1. Pazopanib: Arguing for a third way
Antoine Bianchi
Alban Delepierre
Pierre Mouy

2. Summary What is Renal cell carcinoma ?
Why using TKI as RCC treatments ?
What are the available TKI? What are their strenghts and weakness ?
How will pazopanib enter the RCC market ?

3. Renal cell Carcinoma ( RCC)
Accounts for 85 % of all malignant kidney tumours
Most agressive of the urologic cancers
40000 deaths/year
Classical diagnosis : -Flank pain
Hematuria
Palpable abdominal mass
Extremely poor prognosis when advanced
Median of survival =13 months
Risks factors : Hereditary VHLp mutation, smoking, obesity, HTA
More frequent for man between 60 and 70 years old

4. The RCC market $ 1 billion in 2006
RCC market is expected to more than double before 2017 Decision ressources inc Pharmacor report’s Renal cell carcinoma
Année de lancement du sutent 68% d’augmentation de CA
Source: IMS health

5. Approved therapies before TKIs
Role of surgery:
(early stage tumours)
for 25% of patients
5-years survival rates up to 90-95%
Chirurgie en 1ere ligne car on parle de tumeurs solides
Bevacizumab, Ac monoclonal anti-VEGF: bloque les effets de VEGF sur l’invasion, la croissance, la migration et le dvpt de métastases (injection IV toutes les 2 semaines à forte dose: 10 mg/kg)

6. Approved therapies before TKIs
First line systemic treatment after metastasis
Good or intermediate prognosis
Bevacizumab + IFNα
Age<60, good performance status
High dose IL-2
limited Efficacity, side effects ++
bad cost-effectivness
RCC patients needed improvement in treatment !!

7. scheme of action 75% of RCC comes from
pVHL mutation (Von Hippel-Lindau protein)

8. Angiogenesis a crucial step in growth tumor
New blood vessels are required to support the growth of a tumor beyond the size 1 to 2 mm3
Tumour cells promoting pro- angiogenic factors
“angiogenic Switch” due to the tumor hypoxia
In normal physiological circumstances, angiogenesis is well controlled by pro- and anti-angiogenic factors and is only promoted during the menstrual cycle, pregnancy, and during wound healing and repair [19]. Though, in cancer, this balance of pro- and anti-angiogenic factors is dis-turbed, resulting in the so-called ‘angiogenic switch’.
Tumor cells secrete a number of pro-angiogenic factors that stimulate the proliferation and migration of endothelial cells, resulting in the outgrowth of new capillaries into the tumor. VEGF signaling through its receptor is the major inducer of angiogenesis

9. Kinome 30 families : VEGF-R PDGF-R 518 protein kinases
Tyrosine kinase group
30 families :
> VEGFR
> PDGFR
> FGFR
> EGFR
RAF
Cell signaling technology

10. What is a tyrosine kinase receptor ?

11. Molecular mechanism of action of TKI
Coloured molecule: ATP
Gray molecule: inhibitor

12. Why using TKIs for Kidney cancer treatment ?
Many kidney cancers are associated with a kinase mutation responsible for angiogenesis factors overexpression
TKIs are targeted therapies: increasing response and reducing side effects.

13. What are the available TKI? What are their strenghts and weakness ?

14. 2005

15. Kinase inhibited by Sorafenib
Kinase affinity profile
Ki app (nM)
VEGFR-1 15
VEGFR-2 8
VEGFR-3 10
PDGFR-a 30
PDGFR-b 14
C-Kit
2.4
Sorafenib 15

16. Sorafenib scheme of action

17. Clinical trial: TARGET study
Patient with advanced metastasic RCC
On patients having received a prior systemic therapy
400mg twice a day
Versus placebo
Primary endpoints:
OS: Overall Survival
Secondary endpoints:
PFS: Progression free survival
Quality of life
Overall response

18. TARGET study: results

19. TARGET study: results
Cross-over: 48% of patient under placebo switched to Sorafenib

21. Tumor response rate Overall Response 84% RESPONSE SORAFENIB
Objective response
10%
 Complete
<1%
 Partial
Stable disease
74%
PFS
5,5 month vs 2,8 month (placebo)
P<0.001 OS
19,3 month vs 15,9 month (placebo)
P=0.05
Overall
Response
84%
new

22. Adverse effects of Sorafenib
ESCUDIER B, Sorafenib for Treatment of Renal Cell Carcinoma: Final Efficacy and Safety Results of the Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial, 2009
Bernard Escudier, et al

23. Conclusion on Sorafenib
The TARGET study gave agreement as a second line treatment for RCC
the first-in-class in RCC

24. 2006

25. Kinase inhibited by Sunitinib
Kinase affinity profile
Ki app (nM)
VEGFR-1
229
VEGFR-2 51
VEGFR-3 30
PDGFR-a 28
PDGFR-b 7
C-Kit
0,45
Sunitinib is less selective
Sorafenib
Sunitinib 25

26. Clinical trial: Methods
Patients with advanced metastasic RCC untreated
50mg once a day
4 weeks of treatment, 2 weeks of treatment holiday
Versus Interferon- (was the best available treatment)
Primary endpoints:
PFS: Progression free survival
Secondary endpoints:
OS: Overall Survival
Quality of life
Overall response

27. Clinical trial results
Sutent average PFS is 11,8 months, compared with 5,5 months for patients receiving interferon alfa.
Overall Survival and Updated Results for Sunitinib Compared With Interferon Alfa in Patients With Metastatic Renal Cell Carcinoma Robert J. Motzer et al.

28. Clinical trial results: Tumor response
SORAFENIB
SUNITINIB
Objective response
10%
31%
 Complete
<1%
Partial
Stable disease
74%
48%
PFS
5,5 month vs 2,8 month (placebo)
P<0.001
11 month vs 5month (Ifn-a) OS
19,3 month vs 15,9 month (placebo)
P=0.05
26,4 month vs 21,8 month (Ifn-a)
P<0.02
new

29. Clinical trial results:
Adverse effects
Side effect
Sorafenib (All Grades)
Sunitinib (All Grades)
Fatique
29%
51%
Diarrhea
48%
53%
Nausea
19%
44%
Mucositis/Stomatitis NA
25%
Anorexia
14%
31%
Rash/desquamation
28%
40%
Hand-foot desquamation
30%
20%
Alopecia
27%
Hypertension
17%
24%
Dyspnea

30. Conclusion on sunitinib
More efficient than Ifn-a.
Came as first line because of comparison with interferon
Best in class
More high grade side effects
Requires treatment holiday
BUT

31. Understanding the use of targeted therapies in RCC
Robert J. Amato, Targeted Therapy and Renal Cell Carcinoma:  Are We Making Progress? 2007

32. Therapeutic scheme before Pazopanib

33. Therapeutic scheme before Pazopanib
Marco Antonio Arap, New directions in the management of renal cell carcinoma
2007

34. Votrient, Pazopanib
2009

35. Kinase profile of Pazopanib
Kinase affinity profile
Ki app (nM)
VEGFR-1 10
VEGFR-2 4
VEGFR-3 6
PDGFR-a 2
PDGFR-b 5
C-Kit 15
Sorafenib
Sunitinib
Pazopanib 35

36. Scheme of action, Pazopanib
VEGF-A/B
PDGF-a/b
VEGF-C
VEGFR-1/2
PDGFR Pz
VEGFR-3 Pz Pz Pz Pz Pz Pz

37. Clinical trial of Pazopanib
Patient with metastasic RCC
800mg once a day
No treatment holiday
versus placebo
Half patient naïve and half with prior cytokine treatment
Primary endpoints:
PFS: Progression free survival

38. Clinical trial of Pazopanib
Pazopanib : 9,2 months
Placebo : 4,2 months N
PFS
5 months
10 months
15 months
20 months
Pazopanib
290
9.2
159 (55%)
76 (26%)
29 (10%) 6
0,02
Placebo
145
4.2 38 14 2
Cora N. Sternberg A randomized, double-blind phase III study of pazopanib in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma, 2009

39. Clinical trial of Pazopanib
RESPONSE
SORAFENIB
SUNITINIB
PAZOPANIB
Objective response
10%
31%
30%
Complete
<1% 0%
Partial
Stable disease
74%
48%
38%
PFS
5,5 month vs 2,8 month (placebo)
11 month vs 5month (Ifn-a)
9,2 month vs 4,2 month (placebo) OS
19,3 month vs 15,9 month (placebo)
26,4 month vs 21,8 month (Ifn-a)
21,1 month vs 18,7 month (placebo)
new

40. Clinical trial of Pazopanib
Pazopanib (n = 290)
Placebo (n = 145)
Overall Response rate
30% 3%
Treatment-naive
32% 4%
Cytokine-pretreated
29%
Cora N. Sternberg A randomized, double-blind phase III study of pazopanib in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma, 2009

41. Overview of clinical trial results
Treatment naïve
Cytokine Refractory OS
PFS
Sorafenib
5,8 mos.
(Phase II results only)
5,9 mos.
10,7 mos*.
Sunitinib
11 mos.
8,7 mos.
26,4 mos.
Pazopanib
11,1 mos.
7,4 mos.
21.1 mos.
* : Cross-over

42. Conclusion on clinical trial
Pazopanib is efficacy SO
Why is pazopanib a real progress in RCC treatment ?

43. Looking at Adverse effects…
Side effect
Sorafenib (All Grades)
Sunitinib (All Grades)
Pazopanib (all grades)
Fatique
29%
51%
19%
Hypertension
17%
28%
40%
Neutropenia
18%
25%
34%
Thrombopenia
12%
31%
32%
Rash/desquamation
20%
<1%
Diarrhea
48%
53%
52%
Nausea
44%
26%
Anorexia
14%
22%
Hand-foot desquamation
33% NA 6%
Alopecia
27%
24% 8%
Dyspnea 7%

44. Myelosuppression
is a decrease in the production of blood cells in bone marrow.
Red blood cells  anemia
White blood cells  leukopenia or neutropenia
Platelets  thrombocytopenia
Neutropenia  bacterial infections.
thrombocytopenia  haemostasis.
TKIs cause many Neutropenia and thrombocytopenia.

45. High grade Myelosuppression
myelosuppression is observed with the 3 Tyrosine Kinase Inhibitors.
Frequency of Myelosuppression grade 3/4
TKI’s
Sorafenib
Sunitinib
Pazopanib
Neutropenia 5%
12% 1%
Thrombocytopenia 8%
R KUMAR; Br J Cancer November 17; 101(10): 1717–1723. 45

46. Why TKIs cause Myelosuppression?
VEGFR are essential for hematopoiesis and one of the main target of those TKIs.
Ki app (nM)
Sorafenib
Sunitinib
Pazopanib
VEGFR-1 10
229 15
VEGFR-2 4 51 8
VEGFR-3 6 30
R KUMAR; Br J Cancer November 17; 101(10): 1717–1723.

47. Why is Pazopanib causing less high grade myelosuppression?
Other Receptors are implied in haematopoiesis: Flt-3; C-Kit
Cellular IC50 for inhibition
IC50 (nM)
Receptors
Sorafenib
Sunitinib
Pazopanib
C-Kit 15
0.45
2.4
Flt-3 22
0.6
230
R KUMAR; Br J Cancer November 17; 101(10): 1717–1723. 47

48. Arterial hypertension with TKIs Hypertension all grade
SORAFENIB
17% 4%
SUNITINIB
30% 8%
PAZOPANIB
40%

49. Fatigue observed with TKis
Sorafenib (All Grades)
Sunitinib (All Grades)
Pazopanib (all grades)
Fatique
29%
74%
19%
Hypothyroidism plays a major part in treatment-induced fatigue

50. Hypothyroidism with TKIs
Sorafenib
Sunitinib
Pazopanib
Hypothyroidism
41%
85% 7%
Pazopanib must be less inhibiting a kinase implied in the thyroid function
Available hypothesis are:
Inhibition of iodine uptake
Inhibition of thyroid peroxydase
Regression of the gland vascularisation
Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy

51. Health- Related Quality of Life
Global health status / quality of life was compared using prespecified HRQoL indices
-EORTC-QLQ-C30
-EQ-5D Index
-EQ-5D-VAS
There was no difference between pazopanib and placebo (P > 0.05) at any of the on-therapy assessment time points.
Cora N. Sternberg A randomized, double-blind phase III study of pazopanib in treatment-naive and
cytokine-pretreated patients with advanced renal cell carcinoma, 2009

52. Conclusion on adverse effects
Pazopanib really reduces adverse effects of TKI treatment in RCC
Adverse effects will now play a keyrole in the TKI developpement strategy
Will the the upcoming molecule be better than pazopanib ?

53. New coming indication
Lots of on-going studies for theses TKIs in RCC indication
Sorafenib vs interferon
ASSURE Sorafenib or Sunitinib as adjuvant
COMPARZ study ( Ph III )
Pazopanib vs Sunitinib
875 patients enrolled with advanced/metastatic RCC
datas expected during 2010
Sorafenib vs interferon, si ça marche le sutent va avoir mal (celui qui a le plus d’ES)
Provide a direct compararison of the efficacity, safety and tolerability for Sunitinib and Pazopanib

54. The third way : TOLERANCE
↘ myelosuppression
↘ hypothyroidism

55. Thanks for your attention

56. Bibliography
The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; A Review Ferry A.L.M. Eskens, Jaap Verweij
Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors R Kumar, M-C Crouthamel, DH Rominger, RR Gontarek, PJ Tummino RA Levin and AG King
Overall Survival and Updated Results for Sunitinib ComparedWith Interferon Alfa in PatientsWith Metastatic Renal Cell Carcinoma Robert J. Motzer, and all
Novel agents for renal cell carcinoma require novel selection paradigms to optimise first-line therapy Manuela Schmidinger, Christoph C. Zielinski
Efficacy and safety of sorafenib in patients with advanced renal cell carcinoma with and without prior cytokine therapy, a subanalysis of TARGET S.Negrier and all

57. The upcoming molecules

58. RECENTIN : Cediranib AstraZeneca Oral inhibitor of the :
VEGF-R 1/2/3
C-kit
PDGF-R
Efficacy Racenta vs Placebo
Phase II, active, not recruiting

59. Axitinib (Bayer, AG013736)
Inhibs specifically: VEGFR and PDGFR b
Low effects on C-kit or flt-3
No cross resistance with sorafenib

60. Axitinib (Bayer, AG013736) Phase 2 results Side effect
Pazopanib (all grades)
Axitinib
Phase 2 results
Fatique
19%
51%
Diarrhea
52%
59%
Rash/desquamation
<1%
11%
Hypertension
40%
57%

61. Axitinib (Bayer, AG013736) 2 ongoing phase III trials
Patients with metastasic RCC where sorafenib failed
Versus sorafenib
Likely to be in second line
If results are convincing, Axitinib must be compared to pazopanib to aim the first line.

62. (Phase II results only)
Axitinib (Bayer, AG013736)
Phase 2 results, on 52 Patients
PFS OS
Objective response rate (ORR)
Sorafenib
5,8 mos.
(Phase II results only)
10,7 mos.
10%
Pazopanib
11,1 mos.
21.1 mos.
30%
Axitinib
(Phase 2 results)
15,7 mos
29,9 mos
44,2%

63. The ideal kinase inhibiting profile in RCC
The perfect tyrosine kinase inhibitor treating RCC
should inhib:
VEGFR 1-2-3
PDGFR a-b
Raf
Without inhibiting
FLT-3
C-kit