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Pius-Hospital Oldenburg

Pius-Hospital Oldenburg. Frank Griesinger Professor at the University of G ö ttingen and Chair of the Department of Medical Oncology, Pius-Hospital, Oldenburg, Germany. Professor of Internal Medicine and Haematology and Medical Oncology at the University of G ö ttingen

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Pius-Hospital Oldenburg

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  1. Pius-Hospital Oldenburg Frank GriesingerProfessor at the University of Göttingen and Chair of the Department of Medical Oncology, Pius-Hospital, Oldenburg, Germany • Professor of Internal Medicine and Haematology and Medical Oncology at the University of Göttingen • Chair of the Department of Medical Oncology at the Pius-Hospital, Oldenburg, Germany • Member of the German Cancer Society and the steering committee of the German Lung Cancer Study Group • Co-author of more than 50 papers in international peer-reviewed journals

  2. Anti-vascular endothelial growth factor (VEGF) therapy: a revolution in care for patients with renal cell cancer (RCC) Frank Griesinger Pius-Hospital OldenburgGermany

  3. Historical approaches to RCC therapy IL-2 = interleukin-2; IFN = interferon alpha; BSC = best supportive care

  4. Historical approaches to RCC therapy • Nephrectomy is curative in a proportion of patients diagnosed early • 30% of patients present with metastatic disease (Stage IV) • RCC is insensitive to radiotherapy, chemotherapy and hormone therapy • Immunotherapy produces a response rate of up to 20% and median overall survival (OS) of 13 months • New therapeutic options are required

  5. Rationale for anti-VEGF therapy in RCC Disruption of VHL protein prohibits the pathway leading to HIF degradation causing HIF accumulation VHL complex VHL protein HIF X Normoxia Hypoxia HIF accumulation Tagged for degradation TGF, PDGF VEGF HIFα degradation VHL = von Hippel-Lindau HIF = hypoxia-inducible factor- TGF = transforming growth factor- PDGF = platelet-derived growth factor Angiogenesis Autocrine growth stimulation Adapted from Linehan WM, et al. J Urol 2003;170:2163–72

  6. Bevacizumab 3mg/kg every 2 weeks Placebo (n=40) PD Progressive metastatic RCC (IL-2 failure or ineligible) Bevacizumab 3mg/kg every 2 weeks (n=37) PD Bevacizumab 10mg/kg every 2 weeks (n=39) PD Initial trials of bevacizumab in RCC: AVF0890g • Phase II trial of bevacizumab monotherapy in RCC (AVF0890g): study design • Primary endpoints: time to progression and response rate • Secondary endpoints: survival and safety PD = progression of disease Yang JC, et al. N Engl J Med 2003;349:427–34

  7. Single-agent bevacizumab improves PFS in mRCC 100 80 60 40 20 0 Bevacizumab 10mg/kg every 2 weeks; p<0.001 Bevacizumab 3mg/kg every 2 weeks Placebo Patients progression-free (%) 2.5 3.0 4.8 0 6 12 18 24 30 36 Months from date on-study PFS = progression-free survivalmRCC = metastatic renal cell cancer Yang JC, et al. N Engl J Med 2003;349:427–34

  8. Safety profile of bevacizumab in mRCC 1Yang JC, et al. N Engl J Med 2003;349:427–34 2Bukowski RM, et al. J Clin Oncol 2007;25:4536–41

  9. Phase III trial of first-line bevacizumabin RCC (AVOREN) Bevacizumab + IFN-a2a (n=327) PD RCC patients (n=649) 1:1 IFN-a2a + placebo (n=322) PD • Bevacizumab/placebo 10mg/kg i.v. every 2 weeks until progression • IFN-2a 9MIU s.c. 3 times weekly (maximum of 52 weeks) (dose reduction allowed) • Multinational ex-US study: 101 study sites in 18 countries • Stratification factors: country and Motzer score i.v. = intravenous; IFN-2a = interferon-alpha2a MIU = million international units s.c. = subcutaneous Escudier B, et al. Lancet 2007;370:2103–11

  10. Objectives Primary objective • To evaluate the efficacy of the combination of bevacizumab plus IFN-a2a as compared with IFN-a2a alone based on OS Secondary objectives • PFS, time to disease progression, time to treatment failure and objective response rates of bevacizumab plus IFN-a2a compared with IFN-a2a alone • Safety profile of bevacizumab plus IFN-a2a versus IFN-a2a alone • Pharmacokinetics and pharmacodynamics of bevacizumab Escudier B, et al. Lancet 2007;370:2103–11

  11. Key eligibility criteria Inclusion criteria • Confirmed metastatic RCC with >50% clear cell histology • Nephrectomy • KPS 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 KPS = Karnofsky performance statusRECIST = Response Evaluation Criteria in Solid Tumors CNS = central nervous system Escudier B, et al. Lancet 2007;370:2103–11

  12. Statistical design and interim analysis • Sample size calculation • 80% power to detect an improvement in OS 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 PFS analysis to occur at the time of an interim OS analysis • ≥90% power to detect an improvement in PFS with a HR of 0.71 at a significance level of 0.05 • the study would be unblinded after the final PFS analysis and continued on survival follow-up HR = hazard ratio Escudier B, et al. Lancet 2007;370:2103–11

  13. Patient characteristics* Escudier B, et al. Lancet 2007;370:2103–11 *Based on intent-to-treat (ITT) population

  14. Tumour response *Patients with measurable disease only Escudier B, et al. Lancet 2007;370:2103–11

  15. Bevacizumab combined with IFN improves PFS over IFN alone 1.0 0.8 0.6 0.4 0.2 0 HR=0.63, (95% CI: (0.52–0.75) p<0.0001 Median PFS: Probability of being progression-free Bevacizumab + IFN = 10.2 months Placebo + IFN = 5.4 months 5.4 10.2 0 6 12 18 24 Number ofpatients at risk Placebo + IFN 322 137 59 15 0 Bevacizumab+ IFN 327 196 107 18 0 Months IFN = interferon; CI = confidence interval Escudier B, et al. Lancet 2007;370:2103–11

  16. Subgroup analysis for PFS in AVOREN HR 0.2 0.5 1 2 5 Escudier B, et al. Lancet 2007;370:2103–11

  17. Interim analysis of OS(251 of 450 scheduled events) Probability of survival HR=0.75 (95% CI: 0.58–0.97), p<0.0267* Median OS: 1.0 0.8 0.6 0.4 0.2 0 Bevacizumab + IFN = not reached Placebo + IFN = 19.8 months 19.8 0 6 12 18 24 30 Number ofpatients at risk Placebo + IFN 322 262 176 53 1 0 Bevacizumab + IFN 327 275 197 60 2 0 Months *Stratified by Motzer score and region category; prespecified level of significance p=0.0056; Escudier B, et al. Lancet 2007;370:2103–11

  18. Overview of AEs* *Based on safety population†3/8 deaths were possibly related to bevacizumab Escudier B, et al. Lancet 2007;370:2103–11

  19. Selected grade 3/4 AEs* Escudier B, et al. Lancet 2007;370:2103–11 *Based on safety population

  20. Analysis of efficacy and safety of reduced-dose IFN in AVOREN • The standard dose of IFN-2a was 9MIU 3 times weekly s.c. • IFN-2a was withheld if grade 3 AE attributable to IFN-a2a developed • IFN-2a was restarted with one dose level reduction (6MIU) if toxicity resolved to grade <1 within the first 28 days • If a subsequent grade 3 AE developed, IFN-2a dose was reduced to 3MIU (3 times weekly) • No re-escalation of the IFN-2a dose was allowed • Concurrent bevacizumab was maintained at the standard dose without reduction

  21. Tumour response and clinical benefit in bevacizumab-treated patients in the total and reduced-dose IFN populations *Clinical benefit = OR rate + SD rate; OR =overall response Melichar B, et al. Eur J Cancer Suppl 2007;5:304 (Abstract 4518)

  22. PFS for bevacizumab-treated patients in the total and reduced-dose populations 1.0 0.8 0.6 0.4 0.2 0 Bevacizumab + reduced dose IFN-a2a All bevacizumab + IFN-a2a patients PFS estimate 0 3 6 9 12 15 18 21 24 Number ofpatients at risk Placebo + IFN 327 259 196 170 107 54 18 6 0 Bevacizumab + IFN 131 118 96 88 55 28 12 4 0 Months

  23. Grade 3 AEs 6 weeks before and 6 weeks after IFN dose reduction 6 weeks before reduction 6 weeks after reduction Patients (%) Placebo Bevacizumab

  24. AVOREN trial – overall conclusions • Addition of bevacizumab to IFN statistically and clinically significantly improves PFS and tumour response, with a trend in favour of improved survival • Bevacizumab with IFN significantly improves PFS and RR in predefined patient subgroups • Treatment was well tolerated and no new toxicities emerged outside of those known with IFNand bevacizumab • IFN dose can be reduced to manage side effects while maintaining observed improvements in response rateand PFS

  25. After AVOREN, where are we now in RCC? VEGFR = VEGF receptor; PDGFR = PDGF receptor; Flt-3 = fms-like tyrosine kinase-3;TKI = tyrosine-kinase inhibitor; mTOR = mammalian target of rapamycin Adapted from Bellmunt J. Eur Urol 2007;(Suppl. 6):484–91

  26. After AVOREN, where are we now in RCC? (cont’d) • Rapid expansion in available active therapies • cytokines → bevacizumab, temsirolimus, sorafenib and sunitinib • Significant improvements in some outcomes: response rate and PFS but not (yet) OS or cure • Some questions still need to be addressed • does immunotherapy have a long-term role? • how can these agents be combined and/or sequenced, i.e. develop multiple lines of therapy? • can therapy be sequenced to maximise survival? • can patients most likely to respond be identified?

  27. Combining novel agents with IFNα 1Escudier B, et al. Lancet 2007;370:2103–11;2Hudes G, et al. N Engl J Med 2007;356:2271–81; 3Bracarda S, et al. J Clin Oncol 2007;25(Suppl. 1):259s (Abstract 5100) 4Kondagunta GV, et al. J Clin Oncol 2007;25(Suppl. 1):260s (Abstract 5101)

  28. What is the role of immunotherapy? • Immunotherapy produces durable CRs • novel agents impact OR, SD and PFS • Combining bevacizumab with immunotherapy • IFN (AVOREN) • improved PFS and RR, flexible dosing • IL-2 • well tolerated with promising antitumour activity • Immunotherapy still has a role as part of first-line therapy, but not as a single agent Ernstoff MS, et al. J Clin Oncol 2007;25(Suppl. 1):651s (Abstract 15524) Garcia JA, et al. J Clin Oncol 2007;25(Suppl. 1):260s (Abstract 5103)

  29. Trials of bevacizumab in combination with novel agents in RCC: efficacy 1Feldman DR, et al. J Clin Oncol 2007;25(Suppl. 1):259s (Abstract 5099) 2Sosman JA, et al. J Clin Oncol 2006;24(Suppl. 1):128s (Abstract 3031) 3Merchan JR, et al. J Clin Oncol 2007;25 (Suppl. 1):243s (Abstract 5034)

  30. Trials of bevacizumab in combination with novel agents in RCC: safety DLT = dose limiting toxicity 1Feldman DR, et al. J Clin Oncol 2007;25(Suppl. 1):259s (Abstract 5099)2Sosman JA, et al. J Clin Oncol 2006;24(Suppl. 1):128s (Abstract 3031)3Merchan JR, et al. J Clin Oncol 2007;25(Suppl. 1):243s (Abstract 5034)

  31. Data suggest bevacizumab is an excellent partner for combination therapy • Combining bevacizumab 10mg/kg with cytokines, sunitinib or temsirolimus is feasible1–3 (further studies needed for sorafenib) • No definitive data regarding combinations of sorafenib, sunitinib and temsirolimus in RCC available • VEGF increase with TKIs; therefore, rationale for addition of bevacizumab 1Feldman DR, et al. J Clin Oncol 2007;25(Suppl. 1):259s (Abstract 5099)2Sosman JA, et al. J Clin Oncol 2006;24(Suppl. 1):128s (Abstract 3031)3Azad NS, et al. J Clin Oncol 2006;24(Suppl. 1):121s (Abstract 3004)

  32. Rationale for sequencing therapy • Efficacy of different agents depends on when they are used • cytokine use predominantly first line; no accepted role as second-line therapy • bevacizumab more effective first line than later • OS likely to be maximised by use of all available active agents • Use of agents that inhibit different pathways may be expected to have further efficacy following progression

  33. Summary of data for anti-VEGF(R) therapy following prior anti-VEGF(R) therapy 1Hutson TE, et al. Eur J Cancer Suppl 2007;5:301 (Abstract 4510); 2Drabkin HA, et al. J Clin Oncol 2007;25(Suppl. 1):245s (Abstract 5041); 3Sablin MP, et al. J Clin Oncol 2007;25(Suppl. 1):244s (Abstract 5038); 4Dham A, et al. J Clin Oncol 2007;25(Suppl. 1):261s (Abstract 5106)

  34. What do data suggest about sequencing therapy for RCC? • Cytokines should be used first line • All novel agents are effective as second-line therapy after cytokines • efficacy appears to differ, sunitinib1 and sorafenib1–3 having greater efficacy than bevacizumab • Sorafenib and sunitinib are active in second-line after bevacizumab4and also each other • Sequencing available therapies should be investigated further to maximise use of all available therapies • current data suggest that first-line bevacizumab-based combinations may be optimal, allowing patients to receive subsequent sunitinib/sorafenib-based therapy 1Tamaskar I, et al. J Clin Oncol 2006;24(Suppl. 1):240s (Abstract 4597) 2Drabkin HA, J Clin Oncol 2007;25(Suppl. 1):245s (Abstract 5041) 3Rini BI, et al. J Clin Oncol 2006;24(Suppl. 1):222s (Abstract 4522) 4Dham A, Dudek AZ. J Clin Oncol 2007;25(Suppl. 1):261s (Abstract 5106)

  35. Patient selection for novel agents • No evidence that VEGF status influences outcomes with VEGF-inhibiting therapy • VEGF levels do not appear to predict for response to anti-VEGF(R) therapy • Motzer risk may affect outcomes and temsirolimus appears to be effective only in patients with poor Motzer risk • Motzer risk designed to be used for immunotherapy • Currently, no basis on which to select patients for VEGF-inhibiting therapy

  36. Trials providing further insights: the BeST trial Bevacizumab 10mg/kg twice weekly (n=90) PD Bevacizumab 10mg/kg twice weekly + temsirolimus 25mg once weekly (n=90) PD Metastatic RCC (stratification by prior therapy and MSKCC risk category) Bevacizumab 10mg/kg twice weekly + sorafenib 200mg b.i.d. days 1–5 of 7 (n=90) PD Temsirolimus 25mg once weekly + sorafenib 200mg b.i.d. days 1–5 of 7 (n=90) PD • Primary endpoints: PFS • Secondary endpoints: safety, RR, OS, SD rate at 6 months MSKCC = Memorial Sloan-Kettering Cancer Center; b.i.d. = twice daily

  37. Trials providing further insights: study 3311 Bevacizumab + temsirolimus (n=411) PD RCC patients (n=822) 1:1 Bevacizumab + IFN-2a (n=411) PD • Global study: ~25 countries, ~200 sites • Stratification factors: nephrectomy and Motzer score

  38. Conclusions • A number of active agents now available • complete sequence of treatment should be considered before starting first-line therapy • Data indicate that bevacizumab should be the partner of choice when considering trials of VEGF-inhibiting therapy • Bevacizumab plus IFN provides flexible treatment for patients with mRCC, allowing reduction of IFN dose to improve tolerability and manage toxicity without compromising efficacy • Trials of bevacizumab in mRCC should be performed first-line to ensure patients have further options for therapy in second- and third-line • Currently, no rationale to select patients for therapy

  39. RCC treatment algorithm: 2007 Modified from Bukowski RM, presented at ASCO 2007; adapted from Atkins, presented at ASCO 2006

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