Targeted Therapy for Renal Cell Cancer

1. Targeted Therapy for Renal Cell Cancer Dr.Mahmoodzadeh Oncologist-Hematologist

2. Kidney Neoplasms • Primary or Secondary (metastatic) • Renal cell carcinoma (RCC) represents 80-85% of primary renal neoplasms • Transitional cell carcinoma 8% • 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 • 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) • 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 • Surgery is palliative therapy • Solitary metastatic site • Solitary recurrence following nephrectomy • Symptoms related to bulkiness of disease including pain, nausea, or GI obstruction

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

6. Targeted Therapy • 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. Whatis a tyrosine kinase receptor ?

9. VEGF Pathway Inhibition • 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 - Bevacizumab (Avastin)

10. Sunitinib • 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

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. 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) SUTENT dose may be easily adjusted in 12.5-mg increments

14. Sorafenib • 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 • 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

15. TherapeuticschemebeforePazopanib

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

17. Kinase profile of Pazopanib Sorafenib Sunitinib Pazopanib 17

18. Scheme of action, Pazopanib VEGF-A/B PDGF-a/b VEGF-C VEGFR-1/2 PDGFR Pz VEGFR-3 Pz Pz Pz Pz Pz Pz

19. Clinical trial of Pazopanib • Patient withmetastasic RCC • 800mg once a day • No treatmentholiday • versus placebo • Half patient naïve and halfwithprior cytokine treatment • Primary endpoints: • PFS: Progression free survival

20. Overview of clinical trial results * : Cross-over

21. Bevacizumab • 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 • 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

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

24. Axitinib (Bayer, AG013736) • Inhibsspecifically: VEGFR 1-2-3 and PDGFR b • Loweffects on C-kit or flt-3 • No cross resistancewithsorafenib

25. The ideal kinase inhibiting profile in RCC The perfect tyrosine kinase inhibitortreating RCC • shouldinhib: • VEGFR 1-2-3 • PDGFR a-b • Raf • Withoutinhibiting • FLT-3 • C-kit

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 • Severe toxicity including hypotension, capillary leak syndrome, MI, renal insufficiency, pulmonary edema, hepatic dysfunction, CNS dysfunction • Treatment requires ICU monitoring • Used for patients that can tolerate side effects

27. Chemotherapy • RCC is only minimally responsive to chemotherapy • 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 • Limited data reveals some response in non-clear cell RCC to Carboplatin, Cisplatin plus Gemcitabine

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

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

31. Thanks for your attention