Antoine Bianchi Alban Delepierre Pierre Mouy 1. What is Renal cell carcinoma ? Why using TKI as RCC treatments ? What are the available TKI? What.

Antoine BianchiAlban DelepierrePierre Mouy

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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 ?

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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:

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(early stage tumours)

for 25% of patients

5-years survival rates up to 90-95%

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limited Efficacity, side effects ++bad cost-effectivness

RCC patients needed improvement in treatment !!

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75% of RCC comes from pVHL mutation (Von Hippel-Lindau protein)

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-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

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Cell signaling technology

VEGF-RPDGF-R

RAF

KinomeKinome

-518 protein kinases

- Tyrosine kinase group30 families :

-> VEGFR-> PDGFR-> FGFR-> EGFR

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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.

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2005

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Sorafenib

Kinase affinity profile

Ki app (nM)

VEGFR-1 15

VEGFR-2 8

VEGFR-3 10

PDGFR- 30

PDGFR- 14

C-Kit 2.4

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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

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www.nexavar-international.com

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Cross-over: 48% of patient under placebo switched to Sorafenib



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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%

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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

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2006

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SunitinibSorafenib


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

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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.

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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

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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

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Understanding the use of targeted therapies in RCC

Robert J. Amato, Targeted Therapy and Renal Cell Carcinoma: Are We Making Progress? 2007

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Marco Antonio Arap, New directions in the management of renal cell carcinoma2007

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2009

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SunitinibSorafenib Pazopanib


Ki app (nM)

VEGFR-1 10

VEGFR-2 4

VEGFR-3 6

PDGFR- 2

PDGFR- 5

C-Kit 15

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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

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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

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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%

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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

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Pazopanib is efficacy

SO

Why is pazopanib a real progress in RCC treatment ?

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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%

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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.

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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%

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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


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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


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Hypertension all grade

Grade 3/4

SORAFENIB 17% 4%

SUNITINIB 30% 8%

PAZOPANIB 40% 4%

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Sorafenib (All Grades)

Sunitinib (All Grades)

Pazopanib (all grades)

Fatique 29% 74% 19%

• Hypothyroidism plays a major part in treatment-induced fatigue

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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

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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.


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 ?

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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

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Provide a direct compararison of the efficacity, safety and tolerability for Sunitinib and Pazopanib

↘ myelosuppression↘ hypothyroidism

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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

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AstraZeneca

Oral inhibitor of the :◦ VEGF-R 1/2/3◦ C-kit◦ PDGF-R

Efficacy Racenta vs Placebo

Phase II, active, not recruiting

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Inhibs specifically: VEGFR 1-2-3 and PDGFR

Low effects on C-kit or flt-3

No cross resistance with sorafenib

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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.

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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

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Antoine Bianchi Alban Delepierre Pierre Mouy 1. What is Renal cell carcinoma ? Why using TKI as RCC treatments ? What are the available TKI? What.

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