1250P - Epidermal growth factor receptor (EGFR) and ABCG2 polymorphisms and treatment outcome in the randomized phase III TORCH trial in advanced non-small...

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Pathology/Molecular Biology
Translational Research
Non-small-cell lung cancer
Basic Scientific Principles
Basic Principles in the Management and Treatment (of cancer)
Presenter Geoffrey Liu
Citation Annals of Oncology (2014) 25 (suppl_4): iv426-iv470. 10.1093/annonc/mdu349
Authors G. Liu1, M. Di Maio2, M. Tsao3, D. Cheng4, Z. Chen4, R. Wierzbicki5, F. Riccardi6, M. Spatafora7, V. Adamo8, A. Favaretto9, R. Bianco10, R.W. Gregg11, R. Costanzo12, S. Signoriello13, C.A. Butts14, F. Ciardiello15, R. Feld16, C. Gallo13, C. Gridelli17, F. Perrone2
  • 1Department Of Medical Oncology, Princess Margaret Hospital, University Health Network, M5G 2M9 - Toronto/CA
  • 2Clinical Trials Unit, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, 80131 - Napoli/IT
  • 3Pathology Department, Princess Margaret Cancer Centre, Toronto/CA
  • 4Applied Molecular Oncology, Princess Margaret Hospital, Ontario Cancer institute, Toronto/CA
  • 5Oncology, LakeRidge Health (Oshawa), Oshawa/CA
  • 6Medical Oncology, Cardarelli Hospital, Napoli/IT
  • 7Pneumology, V.Cervello Hospital, Palermo/IT
  • 8Human Pathology, Unit of Integrated Therapies in Oncology, University Policlinic "G. Martino", 98125 - Messina/IT
  • 9Oncologia Medica 2, Istituto Oncologico Veneto IOV-IRCCS, IT-35128 - Padova/IT
  • 10Medical Oncology, University Federico II, Napoli/IT
  • 11Oncology, Cancer Centre of Southeastern Ontario, CA-K7L 5P9 - Kingston/CA
  • 12Thoraco-pulmonary, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, Napoli/IT
  • 13Medical Statistics, Second University, Napoli/IT
  • 14Department Of Oncology, University of Alberta Cross Cancer Institute, T6G 1Z2 - Edmonton/CA
  • 15Dip. Medico Chirurgico Di Internistica, Seconda Università Studi di Napoli Policlinico Federico II, 80131 - Napoli/IT
  • 16Medical Oncology, Princess Margaret Hospital, Toronto/CA
  • 17Medical Oncology, Azienda Ospedaliera S. Giuseppe Moscati, 83100 - Avellino/IT

Abstract

Aim

In the TORCH trial, molecularly unselected pts with advanced NSCLC were randomized to erlotinib or cisplatin + gemcitabine (CisGem) as first line within planned treatment sequences. To confirm previous data or explore new biomarkers, polymorphisms potentially affecting erlotinib activity (EGFR-216G > T [EGFR216], EGFR-191C > A [EGFR191], EGFR intron 1 CA-dinucleotide-repeat [CADR], ABCG2 + 421C > A [ABCG2]) were tested and the interaction with treatment was studied.

Methods

Genotyping was by Sanger sequencing and Taqman. Interaction between each polymorphism and treatment outcome was tested by Cox model for progression-free survival (PFS) and by Zelen exact test for response rate (RR) and toxicity (skin and diarrhoea).

Results

EGFR216 (known in 240 pts): G/G 32%, T/G 43%, T/T 25%. EGFR191 (240 pts): C/C 81%, A/C 17%, A/A 2%. ABCG2 (257 pts): C/C 85%, A/C 14%, A/A 1% (A/- 15%). CADR (262 pts): short/short (S/S) 28%, long/short 31%, long/long 40%. EGFR216 and EGFR191 had no significant interaction with treatment outcomes. ABCG2 polymorphism has no interaction with RR and toxicity but significantly affects treatment effect on PFS (interaction p = 0.039). HR (erlotinib vs CisGem) 1.69 (95% CI 1.28 – 2.23) in ABCG2 C/C and 0.71 (95% CI 0.34 – 1.47) in ABCG2 A/-. HR for ABCG2 A/- vs C/C was 0.68 (95% CI 0.40 – 1.14) and 1.47 (95%CI 0.90-2.44) in erlotinib and Cis/Gem arm respectively. CADR polymorphism was associated with skin toxicity but not diarrhoea: erlotinib produced more severe skin toxicity in CADR S/S pts (20% vs 6%, odds ratio 4.15, 95% CI 1.30-13.25, p = 0.013), while no severe skin toxicity was reported with CisGem.

Conclusions

TORCH data: (a) do not confirm previous evidence on the value of EGFR216 as predictive of EGFR TKI effect; (b) confirm no value of EGFR191; (c) suggest that erlotinib efficacy might be higher in ABCG2 A/- cases; and (d) suggest that skin toxicity of erlotinib might be higher in CADR S/S cases.

Disclosure

M. Di Maio and C. Gridelli: acted as consultant for Eli Lilli, Roche and received honoraria from Eli Lilli, Roche; M. Tsao: acted as consultant for AstraZeneca, Roche; he received honoraria from AstraZeneca, Roche and he received a research funding from Roche; C.A. Butts: acted as consultant for Roche and received honoraria from Roche; R. Feld: acted as consultant for Roche, received honoraria from Roche and received a research funding from Roche; F. Perrone: received honoraria from Roche and received a research funding from Roche. All other authors have declared no conflicts of interest.