Bevacizumab Beyond Progression ? Axel Grothey Professor of Oncology Mayo Clinic Rochester Axel Grothey Professor of Oncology Mayo Clinic Rochester

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  • Bevacizumab Beyond Progression ? Axel Grothey Professor of Oncology Mayo Clinic Rochester Axel Grothey Professor of Oncology Mayo Clinic Rochester
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  • Continuation of Chemotherapy Beyond Progression FOLFOX FOLFIRITournigand FOLFIRI FOLFOXTournigand LV5FU2 FOLFIRIFOCUS LV5FU2 FOLFOXFOCUS Irino Irino + CetuximabBOND, Saltz FOLFOX FOLFIRITournigand FOLFIRI FOLFOXTournigand LV5FU2 FOLFIRIFOCUS LV5FU2 FOLFOXFOCUS Irino Irino + CetuximabBOND, Saltz
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  • Cell membrane VEGF-A VEGF-R1 (Flt-1) Migration Invasion Survival VEGF-R3 (Flt-4) Lymphangio- genesis VEGF-R2 (KDR/Flk-1) Proliferation Survival Permeability PlGF VEGF-B VEGF-C, VEGF-D Functions VEGF Biology
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  • VEGF-A VEGF-R1 (Flt-1) Migration Invasion Survival VEGF-R3 (Flt-4) Lymphangio- genesis VEGF-R2 (KDR/Flk-1) Proliferation Survival Permeability PlGF VEGF-B VEGF-C, VEGF-D Functions Large molecule VEGF inhibitors Bevacizumab Ramucirumab Aflibercept (VEGF Trap)
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  • Characteristics of Anti-EGFR vs Anti-VEGF Therapy Minimal single agent activity In combination with chemo consistent increase in PFS Decrease in interstitial pressure, better delivery of chemo? Normalization of vasculature, better oxygenation? Minimal single agent activity In combination with chemo consistent increase in PFS Decrease in interstitial pressure, better delivery of chemo? Normalization of vasculature, better oxygenation? Single agent activity In combination with chemo consistent increase in RR Increased chemo- and radio-sensitivity Resensitization of tumors to chemo (CPT11) Anti-VEGF mAbAnti-EGFR mAb Main target: Tumor cells - genetically instable - Main target: Endothelial cells - genetically stable -
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  • Is There a Rationale to Continue Bevacizumab Beyond Progression?
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  • Continuation of Bevacizumab Beyond Progression - PRO Mechanism of action targets genetically stable (endothelial) cells Decreased intratumoral interstitial pressure leads to higher concentrations of chemotherapeutic agents Normalization of vasculature and better oxygenation Cytotoxic effects of all (?) chemotherapeutics, regardless of line of therapy enhanced Mechanism of action targets genetically stable (endothelial) cells Decreased intratumoral interstitial pressure leads to higher concentrations of chemotherapeutic agents Normalization of vasculature and better oxygenation Cytotoxic effects of all (?) chemotherapeutics, regardless of line of therapy enhanced
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  • Inadequate for tumor growth Dynamic Effects of Anti-VEGF Therapy on Tumor Vasculature Normal Tumor vasculatureDays 2-5: normalized Anti-VEGFR Early effects (days 2-5): Hypoxia / Oxygenation Tumor vessel pruning Late effects (day 5): inhibition of blood vessel growth Winkler et al. Cancer Cell. 2004;6:553; Jain. Nat Med. 2003;9:685.
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  • Placebo Anti-VEGF mAb *P
  • I4T-MC-JVBBPhase III Trial 2 nd Line FOLFIRI +/- Ramucirumab Stratification factors: Region KRAS status First-line TTP (6 mos) 1:1 mCRC after failure FP/oxaliplatin + BEV regimen R 525 pts Ramucirumab IV + FOLFIRI q 2 weeks 525 pts Placebo + FOLFIRI q 2 weeks 35 Primary EP: OS PIs: Tabernero, Grothey
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  • Cytokine increase on BEV therapy Kopetz et al., JCO 2010
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  • Regorafenib A Multi-Kinase Inhibitor Cellular Phosphorylation AssaysIC 50 nM VEGFR-2 Phosphorylation, 293 Cells8 TIE2-Receptor Phosphorylation, CHO Cells 31 PDGFR- Phosphorylation, Aortic SM Cells90 mVEGFR3 Phosphorylation, 293 Cells150 Mutant RET Phosphorylation, Thyroid TT Cells 10 Mutant c-KIT Phosphorylation, GIST 882 Cells20 FGF-10 FGFR MCF-7 Cells 150-300 MAPK ERK-P HCC, HepG2 Cells500 Cell Proliferation Assays IC 50 nM VEGF/HuVEC (2% FCS) BrdU 4 bFGF/ HuVEC (2% FCS) BrdU 120 PDGFBB/Aortic SM (0.1% BSA) BrdU 121 Thyroid TT RET C643W (10% FCS) 33 GIST 882 KIT K642E (10% FCS) 45 Breast, MDA MB 231 (10% FCS) 570 Melanoma, A375 (10% FCS) 900 HCC HepG2 (10% FCS) 560
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  • Regorafenib Salvage Therapy Registration Trial Primary endpoint OS:increase OS from 4.5 to 6.0 months; HR = 0.75 Significance level/power: 0.025 (one-sided)/90% Accrual period (months): 26 ( accrual rate 30 pat./month) Study duration (months): 31.5 Total number of events: 582 Total number of patients: 690 Primary endpoint OS:increase OS from 4.5 to 6.0 months; HR = 0.75 Significance level/power: 0.025 (one-sided)/90% Accrual period (months): 26 ( accrual rate 30 pat./month) Study duration (months): 31.5 Total number of events: 582 Total number of patients: 690 Primary endpoint: OS CRC 3rd/4th line Regorafenib 160 mg od 3wks on/1 wk off + BSC Placebo + BSC 2:1 randomization Accrual completed Feb 2011, within 9 mos
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  • Conclusions Continuation of BEV beyond progression (BBP) has Preclinical rationale and Support from results of observational cohort studies However Financial and biological implications of this concept mandate prospective evaluation in randomized phase III trials before BBP can be considered standard of care A pivotal European trial has completed accrual results are awaited for late 2011 Continuation of BEV beyond progression (BBP) has Preclinical rationale and Support from results of observational cohort studies However Financial and biological implications of this concept mandate prospective evaluation in randomized phase III trials before BBP can be considered standard of care A pivotal European trial has completed accrual results are awaited for late 2011
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  • How A Cancer Cell Works