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Phase III Trial of Pazopanib in Locally Advanced and/or Metastatic Renal Cell Carcinoma

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. Hawkins 9

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Phase III Trial of Pazopanib in Locally Advanced and/or Metastatic Renal Cell Carcinoma

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  1. Phase III Trial of Pazopanib in Locally Advanced and/or Metastatic Renal Cell Carcinoma Cora N. Sternberg,1 Cezary Szczylik,2 Eun S. Lee,3Pamela Salman,4 Jozef Mardiak,5 Ian D. Davis,6Lini Pandite,7 Mei Chen,8 Lauren McCann,8Robert 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

  2. Disclosures Research Funding Cougar Biotech, Wyeth Consultancy Agreements Sanofi Aventis, Pfizer, Novartis,GSK

  3. Pazopanib 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.

  4. 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

  5. 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

  6. 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) Randomization2:1 Pazopanib 800 mg qd(n = 290) Matching Placebo(n = 145) Option to receive pazopanib via an open-label study at progression

  7. 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 • 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.

  8. Demographic and Baseline Disease Characteristics

  9. PFS in Overall Study Population 1.0 Hazard Ratio = 0.46 95% CI (0.34, 0.62) P value < 0.0000001 Median PFS Pazopanib: 9.2 mo Placebo: 4.2 mo 0.8 0.6 Proportion Progression-Free 0.4 0.2 Pazopanib Placebo 0.0 0 5 10 15 20 Months Patients at risk Pazopanib 290 159 76 29 6 Placebo 145 38 14 2

  10. PFS in Treatment-Naive Subpopulation 1.0 Hazard Ratio = 0.40 95% CI (0.27, 0.60) P value < 0.0000001 Median PFS Pazopanib: 11.1 mo Placebo: 2.8 mo 0.8 0.6 Proportion Progression-Free 0.4 0.2 Pazopanib Placebo 0.0 0 5 10 15 20 Months Patients at risk Pazopanib 155 34 39 11 1 Placebo 78 22 7 2

  11. PFS in Cytokine-Pretreated Subpopulation 1.0 Hazard Ratio = 0.54 95% CI (0.35, 0.84) P value < 0.001 Median PFS Pazopanib: 7.4 mo Placebo: 4.2 mo 0.8 0.6 Proportion Progression-Free 0.4 0.2 Pazopanib Placebo 0.0 0 5 10 15 20 Months Patients at risk Pazopanib 135 75 37 18 5 Placebo 67 16 7

  12. 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 < 0.001 by log-rank test for all.

  13. Tumor Response

  14. 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: 21.1 mo Placebo: 18.7 mo 0.4 0.2 Pazopanib Placebo 0.0 0 5 10 15 20 25 Months Patients at risk Pazopanib 290 254 214 115 20 1 Placebo 145 115 93 52 6 O’Brien-Fleming boundary for futility / superiority: P = 0.201 / 0.004 (1-sided)

  15. Most Common Adverse Events ( 10%) Median exposure: pazopanib7.4 (0 - 23) vs placebo3.8 (0 - 22) months

  16. Selected Class Effectsa

  17. Laboratory Abnormalities

  18. 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

  19. 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

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

  21. Many Thanks to the Patients and Investigators 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 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 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 • Antonino Bonaventura • Ashley Cheng • Ian D. Davis • Richard Epstein • Baofa Hong • Sung-Joon Hong • Richard Isaacs Asia/Pacific • Choung-Soo Kim • Eun-Sik Lee • Raymond Lowenthal • Yanqun Na • Anne O'Donnell • Chris Wynne

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