Genitourinary Oncology ASCO 2009

Toni K. Choueiri, MDDana-Farber Cancer Institute

Harvard Medical SchoolBoston, Massachusetts

U.S.A.

Bevacizumab plus Interferon-alpha versus Interferon-alpha Monotherapy in Patients with Metastatic Renal Cell Carcinoma:

Results of Overall Survival for CALGB 90206

Brian I. Rini1, Susan Halabi 2,3, Jonathan E. Rosenberg4, Walter M. Stadler5, Daniel A.Vaena6, James N. Atkins7, Joel Picus8, Piotr Czaykowski9, Janice

Dutcher10 and Eric J. Small4

1. Cleveland Clinic Taussig Cancer Institute, Cleveland, OH2. Department of Biostatistics / Bioinformatics, Duke University Medical Center, Durham, NC3. CALGB Statistical Center, Durham, NC 4. University of California San Francisco, San Francisco, CA5. University of Chicago Medical Center, Chicago, IL6. University of Iowa, Iowa City, IA7. Southeast Cancer Control Consortium Inc.8. Washington University, St. Louis, MO9. University of Manitoba, Winnipeg, Manitoba; NCI Canada, Kingston, ON, Canada 10. New York Medical College, NY, NY; Eastern Cooperative Oncology Group, Boston, MA

Background

• Bevacizumab (BEV) plus interferon alpha (IFN) demonstrated a superior objective response rate and progression-free survival (PFS) versus IFN monotherapy in metastatic RCC patients in 2 phase III trials1,2

• The primary objective of CALGB 90206 was to compare overall survival (OS) for metastatic RCC patients receiving BEV plus IFN or IFN monotherapy

1. Escudier B et al. Lancet, 20072. Rini BI et al. JCO 2008

Study Schema

RANDOMIZE

IFNA 9 MU TIW

IFNA 9 MU TIW +

Bevacizumab 10 mg/kg IV

q d1 and d15

STRATIFY

• Patients stratified for nephrectomy status (yes/no) and MSKCC risk group (0 risk factors vs. 1-2 risk factors vs. 3 or more risk factors)*

Eligibility Criteria• Confirmed metastatic RCC with a

component of clear cell histology• Karnofsky PS ≥ 70%• Measurable or evaluable disease

(by RECIST)• No prior systemic treatment• Adequate end-organ function• No CNS metastases• BP < 160/90 with meds• No DVT within 1 year or arterial

thrombotic event within 6 months• Prior nephrectomy not required

* Motzer R et al., JCO 20(1), 2002

• The primary endpoint was OS, defined as the time from randomization to death due to any cause

• The trial was designed with 86% power to detect a hazard ratio (HR) of 0.76 (assumed median OS improvement 13 to 17 months), assuming a two-sided type I error of 0.05

• The primary analysis was an intent-to-treat approach using the stratified log-rank statistic, and the present analysis was based on the target number of 588 deaths

• Secondary endpoints: Progression-free survival (PFS), objective response rate (RECIST criteria), safety

Statistical Methods

Patient DispositionPatients consented

(n=732)

IFNA monotherapy (n=363)

Discontinued Treatment (n=346)

PD / Death (n=218)Toxicity (n=66)

Refused further tx (n=33)Other (n=24)

Lost to follow-up (n=4)D/C after achieving CR (n=1)

Analyzed (n=363)

Bevacizumab+ IFNA (n=369)

Discontinued Treatment (n=349)

PD / Death (n=200)Toxicity (n=80)

Refused further tx (n=40)Other (n=25)

Lost to follow-up (n=2)D/C after achieving CR (n=2)

Analyzed (n=369)

Never started tx (n=13)

Never started tx (n=3)

Baseline Demographics and Clinical Characteristics (n=732)Bevacizumab plus

IFN (n=369)IFN monotherapy

(n=363)

Sex – no. (%) Male Female

269 (73%)100 (27%)

239 (66%)124 (34%)

Median Age, years (inter-quartile range)

61 (56-70)

62 (55-70)

ECOG performance status – no. (%) 0 1 2

230 (62%)132 (36%)

7 (2%)

227 (62%)133 (37%)

3 (1%)

Previous nephrectomy – no. (%) 312 (85%) 308 (85%)

Previous radiation therapy – no. (%) 35 (9%) 38 (10%)

Common Sites of Metastases Lung Lymph node Bone Liver

252 (68%)130 (35%)104 (28%) 74 (20%)

254 (70%)129 (36%)109 (30%) 73 (20%)

Number of adverse risk factors 0 (favorable) 1-2 (intermediate) ≥ 3 (poor)

97 (26%)234 (64%) 38 (10%)

95 (26%)231 (64%) 37 (10%)

Time(months)

Ove

rall

Sur

viva

l (pr

obab

ility

) IFN BEV/IFNStratified log-rank p=0.069

Kaplan-Meier Overall Survival Curves by Treatment Arm

0 6 12 18 24 30 36 42 48 54 60

0.0

0.2

0.4

0.6

0.8

1.0

363 286 221 177 148 118 98 64 37 10 1369 314 242 190 160 139 116 94 42 17 2

IFNBEV/IFN

Number of Patients at Risk

---- BEV/IFN: Median OS 18.3 months

IFN: Median OS 17.4 months

Kaplan-Meier Overall Survival by Treatment Arm

Overall Survival by MSKCC Risk Status*

Median OS (months)

Risk Group %BEV/IFN IFN HR

Favorable (0 risk factors) 26 32.5 33.5 0.89

(p = 0.524)

Intermediate (1-2 risk factors) 64 17.7 16.1 0.87

(p = 0.174)

Poor (≥ 3 risk factors) 10 6.6 5.7 0.76

(p = 0.25)

* Motzer R et al., JCO 20(1), 2002

Second-line Therapy Received in Patients who Discontinued Protocol Therapy for Any Reason Other Than Death

Bevacizumab + IFN (n=351)

IFN monotherapy (n=350)

Percentage of patients receiving any second-line therapy

54% 62%

VEGF-targeted therapy 37% 46%

Bevacizumab 6% 14%

Chemotherapy 18% 14%

Investigational therapy 11% 18%

Cytokines 13% 14%

* Fifty-six percent of patients overall received at least one subsequent systemic therapy

Median OS (months) according to treatment arm and subsequent therapy

Bevacizumab + Interferon

Interferon Total(unstratified log-rank p comparing arms)

Stratified HR

Received 2nd-line

therapy

(n=408)

31.4 26.8 28.2(p=0.079)

0.80 (p=0.055)

Did not receive 2nd-line therapy

(n=324)

13.1 9.1 10.2(p=0.059)

0.82 (p=0.108)

Total 18.3 17.4 18.1 (p=0.097)

0.86 (p=0.069)

Variable

Received non protocol treatment* (n=408)

Did not receive non protocol treatment (n=324 )

p-value

Gender

Male

Female

70%

30%

79%

31% 0.687

Median Age, years

(inter-quartile range)

61

(55-69)

62

(56-71) 0.019

ECOG PS

0

1

2

67%

32%

1%

56%

42%

2%

0.012

Previous nephrectomy 88% 80% 0.004

Previous XRT 12% 8% 0.064

Sites of Metastases

Lung

Lymph node

Bone

Liver

70%

35%

29%

17%

68%

36%

29%

24%

0.572

0.756

0.935

0.020

MSKCC risk group

0 (favorable)

1-2 (intermediate)

≥ 3 (poor)

29%

64%

6%

22%

62%

15%

<.001

Baseline characteristics of patients according to subsequent therapy

* There was no difference in baseline characteristics for patient who received subsequent therapy by treatment assignment

Variable

NephrectomyYes (N = 620)No (N =112)

MSKCC0 (N = 192)1 (N = 465)2+ (N = 75)

Liver MetsYes (N = 147)No (N = 585)

Age< 44.8 (N = 363)>= 44.8 (N = 369)

GenderMale (N = 508)Female (N = 224)

TotalN = 732

Median BEV/IFN

20.2 (17.1, 25.0)15.7 (10.1, 20.6)

32.5 (21.6, 43.7)17.7 (15.6, 22.5)6.6 (5.9, 8.9)

15.8 (10.1, 21.0)20.3 (17.0, 24.3)

18.1 (14.9, 21.7)20.8 (16.4, 27.1)

18.7 (16.1, 24.3)17.6 (14.4, 24.0)

18.3 (16.5, 22.5)

Survival (months) IFN

18.8 (15.7, 23.5)9.4 (5.7, 16.1)

33.5 (24.3, 39.4)16.1 (13.4, 19.9)5.7 (4.4, 9.2)

9.4 (7.5, 17.1)19.2 (15.9, 21.7)

16.2 (13.7, 20.0)18.8 (13.8, 27.0)

18.6 (15.8, 24.3)14.1 (10.4, 20.0)

17.2 (14.4, 20.0)

p-value

0.28720.0381

0.51890.16880.2439

0.0830.1824

0.5980.6813

0.43450.0687

0.069

0 0.5 1 1.5 2

Forest Plot of Overall Survival in Select Subgroups

BEV/IFN better IFN better

Kaplan-Meier Progression-Free Survival by Treatment Arm

0 6 12 18 24 30 36 42 48

Time(months)

0.0

0.2

0.4

0.6

0.8

1.0

Pro

gre

ssio

n-F

ree S

urv

ival P

robabili

ty

IFNBEV/IFN, Stratified log-rank p<0.0001

363 145 77 47 36 30 7

369 218 129 84 55 37 26 20 10

IFN

BEV/IFN

Number of Patients at Risk

-- Median PFS 8.4 months Median PFS 4.9 months HR= 0.71 (95% CI=0.6-0.8)

Objective Response

Note: patients with measurable disease only

Bev + IFN (n=325) IFN (n=314)

Overall Response rate 25.5% [95% CI = 20.9-30.6]

13.1%[95% CI = 9.5-17.3]

CR 3.7% 1.9%

PR 23.4% 12.7%

p < 0.0001

Duration of response 11.9 months [95% CI = 8.3 – 14.8]

9.7 months[95% CI = 7.6 – 19.8]

p = 0.362

Adverse event

Bevacizumab + IFN

(n=366)

IFN

(n=352)

Any grade 3/4 adverse event 79% 61%

Fatigue/asthenia/malaise 37% 30%

Anorexia 17% 8%

Proteinuria 15% <1%

Hypertension 11% 0%

Hemorrhage 2% <1%

Venous thromboembolism 2% 1%

Gastrointestinal perforation <1% 0%

Arterial ischemia 1% 0%

Frequency of selected grade 3 or 4 AEs

Conclusions

• Overall survival is greater in patients with metastatic clear cell RCC receiving bevacizumab plus interferon as initial systemic therapy compared to interferon alone, but does not meet pre-defined criteria for significance

• Although the effect of bevacizumab plus IFN on OS is preserved regardless of subsequent treatment, the most robust OS is achieved in patients with favorable underlying disease biology who are able to receive subsequent therapy

• The combination of bevacizumab and IFN as initial therapy in metastatic RCC patients results in a significantly greater progression-free survival and objective response rate versus IFNA monotherapy

• Toxicity is greater in the combination therapy arm, including more fatigue, anorexia, hypertension and proteinuria

Final results of the phase III, randomised, double-blind AVOREN trial of first-line

bevacizumab + interferon-2a in metastatic renal cell carcinoma

Escudier B, Bellmunt J, Negrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S on behalf of the AVOREN investigators

*PFS is the primary endpoint for regulatory approval in the USAEscudier, et al. Lancet 2007

AVOREN study design

• Endpoints– primary:* OS– secondary: PFS, TTP, TTF, RR, safety

• Treatment– bevacizumab/placebo 10mg/kg i.v. q2w– IFN 9MIU s.c. t.i.w. (maximum 52 weeks)

IFN + Bevacizumab (n=327)

IFN + placebo (n=322)

PDNephrectomised patients with advanced RCC

(n=649)

Stratification:Country

MSKCC risk group

1:1

PD

Summary of published AVOREN data

• Final analysis of PFS performed at the time of the interim analysis– significant increase from 5.4 to 10.2 months when bevacizumab is

combined with IFN (HR=0.63; p=0.0001)1

– good safety profile

• By reducing the IFN dose for safety issues – PFS benefit is maintained2

– decreased incidence of grade 3/4 events2

1. Escudier, et al. Lancet 2007; 2. Melichar, et al. Ann Oncol 2008

Independent review of PFS and ORR

Investigator1 IRC2

IFN + Bevacizumab

(n=327)

IFN +placebo(n=322)

IFN + Bevacizumab

(n=288)

IFN + placebo(n=281)

ORR (%) 31 13 31 12

p value <0.0001 <0.0001

Median PFS (months) 10.2 5.4 10.4 5.5

HR (95% CI) 0.63 (0.52–0.75) 0.57 (0.45–0.72)

p value <0.0001 <0.0001

1. Escudier, et al. Lancet 2007; 2. Roche, data on file

Objectives

• Final analysis of OS

• Clinical cut-off September 2008

• Median follow-up: 22 months

• Statistical considerations– required 445 events from 649 randomised patients– 80% power to detect an improvement in OS from

13 to 17 months – corresponding to an HR of 0.76 at a two-sided overall significance

level of 0.05

Final OS: unstratified and stratified analyses

Cox regression p value

HR 95% CI Log-rank Wilcoxon

Unstratified 0.91 0.76–1.10 0.3360 0.2046

Stratified* 0.86 0.72–1.04 0.1291 0.0969

*Stratified by Motzer score and region

Pro

babi

lity

of s

urvi

val

Final OS

Patients at risk (n)

IFN + Bevacizumab 327 278 237 194 157 124 84 27

IFN + placebo 322 262 216 177 141 113 78 22

21.3 23.3

0 6 12 18 24 30 36 42Time (months)

1.0

0.8

0.6

0.4

0.2

0

IFN + Bevacizumab (n=327)

IFN + placebo (n=322)

HR=0.86 (95% CI: 0.72–1.04)

p=0.1291 (stratified*)

*Stratified by Motzer score and region

Multiple Cox regression analysis for OS

• A multiple Cox regression model controls for several predetermined baseline prognostic factors that influence survival independent of treatment

• Variables included in the analysis– gender, age, Motzer score, location of metastases (lung, bone,

liver), body weight loss, number of sites, baseline SLD, region, baseline VEGF, and some lab values (albumin, creatinine, alkaline phosphatase, WBC count, platelets)

• Adjustment for these factors resulted in an improved treatment effect– HR=0.78 (95% CI: 0.63–0.96); p=0.0219

Final OS in reduced-dose IFN population

26.023.3

Pro

babili

ty o

f su

rviv

al

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 36 42

Time (months)Patients at risk (n)

Bevacizumab + reduced-dose IFN 131 116 102 85 72 57 38 16

Bevacizumab + IFN 327 278 237 194 157 124 84 27

Bevacizumab + reduced-dose IFN (n=131)Bevacizumab + IFN (n=327)

Censoring patients at time of crossover (n=13)

IFN + Bevacizumab

(n=327)

IFN + placebo

(n=322)

Patients with event, n (%) 220 (67.3) 224 (69.6)

Patients without events, n (%) 107 (32.7) 98 (30.4)

Median OS, months (95% CI) 23.3 (20–27) 20.8 (18–24)

HR (95% CI) 0.84 (0.70–1.02)

p value (Log-rank test)* 0.0766

*Stratified by Motzer score and region

Censoring crossover patients

Pro

babili

ty o

f su

rviv

al

Patients at risk (n)

Bevacizumab + IFN 327 278 237 194 157 124 84 27IFN + placebo 322 262 216 173 131 101 69 19

0 6 12 18 24 30 36 42Time (months)

1.0

0.8

0.6

0.4

0.2

023.320.8

IFN + Bevacizumab (n=327)IFN + placebo (n=322)HR=0.84 (95% CI: 0.70–1.02)p=0.0766*

*Stratified by Motzer score and region

Summary of subsequent medical therapies

Treatment, n (%)

IFN + Bevacizumab

(n=327)

IFN + placebo

(n=322)

Total patients with ≥1 treatment 180 (55) 202 (63)

VEGF inhibitors

Sunitinib 83 (25) 92 (29)

Sorafenib 60 (18) 50 (16)

Bevacizumab 10 (3) 12 (4)

Other* 7 (2) 6 (2)

mTOR inhibitors‡ 14 (4) 6 (2)

Cytokines 32 (10) 52 (16)

Chemotherapy§ 28 (9) 47 (15)

*Protein TKI, pazopanib, erlotinib, blinded sorafenib, blinded sunitinib, angiogenesis inhibitors NOS, VEGF inhibitor NOS‡Temsirolimus, everolimus (RAD001)§Antimetabolites, vinca alkaloids and antineoplastic agents

Regional variation in subsequent treatment with TKIs

IFN + Bevacizumab IFN + placebo

Therapy

Western Europe(n=180)

Eastern Europe and other(n=147)

Western Europe(n=177)

Eastern Europe and other(n=145)

TKIs, n (%)

Sunitinib 52 (29) 31 (21) 64 (36) 28 (19)

Sorafenib 51 (28) 9 (6) 48 (27) 2 (1)

Regional variation in OS

IFN + Bevacizumab IFN + placebo

Western Europe(n=180)

Eastern Europe and other(n=147)

Western Europe(n=177)

Eastern Europe and other(n=145)

Events, n (%) 120 (67) 100 (68) 125 (71) 99 (68)

Median OS, months (95% CI) 24.5 (21–29) 23.1 (17–27) 23.7 (21–28) 17.1 (13–22)

HR (95% CI)* 0.93 (0.71–1.21) 0.92 (0.71–1.20)

p value (log-rank)*

0.5922 0.5336

*Stratified by Motzer score and region

OS by post-protocol therapies

IFN + Bevacizumabvs IFN + placebo (n)

Median OS

IFN + Bevacizumab

(months)

IFN + placebo (months)

HR (95% CI)

Subsequent TKI*‡ 113 vs 120 38.6 33.6 0.80(0.56–1.13)

Subsequent sunitinib 83 vs 92 43.6 39.7 0.88 (0.58–1.35)

Subsequent sorafenib 60 vs 50 38.6 30.7 0.73(0.44–1.20)

*Subsequent therapy defined as any post-protocol therapy, any line (before or after PD)‡TKIs include sunitinib, sorafenib, pazopanib, erlotinib, blinded sorafenib, blinded sunitinib and unspecified protein TKI

Subgroup analysis of OS in AVOREN

0.2 0.5 1 2 5

Baseline risk factor Total (n) HR HR 95% CI

All patients 649 0.86 0.72–1.04

410

239

0.78

0.99

Age (years)

<65

≥650.61–0.99

0.73–1.35

Baseline VEGF > median

No

Yes192

192

0.74

0.88

0.50–1.10

0.62–1.24

192

457

0.90

0.84

Sex

Female

Male0.64–1.27

0.66–1.05

Motzer score

Favourable

Intermediate

Poor

180

366

55

0.86

0.83

0.86

0.57–1.30

0.65–1.06

0.47–1.59

Per cent body weight loss

10

>10

501

81

0.88

0.60

0.70–1.09

0.35–1.04

No. of metastatic sites

1

2

>2

152

242

252

0.81

1.02

0.74

0.52–1.27

0.73–1.41

0.55–0.99

Subgroup analysis of OS in AVOREN (cont’d)

Baseline risk factor Total (n) HR HR 95% CI

0.70–1.09

0.58–1.32

Bone metastases

No

Yes

521

125

0.87

0.88

565

81

0.88

0.68

Tumour in lung only

No

Yes0.72–1.08

0.36–1.28

0.2 0.5 1 2 5

Lung metastases

No

Yes

173

473

1.10

0.77

0.73–1.66

0.61–0.96

Liver metastases

No

Yes

508

138

0.76

1.30

0.62–0.95

0.85–1.98

Pro

babi

lity

of s

urvi

val

Time (months)

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 36 42

Patients at risk (n)

Bevacizumab + IFN 258 228 204 169 140 112 77 24IFN + placebo 250 211 173 140 111 91 61 17

Median OS

IFN + Bevacizumab (n=258)

IFN + placebo (n=250)

HR=0.76 (95% CI: 0.62–0.95)p=0.0155*

OS in patients without liver metastases at baseline

21.4 27.5

*Stratified by Motzer score and region

Conclusions

• Although not statistically significant, a trend towards improved OS was observed with bevacizumab + IFN combination. The results have been confounded by– post-protocol bevacizumab– subsequent therapies

• Patients with bevacizumab + reduced doses of IFN had similar OS to the whole bevacizumab + IFN population

• Treatment effect is significant when adjusted for prognostic factors

• This analysis confirms the activity of this treatment in first line metastatic RCC with good or intermediate risk

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

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

• An oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-Kit

• Clinical efficacy demonstrated in advanced RCC in a Phase II study1

1. Hutson TE, et al. J Clin Oncol. 2007;25(suppl):18S:5031.

A Global, Randomized, Double-Blind Study to Evaluate Efficacy and Safety of Pazopanib in Advanced RCC (VEG105192)

80 Sites in 22 countriesEnrolled: Apr 06 - Apr 07

EuropeAustriaCzech RepublicEstoniaIrelandItalyLatviaLithuaniaPolandRussiaSlovakiaTunisiaEnglandUkraine

South AmericaArgentinaBrazilChile

Asia/PacificAustraliaChina/HKIndiaKoreaNew ZealandPakistan

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

Study Design

Pazopanib 800 mg qd(n = 290)

Matching Placebo(n = 145)

Option to receive pazopanib via an open-label study at progression

Stratification• ECOG PS 0 vs 1• Prior nephrectomy• Rx-naive (n = 233) vs 1 cytokine

failure (n = 202)

Patients with advanced RCC(N = 435)

Randomization2:1

Endpoints and Analysis PlanPrimary:

– 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

– 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

PFS and ORR results presented here are based on independent review.

Pazopanib (n = 290)

Placebo(n = 145)

Median age (range), yrs 59.0 (28 – 85) 60.0 (25 – 81)

Gender, % male 68 75

Metastatic sites,% Lung Lymph node Bone Liver

74

54 28

26

7359 26 22

Number of organs involved, % 1 & 2 ≥ 3

45 55

4852

ECOG PS 0 / 1, % 42 / 58 41 / 59

MSKCC risk category, % Favorable Intermediate Poor / Unknown

39

55 3 / 3

3953

3 / 4

Demographic and Baseline Disease Characteristics

PFS in Overall Study Population 1.0

0.0

0.2

0.4

0.6

0.8

0 5 10 15 20Months

Pro

po

rtio

n P

rog

ress

ion

-Fre

e

Patients at risk Pazopanib 290 159 76 29 6 Placebo 145 38 14 2

Hazard Ratio = 0.4695% CI (0.34, 0.62)P value < 0.0000001

Median PFSPazopanib: 9.2 moPlacebo: 4.2 mo

PazopanibPlacebo

PFS in Treatment-Naive Subpopulation 1.0

0.0

0.2

0.4

0.6

0.8

0 5 10 15 20Months

Pro

po

rtio

n P

rog

ress

ion

-Fre

e

Patients at risk Pazopanib 155 34 39 11 1 Placebo 78 22 7 2

Hazard Ratio = 0.4095% CI (0.27, 0.60)P value < 0.0000001

Median PFSPazopanib: 11.1 moPlacebo: 2.8 mo

PazopanibPlacebo

PFS in Cytokine-Pretreated Subpopulation

1.0

0.0

0.2

0.4

0.6

0.8

0 5 10 15 20Months

Pro

po

rtio

n P

rog

ress

ion

-Fre

e

Patients at risk Pazopanib 135 75 37 18 5 Placebo 67 16 7

Hazard Ratio = 0.5495% CI (0.35, 0.84)P value < 0.001

Median PFSPazopanib: 7.4 moPlacebo: 4.2 mo

PazopanibPlacebo

Subgroup Analysis of PFS

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

Favors pazopanib Favors placebo

1.2

Hazard Ratio (95% CI)Baseline Factor

P < 0.001 by log-rank test for all.

Tumor Response

Pazopanib (n = 290)

Placebo(n = 145)

ORR (CR + PR), % Overall population Treatment-naive Cytokine-pretreated

3032

29

34

3

Duration of response, weeks 59

─

Interim Analysis of Overall Survival

O’Brien-Fleming boundary for futility / superiority: P = 0.201 / 0.004 (1-sided)

1.0

0.0

0.2

0.4

0.6

0.8

0 5 10 15 20Months

Pro

po

rtio

n S

urv

ivin

g

Patients at risk Pazopanib 290 254 214 115 20 1 Placebo 145 115 93 52 6

Hazard Ratio = 0.7395% CI (0.47, 1.12)P value = 0.02 (1-sided)

Median OSPazopanib: 21.1 moPlacebo: 18.7 mo

PazopanibPlacebo

25

48% of placebo patients received pazopanib after PD

Most Common Adverse Events ( 10%)

Median exposure: pazopanib 7.4 (0 - 23) vs placebo 3.8 (0 - 22) months

Adverse Event

Pazopanib (n = 290) % Placebo (n = 145) %

All Grs Gr 3 Gr 4 All Grs Gr 3 Gr 4

Any eventa 92 33 7 74 14 6

Diarrhea 52 3 < 1 9 < 1 0

Hypertension 40 4 0 10 < 1 0

Hair color changes 38 < 1 0 3 0 0

Nausea 26 < 1 0 9 0 0

Anorexia 22 2 0 10 < 1 0

Vomiting 21 2 < 1 8 2 0

Fatigue 19 2 0 8 1 1

Asthenia 14 3 0 8 0 0

Hemorrhageb 13 1 < 1 5 0 0

Abdominal pain 11 2 0 1 0 0

Headache 10 0 0 5 0 0

a 4% of patients in pazopanib arm and 3% of patients in placebo arm had grade 5 adverse events.b Included hemorrhage from all sites; 1% patients in pazopanib arm had grade 5 events.

Selected Class Effectsa

Pazopanib(n = 290)

Placebo(n = 145)

Adverse Event All Grades, % All Grades, %

Proteinuria 9 0

Hypothyroidism 7 0

Hand-foot syndrome 6 (< 1)

Mucositis / Stomatitis 4 / 4 < 1 / 0

Arterial thromboembolic 3b 0a Associated with multi-target receptor tyrosine kinase inhibitors.b 2% of arterial thromboembolic events were grade 3.

Health-Related Quality of Life

• Global health status / quality of life was compared using 3 prespecified 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

Pazopanib Summary

• Significant improvement in PFS and RR compared with placebo in treatment-naive and cytokine-pretreated patients

• Significant improvement in PFS was observed in all subgroups

• The safety profile was acceptable

• Results indicate a favorable risk / benefit profile in the treatment of patients with treatment-naive and cytokine-pretreated advanced RCC

• Interim OS data are not yet mature