Frank Griesinger Professor 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 Pius-Hospital Oldenburg

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

Historical approaches to RCC therapy Stage of RCC Therapeutic goals Primary or first-line treatment options Further or second-line therapy options I–IIICureRadical or nephron-sparing nephrectomy IL-2 or IFN  immunotherapy at relapse BSC IVExtend survival Stabilise disease Palliation Nephrectomy (if possible) IL-2 or IFN  immunotherapy Cytoreductive nephrectomy in appropriate patients prior to immunotherapy BSC (including radiotherapy, metastasectomy or bisphosphonates for bone metastases) IL-2 = interleukin-2; IFN  = interferon alpha; BSC = best supportive care

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

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

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

Patients progression-free (%) Bevacizumab 10mg/kg every 2 weeks; p<0.001 Bevacizumab 3mg/kg every 2 weeks Placebo Months from date on-study Single-agent bevacizumab improves PFS in mRCC PFS = progression-free survival mRCC = metastatic renal cell cancer Yang JC, et al. N Engl J Med 2003;349:427–

Safety profile of bevacizumab in mRCC Adverse event (AE) Bevacizumab second-line 1 Bevacizumab first-line 2 grade 3/4 Proteinuria (%)8 6 Hypertension (%) Bleeding (%)0 4 Chest pain (%)5 – Gastrointestinal perforation (%) –0 Neutropenia (%) –0 Diarrhoea (%) –0 Hand-foot syndrome (HFS) (%) –0 Nausea and vomiting (%) –0 Stomatitis (%) –0 1 Yang JC, et al. N Engl J Med 2003;349:427–34 2 Bukowski RM, et al. J Clin Oncol 2007;25:4536–41

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 Bevacizumab + IFN-  2a (n=327) IFN-  2a + placebo (n=322) PD Escudier B, et al. Lancet 2007;370:2103–11 RCC patients (n=649) i.v. = intravenous; IFN-  2a = interferon-alpha2a MIU = million international units s.c. = subcutaneous 1:1 Phase III trial of first-line bevacizumab in RCC (AVOREN)

Primary objective To evaluate the efficacy of the combination of bevacizumab plus IFN-  2a as compared with IFN-  2a alone based on OS Secondary objectives PFS, time to disease progression, time to treatment failure and objective response rates of bevacizumab plus IFN-  2a compared with IFN-  2a alone Safety profile of bevacizumab plus IFN-  2a versus IFN-  2a alone Pharmacokinetics and pharmacodynamics of bevacizumab Objectives Escudier B, et al. Lancet 2007;370:2103–11

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 status RECIST = Response Evaluation Criteria in Solid Tumors CNS = central nervous system Key eligibility criteria Escudier B, et al. Lancet 2007;370:2103–11

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

Variable IFN-  2a + placebo (n=322) Bevacizumab + IFN-  2a (n=327) Female (%) Male (%) Median age, years (range)60 (18–81)61 (30–82) KPS (%) Sites of metastases (%) Lung Lymph nodes Bone Liver Motzer risk score (%) Favourable Intermediate Poor Not available *Based on intent-to-treat (ITT) population Patient characteristics* Escudier B, et al. Lancet 2007;370:2103–11

Response IFN-  2a + placebo (n=289) Bevacizumab + IFN-  2a (n=306) Overall response rate (RR) (%)* Complete response (CR) Partial response (PR) p= Median duration of response (months) Median duration of stable disease (SD) (months) *Patients with measurable disease only Tumour response Escudier B, et al. Lancet 2007;370:2103–11

HR=0.63, (95% CI: (0.52–0.75) p< Median PFS: Bevacizumab + IFN = 10.2 months Placebo + IFN = 5.4 months Probability of beingprogression-free Number of patients at risk Placebo + IFN Bevacizumab + IFN Months Bevacizumab combined with IFN improves PFS over IFN alone IFN = interferon; CI = confidence intervalEscudier B, et al. Lancet 2007;370:2103–11

Baseline risk factorTotal (n)HR All patients Sex Female Male Age (years) <40 40–64  Number of metastatic sites  2 > Motzer score Favourable Intermediate Poor HR Subgroup analysis for PFS in AVOREN Escudier B, et al. Lancet 2007;370:2103–11

*Stratified by Motzer score and region category; prespecified level of significance p=0.0056; HR=0.75 (95% CI: 0.58–0.97), p<0.0267* Median OS: Bevacizumab + IFN = not reached Placebo + IFN = 19.8 months Probability of survival Number of patients at risk Placebo + IFN Bevacizumab + IFN Months Interim analysis of OS (251 of 450 scheduled events) Escudier B, et al. Lancet 2007;370:2103–11

IFN-  2a + placebo (n=304) Bevacizumab + IFN-  2a (n=337) Median duration of treatment Bevacizumab/placebo (months) Dose intensity (%) IFN-  2a (months) Dose intensity (%) Grade ≥3 AE (%) Serious AE Discontinuation due to AE (%) Any study drug Bevacizumab/placebo IFN-  2a Death not due to PD (%) 2 2 † *Based on safety population † 3/8 deaths were possibly related to bevacizumab Overview of AEs* Escudier B, et al. Lancet 2007;370:2103–11

Number of patients (%) AE IFN-  2a + placebo (n=304) Bevacizumab + IFN-  2a (n=337) Any grade 3/4 AE 137 (45)203 (60) Fatigue/asthenia/malaise 46 (15) 76 (23) Proteinuria 0 (0) 22 (6.5) Neutropenia 7 (2)15 (4) Hypertension 2 (0.7) 13 (3.9) Haemorrhage 1 (0.3) 11 (3.3) Diarrhoea 3 (<1) 7 (2) Venous thromboembolism 2 (0.7) 6 (1.8) Gastrointestinal perforation 0 (0) 5 (1.5) Arterial ischaemia 1 (0.3) 4 (1.2) HFS 0 (0) Stomatitis/mucosal inflammation 0 (0) *Based on safety population Selected grade 3/4 AEs* Escudier B, et al. Lancet 2007;370:2103–11

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-  2a 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

Tumour response and clinical benefit in bevacizumab-treated patients in the total and reduced-dose IFN populations Total populationReduced-dose population Placebo (n=289) Bevacizumab (n=306) Placebo (n=94) Bevacizumab (n=124) Response, n (%) OR CR PR 37 (13) 6 (2) 31 (11) 96 (31) 4 (1) 92 (30) 16 (17) 4 (4) 12 (13) 39 (32) 2 (2) 37 (30) SD, n (%)144 (50)141 (46)58 (62) 71 (57) Clinical benefit,* n (%)181 (63)237 (77)74 (79)110 (89) PD, n (%) Not evaluable, n 95 (33) (20) 8 18 (19) 2 13 (11) 1 Median duration of tumour response, months *Clinical benefit = OR rate + SD rate; OR =overall response Melichar B, et al. Eur J Cancer Suppl 2007;5:304 (Abstract 4518)

Number of patients at risk Placebo + IFN Bevacizumab + IFN PFS estimate Months Bevacizumab + reduced dose IFN-  2a All bevacizumab + IFN-  2a patients PFS for bevacizumab-treated patients in the total and reduced-dose populations

Grade  3 AEs 6 weeks before and 6 weeks after IFN dose reduction Patients (%) BevacizumabPlacebo 6 weeks before reduction 6 weeks after reduction

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 IFN and bevacizumab IFN dose can be reduced to manage side effects while maintaining observed improvements in response rate and PFS

After AVOREN, where are we now in RCC? DrugTargetDescriptionClinical development stage in RCC Bevacizumab VEGFRecombinant humanised monoclonal antibody Bevacizumab + IFNα is approved in the EU for use in first-line therapy of advanced and/or metastatic RCC Sunitinib VEGFR, PDGFR, c-KIT, Flt-3 Small-molecular TKI Approved in the USA for advanced RCC Approved in the EU for advanced and/or metastatic RCC after failure of IFNα or IL-2 – now extended to include first-line use Phase III (adjuvant) Sorafenib VEGFR-2, VEGFR-3, PDGFR, c-KIT, Flt-3, RET, RAF-1, Dual-action multikinase inhibitor Approved in the USA for advanced RCC Approved in the EU for advanced RCC following failure or unsuitability for immunotherapy Phase III (adjuvant) Temsirolimus mTORRapamycin ester inhibitor of mTOR Approved in the USA for advanced RCC Approved in EU as first-line therapy for poor-risk advanced RCC Adapted from Bellmunt J. Eur Urol 2007;(Suppl. 6):484–91 VEGFR = VEGF receptor; PDGFR = PDGF receptor; Flt-3 = fms-like tyrosine kinase-3; TKI = tyrosine-kinase inhibitor; mTOR = mammalian target of rapamycin

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?

Combining novel agents with IFNα StudyTherapyConclusions Escudier 1 Bevacizumab/IFN  vs IFN  Bevacizumab plus IFN  significantly improves PFS and RR compared with IFN  alone; IFN  side effects easily manageable whilst maintaining benefits Hudes 2 Temsirolimus vs IFN  vs temsirolimus/IFN  Combining temsirolimus with IFN  does not improve outcomes compared to temsirolimus alone Bracarda 3 Sorafenib/IFN  (9MU) vs sorafenib/IFN  (3MU) Sorafenib does not add to the benefit of IFN  first-line Kondagunta 4 Sunitinib/IFN  (with dose interruptions and reductions) Sunitinib and IFN tolerable only at reduced doses of both agents; efficacy no better than IFN  alone 1 Escudier B, et al. Lancet 2007;370:2103–11; 2 Hudes G, et al. N Engl J Med 2007;356:2271–81; 3 Bracarda S, et al. J Clin Oncol 2007;25(Suppl. 1):259s (Abstract 5100) 4 Kondagunta GV, et al. J Clin Oncol 2007;25(Suppl. 1):260s (Abstract 5101)

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)

Trials of bevacizumab in combination with novel agents in RCC: efficacy CombinationnEfficacy Bevacizumab + sunitinib 1 20  Seven PRs and seven SDs (two with tumour reductions >30% but not confirmed due to withdrawal) Bevacizumab + sorafenib 2 24  Few patients with progressive disease  ~40% partial response rate  15% of patients with near partial response Bevacizumab + temsirolimus 3 12  Eight PRs and three SDs 1 Feldman DR, et al. J Clin Oncol 2007;25(Suppl. 1):259s (Abstract 5099) 2 Sosman JA, et al. J Clin Oncol 2006;24(Suppl. 1):128s (Abstract 3031) 3 Merchan JR, et al. J Clin Oncol 2007;25 (Suppl. 1):243s (Abstract 5034)

Trials of bevacizumab in combination with novel agents in RCC: safety CombinationnSafety findings Bevacizumab + sunitinib 1 20  Two DLTs (diffuse haemorrhage, epistaxis)  Phase II dose will be bevacizumab 10mg/kg plus either sunitinib 37.5mg or 50mg Bevacizumab + sorafenib 2 24  Sorafenib-associated DLTs (HFS and anorexia) prevented full-dose therapy  Optimal dosing to be defined Bevacizumab + temsirolimus 3 12  Full doses of both agents (bevacizumab 10mg/kg, temsirolimus 25mg) tolerated  DLTs = grade 3 hypertriglyceridaemia, mucositis  AE profile additive DLT = dose limiting toxicity 1 Feldman DR, et al. J Clin Oncol 2007;25(Suppl. 1):259s (Abstract 5099) 2 Sosman JA, et al. J Clin Oncol 2006;24(Suppl. 1):128s (Abstract 3031) 3 Merchan JR, et al. J Clin Oncol 2007;25(Suppl. 1):243s (Abstract 5034)

Data suggest bevacizumab is an excellent partner for combination therapy Combining bevacizumab 10mg/kg with cytokines, sunitinib or temsirolimus is feasible 1–3 (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 1 Feldman DR, et al. J Clin Oncol 2007;25(Suppl. 1):259s (Abstract 5099) 2 Sosman JA, et al. J Clin Oncol 2006;24(Suppl. 1):128s (Abstract 3031) 3 Azad NS, et al. J Clin Oncol 2006;24(Suppl. 1):121s (Abstract 3004)

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

Summary of data for anti-VEGF(R) therapy following prior anti-VEGF(R) therapy TrialnComments Sunitinib following bevacizumab 1 61  14 PRs, 36 SDs; PFS 30 weeks  No association between sensitivity to sunitinib and prior response to bevacizumab Sorafenib following bevacizumab  PR 2.5%, SD 77.5% Sequential sorafenib and sunitinib 3 90  PR to sunitinib after sorafenib = 15%  PR to sorafenib after sunitinib = 9%  Six PDs, three PRs with both drugs Sequential sorafenib and sunitinib 4 37  PR to sunitinib after sorafenib = 17%  PR to sorafenib after sunitinib = not reached  Median duration of SD=32 and 8 weeks 1 Hutson TE, et al. Eur J Cancer Suppl 2007;5:301 (Abstract 4510); 2 Drabkin HA, et al. J Clin Oncol 2007;25(Suppl. 1):245s (Abstract 5041); 3 Sablin MP, et al. J Clin Oncol 2007;25(Suppl. 1):244s (Abstract 5038); 4 Dham A, et al. J Clin Oncol 2007;25(Suppl. 1):261s (Abstract 5106)

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, sunitinib 1 and sorafenib 1–3 having greater efficacy than bevacizumab Sorafenib and sunitinib are active in second-line after bevacizumab 4 and 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 1 Tamaskar I, et al. J Clin Oncol 2006;24(Suppl. 1):240s (Abstract 4597) 2 Drabkin HA, J Clin Oncol 2007;25(Suppl. 1):245s (Abstract 5041) 3 Rini BI, et al. J Clin Oncol 2006;24(Suppl. 1):222s (Abstract 4522) 4 Dham A, Dudek AZ. J Clin Oncol 2007;25(Suppl. 1):261s (Abstract 5106)

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

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

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

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

RCC treatment algorithm: 2007 RegimenSetting Therapy Options Treatment-naïve patient Motzer risk: good or intermediate Bevacizumab  IFN  Sunitinib Cytokines Sorafenib? Motzer risk: poor Temsirolimus Sunitinib Sorafenib? Treatment- refractory patient (  second line) Cytokine refractory Sorafenib Sunitinib Refractory to VEGF/VEGFR or mTOR inhibitors Investigational? Sequential? TKIs or VEGF inhibitor Modified from Bukowski RM, presented at ASCO 2007; adapted from Atkins, presented at ASCO 2006