INTEGRATION OF SURGERY AND SYSTEMIC THERAPY FOR ADVANCED RENAL CELL CARCINOMA IN THE TARGETED THERAPY ERA

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1 INTEGRATION OF SURGERY AND SYSTEMIC THERAPY FOR ADVANCED RENAL CELL CARCINOMA IN THE TARGETED THERAPY ERA Dr. Michael J. Metcalfe PGY-4 Department of Urologic Sciences University of British Columbia October 9, 2013 Integration of Surgery and Systemic Therapy for mrcc 1. Review cytoreductive nephrectomy in the molecular targeted therapy era. 2. The effect of targeted therapy on the primary tumor in unresected disease and benefits of converting unresectable to resectable disease. 3. Risks and benefits of neoadjuvant targeted therapy. 4. Role of Adjuvant therapy with targeted therapy. 5. Review of Available Clinical Trials at VGH 1

2 Case #1 71 F w/ 20cm Renal Mass Horseshoe Kidney egfr = 40 2 Liver Met s Case # 1-71 F, 20 cm RCC in Horseshoe Kidney 2

3 Case # 1-71 F, 20 cm RCC in Horseshoe Kidney Case # 1-71 F, 20 cm RCC in Horseshoe Kidney 3

4 Case # 1-71 F, 20 cm RCC in Horseshoe Kidney Case # 1-71 F, 20 cm RCC in Horseshoe Kidney 4

5 Case # 1-71 F, 20 cm RCC in Horseshoe Kidney Case # 1-71 F, 20 cm RCC in Horseshoe Kidney 5

6 Cytoreductive Nephrectomy 100 SWOG [1] Median Survival, Mos IFN-α + nephrectomy (n = 120) 11.1 IFN-α (n = 121) EORTC [2] Median Survival, Mos IFN-α + nephrectomy (n = 42) 17.0 IFN-α (n = 42) 7.0 Survival (%) P = P =.03 Survival (%) Mos Mos 1. Flanigan RC, et al. N Engl J Med. 2001;345: Mickisch GH, et al. Lancet. 2001;358: SEER data - Survival After Cytoreductive Nephrectomy NO SURGERY CYTOREDUCTIVE NEPHRECTOMY 5372 patients with mrcc in the SEER database: 2447 had CRN versus 2925 who had not Compared in a matched pair analysis No-CRN: 2.5-fold greater rate of overall and cancer-specific mortality 22month vs. 17 month overall Survival Urology

7 Can we Predict Who will Benefit From CN CN? 1. Elevated LDH 2. Low Albumin 3. Symptom 4. Liver met s 5. Adenopathy 6. > ct3 CULP Cancer 2010 Mechanism of Cytoreductive Nephrectomy? Reduction in Tumor Burden? Immunologic: Surgery induces exposure of Tumor antigens? Removal of secreted growth factor that promotes progression and metastasis Wood Eur Urol 2010, CWU 10 7

8 Evolution of treatment options in mrcc: FDA approved therapy IFN- α High- dose interleukin- 2 1 Sorafenib (Dec 2005) 2 Sunitinib (Jan 2006) 3 Temsirolimus (May 2007) 4 Everolimus (Mar 2009) 7 Bevacizumab + IFN 5,6 (Jul 2009) Axitinib (Jan 2012) Pazopanib 8 (Oct 2009) 1. Fyfe et al. J Clin Oncol 1995;13:688 96; 2. Escudier et al. N Engl J Med 2007;356:125 34; 3. Motzer et al. N Engl J Med 2007;356:115 24; 4. Hudes et al. N Engl J Med 2007;356: ; 5. Escudier et al. Lancet 2007;370: ; 6. Rini et al. J Clin Oncol 2008;26:5422 8; 7. Motzer et al. Lancet 2008;372:449 56; 8. Sternberg et al. J Clin Oncol 2010;DOI: /JCO RCC Therapy: Targeting VEGF at Multiple Levels Mutant pvhl HIF Everolimus Temsirolimus Bevacizumab VEGF PDGF mtor Axitinib VEGFR Sunitinib Sorafenib Pazopanib PDGFR Kaelin WG Jr. Clin Cancer Res. 2004;10:6290S-6295S 8

9 Targeted Therapy vs. IFN-a First line Treatment of metastatic RCC N ORR vs IFN-α, % Median PFS vs IFN-α, Mos Sunitinib vs IFN-α [1] vs vs 5* P <.001 Bevacizumab + IFN-α vs IFN-α [2] Bevacizumab + IFN-α vs IFN-α [3] Sorafenib vs IFN-α [4] (phase II) vs vs 5.5* P < vs vs 4.9 P < vs vs. 5.6* P =.504 Pazopanib vs placebo [5] vs vs 2.8 P <.0001 Temsirolimus vs IFN-α [6] vs vs 3.1* (poor risk) P <.001 Final Median OS vs IFN-α, Mos 26.4 vs 21.8 P = vs 21.3 P = vs 17.4 P =.069 NA NA 10.9 vs 7.3 P = Motzer RJ, et al. J Clin Oncol. 2009;27: Escudier BJ, et al. ASCO Abstract Rini BI, et al. J Clin Oncol Abstract LBA Escudier BJ, et al. J Clin Oncol. 2009;27: Sternberg CN, et al. J Clin Oncol. 2010;28: Hudes G, et al. N Engl J Med. 2007;356: PROGRESSION FREE SURVIVAL Median OS: Sunitinb IFN HR 0.821; p=0.051 Objective Response rate: Sunitinb 47% IFN 12% Motzer NEJM 2007, Motzer JCO

10 314 patients CN without CN VEGFi Naïve Median start of therapy 5 months post CN CN associated with: Improved TTF Improved OS Choueri J UROL

11 Amount of Tumor removed associated with Improved Survival N = 46 Clear Cell RCC cm (median) Barbastefano, BJUI 2010 ARGUMENTS AGAINST CN 1. Only proven prospective benefit is in the interferon setting and this does not apply due to different MOA. Only level 1 evidence we have is supportive of CN Retrospective data supports this evidence in current era Targeted therapy only proven in the nephrectomy population 2. Survival Benefit is Modest 5 Month improved overall survival given morbidity of surgery Surgery is not for everyone. 3. Cases of complete disease response with primary therapy occur Objective response rate is only 30% to Sunitinib 4. Significant Systemic Disease Progression in post operative period may occur Valid risk, needs to be validated 5. Patient may not ever get systemic therapy 95% of pt. in SWOG CN trial went onto systemic therapy 11

12 CARMENA TRIAL - Phase 3 RCT: Nephrectomy with Adjuvant Sunitinib vs. Sunitinib without Nephrectomy as First Line in Metastatic RCC N= 576 Nephrectomy Sunitinib 50 mg 4/2 Sunitinib 50 mg 4/2 Primary Objective: Overall Survival (non-inferiority) PI Amaud Majaan, CCAFU CYTOREDUCTIVE NEPHRECTOMY Randomized Trial data from Interferon era is only RCT data we have to date. Retrospective data support CN with targeted therapy. Benefit of targeted therapy primarily shown post CN. Cytoreductive Nephrectomy should be performed in all suitable patients with resectable disease and is still gold standard. There is a subset of pt. t where the risks and morbidity of cytoreductive nerphrectomy outweigh the benefits. We await further Level 1 evidence through the CARMENA Trial. 12

13 Case #2 54 F Multiple Chest Lesions Tumor Thrombus above diaphragm Loss of border between liver and kidney Case #2 Urgent Biopsy: Clear cell RCC MSKCC - Int. risk ECOG

14 Case #2 Tumor is considered Unresectable Case #2 Management? 14

15 CUA 2013 Consensus Statement Setting Patients Therapy (LEVEL 1) Untreated Good/Int Risk Sunitinib Bevacizumab Pazopanib Other Options HD IL-2 Sorafenib Observation Poor Risk Temsirolimus Sunitinib 2nd Line Cytokine Refractory Sorafenib Pasopanib Axitinib Sunitinib Bevacizumab+IFN Prior VEGF Everolimus Any 2 nd unused targeted therapy Prio mtor Axitinib CUA Consensus Statement CUAJ 2013 After 2 Cycles of Sunitinib 15

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18 Radical Nephrectromy Performed No Active tumor in kidney or Tumor thrombus All Necrotic TUMOR!! Nephrectomy post Targeted Therapy, is it safe? Retrospective Review in 173 patients who underwent CN with synchronous M1 disease. 70 Pt. s Pre-op. Systemic targeted therapy. 103 Immediate Cytoreductive Nephrectomy performed. Chapin et al Eur Urol

19 Nephrectomy post targeted Therapy, is it safe? No significant difference in: Any Complication (53.4% vs. 65.7%; p=0.085) Major Complication (30.2% vs. 29.4%; p=0.999) Fascial Dehiscence (0% vs. 2.9%; p=0.162) DVT (1.9% vs. 12.9%; p= 0.121) PE (5.8% vs. 2.9%; p= 0.382) Neoadjuvant therapy had a significantly greater risk of: Complication > 90 days (15.9% vs. 3.8%; p=0.013) Superficial Dehiscence (5.8% vs. 24.3%; p=0.002) Wound Infection (2.9% vs. 12.9%; p=0.015) Chapin et al Eur Urol 2011 Phase II Trial: Effect of Sunitinib on Primary Renal Cell Carcinoma and Facilitation of Subsequent Surgery Biopsy Proven RCC with UNRESECTABLE Primary Tumor: Large (>15 cm) Bulky Lymphadenopathy (>4cm, encasement of vessels) Advanced Venous Thrombosis Proximity to vital structures. Sunitinb 50 mg X 12 weeks CONTINUE SUNITINIB Patients who do not convert to being resectable AND Patients who become resectable but harbour residual / metastatic disease. DISCONTINUE SUNITINIB Primary tumor becomes resectable & post op have NO EVIDENCE of Disease. Rini J Urol

20 N=30 (35 total Tumors) 19 with distant met s 27 tumours Clear Cell 8 Non-Clear Cell Rini J Urol 2012 Phase II Trial: Effect of Sunitinib on Primary Renal Cell Carcinoma and Facilitation of Subsequent Surgery Tumor reduction: Median decrease in size 22% (1.2cm) For clear cell histology (-28%) (1.7cm) 17 tumour removed with Nephrectomy (All viable tumour on Pathology) 3 Pt. s had residual disease resumed therapy. 1 later underwent resection of pulmonary met, then stopped Tx. 1 patient had a late local recurrence and underwent resection. 18 Tumours remained in situ. 3 pt. s had progression. Conclusion: 17/35 (49%) of unresectable tumors may be resectable post sunitinb. Rini J Urol

21 Effect of Targeted Therapy on in Situ Primary Tumour Trial Therapy N Number of patients with reduction in size Rini 2012 Hallenth al 2010 Bex 2010 Sunitinib (50 OD) (median 3 cycles) Sunitinib 37.5 (3 months) Sunitinib 50mg (4 wk/2wk) Number of patients who went on to resection 93% (28) 43% (13) 85% (17) 40% (8) 60% (6) 30% (3) N= 25 Level II Thrombi 72% level III - 20% Level IV 8% Sunitinib First Line in 12/25 patients Results: 7 (28%) had increase in height. 7 (28%) No Change. 11 (44%) had a decrease. 1 patient had change of operative approach. Eur Urol 2011, GU ASCO

22 Cytoreductive Nephrectomy after Targeted Therapy Targeted Therapy may: - Modest decrease in size of primary tumor in 60-93% of patients. - Majority of patients will have progression of tumour thrombus as opposed to regression. - Allow 30-43% of patients with unresectable disease develop resectable disease. - Result in a slight increase in wound complications. Case #3 : 54 yo male from Northern BC Urgent Referral Large 18 cm (R) renal tumor in morbidly obese male (220 Kg = 486 lbs) 1) Thrombus up to level of hepatic veins 2) 2 hepatic lesions 3) Lymph node compressing Contralateral Renal Vein 22

23 PLAN: Discussion with Medical Oncology 2) Plan- Enroll in RCT - randomised to pre-operative sunitinib arm. F/U- After 4 cycles of Sutent Before After 1) Primary mass reduced in size from 18cm to 12 cm 2) Thrombus reduced to renal vein 3) Liver lesions- complete regression 23

24 COURSE 1) Radical Nephrectomy, thrombectomy, and RPLND via Chevron Incision 2) EBL: 400c No transfusions required 3) 4 days in Hospital, no complications / no wound complications 4) Pathology: - Fuhrman 3/3 - Margins Negative - RPLND (including large 1.3 cm node) Necrotic Scar tissue Neoadjuvant Targeted Therapy Why? Preoperative systemic Therapy may eliminate micrometastatic disease Primary Tumor Downstaging/downsizing may: decrease surgical morbidity, allow nephron sparing surgery or convert open case to MIS case. Evidence of response to therapy can potentially influence future therapy selection. Why NOT? Tumor may progress locally, regionally and/or systemically on therapy. Tumor may progress while on break from treatment for surgery. Lose chance of cure Toxicity may increase morbidity of therapy. 24

25 Progression of Caval Thrombus on therapy. Bex Acta Oncoligica patients with resectable stage 2 Renal Masses or greater Neoadjuvant Sorafenib (400mg po BID) Median Treatment duration 33 days, Median of 3 days off of therapy Stage: 17 patients with localized, 13 (43%) had metastatic disease. Histology: Clear Cell 70% (n=21) Papillary 4 Chromophobe 2 (excluded TCC x1, Liposarcoma x1) 25

26 Median Tumor response was 9.6% 5 Patients had Tumor growth. No progression to unresectable disease No progression of caval thrombus No Progression by RECIST. 93% had stable disease (RECIST) 2 Patients with Partial Response. 4 patients downstage T2 à T1.Complications: No Dehiscence 1 Superficial Wound Breakdown 1 MI Cowey JCO 2012 Untreated patients with Metastatic RCC with primary tumours radiologically considered to be resectable. 50 patients systemic therapy x 8 weeks then restaged: 23 received Bevacizumab plus Erlotinib 27 Bevacizumab Pt. s who had progressive disease or declining performance status had their Nephrectomy deferred. 26

27 42/ 50 patients underwent Nephrectomy. 6 (12%) clinical or radiographic progression 1 death in MVC 1 pt. had drug related toxicity Median Progression Free Survival was 11.0 month ( ). Compared to 4.8 months 1 Median Overall Survival was 25.4 months. Two patients died < 2months post Nx. 1. pt4n2 7 L blood loss, 14 units of blood, post-op sepsis, then PE POD Multiorgan Failure 7 Day post-op. 1. Yang NEJM Jonasch E, Wood C JCO 2009 Eur Urol 2011 Two single arm, Phase 2, prospective study evaluating upfront sunitinb prior to nephrectomy. Untreated, newly diagnosed, biopsy proven mccrcc and deemed resectable. intermediate or poor risk (MSKCC) 2 or 3 cycles of sunitinib (50mg po once daily) prior to planned Nx. Post Nx - Continued on Sunitinb until progression. Patients with symptomatic progression prior to Nephrectomy did not undergo surgery. 27

28 (metastatic sites) Thromboembolic disease while on Sunitinib OS = 15.2 Months PFS = 6.3 Months Phase III Sutent RCT: PFS = 11 months 1 OS 26.4 months 2 1. Motzer NEJM Motzer JCO

29 SURTIME Phase III Clinical Trial Neoadjuvant vs. Adjuvant Sunitinib in patients with Synchronous Metastatic RCC and Primary in Situ N=440 Randomisation Sunitinib Nephrectomy Nephrectomy Sunitinb Clear Cell Histology Resectable Primary Asymptomatic Metastatic Disease. T1-T2 disease. Primary End Point= Progression Free Survival PI Dr. Axel Bex EORTC GU Multidisciplinary Study Update Oct. 2013: Global Accrued 64 Global Target Pre-surgical Targeted Therapy Unresectable disease should be started on Targeted therapy and re-evaluated. Response to therapy is associated with improved overall survival and may help risk strategy. No role for Neoadjuvant therapy outside of clinical trials: significant risk of progression and lack of objective response in too many patients. 29

30 Adjuvant Therapy PRE Targeted Therapy: 11 Trials all negative results. Currently 5 RCTs for targeted therapy: PROTECT Pazopanib in High Risk EVEREST Everolimus in High Risk ASSURE - Sorafenib vs Sunitinib in High Risk SORCE Sorafenib in High or Int Risk RCC S-Trac Sunitinib in High Risk Conclusions 1. If Possible cut it out. Cytoreductive nephrectomy is recommended and likely still has benefit in targeted therapy era await CARMENA 2. If you can t cut it out try medicine, then wait and see if you can cut it out. Targeted therapy offer s benefit of downstaging mrcc in some patients and allows for more patients to undergo resection of the primary or metastasis if initially unresectable this is safe, likely beneficial. 3. Don t delay cutting it out. Neoadjuvant targeted therapy has a mild increase in complications at time of nephrectomy and has risks of progression on or off therapy and its role needs to be determined in prospective randomized trials. 4. Optimal drug, timing and dose of either neoadjuvant vs adjuvant therapy is yet to be determined. 30

31 Conclusion Always Consider randomized trials SURTIME Currently enrolling. Monthly Renal Cancer Rounds are held at VGH with Urology, Medical Oncology & Radiology - always welcome to review cases. Accelerated Metastasis after Short-Term Treatment Sunitinib Short Term Sunitinib NO Sunitinib Ebos Cancer Cell Research

32 N= 61 Median 15 mo follow up. Abel, Wood. Eur Urol 2011 Decrease in skin microvascular density induced by Sunitinib is a reversible phenomenon Measurement of capillary density during the first treatment cycle of sunitinib 50 mg/day in a 4 weeks on 2 weeks off schedule. The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please journals.permissions@oxfordjournals.org De Boer Annals of Oncology

33 Results of Targeted Therapy on Primary N= 12 Nephrectomy post sunintinb. Median volume reduction was 31%. Van Der Welt Clin Canc Research 2008 Downstaging for Nephron Sparing Considerations. Up to 4% of patients with tumors less than 2cm had met s SEER data 35% of patients with met s underwent surgery, 2% of these had partial Nx. SEER Data 56,011 patients b/w 2005 Dx with RCC. Those who underwent partial Nx. Were 0.49 times less likely to die of RCC. Conclusion: It may be safe to consider partial Nx. In the setting of metastatic disease. Hellenthal NJ, Urologic Oncology: Seminars and Original Investigations

34 New Therapies Pazopanib - A presurgical phase 2 study investigating 12 wk of pazopanib prior to nephrectomy in 95 patients with metastatic clear-cell renal cancer is now open.? favorable toxicity profile associated with pazopanib is behind the rationale for this trial. Axitinib - A presurgical phase 2 study evaluating axitinib in locally advanced RCC is currently underway. Metastasectomy Complete vs. Incomplete resection 44% 5 yr survival vs. 14% Favorable Prognostic indicators solitary met Age<60 Disease free interval of 1 yr pulm mets better outlook than Brain Renal mass <4 cm Similar 5-year Survival rates with Curative resection upon 2 nd and third recurrence. Kavolius JP J Clin Oncol (1998) 34

35 N = 38 Inclusion: mrcc with responsive disease after TKI potentially resectable met s 90% of the patients received adjuvant therapy. Median Survival 4.7 eyars. 5.6 years sned 1.4 years NED. Daliani BJUI 2009 TKI for Life? What do we do post Neoadjuvant/ Adjuvant therapy after complete remission? In 28 patients post CR after TKI plus local treatment, 25 Patients stopped treatment and 12 (48%) remain in remission after a median follow up of 322 days. Abiges JCO

36 Cytoreductive Nx SWOG- Randomized IFN vs. Nx/IFN (2001) 1 OS greater (11 vs. 8 months) in Nx/IFN group EORTC- Randomized IFN vs Nx/IFN (2001) 2 -OS greater (17 vs 7 mo) in combined group Guidelines (2010) 3 >75% tumor debulking No CNS or liver dz Adequate cardic/pulm fxn ECOG PS 0-1 Factors Associated with Adverse Outcomes Serum LDH Serum albumin Retroperitoneal or subdiaphragmatic Pathology Symptomatic Presentation due to Met s >T3 Tumor Liver Met s 1. Flanigan RC, et al. N Engl J Med. 2001;345: Mickisch GH, et al. Lancet. 2001;358: CULP SH et al. Cancer

37 N= 275 (52 included in case control match for CN with TKI) Overall Survival: Prior Nx associated with HR 0.42 (p<0.001) Multivariate Analysis: Dx to Tx < 12 mo <1 Met. Site Normal Hgb LDH <1.5 Karnofskiy PS >80% NON CLEAR CELL PATHOLOGY Median survival of patients with sarcomatoid features was 4.9 months vs 17.7 for those with nonsarcomatoidhistology (p 0.01). Similarly median disease specific survival of patients with nonclear cell histology was significantly worse than of those with clear cell metastatic RCC (9.7 vs 20.3 months) 37

38 Poor Risk Factors in Advanced Untreated RCC: MSKCC Criteria MSKCC Criteria 2002 [1] KPS < 80% Time from diagnosis to treatment with IFN-α Hemoglobin LDH Corrected serum calcium < 12 mos < LLN > 1.5 x ULN > 10.0 mg/dl Risk Group by No. of Risk Factors Favorable 0 Intermediate 1 or 2 Poor 3-5 Independent validation at the Cleveland Clinic identified 2 additional prognostic factors [2] Previous radiotherapy Presence of lung, hepatic, retroperitoneal nodal metastasis Platelet and neutrophil counts > ULN identified as adverse prognostic factors for patients treated with VEGF-targeted therapies [3] 1. Motzer RJ, et al. J Clin Oncol. 2002;20: Mekhail TM, et al. J Clin Oncol. 2005;23: Heng DY, et al. J Clin Oncol. 2009;27: Liver Metastasis 43 patients underwent surgery for RCC hepatic met s. No mention on TKI use --- do not include Hatzaras, HPB

39 Survival Distribution Function Temsirolimus Phase III Trial in Poor-Risk RCC*: Tem ± IFN-α; OS by Treatment 3/6 Poor-Risk Features: LDH > 1.5 x ULN Hb < LLN Ca ++ (corrected) > 10 mg/dl KPS Initial diag to random < 1 yr Multiple sites of metastases mrcc (N = 626) Arm 1: IFN Arm 3: IFN + Tem Arm 2: Tem R A N D O M I Z A T I O N Parameter Median survival, Mos Comparisons IFN-α 3 MU-18 MU (n = 207) CR + PR: 4.8% CR + PR + SD : 15.5% Tem 25 mg QW (n = 209) CR + PR: 8.6% CR + PR + SD: 32.1% IFN-α 3 MU-6 MU + Tem 15 mg QW (n = 210) CR + PR: 8.1% CR + PR + SD: 28.1% IFN Arm 1 (n = 207) Tem Arm 2 (n = 209) Tem + IFN Arm 3 (n = 210) Arm 2 to Arm 1 Arm 3 to Arm 1 Stratified log-rank P Time to Death (Mos) *Modified MSKCC poor risk. Stratified by country and nephrectomy status. SD 24 wks. Hudes G, et al. N Engl J Med. 2007;356: Temsirolimus vs IFN-α: Correlation With Survival in First-line, Poor-Risk mrcc Subgroup n HR (95% CI) Histology Clear cell Other Age < 65 yrs 65 yrs Prognostic Risk Intermediate Poor Temsirolimus Better IFN-α Better Hudes G, et al. N Engl J Med. 2007;356: Dutcher JP, et al. Med Oncol. 2009;26: Dutcher JP, et al. ASCO Abstract

40 The Biology of Clear-Cell RCC: VHL Gene Mutation Elongin B CUL2 E2 Rbx1 Elongin C VHL complex disrupted VHL protein β-domain Mutant α-domain HIFα accumulation Activation of hypoxia-inducible genes VEGF Glut1 PDGF Angiogenesis Autocrine Growth Glucose Transport Stimulation Bratslavsky G, et al. Clin Cancer Res. 2007;13: Shaw GL in Urologia Internationalis July 2012 looked at: 22 patients with neoadj. To 28 no Tx. and they found slightlly more blood loss, longer OR time and length of stay commenting on fibrosis loss of tissue planesand abnormal blood vessel formation. 40

41 Neoadjuvant therapy Is it beneficial? 10 consecutive mrcc patients treated with sunitinib who had surgically unresectable disease. Surgery- Limiting tumour sites (SLTs) were defined as primary retroperitoneal lesions with direct invasion into adjacent organs or vital structures. Sunitinib 50mg/day for 4 weeks on and 2 weeks off. RECIST criteria used. 6/10 patients had a tumour reduction with a median 14%. 3 patients went on to cytoreductive Nephrectomy. Bex A, World Journal of Urol (2009) 41

42 Comparison of Study Patients in Adjuvant Trials ASSURE SORCE S-TRAC pt1b, G3-4, No pt2-4, any G, No Any p, any G, N+ *fully resected) ECOG 0-1 Clear cell, non clear cell pathology No collecting duct or medullary Leibovich score 3-11 (intermediate high risk) WHO PS 0-1 Clear cell and non clear cell High risk as per UICC criteria ECOG 0-2 Predominant clear cell 1932 pts 1656 pts 500 pts Start: May 2006 June 2007 July 2007 End: April 2016 Aug 2012 Dec 2010 Comparison of Study Patients in Adjuvant Trials Trial Name Intervention Primary Outcome ASSURE (Finsihed ACCural) UBC SORCE S-TRAC (FINISHED ACCURAL 1? 1 year away. Arm A: Sunitinib OD 4 wk, rest 2 wk, sorafenib placebo Arm B: Sorafenib bid 6 wk, sunitinib placebo Arm C: Placebo as in Arm A or B Arm I: 3 yr placebo Arm II: 1 yr sorafenib, then 2 yr placebo Arm III: 3 yr sorafenib Arm A: 1 yr sunitinib 50mg 4 wk on, 2 off Arm B: 1 yr placebo DFS DFS DFS Secondary Outcome OS QoL MFS OS Tox Costeffectiveness OS Safety Tolerability QoL 42

43 Axitinib: Recently Approved Potent and Selective VEGFR TKI Most Potent for VEGFR-1, -2, and -3 Most Selective for VEGFR -1, -2, and -3 More potent Less potent Potency: IC50 (nm) Axitinib [1] Sunitinib [3] Pazopanib [4] Sorafenib [2] VEGFR-1 VEGFR-2 VEGFR-3 Target Selectivity Axitinib [1] Sorafenib [2] Sunitinib [3] Pazopanib [4] VEGFR PDGFR b c-kit FLT CSF-1R ND + + Raf-1 ND + ND ND +: inhibition of receptor kinase comparable ( 5 times) to potency for VEGFR-2 ND: not determined 1. Hu-Lowe DD, et al. Clin Cancer Res. 2008;14: Wilhelm SM, et al. Cancer Res. 2004;64: Roskoski R. Biochem Biophys Res Commun. 2007;356: Kumar R, et al. Mol Cancer Ther. 2007;6: AXIS Trial: PFS (IRC Assessment) Probability of PFS Axitinib Sorafenib mpfs, Mos Stratified HR: (95% CI: ; log-rank P <.0001) 95% CI Patients at Risk, n Mos Axitinib Sorafenib Rini BI, et al. Lancet. 2011;378: