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 ?

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

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

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)

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 !!

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

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

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

What is a tyrosine kinase receptor ?

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

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.

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

2005

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

Sorafenib scheme of action

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

TARGET study: results www.nexavar-international.com

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

www.nexavar-international.com

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

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

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

2006

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

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

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.

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

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

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

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

Therapeutic scheme before Pazopanib

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

Votrient, Pazopanib 2009

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

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

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

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

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

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

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

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

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%

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.

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. 2009 November 17; 101(10): 1717–1723. 45

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. 2009 November 17; 101(10): 1717–1723.

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. 2009 November 17; 101(10): 1717–1723. 47

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

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

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

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

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 ?

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

The third way : TOLERANCE ↘ myelosuppression ↘ hypothyroidism

Thanks for your attention

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

The upcoming molecules

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

Axitinib (Bayer, AG013736) Inhibs specifically: VEGFR 1-2-3 and PDGFR b Low effects on C-kit or flt-3 No cross resistance with sorafenib

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%

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.

(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%

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