TERAPIA della MALATTIA METASTATICA. Cambiamenti nella pratica clinica del carcinoma del Colon dopo l ASCO Mantenimento

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1 TERAPIA della MALATTIA METASTATICA Cambiamenti nella pratica clinica del carcinoma del Colon dopo l ASCO 2012 Mantenimento Roberto Labianca Ospedali Riuniti Bergamo

2 TERAPIA della MALATTIA METASTATICA Cambiamenti nella pratica clinica del carcinoma del Colon dopo l ASCO 2012 Mantenimento Dove siamo

3 Studio di fase III: XELOX ± bevacizumab vs FOLFOX4 ± bevacizumab (NO16966) Studio randomizzato di fase III, fattoriale 2 x 2 Pazienti con CCR metastatico non pretrattato (n= 1920) FOLFOX4 XELOX Bevacizumab 5 mg/kg ogni 2 settimane Placebo Bevacizumab 7,5 mg/kg ogni 3 settimane Placebo PRO PRO PRO PRO Endpoint principali Tempo alla progressione con XELOX (± bevacizumab) almeno equivalente rispetto a FOLFOX4 (± bevacizumab) Tempo alla progressione con bevacizumab + XELOX/FOLFOX superiore rispetto a XELOX/FOLFOX Mantenimento - Dove siamo

4 PFS in NO16966: General and On-Treatment Populations PFS estimate 1.0 FOLFOX or XELOX + placebo FOLFOX or XELOX + bevacizumab HR=0,83 (IC 97,5%): 0,72-0,95) p=0, HR=0,63 (IC 97,5%): 0,52-0,75) p<0, Months Bev-containing arm: Separation after 6 months occurs between the PFS for General vs. On-treatment populations Saltz LB, ASCO 2007 Mantenimento - Dove siamo

5 Mantenimento - Dove siamo Trials of maintenance therapy Design n Duration of Induction Maintenance Spanish TTD/MACRO 2 arm Continuation of induction vs Bevacizumab Swiss SAKK 2 arm Bevacizumab vs observation German AIO 3 arm FU or Cape/Bevacizumab vs Beva vs observation Dutch CAIRO 2 arm Low dose Cape/Beva vs. observation French DREAM 2 x 2 arm Bevacizumab-erlotinib vs Bevacizumab

6 Mantenimento - Dove siamo RANDOMIZATION MACRO: bevacizumab + XELOX with singleagent bevacizumab maintenance therapy Untreated mcrc (Neo)adjuvant therapy 6 months prior to study entry If adjuvant therapy administered, no disease progression during treatment or <6 months of its completion No prior radiotherapy to target lesions (n=480) Bevacizumab + XELOX until PD Bevacizumab + XELOX 6 cycles Bevacizumab until PD Prospective, randomized, phase III study Primary endpoint: PFS Secondary endpoints: OS, ORR, time to response, duration of response, number of treatment cycles, safety Tabernero, et al. ASCO 2010

7 Mantenimento - Dove siamo MACRO: Duration of PFS Comparable Between Beva vs XELOX + Beva No significant difference between treatment arms in any efficacy outcome Noninferiority of bevacizumab vs XELOX + bevacizumab cannot be confirmed The median PFS HR 95% CI ( ) beyond the planned noninferiority limit of 1.32 Outcome Bevacizumab (n = 241) XELOX/ Bevacizumab (n = 239) HR (95% CI) OR (95% CI) Median PFS,* mos Median OS,* mos ( ) 1.04 ( ) Confirmed objective response, % ( ) *Median follow-up: mos. Tabernero et al, ASCO 2010

8 Mantenimento - Dove siamo NORDIC ACT: Ph 3 Study of Maintenance Avastin ± Erlotinib after Avastin + Chemo in 1L mcrc Induction phase Maintenance phase 1L mcrc (N=249) XELOX, XELIRI, FOLFOX or FOLFIRI (investigator s choice) + BV ( 18 wks) No PD (n=161) Avastin 7.5 mg/kg q3w Avastin 7.5 mg/kg q3w + erlotinib 150 mg qd Treat to PD or toxicity Results median PFS from start of maintenance therapy: 5.9 (A+T) vs 4.2 months (A mono), HR=0.81, p=0.24 immature OS: 19.9 (A+T) vs 22.2 months (A mono) ORR: FOLFOX-Avastin 52%, XELOX-Avastin 44%, FOLFIRI-Avastin 50%, XELIRI-Avastin 55% Avastin + Tarceva was more toxic than Avastin mono, but side effects were manageable Conclusion: Supports combinability of Avastin as part of maintenance therapy Johnsson, et al. ASCO Abstract 3526.

9 PFS estimate Mantenimento - Dove siamo NORDIC ACT: PFS* Avastin + Tarceva (n=79) Avastin (n=80) HR 0.81 (95% CI ); p= Time (months) *Maintenance phase; add 18 weeks for total PFS Johnsson, et al. ASCO 2011 (abstract 3526)

10 TERAPIA della MALATTIA METASTATICA Cambiamenti nella pratica clinica del carcinoma del Colon dopo l ASCO 2012 Mantenimento Le novità dopo ASCO

11 Mantenimento - Le novità dopo ASCO Phase III DREAM trial: study design Induction Maintenance Previously untreated mcrc (n=700) Avastin + mfolfox7 Avastin + XELOX2 Avastin + FOLFIRI CR PR SD R (n=446) Avastin (n=224) Avastin + Tarceva (n=222) PD PD Primary endpoint: PFS from randomisation Secondary endpoints: RR, OS, OS from maintenance, OS by KRAS mutation status, duration without CT mfolfox7 or XELOX4: Avastin 5mg/kg every 2 weeks ± Tarceva 100mg/day During chemotherapy pause: Avastin 7.5mg/kg every 3 weeks ± Tarceva 150mg/day Tournigand, et al. ASCO 2012 (Abstract LBA3500)

12 PFS estimate PFS estimate Phase III DREAM trial: efficacy 1.0 Maintenance PFS (from randomisation) Avastin (n=224) 1.0 PFS from registration (randomised population) Avastin (n=224) Avastin + Tarceva (n=222) HR: 0.73 (95% CI: ) p= Avastin + Tarceva (n=222) HR: 0.73 (95% CI: ) p= Time (months) Time (months) OS (all patients, n=700): 25.4 months (95% CI ) Mantenimento - Le novità dopo ASCO Tournigand, et al. ASCO 2012 (Abstract LBA3500)

13 Mantenimento - Le novità dopo ASCO Phase III DREAM trial: safety Selected grade 3/4 AEs, % Avastin (n=219) Avastin + Tarceva (n=218) Neutropenia 0 0 Anaemia Thrombocytopenia Febrile neutropenia 0 0 Nausea Vomiting Mucositis Hand-foot syndrome Venous thrombosis 0 0 Proteinuria Hypertension Diarrhoea 1 9 Skin toxicity 0 20 Tournigand, et al. ASCO 2012 (Abstract LBA3500)

14 Mantenimento - Le novità dopo ASCO Phase III DREAM trial: author conclusions Combining Avastin with Tarceva as maintenance therapy following induction with Avastin-based therapy significantly increases maintenance PFS Avastin + Tarceva is well tolerated, but the incidences of diarrhoea and skin toxicity are increased These results suggest that Tarceva may be active in patients with mcrc and provide a clinical rationale for double inhibition of VEGF and EGFR Tournigand, et al. ASCO 2012 (Abstract LBA3500)

15 Mantenimento - Le novità dopo ASCO Waiting for CAIRO-3 Trial PFS1 PFS2 MTD chemotherapy 6 cycles of XELOX/BV SD PR CR PD R A N D O M I Z E not eligible observation LD Cape + Beva P R O G R E S S I O N MTD chemo + Beva P R O G R E S S I O N

16 TERAPIA della MALATTIA METASTATICA Cambiamenti nella pratica clinica del carcinoma del Colon dopo l ASCO 2012 Mantenimento La vostra opinione