelova; Annette Bryant; Thomas Jones; Paula Proszek; Matteo Fassan; Jens C Hahne; Michael Hubank; Chiara Braconi; Andrea Sottoriva; Nicola Valeri Journal: Cancer Discov Date: 2018-08-30 Impact factor: 39.397