1. Desarrollo clínico del Bevacizumab en el tratamiento del cáncer renal metastásico Dr Miguel A. Climent Instituto Valenciano de Oncología

2. 1. Yang, et al. NEJM 2003; 2. Bukowski, et al. J Clin Oncol 2007; 3. Hainsworth et al. ASCO 2005 (Abstract 4542); 4. Escudier, et al. Lancet 2007; 5. Rini, B. ASCO GU 2008 (Abstract 350) Perspectiva histórica del desarrollo clínico 200320042005200620072008 Single-arm phase II trials of bevacizumab plus erlotinib, imatinib conducted 2,3 Multiple phase I and II trials of bevacizumab plus novel agents conducted Phase III trials report Escudier ASCO 2007 4 Rini ASCO 2008 5 Bevacizumab + IFN approved for first-line use First randomised phase II trial demonstrating activity in RCC 1 Two phase III trials of bevacizumab + IFN initiated 2,3 Phase III trials complete recruitment 4

3. Evolving treatment landscape in RCC 1.ESTUDIOS FASE II EN MONOTERAPIA Y COMBINACIÓN CON ERLOTINIB 2.ESTUDIOS FASE III EN COMBINACIÓN CON INTERFERON 3.NUEVAS PERSPECTIVAS DE COMBINACIONES CON BEVACIZUMAB Perspectiva histórica del desarrollo clínico

4. Estudios fase II randomizado bevacizumab frente a placebo en segunda línea (AVF0890g) Pacientes con cancer renal avanzado de células claras Enfermedad medible Tratamiento previo con interleukina (o contraindicación para recibirla) Randomización (116 pts): placebo (40 pts) bevacizumab bajas dosis: 3 mg/kg/2sem (37 pts) bevacizumab altas dosis: 10 mg/kg/2sem (39 pts) Objetivo principal: tiempo a la progresión tasa de respuestas supervivencia global

5. Estudios fase II randomizado bevacizumab frente a placebo en segunda línea (AVF0890g) Second line (trial AVF0890g) 1 Patients progression free (%) Time (months) 100 80 60 40 20 0 061218243036 4.83.02.5 Avastin 10mg/kg (PFS 4.8 months) Avastin 3mg/kg (PFS 3.0 months) Placebo (PFS 2.5 months) 1. Bevacizumab 10 mg/kg frente placebo2,55p<0,001 Bevacizumab 3 mg/kg frente placebo1,26p=0,053 HR p

6. Estudio fase II comparativo bevacizumab+erlotinib frente a bevacizumab. Pacientes con cáncer renal metastásico predominantemente de células claras Primera línea Nefrectomía previa Randomización: 104 pts. bevacizumab 10 mg/kg/2 sem + placebo bevacizumab 10 mg/kg/2sem + erlotinib 150 mg/día Objetivo principal: supervivencia libre de progresión tasa de respuestas supervivencia global

7. Avastin is active as a single agent in mRCC Time (months) 100 80 60 40 20 0 03691215 Patients progression free (%) Time (months) 8.5 9.9 1. Yang, et al. NEJM 2003; 2. Bukowski, et al. JCO 2007 Avastin + Tarceva Avastin + placebo First line (trial RACE) 2 HR=0.86 (95% CI: 0.50–1.49) p=0.58 Estudio fase II comparativo bevacizumab+erlotinib frente a bevacizumab. Bevacuzumab + placebo9,9 m13% Bevacizumab + erlotinib8,5 m14% PFS ORR

8. AVOREN A randomized, double-blind, placebo-controlled phase III study to evaluate the efficacy and safety of bevacizumab in combination with interferon alfa-2a (Roferon) versus interferon alfa-2a and placebo as first-line treatment administered to nephrectomized patients with metastatic clear cell renal cell carcinoma B. Escudier, P. Koralewski, A. Pluzanska, A. Ravaud, S. Bracarda, C. Szczylik, C. Chevreau, M. Filipek, B. Melichar, N. Moore

9. Avastin + IFN-  2a (n=327) IFN-  2a + placebo (n=322) PD Patients with advanced RCC (n=649) Stratification: Country MSKCC risk group 1:1 PD Escudier, et al. Lancet 2007 AVOREN Bevacizumab/placebo 10mg/kg i.v. q2w until progression IFN-  2a 9MIU s.c. three times/week (maximum of 52 weeks) (dose reduction allowed) Multinational ex-US study: 101 study sites in 18 countries Stratification factors: country and Motzer score

10. Objectives Primary objective To evaluate the efficacy of the combination of bevacizumab plus IFN-α2a as compared with IFN-α2a alone based on overall survival Secondary objectives Progression-free survival, time to disease progression, time to treatment failure and objective response rates of bevacizumab plus IFN-α2a compared with IFN-α2a alone Safety profile of bevacizumab plus IFN-α2a versus IFN-α2a alone Pharmacokinetics and pharmacodynamics of bevacizumab AVOREN

11. Statistical design Sample size calculation 80% power to detect an improvement in overall survival from 13 to 17 months with a HR of 0.76 at a significance level of 0.05 required 445 events among 638 patients interim analysis prespecified at 250 events A final progression-free survival analysis was specified in the Statistical Analysis Plan to occur at the time of an interim overall survival analysis at least 90% power to detect an improvement in progression-free survival with a HR of 0.71 at a significance level of 0.05 the study would be unblinded after the final progression-free survival analysis and continued on survival follow-up AVOREN

12. Key eligibility criteria RECIST = Response Evaluation Criteria in Solid Tumors; CNS = central nervous system Inclusion criteria Confirmed metastatic RCC with >50% clear cell histology Nephrectomy Karnofsky performance status of ≥70% Measurable or non-measurable disease (according to RECIST) Exclusion criteria Prior systemic treatment for metastatic RCC disease Evidence of current CNS metastases or spinal cord compression Evidence of bleeding diathesis or coagulopathy Full therapeutic doses of oral or parenteral anticoagulants AVOREN

13. Patient characteristics VariableIFN + placebo (n=322)Avastin + IFN (n=327) Female (%)2732 Male (%)7368 Median age, years (range)60 (18–81)61 (30–82) Karnofsky performance status (%) 100 90 80 70 39 16 7 44 32 18 6 Sites of metastases (%) Lung Lymph nodes Bone Liver 59 36 20 19 62 34 18 Motzer risk score (%) Favourable Intermediate Poor Not available 29 56 8 7 27 56 9 Escudier, et al. Lancet 2007 AVOREN

14. Tumor response (Investigator assessed) Response IFN + placebo (n=289) Bevacizumab + IFN (n=306) Overall response rate (%)* Complete response Partial response 13 2 11 31 1 30 Median duration of response (months) Median duration of stable disease (months) 11 7 13 10 *Patients with measurable disease only p<0.0001 AVOREN

15. Independent review of PFS and ORR Investigator 1 IRC 2 IFN + Bevacizumab (n=327) IFN + placebo (n=322) IFN + Bevacizumab (n=288) IFN + placebo (n=281) ORR (%)31133112 p value<0.0001 Median PFS (months)10.25.410.45.5 HR (95% CI)0.63 (0.52–0.75)0.57 (0.45–0.72) p value<0.0001 1. Escudier, et al. Lancet 2007; 2. Roche, data on file

16. Tumor response* Bevacizumab + IFN (n=306) IFN + placebo (n=289) 100 80 60 40 20 0 –20 –40 –60 –80 –100 100 80 60 40 20 0 –20 –40 –60 –80 –100 –30 Percentage change of sum longest diameter of target lesions *Patients with measurable disease only; investigator assessed 39%70% AVOREN

17. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 No. of patients at risk Avastin + IFN327196107180 IFN + placebo322137 59150 Progression free survival Probability of being progression free Time (months) 06121824 Avastin + IFN IFN + placebo 5.410.2 Escudier, et al. Lancet 2007 HR=0.63; p<0.0001 AVOREN

18. HR=0.60, p=0.004 Median progression-free survival: Bevacizumab + IFN = 12.9 months Placebo + IFN = 7.6 months Probability of being progression-free Number of patients at risk Placebo + IFN93572570 Bevacizumab + IFN87653980 Time (months) 06121824 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 7.612.9 PFS: Motzer subgroup – favorable AVOREN

19. Bevacizumab + IFN = 10.2 months Placebo + IFN = 4.5 months Probability of being progression-free 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Time (months) 06121824 HR=0.55, p<0.0001 Median progression-free survival: PFS: Motzer subgroup – intermediate Number of patients at risk Placebo + IFN180672860 Bevacizumab + IFN1831126090 4.5 10.2 AVOREN

20. PFS: Motzer subgroup – poor Probability of being progression-free Number of patients at risk Placebo + IFN252110 Bevacizumab + IFN297100 Time (months) 06121824 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Bevacizumab + IFN = 2.2 months Placebo + IFN = 2.1 months HR=0.81, p=0.457 Median progression-free survival: AVOREN

21. Subgroup analysis for progression-free survival in AVOREN Baseline risk factorTotal (n)HR All patients6490.63 Sex Female Male 193 456 0.60 0.64 Age (years) <40 40–64  65 26 384 239 0.65 0.54 0.77 Number of metastatic sites  2 >2 394 252 0.67 0.54 Motzer score Favorable Intermediate Poor 180 363 54 0.60 0.55 0.81 0.20.5125 HR AVOREN subgroups analyses

22. 0.20.5125 Baseline risk factorTotal (n)HR All patients6490.63 Age (years) <654100.54  652390.77 Creatinine clearance Low1910.65 High/normal1310.60 VEGF levels above median No1910.45 Yes1910.67 MSKCC score Favourable1800.60 Intermediate3630.55 Poor 540.81 RCC histology Clear cell5640.64 Mixed 850.53 Escudier, et al. Lancet 2007 AVOREN

23. HR=0.75 (95% CI: 0.58–0.97), p<0.0267* Median overall survival: Bevacizumab + IFN = NR † IFN + placebo = 19.8 months Probability of survival Interim analysis of overall survival Number of patients at risk IFN + placebo 3222621765310 Bevacizumab + IFN3272751976020 Time (months) 0612182430 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 19.8 *Stratified by Motzer score and region category; unstratified analysis HR=0.79, p=0.067; prespecified level of significance p=0.0056; † Not reached AVOREN

24. Probability of survival Final OS Patients at risk (n) IFN + Bevacizumab 3272782371941571248427 IFN + placebo 3222622161771411137822 21.323.3 06121824303642 Time (months) 1.0 0.8 0.6 0.4 0.2 0 IFN + Bevacizumab (n=327) IFN + placebo (n=322) HR=0.86 (95% CI: 0.72–1.04) p=0.1291 (stratified*) *Stratified by Motzer score and region AVOREN

25. Censoring crossover patients Probability of survival Patients at risk (n) Bevacizumab + IFN3272782371941571248427 IFN + placebo 3222622161731311016919 06121824303642 Time (months) 1.0 0.8 0.6 0.4 0.2 0 23.320.8 IFN + Bevacizumab (n=327) IFN + placebo (n=322) HR=0.84 (95% CI: 0.70–1.02) p=0.0766* *Stratified by Motzer score and region AVOREN

26. Summary of subsequent medical therapies Treatment, n (%) IFN + Bevacizumab (n=327) IFN + placebo (n=322) Total patients with ≥1 treatment180 (55) 202 (63) VEGF inhibitors Sunitinib83 (25)92 (29) Sorafenib60 (18)50 (16) Bevacizumab10 (3)12 (4) Other* 7 (2) 6 (2) mTOR inhibitors ‡ 14 (4) 6 (2) Cytokines32 (10)52 (16) Chemotherapy § 28 (9)47 (15) *Protein TKI, pazopanib, erlotinib, blinded sorafenib, blinded sunitinib, angiogenesis inhibitors NOS, VEGF inhibitor NOS ‡ Temsirolimus, everolimus (RAD001) § Antimetabolites, vinca alkaloids and antineoplastic agents AVOREN

27. Regional variation in subsequent treatment with TKIs IFN + BevacizumabIFN + placebo Therapy Western Europe (n=180) Eastern Europe and other (n=147) Western Europe (n=177) Eastern Europe and other (n=145) TKIs, n (%) Sunitinib52 (29)31 (21)64 (36)28 (19) Sorafenib51 (28)9 (6)48 (27)2 (1) AVOREN

28. Regional variation in OS IFN + BevacizumabIFN + placebo Western Europe (n=180) Eastern Europe and other (n=147) Western Europe (n=177) Eastern Europe and other (n=145) Events, n (%)120 (67)100 (68)125 (71)99 (68) Median OS, months (95% CI)24.5 (21–29)23.1 (17–27)23.7 (21–28)17.1 (13–22) HR (95% CI)*0.93 (0.71–1.21)0.92 (0.71–1.20) p value (log-rank)* 0.59220.5336 *Stratified by Motzer score and region AVOREN

29. Subgroup analysis of OS 0.20.5125 Baseline risk factorTotal (n) HR 95% CI All patients6490.860.72–1.04 410 239 0.78 0.99 Age (years) <65 ≥65 0.61–0.99 0.73–1.35 Baseline VEGF > median No Yes 192 0.74 0.88 0.50–1.10 0.62–1.24 192 457 0.90 0.84 Sex Female Male 0.64–1.27 0.66–1.05 Motzer score Favourable Intermediate Poor 180 366 55 0.86 0.83 0.86 0.57–1.30 0.65–1.06 0.47–1.59 Per cent body weight loss  10 >10 501 81 0.88 0.60 0.70–1.09 0.35–1.04 AVOREN

30. No. of metastatic sites 1 2 >2 152 242 252 0.81 1.02 0.74 0.52–1.27 0.73–1.41 0.55–0.99 Subgroup analysis of OS (cont’d) Baseline risk factorTotal (n)HR 95% CI 0.70–1.09 0.58–1.32 Bone metastases No Yes 521 125 0.87 0.88 565 81 0.88 0.68 Tumour in lung only No Yes 0.72–1.08 0.36–1.28 0.20.5125 Lung metastases No Yes 173 473 1.10 0.77 0.73–1.66 0.61–0.96 Liver metastases No Yes 508 138 0.76 1.30 0.62–0.95 0.85–1.98 AVOREN

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

32. Standard dose of IFN was 9MIU tiw s.c. IFN was withheld if grade 3 adverse event attributable to IFN developed IFN was restarted with one dose level reduction to 6 or 3MIU upon resolution of toxicity to grade  1 no re-escalation of IFN dose was allowed No dose reduction of Avastin Patients who received  1 dose reductions of IFN were included in the analysis Escudier, et al. Lancet 2007 AVOREN

33. Tolerability improved by IFN dose reduction FatiguePyrexiaAnorexiaNauseaAstheniaFlu-likeVomiting Depression illness 25 20 15 10 5 0 Patients (%) Melichar, et al. Ann Oncol 2008, Abril AVOREN

34. PFS in patients treated with Bevacizumab + reduced- dose IFN 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Time (months) 03691215182124 No. of patients at risk Avastin + reduced- dose IFN131118 96 88 55281240 All Avastin + IFN 327259196170107541860 Median PFS Avastin + reduced-dose IFN All Avastin + IFN patients Probability of being progression free Melichar, et al. Ann Oncol (In press)

35. PFS in patients treated with Bevacizumab + reduced- dose IFN

36. Estudio Prospectivo:“Evidence for Avastin + low-dose IFN (BEVLiN) Open-label, single-arm, phase II, multicentre study n=150 patients with clear cell metastatic RCC, good and intermediate risk Continue treatment until progression No dose modification permitted with IFN or Avastin (except for safety) Primary objective PFS of Avastin + low-dose IFN Secondary objectives further define the safety profile of Avastin + low-dose IFN historical comparator AVOREN assess second-line therapy ancillary studies – QoL, biomarkers Ongoing IFN 3MIU s.c. tiw Avastin 10mg/kg i.v. every 2 weeks

37. Extensión del estudio BEVLiN IFN 3MIU s.c. tiw Avastin 10mg/kg i.v. every 2 weeks Avastin + RAD001 PD Sunitinib Objectives primary: TTF secondary: OS, safety, ORR, TTP Assumptions Implement TML option for patients who progress Potentially implement randomisation against sunitinib second line – currently defining impact on patient numbers and budget

38. CALGB 90206: A Phase III Trial of Bevacizumab Plus Interferon-alpha versus Interferon-alpha Monotherapy in Metastatic Renal Cell Carcinoma Brian I. Rini 1, Susan Halabi 2,3, Jonathan E. Rosenberg 4, Walter M. Stadler 5, Daniel A.Vaena 6, San-San Ou 3, Laura Archer 3, James N. Atkins 7, Joel Picus 8, Simon Tanguay 9, Janice Dutcher 10 and Eric J. Small 4 1. Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 2. Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC 3. CALGB Statistical Center, Durham, NC 4. University of California San Francisco, San Francisco, CA 5. University of Chicago Medical Center, Chicago, IL 6. University of Iowa, Iowa City, IA 7. Southeast Cancer Control Consortium Inc. 8. Washington University, St. Louis, MO 9. McGill University, Montreal, Quebec and the National Cancer Institute Canada, Toronto, ON, Canada 10. New York Medical College, NY, NY and the Eastern Cooperative Oncology Group, Boston, MA

39. Study Schema R A N D O M IZ E IFNA 9 MU TIW IFNA 9 MU TIW + Bevacizumab 10 mg/kg IV q d1 and d15 STRATIFYSTRATIFY Patients stratified for nephrectomy status (yes/no) and MSKCC risk group (0 risk factors vs. 1-2 risk factors vs. 3 or more risk factors)* Eligibility Criteria Confirmed metastatic RCC with a component of clear cell histology Karnofsky PS ≥ 70% Measurable or evaluable disease (by RECIST) No prior systemic treatment for RCC Adequate end-organ function No CNS metastases BP < 160/90 with meds No DVT within 1 year or arterial thrombotic event within 6 months Prior nephrectomy not required * Motzer R et al., JCO 20(1), 2002 CALGB 90206

40. Baseline Demographics and Clinical Characteristics (n=732) Bevacizumab plus IFNA (n=369) IFNA monotherapy (n=363) Sex – no. (%) Male Female 269 (73%) 100 (27%) 239 (66%) 124 (34%) Median Age, years (inter-quartile range) 61 (56-70) 62 (55-70) ECOG performance status – no. (%) 0 1 2 230 (62%) 132 (36%) 7 (2%) 227 (62%) 133 (37%) 3 (1%) Previous nephrectomy – no. (%)312 (85%) 308 (85%) Previous radiation therapy – no. (%)35 (9%) 38 (10%) Common Sites of Metastases Lung Lymph node Bone Liver 252 (68%) 130 (35%) 104 (28%) 74 (20%) 254 (70%) 129 (36%) 109 (30%) 73 (20%) Number of adverse risk factors 0 (favorable) 1-2 (intermediate) ≥ 3 (poor) 97 (26%) 234 (64%) 38 (10%) 95 (26%) 231 (64%) 37 (10%) CALGB 90206

41. Objective Response Note: patients with measurable disease only Bev + IFNA (n=325)IFNA (n=314) Overall Response rate25.5% [95% CI = 20.9-30.6] 13.1% [95% CI = 9.5-17.3] CR 3.4% 1.3% PR23.4%12.7% p < 0.0001 Duration of response11.9 months [95% CI = 8.3 – 14.8] 9.7 months [95% CI = 7.6 – 19.8] p = 0.362 CALGB 90206

43. MSKCC Prognostic groups Median PFS (months) Risk Group% Bev + IFNA (n=369) IFNA (n=363) Favorable (0 risk factors)2611.15.7 (p = 0.0012) Intermediate (1-2 risk factors)648.45.3 (p = 0.0017) Poor (≥ 3 risk factors)103.32.6 (p = 0.25) CALGB 90206

44. ---- BEV/IFN: Median OS 18.3 months IFN: Median OS 17.4 months Kaplan-Meier Overall Survival by Treatment Arm CALGB 90206

45. Overall Survival by MSKCC Risk Status * Median OS (months) Risk Group% BEV/IFN (n=369) IFN (n=363) Favorable (0 risk factors)2632.533.5 (p = 0.524) Intermediate (1-2 risk factors)6417.716.1 (p = 0.174) Poor (≥ 3 risk factors)106.65.7 (p = 0.25) * Motzer R et al., JCO 20(1), 2002 CALGB 90206

46. Therapy Received in Patients who Discontinued Protocol Therapy for Any Reason Other Than Death Bevacizumab + IFN (n=351) IFN monotherapy (n=350) Percentage of patients receiving any second-line therapy 54% 62% VEGF-targeted therapy37% 46% Bevacizumab 6% 14% Chemotherapy18% 14% Investigational therapy11% 18% Cytokines13% 14% * Fifty-six percent of patients overall received at least one subsequent systemic therapy CALGB 90206

47. Adverse event Bevacizumab + IFNA (n=366) IFNA (n=349) Any grade 3/4 adverse event289 (79%) 213 (61%) Fatigue/asthenia/malaise134 (37%) 104 (30%) Anorexia 63 (17%) 28 (8%) Proteinuria 56 (15%) 1 (<1%) Hypertension 36 (11%)0 (0) Hemorrhage 5 (2%) 1 (<1%) Venous thromboembolism 6 (2%) 3 (1%) Gastrointestinal perforation 1 (<1%) 0 (0) Arterial ischemia 5 (1%) 0 (0) Selected grade 3 or 4 adverse events CALGB 90206

48. Conclusions Bevacizumab + IFN is an option in first-line treatment for patients with metastatic/advanced RCC Bevacizumab + IFN significantly improves PFS as first-line therapy of patients with metastatic RCC Although not statistically significant, a trend towards improved OS was observed with bevacizumab + IFN combination. The results have been confounded by post-protocol bevacizumab subsequent therapies It seems that if IFN dose is reduced to manage side effects, clinical benefit is maintained Bevacizumab plus IFN has a well-characterised tolerability profile

49. Combinación aumenta supervivencia en Oncología: mama, pulmón, colon, testículo, Ewing´s, osteosarcoma, LNH, leucemias … ¿ combinar o secuenciar? En contra de combinar: – Tratamientos paliativos – Más fármacos = más toxicidad (disminuir dosis) A favor de combinar: – Más fármacos, más actividad inicial – Estudios de “tracking” en USA sugieren que 1/3 pacientes que progresan a una línea de tratamiento, no pueden seguir ttos. – Aparición de clones resistentes es función del tiempo (Goldie Coldman) ¿ SE PUEDE MEJORAR RESULTADOS EN CCR CON TERAPIA COMBINATORIA ?

50. VEGFR VEGF pVHL X HIF mTOR Temsirolimus Everolimus Sunitinib Sorafenib Axitinib Pazopanib Avastin Adapted from Kaelin. Clin Cancer Res 2004 Combining therapy: vertical combination

51. Combining therapy: horizontal combination VEGFR VEGF pVHL HIF PDGFR PDGF TGF-  EGFR Avastin Sunitinib Sorafenib X Tarceva Adapted from Kaelin. Clin Cancer Res 2004

52. Bevacizumab, Sorafenib, Temsirolimus trial Metastatic RCC (stratification by prior therapy and MSKCC risk category) Avastin (n=90) PD Avastin + temsirolimus (n=90) PD Avastin + sorafenib (n=90) PD Temsirolimus + sorafenib (n=90) Primary endpoints: PFS Secondary endpoints: safety, RR, OS, SD at 6 months PI: Keith Flaherty, duration March 2008–February 2012 US / Canada Ongoing BeST trial

53. Global study: ~25 countries, ~200 sites Stratification factors: nephrectomy and Motzer score PI: Bernard Escudier and Brian Rini, duration March 2008–February 2012 Ongoing ( n= 26 so far) Avastin + temsirolimus (n=411) Avastin + IFN-  2a (n=411) PD Metastatic RCC patients (n=822) 1:1 INTORACT Avastin + temsirolimus versus Avastin + IFN-  PD Study 3311

55. TTP= 5,3 meses OS= 14,5 meses

56. Avastin +everolimus Avastin + IFN-  2a PD Metastatic RCC patients 1:1 RECORD 1: Avastin + everolimus versus Avastin + IFN-  PD

57. Sequential Two-agent Assessment in RCC Therapy Target enrolment: 240 patients Endpoints: PFS, OS, ORR, PD Avastin Temsirolimus Sunitinib Avastin Sunitinib START trial concept Eligibility criteria Clear cell mRCC No CNS mets Nephrectomy No prior systemic therapy MD Anderson

58. Conclusiones Los datos hasta la fecha y los perfiles de tolerabilidad favorecen a Avastin como compañero de combinación Los ensayos aleatorizados han sido iniciados para direccionar el potencial de Avastin Para maximizar los resultados del paciente, podría considerarse la secuencia completa de tratamiento antes de empezar la terapia de primera línea Avastin puede jugar un papel central en los avances futuros del tratamiento del RCC

59. Aflibercept: A protein comprised of segments of the extracellular domains of human vascular endothelial growth factor receptors 1 (VEGFR1) and 2 (VEGFR2) fused to the constant region (Fc) of human IgG1 with potential antiangiogenic activity. Estudios fase III: próstata, pulmón, colorecto. Estudios fase II en otras patologías PTC 299: Is a novel, orally administered, small molecule designed to inhibit the production of VEGF by targeting the post- transcriptional processes that regulate VEGF synthesis Estudios preclínicos Nuevas moléculas antiangiogénicas

60. INGN 241: Stimulates the immune system to attack cancer cells through IL-24 dependent mechanisms. Efecto potenciador de bevacizumab en cáncer de pulmón IMC 1121B o ramucirumab: Ac antiVEGFR-2 Estudios Fase II en cáncer de mama, ovario, próstata, colorecto y pulmón CDP 791: CDP-791 takes the novel approach of targeting and blocking VEGFR-2 on blood vessel cells Fase II en cáncer de pulmón

61. Gracias por su atención

62. Tolerability of single-agent Avastin in RCC typical based on extensive experience Adverse event Avastin first line 1 Avastin second line 2 Grade 3/4 (%) Proteinuria 6 8 Hypertension2621 Bleeding 4 0 Chest painNR 5 GI perforation 0NR Neutropenia 0NR Diarrhoea 0NR Hand-foot syndrome 0NR Nausea + vomiting 0NR Stomatitis 0NR 1. Bukowski, et al. JCO 2007; 2. Yang, et al. NEJM 2003 NR = not reported

63. CALGB 90206