1. Targeted Therapy for Renal Cell Cancer Dr.MahmoodzadehOncologist-Hematologist

2. Kidney Neoplasms Primary or Secondary (metastatic) Primary or Secondary (metastatic) Renal cell carcinoma (RCC) represents 80-85% of primary renal neoplasms Renal cell carcinoma (RCC) represents 80-85% of primary renal neoplasms Transitional cell carcinoma 8% Transitional cell carcinoma 8% Rare tumors include: Rare tumors include: - Oncocytomas - Collecting duct tumors - Renal sarcomas - Nephroblastoma (Wilms’ tumor in children) - Renal medullar carcinoma (Sickle cell disease)

3. Pathogenesis of VHL Von Hippel-Lindau protein, product of VHL gene, is a tumor suppressor Von Hippel-Lindau protein, product of VHL gene, is a tumor suppressor VHL inhibits hypoxia-inducible genes involved in angiogenesis such as VEGF, TGF-a, GLUT-1 VHL inhibits hypoxia-inducible genes involved in angiogenesis such as VEGF, TGF-a, GLUT-1 VHL destabilizes and promotes ubiquination of HIF-a (hypoxia-inducible factor) VHL destabilizes and promotes ubiquination of HIF-a (hypoxia-inducible factor) Loss of VHL results in tumor angiogenesis, tumor-cell proliferation epithelial cell proliferation Loss of VHL results in tumor angiogenesis, tumor-cell proliferation epithelial cell proliferation

4. Advanced RCC Treatment Primary treatments are systemic therapy with molecularly targeted therapy or immunotherapy Primary treatments are systemic therapy with molecularly targeted therapy or immunotherapy Surgery is palliative therapy Surgery is palliative therapy - Solitary metastatic site - Solitary recurrence following nephrectomy - Symptoms related to bulkiness of disease including pain, nausea, or GI obstruction

5. Many kidney cancers are associated with a kinase mutation responsible for angiogenesis factors overexpression Many kidney cancers are associated with a kinase mutation responsible for angiogenesis factors overexpression TKIs are targeted therapies: increasing response and reducing side effects. TKIs are targeted therapies: increasing response and reducing side effects. 5 Why using TKIs for Kidney cancer treatment ?

6. Targeted Therapy Based on advances in the understanding of the molecular biology of RCC Based on advances in the understanding of the molecular biology of RCC - Highly vascularlized tumor with increased VEGF and EGFR expression - Tumor growth mediated via VEGF pathway and mammalian target of rapamycin (mTOR) pathway

7. What is a tyrosine kinase receptor ? 7

9. VEGF Pathway Inhibition Tyrosine kinase (TK) inhibitors block the intracellular domain of the VGEF receptor Tyrosine kinase (TK) inhibitors block the intracellular domain of the VGEF receptor - Sunitinib (Sutent) - Sorafenib (Nexavar) Monoclonal antibody that binds circulating VEGF preventing the activation of the VEGF receptor Monoclonal antibody that binds circulating VEGF preventing the activation of the VEGF receptor - Bevacizumab (Avastin)

10. Sunitinib Two phase II trials evaluating activity and safety in previously treated advanced RCC Two phase II trials evaluating activity and safety in previously treated advanced RCC - 25-36% of patients had an objective response - Progression free survival (PFS) 8.3-8.7 months - Median survival 16.4 months Side effects include fatigue, HTN, nausea, diarrhea, mucositis, and hypothyroidism Side effects include fatigue, HTN, nausea, diarrhea, mucositis, and hypothyroidism

11. Sunitinib Phase III trial 750 pts with untreated stage IV RCC Sunitinib vs. INFa Sunitinib showed prolonged median PFS 11 vs. 5m and higher response rate of 31% vs. 6% Motzer RJ, et al. NEJM. 2007;356:115-124

13. 13 SUTENT Efficacy and Safety Were Demonstrated Using a 50-mg Starting Dose No dose adjustment is recommended based on age, race, gender, body weight, creatinine clearance, ECOG performance status score, or hepatic impairment (Child-Pugh Class A or B) No dose adjustment is recommended based on age, race, gender, body weight, creatinine clearance, ECOG performance status score, or hepatic impairment (Child-Pugh Class A or B) SUTENT dose may be easily adjusted in 12.5-mg increments

14. Sorafenib Phase II and phase III trials in advanced RCC Phase II and phase III trials in advanced RCC Phase III TARGET study of 903 previously tx pts w/ stage IV RCC randomized to Sorafenib vs. placebo Phase III TARGET study of 903 previously tx pts w/ stage IV RCC randomized to Sorafenib vs. placebo - Sorafenib improved median PFS 5.5 vs. 2.8m - No statistically significant survival benefit, median survival of 17.8 vs. 15.2 m Side effects include HTN, fatigue, rash, hand- foot syndrome, diarrhea, nausea Side effects include HTN, fatigue, rash, hand- foot syndrome, diarrhea, nausea

15. 15

16. 16 Marco Antonio Arap, New directions in the management of renal cell carcinoma 2007

17. Kinase profile of Pazopanib 17 Suniti nib Sor afen ib Pazop anib Kinase affinity profile Ki app (nM) VEGFR-110 VEGFR-24 VEGFR-36 PDGFR-  2 PDGFR-  5 C-Kit15

18. 18 Pz Pz Pz Pz Pz Pz VEGF-A/B VEGF-C PDGF-  PDGFR VEGFR- 1/2 VEGFR-3 Pz

19. Patient with metastasic RCC Patient with metastasic RCC 800mg once a day 800mg once a day No treatment holiday No treatment holiday versus placebo versus placebo Half patient naïve and half with prior cytokine treatment Half patient naïve and half with prior cytokine treatment  Primary endpoints: ◦ PFS: Progression free survival 19 Clinical trial of Pazopanib

20. Overview of clinical trial results Treatment naïveCytokine RefractoryOS PFS Sorafenib 5,8 mos. (Phase II results only) 5,9 mos.10,7 mos*. Sunitinib11 mos.8,7 mos.26,4 mos. Pazopanib11,1 mos.7,4 mos.21.1 mos. * : Cross-over 20

21. Phase II trial of 116 pts, Bevacizumab increased TTP 4.8 vs. 2.5m for placebo group. Phase II trial of 116 pts, Bevacizumab increased TTP 4.8 vs. 2.5m for placebo group. -No difference in median survival Phase III AVOREN trial of 648 untreated pts Phase III AVOREN trial of 648 untreated pts - INFa plus Avastin or placebo - Avastin group resulted in PFS of 10.2 vs. 5.4 m. - Unclear activity as single agent however Not FDA approved, but can be used as second-line therapy Not FDA approved, but can be used as second-line therapy Bevacizumab

22. mTOR Pathway Inhibition Temsirolimus (TMSR) is a rapamycin analog that inhibits mTOR kinase Temsirolimus (TMSR) is a rapamycin analog that inhibits mTOR kinase Phase III trial 626 untreated poor-prognosis pts with stage IV RCC tx w/ TMSR, TMSR +INFa, or INFa. Phase III trial 626 untreated poor-prognosis pts with stage IV RCC tx w/ TMSR, TMSR +INFa, or INFa. - TMSR prolonged survival compared to INFa (10.9 vs. 7.3m) and prolonged PFS (3.8 vs. 1.9m) - Benefit greater in non-clear cell RCC

23. AstraZeneca AstraZeneca Oral inhibitor of the : Oral inhibitor of the : VEGF-R 1/2/3 VEGF-R 1/2/3 C-kit C-kit PDGF-R PDGF-R Efficacy Racenta vs Placebo Efficacy Racenta vs Placebo Phase II, active, not recruiting Phase II, active, not recruiting RECENTIN : Cediranib 23

24.  Inhibs specifically: VEGFR 1-2-3 and PDGFR   Low effects on C-kit or flt-3  No cross resistance with sorafenib Axitinib (Bayer, AG013736) 24

25. The perfect tyrosine kinase inhibitor treating RCC  should inhib: o VEGFR 1-2-3 o PDGFR  o Raf  Without inhibiting ◦ FLT-3 ◦ C-kit The ideal kinase inhibiting profile in RCC 25

26. Immunotherapy Immunotherapy with IL-2 activates immune response against RCC resulting in tumor remission rates 10-20% with median duration of 19-91 months Immunotherapy with IL-2 activates immune response against RCC resulting in tumor remission rates 10-20% with median duration of 19-91 months Severe toxicity including hypotension, capillary leak syndrome, MI, renal insufficiency, pulmonary edema, hepatic dysfunction, CNS dysfunction Severe toxicity including hypotension, capillary leak syndrome, MI, renal insufficiency, pulmonary edema, hepatic dysfunction, CNS dysfunction Treatment requires ICU monitoring Treatment requires ICU monitoring Used for patients that can tolerate side effects Used for patients that can tolerate side effects

27. Chemotherapy RCC is only minimally responsive to chemotherapy RCC is only minimally responsive to chemotherapy 83 clinic trials involving over 4000 pts, overall response rate is only 6% 83 clinic trials involving over 4000 pts, overall response rate is only 6% On-going clinical trials of combination chemotherapy including Gemcitabine and 5-FU On-going clinical trials of combination chemotherapy including Gemcitabine and 5-FU Limited data reveals some response in non-clear cell RCC to Carboplatin, Cisplatin plus Gemcitabine Limited data reveals some response in non-clear cell RCC to Carboplatin, Cisplatin plus Gemcitabine

28. Radiation Therapy RCC relatively radioresistant RCC relatively radioresistant XRT has limited use in metastatic disease XRT has limited use in metastatic disease - Painful bone or recurrent abdominal metastases - Brain metastases

29. Summary RCC is relatively rare but increasing incidence RCC is relatively rare but increasing incidence Associated with tobacco and inherited disorders Associated with tobacco and inherited disorders Surgery is the only curative modality for Stage I, II, and III Surgery is the only curative modality for Stage I, II, and III Stage IV disease holds poor prognosis despite advancements in molecular understanding Stage IV disease holds poor prognosis despite advancements in molecular understanding IL-2, Sorafenib, Sunitinib, and Temsirolimus are FDA approved treatments for advanced RCC IL-2, Sorafenib, Sunitinib, and Temsirolimus are FDA approved treatments for advanced RCC

31. Thanks for your attention 31