The Role of Pazopanib in the Treatment of Renal Cell Cancer

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. 2010 Feb20;28(6):1061-8

4. Pazopanib 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 Kinase affinity profile

5. Kinase Selectivity of Various VEGFR TKIs Pazopanib Sunitinib Sorafenib VEGFR, PDGFR, c-Kit FLT3 VEGFR, PDGFR, c-Kit • 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,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 Sternberg CN, et al. Pazopanib in locally advanced or metastatic renalcell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010 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. 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.

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

13. Primary Endpoint – PFS(Overall Study Population) 1.0 Hazard Ratio = 0.46 95% CI (0.34, 0.62) P value < 0.0001 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 Reproduced with permission from Sternberg CN, et al. J Clin Oncol. 2010;28:1061-8.

14. PFS in Subpopulations Hazard Ratio = 0.54 95% CI (0.35, 0.84) P value < 0.001 Median PFS Pazopanib: 7.4 mo Placebo: 4.2 mo Hazard Ratio = 0.40 95% CI (0.27, 0.60) P value < 0.001 Median PFS Pazopanib: 11.1 mo Placebo: 2.8 mo Cytokine-pretreated Treatment-naive 1.0 1.0 0.8 0.8 0.6 0.6 Proportion Progression-Free Proportion Progression-Free 0.4 0.4 0.2 0.2 Pazopanib Placebo Pazopanib Placebo 0.0 0.0 0 0 5 5 10 10 15 15 20 20 Months Months 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 < 0.001 by log-rank test for all.

16. Tumor response

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: 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)

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

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

21. Prolonged Duration of Crossover Treatment

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 * 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

25. Most Common AEs Regardless of Causality (≥ 10%) a 4% of patients in pazopanib arm and 3% of patients in placebo arm had grade 5 AEs. bIncluded hemorrhage from all sites.

26. Selected Class Effects Associated With VEGFR TKI Inhibitorsa a AEs with incidence of <10% in the pazopanib arm regardless of causality.

27. Laboratory Abnormalities

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 1. N Engl J Med. 2007;356:115-124; 2. N Engl J Med. 2007;356:2271-2281; 3. Escudier Lancet. 2007;370:2103-2111; 4. Rini B. 2009 ASCO; 5. J Clin Oncol. 2009 Jul 1010;27(20):3312-8; 6. Lancet. 2008 ;372(9637):449-56; 7. J Clin Oncol. 2010 Feb 20;28(6):1061-8 *Independent central review.# including cytokine, bevacizumab

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)

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 233 Pazopanib vs. placebo 750 Sunitinib vs. IFN1 649 Bevacizumab + IFN vs. IFN(Avoren) 2 Second-line 202 Pazopanib vs. placebo 903 Sorafenib vs. placebo3 0.2 0.4 0.6 0.8 1.0 Favours Targeted Therapy Favours Control 1 Motzer RJ, et al. J Clin Oncol 2009a; 27(22):3584-3590. 2Escudier B, et al. Lancet 2007;370:2103–2111 3 Escudier B, et al. N Engl J Med 2007a; 356(2):125-134.

34. Indirect comparisons of PFS HR (95% CI) adjusting for differences in control arm Sunitinib vs. Bevacizumab/IFN: HR= 0.75 (95% CI: 0.55-0.93)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

35. Comparison of selected* AEs of pazopanib vs sunitinib - I

36. Comparison of selected* AEs of pazopanibvssunitinib - II

37. Comparison of selected* AEs of pazopanib vs sunitinib - III

38. VEG108844: A Phase III Study to Evaluate Efficacy and Safety of Pazopanib Versus Sunitinib OS PFS RANDOMIZE • Stratified by: • KPS, • LDH, • Prior nephrectomy SCR E E N n=438 Pazopanib 800mg QD continuous dosing 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

39. RCC Treatment Algorithm: 2010 NCCN 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