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Pazopanib : Arguing for a third way

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 ?.

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Pazopanib : Arguing for a third way

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  1. Pazopanib: Arguing for a thirdway 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. RenalcellCarcinoma ( RCC) • Accounts for 85 % of all malignantkidneytumours • Most agressive of the urologic cancers • 40000 deaths/year • Classicaldiagnosis : -Flank pain • Hematuria • Palpable abdominal mass • Extremelypoorprognosiswhenadvanced • 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 Source: IMS health

  5. ApprovedtherapiesbeforeTKIs Role of surgery: (early stage tumours) for 25% of patients 5-years survival rates up to 90-95%

  6. ApprovedtherapiesbeforeTKIs limitedEfficacity, sideeffects ++ badcost-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 growthtumor • 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. Kinome VEGF-R PDGF-R • 518 protein kinases • Tyrosine kinase group • 30 families : • > VEGFR • > PDGFR • > FGFR • > EGFR RAF Cell signaling technology

  10. Whatis a tyrosine kinase receptor ?

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

  12. WhyusingTKIs 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 theirstrenghts and weakness ?

  14. 2005

  15. Kinase inhibited by Sorafenib Sorafenib 15

  16. Sorafenib scheme of action

  17. Clinical trial: TARGET study • Patient withadvancedmetastasic RCC • On patients havingreceived a priorsystemictherapy • 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 www.nexavar-international.com

  19. TARGET study: results • Cross-over: 48% of patient under placebo switched to Sorafenib www.nexavar-international.com

  20. www.nexavar-international.com

  21. Tumorresponse rate Overall Response 84%

  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 Sorafenib Sunitinib 25

  26. Clinical trial: Methods • Patients withadvancedmetastasic RCC untreated • 50mg once a day • 4 weeks of treatment, 2 weeks of treatmentholiday • Versus Interferon- (was the best availabletreatment) • 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: Tumorresponse

  29. Clinical trial results: Adverse effects

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

  32. TherapeuticschemebeforePazopanib

  33. TherapeuticschemebeforePazopanib Marco Antonio Arap, New directions in the management of renal cell carcinoma 2007

  34. Votrient, Pazopanib 2009

  35. Kinase profile of Pazopanib 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 withmetastasic RCC • 800mg once a day • No treatmentholiday • versus placebo • Half patient naïve and halfwithprior cytokine treatment • Primary endpoints: • PFS: Progression free survival

  38. Clinical trial of Pazopanib Pazopanib : 9,2 months Placebo : 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. Clinical trial of Pazopanib

  40. Clinical trial of Pazopanib 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 * : Cross-over

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

  43. Lookingat Adverse effects…

  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.

  45. High grade Myelosuppression • myelosuppressionisobservedwith the 3 Tyrosine Kinase Inhibitors. R KUMAR; Br J Cancer. 2009 November 17; 101(10): 1717–1723. 45

  46. WhyTKIs cause Myelosuppression? • VEGFR are essential for hematopoiesis and one of the main target of thoseTKIs. R KUMAR; Br J Cancer. 2009 November 17; 101(10): 1717–1723.

  47. WhyisPazopanibcausinglesshigh grade myelosuppression? • OtherReceptors are implied in haematopoiesis: Flt-3; C-Kit R KUMAR; Br J Cancer. 2009 November 17; 101(10): 1717–1723. 47

  48. Arterial hypertension withTKIs

  49. Fatigue observedwithTKis • Hypothyroidism plays a major part in treatment-induced fatigue

  50. HypothyroidismwithTKIs • 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

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