1. Ezra E. W. Cohen, MD, FRCPC Assistant Professor Department of Medicine, Hematology/Oncology University of Chicago Chicago, Illinois Multitargeted Tyrosine Kinase Inhibitors: Clinical Advances, Synergistic Approaches, and Future Development This program is supported by an educational donation from

2. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies About These Slides Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.  Users are encouraged to include these slides in their own presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent.  These slides may not be published or posted online or used for any other commercial purpose without written permission from Clinical Care Options.  We are grateful to Ezra E. W. Cohen, MD, MRCPC, of the Department of Medicine, Hematology/Oncology, University of Chicago, Chicago, Illinois, who aided in the content creation of these slides.

3. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Single vs Multikinase Inhibitors  Single kinase inhibitors –Theoretically more specific –Fewer off-target effects –Fewer toxicities –Likely not absolutely achievable with small- molecule inhibitors  Multikinase inhibitors –Theoretically target several pathways –Most cancers are not driven by a single protein aberration –More off-target effects –Possibly more toxic

4. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Fabian MA, et al. Nat Biotechnol. 2005;23:329-336. Kinase Interactions  Many receptors involved –Varying degrees of specificity

5. clinicaloptions.com/oncology Navigating Multiple Pathways: Targeted Therapies Multitude of Possibilities: Targets, Agents, and Pathways VEGFR EGFR PDGFR ABL Tumor CellEndothelial Cell EGF PDGF VEGF

6. clinicaloptions.com/oncology Navigating Multiple Pathways: Targeted Therapies Intracellular mTKI Targets EGFR PDGFR VEGFR Abl JAK Src Raf MAPK MEKERKRas PI3-K AKT Raf MAPK MEKERKRas PI3-K AKT Tumor CellEndothelial Cell Proliferation/Survival Metastasis Angiogenesis Transcription STAT Erlotinib LapatinibGefitinib Vandetanib Sunitinib Sorafenib Dasatinib Nilotinib Imatinib Axitinib Motesanib

7. Multitargeted Agents

8. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies VEGFR-1 VEGFR-2 FLT4 Fms Split Kinase Domain RTKs Sunitinib (SU11248): A Multitargeted Receptor TKI  IC 50 (nM) [1] –VEGFR2: 4 –PDGFRβ: 39 –KIT: 1 –FLT3 (WT): 8 –EGFR: > 10,000 1. Chow LQ, et al. J Clin Oncol. 2007;25:884-896. PDGFR-a PDGFR-b CSF1R KIT FLT3  Effective against VEGFR, PDGFR, KIT, and FLT3 at mM concentration  Targets receptors involved in both tumor cell proliferation and angiogenesis  No significant activity against other RTKs (ie, EGFR); tested against > 40 other RTKs and protein kinases  Activity in GIST, renal, breast, etc

9. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Sunitinib vs IFN in mRCC: PFS (Independent Central Review) Motzer RJ, et al. N Engl J Med. 2007;356:115-124. Copyright © 2007 Massachusetts Medical Society. All rights reserved. No. at risk, sunitinib:23590322 No. at risk, IFN-  :15242180 Sunitinib Median PFS: 11 months (95% CI: 10-12) Interferon alfa Median PFS: 5 months (95% CI: 4-6) Time (Mos) 01234567891011121314 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 PFS Probability Hazard ratio: 0.42 (95% CI: 0.32-0.54) P <.001

10. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Sorafenib (BAY 43-9006): A Signal Transduction Inhibitor  Inhibits both Raf kinase and VEGFR  Inhibits tumor cell proliferation and angiogenesis  Activity in various cancers  Approved by FDA to treat renal cell carcinoma MoleculeIC 50, mM ± SD Raf-16 ± 3 VEGFR-290 ± 15 VEGFR-320 ± 6 PDGFR-ß57 ± 20 C-kit68 ± 21 Flt358 ± 20 EGFRInactive at 10,000 Wilhelm SM, et al. Cancer Res. 2004;64:7099-7109.

11. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Ratain MJ, et al. J Clin Oncol. 2006;24:2505-2512. Sorafenib (BAY 43-9006): Study 100391 Objectives (Phase II)  Randomized discontinuation trial  Primary endpoint –For patients with metastatic, refractory solid tumors who achieve SD after initial 12-week course of sorafenib, determine percentage remaining progression free after additional 12 weeks of sorafenib  Secondary endpoints –PFS –Tumor response rate –Safety

12. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Patients with refractory solid tumors* treated with initial 12-week induction course of sorafenib 400 mg BID (N = 502) Week 24: tumor assessment Ratain MJ, et al. ASCO 2005. Abstract 4544. *40% RCC, 28% CRC, 32% other types. † Crossover allowed. ≥ 25% shrinkage Continue sorafenib (open label) Tumor growth/ shrinkage < 25% Randomized ≥ 25% growth Off study Sorafenib 400 mg BID Placebo † Sorafenib Phase II Study 100391: Patients with SD Randomized

13. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies *Investigator assessed. Ratain MJ, et al. Phase II Placebo-Controlled Randomized Discontinuation Trial of Sorafenib in Patients With Metastatic Renal Cell Carcinoma. J Clin Oncol. 2006;24:2505-2512. Reprinted with permission from the American Society of Clinical Oncology 200 0.00 0.25 0.50 0.75 1.00 Proportion of Patients Progression Free 0100300400500 Days From Randomization Sorafenib (n = 32) Placebo (n = 33) Censored Median PFS* From Randomization Placebo: 6 weeks Sorafenib: 24 weeks P =.0087 12-Week Run-in Period -84 Sorafenib Phase II Study 100391: PFS in RCC Patients

14. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Sorafenib vs Placebo in Advanced HCC (SHARP Study, Phase III) Primary endpoints: OS, time to symptomatic progression Secondary endpoint: TTP (independent review) Llovet JM, et al. ASCO 2007. Abstract LBA1. Stratified by macroscopic vascular invasion and/or extrahepatic spread; ECOG PS; geographical region Patients with advanced hepatocellular carcinoma, ECOG PS ≤ 2, no previous systemic treatment (N = 602) Sorafenib 400 mg PO BID, continuous dosing (n = 299) Placebo 2 tablets PO BID, continuous dosing (n = 303)

15. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Sorafenib vs Placebo in Advanced HCC (SHARP): Response Time to symptom progression (FSHI8-TSP scoring): no significant differences between treatment groups (P =.77) Llovet JM, et al. ASCO 2007. Abstract LBA1. *RECIST criteria, independent review. Result Sorafenib (n = 299) Placebo (n = 303) Overall response,* n (%)  CR 0 (0)  PR 7 (2.3)2 (0.7) SD, n (%) 211 (71)204 (67) PD, n (%)54 (18)73 (24) PFS rate at Month 4, %6242 Median treatment duration, wks2319

16. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Sorafenib vs Placebo in Advanced HCC (SHARP): OS Llovet JM, et al. ASCO 2007. Abstract LBA1. HR (S/P): 0.69 (95% CI: 0.55-0.88; P =.00058) Regimenn Median OS, wks Sorafenib29946.3 (95% CI: 40.9-57.9) Placebo30334.4 (95% CI: 29.4-39.4)

17. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies *Converted from the value obtained by Western +2.3% BSA Axitinib: A Potent and Selective Inhibitor of VEGFR-1, -2, and -3 ReceptorIC 50, nM VEGFR-10.1* VEGFR-20.2 VEGFR-30.1-0.3 PDGFR-ß1.6 PDGFR-  5.0 C-kit1.7 CSF-1R73 FGFR-1231 Flt3>1000 RET>1000

18. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies *Excludes 15 patients ineligible for response assessment 6 PR have been confirmed by independent review Cohen EE, et al. ASCO 2007. Abstract 6008. Response by investigator assessment (RECIST criteria)*:  PR: 18 pts (30%, 95% CI: 18.9% to 43.2%)  SD: 23 pts (48%)  Any tumor shrinkage: 47 pts (78%) Maximum Change in Target Lesions (%) PR SD/PD -20 40 0 20 -40 -60 -80 -100 -120 Phase II Study of Axitinib in Thyroid Cancer: % Reduction in Target Lesions

19. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Other mTKIs in Thyroid Cancer: Phase II Studies  Motesanib diphosphate, progressive DTC (N = 93) [1] : PR in 14%, durable (≥ 24 weeks) SD in 35%  Vandetanib in locally advanced/metastatic hereditary MTC (N = 30) [2] : confirmed PR in 17%, durable (≥ 24 weeks) SD in 50%  Sorafenib in metastatic PTC (N = 19) [3] : PR in 26%, SD in 42% 1. Sherman SI, et al. ASCO 2007. Abstract 6017. 2. Wells S, et al. ASCO 2007. Abstract 6018. 3. Gupta V, et al. ASCO 2007. Abstract 6019.

20. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Spano J, et al. ECCO 2007. Abstract 3506. Primary endpoint: OS Stratified by locally advanced vs metastatic disease, ECOG PS 0-1 vs 2 Gemcitabine ± Axitinib in Pancreatic Cancer: Randomized Phase II Trial 2:1 randomization Patients with pancreatic cancer, ECOG PS ≤ 2, and no previous treatment with gemcitabine or VEGF/VEGFR inhibitors (N = 103) Axitinib 5 mg PO BID + Gemcitabine 1000 mg/m 2, Days 1, 8, 15 of 28-day cycle ( n = 69) Gemcitabine 1000 mg/m 2, Days 1, 8, 15 of 28-day cycle (n = 34)

21. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Phase II Trial of Gemcitabine ± Axitinib in Pancreatic Cancer: OS Spano J, et al. ECCO 2007. Abstract 3506. Hazard ratio: 0.707 (95% CI: 0.44-1.13) Regimen Median OS, mo Axitinib + gemcitabine 6.9 mo (95% CI: 5.3-10.1) Gemcitabine alone 5.6 mo (95% CI: 3.9-8.8)

22. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Motesanib Diphosphate (AMG 706): Oral Multitargeted TKI 1. Polverino A, et al. Cancer Res. 2006;66:8715-8721. 2. Rosen LS, et al. J Clin Oncol. 2007;25:2369-2376.  Selective targeting of VEGFR1-3, PDGFR, c-Kit  Potent inhibitor of angiogenesis [1]  Well tolerated, evidence of activity in refractory advanced tumors [2] : –Of 67 assessable patients, PR in 5 (7%) and SD in 35 (49%) –Responders –Thyroid cancer (n = 3) –Renal cell carcinoma –Leiomyosarcoma

23. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Chemical Structure Vandetanib (ZD6474): Novel Antiangiogenic Agent  Orally active, small molecule  Selective inhibitor of VEGFR2-TK  Activity against EGFR-TK N N N O O F Br N Wedge SR, et al. Cancer Res. 2002;62:4645-4655. Kinase Selectivity KinaseIC 50 (µM) KDR (VEGFR-2)0.04 Flt-4 (VEGFR-3)0.11 Flt-1 (VEGFR-1)1.6 EGFR0.5 ErbB-2> 20 Ret0.10

24. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Heymach JV, et al. ASCO 2006. Abstract 7016. Docetaxel ± Vandetanib in NSCLC: Randomized Phase II Trial Patients with NSCLC who failed first-line platinum-based chemotherapy Primary endpoint: PFS Run-in phaseRandomized phase Placebo + Docetaxel 75 mg/m 2 every 21 days (n = 41) Vandetanib 300 mg + Docetaxel 75 mg/m 2 every 21 days (n = 44) Vandetanib 100 mg + Docetaxel 75 mg/m 2 every 21 days (n = 42) Vandetanib 100 mg (n = 4) or 300 mg (n = 11) daily + Docetaxel 75 mg/m 2 every 21 days

25. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Heymach JV, et al. ASCO 2006. Abstract 7016. Docetaxel ± Vandetanib in NSCLC: PFS Regimen Median PFS, wksHR (P Value) Vandetanib 100 mg + docetaxel 18.70.635 (.074) Vandetanib 300 mg + docetaxel 17.00.829 (.416) Docetaxel alone 12.0

26. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Lapatinib: Dual Kinase Inhibitor  Orally active small-molecule TKI –EGFR –EGFR type 2 (HER2, or HER2/neu)  Preclinical data: not cross-resistant with trastuzumab [1]  Lapatinib + capecitabine –Active in patients with HER2+ MBC who progressed on trastuzumab therapy –Phase III, randomized, open-label study [2] : capecitabine ± lapatinib in patients with HER2+ MBC previously treated with an anthracycline, a taxane, and trastuzumab 1. Konecny GE, et al. Cancer Res. 2006;66:1630-1639. 2. Geyer CE, et al. N Engl J Med. 2006;355;2733-2743.

27. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies XL880: A MET/VEGFR Inhibitor  MET activation promotes tumor cell survival, proliferation  MET (and VEGF) promote angiogenesis  Dual inhibition of MET and VEGFR: blockade of tumor escape mechanisms in response to hypoxia  XL880 (MET/VEGFR2) –Well tolerated with clear antitumor activity in phase I studies (N = 55) –5 PR, 20 MR or prolonged (> 3 mos) SD [1] –Phase II studies –Head and neck cancer –Gastric cancer –Papillary RCC 1. Eder JP, et al. ASCO 2007. Abstract 3526.

28. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Patient Selection and Multitargeted TKIs  Factors to consider when selecting a multitargeted TKI –Agent profile: Are the inhibited kinases relevant to the cancer being treated? –Oncogenic driver: What is the likelihood that the specific agent will inhibit the desired kinase? –Affinity –Pharmacokinetics –Pharmacodynamics

29. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Early Management of Toxicity  Hypertension  Diarrhea  Rash  Hand-foot syndrome  Cardiovascular toxicity  Others

30. clinicaloptions.com/oncology Translating Science Into Clinical Practice: Targeted Therapies Conclusions  Multitargeted TKIs have demonstrated efficacy in multiple tumor types  Response rates and improvements in survival (benefit) do not necessarily parallel each other  Toxicity profiles of multitargeted TKIs are very different than conventional cytotoxic agents and depend on the kinases being inhibited  Future success depends on individualized therapy –Paradigm shift away from one drug/regimen for one cancer

31. Go Online for More Content From “Targeted Therapies” Download Slidesets including PowerPoint Animations illustrating key concepts in Targeting EGFR, Multikinase Inhibition, and the Tumor Microenvironment Earn CME Credit: Read Online Modules addressing these important topic areas in detail clinicaloptions.com/oncology