Treatment Options in RCC: Past, Present and Future. Pr Stéphane Oudard, MD, PhD Georges Pompidou Hospital Paris, France

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1 1 Treatment Options in RCC: Past, Present and Future Pr Stéphane Oudard, MD, PhD Georges Pompidou Hospital Paris, France

2 2 Renal Cell Carcinoma (RCC) 208,500 new cases of kidney cancer are diagnosed this year worldwide 101,900 deaths In the Europe Union 1 46,000 new cases of kidney cancer are diagnosed each year 25-30% of patients have metastatic disease at diagnosis Prognosis: SEER 5-year 5 relative survival rates 71 to 97% if localized, confined by renal capsule (T1-2) 20 to 53% if locally advanced (T3-4, N+) < 10% if distant metastases 1 Levy F et al. Annal Oncol 2004;

3 3 Renal Cell Carcinoma (RCC) Newly diagnosed metastatic RCC have been classified by MSKCC model 1 Low Karnofsky PS (< 80%) Lactate dehydrogenase level > 1.5 time (upper limit of N) Hemoglobin level < lower limit of N High corrected serum calcium level (> 10 mg/dl) Absence of nephrectomy No prognostic factor: OS 22 months 1 prognostic factor : OS 11.9 months > 2 prognostic factors: OS 5.4 months 1 Motzer R et al. J Clin Oncol 1999;17:

4 4 Different tumor types and Rational for Antiangiogenic use Kidney cancer: Highly vasculature tumor Vascularization due to a GF: VEGF (Vascular( Endothelial Growth Factor) Overexpression of VEGF is often linked to Von Hippel Lindau (VHL) gene mutation (>( 70% clear cell carcinoma)

5 5 Underlying Biology of clear cell RCC Loss of VHL gene function in clear-cell cell RCC results in up-regulated expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) 1 VEGF and PDGF promote tumour angiogenesis that may contribute to tumour hypervascularity in RCC 1 Kaelin WG Jr. Clin Cancer Res 1994;10:6290s 6295s * DNA-Hypoxia response element *

6 ANGIOGENESIS : A DYNAMIC BALANCE BETWEEN ACTIVATORS AND INHIBITORS HIF ON switch ACTIVATORS Growth factors (VEGF, bfgf, PDGF, PlGF) Angiopoietin 1 Fibrinolytic enzymes (tpa, upa) MMPs Cytokins (TNF, TGF, IL8) ECM proteins (laminin) INHIBITORS MEC proteins Angiopoietin 2 TIMPs Cytokins (IL-10) Angiostatin, Endostatin Thrombospondins Netrin1/Unc5B AGT (serpins) Angiopoietin like 4 OFF 6

7 VEGF Overexpression and Abnormal blood vessels Thurston et al. Science 1999, Vol

8 Metastatic RCC An area of Unmet Medical Need mrcc is generally resistant to standard chemotherapy Nephrectomy mainstay of treatment Cytokine therapy (IL-2 2 or IFN-α) standard of care until now only a minority of patients experience clinical benefit 1 adverse events may be problematic second-line treatment with alternative cytokines produces responses in <5% of patients 2 Alternative agents are urgently needed Current drug treatments are limited, not effective and toxic 1 Bukowski RM. Semin Urol Oncol 2001;19: Escudier B et al. J Clin Oncol 1999;17:

9 Cytokine Therapy in Phase III Trials Regimen No. of Pts % Response Survival Benefit MRCRCC 1 IFN MPA* % 2% Yes Pyrhonen et al 2 Vinblastine IFN + Vinblastine % 16.5% Yes Negrier et al 3 IL-2 IFN IL IFN % 8% 19% No Yang et al 4 High dose IL-2 Low dose IL-2 SQ IL % 11% 10% 1 Lancet 1999;353:14; 2 JCO 1999,17: , 3 NEJM 1998;338:1272; 4 JCO 2003;21:3127; *Medroxyprogesterone No 10

10 Therapeutic Targets in RCC β pvhl α = HIF mtor Bevacizumab Temsirolimus VEGF VEGFR PDGF PDGFR Axitinib Sunitinib Sorafenib Other potential targets: Raf kinase and EGFR Kaelin WG. Nat Rev Cancer 2002;2:

11 12 Sunitinib Mechanism of Action in RCC Loss of VHL Protein Function VEGF PDGF VEGFR VEGF PDGF PDGFR Vascular Endothelial Cell Pericyte/Fibroblast/ Vascular Smooth Muscle Sunitinib Vascular permeability Cell survival, proliferation, migration Vascular formation, maturation Inhibition of RCC pathogenesis and progression

12 Phase II Evaluation of Sunitinib in Metastatic RCC Two Independent, Single-Arm, Multicenter, Phase II Studies 1, 2 (Study 014: N=63; Study 1006: N=106) Patients with Advanced Disease and Failure of of Prior Cytokine Therapy Sunitinib Continue Sunitinib Treatment Unless Progression or or Intolerability Dosing schedule 4 weeks on, 2 week off (4/2) Sunitinib 50mg/day* Sunitinib *Dose reduction permitted (to 37.5mg/day and then to 25mg/day) 1 Motzer et al, JCO 2006;24(1):16-24 ; 2 Motzer et al, JAMA 2006;295:

13 Sunitinib Phase II: Patient Characteristics Study 014 (N=63) Study 1006 (N=105) Pooled Analysis (N=168)* Median age (years) ECOG PS 0/1 (%) 54/45 54/46 54/46 Clear cell/other histology (%) 87/13 100/0 95/5 Prior nephrectomy (%) Prior radiation therapy (%) Number of metastatic sites (%) > *One patient was omitted from the efficacy analysis of study 1006 due to a change in diagnosis 16

14 19 Sunitinib therapy for patients with mrcc: Updated results of two phase II trials (2007) Updated efficacy data for 168 evaluable pts: ORR : 45% (95% CI: 39%, 54%) Median PFS: 8.4 Mo (95%( CI: 7.9, 10.7) Median OS: 22.3 Mo (95% CI: 14.8, 36.0) Median duration of response : 11.6 Mo (95% CI: 9.9, 15.2) Patients alive at 2 years : 48% 20 pts remain on treatment with sunitinib longest pt on the drug for >3.5 years with PR for >3 years 1 pt with a complete response for >2 years Motzer R et al, J Urol 2007

15 20 Progression-Free Survival in Responders and Non- Responders (Studies 014 and 1006) Progression-Free Survival (Months) Responders (N=71) Stable disease 3 3 months (N=41) Stable disease <3 months or progressive disease (N=56) 14.8 (95% CI: ) 7.9 (95% CI: ) 2.1 (95% CI: ) 2.3)

16 21 Interpretation of response in mrcc treated by AA using RECIST Criteria

17 Dynamic contrast enhanced (DCE) imaging 22

18 22 Dynamic contrast enhanced (DCE) imaging Before injection of drug contrast

19 22 Dynamic contrast enhanced (DCE) imaging Before injection of drug contrast VCS

20 22 Dynamic contrast enhanced (DCE) imaging Before injection of drug contrast VCS Aortic vessel

21 22 Dynamic contrast enhanced (DCE) imaging Before injection of drug contrast VCS Aortic vessel After drug contrast

22 Aorte Before treament Metastasis Aorte Metastasis Analyse réalisée à l HEGP, radiologie vasculaire, Pr CA Cuenod/ L Fournier 23

23 Aorte Before treament Metastasis Aorte After treatment Metastasis Analyse réalisée à l HEGP, radiologie vasculaire, Pr CA Cuenod/ L Fournier 23

24 28 Phase 3 Randomized Trial of Sunitinib malate (SU11248) versus Interferon-alfa as First-line Systemic Therapy for Patients with Metastatic Renal Cell Carcinoma RJ Motzer, TE Hutson,, P Tomczak, MD Michaelson, RM Bukowski,, O Rixe, S Oudard, ST Kim, CM Baum, RA Figlin and the SU11248 Study Group Supported by Pfizer Inc MSKCC

25 30 Randomization & Study Treatment N=750 Stratification Factors LDH 1.5 vs >1.5xULN ECOG PS 0 vs 1 Presence vs Absence of Nephrectomy R A N D O M II Z A T II O N Sunitinib (n=375) mg po podaily on on Schedule 4/2 4/2 (4 (4 weeks on/2 weeks off) IFN-α (n=375) 3 MU TIW 1 st st week 6 MU TIW 2 nd nd week 9 MU TIW 3 rd rd week thereafter; SC SC Injection Repeated 6-week 6 cycles Response and safety assessments Dose reduction for toxicity Treatment continued unless progression or intolerance

26 32 Best Response Response (RECIST) Sunitinib (n=374) Investigator Assessment IFN-α (n=373) Independent Central Review Sunitinib (n=365) IFN-α (n=346) No. of patients (%) Objective response* 174 (46) 45 (12) 142 (39) 29 (8) Complete response 5 (1) 4 (1) 0 0 Partial response 169 (45) 41 (11) 142 (39) 29 (8) Stable Disease 152 (41) 205 (55) 146 (40) 165 (48) PD or Not evaluable 48 (13) 123 (33) 77 (21) 152 (44) *Sunitinib vs IFN-α: P<

27 Progression-Free Survival (Independent Central Review) 1.0 Progression-free survival probability Hazard Ratio= % CI (0.439, 0.658) p< Sunitinib Median: 11.0 months (95% CI: ) IFN- α Median: 5.1 months (95% CI: ) No. at Risk Time (Months) Sunitinib:

28 34 Progression-Free Survival by MSKCC Risk Status* MSKCC Risk Factors: 0 (Favorable) Independent Central Review MSKCC Risk Factors: 1 2 (Intermediate) MSKCC Risk Factors: 3 (Poor) Progression-free survival probability Sunitinib (n=143) Median not reached IFN-α (n=121) Median: 8 months (95% CI: 7 NA) Hazard ratio=0.371 (95% CI: ) Hazard ratio=0.388 (95% CI: ) Sunitinib (n=209) Median: 11 months (95% CI: 11 11) IFN-α (n=212) Median: 4 months (95% CI: 3 4) Sunitinib (n=23) Median: 4 months (95% CI: 1 10) IFN-α (n=25) Median: 1 month (95% CI: 1 2) Hazard ratio=0.534 (95% CI: ) Time (months) Time (months) Time (months) *Motzer et al. J Clin Oncol 2002;20: ; excludes 17 pts from IFN-α with missing data

29 35 Patient Baseline Characteristics Predictive of Progression-free Survival for 375 Patients Treated on the Sunitinib arm of the Phase 3 Trial

30 Progression-free Survival According to Risk Factors Derived from Sunitinib Treated Patients Risk Factors 0 N 112 Median PFS (months) % CI (months) Progression-free survival probability ECOG PS (0 vs. 1) Time from diagnosis to treatment ( 1( 1 yr vs. < 1 yr) Corrected calcium ( 10 vs. >10 mg/dl dl) *Outcome by investigator assessment Time (Months) Motzer R, ASCO

31 Overall Survival Overall Survival Probability Hazard Ratio = 0.65 (95% CI: ) P = * Sunitinib (n=375) Median not reached IFN-α (N=375) Median not reached Time (Months) No. at Risk Sunitinib: No. at Risk IFN-α: *The observed p-value did not meet the pre-specified level of significance for this interim analysis 38

32 Treatment-Related Adverse Events Event Fatigue Diarrhea Nausea Stomatitis Hypertension Hand-foot syndrome Ejection fraction decline Pyrexia Chills Myalgia Flu-like like symptoms All grade Sunitinib (%) Grade 3/4 7 5* 3 1 8* 5* <1 0 All grade IFN-α (%) Grade 3/4 11/<1* 0 1 <1 < <1 <1 * Greater frequency, P <

33 40 Laboratory Abnormalities Sunitinib (%) IFN-α (%) Event All grade Grade 3/4 All grade Grade 3/4 Neutropenia 72 11/1* 46 7 Anemia 71 3/<1 64 4/<1 Thrombocytopenia 65 8* 21 0 Lymphopenia * Hypophosphatemia 36 4/< Hyperamylasemia 31 4/1* 28 2/<1 * Greater frequency, P <0.05

34 41 Asthenia Fatigue is often cited as one of the most common reasons for discontinuation of treatment Fatigue is multifactorial A greater risk of fatigue is likely where the patient profile is : Elderly and frail Large tumour burden MANAGEMENT OF FATIGUE Provide counseling on what to expect from treatment and psychological support where feasible Determine whether the patient is suffering from anemia/ hypothyroidism (check every 2-33 cycles), depression For first 2 to 3 cycles provide close support and involvement with patient to counsel and motivate on coping with fatigue At end of 2nd cycle conduct a focused check-up with the patient on the level of fatigue level and impact on quality of life Modify dosage to 37.5mg where fatigue is disruptive to quality of life Enable patient to self monitor after 3rd cycle

35 Endocrine toxicity HYPOTHYROIDISM Frequent event with Sunitinib Sunitinib: Increase TSH level during treatment in 70% of the pts In daily practice Dosage of T4 & TSH before treatment and then every 3 months Supplementation in case of hypothyroïdism Rini BI et al, J Natl Cancer Inst

36 43 Hypertension A full cardiovascular screening should be performed before commencement of treatment to identify any compounding factors to hypertension If Hypertension exists, treat it and delay commencement of treatment until the hypertension is under control MANAGEMENT OF HYPERTENSION Check and control HT before commencing treatment Measure 3 / week during the first 2 cycles Conduct a 2nd full CV screening at 12 weeks Measure 1 / month after the first 2 cycles Adapt HT treatment to reflect the discontinuous treatment cycle, knowing that 2-week 2 off-cycle relieves side effects

37 Hypertension: check blood pressure Azizi M, Chedid A & Oudard S, N Engl J Med

38 45 Cardiac dysfunctions (Sunitinib) Due to mitochondrial injuries and cardiomyocyte apoptosis 11% of pts had cardiovascular event: cardiac heart dysfunction and a coronary artery diseases Sunitinib induces increase in mean systolic and diastolic blood pressure (47%) Associated with asymptomatic LVEF reduction (28%) LVEF is recommended to monitor this side effect especially in at risk patients This toxicity usually resolved upon treatment discontinuation

39 50 Sunitinib is Effective Therapy for Metastatic RCC January 2006: US FDA approval for advanced RCC July 2006: EMEA conditional approval for the treatment of cytokine-refractory advanced and/or metastatic RCC January 2007: EMEA approval for the first-line treatment of advanced and/or metastatic RCC

40 53 Sunitinib Expanded Access Study Patient Characteristics Median age, (range) ECOG PS* Prior nephrectomy Histology* Clear cell Other - - * Missing: PS = 2%, histology = 0.4% n = 2, (19-85) 1985 (84.8%) 308 (13.2%) 2118 (90.5%) 2056 (87.8%) 276 (11.8%)

41 54 Sunitinib Expanded Access Study Patient Characteristics Prior therapy Antiangiogenic Cytokines - - n = 2, (7.1%) 1938 (82.8%) Prior cytokine Rx (n = 1,840) 0 favourable 1-2 intermediate 3 poor 532 (28.9%) 606 (32.9%) 181 (9.8%)

42 Sunitinib cross the brain blood barrier Annal Oncol

43 Exposure-Response of Sunitinib in Metastatic Renal Cell Carcinoma (mrcc): a Population Pharmacokinetic/Pharmacodynamic (PKPD) Approach Objectives Meta-analysis analysis of pharmacokinetic and efficacy data from all clinical studies with single-agent sunitinib in mrcc To evaluate differences in response to sunitinib as a function of individual sunitinib exposures To evaluate relative efficacy of sunitinib 50 mg/day on 4/2 schedule vs mg/day on CD schedule Total number of patients: 237 Treatment naïve 42 / Cytokine Refractory 195 Houk BE, ASCO

44 Probability of PR or CR in mrcc Increased with Mean Daily Sunitinib Exposure Probability of a response 1.0 Mean 95% CI P=0.023 for AUC AUCss sunitinib (ug hr/ml) PR = partial response; CR = complete response 63

45 66 Conclusions In mrcc, sunitinib displays greater efficacy in patients with the highest exposures higher probability of PR with increasing exposure longer TTP and OS with higher exposure greater changes in tumor volume with higher exposure Sunitinib 37.5 mg/day CD appears equally effective as 50 mg/day 4/2 schedule Similar trends displayed with exposure in GIST Ongoing exposure-response response work in breast, lung and colorectal cancer

46 Plasma VEGF level at D0, D28 and D42 for each patient (n = 33 pts) VEGF plasma level (ng/ml de plasma) J0 J28 J42/J0 J28 J42/J0 J28 J42/J0 J28 J42/J0 J28 J42 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 67

47 Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study Study design Multicenter phase II study: Axitinib (AG ) 5 mg twice daily Number pts: 52 pts Primay endpoint: OR (RECIST criteria) Results ORR: 44% with 2 CR and 21 PR Stable patients: 22 pts corresponding to a clinical benefit of 86% Median response duration : 23 months Median time to progression: 15.7 months Median overall survival: 29.9 months Toxicity: asthenia, diarrhea, hypertension Rixe O et al, Lancet Oncol

48 Activity of Axitinib using RECIST criteria Rixe O et al, Lancet Oncol

49 Eligibility criteria Histologically/cytologically confirmed, unresectable and/or metastatic disease Clear cell histology Measurable disease Failed one prior systemic therapy in last 8 months ECOG PS 0 or 1 Good organ function (1:1) Randomization n~884 Stratification Motzer criteria Country Sorafenib 400 mg bid Placebo Major endpoints PFS (alpha=0.01) Survival (alpha=0.04) No brain metastasis 73

50 SORAFENIB RESULTS 74

51 Final Results of the phase 3 trial of Sorafenib in Advanced RCC (TARGETs) n=903 patients Sorafenib vs Placebo Final analysis (561 events) 48 % of placebo patients have cross-over over to Sorafenib Median OS (months( months) Sorafenib Placebo Statistical Significance 1st Analysis NR 14.7 NS May nd Analysis NS Nov 2005 Final NS Sept 2006 Censored S June

52 76 Phase III TARGET : Sorafenib toxicity Tolérance Grade 3/4 Hand foot syndrome 6% Diarrhea 5% Neutropenia 13% Hypophosphatemia 13% Hyperamylasemia 12%

53 Phase II Trial of Sorafenib vs IFN as 1st- Line Treatment in mrcc: Study Design Eligibility Criteria Confirmed, unresectable and/or metastatic disease Clear cell histology Measurable disease No prior systemic therapy All MSKCC risk groups No brain metastasis (N=189) R A N D O M I Z A T I O N (n=97) (n=92) Sorafenib 400 mg bid IFN 9 MIU tiw Progression Sorafenib 600 mg bid Primary end points: PFS Escudier B, et al. ASCO Abstract 4501 (Oral presentation) 77

54 Progression-free Survival: Period 1 Independent Assessment Progression-free survival (% patients) Median PFS Sorafenib = 5.7 months IFN = 5.6 months Hazard ratio = 0.88 (95% CI: ) P=0.504 (log-rank test) Time from randomization (months) Patients at risk Sorafenib IFN Escudier B, et al; Presented at the 5th International Symposium on Targeted Anticancer Therapies; Amsterdam,; 8 March 2007 and ASCO

55 79 A Phase 2 trial of intra-patient dose- escalated sorafenib in patients with mrcc Phase 2 second line study n=44 Escalation from 400 mg bid to 800 mg bid 93 % of the patients could be dose escalated 32 pts at 1600 mg CR 16 % (7) PR 39 % (17) SD > 6 months 20 % PFS 8.4 months Well tolerated? Amato R. ASCO 2007, Abstract 5026

56 Growth factors and m-tor m signaling pathway Growth Factors IGF-1, VEGF, ErbB, etc Oxygen, energy, and nutrients Ras/Raf pathway kinases S6 S6K 1 PTEN TSC2 TSC1 PI3-K Akt/PK B Protein Production Cell Growth and Proliferation mtor Ras/Raf Abl ER Angiogenesis RAD001 CCI-779 4E-BP1 elf-4e Normal Cells: role of mtor in angiogenesis and proliferation Deregulation of mtor pathway frequent in different tumor types Cancer cells: RAD001 and CCI-779 Anti-proliferative effect Inhibition of angiogenesis Potentialisation of chemotherapy and targeted drugs 86

57 Temsirolimus Results mtor kinase inhibitor Inhibits translation of several key proteins that regulate cell cycle progression and angiogenesis Global ARCC Trial Temsirolimus vs. IFN Temsirolimus + IFN vs. IFN Modified MSKCC criteria (Poor-Risk Feature Patients) Minimum of 3 following criteria LDH > 1.5 x ULN Hb < LLN Ca ++ > 10 mg/dl Time from diagnosis to first treatment < 1 yr Karnosfky PS Multiple organ sites of metastasis 87

58 88

59 ESTABLISHED IN 1812 July 31, 2003 VOL. 349 (5) A Randomized Trial of Bevacizumab, an Anti Vascular Endothelial Growth Factor Antibody, for Metastatic Renal Cancer N = 79 Phase II 90

60 AVOREN (Bevacizumab): study design IFN-α2a + bevacizumab (n=327) PD RCC patients (n=649) 1:1 IFN-α2a + placebo (n=322) Bevacizumab/placebo 10 mg/kg i.v. q2w until progression IFN-α2a 9 MIU s.c. three times/week (maximum of 52 weeks) (dose reduction allowed) Multinational ex-us study: 101 study sites in 18 countries PD Stratification factors: country and Motzer score PD = progression of disease; i.v. = intravenous; s.c. = subcutaneous P.I. Bernard Escudier 91

61 92 AVOREN study: Tumor response* 100 IFN + placebo (n=289) 100 Bevacizumab + IFN (n=306) Percentage change of sum longest diameter of target lesions % 70% *Patients with measurable disease only; investigator assessed

62 93 Progression-free survival (investigator assessed) Probability of being progression-free Number of patients at risk HR=0.63, p< Median progression-free survival: Bevacizumab + IFN = 10.2 months IFN + placebo = 5.4 months Time (months) IFN + placebo Bevacizumab + IFN

63 Interim analysis of overall survival (251 of 450 scheduled events) Probability of survival Number of patients at risk HR=0.75 (95% CI: ), p<0.0267* Median overall survival: Bevacizumab + IFN = NR IFN + placebo = 19.8 months Time (months) IFN + placebo Bevacizumab + IFN *Stratified by Motzer score and region category; unstratified analysis HR=0.79, p=0.067; prespecified level of significance p=0.0056; Not reached

64 Selected grade 3/4 adverse events* Number of patients (%) Adverse event Any grade 3/4 adverse event Fatigue/asthenia/malaise Proteinuria Hypertension Hemorrhage Venous thromboembolism Gastrointestinal perforation Arterial ischemia *Based on safety population IFN + placebo (n=304) 137 (45) 46 (15) 0 (0) 2 (0.7) 1 (0.3) 2 (0.7) 0 (0) 1 (0.3) Bevacizumab + IFN (n=337) 203 (60( 60) 76 (23( 23) 22 (6.5( 6.5) 13 (3.9( 3.9) 11 (3.3( 3.3) 6 (1.8) 5 (1.5) 4 (1.2) 95

65 96 Side effect with IFN: dose reduction wo lost in efficacy? Clear relationship between IFN dose and toxicity Dose reduction is associated with a better quality of life In the Avoren Study: 40% pts 131/327 have a decrease in IFN in the Bevacizumab + IFN arm Maintenance of the same ORR?

66 100 Treatment Algorithm in mrcc mrcc first line treatment No more indication of IFN For young pts PS=0, one metastatic site, high CAIX : IL + IFN SUTENT for all the other indications TORICEL for modified Motzer prognosis group? AVASTIN + IFN mrcc second line treatment Nexavar If Nexavar first line: Sutent second line Prospective clinical trials: RAD001

67 101 Treatment Algorithm in mrcc Adjuvant therapy: high risk of relapse Ongoing clinical trials (S-TRAC, SORCE, ASSURE) Neoadjuvant therapy: non operable patients, treatment with sutent Surgery possible Indication of nephrectomy in metastatic situation?

68 S-TRAC: Sunitinib Phase III Trial in Adjuvant Renal Cancer Treatment Begin accrual in Europe High-risk patients according to UISS Staging System* N=236 Endpoint: DFS N E P H R E C T O M Y Stratify R A N D O M I S E Sunitinib 50 mg/day 4 weeks on/2 weeks off for 1 year Placebo for 1 year *T3 N0 or NX, M0, Fuhrman s grade 2, ECOG 1 or T4 N0 or NX, M0, any Fuhrman s grade, and any ECOG status or Any T, N1-2, M0, any Fuhrman s grade, and any ECOG status NCT Clinicaltrials.gov 102

69 ASSURE Phase III Trial: Adjuvant Sorafenib Sunitinib Unfavourable REnal Cell Carcinoma ECOG study; currently recruiting Non-metastatic RCC Disease stage II IV N=1,332 N E P H R E C T O M Y Stratify* R A N D O M I S E Sunitinib 50 mg/day 4 weeks on/2 weeks off Total = 9 cycles Sorafenib 400 mg twice daily for 6 weeks Total = 9 cycles Placebo twice daily for 6 weeks Total = 9 cycles Primary endpoint: DFS at 5 years Duration: 1 year *UISS (II V); Histologic subtype clear-cell/non-clear cell Biopsy at recurrence NCT Clinicaltrials.gov 103

70 SORCE Phase III Trial: SOrafenib in Patients with Resected Primary Renal CEll Carcinoma Patients with high and intermediate risk resected RCC Planned N=1,656 N E P H R E C T O M Y Stratify R A N D O M I S E Sorafenib 400 mg twice daily for 3 years (n=621) Sorafenib 400 mg twice daily for 1 year followed by placebo for 2 years (n=621) Placebo for 3 years (n=414) 1º end point: Disease-free survival 2º end points: RCC-specific survival time, toxicity, QOL and biomarkers Duration: 1 vs. 3 years NCT Clinicaltrials.gov 104

71 105 CARMENA TRIAL: Impact of the radical nephrectomy on the outcome in mrcc n=576 Metastatic RCC Biopsy, Clear Cell RCC R A N D O M I Z A T I O N 1:1 RN and then SUTENT 50 mg PO/J 4 S / 2 S SUTENT 50 mg PO/J 4 S / 2 S PI : Pr Arnaud Mejean

72 PREINSUT study: Sunitinib before and after nephrectomy in mrcc Eligibility criteria Clear cell carcinoma Operable tumor ECOG PS 0 or 1 Normal organic fonctions Mesurable metastases No brain met Tissu bank Exploratory Phase II, N =100 pts, 16 centers in France 2 cycles Sunitinib 50 mg/d (4 wk ON /2 wk OFF) Nephrectomy : week 12 After 2 wk of cicatrisation, Sunitinib 50 mg/j until progression or unacceptable toxicity Follow-up: 2 years Promotion: INCa/PHRC

73 107 Neoadjuvant strategy: T3N2M0 possibility of surgery after two cycles of Sutent Pre chir 1 Post Sutent 2 cycles Post chir 1 Post Sutent 5 cycles

74 107 Neoadjuvant strategy: T3N2M0 possibility of surgery after two cycles of Sutent Pre chir 1 Post Sutent 2 cycles Post chir 1 Post Sutent 5 cycles

75 108 Neoadjuvant strategy for patients with only one kidney left: possibility of conservative surgery after two cycles of Sutent Radical Nephrectomy Partial Nephrectomy

76 108 Neoadjuvant strategy for patients with only one kidney left: possibility of conservative surgery after two cycles of Sutent Radical Nephrectomy Sutent Partial Nephrectomy

77 108 Neoadjuvant strategy for patients with only one kidney left: possibility of conservative surgery after two cycles of Sutent Radical Nephrectomy Sutent Partial Nephrectomy

78 110 What is next? Sunitinib schedule regimen? Intermittent treatment or continuous How circumvent angiogenic-resistance? Targeted drugs + cytokines? Higher RR, higher toxicities, which dose intensity? Horizontal drug combinations? Inhibition of KDR, PDGFR and EGFR Vertical drug combinations? Inhibition of HIF, VEGF and KDR

79 111 Vertical Combinations: : Inhibition of VEGF at different levels HIF TOR Inhibiteur (CCI- 779) HSP-90 antagoniste (17-AAG) VEGF Bevacizumab, VEGF Trap KDR SU11248, BAY , AG

80 Horizontal Combinations: : Inhibition of VEGF at different levels β pvhl α HIF Bevacizumab, VEGF Trap VEGF PDGF TGFα KFR PDGFR EGFR SU11248, BAY , AG SU11248, BAY , AG Erlotinib, Gefitinib, CCI-779, BAY

81 113 Conclusions Mechanism-directed RCC therapy based on tumor-specific molecular feature is validated Sunitinib significantly improves RR and PFS versus IFN in first line setting Sorafenib significantly improves PFS versus placebo in second line setting Temsirolimus significantly improves PFS and survival versus IFN in modified poor risk population Bevacizumab and IFN significantly improves RR and PFS versus IFN in first line setting Sunitinib is the new standard reference for the first-line treatment of mrcc New drugs seem to be interesting (Axitinib( Axitinib, pazopamib,, etc ) There is a potential benefit of subsequent anti-angiogenic angiogenic therapies