LE SECONDE LINEE E OLTRE

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1 LE SECONDE LINEE E OLTRE Gravedona 14 novembre 2012 MARINA GARASSINO ISTITUTO NAZIONALE DEI TUMORI MILANO

2 MULTIDISCIPLINARY TEAM PATIENT

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16 LUX-Lung 1: Rationale Afatinib is an irreversible EGFR and HER2 inhibitor with preclinical activity against NSCLC with T790M mutations (EC 50 : 99 nm, NCI-1975) Resistance T790M mutations are detected in ~50% of patients previously responsive to gefitinib/erlotinib No approved therapy available for locally advanced or metastatic NSCLC in patients who have failed CT and progressed after treatment with EGFR TKI

17 Trial design N=585 Patients with: Adenocarcinoma of the lung Stage IIIB/IV Progressed after one or two lines of chemotherapy (incl. one platinumbased regimen) and 12 weeks of treatment with erlotinib or gefitinib ECOG 0 2 Randomization 2 : 1 Oral BIBW mg once daily plus best supportive care Oral placebo once daily plus best supportive care Primary endpoint: Overall survival (OS) Secondary: PFS, RECIST response, QoL, safety Countries: North America, Europe, Asia Status: Recruitment complete, DBL for primary analysis 6 July 2010

18 Disease control rate and objective responses Independent Investigator Afatinib (%) Placebo (%) Afatinib (%) Placebo (%) PR, regardless of confirmation PR, confirmed 13.3* ** SD DCR (CR+PR+SD), confirmed * P < 0.01 compared to placebo ** P < compard to placebo Median duration of response: 6 months Median duration of response: 6 months

19 Waterfall plots by independent review

20 PFS by independent review HR = 0.38

21 Overall survival Nessun vantaggio in sopravvivenza

22 Summary of anticancer therapy after treatment discontinuation Anticancer therapy Afatinib (%) Placebo (%) Any Chemotherapy Pemetrexed Docetaxel Vinorelbine Other EGFR TKI Anti-angiogenesis 4 6 Radiotherapy 9 14 Placebo arm received 25% more types of chemotherapy than the afatinib arm (1.32 types of chemo per patient vs. 1.06).

23 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 Meeting. Presented data is the property of the author Annual 1 2 Meeting

24 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 Annual 1 2 Meeting

25 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 Annual 1 2 Meeting

26 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) Annual 1 2 Meeting

27 Molecular study Work-Flow 52 CENTRES REGISTRATION CENTRALIZATION OF SPECIMENS COLLECTED AT DIAGNOSIS & HISTOLOGICAL REVISION H FBF max 7 days EGFR /KRAS CROSS-VALIDATED IN 2 INDEPENDENT LABS EGFR Sanger s sequencing confirmed by RFLP KRAS HRMA confirmed by Sanger s sequencing Annual 1 2 Meeting

28 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 Annual 1 2 Meeting

29 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 Annual 1 2 Meeting

30 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) Annual 1 2 Meeting

31 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 Annual 1 2 Meeting

32 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 Annual 1 2 Meeting

33 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 Annual 1 2 Meeting

34 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 Annual 1 2 Meeting

35 targets ALTERAZIONE % adenoca % squamosi FARMACO EGFR MUTAZIONE 10-40% 2-5% Gefitinib, erlotinib, afatinib, PF EML-4-ALK TRASLOCAZIONE 5-7% RARA Crizotinib, ASP3026, AP26113, CH LDK- 378, HSP90 INIBITORI ROS1 TRASLOCAZIONE 2% RARA Crizotinib, ASP3026, AP26113, CH LDK- 378, HSP90 INIBITORI RET TRASLOCAZIONE 2% RARA VANDETANIB HER-2 MUTAZIONE O AMPLIFICATIONE 2-6% RARA-2% TRASTUZUMAB, PF , AFATINIB PI3K ATTIVAZIONE 10-30%, 3% 5%, 2% GDC-0941, GDC-0980, XL- 765,BEZ-235, BKM120, BYL719, PF MET AMPLIFICAZIONE <10% <10% XL184,ARQ917, MetMab KRAS MUTAZIONE 10-30% 3-5% Sorafenib, AZD6244, GSK , AS703026, RO ,MEK162 RAF MUTAZIONE 3% 2% Sorafenib, AZD6244, GSK , AS703026, RO ,MEK162 FGFR1 AMPLIFICAZIONE 5% 20% BJG398, AZD4547, TKI258, EOS3810

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37 Conclusioni Si profila uno scenario delle seconde linee personalizzato sulle caratteristiche molecolari I pazienti con EGFR mutato che non era noto in prima linea, useranno un EGFR TKI Nei pazienti in progressione dopo I linea con un EGFR TKI è considerabile un EGFR TKIs irreversibile o chemioterapia (utile rebiopsia) Il ruolo degli EGFR TKIs nei pazienti wt è al momento pending Nei pazienti con la traslocazione di ALK crizotinib è il trattamento di scelta

38 Conclusioni-2 Sono in via di sviluppo ALK inibitori di seconda generazione Sono in via di riconoscimento numerose mutazioni driver negli squamocellulari (DDR-1, FGFR-1) Il ruolo delle terze linee è al momento ancora ambiguo

39 Grazie per l attenzione