1. The Role of Pazopanib in the Treatment of Renal Cell Cancer
Robert Hawkins
University of Manchester
and
The Christie Hospital, Manchester

2. Range of Drugs / Targets for RCC

3. Overview Pazopanib
Pazopanib is the most recently licensed drug for treatment of RCC
Pazopanib is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-Kit
Phase II studies showed response rate of around 33% and PFS ~ 11 months
Initial results of Phase III study published*
Pazopanib has thus far been approved for the treatment of advanced RCC in the US, Europe, Australia, Canada, Chile, New Zealand, and Russia
Final overall survival (OS) results and safety update are presented
* Sternberg CN, et al. Pazopanib in locally advanced or metastatic renalcell carcinoma: results of a randomized phase III trial. J Clin Oncol Feb20;28(6):1061-8

4. Pazopanib Kinase affinity profile
Kiapp (nM)
VEGFR-1 15
VEGFR-2 8
VEGFR-3 10
PDGFR-α 30
PDGFR-β 14
c-Kit
2.4
Flt-3
230
Oral Multi-kinase angiogenesis inhibitor targeting VEGFR, PDGFR and c-Kit tyrosine kinases
Selectively inhibits VEGF-mediated endothelial cell proliferation
Arrests growth of human tumour xenografts in mice
Active in in vivo angiogenesis assay 7 7

5. Kinase Selectivity of Various VEGFR TKIs
VEGFR, PDGFR,
c-Kit
FLT3
VEGFR, PDGFR, c-Kit
Pazopanib
Sorafenib
Sunitinib
Figure: Kinase interaction maps for pazopanib, sorafenib and sunitinib. Kinases found to bind are marked with red circles, where larger circles indicate higher-affinity binding. Interactions with Kd < 3 μM are shown.
Selectivity scores = {number of binding interactions with Kd<100 nM/number of kinases tested (290)}.
Ratio of selectivity scores for sunitinib and sorafenib compared to pazopanib.
Adapted from Supplementary Table 4, Karaman, 2008
Pazopanib binds to 5 times fewer kinases than Sunitinib with Kd <100 nM.
Adapted from Karaman et al. Nat Biotech. 2008;26:127.

6. Phase III Trial of Pazopanib in Locally Advanced and/or Metastatic Renal Cell Carcinoma
Cora N. Sternberg,1 Cezary Szczylik,2 Eun S. Lee,3 Pamela Salman,4 Jozef Mardiak,5 Ian D. Davis,6 Lini Pandite,7 Mei Chen,8 Lauren McCann,8 Robert E. Hawkins9
1San Camillo and Forlanini Hospitals, Rome, Italy; 2Military Institute of Medicine, Warsaw, Poland; 3National Cancer Center, Gyeonggi-do, Korea; 4Fundación Arturo López Pérez, Santiago, Chile; 5National Oncological Institute, Klenová, Bratislava, Slovakia; 6Austin Hospital, Melbourne, Australia; 7GlaxoSmithKline, Inc., Research Triangle Park, NC, USA; 8GlaxoSmithKline, Inc., Collegeville, PA, USA; 9University of Manchester and Christie Hospital NHS Foundation Trust, Manchester, UK
Sternberg CN, et al. Pazopanib in locally advanced or metastatic renalcell carcinoma: results of a randomized phase III trial. J Clin Oncol Feb20;28(6):1061-8

7. A global, randomized, double-blind study to evaluate efficacy and safety of pazopanib in advanced RCC (VEG105192)
80 Sites in 22 countries
Enrolled: Apr 06 - Apr 07
Europe
Austria
Czech Republic
Estonia
Ireland
Italy
Latvia
Lithuania
Poland
Russia
Slovakia
Tunisia
England
Ukraine
Asia/Pacific
Australia
China/HK
India
Korea
New Zealand
Pakistan
South America
Argentina
Brazil
Chile

8. Patient Eligibility Locally advanced and/or metastatic RCC
Clear-cell histology
Treatment-naive or failure of 1 prior cytokine therapy
Measurable disease by RECIST
ECOG PS 0 or 1
Adequate organ function
Age  18 years

9. Patients with advanced RCC (N = 435)
Study Design
Patients with advanced RCC (N = 435)
Stratification
ECOG PS 0 vs 1
Prior nephrectomy
Rx-naive (n = 233) vs 1 cytokine failure (n = 202)
Randomization 2:1
Pazopanib 800 mg qd (n = 290)
Matching Placebo (n = 145)
Option to receive pazopanib via an open-label study at progression. 38 7 12

10. Why a Placebo Controlled Trial?
Nov 05 – Protocol finalised: cytokines were the only approved treatment, they are associated with low efficacy and significant safety concerns. Placebo allows characterisation of efficacy and particularly safety
Apr 06 – pazopanib enrollment started
Jul 06 – sorafenib + sunitinib received EU approval for cytokine pre-treated population
Jan 07 – sunitinib receives full approval for advanced and/or metastatic RCC
Apr 07 – pazopanib enrollment completes
2008 – supplies of sunitinib available for large clinical trials

11. Endpoints and Analysis Plan
Primary:
Progression-free survival (PFS)
> 90% power to detect 80% improvement in median PFS
Adequately powered in the treatment-naive, cytokine-pretreated subpopulations
Secondary:
Overall survival (OS)
90% power to detect a 50% improvement in median OS
Final OS analysis performed when 290 deaths were accrued
Occurred March 2010
Stratified log-rank test
Overall response rate (ORR), duration of response, safety, health-related quality of life (HRQoL)
Analysis Plan:
One single analysis for PFS, one planned interim analysis for OS (at the time of PFS analysis)
Clinical cutoff: May 23, 2008

12. Baseline Patient Characteristics
Pazopanib
(N = 290)
Placebo
(N = 145)
Median age, yrs (range)
59 (28 – 85)
60 (25 – 81)
Gender, % male 68 75
Number of organs involved, % or 2 vs. ≥ 3
45 / 55
48 / 52
Most common metastatic sites, % Lung Lymph node
73 59
ECOG PS, % 0 vs.1
42 / 58
41 / 59
MSKCC risk category, % Favorable Intermediate Poor / Unknown
/ 3
/ 4
Prior systemic treatment, % Treatment-naive Cytokine-pretreated
53 47

13. Primary Endpoint – PFS (Overall Study Population)
1.0
0.0
0.2
0.4
0.6
0.8 5 10 15 20
Months
Proportion Progression-Free
Patients at Risk
Pazopanib
Placebo
Hazard Ratio = 0.46
95% CI (0.34, 0.62)
P value <
Median PFS
Pazopanib: 9.2 mo
Placebo: 4.2 mo
Pazopanib
Placebo
Reproduced with permission from Sternberg CN, et al. J Clin Oncol. 2010;28:

14. Proportion Progression-Free Proportion Progression-Free
PFS in Subpopulations
Treatment-naive
Cytokine-pretreated
1.0
0.0
0.2
0.4
0.6
0.8 5 10 15 20
Months
Proportion Progression-Free
Hazard Ratio = 0.40
95% CI (0.27, 0.60)
P value < 0.001
Median PFS
Pazopanib: mo
Placebo: mo
Pazopanib
Placebo
1.0
0.0
0.2
0.4
0.6
0.8 5 10 15 20
Months
Proportion Progression-Free
Hazard Ratio = 0.54
95% CI (0.35, 0.84)
P value < 0.001
Median PFS
Pazopanib: mo
Placebo: mo
Pazopanib
Placebo
Reproduced with permission from Sternberg CN, et al. J Clin Oncol. 2010;28:1061-8

15. Subgroup analysis of PFS
Baseline Factor
Hazard Ratio (95% CI)
Primary analysis
MSKCC risk: Favorable
MSKCC risk: Intermediate
Female
Male
Age < 65 yrs
Age  65 yrs
ECOG PS 0
ECOG PS 1
0.2
0.4
0.6
0.8
1.0
1.2
Favors pazopanib
Favors placebo
P < by log-rank test for all.

16. Tumor response Pazopanib (n = 290) Placebo (n = 145)
ORR (CR + PR), % Overall population Treatment-naive Cytokine-pretreated
30 32 29
3 4 3
Duration of response, weeks 59 ─

17. Interim analysis of overall survival
1.0
48% of placebo patients received pazopanib after PD
0.8
0.6
Proportion Surviving
Hazard Ratio = 0.73
95% CI (0.47, 1.12)
P value = 0.02 (1-sided)
Median OS
Pazopanib: mo
Placebo: mo
0.4
0.2
Pazopanib
Placebo
0.0 5 10 15 20 25
Months
Patients at risk
Pazopanib
Placebo
O’Brien-Fleming boundary for futility / superiority: P = / (1-sided) 20 20

18. 80 (54%) of placebo patients crossed over
Months 21

19. Overall Survival Is Confounded
Pazopanib was available to patients who progressed on placebo
Early and frequent crossover of placebo patients to pazopanib
Crossover occurred as early as 6 weeks
Prolonged pazopanib treatment following crossover

20. Subsequent Anticancer Therapies
Placebo N = 145
Pazopanib N = 290
Any systemic therapy, % 66 30
Any anti-VEGF/R or mTOR inhibitor, % 63 22
Pazopanib 54
< 1
Sunitinib 8 12
Sorafenib 5 11
mTOR inhibitors 4 3
Any cytokine / other, %
6 / 1
9 / 3
Line(s) of subsequent therapy received, % 1 2 7
≥ 3 23

21. Prolonged Duration of Crossover Treatment
Crossed Over to Pazopanib
N = 80
Randomized to Pazopanib in Pivotal Study
N = 290
Median duration on pazopanib
9.7 months
7.4 months
On pazopanib for ≥ 12 months
43%
32%

22. Post Hoc Analyses to Adjust for Crossover
Two independent analyses were performed to adjust for crossover
Methods make different assumptions; therefore, consistency in results implies robustness
IPCW (Inverse Probability of Censoring Weighted) adjusted for all subsequent treatments
RPSFT (Rank Preserving Structural Failure Time) with assumption that for each day of pazopanib treatment patient lives some portion of a day longer (or shorter)

23. OS Results Adjusted for Crossover
Method
Risk Reduction of Death
HR (95% CI)
P Value
IPCW
50%
0.504
(0.315, 0.762)
0.002
RPSFT
57%
0.43
(0.215, 1.388)
0.172*
* P value is expected to closely match unadjusted results.

24. Safety Update
Pazopanib arm has had a 30% increase in cumulative exposure since final PFS
93 patients (32%) received pazopanib for >12 months
43 patients (15%) received pazopanib for > 24 months
23 patients (8%) received pazopanib for > 36 months
No significant changes to the type, frequency, or severity of adverse events (AEs) were observed
No new safety signals were detected 27

25. Most Common AEs Regardless of Causality (≥ 10%)
Adverse Event
Pazopanib (n = 290), %
Placebo (n = 145), %
All Grs
Gr 3
Gr 4
Any eventa 93 36 9 74 17 6
Diarrhea 52 4
< 1
Hypertension 40 10
Hair color changes 38 3
Nausea 26
Anorexia 24 2 12
Vomiting 21
Fatigue 20 1
Asthenia 14
Hemorrhageb
Abdominal pain 11
Headache 5
Proteinuria
Weight decreased
a 4% of patients in pazopanib arm and 3% of patients in placebo arm had grade 5 AEs.
b Included hemorrhage from all sites. 28

26. Selected Class Effects Associated With VEGFR TKI Inhibitorsa
Pazopanib
(n = 290)
Placebo
(n = 145)
Adverse event, %
All Grades
Grades ≥ 3
Mucositis / stomatitis 9
< 1
Hypothyroidism 7
Hand-foot syndrome 6
Arterial thromboembolic 4 3
Myocardial dysfunction
a AEs with incidence of <10% in the pazopanib arm regardless of causality.

27. Laboratory Abnormalities
Pazopanib (n = 290), %
Placebo (n = 145), %
All Grs
Gr 3
Gr 4
Chemistry labs
ALT 53 11 2 23 1
AST 7
< 1 19
Hyperglycemia 43 33
Hyperbilirubinemia 37 3
Hypophosphatemia 36 5 13
Hypocalcemia 35 26
Hyponatremia 4 24
Hypoglycemia 18
Hypokalemia 10
Hematology labs
Leukopenia 38
Neutropenia 6
Thrombocytopenia 34
Lymphopenia
Anemia 31

28. Health-related quality of life
Global health status / quality of life was compared using 3 pre-specified HRQoL indices
EORTC-QLQ-C30
EQ-5D Index
EQ-5D-VAS
There was no difference between treatment with pazopanib and placebo (P > 0.05) at any of the on-therapy assessment time points

29. Conclusions Study met primary endpoint of improvement in PFS
Final OS result is not significant
Analysis is confounded by early, frequent, and prolonged treatment with pazopanib and other therapies following crossover
Results from Phase II studies are consistent
Analyses to adjust for crossover suggest an OS benefit with pazopanib treatment
No significant changes to the type, frequency, or severity of AEs were observed with longer follow-up
Pazopanib has a well characterised and manageable safety profile

30. Phase III Clinical Trials of mRCC
Published in
Patients, n
Treatment Arms
ORRC/CB%
mPFS(m)
mOS(m)
Motzer et al.1
750
Low/intermediate
Sunitinib
37 (31*)/ 84 (79*)
11.0*
26.4
IFN-α
9 (6*)/66 (55*)
5.0*
21.8
AVOREN 3
649
IFN-α + Bevacizumab
31/77
10.2
23.3
13/63
5.4
21.3
CALGB
732
25.5
8.5
18.3
13.1
5.2
17.4
ARCC 2
626 Intermediate/poor
Temsirolimus
8.6/32.1
5.5
10.9
4.8/15.5
3.1
7.3
Temsirolimus + IFN-α
4.7
8.4
VEG
435
Naïve or 1 cytokine failed
Pazopanib(1L/2L)
30(32/29)
9.2(11.1/7.4)
21.1
Placebo(1L/2L)
3(4/3)
4.2(2.8/4.2)
18.7
TARGET 5
903
cytokine failed
Sorafenib
10/84
17.8
Placebo
2/55
2.8
15.2
RECORD-1 6
410
Sunitinib/sorafenib failed#
Everolimus
1/64
4.6 NR
0/32
1.8
8.8
IFN-α, interferon-alfa; mRCC, metastatic renal cell carcinoma; ORRC/CB, overall response rate/clinical benefit; PFS, progression-free survival.
This table summarizes results from first‑line treatments for metastatic kidney cancer. These are the phase III trials (and a phase II trial) that established these agents and combinations as standard of care. The response rates varied from approximately 2% to 10% with sorafenib or temsirolimus to 25% to 30% with bevacizumab plus interferon to nearly 40% to 50% with sunitinib. Median progression‑free survival times were approximately  months with the experimental (and now standard of care) agents vs 5.0 months for historic interferon.
*Independent central review. # including cytokine, bevacizumab
1. N Engl J Med. 2007;356: ; 2. N Engl J Med. 2007;356: ; 3. Escudier Lancet. 2007;370: ; 4. Rini B ASCO; 5. J Clin Oncol Jul 1010;27(20): ; 6. Lancet ;372(9637):449-56; 7. J Clin Oncol Feb 20;28(6):1061-8 33

31. Pivotal Study Considerations
Pivotal study initiated at time when no other TKI’s available or approved
The pivotal trial for pazopanib demonstrates a favourable risk-benefit profile
No direct comparisons of targeted agents are available for advanced RCC
Indirect comparisons were conducted following discussion with regulatory authorities to place the risk-benefit of pazopanib in the context of approved agents

32. Median PFS (95% CI) Treatment 1st Line 2nd Line Pazopanib (Overall)
9.2 (7.4, 12.9)
Pazopanib
11.1 (7.4, 14.8)
7.4 (5.6, 12.9)
Sunitinib
11 (10, 12)
Bevacizumab/IFN
10.2 (7.8, 11.1)
Sorafenib
5.5 (4.6, 5.7)

33. Pazopanib in the Context of VEGF Targeted Therapies: A Comparison of PFS Hazard Ratios in Phase III Trials
No. of Subjects
Hazard Ratio
Pazopanib (overall)
435
First-line
Pazopanib vs. placebo
233
Sunitinib vs. IFN1
750
Bevacizumab + IFN vs. IFN (Avoren) 2
649
Second-line
Pazopanib vs. placebo
202
Sorafenib vs. placebo3
903
0.2
0.4
0.6
0.8
1.0
1 Motzer RJ, et al. J Clin Oncol 2009a; 27(22):
2 Escudier B, et al. Lancet 2007;370:2103–2111
3 Escudier B, et al. N Engl J Med 2007a; 356(2):
Favours Targeted
Therapy
Favours Control 36 36

34. Overall suggests Pazopanib not inferior to other agents
Indirect comparisons of PFS HR (95% CI) adjusting for differences in control arm
IFN vs MPA
Pazopanib
vs.
Sunitinib
Bev/IFN
(AVOREN)
(CALGB)
0.88
0.76
0.65
0.58
PERCY Quattro trial1
(0.48, 1.19)
(0.41, 1.02)
(0.37, 0.89)
0.72
0.93
0.79
0.70
MRCRCC trial2
(0.55, 1.56)
(0.48, 1.32)
(0.43, 1.16)
Sunitinib vs. Bevacizumab/IFN: HR= 0.75 (95% CI: )3
Overall suggests Pazopanib not inferior to other agents
Confidence intervals from indirect comparisons reflect the inherent variability from including
multiple trials and limitations in sample size
1PERCY Quattro trial, Negrier, Cancer 2007; 2MRCRCC Lancet 1999; 3Mills, BMC Cancer. 2009 37

35. Comparison of selected* AEs of pazopanib vs sunitinib - I
Event(%)
Pazopanib (n=290)
Sunitinib (n=375)
All
G3-4
Altered taste 8 NA 44
<1
Anorexia/decreased appetite 22 2 38
Nausea 26 3
Arthralgia 7 18 1
Asthenia 14 17 4
Fatigue 19 51
Handfoot syndrome 6 20 5
Mucositis/stomatitis 10
20/25
2/1
Rash
Hemorrhage(bleeding) 13 30

36. Comparison of selected* AEs of pazopanib vs sunitinib - II
Event(%)
Pazopanib (n=290)
Sunitinib (n=375)
All
G3-4
Leukopenia 37 78 5
Neutropenia 34 1 72 12
Lymphocytopenia 31 4 59
Anemia 22 2 71
Thrombocytopenia 32 65 8
Decline in ejection fraction NA 10

37. Comparison of selected* AEs of pazopanib vs sunitinib - III
Event(%)
Pazopanib (n=290)
Sunitinib (n=375)
All
G3-4
Hair color change 38
<1 14
Alopecia 8 NA
Hypertension 40 4 24
ALT increased 53 12 46 3
AST increased 7 52 2
Total bilirubin increased 36 19 1
Diarrhea 5
Vomiting 21
Pyrexia
Headache 10 11

38. Patient population: Advanced RCC, treatment naïve (1L)
VEG108844: A Phase III Study to Evaluate Efficacy and Safety of Pazopanib Versus Sunitinib
RANDOMIZE
Stratified by:
KPS,
LDH,
Prior nephrectomy
SCR E N
n=438
Pazopanib 800mg QD continuous dosing OS
PFS
Sunitinib 50mg QD
4 wk on/ 2wk off
n=438
Patient population: Advanced RCC, treatment naïve (1L)
Study Design: Randomized, open-label, non-inferiority
Primary endpoint: PFS
Secondary endpoints: OS, RR, time to response, duration of response, safety/tolerability, QoL
Stratification
KPS: (70/80 v. 90/100)
LDH: >1.5 v. ≤1.5 xULN
Prior Nephrectomy: Y v. N 41

39. RCC Treatment Algorithm: 2010 NCCN
Treatment Status
Patient Status
Therapy (category 1)
Other Options (≥ category 2)
Untreated
Good or intermediate risk
Sunitinib
Pazopanib
Bevacizumab + IFN
High-dose IL-2 Sorafenib Clinical trial Best supportive care
Poor risk
Temsirolimus
Clinical trial
Previously treated
Failed cytokines
Sorafenib
Sunitnib
Bevacizumab
Failed TKI inhibitor
Everolimus
Sorafenib Sunitinib Temsirolimus IFN, high dose IL-2 Bevacizumab Low dose IL-2+-IFN Best supportive care
Preferred: clinical trial
IFN, interferon; IL, interleukin; mTOR, mammalian target of rapamycin; RCC, renal cell carcinoma; VEGFR, vascular endothelial growth factor receptor.
This treatment algorithm helps evaluate patients in terms of previous treatment status as well as risk group and what treatment that they failed previously (eg, cytokines, VEGF-directed, or mTOR‑directed therapy). Several agents with level 1 evidence have been shown in prospective phase III trials to have either progression‑free survival or overall survival benefits.
In addition, there are many treatment approaches with level 2 evidence or greater for benefit in the various settings. Of note, “clinical trial” is listed several times, underscoring some of the uncertainties about which agent may be most beneficial in a certain setting.
Adapted from 2010 NCCN practice guideline

40. Overall Summary
Very Exciting Time in systemic treatment of metastatic RCC
Many new active drugs
Clear Palliative Benefit
Benefit Clearest in Clear Cell Tumours with Intermediate prognosis
? Potential benefit for immunotherapy in good prognosis patients first
Should not forget HDIL2 for selected patients
May be the potential to combine new drugs for greater efficacy
Role of Nephrectomy in Metastastic RCC needs re-evaluation
? Needed at all
? Neoadjuvant Therapy Beneficial
Place in Adjuvant therapy for high risk patients remains to be established