1. Expert Insight Into Optimal Treatment for Individuals With Advanced Renal Cell Cancer
This program is supported by an educational grant from

2. Therapeutic Decision Making in Advanced Renal Cell Carcinoma: A 2012 Perspective
Robert Motzer, MD Attending Physician Memorial Sloan-Kettering Cancer Center New York, New York

3. About These Slides
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4. Faculty Disclosure
Robert Motzer, MD, has disclosed that he has received consulting fees from Pfizer.

5. Outline Renal cell carcinoma incidence and biology
Interactive Decision Support Tool
First-line therapy
Salvage therapy
Management of treatment-related adverse events
Surgery in advanced RCC
Nonclear-cell RCC
Future directions
RCC, renal cell carcinoma.

6. Background and Treatment of mRCC
~ 64,770 new cases of kidney/renal pelvis cancers will be diagnosed in the US in 2012 with an estimated 13,570 deaths[1]
~ 75% are clear-cell RCC[2]
~ 25% to 30% of pts with RCC are diagnosed with metastatic disease[2]
Before the Era of Targeted Agents
Cytokine-based therapy was associated with a median PFS of 3-5 mos[3-5] and median OS of 13 mos[6]
mRCC, metastatic renal cell carcinoma; OS, overall survival; PFS, progression-free survival.
Current Situation
Targeted agents have resulted in substantial improvements in treatment outcomes for patients with mRCC[5,7,8]
1. Siegel R, et al. CA Cancer J Clin. 2012;62: Motzer RJ, et al. N Engl J Med. 1996;335: Rini BI, et al. J Clin Oncol. 2008;26: Escudier B, et al. Lancet. 2007;370: Motzer RJ, et al. N Engl J Med. 2007;356: Coppin C, et al. Cochrane Database Syst Rev. 2005;1:CD Mulders P. Eur Urol Suppl. 2008;7: Ljungberg B, et al. Eur Urol. 2010;58:

7. The Biology of Clear-Cell RCC: VHL Gene Mutation
CUL2
Rbx1
VHL complex
disrupted
Elongin B
Elongin C
VHL protein
β-domain
Mutant α-domain
HIFα
accumulation
Activation of hypoxia-inducible genes
HIF, hypoxia-inducible factor; PDGF, platelet-derived growth factor; RCC, renal cell carcinoma; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau gene.
VEGF
PDGF
Glut1
Autocrine Growth
Stimulation
Angiogenesis
Glucose Transport
Bratslavsky G, et al. Clin Cancer Res. 2007;13:

8. RCC Therapy: Targeting VEGF at Multiple Levels
Everolimus
Temsirolimus
Mutant pVHL
HIF
mTOR
Bevacizumab
VEGF
PDGF
HIF, hypoxia-inducible factor; mTOR, mammalian target or rapamycin; PDGF, platelet-derived growth factor; RCC, renal cell carcinoma; VEGF, vascular endothelial growth Factor.
Sunitinib
Sorafenib
Pazopanib
VEGFR
PDGFR
Axitinib
Kaelin WG Jr. Clin Cancer Res. 2004;10:6290S-6295S.

9. Patient Management and Therapy Selection in Advanced RCC: Considerations
Previous nephrectomy
Patients with intact primary tumor may benefit from surgical resection
Tumor histology
Evidence supporting the current therapeutic paradigm is largely limited to clear-cell RCC
Extent of metastases
Patients with 1-3 metastatic sites or those with metastases affecting QoL may benefit from additional treatment interventions including surgery, radiation, and/or bone-modifying agents
Previous systemic therapy
Preexisting comorbidities
Patient considerations
Cost
Convenience vs compliance
QoL, quality of life; RCC, renal cell carcinoma.

10. Interactive Decision Support Tool (IDST): 1 Tool, 3 Expert Recommendations
In the IDST (available at: the above variables were used to make treatment decisions.

11. Experts Were Asked How They Would Treat Patients, With the Following Options
Axitinib
Bevacizumab/interferon
Everolimus
Interferon
High-dose interleukin-2
Pazopanib
Sorafenib
Sunitinib
Temsirolimus
No treatment
RCC IDST. Available at:

12. An Expert Insight Is Shown With Each Expert’s Treatment Recommendations
RCC IDST. Available at:

13. First-line Therapy

14. Case 1
72-yr-old greenhouse worker returned for a follow-up exam after a partial nephrectomy 14 mos ago for a 5.6-cm tumor on his right kidney
PMH
Diabetes, HTN; both controlled with medication
Current evaluation
ECOG PS 0
Lab values normal except for anemia (Hb: 7.8 g/dL)
CT scan: new metastases to both lungs, multiple lymph nodes, and bone lesions to the pelvis, ribs, and vertebrae
CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; Hb, hemoglobin; HTN, hypertension; PMH, past medical history; PS, performance status.

15. Which agent would you recommend for this patient?
Axitinib
Bevacizumab/interferon
Everolimus
Interferon
High-dose interleukin-2
Pazopanib
Sorafenib
Sunitinib
Temsirolimus
No treatment

16. IDST Expert Insight Results: Case 1
First choice
Expert 1: pazopanib
Expert 2: sunitinib
Expert 3: sunitinib
Patient characteristics
Extensive metastatic clear-cell RCC
No previous systemic therapy
MSKCC intermediate risk (anemia)
ECOG PS 0
Alternative agents recommended by the 3 experts for this patient included bevacizumab plus interferon, high-dose IL-2, or sorafenib
High-dose IL-2 was recommended as an option only for patients with the highest PS scores
ECOG, Eastern Cooperative Oncology Group; IL-2, interleukin-2; MSKCC, Memorial Sloan-Kettering Cancer Center; PS, performance status; RCC, renal cell carcinoma.
RCC IDST. Available at:

17. Case 2
76-yr-old retired nurse presents with lower left back pain and hematuria
PMH is unremarkable except for arthritis and osteoporosis
Her current workup reveals
8-cm mass on the left kidney, lesions in the liver and right lung
ECOG PS 1
Laboratory tests identify anemia, LDH 3 x ULN, and serum calcium 10.5 mg/dL
Biopsy results confirm clear-cell RCC
ECOG, Eastern Cooperative Oncology Group; PMH, past medical history; LDH, lactate dehydrogenase; PS, performance status; RCC, renal cell carcinoma; ULN, upper limit of normal.

18. Which agent would you recommend for this patient?
Axitinib
Bevacizumab/interferon
Everolimus
Interferon
High-dose interleukin-2
Pazopanib
Sorafenib
Sunitinib
Temsirolimus
No treatment

19. IDST Expert Insight Results: Case 2
All 3 experts selected temsirolimus as their first choice for this patient
The alternate choices for this patient were pazopanib (1 expert) or sunitinib (2 experts)
Patient characteristics
Extensive metastatic clear-cell RCC
No previous systemic therapy
MSKCC poor risk (anemia, elevated LDH, elevated serum calcium)
ECOG PS 1
ECOG, Eastern Cooperative Oncology Group; IDST, Interactive Decision Support Tool; LDH, lactate dehydrogenase; MSKCC, Memorial Sloan-Kettering Cancer Center; PS, performance status; RCC, renal cell carcinoma.
RCC IDST. Available at:

20. Poor Risk Factors in Advanced Untreated RCC: MSKCC Criteria
KPS
< 80%
Time from diagnosis to treatment with IFN-α
< 12 mos
Hemoglobin
< LLN
LDH
> 1.5 x ULN
Corrected serum calcium
> 10.0 mg/dL
Risk Group by No. of Risk Factors
Favorable
Intermediate
1 or 2
Poor
3-5
Independent validation at the Cleveland Clinic identified 2 additional prognostic factors[2]
Previous radiotherapy
Presence of lung, hepatic, retroperitoneal nodal metastasis
Platelet and neutrophil counts > ULN identified as adverse prognostic factors for patients treated with VEGF-targeted therapies[3]
IFN, interferon; KPS, Karnofsky performance status; LDH, lactate dehydrogenase; LLN, lower limit of normal; MSKCC, Memorial Sloan-Kettering Cancer Center; RCC, renal cell carcinoma; ULN, upper limit of normal.
1. Motzer RJ, et al. J Clin Oncol. 2002;20: Mekhail TM, et al. J Clin Oncol. 2005;23: Heng DY, et al. J Clin Oncol. 2009;27:

21. High-Dose IL-2 vs Subcutaneous IL-2 + IFN for Patients With mRCC: Phase III Trial
Tumor Response
IL-2 + IFN
(n = 91)
HD IL-2
(n = 95)
P Value
Patients %
Overall response 9
9.9 22
23.2
.018 CR 3
3.3 8
8.4
.214 PR 6
6.6 14
14.7
Durable 3-yr CR 7
7.4
.014
Response by stratification criteria
Liver or bone metastases
1/39
2.6
10/44
22.7
.008
Primary tumor in place
0/27
6/29
20.7
.024
AE, adverse event; CR, complete response; HD, high dose; IFN, interferon; IL-2, interleukin-2; mRCC, metastatic renal cell carcinoma; PR, partial response.
Grade 3, 4 toxicities more common in HD IL-2 arm vs IL-2 + IFN
Hypotension: 56.8% vs 1.1%
Neurologic AEs: 14.7% vs 3.3%
Hematologic, pulmonary, renal/electrolytes: 13.7% vs 0%, 1.1%, 3.3%, respectively
McDermott DF, et al. J Clin Oncol. 2005;23:

22. First-line Treatment of RCC Overview
Study N
ORR vs IFN-α, %
Median PFS vs IFN-α, Mos
Final Median OS vs IFN-α, Mos
Sunitinib vs IFN-α[1]
750
47.0 vs 12.0
11 vs 5* P < .001
26.4 vs 21.8 P = .051
Bevacizumab + IFN-α vs IFN-α[2]
649
31.0 vs 12.0
10.4 vs 5.5* P < .0001
23.3 vs 21.3 P = .1291
Bevacizumab + IFN-α vs IFN-α[3]
732
25.5 vs 13.1
8.4 vs 4.9 P < .0001
18.3 vs P = .069
Sorafenib vs IFN-α[4] (phase II)
189
5.2 vs 8.7
5.7 vs. 5.6* P = .504 NA
Pazopanib vs placebo[5]
233
32.0 vs 4.0
11.1 vs 2.8 P < .0001
Temsirolimus vs IFN-α[6] (poor risk)
626
8.6 vs 4.8
5.5 vs 3.1* P < .001
10.9 vs 7.3 P = .008
IFN, interferon; NA, data not provided in the original study; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RCC, renal cell carcinoma.
*Independent assessment.
1. Motzer RJ, et al. J Clin Oncol. 2009;27: Escudier BJ, et al. ASCO Abstract Rini BI, et al. J Clin Oncol Abstract LBA Escudier BJ, et al. J Clin Oncol. 2009;27: Sternberg CN, et al. J Clin Oncol. 2010;28: Hudes G, et al. N Engl J Med. 2007;356: 22 22

23. Quality of Life for Patients With mRCC Receiving First-line Sunitinib vs IFN-α
QoL superior across all endpoints with sunitinib vs IFN-α
Patients receiving sunitinib reported better scores for FKSI-DRS vs those receiving IFN-α
Primary QoL endpoint
Indicates that patients receiving sunitinib experienced fewer disease-specific symptoms
Outcomes similar for patient groups in the US and EU, indicating minimal variation in QoL reporting or treatment experience
FKSI-DRS, Function Assessment of Cancer Therapy - Kidney Symptom Index - Disease-Related Symptoms; IFN, interferon; mRCC, metastatic renal cell carcinoma; QoL, quality of life.
Cella D, et al. ASCO Abstract 6529.

24. Pazopanib vs Sunitinib as First-line Tx for Clear-Cell mRCC: Phase III COMPARZ
Pazopanib 800 mg/day
Patients with locally advanced or mRCC
clear-cell histology,
no previous systemic therapy, measurable disease by CT/MRI
(N = 927)
RANDOM I Z A T ON
CT, computed tomography; mRCC, metastatic renal cell carcinoma; MRI, magnetic resonance imaging; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; QoL, quality of life.
Sunitinib 50 mg/day (schedule 4/2)
Primary endpoint: PFS
Secondary endpoints: OS, ORR, time to response, duration of response, safety, QoL
ClinicalTrials.gov. NCT 24

25. Survival Distribution Function
Temsirolimus Phase III Trial in Poor-Risk RCC*: Tem ± IFN-α; OS by Treatment R A N D O M I Z T N†
3/6 Poor-Risk Features:
LDH > 1.5 x ULN
Hb < LLN
Ca++ (corrected) > 10 mg/dL
KPS 60-70
Initial diag to random < 1 yr
Multiple sites of metastases mRCC
(N = 626)
IFN-α 3 MU-18 MU (n = 207)
CR + PR: 4.8%
CR + PR + SD‡: 15.5%
Tem 25 mg QW (n = 209)
CR + PR: 8.6%
CR + PR + SD: 32.1%
IFN-α 3 MU-6 MU + Tem 15 mg QW (n = 210) CR + PR: 8.1%
CR + PR + SD: 28.1%
1.0
Parameter
IFN Arm 1 (n = 207)
Tem Arm 2 (n = 209)
Tem + IFN Arm 3 (n = 210)
Median survival, Mos
7.3
10.9
8.4
Comparisons
Arm 2 to Arm 1
Arm 3 to Arm 1
Stratified log-rank P
.008
.70
0.8
CR, complete response; IFN, interferon; KPS, Karnofsky Performance Scale; LDH, lactate dehydrogenase; LLN, lower limit of normal; mRCC, metastatic renal cell carcinoma; MSKCC, Memorial Sloan-Kettering Cancer Center; MU, million units; OS, overall survival; PR, partial response; QW, each week; SD, stable disease; Tem, temsirolimus; ULN, upper limit of normal.
0.6
Survival Distribution Function
Arm 2: Tem
0.4
Arm 1: IFN
0.2
Arm 3: IFN + Tem 5 10 15 20 25 30 35
Time to Death (Mos)
*Modified MSKCC poor risk. †Stratified by country and nephrectomy status. ‡SD  24 wks.
Hudes G, et al. N Engl J Med. 2007;356: 25

26. Temsirolimus vs IFN-α: Correlation With Survival in First-line, Poor-Risk mRCC
Subgroup n
HR (95% CI)
Histology Clear cell Other
339 73
Age < 65 yrs
≥ 65 yrs
Prognostic Risk Intermediate Poor
CI, confidence interval; HR, hazard ratio; IFN, interferon; mRCC, metastatic renal cell carcinoma.
0.5
1.0
1.5
2.0
Temsirolimus Better
IFN-α Better
Hudes G, et al. N Engl J Med. 2007;356: Dutcher JP, et al. Med Oncol. 2009;26: Dutcher JP, et al. ASCO Abstract 5033.

27. PFS in Untreated RCC by Risk Group
Agent(s)
PFS, Mos
Good
Intermediate
Poor
HR vs IFN
Sunitinib[1,2]
11.0
14.5
10.6
3.7
0.54
Pazopanib[3]
11.1 --
0.40
(vs placebo)
Bev + IFN (AVOREN)[4]
10.2
12.9
2.2
0.63
Bev + IFN (CALGB 90206)[5]
8.5
8.4
3.3
0.71
Sorafenib[6]
5.7
Trend for improved PFS (HR:1.16)
0.88
Temsirolimus[7]
3.8 NA
3.8* NR
Bev, bevacizumab; HR, hazard ratio; IFN, interferon; MSKCC, Memorial Sloan-Kettering Cancer Center; NA, not applicable; NR, not reported; PFS, progression-free survival; RCC, renal cell carcinoma.
*Included patients classified as intermediate risk per MSKCC (31% of temsirolimus group).
1. Motzer RJ, et al. J Clin Oncol. 2009;27: Motzer RJ, et al. ASCO Abstract Sternberg CN, et al. J Clin Oncol. 2010;28: Escudier B, et al. Lancet. 2007;370: Rini BI, et al. J Clin Oncol. 2008;26: Escudier B, et al. J Clin Oncol. 2009;27: Hudes G, et al. N Engl J Med. 2007;356: 27

28. Salvage Therapy

29. Case 3
61-yr-old high school athletic director diagnosed with metastatic clear-cell RCC 8 mos ago
Initiated sunitinib
Achieved SD as best response
Returns complaining of fatigue with an ECOG PS of 1
CT scans show progression at multiple sites
CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; PS, performance status; RCC, renal cell carcinoma; SD, stable disease.

30. Which agent would you recommend for this patient?
Axitinib
Bevacizumab/interferon
Everolimus
Interferon
High-dose interleukin-2
Pazopanib
Sorafenib
Sunitinib
Temsirolimus
No treatment

31. IDST Expert Insight Results: Case 3
First choice
Expert 1: axitinib
Expert 2: everolimus
Expert 3: axitinib
Patient characteristics
Extensive metastatic clear-cell RCC
Previous sunitinib
ECOG PS 1
For this patient, either axitinib or everolimus were the first 2 choices of each of the 3 experts
Alternative agents recommended by at least 1 out of the 3 experts for this patient included bevacizumab plus interferon, pazopanib, or sorafenib
ECOG, Eastern Cooperative Oncology Group; IDST, Interactive Decision Support Tool; PS, performance status; RCC, renal cell carcinoma.
RCC IDST. Available at:

32. Case 3
The athletic director is treated with everolimus but returns 5 mos later with a deteriorating ECOG PS
CT scans show further evidence of disease progression
CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; PS, performance status.

33. Which agent would you recommend for this patient now?
Axitinib
Bevacizumab/interferon
Everolimus
Interferon
High-dose interleukin-2
Pazopanib
Sorafenib
Sunitinib
Temsirolimus
No treatment

34. IDST Expert Insight Results: Case 3
First choice
Expert 1: axitinib
Expert 2: sorafenib
Expert 3: axitinib
Patient characteristics
Extensive metastatic clear- cell RCC
Previous sunitinib and everolimus
ECOG PS 2
Alternative agents recommended by at least 1 out of the 3 experts for this patient included bevacizumab plus interferon, or pazopanib (2 experts)
1 expert recommended no further therapy for this patient
All of the experts agreed that a clinical trial, if available, would be a reasonable option
ECOG, Eastern Cooperative Oncology Group; IDST, Interactive Decision Support Tool; PS, performance status; RCC, renal cell carcinoma.
RCC IDST. Available at:

35. Sorafenib Activity in Patients With TKI-Refractory mRCC
Agent
Population N
TTP/PFS, Mos
OS, Mos
Sorafenib[1]
Sunitinib refractory 52
3.7
7.3
Sorafenib*[2] 27
4.4 16
Bevacizumab refractory 20
*Tumor burden reduction ≥ 5% observed in 30% of patients (43% of patients had SD).
mRCC, metastatic renal cell carcinoma; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; SD, stable disease; TKI, tyrosine kinase inhibitor; TTP, time to progression.
1. Di Lorenzo G, et al. J Clin Oncol. 2009;27: Garcia JA, et al. Cancer. 2010;116: 35

36. Everolimus vs Placebo: Survival Outcomes of RECORD-1
PFS Central Radiology Review OS
100
HR: 0.33 (95% CI: )
Median PFS, Mos
Everolimus : 4.90
Placebo: 1.87
Log-rank P < .001
100
HR: 0.87 (95% CI: )
Kaplan-Meier Median, Mos
Everolimus : 14.78
Placebo: 14.39
Log-rank P = .162 80 80 60 60
Probability (%)
Everolimus (n = 277)
Placebo (n = 139) 40 40
Everolimus (n = 277) 20 20
Placebo (n = 139)
CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival. 2 4 6 8 10 12 14 2 4 6 8 10 12 14 16 18 20 22 24
Mos
Mos
Patients at Risk, n
Everolimus
277
192
115 51 26 10 1
Placebo
139 47 15 6 2
Patients at Risk, n
Everolimus
277
267
240
204
164
155
131
101 61 30 6
Placebo
139
117
100 88 74 56 43 27 13 3
Motzer RJ, et al. Cancer. 2010;116:

37. RECORD-1: Previous Therapies
Previous Treatment, %
Everolimus (n = 277)
Placebo (n = 139)
Nephrectomy 97 96
Radiotherapy 31 27
VEGFR-TKI therapy
Sunitinib 45 43
Sorafenib 29
Both 26
Other systemic therapy
Immunotherapy 65 67
Chemotherapy 13 16
Hormone therapy 2 4
Other 5 3
Motzer RJ, et al. Cancer. 2010;116:

38. Axitinib: Recently Approved Potent and Selective VEGFR TKI
Most Potent for VEGFR-1, -2, and -3
Most Selective for VEGFR -1, -2, and -3
More potent
0.01
Target Selectivity
Axitinib[1]
Sorafenib[2]
Sunitinib[3]
Pazopanib[4]
VEGFR-2 +
PDGFR b
c-kit
FLT-3
CSF-1R ND
Raf-1
Axitinib[1]
0.1
Sunitinib[3]
Pazopanib[4]
Sorafenib[2] 1
Potency: IC50 (nM) 10
+: inhibition of receptor kinase comparable (≤ 5 times) to potency for VEGFR-2
ND: not determined
c-KIT, v-kit Hardy-Zukerman 4 feline sarcoma viral oncogene homolog; FLT, FMS-like tyrosine kinase; CSF, colony-stimulating factor; ND, not determined; PDGFR, platelet-derived growth factor; Raf, v-raf-1 murine leukemia viral oncogene homolog 1;TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor.
100
Less potent
VEGFR-1
VEGFR-2
VEGFR-3
1000
1. Hu-Lowe DD, et al. Clin Cancer Res. 2008;14: Wilhelm SM, et al. Cancer Res. 2004;64: Roskoski R. Biochem Biophys Res Commun. 2007;356: Kumar R, et al. Mol Cancer Ther. 2007;6:

39. Treat until PD, unmanageable AE, or withdrawal of consent
Phase III AXIS Study : Axitinib vs Sorafenib as Second-line Therapy for mRCC
Stratified by previous regimen, ECOG PS (0 vs 1)
Axitinib* 5 mg BID
(n = 361)
Patients with clear-cell mRCC, refractory to 1 previous first-line therapy (N = 723)
Treat until PD, unmanageable AE, or withdrawal of consent
AE, adverse event; BID, twice daily; ECOG, Eastern Cooperative Oncology Group; mRCC, metastatic renal cell carcinoma; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PS, performance status; QoL, quality of life; RECIST, Response Evaluation Criteria In Solid Tumors.
Sorafenib 400 mg BID
(n = 362)
*Starting dose 5 mg BID with option for dose titration to 10 mg BID.
Primary endpoint: PFS (independent review committee [IRC])
Secondary endpoints: OS, ORR (RECIST), duration of response, safety, QoL
Rini BI, et al. Lancet. 2011;378: 39

40. AXIS Trial: PFS (IRC Assessment)
1.0
mPFS, Mos
95% CI
0.9
Axitinib
Sorafenib
0.8
0.7
Stratified HR: (95% CI: ; log-rank P < .0001)
0.6
Probability of PFS
0.5
0.4
0.3
0.2
CI, confidence interval; HR, hazard ratio; IRC, Independent Review Committee; mPFS, median progression-free survival.
0.1 2 4 6 8 10 12 14 16 18 20
Mos
Patients at Risk, n
Axitinib
361
256
202
145 96 64 38 20 10 1
Sorafenib
362
224
157
100 51 28 12 6 3 1
Rini BI, et al. Lancet. 2011;378:

41. AXIS Trial: Efficacy Results
PFS by Previous Regimen
Previous Treatment Regimen
Axitinib (n = 361)
Sorafenib (n = 362) HR
P Value*
Cytokines (n = 251)
IRC
Investigator
12.1
12.0
6.5
8.3
0.464
0.636
< .0001
.0049
Sunitinib (n = 389)
4.8
3.4
4.5
0.741
.0107
.0002
Temsirolimus (n = 24)
10.1
2.6
5.3
5.7
0.511
1.210
.1425
.6342
Bevacizumab (n = 59)
4.2
4.7
1.147
0.753
.6366
.2126
ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; IRC, Independent Review Committee; PFS, progression-free survival; PS, performance status.
*1-sided log-rank test stratified by ECOG PS.
Rini BI, et al. Lancet. 2011;378:

42. (estimated enrollment
Temsirolimus vs Sorafenib for Patients With Advanced RCC Failing Sunitinib
Phase III international, prospective, randomized, open-label, outpatient, multicenter study
Stratified by nephrectomy status, MSKCC prognostic group, duration sunitinib response, RCC tumor histology
Patients with mRCC, RECIST-defined PD while receiving first-line sunitinib, measurable disease, no CNS metastases, no previous therapy other than sunitinib
(estimated enrollment
N = 508)
Temsirolimus 25 mg IV/wk
Sorafenib 400 mg PO BID
BID, twice daily; CNS, central nervous system; CR, complete response; IV, intravenous; mRCC, metastatic renal cell carcinoma; MSKCC, Memorial Sloan-Kettering Cancer Center; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PO, orally; PR, partial response; RCC, renal cell carcinoma; RECIST, Response Evaluation Criteria In Solid Tumors; RR, response rate.
Primary endpoints: PFS (independent assessment), safety, and tolerability
Secondary endpoints: PFS (investigator assessment), RR (CR & PR), OS, PFS at 12, 24, 36 wks (independent assessment), duration of response
ClinicalTrials.gov. NCT

43. Treatment-Related Adverse Events and Their Management

44. Treatment-Related Toxicities in Advanced Renal Cell Carcinoma
VEGF blockade (bevacizumab and VEGFR TKIs)
HTN, proteinuria, wound healing, bleeding
Higher incidence of grade 3/4 HTN with TKIs vs bevacizumab
VEGFR TKI class toxicities
Rash, HFSR, hair/skin depigmentation, cardiac dysfunction, myelosuppression, hypothyroidism, liver dysfunction
Incidence and severity vary with specific TKI
Other VEGF/VEGFR agent toxicities, predominantly grade 1/2
Diarrhea, nausea/vomiting, fatigue, asthenia
mTOR class toxicities
Hypercholesterolemia, hypertriglyceridemia, hyperglycemia, hypophosphatemia, pneumonitis
HFSR, hand-foot skin reaction; HTN, hypertension; mTOR, mammalian target of rapamycin; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor.
Schmidinger M, et al. Cancer Treat Rev. 2010;36:

45. Comparative VEGF TKI Toxicity in Recent Trials of Advanced RCC
Pazopanib vs sunitinib[1]
Diarrhea, elevated ALT and bilirubin more common with pazopanib
HFS, mucositis, stomatitis, myelosuppression, dysgeusia, and fatigue (by FACIT-F) more common with sunitinib
HTN, AST elevation similar with each
Axitinib vs sorafenib[2]
HTN, fatigue, nausea more common with axitinib
HFS, rash, hypophosphatemia more common with sorafenib
Diarrhea, myelosuppression, ALT/AST elevations similar with each
ALT, alanine aminotransferase; AST, aspartate aminotransferase; HFS, hand-foot syndrome; HTN, hypertension; TKI, tyrosine kinase inhibitor;
1. Escudier BJ, et al. ASCO Abstract CRA Rini BI, et al. Lancet. 2011;378:

46. Incidence of Metabolic Abnormalities With mTOR Inhibitors Across Trials
Grade ≥ 3 Adverse Events, %
Everolimus[1]
(n = 269)
Temsirolimus[2]
(n = 208)
Hyperglycemia 12 11
Hyperlipidemia/hypertriglyceridemia
< 1 3
Hypophosphatemia 4 NR
Hypercholesterolemia 1
NR, not reported.
1. Motzer RJ, et al. Lancet. 2008;372: Hudes G, et al. N Engl J Med. 2007;356:

47. Key Issues in Treatment-Related Toxicity Management in Advanced RCC
Maximizing exposure to therapeutic agents correlates with improved clinical outcomes for patients with advanced RCC
Dose reduction or discontinuation should be limited to patients experiencing severe (grade 3/4) toxicities that do not resolve to grade 1 or lower by withholding therapy
Emergent adverse events should be aggressively managed
Monitor LFTs in patients receiving TKI therapy (especially pazopanib)
Symptomatic management of dermatological and gastrointestinal toxicities such as rash, diarrhea, mucositis
LFT, liver function test; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor.
Houk BE, et al. Cancer Chemother Pharmacol. 2010;66: Eisen T, et al. J Natl Cancer Inst. 2012;104:

48. Treatment-Related Toxicity Management in Advanced RCC: Comorbidities
Patients with history of diabetes
Optimize glycemic control before treatment
Monitor during treatment, especially with mTOR inhibitors
Patients with history of heart disease
Pretreatment evaluation for signs of heart failure, subclinical cardiovascular disease
On-treatment monitoring
Ongoing evaluation for heart failure
Exclude pulmonary embolism, hypothyroidism, or other causes of heart failure
RCC, renal cell carcinoma.
Eisen T, et al. J Natl Cancer Inst. 2012;104:

49. The Role of Surgery in Metastatic RCC
RCC, renal cell carcinoma.

50. Cytoreductive Nephrectomy
SWOG[1]
Median Survival, Mos
IFN- + nephrectomy (n = 120)
11.1
IFN- (n = 121)
8.1
EORTC[2]
Median Survival, Mos
IFN- + nephrectomy (n = 42)
17.0
IFN- (n = 42)
7.0
100
100 80
P = .05 80
P = .03 60 60
Survival (%)
Survival (%) 40 40
EORTC, European Organization for the Research and Treatment of Cancer; IFN, interferon; SWOG, Southwest Oncology Group. 20 20 24 48 72 96 12 24 36
Mos
Mos
1. Flanigan RC, et al. N Engl J Med. 2001;345: Mickisch GH, et al. Lancet. 2001;358: 50

51. Cytoreductive Nephrectomy: Guidelines
> 75% tumor debulking
No CNS metastases
Adequate pulmonary and cardiac function
ECOG PS 0 or 1
Predominantly clear-cell histology
Quantify the tumor’s biology and its affect on the patient
Performance score
Tumor distribution
Comorbidity Index
CNS, central nervous system; ECOG PS, Eastern Cooperative Oncology Group performance status.
Culp SH, et al. Cancer. 2010;116:

52. Cytoreductive Nephrectomy: Factors Associated with Adverse Outcome
Serum LDH > ULN
Serum albumin < LLN
Retroperitoneal or supradiaphragmatic adenopathy
Symptomatic presentation due to metastases
≥ T3 tumor
Liver metastasis
LDH, lactate dehydrogenase; LLN, lower limit of normal; ULN, upper limit of normal
Culp SH, et al. Cancer. 2010;116:

53. Metastasectomy in Renal Cell Carcinoma
Characteristics associated with improved survival in patients undergoing metastasectomy for first recurrence
Disease-free interval > 1 yr
Single site of metastasis
Lung better than brain
5-yr survival of 44%
Similar 5-yr survival rates with curative resection upon second and third recurrence
Kavolius JP, et al. J Clin Oncol. 1998;16:

54. Nonclear-Cell Renal Cell Carcinoma

55. Nonclear-Cell RCC Histologic Subtypes and Resistant Phenotypes
Frequency
Gene
Clear cell
75%
VHL
Papillary type 1 5%
c-Met
Papillary type 2
10% FH
Chromophobe 5%
BHD
Oncocytoma 5%
BHD
BHD, Birt-Hogg-Dube syndrome gene; FH, fumarate hydratase gene; RCC, renal cell carcinoma; VHL, von Hippel-Lindau gene.
Sarcomatoid variant is an aggressive form of RCC that can occur in any histology subtype[2]
1. Linehan WM, et al. J Urol. 2003;170: Chowdhury S, et al. Hematol Oncol Clin North Am. 2011;25:

56. Nonclear-Cell RCC: Prognosis and Treatment
5-yr survival rates[1]
Chromophobe: 87.9% (localized)
Papillary: 79.4% (localized), 10.3% (nonlocalized)
Treatment
Clinical trial recommended by all 3 experts
No current standard of care
Targeted therapy
Agents that may be active include sunitinib, sorafenib, temsirolimus, and erlotinib (papillary)[2]
Lower efficacy than in clear-cell RCC
Current evidence limitations: retrospective analyses, small patient populations, lack of confirmed histology
RCC, renal cell carcinoma.
1. Patard JJ, et al. J Clin Oncol. 2005;23: Chowdhury S, et al. Hematol Oncol Clin North Am. 2011;25:

57. Future Directions
New agents
Combination therapy
Markers of efficacy

58. Investigational Agents in Trials
Class
Target(s)
Trial Phase
Tivozanib[1,2]
TKI
VEGFR
III
Dovitinib[2]
FGFR, VEGFR, PDGFR
III (ongoing)
Lenvatinib[3]
II (ongoing)
GDC-0980[4]
Kinase inhibitor
mTOR, PI3 kinase
II (planned)
MDX-1106[1]
MoAb
PD-1
II, III (planned)
AGS-003[5]
Dendritic cell
Tumor antigens
IMA901[6]
Vaccine
Multipeptide
FGFR, fibroblast growth factor receptor; MoAb, monoclonal antibody; mTOR, mammalian target of rapamycin; PD-1, programmed death-1; TKI, tyrosine kinase inhibitor.
1. Gross-Goupil M, et al. Curr Urol Rep. 2012;13: Motzer RJ, et al. ASCO Abstract Boss DS, et al. Br J Cancer. 2012;106: Wallin JJ, et al. Mol Cancer Ther. 2011;10: Amin A, et al. ASCO Abstract Rini BI, et al. ASCO Abstract TPS183.

59. Tivozanib 1.5 mg/day PO, 3 wks of 4-wk cycle
Phase III TIVO-1: Tivozanib (AV-951) vs Sorafenib for Patients With Advanced RCC
Stratified by previous treatments (0, 1), number of metastatic sites (1 vs ≥ 2), geographic region
Patients with recurrent or metastatic clear-cell RCC, previous nephrectomy, ≤ 1 previous systemic therapy, no previous VEGF or mTOR-targeting treatment, ECOG PS 0-1
(N = 517)
Tivozanib 1.5 mg/day PO, 3 wks of 4-wk cycle
(n = 260)
Sorafenib 400 mg PO BID
(n = 257)
BID, twice daily; ECOG PS, ECOG , Eastern Cooperative Oncology Group performance score; ORR, objective response rate; PFS, progression-free survival; PO, orally; RCC, renal cell carcinoma.
Primary endpoint: PFS
Secondary endpoints: ORR, safety
Motzer RJ, et al. ASCO Abstract 4501.

60. TIVO-1: Efficacy Advantage in median PFS with tivozanib
ITT population: 11.9 vs 9.1 mos (HR: 0.797; P = .042)
Previously untreated population: 12.7 vs 9.1 mos (HR: 0.756; P = .037)
ORR improved with tivozanib
33% vs 23% (P = .014)
HR, hazard ratio; ITT, intent-to-treat; ORR, objective response rate; PFS, progression-free survival.
Motzer RJ, et al. ASCO Abstract 4501.

61. TIVO-1: Toxicity Toxicity, % Tivozanib (n = 259) Sorafenib (n = 257)
All Grades
Grade 3 (4)
More with sorafenib
Diarrhea 22 2 32 6
HFS 13 54 17
Alopecia 21
More with tivozanib
HTN 44
24 (2) 34
17 (< 1)
Dysphonia 5
Back pain 14 3 7
HFS, hand-foot syndrome; HTN, hypertension.
Significantly fewer dose interruptions (18% vs 35%) and dose reductions (12% vs 43%) with
tivozanib compared with sorafenib (P < .001 for both comparisons).
Motzer RJ, et al. ASCO Abstract 4501.

62. Dovitinib (TKI258): FGFR as a Target in RCC
Preclinical studies indicate that FGF is a possible escape mechanism after the initiation of anti-VEGF therapy[1]
Phase I: dovitinib in VEGF-refractory RCC[2]
N = 18
1 PR, 2 prolonged SD
MTD: 500 mg 5 days on/2 days off
Modulation of VEGFR-2 and FGFR
Toxicities: nausea, vomiting, diarrhea, hypertension
Enzymatic Assay
Target
TKI258 IC50 nM
FGFR-1 8
FGFR-2 40
FGFR-3 9
FLT3 1
c-KIT 2
VEGFR-1 10
VEGFR-2 13
VEGFR-3
PDGFR-β 12
CSFR-1 15
FGF, fibroblast growth factor; MTD, maximum tolerated dose; PR, partial response; RCC, renal cell carcinoma; SD, stable disease; VEGF, vascular endothelial growth factor.
Casanovas O, et al. Cancer Cell. 2005;8: Angevin E, et al. ASCO Abstract 3563.

63. Phase II TORAVA: Temsirolimus + Bevacizumab for Patients With mRCC
Stratified by center, ECOG PS (0-1 vs 2)
Temsirolimus* + Bevacizumab*
(n = 88) R A N D O M I Z E
Patients with clear-cell mRCC, measurable disease, ECOG PS 0-2; previously untreated
(N = 171) 2 1
Sunitinib*
(n = 42) 1
Bevacizumab* + IFN-α*
(n = 41)
*Dosing: temsirolimus 25 mg/wk IV, bevacizumab 10 mg/kg IV q2wks, sunitinib 50 mg/day PO 4 wks on/2 wks off, IFN-α 9MU SC TIW.
AE, adverse event; ECOG PS, Eastern Cooperative Oncology Group performance score; IFN, interferon; IV, intravenous; mRCC, metastatic renal cell carcinoma; MU, million units; PO, orally; q2wks, every 2 weeks; SC, subcutaneously; TIW, every 3 weeks.
For patients receiving combination temsirolimus and bevacizumab
51% discontinued treatment for reasons other than disease progression
77% experienced grade ≥ 3 AEs
No evidence of synergistic or additive efficacy
Négrier S, et al. Lancet Oncol. 2011;12:

64. INTORACT: Bevacizumab + Temsirolimus vs Bevacizumab + IFN-α for Advanced RCC
Phase IIIb, randomized, open-label study
Bevacizumab 10 mg/kg IV q8w +
Temsirolimus 25 mg IV weekly
Patients with clear-cell, advanced RCC, no CNS metastases, and no previous systemic treatment
(Estimated N = 790)
Bevacizumab 10 mg/kg IV q8w +
IFN-α 9MU SC TIW
CNS, central nervous system; IFN, interferon; IV, intravenous; MU, million units; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; q8wks, every 8 weeks; RCC, renal cell carcinoma; SC, subcutaneously; TIW, three times weekly.
Primary endpoints: PFS (independently assessed)
Secondary endpoints: safety, PFS (investigator assessed), ORR, and OS
ClinicalTrials.gov. NCT

65. OS by HTN Status (DBP ≥ 90 mm Hg) on Sunitinib
With HTN (n = 363) Median OS: 32.2 mos
1.0
0.9
Without HTN (n = 171) Median OS: 14.9 mos
0.8
0.7
P < .0001
0.6
Probability of OS
0.5
0.4
0.3
DBP, diastolic blood pressure; HTN, hypertension; OS, overall survival.
0.2
0.1 5 10 15 20 25 30 35 40 45 50
Mos
Rini BI, et al. J Natl Cancer Inst. 2011;103: 65

66. Go Online for More CCO Coverage of Kidney Cancer!
Interactive Decision Support Tool: Expert faculty help guide the choice of systemic therapy based on your patients’ specific characteristics Downloadable slidesets for your own noncommercial presentations
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