Relatore: Dr.ssa ALKETA HAMZAJ alketa.hamzaj@usl8.toscana.it

1. ADJUVANT AND NEOADJUVANT APPROACHES IN RCC Relatore: Dr.ssa ALKETA HAMZAJ alketa.hamzaj@usl8.toscana.it S.S. ONCOLOGIA MEDICA OSPEDALE SAN DONATO AREZZO

2. RCC: Presentation at diagnosis Localized Locally advanced Metastatic 30% Recurrence

3. Rationale of an adjuvant therapy approach in RCC • Nearly 50% of all pts with RCC will have metastatic disease upfront or during their disease course. • Micrometastatic disease at the time of surgery in pts with recurrent disease following nephrectomy • Use of effective therapy may reduce the risk of relapse

4. Past Adjuvant Therapy Approaches Designed • Radiation therapy • Hormonal therapy • Chemotherapy • Immunotherapy • Vaccines • Monoclonal antibody

5. Adjuvant randomized trials in RCC:

6. Progress in recent years ... • Better prognostic definition of the risk stratification • Advances in knowledge of the molecular biology of RCC • Availability of new target-based treatments, effective in metastatic disease and safe

7. Progress in recent years ... • Better prognostic definition of the risk stratification • Advances in knowledge of the molecular biology of RCC • Availability of new target-based treatments, effective in metastatic disease and safe

8. Defining Risk • Predicting the probability that a subject will experience a certain event in time • Identifing patients at increased risk, which may benefit from adjuvant therapy and reducing toxicity in low-risk pts

9. Current Risk Stratification Algorithms • Postoperative models: • Kattan’s nomogram, Memorial-Sloan-Kettering Cancer Center (Kattan, J Urol 2001): RFS • SSIGN, Mayo Clinic (Frank, J Urol 2002): CSS • UISS (Zisman, J Clin Oncol, 2004): OS • Preoperative models: • Yayciouglu (Urology 2001): RFS • Cindolo (Br J Urol Int 2003): RFS

10. Risk Group Stratification for patients with surgically resected RCC • SSIGN, Mayo Clinic (Frank, J Urol 2002): CSS • UISS (Zisman, J Clin Oncol, 2004): OS

11. Mayo Clinic Score for RCC (SSIGN)* Cancer- specific Survival rate SSIGN Score 5-years C-SS 0-2 3-4 5-6 7-9 >10 100% 91% 64% 47% 0 * Mayo Clinic Stage, Size, Grade and Necrosis score for ccRCC; Frank I, J Urol 2002

12. UCLA Integrated Staging System (UISS*): Pts with RCC undergone surgery Non metastatic pts Metastatic pts Low Low Intermed Intermed High risck High risck * T stage, Grade, ECOG-PS Zisman et al, JCO 2004 Downs TM et al. Crit Rev Oncol Hemato, 2009

13. UCLA Integrated Staging System (UISS): Nonmetastatic patients OS 5 anni: 84% OS 5 anni: 72% OS 5 anni: 44% Zisman et al, JCO 2004

14. UCLA Integrated Staging System (UISS): Metastatic patients OS 5 anni: 30% OS 5 anni: 0% OS 5 anni: 19% Zisman et al, JCO 2004

15. UCLA Integrated Staging System (UISS): Survival Analysis Kaplan–Meier survival analysis of the study population according to the formulated UISS categories separately for metastatic (M+) and nonmetastatic (M−) patients Downs TM et al. Crit Rev Oncol Hemato, 2009

16. Comparison of the SSIGN score and the UISS integrated models of risk stratification Kapoor A. Urologic Oncology, 2009 Downs TM. Crit Rev Oncol Hemato, 2009

17. Progress in recent years ... • Better prognostic definition of the risk stratification • Advances in knowledge of the molecular biology of RCC • Availability of new target-based treatments, effective in metastatic disease and safe

18. New target-based treatments... Bevacizumab Temsirolimus Everolimus Sunitinib Sorafenib Pazopanib Axitinib Brugarolas, NEJM 2007

19. Ongoing Adjuvant Studies for RCC *T3 N0 or NX, M0, Fuhrman’s grade ≥2, ECOG ≥1 or T4 N0 or NX, M0, any Fuhrman grade, and any ECOG PS or any T, N1-2, M0, any Fuhrman’s grade, and any ECOG PS 1NCT00375674; 2NCT00326898; 3NCT00492258 4NCT01120249; 5NCT01235962

20. ASSURE (ECOG 2805)Adjuvant Sorafenib or Sunitinib for Unfavorable REnal Cell Carcinoma Group A Sunitinib 50mg (4 capsules) orally q.d.  4 weeks followed by rest  2 weeks for nine cycles† Primary objective: disease-free survival Secondary objective: OS, QoL, molecular & genetic predictors for DFS Stratification Tumour: pT1b G3-4; pT2-T4 or any T with N+ • Intermediate or high risk • Very high risk Histological sub-type • Clear cell • Non-clear cell (except collecting ductor medullary) ECOG PS • 0 • 1 Surgery • Laparoscopic • Open Group B Sorafenib 400mg (2 tablets) orally b.i.d.  6 weeks for nine cycles† Preregister* Randomisation Nephrectomy Group C Placebo *Accrual goal = 1,332; †one cycle = 6 weeks

21. N=290

22. N=1656 * * 3:3:2 *Crossover to sorafenib permitted

23. PROTECT:A phase fase III randomised, double-blind controlled study, to evaluate efficacy and safety of Pazopanib adjuvant-therapy in pts with localized or locally advanced RCC Pazopanib (800mg QD) NEPHRECTOMY Follow up RANDOMISATION Screening/ baseline N=750 OS DFS 1:1 Matching Placebo Follow up N=750 Tx 12 mo 12 wks Primary objective: DFS N=1500 Secondary objective: OS, Safety, QoL, Biomarkers

24. Neoadjuvant approaches in RCC • Localized disease - What about neoadjuvant therapy to improve outcome? - Neoadjuvant therapy to downsize and facilitate surgery? • Metastatic disease (synchronous) - Cytoriductive nephrectomy is still the standard of care in mRCC? - Can pretreatment help to select pts who may not be cantidates for cytoreductive nephrectomy?

25. Localized disease: neoadjuvant therapy to improve outcome Theoretical advantages to administer presurgical therapy: • Downsizing Partial nephrectomy, Nephrone sparing surgery • Assesment of tumor biology and proangiogenic factors • Decreasing circulating tumor cells • Provide tissue to study the mechanism of action of targeted agents

26. Localized disease: neoadjuvant therapy to improve outcome Potential disadvantages of the presurgical approach: • Increasing risk of perioperative morbidity and/or mortality • Delay potentially curative surgery in nonresponding patients

27. Neoadjuvant therapy to downsize and facilitate surgery • There is no universally accepted definition of resectability • The decision of unresectability is often based on imaging

28. Does downsizing really improveresectability ? Primary tumor downsizing in renal cell carcinoma is more prominent in smaller tumors enabling nephron sparing strategies n= 85 primary tumors from 5 published studies, after pretreatment with sunitinib and sorafenib Kroon et al., Urology 2012

29. Neoadjuvant therapy to downsize and facilitate surgery Multiple Case Reports of effective downsizing of CVT CVT = caval vein thrombus. Harshman et al, 2009; Karakiewicz et al, 2008; Kroeger et al, 2010.

30. Neoadjuvant approaches in metastatic RCC Cytoriductive nephrectomy is still the standard of care in mRCC?

31. Cytoreductive Surgery in the Cytochines Era Combined Analysis 31% decrease in risk of death with nephrectomy Flanigan RC, J Urol 2004

32. Choueiri TK, et al. 2011

33. Multivariate Analysis Demonstrated Better OS in Patients with CN The advantage was mantained if adjusted by prognostic factors* Patients in poor risk group had a marginal benefit (p=0.06) Choueiri TK, et al. J Urol 2011 *Heng DY, et al. J Clin Oncol 2009

34. Overview of Targeted Therapy Pre-surgical Phase II Trials in Renal Cell Carcinoma 1Jonasch e et al, J Clin Oncol 2009; 27(25):4076–4081; 2 Cowey et al, J Clin Oncol 28, 2010 3 Bex A et al, ASCO GU 2010; 4 Powles T et al, ASCO GU 2010 5 Jonasch E et al, ASCO GU 2010 (personal communication)

35. SURTIME: The SURgery and TIMe Phase III Study30073 of Sunitinib and Nephrectomy • Primary endpoint: progression-free survival • Secondary endpoint: OS, association with prognostic gene and protein expression profiles Sunitinib 50 mg/day (Schedule 4/2) Nephrectomy RANDOMISATION Patients with synchronous metastatic RCC and primary tumour in situ N=458 Sunitinib 50 mg/day (Schedule 4/2) Nephrectomy EORTC-GU Group Study NCT01099423

36. CARMENA: Phase III Study of Sunitinib vs Nephrectomy + Sunitinib Nephrectomy RANDOMISATION Metastaticclear-cell RCC Sunitinib 50 mg/day(Schedule 4/2) N=576 Sunitinib 50 mg/day (Schedule 4/2) Primary objective: Is sunitinib alone non-inferior to nephrectomy plus sunitinib in terms of overall survival? PI: Arnaud Mejean (CCAFU, HEGP, Paris, France) NCT00930033

37. Take home message • Adjuvant therapy ? Yes… in high risk surgically resectable RCC Given the risk/benefit profile, no adjuvant treatment is appropriate outside clinical trials

38. Take home message • Neoadjuvant therapy ? No published studies describing the use of neoadjuvant therapy in Nonmetastatic RCC In metastatic RCC cytoreductive nephrectomy is currently used as a standard treatment for patients with good or intermediate risk Benefit less clear in patients with poor prognostic risk Ongoing studies will clarify The value of surgery in the context of targeted therapy The optimal timing of surgery in clinical practice

39. Thank you…