LE SECONDE LINEE E OLTRE Gravedona 14 novembre 2012 MARINA GARASSINO ISTITUTO NAZIONALE DEI TUMORI MILANO
MULTIDISCIPLINARY TEAM PATIENT
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
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 2992 50 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
Disease control rate and objective responses Independent Investigator Afatinib (%) Placebo (%) Afatinib (%) Placebo (%) PR, regardless of confirmation PR, confirmed 13.3* 7.4 0.5** 0.5 14.1 10.8 0.5 0.5 SD 50.8 17.9 49.7 21.0 DCR (CR+PR+SD), confirmed 58.2 18.5 60.5 21.5 * P < 0.01 compared to placebo ** P < 0.0001 compard to placebo Median duration of response: 6 months Median duration of response: 6 months
Waterfall plots by independent review
PFS by independent review HR = 0.38
Overall survival Nessun vantaggio in sopravvivenza
Summary of anticancer therapy after treatment discontinuation Anticancer therapy Afatinib (%) Placebo (%) Any 68 79 Chemotherapy 61 70 Pemetrexed 36 47 Docetaxel 21 26 Vinorelbine 15 19 Other 18 20 EGFR TKI 12 24 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).
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
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. 2005 ** 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
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
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
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
Patients flow 702 registered 554 genotyped 222 randomized 219 ITT analysis 148 not eligible (21%) Insufficient material 124 Not Evaluable for EGFR/KRAS 24 332 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 109 3 Protocol major violations Annual 1 2 Meeting
Progression free survival 1.0 0.9 0.8 0.7 0.6 PFS [ITT] HR 0.69 (95%CI 0.52-0.93) p=0.014 Median mos. 6-mos PFS Docetaxel 3.4 28.9% Erlotinib 2.4 16.9% 0.5 0.4 0.3 0.2 0.1 Docetaxel Erlotinib Patients at risk Docetaxel Erlotinib 0 0 1 2 3 4 5 6 7 Months 110 95 74 43 37 30 22 19 109 90 67 33 24 18 16 11 Annual 1 2 Meeting
Multivariate Analysis HR 95% CI p-value Sex (F vs M) 1.01 0.71 1.44 0.938 Smokers vs never smokers 1.04 0.70 1.55 0.838 ECOG PS (2 vs 0/1) 3.19 1.87 5.43 <0.0001 Histology (adenoca reference) Squamous 1.12 0.79 1.58 0.537 Others 1.15 0.63 2.11 0.644 KRAS (mut vs wt) 0.87 0.62 1.24 0.441 Arm (Doc vs Erl) 0.70 0.52 0.94 0.019 Annual 1 2 Meeting
PFS Subgroup analysis N Pts Hazard Ratio IV, Fixed, 95% CI Hazard Ratio IV, Fixed, 95% CI Test for Interaction All 219 0.69 (0.52-0.93) PS 0/1 203 0.69 (0.51-0.94) PS 2 16 0.85 (0.30-2.42) Adenocarcinoma 152 0.72 (0.51-1.01) Squamous 54 0.62 (0.33-1.15) Others 13 1.23 (0.34-4.40) Female 69 0.77 (0.46-1.27) Male 150 0.67 (0.47-0.95) Never smokers 51 0.61 (0.33-1.12) Smokers (also ex) 168 0.72 (0.52-1.00) KRAS mutated 52 0.84 (0.47-1.52) KRAS wild-type 167 0.65 (0.46-0.90) Favours Docetaxel 0.5 0.7 1.5 2 p=0.848 p=0.421 p=0.734 p=0.534 p=0.237 Favours Erlotinib Annual 1 2 Meeting
Progression Free Survival 1.0 0.9 0.8 0.7 0.6 0.5 PFS by KRAS status HR 0.91 (95%CI 0.65-1.26) p=0.558 Median mos 6-mos PFS Mutated 2.6 25.3% Non mutated 2.4 21.9% 0.4 0.3 Patients at risk Wild-type Mutated 0.2 0.1 Mutated Non mutated 0.0 0 1 2 3 4 5 6 7 Months 167 135 103 56 45 36 28 24 52 43 35 20 16 12 10 9 Annual 1 2 Meeting
Response Rate DOCETAXEL n=94 % ERLOTINIB n=92 % χ 2 test CR 4.3 0.0 PR 9.6 2.2 SD 27.6 20.6 p=0.002 PD 58.5 77.2 RR (CR+PR) 13.9 2.2 p=0.004 DCR (CR+PR+SD) 41.5 22.8 p=0.007 Annual 1 2 Meeting
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
targets ALTERAZIONE % adenoca % squamosi FARMACO EGFR MUTAZIONE 10-40% 2-5% Gefitinib, erlotinib, afatinib, PF-00299804 EML-4-ALK TRASLOCAZIONE 5-7% RARA Crizotinib, ASP3026, AP26113, CH5424802 LDK- 378, HSP90 INIBITORI ROS1 TRASLOCAZIONE 2% RARA Crizotinib, ASP3026, AP26113, CH5424802 LDK- 378, HSP90 INIBITORI RET TRASLOCAZIONE 2% RARA VANDETANIB HER-2 MUTAZIONE O AMPLIFICATIONE 2-6% RARA-2% TRASTUZUMAB, PF- 00299804, AFATINIB PI3K ATTIVAZIONE 10-30%, 3% 5%, 2% GDC-0941, GDC-0980, XL- 765,BEZ-235, BKM120, BYL719, PF-05212384 MET AMPLIFICAZIONE <10% <10% XL184,ARQ917, MetMab KRAS MUTAZIONE 10-30% 3-5% Sorafenib, AZD6244, GSK1120212, AS703026, RO4987655,MEK162 RAF MUTAZIONE 3% 2% Sorafenib, AZD6244, GSK1120212, AS703026, RO4987655,MEK162 FGFR1 AMPLIFICAZIONE 5% 20% BJG398, AZD4547, TKI258, EOS3810
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
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
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