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

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

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

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

Adjuvant randomized trials in RCC: Treatment N Author (year) Outcome of the study RT vs. observation 72 Kjaer (1987) negative MPA vs. observation 136 Pizzocaro (1987) Aut. tumor vaccine + BCG vs. observation 43 Adler (1987) Aut. tumor vaccine ± BCG vs. observation 120 Galligioni (1996) UFT vs. observation 71 Naito (1999) IFN- vs. observation 247 Pizzocaro (2001) IFN- NL vs. observation 283 Messing (2003) HD IL-2 vs. observation 69 Clark (2003) Aut. tumor vaccine vs. observation 553 Jocham (2004) positive in terms of PFS (p=0.02) s.c. IL-2 + IFN- + 5-FU vs. observation 203 Atzpodien (2005)

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

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

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

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

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

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% * Mayo Clinic Stage, Size, Grade and Necrosis score for ccRCC; Frank I, J Urol 2002

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

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

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

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

Comparison of the SSIGN score and the UISS integrated models of risk stratification Parameters Histology validation External Patients Limitations SSIGN TNM stage, size, grade, necrosis ccRCC yes 2656 Reliance upon subjective variable of necrosis. Useful only for ccRCC Does not take into account a pt’s ECOG PS UISS ECOG-PS, Fuhrman grade, TNM stage RCC 8249 Reduced predictive power in non metastatic patients Kapoor A. Urologic Oncology, 2009 Downs TM. Crit Rev Oncol Hemato, 2009

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

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

Ongoing Adjuvant Studies for RCC Trial N Patient characteristics Treatment arms Study duration Primary Endpoint S-TRAC: Sunitinib Phase III TRial in Adjuvant Renal Cancer Treatment1 600 High-risk patients according to UISS Staging System* Sunitinib Placebo 1 year Disease-free survival ASSURE: Adjuvant Sorafenib or Sunitinib for Unfavourable Renal Cell Cancer2 1,923 Non-metastatic RCC; disease stage II–IV Sunitinib Sorafenib Placebo (9 treatment cycles) SORCE: Sorafenib in Patients with Resected Primary RCC at High/Intermediate Risk of Relapse3 1,656 Patients with high- and intermediate- risk resected RCC Sorafenib/ placebo 3 years EVEREST: EVErolimus for Renal Cancer Ensuing Surgical Therapy, A Phase III Study4 1,218 Pathological stage intermediate or very high-risk patients with full or partial nephrectomy Everolimus 9 treatment cycles Recurrence-free survival PROTECT: Pazopanib as an Adjuvant Treatment for Localized Renal Cell Carcinoma5 1,500 Patients with moderately high or high risk of relapse with nephrectomy of localised or locally advanced RCC Pazopanib *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

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† 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 duct or medullary) ECOG PS 1 Surgery Laparoscopic Open Group B Sorafenib 400mg (2 tablets) orally b.i.d.  6 weeks for nine cycles† Preregister* Nephrectomy Randomisation Group C Placebo Primary objective: disease-free survival Secondary objective: OS, QoL, molecular & genetic predictors for DFS *Accrual goal = 1,332; †one cycle = 6 weeks

N=290

*Crossover to sorafenib permitted 3:3:2 *Crossover to sorafenib permitted

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 N E P H R E C T O M Y Screening/ baseline 12 wks Tx 12 mo OS Pazopanib (800mg QD) Follow up DFS N=750 1:1 Matching Placebo R A N D O M I S A T I O N Primary objective: DFS N=1500 Secondary objective: OS, Safety, QoL, Biomarkers

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?

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

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

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

Does downsizing really improve resectability ? 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

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.

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

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

Uno studio retrospettivo, condotto da 7 centri nel nord america , con l’obiettivo di studiare l’impatto della CN sulla sopravvivenza dei pz con mRCC trattati con VEGF targeted therapy. Choueiri TK, et al. 2011

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

Overview of Targeted Therapy Pre-surgical Phase II Trials in Renal Cell Carcinoma Bevacizumab1 Sorafenib2 Sunitinib3 Sunitinib4 Sunitinib5 Number of patients 50 30 20 33 Number of nephrectomies 42 16 21 17 Days off prior to surgery 28 2–14 1 14 Median time of surgery (min) 168 185 180 195 NR Median estimated blood loss 400 (0–7000) 950 (200–3000) 650 (80–3000) 750 (90–4700) Duration in hospital (days) 5 (1–70) 6 (5–13) 8 (7–17) 7 (4–36) Restart therapy (days) 28–42 Complications Clavien-Dindo Grade I 9 (18%) 3 (15%) 2 Grade II Grade III Grade IV Grade V 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)

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

CARMENA: Phase III Study of Sunitinib vs Nephrectomy + Sunitinib R A N D O M I S A T I O N Metastatic clear-cell RCC Sunitinib 50 mg/day (Schedule 4/2) N=576 Sunitinib 50 mg/day (Schedule 4/2) The SURTIME study is designed to assess PFS in patients who receive post-surgical sunitinib versus pre-surgical sunitinib The phase III CARMENA study is comparing sunitinib therapy alone with cytoreductive nephrectomy plus sunitinib The aim of the study is to determine if sunitinib alone is non-inferior to nephrectomy plus sunitinib in terms of overall survival Primary objective: Is sunitinib alone non-inferior to nephrectomy plus sunitinib in terms of overall survival? PI: Arnaud Mejean (CCAFU, HEGP, Paris, France) NCT00930033 36

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

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

Thank you…