1. Lee Ellis, MD, UT MDACC Anti-VEGF Therapy Goes Mainstream Lee M. Ellis, MD UT MD Anderson Cancer Center Houston, TX ASCO 2005 “Advancing the science of clinical oncology”

2. Lee Ellis, MD, UT MDACC What Have We Learned Today About Anti-VEGF Therapy? Bevacizumab (BV) improves effects of chemo in –NSCLC (first line) –mCRC (second line) Dosing of BV (10 vs 5 mg/kg) is probably not an issue in mCRC BV, as monotherapy, remains unproven in mCRC –Although OS was comparable to FOLFOX, we do not have data on therapy after progression (PFS of BV < FOLFOX) PTK/ZK does not improve the effects of FOLFOX in mCRC front line No drug is without toxicity

3. Lee Ellis, MD, UT MDACC Points for Discussion Biology Brief review of trials Mechanisms of Action PTK/ZK: Why different results than BV Toxicities

4. Lee Ellis, MD, UT MDACC VEGF-A VEGF-R1 (Flt-1) Migration Invasion VEGF-R3 (Flt-4) Lymphangio- genesis VEGF-R2 (KDR/Flk-1) Proliferation Survival Permeability Cell membrane VEGF Family and Receptors PlGF VEGF-B VEGF-C, D VEGF-R Functions Neuropilin Survival Migration

5. Lee Ellis, MD, UT MDACC Anti-VEGF Therapy is Not Synonymous With Anti-Angiogenic Therapy Anti-VEGFAnti-angiogenic TargetEndothelial and tumors cells Endothelial cells Inhibits permeabilityYes?? Inhibits further blood vessel growth (hard to prove) YesTBD Effects blood flow and function (Nitric oxide?) YesTBD

6. Lee Ellis, MD, UT MDACC Phase III Trials: Chemo +/- Anti-VEGF Therapy TrialYearMalignancySettingPrimary Endpoint Met? Capecitabine +/- BV 2002mBreast Ca RefractoryNO Paclitaxel +/- BV2005mBreast Ca Front LineYES 5-FU/LV +/- SU5416 2002mCRCFront LineNO IFL +/- BV2003 (AV2107) mCRCFirst LineYES FOLFOX +/- BV2005 (ECOG 3200) mCRCRefractoryYES FOLFOX +/- PTK/ZK 2005 (CONFIRM-1) mCRCFirst LineNO Carbo/Paclitaxel +/- BV 2005 (ECOG 4599) NSCLCFirst LineYES We owe it to our patients to publish the results…good or bad!

7. Lee Ellis, MD, UT MDACC Progression Free Survival ECOG 4599 NSCLC CONFIRM-1 mCRC 1 st (Central Rad Review) ECOG 3200 mCRC 2 nd * * * P < 0.05

8. Lee Ellis, MD, UT MDACC Response Rates ECOG 4599 NSCLC CONFIRM-1 mCRC 1 st (Central Rad Review) ECOG 3200 mCRC 2 nd * * * P < 0.05

9. Lee Ellis, MD, UT MDACC Phase III Trials: Chemo +/- BV TrialDisease SiteFront Line or Refractory  RR + BV Capecitabine +/- BV mBreast CaRefractory10% Paclitaxel +/- BVmBreast CaFront LineMonday IFL +/- BVmCRCFirst Line10% FOLFOX +/- BVmCRC ECOG 3200 Refractory13%* Carbo/Paclitaxel +/- BV NSCLC ECOG 4599 First Line15 * Single agent BV RR in ECOG 3200 = 3%

10. Lee Ellis, MD, UT MDACC Points for Discussion Biology Brief review of trials Mechanisms of Action PTK/ZK: Why different results than BV Toxicities

11. Lee Ellis, MD, UT MDACC Proposed Mechanisms of Action of Anti-VEGF Rx Anti-angiogenic –Difficult to demonstrate in patients How does one explain the increase in RR with chemo when, as a single agent, responses are rare? –“Normalization” of the vasculature with improved delivery of chemo and O 2 (transient) Jain Science 2005, Yang Cancer 2005 –Vascular “constriction” (Sunday 11:15) –Direct effect on tumor cells

12. Lee Ellis, MD, UT MDACC VEGF-A VEGF-R1 (Flt-1) Migration Invasion VEGF-R3 (Flt-4) Lymphangio- genesis VEGF-R2 (KDR/Flk-1) Proliferation Survival Permeability Cell membrane VEGF Family and Receptors PlGF VEGF-B VEGF-C, D VEGF-R Functions Neuropilin Survival Migration

13. Lee Ellis, MD, UT MDACC HT-29 KM12SMLM2 KM12L4 SW480 SW620 GEO RKO VEGFR1  -Actin Parikh et al. Am J Path 2004 VEGFR1 NRP-1 VEGFR1 and NRP-1 on CRC Cells Fan et al. Oncogene, 2005

14. Lee Ellis, MD, UT MDACC Copyright ©2004 by the National Academy of Sciences Castro-Rivera, Emely et al. (2004) PNAS 101, 11432-11437 Expression of VEGFR-1, VEGFR-2, and NP-1, in Lung Cancer Cells In Vitro Anti-VEGF Antibody Decreases Number of Lung Cancer Cells In Vitro VEGFR and NRP-1 on Lung Cancer Cells VEGFR-1 VEGFR-2 Neuropilin-1

15. Lee Ellis, MD, UT MDACC Dynamic Effect of Anti-VEGF Therapy Acute Chronic Decreased flow due to vasoconstriction Direct effect on tumor cells Paradoxical transient increase in chemo delivery Inhibition of blood vessel growth

16. Lee Ellis, MD, UT MDACC Points for Discussion Biology Brief review of trials Mechanisms of Action PTK/ZK: Why different results than BV Toxicities

17. Lee Ellis, MD, UT MDACC Addition of BV to Chemo Improves Efficacy Addition of PTK/ZK Does Not PK? Antibody vs TKI? VEGF Receptor target profile –TKIs do not target Neuropilin on tumor cells

18. Lee Ellis, MD, UT MDACC Morgan, B. et al. J Clin Oncol; 21:3955-3964 2003 Imaging done 2-9 hrs post dosing Half-life PTK/ZK = 3-6 hrs How long is the target affected? With Daily Dosing, We Do Not Know if the Target Was Inhibited for the Entire Dosing Period? Pre PTK/ZK Rx Post PTK/ZK Rx (Day 2) CRC Liver Metastases: DCE-MRI Ki (perfusion/permeability)

19. Lee Ellis, MD, UT MDACC Partial Inhibition of VEGFR is Ineffective!! Stress Induction of VEGF VEGF-R inhibition (stress) leads to a compensatory increase in VEGF levels –PTK/ZK leads to an increase in plasma VEGF in Phase I study in a dose dependent manner Drevs et al. Ann Onc 2005 –Increases in plasma VEGF with VEGFR-2 MoAB Bocci….Hicklin, Kerbel. Cancer Res 2004

20. Lee Ellis, MD, UT MDACC JCO June 20, 2005 Recent studies with TKIs: Longer half-lives or BID dosing

21. Lee Ellis, MD, UT MDACC Just because a trial does not meet its primary endpoint does not mean that the drug is not active! Capecitabine +/ BV in refractory breast cancer PTK/ZK has activity, but in this population with daily dosing, it did not significantly improve the effects of FOLFOX –LDH as a predictive marker could be explored in prospective trials, but it is not ready for prime time. Await OS data, and CONFIRM-2 data Consider alternative dosing schedules after validation of PK

22. Lee Ellis, MD, UT MDACC Points for Discussion Biology Brief review of trials Mechanisms of Action PTK/ZK: Why different results than BV Toxicities

23. Lee Ellis, MD, UT MDACC Adverse Events in Anti-VEGF + Chemo Trials NSCLC (ECOG 4599) C/P +/-BV –HTN 6% –Hemoptysis and death (5 pts) mCRC 2nd line (ECOG 3200) FOLFOX +/-BV vs BV –HTN 6-7% –Hemorrhage 2-3.5% mCRC 1st line (CONFIRM-1) FOLFOX +/- PTK/ZK –HTN 21% –Dizziness 7-8% VEGF Plays Important Roles in Physiology!!! Does HTN contribute to hemorrhage or dizziness, or are they independent effects?

24. Lee Ellis, MD, UT MDACC Although Progress Has Been Made, Our Work Is Not Done!! Improvements in survival are good, but not good enough (~2 mos) (our patients expect more) Identify predictive markers for –efficacy –adverse events Determine the role of combination therapy with other biologics –Will the addition of EGFR inhibitors improve efficacy even further? BV + cetuximab in mCRC BV + erlotinib in NSCLC

25. Lee Ellis, MD, UT MDACC Take Home Messages The addition of BV to chemo improves efficacy –First and second line mCRC –First line NSCLC and Breast Cancer –Be cognizant of HTN, bowel perforations and hemorrhage (infrequent, but important) The role of tyrosine kinase inhibitors targeting VEGFR (PTK/ZK) remains undefined in mCRC –Await overall survival data in CONFIRM-1, and outcomes of CONFIRM-2 Trials Ongoing studies in other malignancies with TKIs –RCC and GIST

26. Lee Ellis, MD, UT MDACC