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NEW WEAPONS IN THE WAR OF CANCER Lodovico Balducci M.D. H. Lee Moffitt Cancer Center Tampa, Florida OK! So Now Are We Ready to Select Drugs for Patients in a More Personalized Way? The war on Cancer started With weapons of Mass destruction Continued With conventional weapons And now has discovered Smart weapons Personalized oncology • Targets of treatment • Predictive factors • Individual rescue 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 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 GROWTH FACTOR RECEPTOR TKI RAS PI3K PTEN PDKI AKT Gsk3 MDM2 BAD NF1 (RAS-GAP) TUBERIN FOXO RHEB GTP SUPPRESSION p53 ACTIVATION Bcl2 DECREASED INCREASED TRANSCRIPTION CELL PROLIFERATION mTOR HIF AMPK LKB1 RHEBGDP Issues of “smart drugs” in the older person • Absorption • Drug interactions • Unexpected complications A disease with multiple targets Is an incurable disease Checov Combinations in Lung Cancer EGFR Inhibitor VEGF Inhibitor Drug X IGF-1R Inhibitor mTOR Inhibitor But which ones? Designed for a population, not an individual patient. EGFR Inhibitor STRATEGIES • ANGIOGENESIS INHIBITORS + CHEMOTHERAPY • ANGIOGENESIS INHIBITORS + TARGETED THERAPY • CHEMOTHERAPY AND TARGETED THERAPY • HORIZONTAL INHIBITION • VERTICAL INHIBITION Breast cancer: bevacizumab + paclitaxel Progression-free Survival Probability DTIC +/- Sorafenib Trial: PFS 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) 1.00 0.75 Hazard Ratio = 0.665 (95%CI: 0.428, 1.034) p = 0.068 0.50 0.25 0.00 0 14 29 43 57 71 86 Weeks From Randomization McDermott et al. J Clin Oncol, in press. Lapatinib pazopanib superior to lapatinib alone Combinations that do not work • Bevacizumab erlotinib in RCC • Bevacizumab+ cetuximab (CAIRO2) • Erlotinib + platinum chemotherapy Gemzar and erlotinib vs Gemzar erlotinib and bevacizumab COMBINATION OF AGENTS TARGETING THE SIGNAL TRANSDUCTION CASCADE • VERTICAL BLOCKADE • HORIZONTAL BLOCKADE • OVERCOMING RESISTANCE Vertical Combinations- Targeting of VEGF at multiple levels HIF ? TOR Inhibitor (temsirolimus or RAD 001) VEGF Bevacizumab KDR Sorafenib Sunitinib Temsirolimus plus Bevacizumab Merchan et al., ASCO 2007 Percent Reduction 40 Maximum Percent Reduction of Target Lesions by Patient 20 * 0 -20 -40 -60 -80 Dose Level 1 Dose Level 2 * = PD (Clinical progression) Combination Targeted Therapy For Advanced NSCLC Inhibitor Erlotinib Bevacizumab 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 Tumor Endothelial cells Herbst RS et al. J Clin Oncol. 2005;23:2544-2555. Phase 2: Bevacizumab With Chemotherapy Or Erlotinib in Advanced NSCLC Bevacizumab + Erlotinib (n=39) Previously treated advanced nonsquamous NSCLC (n=120) Chemotherapy + Bevacizumab (n=40) Chemotherapy (n=41) Median PFS (months) 6 month PFS rate (%) 12 month OS rate (%) 4.4 33.6 57.1 4.8 30.5 53.6 3.0 21.5 31.8 • Randomized, Multicenter Study • Primary endpoint : safety and preliminary efficacy (PFS) • Secondary endpoints: ORR (+ duration); duration of survival Herbst RS et al. J Clin Oncol. 2007;25:4743-4750. Example of vertical inhibition: lapatinib + trastuzumab Phase I / II Sorafenib + Bevacizumab Trial: Treatment Regimen Continue Week 1 2 3 4 5 A A A 6 7 8 9 CR PR Stable treatment for 12 months or until tumor progression A Reevaluate S Enhanced sorafenibtype toxicity 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 Sosman et al Targeted therapy in the elderly • Effectiveness • Toxicity 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) Ramalingam, S. S. et al. J Clin Oncol; 26:60-65 2008 Copyright © American Society of Clinical Oncology TOXICITY OF PC AND PCB IN PATIENTS 70+ Ramalingam et al, JCO, 2008, 26, 60-65 TOXICITY PC PCB P 22 0.9 0 34 6.2 3.5 .06 0.03 .06 .9 0 1.7 0 0.9 6.2 7.9 7.9 4.4 7.9 .03 .002 .03 .03 .01 HEMATO NEUTROPENIA FEVER THROMBOCYTO NON-HEMATO HYPERTENSION PROTEINURIA HEMORRHAGE NAUSEA ANOREXIA TOXICITY PC ABD PCB IN PEOPLE 70+ AND YOUNGER PATIENTS RAMALINGAM ET AL, JCO, 2008, 26, 60-65 TOXICITY PCB >70 NEUTROPENIA MELENA PROTEINURIA WEAKNESS NEUROPATHY DIZZINESS WORST GRADE TOXICITY TRD PC <70 >70 <70 34 3.5 7.9 7.8 3.5 7.9 87 22 0 1.3 2.2 0.6 1.6 71 .02 .005 .001 .02 .05 .003 .001 22 1.8 0 4.3 2.6 2.6 65 15 0 0 3.1 1.5 1.5 61 .08 .07 6.3 2.6 .08 1.8 0 .07 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) Fig 1. Lin, W.-L. et al. J Clin Oncol; 26:2779-2780 2008 Figure 1"> Murgo, A. J. et al. Clin Cancer Res 2008;14:3675-3682 Copyright ©2008 American Association for Cancer Research Figure 2"> Murgo, A. J. et al. Clin Cancer Res 2008;14:3675-3682 Copyright ©2008 American Association for Cancer Research Figure 1"> Hoering, A. et al. Clin Cancer Res 2008;14:4358-4367 Copyright ©2008 American Association for Cancer Research Figure 2"> Hoering, A. et al. Clin Cancer Res 2008;14:4358-4367 Copyright ©2008 American Association for Cancer Research 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) Conclusions • The combination of antiangiogenesis agents with cytotoxic chemotherapy has increased the activity of chemotherapy in breast, colon, and lung cancer and in melanoma 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. 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 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 A CASE FOR GERIATRIC ONCOLOGY • A WORLD GOVERNED BY TECHNOLOGY IS A WORLD OF SLAVES. G. Bernanos: La France contre les robots