1. NEW WEAPONS IN THE WAR OF CANCER Lodovico Balducci M.D. H. Lee Moffitt Cancer Center Tampa, Florida

2. OK! So Now Are We Ready to Select Drugs for Patients in a More Personalized Way?

3. The war on Cancer started With weapons of Mass destruction

4. Continued With conventional weapons

5. And now has discovered Smart weapons

6. Personalized oncology Targets of treatment Predictive factors Individual rescue

7. Smart weapons in medical oncology Hormones Monoclonal antibodies Inhibitors of the signal transduction cascade Drugs that reverse epigenetic changes Others Thalidomide derivatives Proteosome inhibitors Antisense Prodrugs activated in neoplastic cells Drugs that reverse multidrug resistance

9. General issues related to the use of “smart drugs.” End-point of phase I trials: MTD vs target inhibition End point of phase II trials: response rate vs stable disease Duration of treatment Combinations vs single agents Combination with chemotherapy Single vs multiple inhibitors Vertical and Horizontal inhibition of the signaling cascade Mechanisms of resistance (the cancer guerrilla) Enough patients for clinical trials

10. GROWTH FACTOR RECEPTOR TKI PI3K PDKI AKT RAS NF1 (RAS-GAP) PTEN TUBERIN FOXO Gsk3 BAD MDM2 RHEB GTP RHEBGDP mTOR LKB1AMPK HIF DECREASED TRANSCRIPTION INCREASED CELL PROLIFERATION ACTIVATION Bcl2 SUPPRESSION p53

11. Issues of “smart drugs” in the older person Absorption Drug interactions Unexpected complications

12. A disease with multiple targets Is an incurable disease Checov

13. Combinations in Lung Cancer IGF-1R Inhibitor Drug X EGFRInhibitor VEGF Inhibitor mTOR Inhibitor EGFR Inhibitor But which ones? Designed for a population, not an individual patient. But which ones? Designed for a population, not an individual patient.

14. STRATEGIES ANGIOGENESIS INHIBITORS + CHEMOTHERAPY ANGIOGENESIS INHIBITORS + TARGETED THERAPY CHEMOTHERAPY AND TARGETED THERAPY HORIZONTAL INHIBITION VERTICAL INHIBITION

15. Breast cancer: bevacizumab + paclitaxel

16. DTIC +/- Sorafenib Trial: PFS 1.00 0.75 0.50 0.25 0.00 1.00 0.75 0.50 0.25 0.00 0 0 14 29 43 57 71 Weeks From Randomization Progression-free Survival Probability 86 Sorafenib + DTIC (39 events) Median: 21.1 weeks (95% CI: 16.0, 28.0) Placebo + DTIC (42 events) Median: 11.7 weeks (95% CI: 6.1, 17.9) Hazard Ratio = 0.665 (95%CI: 0.428, 1.034) p = 0.068 Hazard Ratio = 0.665 (95%CI: 0.428, 1.034) p = 0.068 McDermott et al. J Clin Oncol, in press.

17. Lapatinib pazopanib superior to lapatinib alone

18. Combinations that do not work Bevacizumab erlotinib in RCC Bevacizumab+ cetuximab (CAIRO2) Erlotinib + platinum chemotherapy

20. Gemzar and erlotinib vs Gemzar erlotinib and bevacizumab

21. COMBINATION OF AGENTS TARGETING THE SIGNAL TRANSDUCTION CASCADE VERTICAL BLOCKADE HORIZONTAL BLOCKADE OVERCOMING RESISTANCE

22. HIF KDR ? TOR Inhibitor (temsirolimus or RAD 001) Bevacizumab Sorafenib Sunitinib Vertical Combinations- Targeting of VEGF at multiple levels HIF VEGF

23. Temsirolimus plus Bevacizumab Merchan et al., ASCO 2007 * = PD (Clinical progression) * * Dose Level 1 Dose Level 2 Percent Reduction Maximum Percent Reduction of Target Lesions by Patient

24. Combination Targeted Therapy For Advanced NSCLC Herbst RS et al. J Clin Oncol. 2005;23:2544-2555. InhibitorErlotinibBevacizumab Mechanism Inhibits tumor cell growth and blocks synthesis of angiogenic proteins (e.g., bFGF, VEGF, TGF-a) by tumor cells Inhibits endothelial cells from responding to the angiogenic protein VEGF bFGF VEGF TGF-a bFGF VEGF TGF-a Endothelial cells Tumor

25. Median PFS (months)6 month PFS rate (%) 12 month OS rate (%) 4.433.657.1 4.830.553.6 3.021.531.8 Bevacizumab + Erlotinib (n=39) Chemotherapy (n=41) Chemotherapy + Bevacizumab (n=40) Previously treated advanced non- squamous NSCLC (n=120) Herbst RS et al. J Clin Oncol. 2007;25:4743-4750. Randomized, Multicenter Study Primary endpoint : safety and preliminary efficacy (PFS) Secondary endpoints: ORR (+ duration); duration of survival Phase 2: Bevacizumab With Chemotherapy Or Erlotinib in Advanced NSCLC

26. Example of vertical inhibition: lapatinib + trastuzumab

27. Continue CR treatment for Week 1 2 345 6 7 8 9 PR 12 months or until  Stable tumor progression AAAA Reevaluate  S  Progression Off treatment Doses: Bevacizumab 3mg/kg, 5 mg/kg, 10mg/kg, IV infusion, q 2 weeks Sorafenib- 200mg, 200mg BID, 400mg BID daily PO Continue CR treatment for Week 1 2 345 6 7 8 9 PR 12 months or until  Stable tumor progression AAAA Reevaluate  S  Progression Off treatment Doses: Bevacizumab 3mg/kg, 5 mg/kg, 10mg/kg, IV infusion, q 2 weeks Sorafenib- 200mg, 200mg BID, 400mg BID daily PO Enhanced sorafenib- type toxicity Phase I / II Sorafenib + Bevacizumab Trial: Treatment Regimen Sosman et al

28. Targeted therapy in the elderly Effectiveness Toxicity

29. Ramalingam, S. S. et al. J Clin Oncol; 26:60-65 2008 Fig 1. Kaplan-Meier curves for (A) overall survival for elderly (PC v PCB), (B) PFS for elderly (PC v PCB), (C) combined overall survival by age groups (PC + PCB), and (D) combined PFS by age groups (PC + PCB)

30. TOXICITY OF PC AND PCB IN PATIENTS 70+ Ramalingam et al, JCO, 2008, 26, 60-65 TOXICITYPCPCBP HEMATO NEUTROPENIA FEVER THROMBOCYTO 22 0.9 0 34 6.2 3.5.06 0.03.06 NON-HEMATO HYPERTENSION PROTEINURIA HEMORRHAGE NAUSEA ANOREXIA.9 0 1.7 0 0.9 6.2 7.9 4.4 7.9.03.002.03.01

31. TOXICITY PC ABD PCB IN PEOPLE 70+ AND YOUNGER PATIENTS RAMALINGAM ET AL, JCO, 2008, 26, 60-65 TOXICITY PCBPC >70 <70 NEUTROPENIA MELENA PROTEINURIA WEAKNESS NEUROPATHY DIZZINESS WORST GRADE TOXICITY TRD 3422 3.5 0 7.9 1.3 7.8 2.2 3.5 0.6 7.9 1.6 8771 6.3 2.6.02.005.001.02.05.003.001.08 2215 1.8 0 0 4.3 3.1 2.6 1.5 65 61 1.8 0.08.07

32. Toxicity of cetuximab in the elderly Bouchachada et al, Crit Rev oncol Hematol, 2008 Skin Rash 75% (11% grade 3) Diarrhea 80% (20% grade 3 and 4)

33. Lin, W.-L. et al. J Clin Oncol; 26:2779-2780 2008 Fig 1.

34. Copyright ©2008 American Association for Cancer Research Murgo, A. J. et al. Clin Cancer Res 2008;14:3675-3682 Figure 1">

35. Copyright ©2008 American Association for Cancer Research Murgo, A. J. et al. Clin Cancer Res 2008;14:3675-3682 Figure 2">

36. Copyright ©2008 American Association for Cancer Research Hoering, A. et al. Clin Cancer Res 2008;14:4358-4367 Figure 1">

37. Copyright ©2008 American Association for Cancer Research Hoering, A. et al. Clin Cancer Res 2008;14:4358-4367 Figure 2">

38. Conclusions Targeted therapy involves: Agents directed to a specific target Targets predictive of response to treatment Overcoming resistance Targeted therapy has been very successful in situations where a single or few targets are responsible to maintain the disease (CML, HER2 positive breast cancer; some B cell malignancies)

39. Conclusions The combination of antiangiogenesis agents with cytotoxic chemotherapy has increased the activity of chemotherapy in breast, colon, and lung cancer and in melanoma

40. Conclusions The combination of 2 or more targeting agents seems to be more effective and safer when the inhibition is vertical, at least in the case of inhibition of the signal transduction cascade.

41. Conclusions The plethora of new agents require more diversified clinical studies: this include phase 0 studies to test the doses providing full inhibition of the target and randomized phase II studies to establish the value of stable disease Scarcity of patients will make the need of including older patients in clinical trials more compelling

42. Conclusions Data on toxicity of targeted agents in older individuals are limited: the risk of thrombosis with avastin and of serious cutaneous reactions with cetuximab appears to increase with age

43. A CASE FOR GERIATRIC ONCOLOGY A WORLD GOVERNED BY TECHNOLOGY IS A WORLD OF SLAVES. G. Bernanos: La France contre les robots