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

Disclosures

Research Funding Cougar Biotech, Wyeth

Consultancy AgreementsSanofi Aventis, Pfizer, Novartis,GSK

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.

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

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

Chemistry labs

ALT 53 10 2 22 1 0

AST 53 7 < 1 19 < 1 0

Hyperglycemia 41 < 1 0 33 1 0

Hyperbilirubinemia 36 3 < 1 10 1 < 1

Hypophosphatemia 34 4 0 11 0 0

Hypocalcemia 33 1 1 26 < 1 < 1

Hyponatremia 31 4 1 24 4 0

Hypoglycemia 17 0 < 1 3 0 0

Hypokalemia 9 1 < 1 2 0 0

Hematology labs

Leukopenia 37 0 0 6 0 0

Neutropenia 34 1 < 1 6 0 0

Thrombocytopenia 32 < 1 < 1 5 0 < 1

Lymphopenia 31 4 < 1 24 1 0

Anemia 22 2 < 1 31 1 < 1

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

• Interim OS data are not yet mature

Pazopanib Conclusions

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

Many Thanks to the Patients and Investigators

South America

• Carlos H. Barrios

• Luis Fein

• Klaus Geissler

• Oleg Gladkov

• Pablo Gonzalez Mella

• Guillermo Lerzo

• Norma Pilnik

• Victor H. Rodrigues

• Pamela Salman

• Mirta Varela

• Juan Zarba

Asia/Pacific

• Choung-Soo Kim

• Eun-Sik Lee

• Raymond Lowenthal

• Yanqun Na

• Anne O'Donnell

• Chris Wynne

Europe

• Olga Ponomarova

• Gunta Purkalne

• Rodryg Ramlau

• Anantbhushan Ranade

• Janusz Rolski

• Mario Roselli

• Armando Santoro

• Giovanni Sbalzarini

• Denise Sheehan

• Yaroslav Shparyk

• Chandrashekar R. Simhadri

• Cora N. Sternberg

• Cezary Szczylik

• Sergei Tjulandin

• Albertas Ulys

• John Wagstaff

• Joanna Wojcik-Tomaszewska

• Milada Zemanova

Europe

• Aziz Abdullah

• Suresh Advani

• Zeba Aziz

• Ali Bahloul

• P.P. Bapsy

• Nawfel Benrais

• Mikhail Biakhov

• Vladimir Bondar

• Sergey Cheporov

• Christian Dittrich

• Luigi Dogliotti

• Richard Greil

• Robert E. Hawkins

• Ali Horchani

• Agnieszka Jagiello-Gruszfeld

• Francis James

• Rasa Janciauskiene

• Andrey Kaprin

• Petr Karlov

Europe

• Maccon Keane

• Rustem Khasanov

• Ivo Kocak

• Michail Kopp

• Evgeny Kopyltsov

• Piotr Koralewski

• Milan Kuta

• Vladimir Lesovoy

• Olexiy Lyulko

• Humera Mahmood

• Michael Marberger

• Jozef Mardiak

• Ernest Marshall

• Ali T. Mosbah

• Nikolay Ognerubov

• Peeter Padrik

• Jurate Pauliukoniene

• Helis Pokker

Asia/Pacific

• Antonino Bonaventura

• Ashley Cheng

• Ian D. Davis

• Richard Epstein

• Baofa Hong

• Sung-Joon Hong

• Richard Isaacs