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
RCC, renal cell carcinoma.

2. 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.

3. Clinical Activity and Safety of Anti–PD-1 Nivolumab (BMS , 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

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: mos (ongoing)
PFS at 24 wks: 56% (median PFS not yet reached)
RCC, renal cell carcinoma.
McDermott DF, et al. ASCO Abstract Topalian SL, et al. N Engl J Med. 2012;366:

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
FDA, US Food and Drug Administration; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.

6. Cabozantinib in Relapsed or Refractory RCC: PFS
1.00
0.75
0.50
0.25
Median PFS, Mos 95% CI Events, n
, – 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 Abstract 4504.

7. 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 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: )
Without HTN (n = 92)
Median OS: 7.2 mos (95% CI: )
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
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
( ) 38
43.5
( ) 20
257
66.3
( ) 15
21.4
( ) 30
190
51.9
( ) 5
8.2
( )
Rini BI, et al. J Natl Cancer Inst. 2011;103:

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
MSKCC, Memorial Sloan-Kettering Cancer Center; RCC, renal cell carcinoma.

10. 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:
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:

11. 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: Latif F, et al. Science. 1993;260: Dalgliesh GL, et al. Nature. 2010;463: Peña-Llopis S, et al. Nat Genet. 2012;44:

12. 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:

13. 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:

14. 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:

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