Pazopanib: the role in the treatment of mRCC M. P. Laguna Department of Urology Academic Medical Center Amsterdam, The Netherlands

No financial interest in any medical or technological company Member of the EAU “Testis Cancer guidelines” working group Board member ESUT Editorial board member J Endourol and Eur Urol

Role of Pazopanib What is known on TKI’s What is Pazopanib Phase II studies Phase III studies How to frame it in the current treatment protocols

TKI’s Similar efficacy profile in favourable / Intermediate risk groups Incidence & severity of AEs varies among TKI’s Spectrum and potency of kinase inhibition differs

Pazopanib in mRCC Targets: TKI inhibitor VEGFR 1,2,3 PDGFR- α, β c - Kit TKI inhibitor Does not inhibit: Flt-3 receptor

Phase II Pazopanib From Randomized to Open label trial (efficacy & safety of Pazopanib 800 mg /d) Primary end point: from progressive disease to RR Secondary: PFD and duration response 225 pat (69% naïve / 31% prior cytokines or Bevacizumab) Favorable & intermediate risk (Hutson TE et al,2009)

Phase II Pazopanib CR /PR complete / partial response, SD stable disease, PD progession disease

Phase II Pazopanib RR 35% (irrespective of prior or no treatment) Median duration 67 weeks Median PFS 52 weeks Maximum % radiological reduction (Hutson TE et al,2009)

Phase II Pazopanib Most common AEs Grade 3-4 up to 8% Diarrhea (63%) Fatigue (46%) Hair depigmentation (43%) Nausea (42%) HT (41%) Grade 3-4 up to 8% Dose reduction in 31% of patients Discontinuation in 15% 2 deaths Courtessy Cleveland Clinic Taussig Cancer Center (Hutson TE et al,2009)

Phase III Pazopanib vs placebo (VEG105192) Randomized – double blind-placebo controlled In treatment naïve & cytokine pretreated End points: efficacy (PFS) & safety

Phase III Pazopanib vs placebo (VEG105192) 435 pat Pazopanib (2): Placebo (1) MSKCC category Favourable Intermediate Poor Pazopanib 39% 55% 3% Placebo 39% 53% 3% 53% cytokine pretreated

Phase III Pazopanib vs placebo (VEG105192) 435 pat Pazopanib (2): Placebo (1) Pazopanib (290) DP 51% Death 4% AE 14% Placebo (145) DP 77% Death 6% AE 3%

Phase III Pazopanib vs placebo Tumor response ORR 30% (3% placebo) Median duration 59 weeks In all population (Sternberg CN et al, J Clin Oncol, 2010)

Phase III Pazopanib vs placebo Tumor response ORR 32% In treatment naïve population (Sternberg CN et al, J Clin Oncol, 2010)

Phase III Pazopanib vs placebo Tumor response ORR 29% In cytokine pretreated population (Sternberg CN et al, J Clin Oncol, 2010)

Phase III Pazopanib vs placebo PFS subgroup analysis independent review

Phase III Pazopanib vs placebo PFS subgroup analysis independent review

Safety (Pazopanib vs placebo) Most frequent AEs Grade 1-2 Diarrhea (52%), HT (40%), hair color changes (38%), nausea (26%), anorexia , vomiting… Low frequency of AEs Grade 3-4 (4%) Arterial thrombotic events in 3% Hemorragic events 13%

Safety (Pazopanib vs placebo) Similar frequency AEs in both subgoup Discontinuation higher in cytokine pretreated (19% vs 12%) Laboratory AEs : most grade 1-2 Death: 4% Pazopanib / 3% Placebo 1% attributable to treatment

Toxicity of TKI’s All grades (%) Constitutional 51 29 34 14 Infection Sunitinib Sorafenib Bevacizumab Pazopanib Constitutional 51 29 34 14 Infection - Metabolic 14-35 41 34-41 Cardiovascular 13-30 16 3-33 13 Respiratory 10 5-13 Bone marrow 75 8 32-37 Gastrointestinal 53 43 20 22-67 Skin & mucosas 40 <10 (Di Lorenzo G et al, 2011)

Toxicity of TKI’s Grade 3-4 (%) Constitutional 11 3 2-12 Infection - Sunitinib Sorafenib Bevacizumab Pazopanib Constitutional 11 3 2-12 Infection - Metabolic 2-18 12 <1 Cardiovascular 3-12 3-4 1-3 Respiratory 2 4 1 Bone marrow 18 13 1-4 Gastrointestinal 5 Skin & mucosas (Di Lorenzo G et al, 2011)

HRQoL (Pazopanib vs placebo) EORTC QLQ-C30 + EQ-5D index +VAS Maintenance of QoL across time No differences Pazopanib vs placebo

In conclusion & on Pazopanib Similar RR and PFS as Sunitinib or Bevacizumab + IFNα Less incidence of all grades (1 -4) constitutional, cardiovascular and skin / mucosas AEs Grade A recommendation in first line (favourable & intermediate risk groups) and in second line for cytokine resistent patients

COMPARZ (VEG 108844) Randomized phase III study Pazopanib 800 mg Secondary Endpoints Pazopanib 800 mg (438 patients) Sunitinib 50 mg PFS OS ORR Safety HRQoL PFS

ROPATAR Randomized phase II study Study endpoints Progression N=50 R A ZAT ION 8 weeks Pazopanib 800 mg/day 8 weeks Everolimus 10 mg/day 8 weeks Pazopanib 800 mg/day 8 weeks Everolimus 10 mg/day SCREEN PFS rate at one year toxicity QoL Time on treatment Rationale for study : Recent studies suggest that resistance to treatment with TKI may be reversible after stopping treatment (Cell 2010; 141;69-80). There is therefore a rationale to alternate treatment to prevent or delay the occurrence of resistance. The hypothesis of the study is that alternating active agents in ccRCC may reduce side effects, improve tolerability and compliance of treatment and prolong progression free survival and overall survival compared to the standard of care. Progression 1st Line Pazopanib 800 mg/day until progression 2nd Line Everolimus 10 mg/day until progression N=50 25