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Michele Milella Oncologia Medica A Istituto Nazionale Tumori Regina Elena Roma

Michele Milella Oncologia Medica A Istituto Nazionale Tumori Regina Elena Roma. Disclosures. I have very strong opinions on this talk’s topic and will try to force and bend available evidence to convince you that I’m right. …In the beginning was Motzer !. Poor risk (20%)

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Michele Milella Oncologia Medica A Istituto Nazionale Tumori Regina Elena Roma

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  1. Michele Milella Oncologia Medica A Istituto Nazionale Tumori Regina Elena Roma

  2. Disclosures I havevery strong opinions on this talk’s topic and willtrytoforce and bendavailableevidenceto convince youthat I’m right.

  3. …In the beginningwasMotzer! Poorrisk (20%) Median PFS: 2.5 mos Median OS: 5 mos 1-yr OS: 20% 2-yr OS: 6% 3-yr OS: 2%

  4. The CCF extension Poorrisk (28%) Median OS: 7.3 mos 1-yr OS: 23%

  5. …but they were meant for immuno/chemotherapy-treated patients! MSKCC CCF

  6. What do weREALLYknow?(I mean: high-qualityscientificevidence…)

  7. The Global ARCC Study:Trial Design RANDOMIZE Hudes et al. N Engl J Med. 2007;356:2271-2281.

  8. Main Inclusion Criteria:Poor Prognostic Factors Patients had at least 3 of 6 “poor prognostic factors” for shortened survival listed below: • Karnofsky performance status 60 or 70 • Hemoglobin less than the lower limit of normal (LLN) • Less than 1 year from time of initial RCC diagnosis to randomization • Corrected serum calcium > 10 mg/dL • Lactate dehydrogenase > 1.5 times the upper limit of normal (ULN) • More than 1 metastatic organ site of disease (sites defined as different tissues with metastasis: lung, liver, bone, kidney, lymph node, etc.) Hudes et al. N Engl J Med. 2007;356:2271-2281.

  9. Baseline Characteristics /Subgroups (ITT Patient Population) Hudes et al. N Engl J Med. 2007;356:2271-2281.

  10. Baseline CharacteristicsPoor Prognostic Factors (ITT Population) • Treatment arms generally well balanced for prognostic factors Hudes et al. N Engl J Med. 2007;356:2271-2281.

  11. Primary EndpointMedian Overall Survival Treatment with TORISEL was associated with a 49% increase in median OS compared with IFN-α 1.00 0.75 Probability of Survival 0.50 0.25 0.00 0 5 10 15 20 25 30 Time From Registration, Months TORISEL (N=209) TORISEL + IFN-α (N=207) IFN-α (N=207) Hudes et al. N Engl J Med. 2007;356:2271-2281.

  12. Secondary Endpoints Hudes et al. N Engl J Med. 2007;356:2271-2281.

  13. Overall Survival Across Patient Subgroups Subgroup No. of Patients Hazard Ratio (95% CI) Age <65 y 287 ≥65 y 129 Sex Male 287 Female 129 Karnofsky performance status ≤70 340 >70 75 Nephrectomy Yes 278 No 138 Histology Clear cell 339 Other 73 Diagnosis to randomization <1 y 338 ≥1 y 78 Hemoglobin level <1 x LLN 340 ≥1 x LLN 76 LDH level ≤1.5 x ULN 315 >1.5 x ULN 84 Corrected serum calcium level ≤10 mg/mL 276 >10 mg/mL 126 Geographic area US 122 W EU, Canada, Australia 87 Asia-Pacific, E EU, Africa, S Amer 207 0.0 0.5 1.0 1.5 2.0 TORISEL Better Interferon- Better Hudes et al. N Engl J Med. 2007;356:2271-2281.

  14. OS by Prognostic Factors (ITT Population) 1 Median Overall Survival in months 2 95% Confidence Interval Hudes et al. N Engl J Med. 2007;356:2271-2281.

  15. Poorprognosispatients:Who are they???? 50 yr-old male mRCC (synchronous) Nefrectomized Hb 13.8 LN and pulmonarynodules KPS 100% 80 yr-oldfemale mRCC (synchronous) No nefrectomy Hb 9.8 Corrected Ca++ 3.45 LN, lung, bone, pancreas KPS 60% Are they the same??? Wouldyoutreatthem the same???

  16. So, Temis the standard of care forpoorriskmRCCpts……but, what are the alternatives?

  17. Well, targeting the VEGF axiscould be an alternative, manywouldsay…

  18. …but, based on which data? Sunitinib ASCO 2008; abstr 16057

  19. …but, based on which data? Bevacizumab/IFNa AVOREN CALGB

  20. …but, based on which data? Sorafenib Pazopanib No data available No data available JCO 2009 Cancer 2011 AnnOncol 2011 JCO 2010

  21. mTTP: 5.0 mos (3.5-6.5) mOS: 9.3 mos (7.3-11.5)

  22. Median OS (with 95% CI) for mRCC patients classified as poor-risk by classical MSKCC criteria upon treatment with selected targeted agents Temsirolimus Sunitinib Bevacizumab/IFN

  23. So, Sunitinibwouldbe the ONLYalternative…but in whichpatients??? Poorriskbyclassical MSKCC criteria Poorriskbybothcriteria Poorriskbymodified MSKCC criteria Intermediate riskbyclassical MSKCC criteria

  24. And it’s gettingmore…

  25. …and more complicated!!!

  26. Risk stratification in the targeted agent era

  27. Validation of the IDC model Poorrisk(30%) Median OS: 7.8 mos

  28. … and yet, we are missing something!

  29. Butdon’tforgetotherthingsmaybeimportanttoo…

  30. Cytoreductive Surgery SWOG 8949 n=246 EORTC Trial n=85 OS= 17 vs 7 months OS=11 vs 8.1 months IFN Nephrectomy + IFN Flanigan RC, NEJM 345:1655, 2001 Mickisch, Lancet 358:966, 2001

  31. Cytoreductive Surgery 31% decrease in risk of death with nephrectomy • Eligibility data: ECOG PS 0-1, clear cell histology, primary resectable • lack of CNS, liver or extensive bone metastases • Absolute benefit diminishes in poor risk groups • We don’t know what mechanism underlies the improvement in survival Flanigan RC J Urol 171:1071, 2004

  32. RCC Consortium Database N= 314 (37% PoorRisk by Heng) • Pts treated with Sunitinib, Sorafenib, Bevacizumab • Retrospective data Benefit of cytoreductive nephrectomy seems to be marginal in poor risk group Choueiri TK, JUrol 185: 60-66, 2011

  33. UpfrontNephrectomy in PoorRisk? PoorRisk Poor Performance status Unresectable PrimayTumor Upfront Systemic Therapy Upfront Therapy Improvement in Overall Patient Status PoorRisk Resectable PrimayTumor Nephrectomy??

  34. The same does not apply to patients treated with VEGF inhibitors… Heng, JCO 2009

  35. And don’t forgetotherthingsmaybeimportanttoo…

  36. VEGFR inhibitors are active in ncc-RCC

  37. VEGFR inhibitors are active in ncc-RCC

  38. VEGFR inhibitors are active in ncc-RCC

  39. …but are still less active than in cc-RCC!!! Modified from: Heng, JCO 2009

  40. Overall Survival by Histologic Subtype (ITT Population) 1 Median Overall Survival in months 2 95% Confidence Interval Data on file, Wyeth Pharmaceuticals Inc.

  41. Tem vs IFN in ncc-RCC Dutcher, Med Oncol 2009

  42. Tem vs IFN in ncc-RCC Dutcher, Med Oncol 2009

  43. And don’t forgetotherthingsmaybeimportanttoo…

  44. LDH levels are predictive of Tem benefit over IFN in poorriskmRCCpatients Low LDH IFNa High LDH Tem Armstrong, JCO 2012

  45. …still a peculiarity of mTOR inhibitors? Modified from Heng, JCO 2009

  46. Conclusions • Temsirolimusis the most appropriate therapeuticchoice in the vastmajorityofpts w at least 3/6 poorriskfeatures(and, by the way, the onlyonesupportedbyevidence….) • In selectedpts w intermediate risk by strict MSKCC criteria, Sunitinibis a reasonablechoice • However, in a fraction of poorriskpts VEGF inhibitorsdramatically alter diseasenaturalhistory(…buthow do weidentifythem???) • Otherfactors, suchasnefrectomystatus, histology, LDHlevels, or the necessitytoobtainanobjectiveresponseshouldbetakeninto account

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