1. Renal cell cancer: Integrating novel agents into a therapeutic algorithm Robert Dreicer, M.D., FACP Chairman Department of Solid Tumor Oncology Taussig Cancer Institute Cleveland Clinic Professor of Medicine Cleveland Clinic Lerner College of Medicine

2. Metastatic Renal Cell Carcinoma: Initial Therapy Considerations Role of cytoreductive nephrectomy Sequential therapy Combination therapy Metastatic Kidney cancer as a chronic disease?

3. Flanigan RC, et al. J Urol 171:1071 2004 Cytoreductive Nephrectomy: Current Status Debulking nephrectomy has become a standard of care in selected patients Combined analysis of two prospective trials demonstrated an overall survival (OS) advantage for the nephrectomy group (mean survival, 13.6 v 7.8 months for the interferon alone arm) Appropriate candidates:  ECOG performance status of 0 or 1  Resectable primary tumor representing the majority of tumor  No evidence of rapidly progressing extrarenal disease  No prohibitive medical comorbidities

4. Cytoreductive Nephrectomy: Current Status Two randomized trials are ongoing Metastatic RCC patients randomized to upfront nephrectomy or not followed by sunitinib for all patients Second study is identical with the exception of delayed nephrectomy in patients initially randomly assigned to sunitinib

5. RCC (Clear Cell) Treatment Algorithm: 2012 SettingPatientsTherapy (level 1evidence) Other Options (≥ level 2) Untreated Good/ Intermediate risk Sunitinib Bevacizumab + IFN HD IL-2 Pazopanib Sorafenib Clinical trial Observation Poor riskTemsirolimusSunitinib Clinical trial Cytokine- refractory SorafenibSunitinib Bevacizumab VEGF-R refractory Everolimus Axitinib Clinical trial Sunitinib Sorafenib mTOR-refractoryClinical trial *Adapted from M Atkins, ASCO 2006 & R Bukowski ASCO 2007

6. Developed as empiric necessity  As drugs came on line, they were used as salvage therapy i.e. sorafenib followed by sunitinib Choice of initial therapy increasingly seen as not as important given therapeutic paradigm  However, some patients have bad disease and don’t get a second line therapy  The absence of data doesn’t mean it doesn’t matter Sequential Therapy

7. Sequenced monotherapy has activity in RCC  Patients with the most favorable underlying biology will have the greatest absolute overall survival as they will receive multiple active treatments Toxicity matters  Significant numbers of patients long-term responders A consensus definition of ‘treatment-refractory’ RCC and identification of prognostic factors would aid in the interpretation of clinical results

8. A critical question for sequential therapy in RCC is an understanding of the mechanism of resistance which could guide the choice of next treatment:  Target a different pathway  Target the same pathway in a different way  Target the same target, but more potently  Take a drug holiday, then restart same drug Sequential Therapy

9. * Inhibitory concentrations (kinase IC50 in nanomoles) for relevant targets VEGF R1 VEGF R2 VEGF R3 PDGFR α PDGFR β KITFLT3RET SorafenibNA9010050-60806846100-150 Sunitinib104 5-1010131-10100-200 Pazopanib103047718472>1000 Axitinib1.20.20.351.61.7>1000 AV-9510.210.160.241.71.6 BAY 73-450616546NR7474401 ABT-8693335314813 The spectrum and potency of VEGF-R inhibitors is not identical

10. Selecting Salvage Therapy Level 1 evidence Two phase III trials  Everolimus  Axitinib

11. RANDOMIZATION2:1 Everolimus Phase III Everolimus 10 mg QD + BSC (n = 272) Placebo + BSC (n = 138) Disease Progression Metastatic RCC (clear cell component) Prior VEGF-R TKI with RECIST PD ≤ 6 months: sunitinib (50%), sorafenib (25%) or both (25%) (other tx. permitted) MSKCC favorable (30%), intermediate (55%), or poor risk (15%)

12. Hazard ratio = 0.30 95% CI [0.22, 0.40] Median PFS Everolimus: 4.0 mo Placebo: 1.9 mo

13. Axitinib vs Sorafenib as Second-line Therapy for Metastatic Renal Cell Carcinoma: Results of the Phase 3 AXIS Trial Treatment-refractory metastatic RCC Axitinib 5 mg BID † 1:1 Sorafenib 400 mg BID Randomization stratified by ECOG PS and type of prior treatment † Starting dose 5 mg BID with option for dose titration to 10 mg BID

14. Rini B, et al. Lancet 2011 378:9807

16. Management of Advanced RCC: Current Status More than 5 years into the “novel agent” paradigm in RCC, some sobering thoughts  We don’t cure folks  Toxicity/cost are issues  Drug holidays  Timing of therapy ( does everyone need treatment immediately) The treatment should not be worse than the disease  Accurate assessment of disease progression Not always what the radiology report states

17. Disparity in Reporting of Progression in Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib According to Radiology and Medical Oncology The medical records of a subset of mRCC patients treated at the Cleveland Clinic who had received sunitinib for > 6 months were retrospectively reviewed All Radiology reports from post-baseline scans (every 2 cycles) were reviewed for text in the body or conclusion of the Radiology report consistent with disease progression (specifically the terms ‘progressive’, ‘new’ and/or ‘interval enlargement/worsening’) Ali H, et al. GU ASCO 2012

18. Disparity in Reporting of Progression in Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib According to Radiology and Medical Oncology 47 patients were identified with characteristics typical of an mRCC population The majority of patients were reported by Radiology to have progression of existing metastatic sites only, with 21% of patients having both existing site progression and new metastatic disease The median lag between Radiology’s report of PD and Med Onc was 2.8 months (range 0-12.6+ months), with 5 patients not yet considered to have progressed by Med Onc In almost 50% of cases the Med Onc call was >3 months later than Radiology Ali H, et al. GU ASCO 2012

19. Management of Advanced RCC: Current Status Level 1 evidence to help drive decision making for front-line and second line therapy is available Optimal front line therapy for good/intermediate risk patients remains unclear (some data is coming- phase III pazopanib vs sunitinib) Optimal therapy for non clear cell remains undefined Combination therapy remains investigational: its more toxic than you would think, don’t try this at home

20. "It's not what you don't know that hurts you; it's what you know that just ain't so." Satchel Paige