1. Renal Cancer: Front line therapy Walter Stadler

2. Pathology Clear cell (conventional) –Fuhrman grading 1-4 Papillary –Type 1 & 2 (by histology) OR Class 1 & 2 (by molecular profiling) –Mucinous-tubular and spindle? –Clear-cell papillary Chromophobe –Genetically related to benign oncocytoma Collecting duct –Genetically related to urothelial –Medullary (only in sickle cell trait or disease) TFE-3 translocation tumor –Same translocation as alveolar-soft part sarcoma –More than one translocation Renal Cancer|

3. Clear cell subtypes By VHL status –Wild type (12%) –HIF-1  /HIF-2  express (57%) –HIF-2  express (30%) 2 – 4 clusters by expression profile –mRNA –miRNA Gordan, et al; Cancer Cell, 2008 Beroukhim, et al; Cancer Res, 2009 CGA Network, Nature, 2013 Brannon, et al, Genes Cancer, 2010

4. Other important alterations Histone modification gene mutatations –SETD2 (histone H3 methyltransferase, ~15%) –JARID1C (histone H3 demethylase) –UTX (histone H3 demethylase) Chromatin remodeling complex mutations –PBRM1 (~40%) –BAP1 (~15%) Ubiquitin E3 ligase complex alterations –SPOP overexpression in 99% ccRCC PI3K/AKT/mTOR pathway activation (28%) Dalgliesh, et al; Nature, 2010 Varela, et al; Nature, 2011 Liu, et al, Science, 2009 Kapur, et al. Lancet Oncol, 2013 CGA Network, Nature, 2013

5. Manola J et al. Clin Cancer Res 2011;17:5443-5450 International prognostic model βSE Square root of days from diagnosis to study entry −0.01920.002 ECOG performance status 0−1.5240.11 ECOG performance status 1−0.8380.11 Number of metastatic sites0.3240.032 Protocol immunotherapy−0.5740.094 Natural log of hemoglobin−2.470.20 Natural log of LDH0.6110.062 Square root of white blood count 0.6230.071 1/Square root of alkaline phosphatase −6.6651.39 Serum calcium0.1050.033

6. AG013736 X X X X X X Sunitinib Sorafenib Pazopanib Axitinib

7. Bevacizumab/IFNA Outcome ---- BEV/IFN: Median OS 18.3 months IFN: Median OS 17.4 months Stratified log-rank p=0.069 0612182430364248 Time(months) 0.0 0.2 0.4 0.6 0.8 1.0 -- Bev/IFNA: median PFS 8.4 months IFNA: Median PFS 4.9 months HR= 0.71 (95% CI=0.6-0.8) Stratified log-rank p<0.0001 Progression Free Survival Overall Survival

8. Kinase interaction map SorafenibSunitinib Karaman, et al Nature Biotech. 26:127, 2008

9. 9 First line: Sunitinib vs IFNA Total Death Sunitinib 190 IFN-  200 Total Death Sunitinib 190 IFN-  200

10. Kaplan–Meier Estimates of Progression-free Survival According to Independent Review. First line: Sunitinib vs Pazopanib Motzer RJ et al. N Engl J Med 2013;369:722-731.

11. 11 First line: Axitinib vs Sorafenib The Lancet Oncology Volume 14, Issue 13 2013 1287 - 1294

12. VEGF Pathway inhibitors in renal cancer Agent(s) Context of Definitive Trial(s) ComparatorNo Prior Therapy Prior IL2 or IFNA Prior VEGF Pathway Outcome Bevacizumab/IFNAIFNAXPFS (bev) SunitinibIFNAXOS (sun) SorafenibPlaceboXPFS (sor) PazopanibPlaceboXXPFS (Paz) AxitinibSorafenibXPFS (Ax) AxitinibSorafenibXNone PazopanibSunitinibXNone TivozanibSorafenibXXOS (sor) DovitinibSorafenibX (and 1 prior mTOR) None

13. VEGF pathway inhibitor toxicities Cardiac (~73%) Hypertension Reversible Posterior Leukoencephalopathy MI CVA CHF Integument Hand/Foot Mucositis Diarrhea Systemic Fatigue Dysgeusia Metabolic Liver toxicity Hypothyroidism Hall, et al. J Am Coll Cardiol HF, 2013

14. mTOR Inhibitors Sirolimus (Rapamycin) Temsirolimus Everolimus (RAD001)

15. 15Renal Cancer| First line: Temsirolimus vs IFNA

16. Comparative and sequential data Everolimus 10 mg/day Sunitinib 50 mg/day*** 2 nd Line *NCT00903175. **Stratified by MSKCC prognostic factors. ***4 weeks on and 2 weeks off. Primary PFS-1 st line Secondary Combined PFS ORR-1 st line OS Safety Study endpoints Cross-over upon progression 1 : 1 RANDOMIZ E** E** Everolimus 10 mg/day SC RE EN Sunitinib 50 mg/day*** 1 st Line N = 471 Motzer, et al; ASCO 2013

17. 17Renal Cancer| Sunitinib versus everolimus sequential

18. mTOR toxicities Metabolic – Hyperglycemia – Hyperlipidemia – Increased creatinine Integument – Diarrhea – Mucositis – Pruritic rash Systemic – Fatigue – Edema – Pneumonitis Infectious risks Hematologic – Thrombocytopenia

19. mTOR inhibitors Agent Context of Definitive Trial ComparatorNo Prior Therapy Prior VEGF Pathway Outcome Temsirolimus*IFNAXOS (tem) EverolimusPlaceboXPFS (ev) TemsirolimusSorafenibXOS (sor) EverolimusSunitinibXOS (sun) *Poor prognosis only, included non-clear cell

20. Non-clear cell: comparative trials Sunitinib vs Temsirolimus –Central European Society for Anticancer Drug Research –Accrual complete, 22 pts total Sunitinib vs Everolimus –Duke sponsored multi-institutional –Accrual complete Sunitinib vs Everolimus –MDAnderson sponsored –108 planned

21. RCC front line therapy VEGF pathway directed agents are active in clear cell RCC –Sunitinib, Pazopanib, Sorafenib, Axitinib and Bevacizumab/IFNA improve PFS –There are biochemical and side-effect profile differences, but little clinical differences –Pazopanib is first line reference standard mTOR inhibitors are active in RCC –Temsirolimus improves survival of poor prognosis RCC over IFNA –Role of mTOR inhibitors is decreasing Immunotherapy is active –HD-IL2 leads to long term complete responses, but only in ~5% of highly selected patients –PD1 pathway inhibitors likely to play a role

22. 22Renal Cancer| RCC front line therapy Current pragmatic decisions based on side effect profiles Future decisions must be based on pathologic and molecular sub-typing