Disclosure Information Relationships Relevant to this Session

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1 Disclosure Information Relationships Relevant to this Session Eli Lilly Please note, all disclosures are reported as submitted to ASCO, and are always available at chicago2012.asco.org

2 TArceva Italian Lung Optimization trial A phase III trial comparing erlotinib versus docetaxel as second-line treatment of NSCLC patients with wild-type EGFR M.C. Garassino, O. Martelli, A. Bettini, I. Floriani, E. Copreni, C. Lauricella, M. Ganzinelli, M. Marabese, M. Broggini, S. Veronese, G. Gherardi, F. Longo, M.A. Fabbri, M. Tomirotti, O. Alabiso, M.G. Sarobba, R. Labianca, S. Marsoni, G. Farina, A. Scanni Fatebenefratelli e Oftalmico Hospital, Milan, Italy On behalf of the TAILOR investigators Presented at the 2012 ASCO Annual. Presented data is the property of the author

3 TAILOR is an independent study sponsored by

4 Background Erlotinib has shown superiority vs best supportive care for the treatment of unselected NSCLC in second and third line * Five RCTs comparing chemo vs EGFR TKIs showed similar OS** All studies randomized unselected patients Only 2 trials reported outcomes by EGFR mutational status (unplanned analyses) in about 18% of randomized patients Possible negative predictive and prognostic role of KRAS * Shepherd FA, N Engl J Med ** Ciuleanu T, J Clin Oncol 2012; Kim ES, Lancet 2008; Maruyama R, J Clin Oncol 2008; Lee DH, Clin Cancer Res 2010; Vamvakas L, ASCO Proc 2010

5 TAILOR objectives 2007 TAILOR is designed as a prospective randomized biomarker-based study in wt-egfr patients treated with erlotinib or docetaxel The main objective was to test the interaction of EGFR expression and amplification (IHC/FISH) and KRAS mutations on treatment 2011 Asco s provisional clinical opinions on EGFR status 2 TAILOR planned interim analyses with IDMC Based on IDMC suggestions TAILOR was amended. The sample size was re-calculated by 2 independent statisticians blinded to the interim analysis results outcomes 1 2 Keedy VL T, J Clin Oncol Farina G, Clin Lung Cancer. 2011

6 Objectives of the study To demonstrate the superiority of docetaxel compared to erlotinib in patients with wt-egfr in terms of Overall Survival (OS) Secondary endpoints were Progression Free Survival (PFS), Response Rate, Safety, Quality of Life

7 Eligibility Criteria Inclusion criteria: Age older 18 years and written informed consent Histologically confirmed advanced NSCLC Confirmed EGFR wild-type Assessment of KRAS status Previous platinum based chemotherapy PS ECOG 0-2 Adequate haematological, liver and renal function Exclusion criteria: Previous chemotherapy with taxanes Previous therapy with anti EGFR agents

8 CROSS OVER NOT ALLOWED TAILOR Study Design Advanced/recurrent Previous platinum based doublet EGFR wild-type KRAS determined ECOG PS 0-2 R 1:1 DOCETAXEL 75 mg/m2 iv day 1,21 OR 35 mg/m2 iv day 1,8,15,28 ERLOTINIB 150 mg po, daily STRATIFICATION minimization approach centre recurrent/progressed type of prior chemotherapy regimen (pem vs gem vs vnb) ECOG-PS (0-1 vs 2) adequacy of tissue sample (optimal vs suboptimal)

9 Statistical Hypothesis 80% power 5% two-sided significance 1-year OS in erlotinib arm to be 20% 12 months minimum follow-up Max 5% lost to follow-up Interim analyses without formal stopping rules for efficacy To detect either a relative mortality reduction or a reduction for progression of 33% (HR 0.67) 199 events / 220 patients required


11 Reported Outcomes For the present analysis: Progression Free Survival Overall Response Safety Overall Survival: Required number of deaths not yet reached

12 Patients flow 702 registered 554 genotyped 222 randomized 219 ITT analysis 148 not eligible (21%) Insufficient material 124 Not Evaluable for EGFR/KRAS not randomized EGFR mutated 79 Non PD 116 Medical decision 33 Patient withdrawal 23 Deaths 64 Lost to Follow-up 14 Others 3 DOCETAXEL 110 ERLOTINIB Protocol major violations

13 DOCETAXEL (n=110) ERLOTINIB (n=109) Median Age, years (range) 67 (35-83) 66 (40-81) Gender ECOG PS Baseline patients demographic Histology Smoking Habit KRAS status Male Female Squamous Adenocarcinoma Others Smokers (also ex) Never-smokers Mutated Wild-type % %

14 Major reported toxicities TOXICITY G3-4 EVENTS DOCETAXEL (n = 104) ERLOTINIB (n = 107) Non haematological toxicity % % Nausea & Vomiting 3 1 Asthenia 8 6 Alopecia (all grades) 29 2 Dermatological toxicity 0 14 Diarrhoea 2 3 Neurological 8 1 Haematological toxicity % % Neutropenia 27 1 Febrile neutropenia 4 0

15 Safety analysis DOCETAXEL (n=104) % ERLOTINIB (n=107) % Patients with SAE Treatment-related SAEs Treatment-related deaths Treatment-related AEs leading to withdrawal Treatment-related AEs leading to dose modification

16 Progression free survival PFS [ITT] HR 0.69 (95%CI ) p=0.014 Median mos. 6-mos PFS Docetaxel % Erlotinib % Docetaxel Erlotinib Patients at risk Docetaxel Erlotinib Months

17 Multivariate Analysis HR 95% CI p-value Sex (F vs M) Smokers vs never smokers ECOG PS (2 vs 0/1) < Histology (adenoca reference) Squamous Others KRAS (mut vs wt) Arm (Doc vs Erl)

18 PFS Subgroup analysis N Pts Hazard Ratio IV, Fixed, 95% CI Hazard Ratio IV, Fixed, 95% CI Test for Interaction All ( ) PS 0/ ( ) PS ( ) Adenocarcinoma ( ) Squamous ( ) Others ( ) Female ( ) Male ( ) Never smokers ( ) Smokers (also ex) ( ) KRAS mutated ( ) KRAS wild-type ( ) Favours Docetaxel p=0.848 p=0.421 p=0.734 p=0.534 p=0.237 Favours Erlotinib

19 Progression Free Survival PFS by KRAS status HR 0.91 (95%CI ) p=0.558 Median mos 6-mos PFS Mutated % Non mutated % Patients at risk Wild-type Mutated Mutated Non mutated Months

20 Response Rate DOCETAXEL n=94 % ERLOTINIB n=92 % χ 2 test CR PR SD p=0.002 PD RR (CR+PR) p=0.004 DCR (CR+PR+SD) p=0.007

21 Conclusions TAILOR is the only prospective head-to-head trial comparing erlotinib vs docetaxel in wild-type EGFR patients Docetaxel significantly improves the PFS, Response Rate and Disease Control Rate over erlotinib Reported toxicity was as expected KRAS does not seem to be a prognostic factor in second line Survival will be analyzed when 199 deaths will occur

22 Centres A.O. Fatebenefratelli e Oftalmico, Milano U.O.C. Oncologia A Policlinico Umberto I, Roma Ospedali Riuniti, Bergamo Ospedale Belcolle, Viterbo Fondazione IRCCS Ospedale Maggiore Policlinico, Milano Ospedale San Pietro Fatebenefratelli, Roma Oncologia Medica, Università di Sassari Ospedale Maggiore della Carità, Novara A.O. Valtellina e Valchiavenna, Sondrio Policlinico Universitario P. Giaccone, Palermo A.O. S. Giovanni Addolorata, Roma Oncologia Medica Ospedale San Camillo Forlanini, Roma A.O. di Lecco Ospedale Centrale di Bolzano A.O. Spedali Civili, Brescia A.O. Policlinico Umberto I, Roma Ospedale di Piacenza Ospedale Civile SS. Annunziata, Sassari A.O. Ospedale Civile di Vimercate A.O. di Legnano A.O. S. Maria degli Angeli, Pordenone Policlinico Universitario di Monserrato Ospedale Valdelsa Campostaggia, Siena Ospedale Valdichiana Nottola, Siena Ospedale S. Giovanni Evangelista, Tivoli A.O. San Carlo Borromeo, Milano Acknowledgments Patients and their families A.O. G. Rummo, Benevento A.O. Melegnano- P.O,. Gorgonzola Ospedale San Paolo, Milano A.O. S. Maria, Terni Ospedali Galliera di Genova Multimedica Santa Maria, Castellanza Ospedale Morelli, A.O. Valtellina e Valchiavenna, Sondalo A.O.U. San Giovanni Battista-Molinette, Torino Ospedale Oncologico Armando Businco, Cagliari Ospedale S. Vincenzo, Taormina Ospedale Pesenti-Fenaroli, Alzano Lombardo ASL SA1-P.O. Umberto I, Nocera Inferiore H S. Giuseppe Antica Sede, Empoli Ospedale Umberto I, Lugo Ospedale Mater Salutis-ASL21 Regione Veneto, Legnago IRCCS Multimedica, Sesto San Giovanni Ospedale S Croce e Carle, Cuneo Ospedale S. Sebastiano, Correggio Ospedale F. Veneziale, Isernia A.O. Luigi Sacco, Milano Ospedale di Fabriano, Ancona A.O. Arcispedale S. Maria Nuova, Reggio Emilia A.O. Busto Arsizio, P.O., Saronno Ospedale San Donato, Arezzo Ospedale Renzetti, Lanciano A. O. U. Careggi, Firenze

23 Acknowledgments STEERING COMMITEE Clinicians Gabriella Farina Marina Chiara Garassino Roberto Labianca Silvia Marsoni Olga Martelli Alberto Scanni Pathologists Marcello Gambacorta Giorgio Gherardi Filippo Bianchi Molecular Biologists Massimo Broggini Monica Ganzinelli Calogero Lauricella Mirko Marabese Silvio Veronese Surgeons Lorenzo Rosso Luigi Santambrogio Data Management Elena Copreni Davide Poli Statisticians Irene Floriani Eliana Rulli Valter Torri Study Coordination Joanna Landi Angela Spena IDMC Roberto D Amico Thomas Fleming Giuseppe Giaccone Edmondo Terzoli Independent Statisticians Stefania Galimberti Maria Grazia Valsecchi