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 Istituto Nazionale per la Ricerca sul Cancro Genova
EGFR pathway
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
TALENT Results TTP OS Gatzemeier U, JCO 2007
TRIBUTE Results OS TTP Herbst RS, JCO 2005
INTACT 1 Trial Endpoints Patients (N=1093) + GEFITINIB 250 mg CDDP + GEM 3 wkly for 6 cycles + GEFITINIB 500 mg until PD + GEFITINIB 250 mg 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 6 6
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 %
INTACT 2 Trial Endpoints Patients (N=1037) + GEFITINIB 250 mg Primary CBDCA AUC 6 + paclitaxel for 6 cycles + GEFITINIB 500 mg until PD + GEFITINIB 250 mg 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 8 8
INTACT 2 Trial: Results OS: G250 9.8 m G500 8.7 m Placebo 9.9 m TTP: G250 5.3 m G500 4.6 m Placebo 5.0 m (P=.0562) RR: G250 30.4 % G500 30 % Placebo 28.7 %
Potential antagonism CT + EGFR TKI Tumor cells were driven to G0/G1 phase by EGFR TKI while CT usually works best in the mitotic phase
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
FAST-ACT Results PFS NPR no difference (80.3% vs 76.9%) Mok T, JCO 2009
Previously untreated stage IIIB/IV NSCLC, PS 0/1 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
FAST-ACT 2 Results HR=0.57 (95% CI 0.47–0.69) p<0.0001 Wu YL, Lancet 2013
PFS and OS in EGFR WT subgroup 1.0 0.8 0.6 0.4 0.2 1.0 0.8 0.6 0.4 0.2 12.2 14.9 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 PFS probability OS probability 5.9 6.7 4 8 12 16 20 24 28 32 36 40 4 8 12 16 20 24 28 32 36 40 Time (months) Time (months)
PFS and OS in EGFR mut subgroup 1.0 0.8 0.6 0.4 0.2 1.0 0.8 0.6 0.4 0.2 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 PFS probability OS probability 6.9 16.8 20.6 31.4 4 8 12 16 20 24 28 32 4 8 12 16 20 24 28 32 36 Time (months) Time (months)
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
FLEX Study Design Pirker R, Lancet 2009 Primary endpoint: OS Secondary endpoints: PFS, ORR, quality of life, safety Pirker R, Lancet 2009
FLEX Study Results OS: 11.3 m vs 10.1 m (P= 0.044) Pirker R, Lancet 2009
FLEX Adverse Events Pirker R, Lancet 2009
Survival according EGFR expression Low EGFR expression P=0.88 Hight EGFR expression P=0.011 Pirker R, Lancet 2012
BMS099 Study Lynch TJ, JCO 2010 1:1 N=676 Primary endpoint: PFS-IRRC Secondary endpoints: OS, ORR, quality of life, safety Lynch TJ, JCO 2010
BMS099 Study Results: PFS IRRC Lynch TJ, JCO 2010
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
Necitumumab
INSPIRE: Study Design Paz-Ares L, Lancet 2015 Primary endpoint: OS Secondary endpoints: PFS, ORR, TTF, safety, immunogenicity of necitumumab, EGFR protein expression Paz-Ares L, Lancet 2015
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
INSPIRE: Toxicity Paz-Ares L, Lancet 2015
Squire: Study Design Thatcher N, Lancet 2015 N=1093 Primary endpoint: OS Secondary endpoints: PFS, ORR, TTF, health status, immunogenicity of necitumumab, safety, pharmacokinetics Thatcher N, Lancet 2015
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
Squire: Subgroup Analysis Thatcher N, Lancet 2015
Squire: Adverse Events Thatcher N, Lancet 2015
EGFR expression Thatcher N, Lancet 2015
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