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Gli inibitori di EGFR in associazione alla chemioterapia nei pazienti wild-type

CHEMO-IMMUNO-TARGET THERAPIES Tre strategie di trattamento nel NSCLC in stadio avanzato Camogli, 29-30 Aprile 2016. Gli inibitori di EGFR in associazione alla chemioterapia nei pazienti wild-type. Erika Rijavec UOS Tumori Polmonari Azienda Ospedaliera Universitaria San Martino IST

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Gli inibitori di EGFR in associazione alla chemioterapia nei pazienti wild-type

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  1. CHEMO-IMMUNO-TARGET THERAPIES Tre strategie di trattamento nel NSCLC in stadio avanzato Camogli, 29-30 Aprile 2016 Gliinibitori di EGFR in associazioneallachemioterapianeipazienti wild-type Erika Rijavec UOS Tumori Polmonari Azienda Ospedaliera Universitaria San Martino IST Istituto Nazionale per la Ricerca sul Cancro Genova

  2. EGFR pathway

  3. TALENT and TRIBUTE Trials TALENT (N=1059): CDDP 80mg/mq gg1 + gemcitabine 1250 mg/mq gg1,8 q21 TRIBUTE (N=1172): CBDCA AUC 6 gg1 + paclitaxel 200 mg/mq gg1, q21 Gatzemeier U, JCO 2007; Herbst RS, JCO 2005

  4. TALENT Results TTP OS Gatzemeier U, JCO 2007

  5. TRIBUTE Results OS TTP Herbst RS, JCO 2005

  6. INTACT 1 Trial CDDP + GEM 3 wkly for 6 cycles + GEFITINIB 250 mg until PD CDDP + GEM 3 wkly for 6 cycles + GEFITINIB 500 mg until PD Endpoints Patients (N=1093) • Age ≥18 years • PS 0-2 • Stage IIIB/IV • No previous chemotherapy Primary • Overall survival Secondary • Response rate • Time to progression • Safety evaluation CDDP + GEM 3 wkly for 6 cycles + placebo until PD Giaccone G, JCO 2004

  7. INTACT 1 Trial: Results OS: G250 9.9 m G500 9.9 m Placebo 10.9 m (P=.460) TTP: G250 5.8 m G500 5.5 m Placebo 6.0 m (P=.76) RR: G250 50.3 % G500 49.7 % Placebo 44.8 %

  8. INTACT 2 Trial CBDCA AUC 6 + paclitaxel for 6 cycles + GEFITINIB 250 mg until PD CBDCA AUC 6 + paclitaxel for 6 cycles + GEFITINIB 500 mg until PD Endpoints Patients (N=1037) • Age ≥18 years • PS 0-2 • Stage IIIB/IV • No previous chemotherapy Primary • Overall survival Secondary • Response rate • Time to progression • Safety evaluation CBDCA AUC 6 + paclitaxel for 6 cycles + placebo until PD Herbst RS, JCO 2004

  9. INTACT 2 Trial: Results OS: G250 9.8 m G500 8.7 m Placebo 9.9 m (P=.64) TTP: G250 5.3 m G500 4.6 m Placebo 5.0 m (P=.0562) RR: G250 30.4 % G500 30 % Placebo 28.7 %

  10. Potential antagonism CT + EGFR TKI Tumorcellsweredriven to G0/G1 phase by EGFR TKI while CT usuallyworks best in the mitoticphase

  11. First-line Asian Sequential Erlotinib plus chemo trial (FAST-ACT) Platinum (d1) Gemcitabine (d1, 8) + Erlotinib D15-28 Q4weeks x 6 cycles Erlotinib Untreated NSCLC IIIB/IV No prior EGFR TKI (N=154) 1:1 Platinum (d1) Gemcitabine (d1, 8) + Placebo D15-28 Q4weeks x 6 cycles Placebo Primary endpoint: NPR at 8 w Secondary endpoints: NPR at 16 w, RR, PFS, OS, duration of response, safety Mok T, JCO 2009

  12. FAST-ACT Results PFS NPR no difference (80.3% vs 76.9%) Mok T, JCO 2009

  13. FAST-ACT 2 Study Design Gemcitabine 1,250mg/m2 (d1, 8) + carboplatin AUC=5 or cisplatin 75mg/m2 (d1) + erlotinib 150mg/day (d15–28); q4wks x 6 cycles GC-erlotinib (n=226) Erlotinib 150mg/day PD Previously untreated stage IIIB/IV NSCLC, PS 0/1 (n=451) 1:1; stratified by stage, histology, smoking status and chemo regimen Gemcitabine 1,250mg/m2 (d1, 8) + carboplatin AUC=5 or cisplatin 75mg/m2 (d1) + placebo (d15–28); q4wks x 6 cycles GC-placebo (n=225) Placebo PD Primary endpoint: PFS Wu YL, Lancet 2013

  14. FAST-ACT 2 Results HR=0.57 (95% CI 0.47–0.69) p<0.0001 HR=0.79 (95% CI 0.64–0.99) p=0.0420 Wu YL, Lancet 2013

  15. PFS and OS in EGFR WT subgroup PFS OS 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 GC-erlotinib (n=69) GC-erlotinib (n=69) GC-placebo (n=67) GC-placebo (n=67) HR=0.97 (0.69–1.36) p=0.8467 RR: 26.1% vs 19.4% HR=0.77 (0.53–1.11) p=0.1612 OS probability PFSprobability 12.2 14.9 5.9 6.7 0 4 8 12 16 20 24 28 32 36 40 0 4 8 12 16 20 24 28 32 36 40 Time (months) Time (months)

  16. PFS and OS in EGFR mut subgroup PFS OS 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 GC-erlotinib (n=49) GC-erlotinib (n=49) GC-placebo (n=48) GC-placebo (n=48) HR=0.25 (0.16–0.39) p<0.0001 RR: 83.7% vs 14.6% HR=0.48 (0.27–0.84) p=0.0092 OS probability PFSprobability 6.9 16.8 20.6 31.4 0 4 8 12 16 20 24 28 32 0 4 8 12 16 20 24 28 32 36 Time (months) Time (months)

  17. Cetuximab • Recombinant human/mouse IgG1 monoclonal antibody • Specifically binds to the EGFR with higher affinity than its natural ligands (TGFa, EGF) • Induce apoptosis and ADCC1 • Preclinical synergistic activity in combination with chemotherapy and radiotherapy

  18. FLEX Study Design N=1125 Primary endpoint: OS Secondary endpoints: PFS, ORR, quality of life, safety Pirker R, Lancet 2009

  19. FLEX Study Results OS: 11.3 m vs 10.1 m (P= 0.044) Pirker R, Lancet 2009

  20. FLEX Adverse Events Pirker R, Lancet 2009

  21. Survival according EGFR expression Low EGFR expression P=0.88 Hight EGFR expression P=0.011 Pirker R, Lancet 2012

  22. BMS099 Study 1:1 N=676 Primary endpoint: PFS-IRRC Secondary endpoints: OS, ORR, quality of life, safety Lynch TJ, JCO 2010

  23. BMS099 Study Results: PFS IRRC Lynch TJ, JCO 2010

  24. Meta-analysis OS: 10.3 m vs 9.4 m (P=0.009) PFS: 4.7 m vs 4.5 m (P=0.045) Pujol JL, Lung Cancer 2014

  25. Necitumumab

  26. INSPIRE: Study Design N=633 Primary endpoint: OS Secondary endpoints: PFS, ORR, TTF, safety, immunogenicity of necitumumab, EGFR protein expression Paz-Ares L, Lancet 2015

  27. INSPIRE: Results OS: 11.3 m vs 11.5 m (P= 0.96) PFS: 5.6 m vs 5.6 (P= 0.96) High EGFR expression was associated to better outcomes in both treatment arms Paz-Ares L, Lancet 2015

  28. INSPIRE: Toxicity Paz-Ares L, Lancet 2015

  29. Squire: Study Design N=1093 Primary endpoint: OS Secondary endpoints: PFS, ORR, TTF, health status, immunogenicity of necitumumab, safety, pharmacokinetics Thatcher N, Lancet 2015

  30. Squire: Results OS: 11.5 m vs 9.9 m (P= 0.01) PFS: 5.7 m vs 5.5 m (P= 0.02) Thatcher N, Lancet 2015

  31. Squire: Subgroup Analysis Thatcher N, Lancet 2015

  32. Squire: Adverse Events Thatcher N, Lancet 2015

  33. EGFR expression Thatcher N, Lancet 2015

  34. Grazie per l’attenzione!

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