Bevacizumab NSCLC

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Charla GGCP/GECP 2-2012

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Bevacizumab NSCLC

  1. 1. Bevacizumab!Martín Lázaro!CHUVI!
  2. 2. Ann Surg 1972;175:409-16 Angiogenic Switch 1-2 mm VEGF Small tumor Larger tumor •  Nonvascular •  Vascular •  Dormant •  Metastatic potential
  3. 3. Ann Surg 1972;175:409-16 Angiogenic Switch 1-2 mm VEGF Small tumor Larger tumor •  Nonvascular •  Vascular •  Dormant •  Metastatic potential
  4. 4. If you have cancer and you are a mouse, we can take good care of you!
  5. 5.        Trial   N   Schema   Results  Johnson et al! 99! Carboplatin/paclitaxel! PFS: 7.4 m (15 arm)!phase II; random! Carbo/paclitaxel/beva 15/7.5! PFS: 4.2 m!JCO 2004!Nishio et al! 180! Cisplatin/gemcitabine! PFS : 5.4 m!phase II; random! Cisplatine/gemcit/beva 15! PFS: 6.6 m!ASCO 2009!
  6. 6.        Trial   N   Schema   Results  Johnson et al! 99! Carboplatin/paclitaxel! PFS: 7.4 m (15 arm)!phase II; random! Carbo/paclitaxel/beva 15/7.5! PFS: 4.2 m!JCO 2004!Nishio et al! 180! Cisplatin/gemcitabine! PFS : 5.4 m!phase II; random! Cisplatine/gemcit/beva 15! PFS: 6.6 m!ASCO 2009!ECOG 4599! 878! Carboplatin/paclitaxel! PFS: 4.5 m!phase III; ! OS: 10.3 m!randomized! ! !NEJM 2006! Carbo/paclitaxel/beva 15 mg/kg! PFS: 6.2 m! OS: 12.3 m!AVAiL! 1043! Cisplatin/gemcitabine! PFS: 6 m!phase III, ! OS: 13 m!randomized! ! !JCO 2009! Cisplatin/gemc/bevacizumab 7.5! PFS: 6.7 m! ! OS: 13.6 m! ! ! Cisplatin/gemc/bevacizumab 15! PFS: 6.5 m ! OS: 13.4 m!
  7. 7. E4599: Efficacy RR: 15% for Carboplatin (CbP) vs 35% for CbP + Bevacizumab PFS OS 100   CbP   100   CbP   CbP  +  bevacizumab   CbP  +  bevacizumab   80   80   P < .001; HR: 0.66 P = .003; HR: 0.79 Median PFS: 6.2 mos vs Median OS: 12.3 mos vs Patients Surviving (%) 60   4.5 mos 60   10.3 mosPatients  With  PFS  (%)   6-mos PFS: 55% vs 33% 1-yr OS: 51% vs 44% 40   1-yr PFS: 15% vs 6% 2-yr OS: 23% vs 15% 40   20   20   0   0   0   6   12   18   24   30   36   0   6   12   18   24   30   36   Mos   Mos   Sandler A, et al. N Engl J Med. 2006;355:2542-2550. .
  8. 8. 13 m6.5 m
  9. 9. Lima ABC, PLoS ONE 2011;6(8):e22681. Fav  CT-­‐bev  Botrel et al; Lung Cancer (2011) doi:10:1016/j.lungcan.2011.01.028
  10. 10. Adverse  events  of  special  interest   Grade  1   Grade  2   Grade  3   Grade  4   Grade  5   Grade  >  3     Number  of   Resolved   Improved   Persistent   Led  to   events   death  Bleeding   32  %   6  %   3  %   <1  %   1  %   4  %      Bleeding        Epistaxis   1347   24  %   3  %   86  %   1  %   3  %   <1  %   10  %   0   1  %     1  %          Pulm  haemorrhage   7  %   1  %   <1  %   <1  %   <1  %   1  %      Hypertension        CNS  bleeding   <1  %   1025   0   76  %   <1  %   9  %   0   15  %  %   <1   <1  %   0  Hypertension   16  %   14  %   5  %   <1  %   0   6  %  Proteinuria   1046   70  %   10  %   20  %   0  Proteinuria   21  %   10  %   3  %   <1  %   0   3  %  Thromboembolism   324   48  %   18  %   26  %   8  %  Thromboembolism   2  %   4  %   5  %   2  %   1  %   8  %  Gastrointestinal   30   60  %   10  %   3  %   27  %  perforation  Gastrointestinal   <1  %   <1  %   1  %   <1  %   <1  %   1  %  perforation   Wound-­‐healing   31   71  %   6  %   23  %   0   complications  Wound-­‐healing   1  %   <1  %   <1  %   <1  %   0   <1  %  complications   Congestive  heart   18   33  %   11  %   22  %   33  %   failure  Congestive  heart   <1  %   <1  %   <1  %   <1  %   <1  %   <1  %  failure  Crino et al; Lancet Oncol 2010; 11:733-40
  11. 11. Adverse  events  of  special  interest   Number  of   Resolved   Improved   Persistent   Led  to   events   death  Bleeding   1347   86  %   3  %   10  %   1  %  Hypertension   1025   76  %   9  %   15  %   0  Proteinuria   1046   70  %   10  %   20  %   0  Thromboembolism   324   48  %   18  %   26  %   8  %  Gastrointestinal   30   60  %   10  %   3  %   27  %  perforation  Wound-­‐healing   31   71  %   6  %   23  %   0  complications  Congestive  heart   18   33  %   11  %   22  %   33  %  failure  Crino et al; Lancet Oncol 2010; 11:733-40
  12. 12. E4599: Efficacy in Elderly SubgroupEfficacy Outcome Elderly (≥ 70 Yrs of Age) Nonelderly (< 70 Yrs of Age) Paclitaxel/ Paclitaxel/ Paclitaxel/ Paclitaxel/ Carboplatin + Carboplatin Carboplatin + Carboplatin Bevacizumab (n = 113) Bevacizumab (n = 320) (n = 111) (n = 306)Median OS, m 11.3 12.1 12.8 9.61-yr OS, % 46 50 53 42Median PFS, m 5.9 4.9 6.2 4.4T-R mortality 6.3 % 2.6 %Ramalingam SS, et al. J Clin Oncol. 2008;26:60-65.Brain Metastases on BevacizumabClinical Trial Patients With CNS Events Brain MetastasesPASSPORT (phase II)1 n = 115 with treated No CNS1st/2nd-line chemo+ bev N = 115 brain mts hemorrhageARIES (observational cohort study)2 n = 101 with brain 1 CNSBevacizumab in 1st-line N = 1518 metastases hemorrhage1.  Fischbach NA, et al. 2009 ASCO. Abstract 8040.2.  Crino L, et al. Lancet Oncol. 2010;11:733-740.
  13. 13. BIOMARKERSVEGF plasma levelsVEGF SNPsICAM-1Citokines/chemokinesHypertension: ECOG1.0   P  =  NS   Medians  0.8   HTN:  14.0  mos   No  HTN:  11.3  mos    0.6  0.4  0.2   0   0   10   20   30   40   50   60   70  
  14. 14. BIOMARKERS RESISTANCEVEGF plasma levels EGFR, FGFR, HGF/ MET associated withVEGF SNPs VEGF inhibitorICAM-1 resistanceCitokines/chemokinesHypertension: ECOG Targeting resistance1.0   P  =  NS   Medians   pathways may reduce0.8   HTN:  14.0  mos   No  HTN:  11.3  mos    0.6   the onset of resistance0.4  0.2   0   0   10   20   30   40   50   60   70  
  15. 15. BIOMARKERS RESISTANCE COMBINEDVEGF plasma levels EGFR, FGFR, HGF/ + erlotinib: MET associated with BeTaVEGF SNPs VEGF inhibitor ATLASICAM-1 resistance + cetuximabCitokines/chemokines S0536Hypertension: ECOG Targeting resistance1.0   P  =  NS   S0819 Medians   pathways may reduce HTN:  14.0  mos  0.8   No  HTN:  11.3  mos     + pemetrexed0.6   the onset of resistance0.4   AVAPERL0.2   Pointbreak 0   0   10   20   30   40   50   60   70  
  16. 16. BEVACIZUMABSummary
  17. 17. BEVACIZUMAB CT + Bev combinationSummary increase the RR and PFS Benefits on overall survival are modest
  18. 18. BEVACIZUMAB CT + Bev combinationSummary increase the RR and PFS Benefits on overall survival are modestHemoptysis remains an issue Anticoagulation: cautionSafe in patients with treated brain metastases
  19. 19. BEVACIZUMAB CT + Bev combinationSummary increase the RR and PFS Benefits on overall survival are modestHemoptysis remains an issue Younger women have greater Anticoagulation: caution benefit from bevacizumabSafe in patients with treated than older women brain metastases Caution with elderly patients

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