Case 1 48-yr-old woman diagnosed with metastatic RCC in 2010 Treated with Axitinib on a clinical trial Sunitinib Pazopanib Everolimus Everolimus plus bevacizumab RCC, renal cell carcinoma.

Are There Novel Agents Out There? Checkpoint-blocking antibodies Nivolumab Ipilimumab Novel endothelial targets FGF receptor blockade: dovitinib Epithelial/stromal targets MET: cabozantinib FGF, fibroblast growth factor.

Clinical Activity and Safety of Anti–PD-1 Nivolumab (BMS-936558, MDX-1106) in Patients With Previously Treated Metastatic Renal Cell Carcinoma DF McDermott,1 CG Drake,2 M Sznol,3 TK Choueiri,4 JD Powderly,5 DC Smith,6 JM Wigginton,7 D McDonald,7 G Kollia,7 A Gupta,7 MB Atkins1 1Beth Israel Deaconess Medical Center, Boston, MA; 2Sidney Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD; 3Yale Cancer Center, New Haven, CT; 4Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston, MA; 5Carolina BioOncology Institute, Huntersville, NC; 6University of Michigan, Ann Arbor, MI; 7Bristol-Myers Squibb, Princeton, NJ

Anti–PD-1 Nivolumab: RCC Cohorts Dose expansion 16 patients enrolled at 10 mg/kg 17 patients enrolled at 1 mg/kg Assessment of antitumor activity Assessment of safety and tolerability of Nivolumab Current analysis for patients treated through 02/2012 34 patients were evaluable for safety 33 patients were evaluable for clinical activity ORR: 27% DOR: 5.6-22.3 mos (ongoing) PFS at 24 wks: 56% (median PFS not yet reached) RCC, renal cell carcinoma. McDermott DF, et al. ASCO 2012. Abstract 4505. Topalian SL, et al. N Engl J Med. 2012;366:2443-2454.

Cabozantinib Inhibitor of MET and VEGF receptor Striking response seen in bone of patients with prostate cancer Agent is being explored in multiple other cancers, including RCC Currently FDA approved for use in patients with progressive, metastatic medullary thyroid cancer FDA, US Food and Drug Administration; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.

Cabozantinib in Relapsed or Refractory RCC: PFS 1.00 0.75 0.50 0.25 Median PFS, Mos 95% CI Events, n 14.7 7.3, – 8 Proportion Progression Free CI, confidence interval; PFS, progression free survival; RCC, renal cell carcinoma 5 10 15 20 Mos From First Dose Choueiri TK, et al. ASCO 2012. Abstract 4504.

Partial Bone Scan Resolution/Pain Relief in Symptomatic Patient With Bone Mets Previous therapies include sorafenib, everolimus, and sunitinib Baseline 7-Wk Follow-up Patient substantially reduced narcotic use by 7 wks; continued on reduced narcotics until Wk 25 Another patient with bone metastases and pain at baseline reported complete resolution of pain by 4 wks Pain free 90+ wks on study Choueiri TK, et al. ASCO 2012. Abstract 4504.

Hypertension as Marker of Efficacy in Pts With Metastatic RCC After Sunitinib Treatment With HTN (n = 442) Median OS: 30.9 mos (95% CI: 27.9-33.7) Without HTN (n = 92) Median OS: 7.2 mos (95% CI: 5.6-10.7) 1.0 0.8 0.6 Probability of OS 0.4 0.2 P < .0001 5 10 15 35 45 50 30 40 20 25 Mos Pts at Risk, n With HTN Without HTN 442 418 377 308 257 224 190 106 29 92 55 38 21 15 7 5 3 1 CI, confidence interval; HTN, hypertension; OS, overall survival; RCC, renal cell carcinoma. With HTN Without HTN Month N S, % 95% CI 10 377 86.3 (82.7-89.2) 38 43.5 (33.0-53.5) 20 257 66.3 (61.5-70.6) 15 21.4 (13.1-31.0) 30 190 51.9 (46.9-56.7) 5 8.2 (3.2-16.1) Rini BI, et al. J Natl Cancer Inst. 2011;103:763-773.

No Other Validated Biomarkers Exist in Metastatic RCC Prognostic MSKCC and Heng criteria Somatic tumor mutations Transcriptomic patterns Chromosomal copy number variations Predictive Hypertension Single nucleotide polymorphisms Cytokines and angiogenic factors MSKCC, Memorial Sloan-Kettering Cancer Center; RCC, renal cell carcinoma.

MSKCC Risk Factor Model in Metastatic RCC 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 risk factors (n = 80 patients) 1 or 2 risk factors (n = 269 patients) 3, 4, or 5 risk factors (n = 88 patients) Risk factors associated with worse prognosis KPS < 80 Low serum hemoglobin (M: 13 g/dL; F: 11.5 g/dL) High corrected calcium (10 mg/dL) High lactate dehydrogenase (300 U/L) No nephrectomy or < 1 yr from Dx to Tx Proportion of Patients Surviving Dx, diagnosis; IFN-α; interferon alpha; KPS, Karnofsky performance status; MSKCC, Memorial Sloan-Kettering Cancer Center; RCC, renal cell carcinoma; Tx, treatment. The Memorial Sloan-Kettering risk-factor model is predictive of patient long-term prognosis This retrospective study was performed on 670 patients with mRCC treated at Memorial Sloan-Kettering Cancer Center. The subsequent model that was developed, identifies prognostic factors that predicted survival for patients with mRCC. Risk factors associated with shorter survival (no prior nephrectomy) were: KPS <80 Low serum hemoglobin (13 g/dL in males,11.5 g/dL in females) High corrected calcium (10 mg/dL) High lactate dehydrogenase (300 U/L) The model predicts that patient prognosis declines as the number of risk factors increases. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Yrs From Start of IFN-α Motzer RJ, et al. J Clin Oncol. 2002;20:289-296. Reference Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M, et al. Interferon-alfa as a comparitive treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20:289-286.

3p Shows Multiple Hits in RCC P arm Q arm VHL 3p25[2] SETD2 3p21.31[3] PBRM1 3p21.1[1] BAP1 3p21.31[4] Andy Futreal Professor, Genomic Medicine MD Anderson RCC, renal cell carcinoma. 1. Varela I, et al. Nature. 2011;469:539-542. 2. Latif F, et al. Science. 1993;260:1317-1320. 3. Dalgliesh GL, et al. Nature. 2010;463:360-363. 4. Peña-Llopis S, et al. Nat Genet. 2012;44:751-759.

Intratumor Heterogeneity and Branched Evolution in Metastatic RCC Ubiquitous Shared primary Shared metastasis Private R1 R2 R3 R9 R5 PreP R4b KDM5C (missense and frameshift) mTOR (missense) Normal tissue SETD2 (frameshift VHL ? R4a M1 M2a M2b PreM SETD2 (missense) KDM5C (splice site) SETD2 (splice site) R8 Biopsy Sites Intratumor heterogeneity analyzed with exome sequencing, chromosome aberration analysis, and DNA ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63% to 69% of all somatic mutations not detectable across every tumor region RCC, renal cell carcinoma. Gerlinger M, et al. N Engl J Med. 2012;366:883-892.

Transcriptomic Stratification of Clear-Cell RCC Reveals Distinct Subtypes and Survival Patterns 0.2 0.4 0.6 0.8 1.0 Median ccA (n = 83): 103 mos ccB (n = 60): 24 mos Uncl (n = 34): 39 mos Survival Probability Dr. Rathmell’s group analyzed a series of ccRCC tumors to show that 2 subtypes of ccRCC exist based on their molecular signature Subtypes (ccA and ccB) are identifiable by a robust set of genes representing distinct biological pathways ccA vs ccB P = .0002 + Uncl P = .0007 50 100 150 200 250 Mos Brannon AR, et al. Genes Cancer. 2010;1:152-163.

Copy Number Changes Associated With Prognosis of RCC Frequency of Chromosomal Imbalances in Stage Clear-Cell Carcinoma 8q – OS Patients With 14q Loss 0.2 0.4 0.6 0.8 1.0 0.1 0.3 0.5 0.7 0.9 High stage Low stage 8q Normal 20 40 60 80 100 P = .0076 P = .0004 8q Loss NS Cases (%) P = .007 8q Gain RCC, renal cell carcinoma. 24.4 18.3 12.2 6.1 54.8 48.7 42.7 36.6 30.5 60.9 % Aneuploid Genome Gains Losses Mos Federico Monzon Director, Cancer Genetics Laboratory Baylor College of Medicine % Chromosomal Arms Imbalanced Monzon FA, et al. Mod Pathol. 2011;24:1470-1479.

Patient tumor and host characteristics Drug properties The right drug for the right patient at the right time