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Bevacizumab Beyond Progression ?

Bevacizumab Beyond Progression ?. Axel Grothey Professor of Oncology Mayo Clinic Rochester. Continuation of Chemotherapy Beyond Progression. FOLFOX  FOLFIRI Tournigand FOLFIRI  FOLFOX Tournigand LV5FU2  FOLFIRI FOCUS LV5FU2  FOLFOX FOCUS Irino  Irino + Cetuximab BOND, Saltz.

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Bevacizumab Beyond Progression ?

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

  2. Continuation of Chemotherapy Beyond Progression • FOLFOX  FOLFIRI Tournigand • FOLFIRI  FOLFOX Tournigand • LV5FU2  FOLFIRI FOCUS • LV5FU2  FOLFOX FOCUS • Irino  Irino + Cetuximab BOND, Saltz

  3. VEGF Biology VEGF-C, VEGF-D PlGF VEGF-B VEGF-A Cell membrane VEGF-R1 (Flt-1) Migration Invasion Survival VEGF-R2 (KDR/Flk-1) Proliferation Survival Permeability VEGF-R3 (Flt-4) Lymphangio- genesis Functions

  4. Large molecule VEGF inhibitors PlGF VEGF-B VEGF-C, VEGF-D VEGF-A Y Bevacizumab Ramucirumab Y Aflibercept (VEGF Trap) VEGF-R1 (Flt-1) Migration Invasion Survival VEGF-R2 (KDR/Flk-1) Proliferation Survival Permeability VEGF-R3 (Flt-4) Lymphangio- genesis Functions

  5. 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) Characteristics of Anti-EGFR vs Anti-VEGF Therapy Anti-EGFR mAb Anti-VEGF mAb Main target: Tumor cells - genetically instable - Main target: Endothelial cells - genetically stable -

  6. Is There a Rationale to Continue Bevacizumab Beyond Progression?

  7. 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

  8. Dynamic Effects of Anti-VEGF Therapy on Tumor Vasculature Early effects (days 2-5): Hypoxia /Oxygenation Tumor vessel pruning Normal Late effects (day 5): inhibition of bloodvessel growth Anti-VEGFR Anti-VEGFR Tumor vasculature Days 2-5: normalized Inadequate for tumor growth Winkler et al. Cancer Cell. 2004;6:553; Jain. Nat Med. 2003;9:685.

  9. 20 Placebo Anti-VEGF mAb 15 10 5 0 Effect of VEGF Inhibition on Vessel Density and Tumoral Chemotherapy Concentration * † Tumor irinotecan concentration (µg/g) Tumor H33342 concentration (100 ng/g) *P<0.09 vs placebo.†P<0.05 vs placebo. Wildiers et al. Br J Cancer. 2003;88:1979.

  10. 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 • In experimental models rapid regrowth of blood vessels after withdrawal of VEGF-inhibitors

  11. Rapid Regrowth of Tumor Blood Vessels Selective inhibition of VEGFR signaling by AG-028262 in RIP-Tag2 mouse tumors Basement membrane sleeves Mancuso et al. JCI 2006

  12. Continuation of Bevacizumab Beyond Progression - CON • Potential alternate pathways to activate angiogenesis apart from VEGF • Ang-system, FGF, PDGF and others • “Co-option” - recruitment of previously established vessels • Vascular remodeling, pericyte activation

  13. The Complex Process of Tumor Angiogenesis

  14. Control AntiVEGF PDGF PDGFR Pericytes Proliferate in Tumors Resuming Growth During Chronic VEGF Blockade Green = SMA (Pericytes) Huang, J. et al. Mol Cancer Res 2004;2:36-42

  15. Pericytes Proliferate in Tumors Resuming Growth During Chronic VEGF Blockade Huang, J. et al. Mol Cancer Res 2004;2:36-42

  16. Continuation of Bevacizumab Beyond Progression - CON • Potential alternate pathways to activate angiogenesis apart from VEGF • Ang-system, FGF, PDGF and others • “Co-option” - recruitment of previously established vessels • Vascular remodeling, pericyte activation • Endothelial cells are not necessarily genetically stable • Concept of cancer stem cells • BEV is not non-toxic (GIP, ATE, HTN, RPLS…) • Treatment alternatives exist most of the times • BEV is expensive

  17. Clinical experience? No prospectively randomized evaluation to date…

  18. BRiTE Registry - Patients with Bevacizumab Beyond Progression (BBP) Evaluablepatients(n=1953) BRiTE: Total N=1953 1445 pts with 1st PD 932 deaths (1/21/07 cut-off) Median follow-up 19.6 mo 1st Progression (n=1445) Physician decision - no randomization No Post-PD Treatment(n=253) No BBP(n=531) BBP(n=642) Grothey et al. JCO 2008

  19. BRiTE: Patient Outcome Based on Treatment Post 1st PD No Post-PD Treatment(n=253) No BBP(n=531) BBP(n=642) Grothey et al. JCO 2008

  20. BRiTE: Continuation of BEV post first progression may increase survival No Treatment (n=253) No BEV post PD (n=531) BEV post PD (n=642) Post-progression Bevacizumab HR=0.48 (0.41-0.57) P<0.001

  21. Multivariate Analysis of Pre- and Post-Treatment Variables on Survival Grothey et al. JCO 2008

  22. No bevacizumab post-PD (n=336) Bevacizumab post-PD (n=406) No post-PD treatment§ (n=282) ARIES: Post-progression observation of bevacizumab treatment Unresectable mCRC treated with first-line chemotherapy(n=1,548) • ARIES* • total n=1,548 • prospective phase III study • primary endpoint: survival beyond progression • secondary endpoint: OS, time to first PD, OS, safety First-line chemotherapy + bevacizumab First progression (n=1,113‡) Physician decision (no randomization) *Non-randomized, observational study ‡1,026 patients were alive 2 months after first PD §No treatment ever or bevacizumab and/or chemotherapy ≥2 months after PD Cohn, et al. ASCO 2010

  23. ARIES: Potential survival benefit from bevacizumab beyond progression *Patients alive 2 months post-PD and starting chemotherapy/biologics <2 months post-PD; no bevacizumab ever post-PD ‡Patients alive 2 months post-PD and starting chemotherapy/biologics + bevacizumab <2 months post-PD §For SBP, t0=PD+2 months **Multivariate model adjusted for patient characteristics Cohn, et al. ASCO 2010

  24. ARIES*:Does bevacizumab extend survival beyond progression? 1.0 0.8 0.6 0.4 0.2 0 Bevacizumab post-PD (n=408) No bevacizumab post-PD (n=336) HR=0.52 (95% CI: 0.42–0.63) p<0.001 Survival beyond progression estimate 7.5 14.1 0 5 10 15 20 25 30 Months *Non-randomized, observational study‡Post-progression bevacizumab versus no bevacizumab study Cohn, et al. ASCO 2010

  25. Limitations of the Analysis • Patients were not randomized • Actual administration dates for BV and CT not collected; missing BV and CT stop dates • Potential bias that patients who survived longer had a greater potential to be treated with BBP – but sensitivity analyses suggest minimal impact of these biases • Possibility of unmeasured factors that may have biased these results  Randomized trial needed!

  26. AIO 0504 / Roche ML18147Multinational European Trial Any-OX+ BEV Any-IRI+ BEV R R Any-IRI Any-IRI+ BEV Any-OX Any-OX+ BEV Accrual completed May 31, 2010 N = 820 Primary EP: OS

  27. Pertinent Side-Effects of Anti-VEGF Therapy • Hypertension • Arterial thrombotic/ thromboembolic events (ATEs) • Gastrointestinal perforation (GIP) • Bleeding • Delayed wound healing • Proteinuria

  28. Attempt at Classification of AEs • Preeclampsia-like syndrome with • hypertension, • proteinuria, and • hypertensive encephalopathy • Hypercoagulabilty with • increased risk for arterial and - less likely - • venous thrombosis and thromboembolic events • Anti-angiogenic syndrome with • decreased wound healing, • risk of gastrointestinal perforation (GIP) and • bleeding

  29. ATE Incidence From Start of BEV Treatment Number of events Months from start of BEV Kozloff et al., Oncologist 2009

  30. Incidence of GIP in BRiTE and in BEV Treatment Arms of Phase III Studies in mCRC Number of events Months from start of BEV Sugrue et al, ASCO, Atlanta, June 2-6, 2006, Kozloff et al., Oncologist 2009

  31. Incidence of BEV-related Safety Events in BRiTE No increase in rates of ATE, bleeding or GI perforation in patients who continued BEV Grothey et al. JCO 2008

  32. EFC10262: VELOURPhase III Trial 2nd Line FOLFIRI +/- VEGF-TRAP (Aflibercept) 32 Aflibercept 4 mg/kg IV+ FOLFIRI q 2 weeks 600 pts mCRC afterfailure of an oxaliplatinbased regimen R 1:1 Placebo + FOLFIRIq 2 weeks Stratification factors: Prior bevacizumab (Y/N) ECOG PS (0 vs 1 vs 2) 600 pts 30% of patients had prior BEV PI: Allegra

  33. VELOUR: Study Design and Endpoints • Multinational, randomized, placebo controlled • 28 Countries / 176 Active Sites • Primary Endpoint: Overall Survival • 90 percent power to detect a 20 % reduction in HR for OS (two-sided log-rank) • Secondary Endpoints: • Progression free survival • Overall response rate • Safety • Aflibercept pharmacokinetics and immunogenicity

  34. VELOUR: Press ReleaseApril 26, 2011 Results to be presented at ESMO GI in Barcelona 2011

  35. I4T-MC-JVBBPhase III Trial 2nd Line FOLFIRI +/- Ramucirumab 35 Ramucirumab IV+ FOLFIRI q 2 weeks 525 pts mCRC afterfailure FP/oxaliplatin+ BEV regimen R 1:1 Placebo + FOLFIRIq 2 weeks 525 pts • Stratification factors: • Region • KRAS status • First-line TTP (<>6 mos) Primary EP: OS PIs: Tabernero, Grothey

  36. Cytokine increase on BEV therapy Kopetz et al., JCO 2010

  37. Regorafenib – A Multi-Kinase Inhibitor

  38. 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 Regorafenib 160 mg od 3wks on/1 wk off + BSC Primary endpoint: OS CRC 3rd/4th line 2:1 randomization Placebo + BSC Accrual completed Feb 2011, within 9 mos

  39. 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

  40. How A Cancer Cell Works

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