Antoine Bianchi
Alban Delepierre
Pierre Mouy
1

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 ?
2
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
3


$ 1 billion in 2006
RCC market is expected to more than double
before 2017 Decision ressources inc Pharmacor report’s Renal cell carcinoma
Source: IMS health
4
Role of surgery:
(early stage tumours)
for 25% of patients
5-years survival rates up to 90-95%
5
First line systemic treatment after metastasis
Good or intermediate prognosis
Age<60, good performance status
Bevacizumab + IFNα
High dose IL-2
limited Efficacity, side effects ++
bad cost-effectivness
RCC patients needed improvement in
treatment !!
6

75% of RCC comes from
pVHL mutation (Von Hippel-Lindau protein)
7
-New blood vessels are required to
support the growth of a tumor
beyond the size 1 to 2 mm3
-Tumour cells promoting proangiogenic factors
-“angiogenic Switch” due to the
tumor hypoxia
8
Kinome
VEGF-R
PDGF-R
-518 protein kinases
RAF
- Tyrosine kinase group
30 families :
-> VEGFR
-> PDGFR
-> FGFR
-> EGFR
Cell signaling technology
9
10
Coloured molecule: ATP
Gray molecule: inhibitor
11


Many kidney cancers are associated with a
kinase mutation responsible for angiogenesis
factors overexpression
TKIs are targeted therapies: increasing
response and reducing side effects.
12
13
2005
14
Kinase affinity profile
Ki app (nM)
Sorafenib
VEGFR-1
15
VEGFR-2
8
VEGFR-3
10
PDGFR-a
30
PDGFR-b
14
C-Kit
2.4
15
16

Patient with advanced metastasic RCC

On patients having received a prior systemic therapy

400mg twice a day

Versus placebo

Primary endpoints:

Secondary endpoints:
◦ OS: Overall Survival
◦ PFS: Progression free survival
◦ Quality of life
◦ Overall response
17
www.nexavar-international.com
18

Cross-over: 48% of patient under placebo switched
to Sorafenib
www.nexavar-international.com
19
www.nexavar-international.com
RESPONSE
Objective response
SORAFENIB
10%
 Complete
<1%
 Partial
10%
Stable disease
74%
Overall
Response
84%
PFS
5,5 month vs 2,8 month (placebo)
P<0.001
OS
19,3 month vs 15,9 month (placebo)
P=0.05
21
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
22
 The
TARGET study gave agreement
as a second line treatment for RCC
 the
first-in-class in RCC
23
2006
24
Kinase affinity profile
Ki app (nM)
Sorafenib
VEGFR-1
229
VEGFR-2
51
VEGFR-3
30
PDGFR-a
28
PDGFR-b
7
C-Kit
0,45
Sunitinib
25

Patients with advanced metastasic RCC untreated

50mg once a day

4 weeks of treatment, 2 weeks of treatment holiday

Versus Interferon-a (was the best available treatment)

Primary endpoints:

Secondary endpoints:
◦ PFS: Progression free survival
◦ OS: Overall Survival
◦ Quality of life
◦ Overall response
26
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.
27
RESPONSE
SORAFENIB
SUNITINIB
Objective response
10%
31%
 Complete
<1%
0
Partial
10%
31%
Stable disease
74%
48%
PFS
5,5 month vs 2,8 month
(placebo)
P<0.001
11 month vs 5month
(Ifn-a)
P<0.001
OS
19,3 month vs 15,9 month
(placebo)
P=0.05
26,4 month vs 21,8
month (Ifn-a)
P<0.02
28
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%
NA
Hypertension
17%
24%
Dyspnea
14%
28%
29





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
30
Understanding the use of
targeted therapies in RCC
Robert J. Amato, Targeted Therapy and Renal Cell Carcinoma: Are We Making Progress? 2007
31
32
Marco Antonio Arap, New directions in the management of renal cell carcinoma
2007
33
2009
34
Kinase affinity profile
Ki app (nM)
VEGFR-1
10
VEGFR-2
4
VEGFR-3
6
PDGFR-a
2
PDGFR-b
5
C-Kit
Sorafenib
15
Sunitinib
Pazopanib
35
VEGF-A/B
PDGF-a/b
VEGFR1/2
PDGFR
Pz
Pz
Pz
VEGF-C
VEGFR-3
Pz
Pz
Pz
Pz
36

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
37
Pazopanib : 9,2 months
Placebo : 4,2 months
N
PFS
5
10
15
20
months months months months
Pazopanib
290
9.2
159
(55%)
76
(26%)
29
(10%)
Placebo
145
4.2
38
14
2
6
0,02
Cora N. Sternberg A randomized, double-blind phase III study of pazopanib in treatmentnaive and cytokine-pretreated patients with advanced renal cell carcinoma, 2009
38
RESPONSE
SUNITINIB
PAZOPANIB
10%
31%
30%
Complete
<1%
0%
<1%
Partial
10%
31%
30%
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)
Objective response
Stable disease
SORAFENIB
39
Pazopanib (n = 290)
Overall Response rate
Placebo (n = 145)
30%
3%
Treatment-naive
32%
4%
Cytokine-pretreated
29%
3%
Cora N. Sternberg A randomized, double-blind phase III study of pazopanib in treatmentnaive and cytokine-pretreated patients with advanced renal cell carcinoma, 2009
40
Sorafenib
Treatment naïve
Cytokine Refractory
PFS
PFS
5,8 mos.
(Phase II results only)
OS
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
41
Pazopanib is efficacy
SO
Why is pazopanib a real progress in
RCC treatment ?
42
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
28%
20%
<1%
Diarrhea
48%
53%
52%
Nausea
19%
44%
26%
Anorexia
14%
40%
22%
Hand-foot
desquamation
33%
NA
6%
Alopecia
27%
24%
8%
Dyspnea
14%
51%
7%
43
 is a decrease in the production of blood cells in bone marrow.
Red blood cells
White blood cells
Platelets
 Neutropenia
 anemia
 leukopenia or neutropenia
 thrombocytopenia
 bacterial infections.
 thrombocytopenia  haemostasis.
44
 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
1%
8%
1%
R KUMAR; Br J Cancer. 2009 November 17; 101(10): 1717–1723.
45

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
10
R KUMAR; Br J Cancer. 2009 November 17; 101(10): 1717–1723.
46
 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. 2009 November 17; 101(10): 1717–1723.
47
Hypertension all grade
Grade 3/4
SORAFENIB
17%
4%
SUNITINIB
30%
8%
PAZOPANIB
40%
4%
48
Sorafenib
(All Grades)
Fatique
29%
Sunitinib (All
Grades)
Pazopanib (all
grades)
74%
19%
• Hypothyroidism plays a major part in treatment-induced fatigue
49
Hypothyroidism
Sorafenib
Sunitinib
Pazopanib
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
50
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
51



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 ?
52

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
Provide a direct compararison of the
efficacity, safety and tolerability for
Sunitinib and Pazopanib
53
↘
myelosuppression
 ↘ hypothyroidism
54
55





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
56
57

AstraZeneca

Oral inhibitor of the :
◦ VEGF-R 1/2/3
◦ C-kit
◦ PDGF-R

Efficacy Racenta vs Placebo

Phase II, active, not recruiting
58

Inhibs specifically: VEGFR 1-2-3 and PDGFR b

Low effects on C-kit or flt-3

No cross resistance with sorafenib
59
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%
60

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.
61
Phase 2 results, on 52 Patients
OS
Objective
response
rate (ORR)
10,7 mos.
10%
11,1 mos.
21.1 mos.
30%
15,7 mos
29,9 mos
44,2%
PFS
Sorafenib
Pazopanib
5,8 mos.
(Phase II results only)
Axitinib
(Phase 2
results)
62
The perfect tyrosine kinase inhibitor treating RCC

should inhib:
o VEGFR 1-2-3
o PDGFR a-b
o Raf

Without inhibiting
◦ FLT-3
◦ C-kit
63