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Case 1

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. Are There Novel Agents Out There?. Checkpoint-blocking antibodies Nivolumab Ipilimumab Novel endothelial targets

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Case 1

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  1. 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

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

  3. 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,4JD Powderly,5 DC Smith,6 JM Wigginton,7D 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

  4. 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) McDermott DF, et al. ASCO 2012. Abstract 4505. Topalian SL, et al. N Engl J Med. 2012;366:2443-2454.

  5. 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

  6. Cabozantinib in Relapsed or Refractory RCC: PFS 1.00 0.75 0.50 0.25 0 Median PFS, Mos 95% CI Events, n 14.7 7.3, – 8 Proportion Progression Free 0 5 20 10 15 Mos From First Dose Choueiri TK, et al. ASCO 2012. Abstract 4504.

  7. Partial Bone Scan Resolution/Pain Relief in Symptomatic Patient With Bone Mets • 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 Previous therapies include sorafenib, everolimus, and sunitinib 7-Wk Follow-up Baseline Choueiri TK, et al. ASCO 2012. Abstract 4504.

  8. 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 P < .0001 0.2 0 0 5 10 15 20 25 30 35 40 45 50 Mos Pts at Risk, n With HTNWithout HTN 442 418 377 308 257 224 190 106 29 92 55 38 21 15 7 5 3 1 Rini BI, et al. J Natl Cancer Inst. 2011;103:763-773.

  9. 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

  10. MSKCC Risk Factor Model in Metastatic RCC 1.0 0 risk factors (n = 80 patients) 1 or 2 risk factors (n = 269 patients) 0.9 3, 4, or 5 risk factors (n = 88 patients) 0.8 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 0.7 0.6 Proportion of Patients Surviving 0.5 0.4 0.3 0.2 0.1 0 4 0 1 2 3 5 6 7 8 9 10 11 15 16 12 13 14 Yrs From Start of IFN-α Motzer RJ, et al. J Clin Oncol. 2002;20:289-296.

  11. 3p Shows Multiple Hits in RCC Q arm P arm Andy Futreal Professor, Genomic Medicine MD Anderson PBRM1 3p21.1[1] VHL 3p25[2] SETD2 3p21.31[3] BAP1 3p21.31[4] 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.

  12. Intratumor Heterogeneity and Branched Evolution in Metastatic RCC • 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 Ubiquitous Shared primary Shared metastasis Private R1 R2 Biopsy Sites R9 R8 KDM5C (missense and frameshift) mTOR (missense) R3 R5 PreP R4b SETD2(splice site) SETD2 (frameshift Normal tissue ? R4a VHL SETD2 (missense) KDM5C (splice site) M1 M2b M2a PreM Gerlinger M, et al. N Engl J Med. 2012;366:883-892.

  13. Transcriptomic Stratification of Clear-Cell RCC Reveals Distinct Subtypes and Survival Patterns • 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 1.0 Median ccA (n = 83): 103 mos ccB (n = 60): 24 mos Uncl (n = 34): 39 mos 0.8 0.6 Survival Probability 0.4 ccA vs ccB P = .0002 + Uncl P = .0007 0.2 0 50 100 150 200 250 Mos 0 Brannon AR, et al. Genes Cancer. 2010;1:152-163.

  14. Copy Number Changes AssociatedWith Prognosis of RCC Frequency of Chromosomal Imbalances in Stage Clear-Cell Carcinoma 8q – OS Patients With 14q Loss 100 80 1.0 0.9 High stage Low stage 8q Normal 60 0.8 P =.0076 0.7 40 0.6 P =.0004 0.5 20 8q Loss 0.4 NS Cases (%) 0.3 P = .007 0.2 8q Gain 0.1 0 0 6.1 12.2 18.3 30.5 36.6 42.7 48.7 24.4 54.8 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.

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

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