1. ASCO 2012
Genito-Urinary cancers
Bertrand TOMBAL, MD, PhD
Cliniques universitaires Saint-Luc
Bruxelles

2.  Prostate
 Kidney
 And what’s left….
 Very few academic trials
 Many pharma sponsor “updated” trials or
post-marketing trials.
 “If you can convince, confuse”

4.  Prostate
 Kidney
 And what’s left….

5. Steve, 72 y.o, PSA 375 ng/ml, multiple bone metastases, T/degarelix 120/80 mg
18 mm
+ 6 m.
13 mm
Courtesy of B.Tombal and F. Lecouvet, CUSL, UCL, Brussels

7. In conclusion, IAD is currently
widely offered to patients with
PCa in various clinical settings,
and its status should no longer be
regarded as investigational (LE: 2).

8. Calais da Silva(1) Klotz(2) Salonen((3))
Loc. adv. (70%) Loc. adv (50%)
Stage Rising PSA
Metastatic (30%) Metastatic (50%)
N enrolled 766 852
N randomized 626 1386 554
Progression IAD/CAD
N 127/107
0.80
HR 0.81 1,08
(0.67-0.98,
(95% CI, p) (0.63–1.05, 0.11) (0.90-1.29, 0.43)
0.024)
Death IAD/CAD
N 169/170 268/256 186/206
OS (years) 8.8/9.1 3.7/3.8
HR 0.99 1.02 1,15 (0.94-1.40)
(95% CI, p) (0.80–1.23, 0,84) 0.86-1.21;0.009 0.17
Death/PCa Increase IAD Increase IAD
1. SEUG/EORTC, Eur Urol. 2009 Jun;55(6):1269-77.
2. NCIC CTG PR.7. J Clin Oncol 29: 2011 (suppl 7; abstr 3)
3. Finnprostate study VII, J Urol. 2012 Jun;187(6):2074-81.

9. Intermittent (IAD) versus continuous androgen deprivation (CAD) in
hormone sensitive metastatic prostate cancer (HSM1PC) patients (pts):
Results of S9346 (INT-0162), an international phase III trial.
Hussain et al., J Clin Oncol 30, 2012 (suppl; abstr 4)
 3040 hormone naïve M1 PCa pts with performance status (PS) 0-2, PSA ≥ 5
ng/ml were treated with 7 months (m) of goserelin + bicalutamide.
 1535 pts achieving PSA ≤4 ng/ml on m 6 and 7 were randomized to CAD or IAD.
 Primary objective: To assess if OS with IAD is non-inferior to CAD
 Median FUp 10 y.
Characteristic of the patients at randomization
IAD (770) CAD (765)
Age (yrs) Median (range) 70 (39,97) 70 (39,92)
Disease extent Extensive 49% 47%
Minimal 51% 53%
Visceral disease 7.1% 6.3%
Bone Pain Present 28% 28%
Gleason score ≥8 27% 27%

10. Overall survival
10 years survival rate
HR (IAD/CAD) = 1.09 (95% CI 0.95, 1.24).

13. Steve, 72 y.o, PSA 375 ng/ml, multiple bone metastases, T/goserelin + CPA 6 wks.
+ 6 m.
Courtesy of B.Tombal and F. Lecouvet, CUSL, UCL, Brussels

14. Neoadjuvant androgen pathway suppression prior to
prostatectomy.
Elahe A. Mostaghel al., J Clin Oncol 30, 2012 (suppl; abstr 4520)
 35men with localized PCa treated for 3 months prior to prostatectomy with
 Goserelin (G), and 5α-reductase inhibiteur dustasteride (D) 3.5 mg QD, antiandrogen
bicalutamide (B) 50 mg QD, and androgen synthesis inhibitor ketoconazole (K) 200 mg TID

15. Neoadjuvant androgen pathway suppression prior to
prostatectomy.
Elahe A. Mostaghel al., J Clin Oncol 30, 2012 (suppl; abstr 4520)
testosterone DHT
Treatment
ng/g (SD) nM ng/g (SD) nM
Untreated 0.21 (0.08) 0.7 4.38 (0.99) 15
G+B 0.07 (0.08) 0.3 0.92 (0.49) 3.2
G+D 0.32 (0.17) 1.1 0.02 (0.02) 0.06
G+B+D 0.33 (0.23) 1.1 0.04 (0.07) 0.15
G+B+D+K 0.24 (0.23) 0.8 0.02 (0.02) 0.08

16. Neoadjuvant androgen pathway suppression prior to
prostatectomy.
Elahe A. Mostaghel al., J Clin Oncol 30, 2012 (suppl; abstr 4520)
G+B G+D G+B+D G+B+D+K
Nadir PSA < 0.2 71% 27% 90% 77%
Pathologic response
CR 0 0 10% 8%
Near CR (≤ 0.2cc) 0 18% 20% 23%

17. From Ryan and Tindall, J Clin Oncol 29:3651-3658. 2011

18. Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate
(LHRHa) on PSA, pathological complete response (pCR), and near pCR
in localized high-risk prostate cancer (LHRPC): Results of a randomized
phase II study.
ME Taplin al., J Clin Oncol 30, 2012 (suppl; abstr 4521)
 58 men ≥ 3 positive biopsies and Gleason ≥ 7 (4+3), T3, PSA ≥ 20 ng/mL or
PSA velocity > 2 ng/mL/year.
 First 12 wks randomized to LHRHa or LHRHa/AA/prednisone (P) 5mg qd.
 After 12 wks and a PBx 12 more wks of LHRHa/AA/P followed by RP

19. Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate
(LHRHa) on PSA, pathological complete response (pCR), and near pCR
in localized high-risk prostate cancer (LHRPC): Results of a randomized
phase II study.
ME Taplin al., J Clin Oncol 30, 2012 (suppl; abstr 4521)
12 wks AA/ 24 wks AA/
p
24 wks LHRHa 24 wks LHRHa
Pathological CR 4% 10% 0.6120
Near CR
11% 24% 0.2992
(≤5mm)
pT3 59% 48%
Positive nodes 11% 28%

20. Identifying the best candidate for radical prostatectomy among patients with
high-risk prostate cancer.
Briganti A, et al. Predict consortium. Eur Urol. 2012 Mar;61(3):584-92.
 “Very high-risk cancers localized
to the prostate are rarely cured
by prostatectomy alone,” Dr.
Taplin said. “Therapies that
combine surgery with older
androgen-inhibiting drugs have
not historically improved
outcomes. This unmet need has
given rise to efforts to develop
new drugs capable of more
completely reducing androgen
levels within the prostate tumors

22. Available options in CRCP
COU-AA-302 Docetaxel
(Abiraterone)
Abiraterone acetate +P
PREVAIL Cabazitaxel
(enzalutamide) Enzalutamide (MDV3100)
Metastasis Symptoms
CRPC
67000+
Sipuleucel-T alpharadin-T

23. Available options in CRCP
Increase in Relative
Hazard ratio
median reduction in
(95% CI; P-value)
survival risk of death
0.65
Abiraterone/P vs. placebo/P1 3.9 months 35%
(0.540.77; P<0.001)
0.63†
MDV3100 vs. placebo 2* 4.8 months 37%
(P<0.0001)
Docetaxel(q3w)/P vs. 0.76
2.4 months 24%
Mitoxantrone/P3 (0.620.94; P=0.009)
0.70
Cabazitaxel/P vs. mitoxantrone/P4 2.8 months 30%
(0.590.83; P<0.0001)
0.78
Sipuleucel T vs. placebo5 4.1 months 22%
(0.61 to 0.98; P:0.03)
0.70
Alpharadin vs. placebo6 2.8 months 31%
(0.55-0.88; P:0.00185)
P: prednisone
1. de Bono, et al. N Engl J Med 2011;364:1995–2005; 2. Medivation Press Release AFFIRM 3rd November 2011; study stopped early following
favourable interim results 95 % CI not stated; 3. Tannock, et al. N Engl J Med 2004;2351:1502–12; 4. de Bono, et al. Lancet 2010; 76:1147–545
; 5. Kantoff, et al. N Engl J Med 2010;363:411–22; 6. Bayer Press Release ALSYMPCA 24th September 2011

24. Interim analysis (IA) results of COU-AA-302, a randomized, phase III study
of abiraterone acetate (AA) in chemotherapy-naive patients (pts) with
metastatic castration-resistant prostate cancer (mCRPC).
Ryan et al., J Clin Oncol 30, 2012 (suppl; abstr LBA4518)
Efficacy endpoints
Patients AA 1000 mg daily
RANDOMIZED 1:1
Co-primary
Progressive chemo- Prednisone 5 mg BID
 rPFS by central review
(Actual= 546)
naïve CRCP patients  OS
N=1088 Secondary
Asymptomatic or mildly  Time to opiate used
symptomatic Placebo daily  Time to
Prednisone 5 mg BID chemotherapy
(Actual= 542)  Time to ECOG-PS
deterioration
 TTPP
Phase 3 multicenter, randomized, double-blind, placebo-controlled study
conducted at 151 sites in 12 countries: USA, Europe, Australia, Canada
Stratification by ECOG performance status 0 vs 1

25. COU-AA-302 Statistical Plan
Overall Assumption rPFS OS
α 0.01 0.04
Power 91% 85%
HR 0.67 0.80
Expected events 378 773
Planned OS Analysis
1Q10 2Q10 3Q10 4Q10 1Q11 2Q11 3Q11 4Q11 1Q12 2Q12 3Q12 4Q12
IA1 IA2 IA3
(~15% OS Events) (40% OS Events) (55% OS events)
116 Events 311 Events 425 Events
 < 0.0001  = 0.0005  = 0.0034
IA = interim analysis. Ho, HR=1.0.
Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

26. AA +P Placebo + P
Population characteristics
(n=546) (n=542)
Median age, years (range) 71(44-95) 70 (44-90)
Median time from initial diagnosis 5.5 5.1
Median PSA (ng/ml) 42.0 37.7
Median alkaline phosphatase (IU/L) 93.0 90.0
Median hemoglobin (g/dl) 13.0 13.1
Gleason ≥8 at initial diagnosis 53.9% 50.0%
Extent of disease
Bone metastases 83% 80%
> 10 bone metastases 48% 47%
Soft tissue or nodes 49.1% 50%
Pain (BPI short form)
0-1 66% 64%
2-3 32% 33%
Ryan et al., J Clin Oncol 30, 2012 (suppl; abstr LBA4518)

27. Ryan et al., J Clin Oncol 30, 2012 (suppl; abstr LBA4518)

28. Ryan et al., J Clin Oncol 30, 2012 (suppl; abstr LBA4518)

29. Other secondary endpoints
AA +P Placebo + P
Median Median HR(95%CI) p
(months) (months)
0.69 (0.57-
Time to opiate use NR 23.7 0.0001
0.0.83)
Time to chemotherapy 0.58 (0.49-
25.2 16.8 <0.0001
initiation 0.69)
Time to ECOG PS 0.82 (0.71-
12.3 10.9 0.0053
deterioration 0.94)
0.49 (0.42-
Time to PSA progression 11.1 5.6 <0.0001
0.57)
Ryan et al., J Clin Oncol 30, 2012 (suppl; abstr LBA4518)

30. Subsequent therapies
AA +P Placebo + P
(n=546) (n=542)
N(%) N(%)
No. with selected subsequent 242 (44.3) 327 (60.3)
therapy for CRPC
Docetaxel 207 (37.9 287 (53.0)
Cabazitaxel 45 (8.2) 53 (9.6)
Ketoconazole 39 (7.1) 63 (11.6)
Sipuleucel-T 27 (4.9) 24 (4.4)
Abiraterone acetate 26 (4.8) 54 (10.0)
Ryan et al., J Clin Oncol 30, 2012 (suppl; abstr LBA4518)

31. Serologic and clinical responses
AA +P Placebo + P
(n=546) (n=542) RR(95%CI) p
N(%) N(%)
PSA decline ≥50% 62% 24% NA <0.0001
N=220 N=218
2.273
RECIST defined objective
36% (1.591- < 0.0001
response
3.247)
Complete response 11% 4%
Partial response 25% 12%
Stable disease 61% 39%
Progressive disease 2% 15%
Ryan et al., J Clin Oncol 30, 2012 (suppl; abstr LBA4518)

32. Side-Effects
AA +P Placebo + P
(n=546) (n=542)
% %
All grades Grade 3/4 All gardes Gradde 3/4
Fatigue 39 2 34 2
Fluid retention 28 0.7 24 1.7
Hypokalemia 17 2 13 2
Hypertension 22 4 13 3
Cardiac disorders 19 6 16 3
Atrial fibrillation 4 1.3 5 0.9
ALT increased 12 5.4 5 0.8
AST increased 11 3 5 0.9
Ryan et al., J Clin Oncol 30, 2012 (suppl; abstr LBA4518)

33. Abiraterone pre-chemotherapy,
a true paradigm shift ?
 Using PFS in Prostate
Cancer
 A risky IDMC decision
 What about the overall
results

34. Prerequisites for accepting PSA as a valid
co-primary
Clearly defined and specified in advance YES
Capable of being ascertained as completely as
YES
possible
Measured in the same way for all subjects YES
Capable of unbiased assessment YES
Reflect tangible clinical benefit? Unknown

35. COU-AA-302 Statistical Plan
Price You Pay:
Biased Estimate of Clinical Benefit

36. Adrenals androgens inhibitor
Patient
% > 50% PSA Duration
Total Drug s
response (months)
(n)
Ketoconazole (400 mg tid) +
Small et al., 19971 50 63 3.5
hydrocortisone
Ketoconazole (400 mg tid) +
Small et al.,19972 20 55 8.5
hydrocortisone + AAW
Ketoconazole (400 mg tid) +
Small et al., 20043 128 27 8.6
hydrocortisone + AAW
Ketoconazole (200 mg tid) +
Harris et al, 20024 28 46 7.5
hydrocortisone
Ketoconazole (400 mg tid) +
Millikan et al., 20015 45 31 NA
hydrocortisone + AAW
Ketoconazole (400 mg tid) + dutasteride
Taplin et al., 20096 57 56 20
(0,5 mg sid) + hydrocortisone
Ryan et al., 2012 Abiraterone AA + P 546 62% 11,1
% PSA response: % of patients achieving 50% decrease in PSA; AAW = anti-androgen withdrawal
1) J
Urol. 1997 157(4):1204-7; 2) Cancer 1997 80(9):1755-9; 3) JCO 2004 22(6):1025-33; 4) J Urol. 2002
168(2):542-5; 5) Urol Oncol. 2001 6(3):111-115; 6) Clin Cancer Res. 2009 15(22):7099-105: 7) JNCI 1994
86(3):222-7; 8) Anticancer Drugs 2004 15(9):843-7.

37. Available options in CRCP
Increase in Relative
Hazard ratio
median reduction in
(95% CI; P-value)
survival risk of death
0.65
Abiraterone/P vs. placebo/P1 3.9 months 35%
(0.540.77; P<0.001)
0.63†
MDV3100 vs. placebo 2* 4.8 months 37%
(P<0.0001)
0.76
Docetaxel(q3w)/P vs. Mitoxantrone/P3 2.4 months 24%
(0.620.94; P=0.009)
0.70
Cabazitaxel/P vs. mitoxantrone/P4 2.8 months 30%
(0.590.83; P<0.0001)
0.78
Sipuleucel T vs. placebo5 4.1 months 22%
(0.61 to 0.98; P:0.03)
0.70
Alpharadin vs. placebo6 2.8 months 31%
(0.55-0.88; P:0.00185)
0,75
Abiraterone + P vs.P ? NR in AA 25%
(0.61-0.93); P 0.0097
P: prednisone
1. de Bono, et al. N Engl J Med 2011;364:1995–2005; 2. Medivation Press Release AFFIRM 3rd November 2011; study stopped early following
favourable interim results 95 % CI not stated; 3. Tannock, et al. N Engl J Med 2004;2351:1502–12; 4. de Bono, et al. Lancet 2010; 76:1147–545
; 5. Kantoff, et al. N Engl J Med 2010;363:411–22; 6. Bayer Press Release ALSYMPCA 24th September 2011

38. Primary, secondary, and quality-of-life endpoint results from the phase III
AFFIRM study of MDV3100, an androgen receptor signaling inhibitor.
J. de Bono et al., J Clin Oncol 30, 2012 (suppl; abstr 4519)

39. Primary, secondary, and quality-of-life endpoint results from the phase III
AFFIRM study of MDV3100, an androgen receptor signaling inhibitor.
J. de Bono et al., J Clin Oncol 30, 2012 (suppl; abstr 4519)
Quality of life response by FACT-P

40. Side effects of interest
All grades Grade ≥ 3
MDV3100 Placebo MDV3100 Placebo
Fatigue 33.6 29.1 6.3 6.3
Cardiac disorders 6.1 7.5 0.9 0.9
Myocardial infarction 0.3 0.5 0.3 0.3
LFT abnormalities 1.0 1.5 0.4 0.4
Seizure 0.6 0.0 0.6 0.6

41. Primary, secondary, and quality-of-life endpoint results from the phase III
AFFIRM study of MDV3100, an androgen receptor signaling inhibitor.
J. de Bono et al., J Clin Oncol 30, 2012 (suppl; abstr 4519)

42.  Prostate
 Kidney
 And what’s left….

43. New agent timelines
pazopanib(6)
Sorafenib(1)
Sunitinib(2)
Everolimus(4)
2005 2006 2007 2008 2009 2010 2011 20012
Axitinib)
temsirolimus(3)
Bevacizumab
+Ifα(5)
1. Motzer RJ, et al. N Engl J Med. 2007;356(2):115-124. 3. Hudes G, et al. N Engl J Med. 2007;356(22):2271-2281. 4. Escudier B, et al. Lancet.
2007;370(9605):2103-2211. 5. Rini BI, et al. J Clin Oncol. 2008;26(33):5422-5428. 6. Motzer RJ, et al. Lancet. 2008;372(9637):449-456. 7.
Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068.

44. Results 1st line targeted therapies
Median PFS Median OS
Agent N ORR(%)
months months
47 vs. 12 11,0 vs. 5 26,4 vs. 21,8
Sunitinib vs. INFα(1,2) 750
P< 0,001 P< 0,001 P=0.051
8,6 vs. 4.8 5,5 vs. 3,1 10,9 vs. 7,1
Temsirolimus vs. INFα(3) 626
NS P<0,0001 P=0,008
INFα 19,8
31 vs. 13 10,2 vs 5,4
Bevacizumab + INFα vs. INFα(4) 649 B/INFα NR
P= 0,0001 P=0,0001
P 0,0267
26 vs. 13 8,5 vs. 5,2
Bevacizumab + INFα vs. INFα(5) 732 NR
P<0,0001 P<0,0001
5,7 vs 5,6
Sorafenib vs INFα(6) 189 5 vs. 9 NR
P=0,504
30 vs. 3 9,2 vs 4,2 21,1 vs. 18,7
Pazopanib vs. placebo 435
P<0,001 P<0,001 P 0,02
1. Motzer RJ et al. NEJM 2007; 2 Motzer RJ et al. JCO 2007; 3. Hudes et al. NEJM 2007; 4. Escudier et al.
Lancet 2007; 5. Rini et al. JCO 2008; Escudier et al. JCO 2006; Sternberg C JCO 2010

45. Results 2nd line targeted therapies
Median PFS Median OS
Agent ORR(%)
months months
10 vs. 2 5,5 vs. 2,8
Sorafenib vs. placebo(1) 17,8 vs 15,2
P< 0,001 P< 0,001
5 vs. 0 4,9 vs. 1,9
Everolimus vs. placebo(2) 14,8 vs. 14,4
NS P<0,0001
6,7 vs. 4,7
Axitinib vs. sorafenib(3)
P < 0.001
1. B. Escudier et al., NEJM 2007; 2. RJ Motzer et al., The Lancet
2008 3 BI Rini et al., The Lancet 2011

46. New agent timelines
pazopanib(6)
Sorafenib(1)
Sunitinib(2)
Everolimus(4) tivozanib
2005 2006 2007 2008 2009 2010 2011 20012
Axitinib)
temsirolimus(3)
Bevacizumab
+Ifα(5)
1. Motzer RJ, et al. N Engl J Med. 2007;356(2):115-124. 3. Hudes G, et al. N Engl J Med. 2007;356(22):2271-2281. 4. Escudier B, et al. Lancet.
2007;370(9605):2103-2211. 5. Rini BI, et al. J Clin Oncol. 2008;26(33):5422-5428. 6. Motzer RJ, et al. Lancet. 2008;372(9637):449-456. 7.
Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068.

47. Tivozanib versus sorafenib as initial targeted therapy for patients with
advanced renal cell carcinoma: Results from a phase III randomized,
open-label, multicenter trial.
R. Motzer et al., J Clin Oncol 30, 2012 (suppl; abstr 4501)
Key eligibility criteria
 Advanced RCC Tivozanib 1.5 mg/day po
RANDOMIZED 1:1
 Clear cell histology 3 weeks on/1 week off
 Measurable disease N=260
 Prior nephrectomy
 0-1 prior therapy but
no VGEF or mTOR Sorafenib 400mg po bid
therapy Continuous
 ECOG PS 0-1 N=257
TIVO-1 Phase 3 superiority of tivozanib vs. sorafenib as first-line targeted therapy
for mRCC

50. PFS assessment
Median PFS (95%CI)
Tivozanib (n=260) Sorafenib (n=257) HR p
Independen 11.9 9.1
0.797 0.042
t (9.3-14.7) (7.3-9.5)
14.7 9.6
Investigator 0.722 0.003
(10.4-16.6) (9.0-11.0)
Tivozanib (n=260) Sorafenib (n=257)
Best overall response, %
Complete response 1 1
Partial response 32 23
Stable disease 52 65
Progressive disease 13 7
ORR 33 23
95%CI 27-39 18-29
p 0,014

51. Treatment emergent AEs
Tivozanib (n=259,%) Sorafenib (n=257,%)
All grade Grade 3(4) All grade Grade 3(4)
Hypertension 44 24(2) 34 17(<1)
Diarrhea 22 2 32 6
Dysphonia 21 0 5 0
Fatigue 18 5 16 4
Weight loss 17 <1 20 3
Asthenia 15 4(<1) 16 3
Hand-foot S. 13 2 54 17
Back pain 14 3 7 2
Nausea 11 <1 8 <1
Dyspnea 10 2 8 2
Decrease appetite 10 <1 9 <1
Alopecia 2 0 21 0

52. Cardiac safety analysis for a phase III trial of sunitinib (SU) or sorafenib
(SO) or placebo (PLC) in patients (pts) with resected renal cell carcinoma
(RCC).
NB Haas et al., J Clin Oncol 30, 2012 (suppl; abstr 4500)
ECOG 2805 (ASSURE)
Stratify Arm A Sunitinib daily
R Risk by TNM for 4 of 6 weeks for 1
E N Stage/Grade year
R
G E Intermediate Risk
Non- A
Metastatic I P High Risk N
Kidney S H Histologic
Cancer D Arm B Sorafenib
T R Subtype
That meets O daily continuously
R E Clear cell
radiologic M for 1 year
A C Non-clear cell
criteria to I
be clinically T T Performance Z
 T1bNany I O status
(resectable) E
O M Surgery
M0 disease Arm C Placebo
N Y Daily
Open vs
1 laparoscopic continuously for
1 year

53.  To determine if patients treated with sunitinib or sorafenib experience
clinically significant decreases in left ventricular ejection fraction.
 Primary endpoint of interest was LVEF decline within 6 months, defined as
LVEF below the institutional lower limit of normal, where the drop is at least
16% from baseline.
MUGA MUGA MUGA MUGA
Treatment with Sorafenib, Sunitinib or Placebo
12 mo
3 mo 6 mo
Randomization End of study
MUGA
Completion of therapy

54. Frequency of clinically significant congestive
heart failure (CHF)
Timepoint Sunitinib Sorafenib Placebo
2 Months - 1 (16%) -
3 Months 6 (16 to 21%) 1 (21%) 2 (19 & 32%)
4 Months 2 (23 & 24%) - -
6 Months 1 (18%) 5 (16 to 19%, 37%) 3 (17 to 19%)
Pts Assessed 397 394 502
Events 9 7 5
Rate 2.3% 1.8% 1.0%
90% CI 1.2 – 3.9% 0.8 – 3.3% 0.4 – 2.1%

55. Patients with Other Events
Other LVEF events defined as one of the following: LVEF decline >=16%
occurring after 6 months, or a grade 2 or 3 left ventricular systolic or
diastolic dysfunction reported via AdEERS or on a case report form
Type of Event Sunitinib Sorafenib Placebo
LVEF decline >=16% 5 2 3
Grade 2 LV Event 5 6 8
Grade 3 LV Event 2 3 -
Pts Assessed 510 507 572
Events (Combined) 21 18 16
Rate 4.3% 5.3% 3.7%
90% CI 2.8 – 5.9% 2.3 – 5.2% 1.8 – 4.2%

56. Axitinib for first-line metastatic renal cell carcinoma (mRCC): Overall
efficacy and pharmacokinetic (PK) analyses from a randomized phase II
study.
B.Rini et al., J Clin Oncol 30, 2012 (suppl; abstr 4503)

57. Axitinib for first-line metastatic renal cell carcinoma (mRCC): Overall
efficacy and pharmacokinetic (PK) analyses from a randomized phase II
study.
B.Rini et al., J Clin Oncol 30, 2012 (suppl; abstr 4503)
 Primary objective To compare the objective response rate
(ORR) in patients receiving axitinib plus dose titration (Arm
A) vs. axitinib plus placebo (Arm B)80% power to detect ≥
25% improvement in ORR
 Secondary objectives
 Progression-free survival
 Axitinib plasma pharmacokinetics
 Blood pressure measurements
…

58. Clinical Efficacy of Axitinib for First-
line Metastatic RCC
Arm C Arm A+B
Total Not eligible for Eligible for
(n=213) dose titration dose titration
(n=91) (n=112)
mPFS (months) 14.5 16.4 14.5
(95% CI) (11.5-17.4) (11.0-19-0) (11.0-19.3)
ORR 48% 59% 43%
(95%CI) (41%-55%) (49%-70%) (34%-53%)

62. Patient preference between pazopanib (Paz) and sunitinib (Sun): Results
of a randomized double-blind, placebo-controlled, cross-over study in
patients with metastatic renal cell carcinoma (mRCC)—PISCES study, NCT
01064310.
B.Escudier et al., J Clin Oncol 30, 2012 (suppl; abstr CRA4502)
Pazopanib Sunitinib
800 mg once daily, 50 mg 4/2,
10 weeks 10 weeks
Patient choice
Randomisation of treatment
to progression
n=169
Sunitinib Pazopanib
50 mg 4/2, 800 mg once daily,
10 weeks 10 weeks
Period 1 2-week washout Period 2 Off study
Double-blind
0 10 Time (weeks) 12 22
 1:1 randomisation, Patients on sunitinib received placebo during 2-week ‘off-
period’

63. Assessment: Questionnaire time points1
Period 1 Washout Period 2
Pazopanib Sunitinib Placebo Sunitinib
Sunitinib Placebo Sunitinib Pazopanib
Weeks
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Patient preference: End of study
EQ-5D: Baseline, washout, end of study
FACIT-Fatigue: Every 2 weeks
SQLQ: Every 2 weeks

64. Primary endpoint: Patient preference for study
treatments (Primary analysis population) 1
100
90% CI (for difference): 37.0-61.5; p<0.001
90
80
70
Patients (%)
60
70%
50 (n=80)
40
30
20 8%
10 22% (n=9)
(n=25)
0
Preferred pazopanib Preferred sunitinib No preference

65. Most common adverse events (>10%; cont’d) 1
Adverse event Pazopanib (n=153) Sunitinib (n=148)
All grades Grade 3 Grade 4 All grades Grade 3 Grade 4
Hair colour changes 17% 0 0 14% 0 0
Mucosal inflammation 16% 0 0 22% 1% 0
Rash 8% <1% 0 11% 0 0
Dysgeusia 16% 0 0 27% 0 0
Headache 14% <1% 0 11% 0 0
Hypertension 23% 8% 0 26%) 9% 0
Epistaxis 5% 0 0 11% <1% 0
Decreased appetite 20% 0 0 19% <1% 0
• Compared with sunitinib, pazopanib was associated with a lower incidence of asthenia, stomatitis
and hand-foot syndrome, and a greater incidence of diarrhoea
Note: The electronic case report form collected relationship to IP without distinguishing which treatment period the
adverse event (AE) was related to. An AE which spanned more than one period was considered to be an AE for the
period during which the AE increased in grade. There is only one label for relationship for the whole event. As such,
it is not always possible to determine which period treatment the AE was related to.
1. GSK data on file.

66. Which reasons influenced their choice?1
Better quality of life
Less fatigue
Less taste change
Less mucositis/stomatitis
Less nausea/vomiting
Pazopanib preferred (n=80)
Less hand-foot syndrome
Sunitinib preferred (n=25)
Better appetite
Less stomach pain
Less diarrhoea
Other
Less hair colour change
0 10 20 30 40 50 60 70
Number of patients
1. Escudier B, et al. ASCO 2012 oral presentation; abstract 4502.

67. Patient preference, a key driver of treatment
choice ?
 Assumption of
equivalent efficacy
 Continuous vs.
intermittent treatment

68.  Prostate
 Kidney
 And what’s left….