Dr.Amokrane, Pr. K.Bouzid Service d Oncologie Médicale CPMC,Alger VI Journées Internationales de Cancérologie de Constantine 15,16 &17 octobre 2010

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1 Dr.Amokrane, Pr. K.Bouzid Service d Oncologie Médicale CPMC,Alger VI Journées Internationales de Cancérologie de Constantine 15,16 &17 octobre 2010

2 in t ro d u c t io n RCC rarement symptomatique, Dg souvent Stade avancé 20-30% d emblée M % Stade localisé évoluent M+ Options de TRT dans RCC avancé: Chirurgie RTE (pas de place) CT (pas de place) Immunothérapie (résultats et survie limités) Thérapie ciblée (bénéfice clinique démontré,intérêt essais et recherches+++)

3 Essa is P h a se III t ria ls : t h é ra p ie s c ib lé e s d a n s R CC (p ré d o m in a n c e à c e llu le s c la ire s ) Sorafenib > Placebo (2nd line after cytokines ; Low + intermediate risk factors) Pazopanib > Placebo (treatment naive and cytokine-pretreated) Sunitinib > IFN (1st line ; Low + intermediate risk factors) IFN + bevacizumab > IFN (1st line; low + intermediate risk) Temsirolimus > IFN (1st line ; Poor risk factors) Everolimus > Placebo (after angiogenesis inhibitors) Improvment in PFS (and OS) as well as in QOL 1. Bukowski R, et al. ASCO Motzer RJ, et al. N Engl J Med Hudes G, et al. N Engl J Med Escudier B, et al. Lancet Rini BI, et al. ASCO GU 2008

4 t h é ra p ie c ib lé e d a n s R CC a va n c é Essa is p h a se III essai Ligne TRT survie Nexavar vs placebo 1,2 Median PFS: 5.5 vs 2.8 months Post cytokines (p<0.001) Median OS: 17.8 vs 14.3 months (p=0.0287) (censoring placebo at Sutent vs IFNα 3,4 1ère ligne crossover) Median PFS: 11 vs 5 (p<0.001) Torisel vs IFN Avastin + IFNα vs placebo + IFNα 5 1 ère ligne (mauvais Pc) Median OS: 26.4 vs 20.0 mois (p=0.0362) (censoring IFN at crossover) medianpfs:5,5vs3,1mois p<0,0001 Median PFS 8,5 vs 5. mois p< Everolimus vs placebo Post TKI Median PFS:4vs 1,9mois p<0,0001 Avastin+IFNvs IFN +placebo 1 ère ligne medianpfs10,2vs5,4 mois p<0.0001

5 S o ra f e n ib c ib la n t le s Ce llu le stu m o ra le s P ro lif e ra t io n e t A n g io g é n è se Cellule tumorale Cellule Endotheliale(péricyte) KIT/Flt-3/RET RAS Apoptose Autocrine loop stimulation Paracrine PDGFR-β PDGF-β RAS VEGF VEGFR-2 RAF MEK ERK Mcl-1 VHL HIF Noyau Sorafenib Mitochondria PDGF VEGF Proliferation Survival Mitochondrie Apoptose Noyau RAF MEK ERK Sorafenib Angiogénèse: Differentiation Proliferation Migration formation tubules 1. Wilhelm SM et al. Curr Pharm Des. 2002;8: ; 2. Wilhelm SM et al. Cancer Res. 2004;64: Adapted from Szcylik C et al. Presented at 2008 ASCO Annual Meeting. May 30-June 3, 2008; Chicago, IL.

6 R e le va n t e vid e n c e f ro m t ria ls o f so ra fe n ib in 1 s t lin e t re a t m e n t o f R CC Study Patients PFS DCR (%) (CR Metastati ECOG PS (n) (months) +PR+SD) c sites 0 1 (%) Phase II ND 53 (%) ( 3) 100 Phase II ND 100 Phase II ( 5) 100 ARCCS ( 3) ND ARCCS = Advanced RCC Sorafenib PFS = progression-free survival DCR = disease control rate CR = complete response PR = partial response SD = stable disease; ND = no data 1. Ratain MJ, et al. J Clin Oncol 2006;24: Jonasch E, et al. Presented at ASCO 2007, Chicago, IL,USA 3. Szczylik C, et al. J Clin Oncol 2007;25 (Abstract 5025) 4. Ryan CW, et al. J Clin Oncol 2007;25 (Abstract 5096)

7 P ro ve n e f f ic a c y a n d sa f e t y o f s o ra f e n ib d e m o n s t ra t e d in la rg e st p h a s e III s t u d y in a d va n c e d R CC: TA R G ET Advanced RCC Clear cell histology Failed one prior systemic therapy in last 8 months ECOG PS 0 or 1 Low or intermediate MSKCC R A N D O M I S E n=451 n=452 Sorafenib 400mg b.i.d. Placebo Sorafenib 400mg b.i.d. n=216 Crossover TARGET = Treatment Approaches in Renal Cancer Global Evaluation Trial Escudier B, et al. N Engl J Med 2007

8 Ef f ic a c it é e t t o lé ra n c e d e TA R G ET: R é su lt a t f in a l PFS :5,5 vs 2,8 mois SG: non atte vs 14,7mois p< p=0,015 SG :19,3 vs 15,9mois crossover) p=0,015 (06 mois post SG : 17,8vs15,2 mois crossover) SG:17,8vs 14,3 mois crossover p=0.146 (16mois post p=0.029 (censoring placebo at Escudier et al JCO vol 27 n

9 E va lua tion du V E G F (TA R G E T) Mauvais Score MSKCC PS 2 VEGF Fact Pc indépendants correlation ces fact Pc et SG p<0.001 VEGF PFS (sorafenib n=180 5,5mois HR=0,64 95%CI placebo n=176 3,3mois HR=0.64(95%CI VEGF PFS sorafenib n= 184 5,5mois HR=0.48(95% placebo n= 172 2,7mois HR= 0.48 (95% )

10 R é su m é TA R G ET Dédoublement PFS pts prétraités RCC avancé Bénéfice clinique du sorafenib/toxicité gérable Gain en SG VEGF ou bénéfice sorafenib/placebo

11 The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) expanded access programme in North America: study design Eligibility criteria Advanced, unresectable, recurrent or metastatic measurable RCC Age 15 years Ineligible for, or no access to, other sorafenib protocols Measurable disease by RECIST Open-label sorafenib 400mg b.i.d. (n=2,502) Treatment continued until PD* or intolerance Any prior systemic therapy ECOG PS 0 2 With/without brain metastases Endpoints include ORR, TTP, PFS, OS and safety Renal impairment not requiring dialysis allowed *Treatment could continue if investigator believed patient would benefit RECIST = Response Evaluation Criteria In Solid Tumors; b.i.d. = twice daily Knox JJ, et al. ASCO 2007, Chicago, IL, USA

12 A R CCS : R é p o n se % patients Réponse Ts patients (n=1,871) 1ère -ligne (n=935) 2ème-ligne (n=936) CR <1 <1 0 PR SD CR + PR + SD PD Knox JJ, et al. ASCO 2007, Chicago, IL, USA

13 A R CCS : R e sp o n se d a n s so u s-p o p u la t io n s % of patients Réponse Pré TRT bevacizumab (n=197) M+ cérébrales (n=50) Papillare histologie (n=118) 1 Chromophobe (n=18) 1 Age > 65 ans (n=762) CR PR SD CR + PR + SD PD Knox JJ, et al. ASCO 2007, Chicago, IL, USA

14 A R C C S : P F S in s t -lin e p a t ie n t s (e x t e n s io n p r o t o c o l) PFS (% patients) 100 Median PFS 8.1 months (95% CI: ) with 64% censoring (n=224) Time (weeks) Knox JJ, et al. ASCO 2007, Chicago, IL, USA Ryan CW, et al. ASCO 2007, Chicago, IL, USA

15 EU-A R CCS : st u d y d e sig n Eligibility criteria Progressive advanced RCC Failure of 1 prior systemic therapy or unsuitable for cytokine therapy ECOG PS 0 2 Life expectancy >2 months Open-label sorafenib 400mg b.i.d. (n=1,155) Treatment continued until PD or intolerance Asymptomatic brain metastases permitted, if controlled (protocol amendment) Ongoing Endpoints include safety, PFS and ORR Data cut-off for analysis: 28 February (35%) patients still on treatment Beck J, et al. ECCO 2007, Barcelona, Spain

16 EU-A R CCS : e f f ic a c it é patients évaluable (n=1,031) evaluation radiographic, (%) 828 (80.3) CR + PR, n (%) 19 (1.8) SD for 8 sem, n (%) 732 (71.0) Controle Mie 751 (72.8) PD, n (%) 77 (7.5) Median PFS, mois (95% Cl) 6.8 ( ) Beck J, et al. ECCO 2007, Berlin, Germany

17 EU-A R CCS : é f f ic a c it é d a n s so u s- p o p Sous-population Numbre patients controle maladie (%) Age <65 ans ans ECOG PS Numbre Sites M Sites M+ Lungs Liver Bones Brain Median PFS (mois) Controle maladie= CR + PR + SD 8 sem Beck J, et al. ECCO 2007, Berlin, Germany

18 S o ra f e n ib d e e ssa i c lin iq u e à la p ra t iq u e c lq e : Resultats sorafenib dans étude ARCCS confirme l efficacité et tolérance retrouvés dans l étudetarget relevant patients souspopulations M+ cérébrales age 65 ans Pts en 2éme ligne Pts en 1ére ligne

19 E ffets indés ira bles de théra pie c iblée R C C Rash ou Hand Foot Skin Reaction Hypertension Cytopenie Proteinurie Gastro- intestinal Muqueuse Sunitinib oui oui oui oui Sorafenib Pazopanib oui oui oui oui oui Bevacizumab + IFN oui oui oui Temsirolimus oui oui oui Everolimus oui oui Puzanov I et al. Presented at: 2008 ASCO Annual Meeting; May 30-June 3, 2008; Chicago, IL.

20 R isq u e c a rd io -va scu la ire Sorafenib, rates of grade 3/4 hypertension 5% in clinical trials 1 4% in EU-ARCCS (expanded access study) 2 Sunitinib, rates of grade 3/4 hypertension 8% vs 1% for IFN (p<0.05) 3 Temsirolimus increased serum triglycerides in 87% of patients increased in serum cholesterol in 83% of patients 4 both are established risk factors for CAD (Cardiac Athresclorotic Disease) Bevacizumab, rates of grade 3/4 hypertension bevacizumab + IFN group 3% versus <1% in the placebo + IFN group 5 1. Escudier B, et al. N Engl J Med 2007;356: Beck J, et al. Eur J Cancer Suppl 2007;5:300 (Abstract O#4506) 3. Sutent Prescribing Information. Available at Accessed 15 January Torisel Prescribing Information. Available at Accessed 15 January Escudier B. J Clin Oncol 2007;25(June 20 Suppl.):18S (Abstract 3)

21 Ta rg e t e d a g e n t s su it a b le f o r p a t ie n t s w it h re n a l im p a irm e n t Level of renal impairment Mild Moderate Severe Dialysis Sorafenib ND Sunitinib ND ND ND Temsirolimus ND ND ND ND Bevacizumab ND ND ND ND ND = no data Kane RC, et al. Clin Cancer Res 2006;12:271 8 Nexavar Prescribing Information. Available at Accessed 21 January 2008 Sutent Prescribing Information. Available at Accessed 21 January 2008 Torisel Prescribing Information. Available at Accessed 21 January 2008 Avastin prescribing information. Available at Accessed 21 January 2008

22 S o ra f e n ib : e sc a la d e d e d o se

23 D os e es c a la tion of s ora fenib a c c ording to tolera bility: open-la bel, pha s e II s tudy des ig n ELIGIBILITY CRITERIA Metastatic RCC Clear cell histology component 1 prior systemic therapy Adequate performance status Adequate organ function Primary endpoint safety Secondary endpoints Sorafenib 400mg b.i.d. days 1 28 (n=44) Increase dose after 4 weeks if no DLT* 41/44 patients Sorafenib 600mg b.i.d. days Increase dose after 4 weeks if no DLT* 32/41 patients Sorafenib 800mg b.i.d. day 57 onwards Continue treatment until PD or intolerance (25/32 patients who received sorafenib 800mg b.i.d. were able to maintain this dose) response rate, progression-free survival (PFS) and overall survival (OS) *Grade 3 4 drug-related adverse event b.i.d. = twice daily; PD = progressive disease DLT = dose-limiting toxicity Amato R, et al. ASCO 2007, Chicago, IL, USA

24 D o se e sca la t io n o f so ra f e n ib : su rviva l a n d t u m o u r re sp o n se Median PFS: months (95% CI: ) Median OS: months (95% CI: ) Best response (RECIST) n (%) Complete response (CR) 7 (16) Partial response (PR) 17 (39) Stable disease (SD) 6 months 9 (20) Progressive disease (PD) 11 (25) RECIST = Response Evaluation Criteria In Amato R, et al. ASCO 2007, Chicago, IL, USA

25 D o se e sca la t io n o f so ra f e n ib : g ra d e 3 4 t o xic it y Treatment was well tolerated with a predictable and manageable toxicity profile Grade 3 4 toxicity Sorafenib 800mg b.i.d. (n=32) n (%) Hypophosphataemia 9 (28) Anaemia 2 (6) Amylase/lipase 1 (3) AST/ALT 1 (3) Fatigue 1 (3) Hand foot skin reaction 1 (3) ST = aspartate aminotransferase LT = alanine aminotransferase Amato R, et al. ASCO 2007, Chicago, IL, USA

26 In c id e n c e m é t a s t a se s c é ré b ra le s :é t u d e re t ro sp e c t ive TA R G ET n = Comparaison placebo, patients recevant sorafenib dans developpt M+ cérébrales (8/66 vs 2/73; p=0.049) Réduction du risque métastase cérébrale à 2 ans (3% vs 12%) Incidence M+ cérébrales (%) Sorafenib Placebo Suivi médian: 12,5 mois (range = ) Analyse retrospective, 2 centrestarget Temps (mois) Massard C, et al Annals of Oncology Advance Acess publié 10/2009

27 P a t ie n t s a ya n t é c h a p p é a u TR T a n t ia n g io g é n iq u e e n 1 è re lig n e

28 A p rè s é c h e c su t e n t, so ra f e n ib a p p o rt e g a in P FS e t b é n é f ic e c lin iq u e Institut Gustave Roussy étude retrospe Median PFS for sunitinib sorafenib (n=22) Sunitinib: 22 weeks Sorafenib: 17 weeks Second therapy First therapy Best response to sunitinib Response to sorafenib (n) PR SD PD PR (n=5) SD (n=12) PD (n=5) 3 2 Sablin MP, et al. ASCO 2007

29 c o n c lu sio n Trois molécules antivegf (pazopanib,sutent et sorafenib Un AC monoclonal (bévacizumab associé IFN) Deux molécules mtor(temsirolimus,everolimus ont montré leur efficacité significative TRT RCC avancé avec prolongation de survie Urgent d améliorer nos connaissances dans résistance et synergie de ces TRT Selection : bonne molécule pour bon patient au bon moment

30 mer ci