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VEGF -Targeted Therapies: Resistance and Revisiting Our Assumptions

VEGF -Targeted Therapies: Resistance and Revisiting Our Assumptions. A reality check now that we have clinical data. Lee M. Ellis, MD Depts. of Surgical Oncology and Cancer Biology U.T. M.D. Anderson Cancer Center Houston, Texas, USA. Disclosures. Ad hoc consulting

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VEGF -Targeted Therapies: Resistance and Revisiting Our Assumptions

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  1. VEGF-Targeted Therapies: Resistance and Revisiting Our Assumptions A reality check now that we have clinical data. Lee M. Ellis, MD Depts. of Surgical Oncology and Cancer Biology U.T. M.D. Anderson Cancer Center Houston, Texas, USA

  2. Disclosures • Ad hoc consulting • Genentech/Roche, sanofi-aventis, Bayer • Most of the data involves bevacizumab as this drug is approved in more disease types than others in the class • Thank you for sharing slides • Lillian Siu • Axel Grothey/Eric Van Cutsem • JosepTabernero/Carmen Allegra • Data collected from searches on Pubmed, Clinicaltrials.gov, ASCO, and AACR websites

  3. Anti-angiogenic Assumptions: Then and Now

  4. Resistance to Anti-VEGF Therapy • Introduction/Background • Resistance in preclinical studies • And were these studies confirmed in the clinic • Resistance/Sensitivity Beyond Progression

  5. Almost All Malignancies Are Inherently Resistant To VEGF Targeted Therapies(Exception-rcc) To Understand Resistance We Need to Better Understand Mechanisms of Action

  6. MOA: Do We (I) Have Any Clue? The benefits of a long career is that you can change you mind many, many times Ellis, Hicklin. Nat Rev Ca 2008

  7. Colon Carcinoma Anti-VEGF Therapy: My Theory on Different Mechanisms of Action in Different Tumor Systems Renal Cell Carcinoma/NETs With diverse MOAs, understanding resistance is likely to be tumor dependent, and/or site dependent.

  8. Resistance to Anti-VEGF Therapy • Introduction/Background • Resistance in preclinical studies • And were these studies confirmed in the clinic • Resistance/Sensitivity Beyond Progression

  9. Most Resistance Manuscripts and Reviews Focus on Redundant Angiogenic Pathways c-Met Ellis, Hicklin, CCR 2008

  10. FGF

  11. FGFs

  12. Hypothesis Generating Clinical Study in CRC Blood drawn at each cycle and at progression

  13. Cytokines Increased Prior to Progression On FOLFIRI + Bev Kopetz JCO 2009

  14. Results of a Recently Reported Clinical Trial Targeting FGF-R in CRC Brivanib Clinicaltrial.gov search May, 2012 The only randomized Phase III trial with FGF inhibitor And others at higher IC50s…. Diaz-Padilla, Siu ExpOpin Invest Drugs 2011

  15. CO.20 Trial: Cetuximab +/- BrivanibK-Ras WT Chemo-refractory CRC Siu et al

  16. Commentary/Discussion • This is but a single study-some hints of activity • Biomarker Driven Study: • Phase II Study of Second-line Irinotecan Plus Brivanib, a Dual Tyrosine Inhibitor of VEGFR and FGFR, in Metastatic Colorectal Cancer Patients Enriched for Elevated Levels of Plasma FGF Following Progression on Bevacizumab-based Treatment: Mike Overman, MDACC • There are numerous bypass pathways • Kopetz/Heymach JCO: B-FGF, HGF, PlGF, Eotaxin, MMP-9, and more • Not all tumors are p-NETs

  17. PlGF VEGF-B VEGF-C VEGF-A VEGF-D PlGF NRP-1/ NRP-2 NRP-2 VEGFR-1 (Flt-1) VEGFR-3 (Flt-4) VEGFR-2 (Flk-1/KDR) Vasculogenesis Angiogenesis Lymphangiogenesis

  18. Induction of PlGF by Anti-VEGF Therapy

  19. The PlGF Debate!

  20. VEGF-TRAP TG-403 PlGF VEGF-B VEGF-C BEVACIZUMAB* VEGF-A VEGF-D 1121B 18F1 Tyrosine Kinase Inhibitors Sunitinib* Sorafenib* Pazopanib* Axitinib* Motesanib Cedirinib Brivanib Many, many others VEGF Targeted Agents in the Clinic or In Clinical Trials Do we see improved outcomes in patients treated with agents that target PlGF/VEGFR-1? NRP-1/ NRP-2 NRP-2 VEGFR-1 (Flt-1) VEGFR-3 (Flt-4) VEGFR-2 (Flk-1/KDR) Vasculogenesis Angiogenesis Lymphangiogenesis * FDA approved agents Ellis, Hicklin Nat Rev Ca. 2008

  21. VELOUR Study Design Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks R A N D O M I Z E 600 Metastatic Colorectal Cancer 1:1 Disease Progression Death Stratification factors: - ECOG PS (0 vs 1 vs 2) - Prior bevacizumab (Y/N) Placebo IV, day 1 + FOLFIRI q2 weeks 600 Primary endpoint: Overall survival Sample size: HR 0.8, 90% power and a 2-sided type I error 0.05 Final analysis of OS: Analyzed at 863th death event using a 2-sided nominal significance level of 0.0466 (α spending function)

  22. Overall Survival, ITT Population 1.4 mo increase in median OS Cut-off date = February 7, 2011; Median follow-up = 22.28 months Presented at ESMO/WCGC meeting 2011, Barcelona: Abstract O-0024

  23. FDA Approvals Of VEGF-Targeted AgentsThat Have Been in Clinical Development for “Awhile” PlGF/VEGFR-1 Targeting If PlGF/VEGFR-1 is important in VEGF/VEGFR-2 resistance, Aflibercept and TKIs should be more effective

  24. Commentary/Discussion • Agents that target VEGF + PlGF are no more efficacious than those that target VEGF • In the only head-head Phase III study in CRC, Chemo + Bev vs Chemo + TKI (Cediranab), the primary endpoint for Cediranib was not met

  25. C-Met/HGF Modified Yap et al. Cancer Drug Targets 2011

  26. Hypothesis: Combination Therapy with a VEGF-R TKI and c-Met TKI Is Better Than Either Therapy Alone “In conclusion, our study indicates a role for HGF/c-Met pathway in development of resistance to antiangiogenic therapy and suggests a potential strategy to circumvent resistance to vascular endothelial the clinic.”

  27. Combination VEGF/Met Targeted Trials

  28. Other Resistance Pathways Not Discussed Untested in the clinic Under investigation: Are we targeting ECs or Cancer Stem Cells or Both? (Notch inhibitors slow in development) Mostly refuted Untested in the clinic

  29. Resistance to Anti-VEGF Therapy • Introduction/Background • Resistance in preclinical studies • And were these studies confirmed in the clinic • Resistance/Sensitivity Beyond Progression

  30. 2008 PFS in Patients Receiving TKIs After Prior VEGFR TKIs

  31. Continuation of VEGF-Targeted Therapy After First Line Progression in mCRC * Met primary endpoint

  32. Primary Endpoint Allegra Abstract #3505

  33. TML18147-OS*: ITT population(“Bev Beyond Progression”) 1.0 Chemo Bev + chemo 0.8 0.6 OS estimate 0.4 0.2 11.2 9.8 0 0 6 12 18 24 30 38 42 48 Time (months) Number at risk Chemo 410 293 162 51 24 7 3 2 0 Bev + chemo 409 328 189 64 29 13 4 1 0 *From randomisation Arnold, Abstract #CRA3503

  34. CORRECT: OS and PFS Regorafenibvs BSC Progression-Free Survival Overall Survival 1.00 1.00 • Regorafenib Placebo • Regorafenib Placebo Median 6.4 mos 5.0 mos 95% CI (5.9–7.3) (4.4–5.8) Median 1.9 mos 1.7 mos (95% CI) (1.9–2.1) (1.7–1.7)) 0.75 0.75 Hazard ratio: 0.77 (95% CI: 0.64–0.94) 1-sided p-value: 0.0052 Hazard ratio: 0.49 (95% CI: 0.42–0.58) 1-sided p-value: <0.000001 Survival distribution function 0.50 Survival distribution function 0.50 0.25 Placebo N=255 0.25 Placebo N=255 Regorafenib N=505 Regorafenib N=505 0 0 50 100 150 200 250 300 350 400 450 0 0 50 100 150 200 250 300 350 Days from randomization Days from randomization • Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p<0.009279 at approximately 74% of events required for final analysis) Grothey et al. ASCO GI 2012 (LBA 385).

  35. Conclusions • The more we learn about the tumor vasculature, the less sure we about the MOA of VEGF-targeted agents • There are numerous redundant pathways that mediate resistance to VEGF-targeted agents • Will we need to inhibit multiplepathways (>2) to obtain meaningful clinical benefit? Is this feasible????? (tox) • VEGF inhibition beyond progression provides some degree of patient benefit…i.e. complete resistance may not occur • Biomarkers of sensitivity and resistance will improve patient outcomes---in my opinion, the only way to make a major advance at this stage • Michael Maitland to discuss

  36. Thank You for Your Attention

  37. TML18147 Study Design (Phase III) Standard 2Lchemo (oxaliplatinor irinotecan-based)*until PD Bev + standard 1L chemo (either oxaliplatin oririnotecan-based)(n=820) Randomize 1:1 PD Bev (2.5mg/kg/wk) + standard 2L chemo (oxaliplatin or irinotecan-based)*until PD * Cross-over: Oxaliplatin→Irinotecan Irinotecan→ Oxaliplatin PD = disease progression Arnold, Abstract #CRA3503

  38. CORRECT Study Design Regorafenib + BSC 160 mg orally once daily 3 weeks on, 1 week off Primary Endpoint: OS 90% power to detect 33.3% increase (HR=0.75), with 1-sided overall a=0.025 • Multicenter, randomized, double-blind, placebo-controlled, phase III • 2:1 randomization • Strat. factors: prior anti-VEGF therapy, time from diagnosis of mCRC, geographical region • Global trial: 16 countries, 114 active centers • 1,052 patients screened, 760 patients randomized within 10 months • Secondary endpoints: PFS, ORR, DCR mCRC after standard therapy R 2:1 Placebo + BSC 3 weeks on, 1 week off Grothey et al. ASCO GI 2012 (LBA 385).

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