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  1. Small and Large-Molecule Angiogenesis Inhibitors: Excitement and Disappointments CT-322 VEGFR2 Adnectin Cediranib VEGFR Kinase Inhibitor Scott Kopetz, MD, PhD Gastrointestinal Medical Oncology University of Texas, M D Anderson Cancer Center

  2. Outline • Anti-Angiogenesis: Where are we now? • Overview of Agents Targeting VEGF • Disappointments: • VEGF Tyrosine Kinase Inhibitors • Excitement: • Large Molecule VEGF inhibitors • Beyond VEGF: Alternate angiogenesis inhibitors

  3. Current Benefits of Anti-Angiogenic Therapy: Bevacizumab in Phase III FOLFOX/XELOX + Bev IFL + Bev IFL FOLFOX/XELOX FOLFOX + Bev FOLFOX Hurwitz et al NEJM 2004; Saltz et al JCO 2008; Giantonio et al JCO 2007

  4. Why the interest in alternate angiogenesis inhibitors? • There is clearly room to improve on anti-angiogenic therapy in CRC • VEGF and angiogenesis are known to be relevant in CRC • Anti-VEGF development is viewed as a lower risk than a completely novel target • Agents with oral bioavailability and lower production costs may have market advantage

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

  6. Large molecule VEGF inhibitors VEGF-A PlGF VEGF-C, VEGF-D Y Y Bevacizumab TB403 Y Ramucirumab (IMC-1121B) Y Y II VGX-100 IMC-18F1 CT-322 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

  7. Small molecule VEGFR inhibitors VEGF-A VEGF-C, VEGF-D PlGF VEGF-B Cell membrane X X X VEGFR Tyrosine Kinase Inhibitors (TKIs) VEGF-R1 (Flt-1) Migration Invasion Survival VEGF-R2 (KDR/Flk-1) Proliferation Survival Permeability VEGF-R3 (Flt-4) Lymphangio- genesis Functions

  8. Small Molecule VEGFR Inhibitors in CRC >10,000 Clinicaltrials.gov

  9. “VEGF” TKIs Vary By Kinase Selectivity and PK

  10. Outline • Anti-Angiogenesis: Where are we now? • Overview of Agents Targeting VEGF • Disappointments: • VEGF Tyrosine Kinase Inhibitors • Excitement: • Large Molecule VEGF inhibitors • Beyond VEGF: Alternate angiogenesis inhibitors

  11. 100 75 50 25 0 0 10 20 30 40 50 60 70 80 90 FOLFOX4 + PTK787 FOLFOX4 5+ Years ago… “First Generation” VEGFR TKIs Semaxinib (SU5416) Negative Study Vatalanib (PTK787) Negative Study Overall Survival 5-FU + SU5416 5-FU Weeks CONFIRM-1 Hecht, ASCO 2005; Pharmacia Press Release Feb 2002

  12. Lessons Learned with “First Generation” VEGFR TKIs VatalanibSemaxinib • Continuous VEGF inhibition appears to be necessary • Pharmacokinetics matter • Phase III trials are too late to determine the optimal pharmacokinetics and biomarkers of activity • Don’t skip Phase II studies!

  13. Strategies Being Employed in “Second Generation” VEGFR TKI studies • Frontline chemo + Bevacizumab vs. VEGFR TKI • Testing superiority of VEGFR TKI • Frontline chemo +/- VEGFR TKI • Demonstrate benefit in “easier” setting • Approval outside of US • Bevacizumab-refractory: Second-line chemo +/- VEGFR TKI • Testing benefit of continued VEGF inhibition • Evaluating relevance of alternate VEGF signaling after bevacizumab • Dual Inhibition: Bevacizumab + VEGF TKI * • More “complete” inhibition of VEGF pathway * Grothey et al ASCO 2010 GI (Colorectal) Poster Session #3549

  14. “Second Generation” VEGFR TKIs: Disappointing Recent Results • Sunitinib • Phase III: First line FOLFIRI +/- Sunitinib • Cediranib • Phase II: Second Line FOLFOX Bev vs. Cediranib • Phase III: First Line FOLFOX Bev vsCediranib • Phase III: First Line FOLFOX +/- Cediranib • Vandetanib • Phase IIB: Second Line FOLFOX +/- Vandetanib

  15. Phase III: Frontline Sunitinib 1st Line Met CRC N=720 patients Primary endpoint: PFS FOLFIRI + Placebo R FOLFIRI + Sunitinib Europe/S.America/Asia study • Phase IIB: First line FOLFOX Bev vsSunitinib • Hecht et al, ASCO 2010 #127 (Tues Poster Disc)

  16. Phase IIB: FOLFOX Bevacizumab vs. FOLFOX Cediranib • Toxicities: Thrombocytopenia, fatigue • More frequent dose reductions in oxaliplatin in cediranib arms 2nd Line mCRC with PD on FOLFIRI N=215 patients No prior anti-VEGF FOLFOX + Bevacizumab FOLFOX + Cediranib 20mg/d R FOLFOX + Cediranib 30mg/d Cunningham, ASCO 2008 Abs 4028

  17. Phase III: Cediranib (HORIZON III) Failed to meet primary endpoint 1st Line Met CRC N=1600 patients Primary endpoint: PFS FOLFOX + Bevacizumab R FOLFOX + Cediranib 20mg/d Europe/US study Press release 3/10/10

  18. Phase III: Cediranib (HORIZON II) “Met PFS endpoint”, but … 1st Line Met CRC N=1050 patients Co-primary endpoint: PFS, OS FOLFOX + Placebo R FOLFOX + Cediranib 20mg/d Europe/Asia study failed to meet OS endpoint. Development in CRC halted. Press release May 2010

  19. Phase IIB: FOLFOX +/- Vandetanib • Once daily oral VEGFR + EGFR TKI • Added toxicities of thrombocytopenia (+15%), diarrhea (+20%) FOLFOX + Placebo 2ndLine mCRC with PD on FOLFIRI N=106 patients No prior bevacizumab FOLFOX + Vandetanib 100mg R FOLFOX + Vandetanib 300mg Yang, ASCO 2009 Abs 4084

  20. Negative studies across multiple regimens Positive Negative Ongoing

  21. Summary of VEGF TKI Activity • Is there activity of VEGF TKI therapies? • In contrast to HCC, RCC, minimal activity seen in CRC • Are they equivalent to bevacizumab? • No evidence • Are they superior to bevacizumab? • Increasingly unlikely • Does the same hold for large-molecule VEGF inhibitors? • Too early Why are VEGF TKIs failing? • Compliance? Possible Toxicities? Unlikely • Failing to understand the difference between targeting VEGF receptor and ligands • The benefit of VEGF inhibition by any method may be less than we think with current chemotherapy regimens

  22. Lessons from “Second Generation” of VEGF TKI Studies • Don’t ignore phase II study results • Biomarker development is still lagging clinical development • Phase II is also too late • Added toxicities are non-trivial • TKIs inhibiting multiple kinases beyond VEGF have not yet shown greater activity

  23. Outline • Anti-Angiogenesis: Where are we now? • Overview of Agents Targeting VEGF • Disappointments: • VEGF Tyrosine Kinase Inhibitors • Excitement: • Large Molecule VEGF inhibitors • Beyond VEGF: Alternate angiogenesis inhibitors

  24. Phase III VEGF Trap (Aflibercept) after Bevacizumab 2ndline CRC (after treatment with oxaliplatin-based therapy) N=1200 patients Primary endpoint: OS FOLFIRI + Placebo R FOLFIRI + Aflibercept 4mg/kg “VELOUR” Study Results expected Dec 2010

  25. Phase IIB ECOG 7208 : Anti-VEGFR2 Monoclonal Antibody after Bevacizumab 2ndline CRC (after oxaliplatin and bevacizumab) KRAS Wild type N=147 patients Primary endpoint: PFS 90% power to detect difference between 4.5 months for control vs. 7.65 months for experimental arm (α = 0.10, β = 0.10) Cetuximab + Irinotecan R Cetuximab + Irinotecan + Ramucirumab (IMC-1121B) Courtesy of H. Hochster, PI

  26. Comparing Anti-VEGFR2 or Anti-VEGFR1 Monoclonal Antibodies after Bevacizumab mFOLFOX6 2ndline CRC (after irinotecan +/- bevacizumab) N=150 patients Primary endpoint: PFS Phase IIB mFOLFOX6 + IMC-1121B (Anti-VEGFR2) R mFOLFOX6 + IMC-18F1 (Anti-VEGFR1) Results Summer 2012

  27. Outline • Anti-Angiogenesis: Where are we now? • Overview of Agents Targeting VEGF • Disappointments: • VEGF Tyrosine Kinase Inhibitors • Excitement: • Large Molecule VEGF inhibitors • Beyond VEGF: Alternate angiogenesis inhibitors

  28. Angiogenic Factors Beyond VEGF Folkman, Nat Rev Drug Discovery 2007

  29. Areas of Excitement: Alternate Angiogenesis Targets Tumors have an inherent or acquired upregulation of one of the redundant pro-angiogenic pathways

  30. Angiogenic Factors Beyond VEGF Folkman, Nat Rev Drug Discovery 2007

  31. Angiopoietins and Tie2 in Angiogenesis Phase IIB AMG-386 (Ang 1/2 neutralizing peptibody) 2ndline CRC (after treatment with oxaliplatin-based therapy) N=138 patients Primary endpoint: PFS FOLFIRI + Placebo R FOLFIRI + AMG-386 Angiogenesis VEGF Results expected late 2010, early 2011 Yu, FutOncol 2005

  32. Single Agent VEGFR + Tie2 TKI: Regorafenib (BAY 73-4506) Phase III Refractory CRC N=690 patients Primary endpoint: OS Regorafenib 160 mg PO 3 weeks on, 1 week off R Placebo “CORRECT” Study Also inhibits PDGFR, FGFR, Kit, RET, Raf Initiated Spring 2010 See Kies et al ASCO 2010 poster 7585

  33. Angiogenic Factors Beyond VEGF Folkman, Nat Rev Drug Discovery 2007

  34. Example: bFGF and Restored Angiogenesis Despite VEGF Inhibition FGF-2 Levels are Increased in Patients at Progression on FOLFIRI + Bevacizumab VEGFR2 resistance can be reversed by targeting FGF Kopetz, et al JCO 2010 Casanovas et al. Cancer Cell ‘05

  35. 64 32 16 8 Fold change in bFGF 4 2 1 0.5 Patients Example: Translating FGF Research to the Clinic Heterogeneous Elevations in bFGF in the clinic Enrichment Phase II Trial: Inhibition of FGFR + VEGFR after Bevacizumab-failure FOLFOX + Bevacizumab-Refractory CRC N=100 screened Primary endpoint: non-comparative PFS Plasma bFGF Levels HIGH plasma bFGF(n=30): Irinotecan 180mg/m2 Brivanib 800mg PO qd Low/normal bFGF (n=30): Irinotecan 180mg/m2 Brivanib 800mg PO qd Opening Fall 201 MDACC: Lieu, Overman PI’s Kopetz, et al JCO 2010

  36. Ongoing Phase III: NCIC Brivanib Refractory CRC KRAS Wild type N=750 patients Primary endpoint: OS Cetuximab R Cetuximab + Brivanib Phase III Studies: Opportunities for Retrospective Evaluation of Plasma Markers NCIC study, Lillian Siu, PI

  37. Conclusions • No evidence yet that anti-angiogenesis agents besides bevacizumab provide meaningful benefit • despite >10,000 enrolled patients • Recommendations for Path Forward: • Look Beyond VEGF: Understanding the mechanisms of acquired and inherent resistance to bevacizumab • Incorporate biomarker-driven enrichment studies • Utilize correlatives from completed randomized trials “Insanity is repeating the same mistakes and expecting different results” Albert Einstein