1235P - Tumor heterogeneity affects the activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR mutant non-small cell...

Date 08 October 2016
Event ESMO 2016 Congress
Session Poster Display
Topics Non-Small Cell Lung Cancer
Presenter Nicola Normanno
Citation Annals of Oncology (2016) 27 (6): 416-454. 10.1093/annonc/mdw383
Authors N. Normanno1, A.M. Rachiglio2, M. Lambiase2, F. Fenizia2, A. Iannaccone2, N. Chicchinelli3, A. Morabito4, A. Montanino4, G. Rocco5, D. Galetta6, E.S. Montagna6, L. Crinò7, V. Ludovini7, B. Vincenzi8, E. Barletta9, C. Pinto10, F. Ferraù11, G. Botti12, M.C. Piccirillo13, F. Perrone13
  • 1Cell Biology And Biotherapy Unit, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, 80131 - Napoli/IT
  • 2Laboratory Of Pharmacogenomics, CROM, Istituto Nazionale Tumori “Fondazione G. Pascale”-IRCCS, Mercogliano (AV)/IT
  • 3Cell Biology And Biotherapy Unit, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, Napoli/IT
  • 4Medical Oncology Unit, Thoracic Department, Istituto Nazionale Tumori “Fondazione G.Pascale”- IRCCS, Napoli/IT
  • 5Thoracic Oncology, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, 80131 - Napoli/IT
  • 6Medical Oncology Department, Istituto Tumori Giovanni Paolo II, 70124 - Bari/IT
  • 7Medical Oncology, Santa Maria della Misericordia Hospital, 06122 - Perugia/IT
  • 8Medical Oncology, Libero Istituto Universitario Campus Bio-Medico (LIUCBM), 00118 - Roma/IT
  • 9Medical Oncology, Azienda Ospedaliera G. Rummo, Benevento/IT
  • 10S. C. Oncologia, Azienda Ospedaliera Arcispedale Santa Maria Nuova - IRCCS, Reggio Emilia/IT
  • 11Medical Oncology, Ospedale San Vincenzo, Taormina/IT
  • 12Dipartimento Di Anatomia Patologica, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, 80100 - Napoli/IT
  • 13Clinical Trial Unit, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, 80131 - Napoli/IT



Recent findings suggest that a fraction of EGFR mutant NSCLC carries additional driver mutations which could potentially affect the activity of EGFR TKIs. We investigated the role of KRAS, NRAS, BRAF, PIK3CA, MET and ERBB2 mutations (other mutations) on the outcome of NSCLC pts treated with EGFR TKIs.


EGFR mutant NSCLC pts who received first line therapy with EGFR TKIs were eligible. Genomic DNA from EGFR mutant NSCLC samples as assessed with routine diagnostic methods, was retrospectively analyzed with the Ion AmpliSeq Colon and Lung Cancer Panel using Ion Torrent semiconductor sequencing. The panel assesses over 500 somatic mutations in 22 genes at a sensitivity of 2%. Mutations were detected using the Ion Reporter Software v4.6.


132 pts, treated between Jun 2008 and Dec 2014 in 7 centers, were enrolled: median age 71 (range 41-92); 70% women; 61% never smokers. Analysis of EGFR mutant samples with NGS revealed the presence of hotspot mutations in genes other than the EGFR, including KRAS, NRAS, BRAF, ERBB2, PIK3CA or MET, in 29/132 cases (22%). In most cases the allelic frequency of the other mutations was different as compared with EGFR mutations, suggesting intra-tumor heterogeneity. A T790M mutation was also found in 9/132 tumor samples (6.8%). The progression free survival (PFS) of pts without other mutations was 11.3 months versus 7 months in pts with other mutations (Log-rank test univariate: p = 0.0298). In a multivariate Cox regression model including the presence of other mutations, age, performance status, smoking status and the presence of T790M mutations, the presence of other mutations was the only factor significantly associated with PFS (Hazard Ratio 1.63, 95% CI 1.04-2.58; p = 0.035). Response rate in pts with or without other mutations was 59% and 68%, respectively (p = 0.349).


These data suggest that a subgroup of EGFR mutant tumors have intra-tumor heterogeneity and that this phenomenon might affect the activity of first line EGFR TKIs.

Clinical trial identification

This observational study was approved by the Ethical Committee of the Pascale Institute: protocol n. 16/14 OSS

Legal entity responsible for the study

Istituto Nazionale Tumori “Fondazione G. Pascale”-IRCCS, Naples, Italy


Associazione Italiana per la Ricerca sul Cancro (AIRC)


All authors have declared no conflicts of interest.