pazopanib : arguing for a third way
DESCRIPTION
Pazopanib : Arguing for a third way. Antoine Bianchi Alban Delepierre Pierre Mouy. 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 ?. - PowerPoint PPT PresentationTRANSCRIPT
Antoine BianchiAlban DelepierrePierre 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
3
Renal cell Carcinoma Renal cell Carcinoma ( RCC)( RCC)
$ 1 billion in 2006
RCC market is expected to more than double before 2017 Decision ressources inc Pharmacor report’s Renal cell
carcinoma
4Source: IMS health
Role of surgery:
5
(early stage tumours)
for 25% of patients
5-years survival rates up to 90-95%
6
limited Efficacity, side effects ++bad cost-effectivness
RCC patients needed improvement in treatment !!
7
75% of RCC comes from pVHL mutation (Von Hippel-Lindau protein)
8
-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
9
Cell signaling technology
VEGF-RPDGF-R
RAF
KinomeKinome
-518 protein kinases
- Tyrosine kinase group30 families :
-> VEGFR-> PDGFR-> FGFR-> EGFR
10
11
Coloured molecule: ATP
Gray molecule: inhibitor
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
14
2005
15
Sorafenib
Kinase affinity profile
Ki app (nM)
VEGFR-1 15
VEGFR-2 8
VEGFR-3 10
PDGFR- 30
PDGFR- 14
C-Kit 2.4
16
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
17
18
www.nexavar-international.com
19
Cross-over: 48% of patient under placebo switched to Sorafenib
www.nexavar-international.com
www.nexavar-international.com
21
RESPONSE SORAFENIB
Objective response 10%
Complete <1%
Partial 10%
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
OverallResponse 84%
22
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
The TARGET study gave agreement as a second line treatment for RCC
the first-in-class in RCC
23
24
2006
25
SunitinibSorafenib
Kinase affinity profile
Ki app (nM)
VEGFR-1 229
VEGFR-2 51
VEGFR-3 30
PDGFR- 28
PDGFR- 7
C-Kit 0,45
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
26
27
Overall Survival and Updated Results for Sunitinib Compared With Interferon Alfa in Patients With Metastatic Renal Cell Carcinoma Robert J. Motzer et al.
Sutent average PFS is 11,8 months, compared with 5,5 months for patients receiving interferon alfa.
28
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
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% NA
Hypertension 17% 24%
Dyspnea 14% 28%
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
31
Understanding the use of targeted therapies in RCC
Robert J. Amato, Targeted Therapy and Renal Cell Carcinoma: Are We Making Progress? 2007
32
33
Marco Antonio Arap, New directions in the management of renal cell carcinoma2007
34
2009
35
SunitinibSorafenib Pazopanib
Kinase affinity profile
Ki app (nM)
VEGFR-1 10
VEGFR-2 4
VEGFR-3 6
PDGFR- 2
PDGFR- 5
C-Kit 15
36
Pz Pz
Pz
Pz
Pz
Pz
VEGF-A/BVEGF-CPDGF-
PDGFR
VEGFR-1/2
VEGFR-3
Pz
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
38
N PFS 5 month
s
10 month
s
15 month
s
20 month
s
Pazopanib 290 9.2 159 (55%)
76 (26%)
29 (10%)
60,02
Placebo 145 4.2 38 14 2
Pazopanib : 9,2 monthsPlacebo : 4,2 months
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
RESPONSE SORAFENIB SUNITINIB PAZOPANIB
Objective response 10% 31% 30%
Complete <1% 0% <1%
Partial 10% 31% 30%
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)
Pazopanib (n = 290) Placebo (n = 145)
Overall Response rate 30% 3%
Treatment-naive 32% 4%
Cytokine-pretreated
29% 3%
40
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
Treatment naïveCytokine
RefractoryOS
PFS PFS
Sorafenib5,8 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
41
Pazopanib is efficacy
SO
Why is pazopanib a real progress in RCC treatment ?
42
43
Looking at Adverse effects…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%
44
is a decrease in the production of blood cells in bone marrow.
Red blood cells anemiaWhite blood cells leukopenia or neutropeniaPlatelets thrombocytopenia
Neutropenia bacterial infections.
thrombocytopenia haemostasis.
45
myelosuppression is observed with the 3 Tyrosine Kinase Inhibitors.
R KUMAR; Br J Cancer. 2009 November 17; 101(10): 1717–1723.
Frequency of Myelosuppression grade 3/4
TKI’s Sorafenib Sunitinib Pazopanib
Neutropenia 5% 12% 1%
Thrombocytopenia 1% 8% 1%
46
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.
47
Cellular IC50 for inhibition
IC50 (nM)
Receptors
Sorafenib Sunitinib Pazopanib
C-Kit 15 0.45 2.4
Flt-3 22 0.6 230
Other Receptors are implied in haematopoiesis: Flt-3; C-Kit
R KUMAR; Br J Cancer. 2009 November 17; 101(10): 1717–1723.
48
Hypertension all grade
Grade 3/4
SORAFENIB 17% 4%
SUNITINIB 30% 8%
PAZOPANIB 40% 4%
49
Sorafenib (All Grades)
Sunitinib (All Grades)
Pazopanib (all grades)
Fatique 29% 74% 19%
• Hypothyroidism plays a major part in treatment-induced fatigue
50
Sorafenib Sunitinib Pazopanib
Hypothyroidism 41% 85% 7%
Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy
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
51
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
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 RCCdatas expected during 2010
53
Provide a direct compararison of the efficacity, safety and tolerability for Sunitinib and Pazopanib
↘ 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
Low effects on C-kit or flt-3
No cross resistance with sorafenib
59
60
Side effect Pazopanib (all grades)
AxitinibPhase 2 results
Fatique 19% 51%
Diarrhea 52% 59%
Rash/desquamation <1% 11%
Hypertension 40% 57%
Phase 2 results
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
62
Phase 2 results, on 52 Patients
PFS OSObjective response rate (ORR)
Sorafenib5,8 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%
The perfect tyrosine kinase inhibitor treating RCC
should inhib:oVEGFR 1-2-3o PDGFR oRaf
Without inhibiting◦ FLT-3◦ C-kit
63