168O - Pooled analysis of the prognostic and predictive value of KRAS mutation status and mutation subtype in patients with non-small cell lung cancer (NS...

Date 27 September 2014
Event ESMO 2014
Session Biomarkers and tumour heterogeneity
Topics Translational Research
Non-small-cell lung cancer
Basic Principles in the Management and Treatment (of cancer)
Presenter Alona Zer
Citation Annals of Oncology (2014) 25 (suppl_4): iv58-iv84. 10.1093/annonc/mdu326
Authors A. Zer1, K. Ding2, S. Lee3, G. Goss4, L.K. Seymour2, P.M. Ellis5, P.A. Bradbury2, C. O'Callaghan2, M. Tsao6, F.A. Shepherd7
  • 1Medical Oncology And Hematology, Princess Margaret Cancer Center, M5T 2M9 - Toronto/CA
  • 2Ncic Clinical Trials Group, Queen's University, Kingston/CA
  • 3Oncology, University College London (UCL) Hospitals & UCL Cancer Institute, NW1 2PG - London/GB
  • 4Medical Oncology, The Ottawa Hospital Cancer Centre, K1H 8L6 - Ottawa/CA
  • 5Medical Oncology, Jurvainski Cancer Centre, L8V 5C2 - Hamilton/CA
  • 6Pathology Department, Princess Margaret Cancer Centre, Toronto/CA
  • 7University Health Network, Princess Margaret Cancer Centre, M5G 2M9 - Toronto/CA



Subset analyses from 9 randomized trials report conflicting results concerning the ability of KRAS mutation (M+) status to predict benefit from E-TKIs. This pooled analysis of 4 trials of E-TKIs v placebo was conducted to clarify the prognostic/predictive roles of KRAS M+ and to explore the importance of M+ subtype.


Data were pooled for patients with known KRAS status from 4 trials of E-TKI v placebo (NCIC CTG BR.21 & TOPICAL - erlotinib in advanced NSCLC; BR.26 - dacomitinib in advanced NSCLC; BR.19 - postoperative gefitinib) Exploratory analyses were performed to identify relationships between M status/subtype, overall (OS), disease-free & progression-free survival (DFS, PFS) with an adjusted Cox model.


KRAS status was known in 1366 patients (787 E-TKI, 579 placebo); 275 (20%) had M+ (252 codon 12; 15 codon 13). In the placebo arm there was no OS difference for patients with KRAS M+ or wild-type (WT) tumors (HR 1.04, CI .82-1.33), nor between M+ codon 12 & 13. Patients with G12C/G12V M+ had significantly longer OS than those with G12D/G12S or G12A/G12R (med OS 9.2, 1.7, 3.9 m, respectively, p = .015). Patients with KRAS WT tumors receiving E-TKIs had significantly improved PFS and a trend for OS (PFS HR .73, CI .63-0.83, p < .001; OS HR .91, CI 0.79-1.04, p = .09) and higher ORR (9.1 v 1.3% p = .02). Patients with KRAS M+ had no benefit (OS HR 1.13, CI 0.85-1.51), PFS (HR 1.02, CI .76-1.36). The interaction was significant for PFS (p = .04), but not OS (p = .17). There was significant OS benefit from E-TKIs in patients with advanced WT adenocarcinoma (HR 0.74, CI 0.6-0.93, p = .008), but not KRAS M+ (HR 1.14, CI 0.77-1.69, interaction p = .06). For G12C/G12V M + , treatment with E-TKIs potentially was harmful (OS HR 1.41, CI 0.97-2.05, p = 0.07) but not G12D/G12S (OS HR 0.49, CI 0.24-1.00, p = 0.05).


KRAS M+ is not homogenous in terms of prognosis or prediction of benefit from E-TKIs. G12C/G12V subtypes are associated with better prognosis but potentially worse outcome with E-TKIs. While G12D/G12S subtypes have poorer prognosis, patients with these mutations appear to benefit from E-TKIs. These observations require validation.


All authors have declared no conflicts of interest.