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  • Frank GriesingerProfessor at the University of Gttingen and Chair of the Department of Medical Oncology, Pius-Hospital, Oldenburg, GermanyProfessor of Internal Medicine and Haematology and Medical Oncology at the University of GttingenChair 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 GroupCo-author of more than 50 papers in international peer-reviewed journals

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

  • Historical approaches to RCC therapyIL-2 = interleukin-2; IFN = interferon alpha; BSC = best supportive care

    Stage of RCCTherapeutic goalsPrimary or first-line treatment optionsFurther or second-line therapy optionsIIII


    Radical or nephron-sparing nephrectomyIL-2 or IFN immunotherapy at relapse BSCIVExtend survival Stabilise disease PalliationNephrectomy (if possible) IL-2 or IFN immunotherapy Cytoreductive nephrectomy in appropriate patients prior to immunotherapy BSC (including radiotherapy, metastasectomy or bisphosphonates for bone metastases)

  • Historical approaches to RCC therapyNephrectomy is curative in a proportion of patients diagnosed early30% of patients present with metastatic disease (Stage IV)RCC is insensitive to radiotherapy, chemotherapy and hormone therapyImmunotherapy produces a response rate of up to 20% and median overall survival (OS) of 13 monthsNew therapeutic options are required

  • Rationale for anti-VEGF therapy in RCCAdapted from Linehan WM, et al. J Urol 2003;170:216372Tagged fordegradationNormoxiaHypoxiaHIFHIF accumulationVEGFTGF, PDGFAngiogenesisAutocrine growth stimulationVHLproteinVHLcomplexXHIF degradationDisruption of VHLprotein prohibits thepathway leading to HIFdegradation causing HIF accumulationVHL = von Hippel-LindauHIF = hypoxia-inducible factor-TGF = transforming growth factor-PDGF = platelet-derived growth factor

  • Phase II trial of bevacizumab monotherapy in RCC (AVF0890g): study designPrimary endpoints: time to progression and response rateSecondary endpoints: survival and safetyInitial trials of bevacizumab in RCC: AVF0890gYang JC, et al. N Engl J Med 2003;349:42734PD = progression of disease

  • Patients progression-free (%)Bevacizumab 10mg/kg every 2 weeks; p
  • Safety profile of bevacizumab in mRCC1Yang JC, et al. N Engl J Med 2003;349:427342Bukowski RM, et al. J Clin Oncol 2007;25:453641

    Adverse event (AE)Bevacizumabsecond-line1Bevacizumabfirst-line2grade 3/4grade 3/4Proteinuria (%)8 6Hypertension (%) 21 26Bleeding (%)0 4Chest pain (%)5 Gastrointestinal perforation (%) 0Neutropenia (%) 0Diarrhoea (%) 0Hand-foot syndrome (HFS) (%) 0Nausea and vomiting (%) 0Stomatitis (%) 0

  • Bevacizumab/placebo 10mg/kg i.v. every 2 weeks until progressionIFN-2a 9MIU s.c. 3 times weekly (maximum of 52 weeks) (dose reduction allowed)Multinational ex-US study: 101 study sites in 18 countriesStratification factors: country and Motzer scoreBevacizumab + IFN-a2a (n=327)IFN-a2a + placebo (n=322)PDPDEscudier B, et al. Lancet 2007;370:210311 RCC patients(n=649)i.v. = intravenous; IFN-2a = interferon-alpha2aMIU = million international unitss.c. = subcutaneous1:1Phase III trial of first-line bevacizumabin RCC (AVOREN)

  • Primary objectiveTo evaluate the efficacy of the combination of bevacizumab plus IFN-a2a as compared with IFN-a2a alone based on OSSecondary objectivesPFS, time to disease progression, time to treatment failure and objective response rates of bevacizumab plus IFN-a2a compared with IFN-a2a aloneSafety profile of bevacizumab plus IFN-a2a versus IFN-a2a alonePharmacokinetics and pharmacodynamics of bevacizumab ObjectivesEscudier B, et al. Lancet 2007;370:210311

  • Inclusion criteriaConfirmed metastatic RCC with >50% clear cell histologyNephrectomyKPS of 70%Measurable or non-measurable disease (according to RECIST)Exclusion criteriaPrior systemic treatment for metastatic RCC diseaseEvidence of current CNS metastases or spinal cord compressionEvidence of bleeding diathesis or coagulopathyFull therapeutic doses of oral or parenteral anticoagulantsKPS = Karnofsky performance status RECIST = Response Evaluation Criteria in Solid Tumors CNS = central nervous systemKey eligibility criteriaEscudier B, et al. Lancet 2007;370:210311

  • Statistical design and interim analysisSample size calculation80% power to detect an improvement in OS from 13 to 17 months with a HR of 0.76 at a significance level of 0.05required 445 events among 638 patientsinterim analysis prespecified at 250 eventsA final PFS analysis to occur at the time of an interim OS analysis90% power to detect an improvement in PFS with a HR of 0.71 at a significance level of 0.05the study would be unblinded after the final PFS analysis and continued on survival follow-upHR = hazard ratioEscudier B, et al. Lancet 2007;370:210311

  • *Based on intent-to-treat (ITT) populationPatient characteristics*Escudier B, et al. Lancet 2007;370:210311

    VariableIFN-a2a + placebo (n=322)Bevacizumab + IFN-a2a (n=327)Female (%)Male (%)27733268Median age, years (range)60 (1881)61 (3082)KPS (%) 100 90 80 70393916 7443218 6Sites of metastases (%) Lung Lymph nodes Bone Liver5936201962341818Motzer risk score (%) Favourable Intermediate Poor Not available2956 8 7275699

  • *Patients with measurable disease onlyTumour response Escudier B, et al. Lancet 2007;370:210311

    ResponseIFN-a2a + placebo (n=289) Bevacizumab + IFN-a2a (n=306)Overall response rate (RR) (%)* Complete response (CR) Partial response (PR)13 21131 1 30p=0.0001Median duration of response (months)Median duration of stable disease (SD) (months)11713 10

  • HR=0.63, (95% CI: (0.520.75) p
  • 0.20.5125HRSubgroup analysis for PFS in AVORENEscudier B, et al. Lancet 2007;370:210311

    Baseline risk factorTotal (n)HRAll patients6490.63Sex Female Male 193 456 0.60 0.64Age (years) 2 394 252 0.67 0.54Motzer score Favourable Intermediate Poor 180 363 54 0.60 0.55 0.81

  • *Stratified by Motzer score and region category; prespecified level of significance p=0.0056; HR=0.75 (95% CI: 0.580.97), p
  • *Based on safety population 3/8 deaths were possibly related to bevacizumabOverview of AEs*Escudier B, et al. Lancet 2007;370:210311

    IFN-a2a + placebo(n=304)Bevacizumab + IFN-a2a (n=337)Median duration of treatment Bevacizumab/placebo (months) Dose intensity (%) IFN-2a (months) Dose intensity (%) 596 5961092 891Grade 3 AE (%)Serious AE45166029Discontinuation due to AE (%)Any study drugBevacizumab/placeboIFN-a2a 12 612281923Death not due to PD (%) 2 2

  • *Based on safety populationSelected grade 3/4 AEs*Escudier B, et al. Lancet 2007;370:210311

    Number of patients (%) AEIFN-a2a + placebo (n=304)Bevacizumab + IFN-a2a (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 (

  • 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 developedIFN-2a was restarted with one dose level reduction (6MIU) if toxicity resolved to grade
  • 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 responseMelichar B, et al. Eur J Cancer Suppl 2007;5:304 (Abstract 4518)

    Total populationReduced-dose populationPlacebo (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) 13 61 (20) 818 (19) 2 13 (11) 1Median duration of tumour response, months 11.1 13.5 9.1 13.6

  • Number of patients at risk Placebo + IFN 327259196170107541860Bevacizumab+ IFN131118968855281240 estimate03691215182124MonthsBevacizumab + reduced dose IFN-a2aAll bevacizumab + IFN-a2a patientsPFS for bevacizumab-treated patients in the total and reduced-dose populations

  • Grade 3 AEs 6 weeks before and 6 weeks after IFN dose reductionPatients (%)BevacizumabPlacebo6 weeks before reduction6 weeks after reduction

  • AVOREN trial overall conclusionsAddition of bevacizumab to IFN statistically and clinically significantly improves PFS and tumour response, with a trend in favour of improved survivalBevacizumab with IFN significantly improves PFS and RR in predefined patient subgroupsTreatment was well tolerated and no new toxicities emerged outside of those known with IFN and bevacizumabIFN 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?Adapted from Bellmunt J. Eur Urol 2007;(Suppl. 6):48491VEGFR = VEGF receptor; PDGFR = PDGF receptor; Flt-3 = fms-like tyrosine kinase-3; TKI = tyrosine-kinase inhibitor; mTOR = mammalian target of rapamycin

    DrugTargetDescriptionClinical development stage in RCCBevacizumab VEGF Recombinant humanised monoclonal antibodyBevacizumab + IFN is approved in the EU for use in first-line therapy of advanced and/or metastatic RCC Sunitinib VE

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