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

2. 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

3. 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

4. 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

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

6. 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)

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

8. 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)

9. 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)

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

11. 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

12. 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%

13. 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)

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

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

16. Phase III Pazopanib vs placebo
PFS subgroup analysis independent review

17. Phase III Pazopanib vs placebo
PFS subgroup analysis independent review

18. 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%

19. 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

20. 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)

21. 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)

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

23. 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

24. 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

25. 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