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Nexavar in Patients with Renal Cell Carcinoma

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Nexavar in Patients with Renal Cell Carcinoma Presentation Transcript

  • 1. Nexavar in Patients with Renal Cell Carcinoma Naomi B. Haas October 4, 2007
  • 2. Historical Management of Advanced-Stage RCC
    • Nephrectomy
    • Metastectomy
      • Solitary lesions
    • Cytokine combination
    • Combined modalities
      • Adjunctive nephrectomy prior to cytokine therapy
      • Cytokine therapy followed by nephrectomy
    • Clinical trials
    National Comprehensive Care Network. Clinical Practice Guidelines in Oncology: Kidney Cancer: Version   2. 2006 . Jenkintown, PA: National Comprehensive Cancer Network; 2006. Figure adapted from Urban BA, Fishman EK. Radiographics . 2000;20:197-212 .
  • 3. RCC is not one disease BHD=Birt-Hogg-Dubé; FH=fumarate hydratase; VHL=von Hippel-Lindau. Modified from Linehan WM et al. J Urol . 2003;170:2163-2172. *2004 WHO lists over 50 different types of kidney cancer (Sarcomatoid variant can occur with any subtype) Undifferentiated type and Collecting duct carcinoma constitute the other 2 types listed in AJCC classification Clear cell 75% Type Incidence (%) Associated mutations VHL Papillary type 1 5% c-Met Papillary type 2 10% FH Chromophobe 5% BHD Oncocytoma 5% BHD
  • 4.  
  • 5. Treatment of Advanced Disease
    • Based in part on risk factors
  • 6. MSKCC Risk Factor Model in mRCC Motzer RJ et al. J Clin Oncol . 2002;20:289-296.
    • Risk factors associated with worse prognosis
    • KPS <80
    • Low serum hemoglobin (13 g/dL/11.5 g/dL: M/F)
    • High corrected calcium (10 mg/dL)
    • High LDH (300 U/L)
    • Time from Dx to IFN-  <1 yr
    Time From Start of IFN -  (years) Proportion Surviving 0 2 16 14 13 11 9 5 4 3 6 15 12 10 8 7 6 0 risk factors (n=80 patients) 1 or 2 risk factors (n=269 patients) 3, 4, or 5 risk factors (n=88 patients) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
  • 7. ADVERSE PROGNOSTIC FACTORS FOR RENAL CELL CARCINOMA Motzer et al, JCO 17:2530-2540, 1999
    • Risk # Risk Factors Median Survival
    • Favorable 0 29 mo.
    • Intermediate 1-2 14 mo.
    • Poor 3 and + 4 mo.
  • 8. Do patients with advanced disease do better with nephrectomy? Performance status matters This issue has not been addressed in the era of targeted therapy
  • 9. Advanced Disease Therapy in 2007
    • Multitargeted tyrosine kinase inhibitors
    • Mammalian target of rapamycin (mTor) inhibitors
    • Anti VEGF antibodies
    • VEGF Trap
    • Other angiogenesis inhibitors-thrombospondin inhibitors, pure PDGFR and VEGFR inhibitors
  • 10.  
  • 11. The molecular profiles associated with the various histologic RCC subtypes have identified logical targets
    • Pathways associated with EGFR, AKT/mTOR, MAPK/MEK, and VEGF are important in RCC
    • Drugs available in 2007
      • Multitargeted TK inhibitors:
        • sunitinib, sorafenib, (FDA approved)
        • GW786034, AG013736,ABT869
      • Antibodies:
        • Bevacizumab
      • Imids: CC-5013
      • mTor inhibitors: temsirilimus, RAD001, rapamycin
  • 12.  
  • 13. Common Treatment related side effects
  • 14. Bevacizumab for mRCC: Phase II Study Design High dose = 10 mg/kg (n=39) Low dose = 3 mg/kg (n=37) Placebo (n=40) Second randomization of placebo group at TTP to low-dose bevacizumab +/- thalidomide. Yang JC et al. N Engl J Med . 2003;349:427-434.
    • 1 ° end points: TTP and ORR
    • 2 ° end point: OS
    • Study arms were balanced for demographics
    mRCC patients (N=116) ECOG PS <2 All patients have prior therapy (mostly IL-2)
  • 15.  
  • 16. Bevacizumab for mRCC: Summary
    • No significant difference in OS between treatment groups
    • High dose (10 mg/kg)
      • PR = 10% (95 CI, 2.9%–24.2%)
      • Significantly prolonged PFS (median 4.8 months, P <.001)
      • Moderate toxicity profile
      • No Grade 4 AE or deaths related to therapy
        • Proteinuria 64% (any grade)
        • Hypertension 36% (any grade)
    • Low dose (3 mg/kg)
      • Not significant
  • 17. Phase III study (AVOREN) of bevacizumab/interferon-α2a vs placebo/interferon- α2a as first-line therapy in metastatic RCC Journal of Clinical Oncology , 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 3 641 patients + nephrectomy + clear cell RCC IFN ( 9 MIU 3x weekly) + bevacizumab(10mg/kg) IVq2w (320) IFN ( 9 MIU 3x weekly) + placebo (321) The addition of BEV to IFN-a2a significantly increased PFS (10.2 vs. 5.4 mo) (HR=0.63; p<0.0001) and objective tumor response rate (30.6% vs. 12.4%; p<0.0001). A trend toward improved OS was observed with the addition of BEV to IFN-a2a (p=0.0670).
  • 18. Sorafenib (Nexavar ® )
    • Small-molecule receptor TKI 1
    • Inhibits VEGFR-2, VEGFR-3, FLT-3, PDGFR, c-KIT, Raf kinases 1
    • Formulation: 200 mg tablets 2
    • Dosing: 2 tablets bid continuous (1 hr ac or 2 hrs pc) 2
    • FDA approved December 20, 2005 for advanced RCC 3
    • Wilhelm SM et al. Cancer Res . 2004;10:7099-7109.
    • Nexavar [package insert]. West Haven, CT: Bayer Pharmaceutical Corporation and Emeryville, CA: Onyx Pharmaceuticals, Inc.; 2005.
    • Food and Drug Administration. FDA approves new treatment for advanced kidney cancer. Available at: www.fda.gov/bbs/topics/NEWS/2005/NEW01282.html. Accessed January 24, 2006.
    N H N H O O O N CI CF 3 NH CH 3
  • 19. Sorafenib for mRCC: Phase II (RDT) Progression-Free Survival Median PFS from randomization Sorafenib=24 weeks Placebo=6 weeks P =.0087 Time From Randomization (days) Proportion of Patients Progression-Free 1.00 0.75 0.50 0.25 0 12-week period 84 0 100 200 300 400 500 Ratain MJ et al. Presented at: ASCO; May 13-17, 2005; Orlando FL. Sorafenib (n=33) Placebo (n=32) Censored
  • 20.  
  • 21. Sorafenib for mRCC: Tumor Reduction* (TARGET) * Investigator assessment. Patients randomized at least 6 weeks before data cut-off of May 31, 2005. Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France. Tumor Reduction Tumor Reduction PR (  30% or reduction, RECIST). Change From Baseline (%)* 25% 76% Change From Baseline (%)* PD (  20% increase, RECIST); Sorafenib (n=451) Placebo (n=452) 0 50 100 150 -50 -100 0 50 100 150 -50 -100
  • 22. Sorafenib for mRCC: Progression-Free Survival* (TARGET) Time From Randomization (months) Proportion of Patients Progression Free 0 0.25 0.50 0.75 1.00 0 4 10 20 2 6 8 12 14 16 18 * Investigator assessment. Independent assessment at planned interim analysis (ASCO 2005) demonstrated doubling of PFS for sorafenib vs placebo (24 vs 12 weeks, P <.000001). Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France. 5.5 2.8 Sorafenib Placebo 0.51 Hazard ratio (S/P) Median (months) PFS Censored observation Placebo (n=452) Sorafenib (n=451)
  • 23. Sorafenib for mRCC: Overall Survival* (TARGET) Time From Randomization (months) Proportion of Patients Overall Survival 0 0.25 0.50 0.75 1.00 0 4 10 20 2 6 8 12 14 16 18 *Interim analysis. Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France. Not reached 14.7 Sorafenib Placebo 0.72 Hazard ratio (S/P) P =.018 Median (months) OS Censored observation Placebo (n=452) Sorafenib (n=451)
  • 24. Conclusions
    • Statistically significant improvement in progression free survival compared to placebo in patients with prior cytokine therapy
    • Improvement in OS may have been affected by crossover and was not achieved in final analysis
  • 25. Randomized Phase II Trial of First-line Treatment With Nexavar vs Interferon in Patients With Advanced Renal Cell Carcinoma: Final Results Adapted from Szczylik C et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
  • 26. First-line Nexavar vs IFN in Advanced RCC—Study Design Period 1 Period 2 Period 1 Period 2
    • Eligibility Criteria
    • Clear-cell histology
    • No prior systemic therapy
    • ECOG Performance Status 0 or 1
    • All MSKCC risk groups
    Open-label randomization 1:1 Stratification MSKCC N=189 PROGRESSION PROGRESSION IFN=interferon. Adapted from Szczylik C et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
    • 1º endpoints:
      • Period 1: PFS (Nexavar vs IFN); database cutoff: 29 Sep 06: 121 PFS events
      • Period 2: PFS and clinical benefit; database cutoff: 31 Dec 06: 52 PFS events
    • 2º endpoints:
      • Quality of life
    Nexavar 400 mg bid N=97 IFN 9 MIU tiw N=92 Nexavar 400 mg bid N=50 Nexavar 600 mg bid N=44
  • 27.
    • Period 1: Nexavar vs IFN
      • Median PFS comparable between IFN (5.6 mo) and Nexavar (5.7 mo)*
      • Clinical benefit and tumor shrinkage greater with Nexavar than IFN
      • Quality of life was markedly better with Nexavar vs IFN
      • Adverse events as expected with Nexavar and IFN
    • Period 2: crossover, dose escalation
      • IFN to Nexavar crossover mirrored results of TARGET study
      • Nexavar 400 -> 600 mg bid
        • Well tolerated
        • Additional benefit following dose escalation
          • Delay of progression for 4.1 months
          • Improvement of clinical outcome for 46% of patients
          • Quality of life benefit was maintained
    First-line Nexavar vs IFN in Advanced RCC—Results *Hazard ratio (IFN/NEX)=0.883 (95% CI: 0.613-1.272.) TARGET=Treatment Approaches in Renal Cancer Global Evaluation Trial. Adapted from Szczylik C et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
  • 28. Sunitinib (Sutent ® )
    • Small-molecule receptor TKI 1
    • Inhibits all VEGFRs, PDGFR-a, PDGFR-b, c-KIT, and FLT-3 1
    • Formulation: 12.5 mg, 25 mg, 50 mg capsules 2
    • Dosing: 50 mg qd ± food ( 4 wks on, 2 wks off) 2
    • FDA approved January 26, 2006 for advanced RCC
    • Pietras K, Hanahan D. J Clin Oncol. 2005;23:939-952.
    • Sutent [package insert]. New York, NY: Pfizer Inc.; 2006.
    H 3 C CH 3 F O O CH 3 CH 3 N H N H N N H
  • 29.  
  • 30. Results
    • Median PFS 11 months for sunitinib vs. 5 months for IFN-α (p<0.000001)].
    • The objective response rate by third-party independent review was 31% for sunitinib vs. 6% for IFN-α (p<0.000001).
    • 8% withdrew from the study due to adverse event on sunitinib arm vs. 13% on IFN-α arm.
  • 31.  
  • 32. Conclusion
    • Statistically significant improvement in PFS and objective response rate for sunitinib over IFN-α in first-line treatment of patients with metastatic RCC
  • 33. Targeted Therapy: More Questions Than Answers
    • First Line:Should we combine these agents?
      • Sequentially or concurrently?
      • Vertical inhibition or horizontal inhibition?
    • Which Type of Agent should be used first? mTKI or mTor inhibitor?
    • At Progression
      • Dose escalation of mTKI vs other mechanism?
  • 34.
    • Treatment duration-are these agents purely angiostatic?
    • Assessment of Response-
      • Which is more important: RECIST or PFS?
    • Predictors of Response
      • Blood flow/ vascularity
      • histology
      • Imaging- PET/CT, DCE/MRI, CT
    • Role of agents-Adjuvant?, First-line? Before or after cytokines?
    • Exposure to agent- drug levels of sunitinib correlated with response
    • Dose escalation of agent –some patients can tolerate dose escalation at the time of progression
    • How to treat non clear cell and other variants
  • 35. Sequential Use of Nexavar and Sunitinib: Retrospective Analysis in 90 Patients
  • 36. MKI Sequencing: Study Design N=90 4 sites in France RCC patients in expanded access programs
    • Reviewed
    • Patient demographics
    • MSKCC
    • No. of metastatic sites
    • Efficacy
    • OS
    • PFS
    • Best response
    • Safety
    Retrospective review of sequential therapy with MKIs in RCC Nexavar -> Sunitinib n=68 Sunitinib -> Nexavar n=22 MKI=multikinase inhibitor. Adapted from Sablin MP et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
  • 37. MKI Sequencing: Results
    • 68 patients received Nexavar first, while 22 received sunitinib first
    • The 2 groups are comparable in terms of ECOG PS and MSKCC groups
    • 38% of the patients in the Nexavar->sunitinib group are still on   treatment vs 19% in the sunitinib->Nexavar group
    • 50% of the patients have died in the sunitinib->Nexavar group compared to 32% in the Nexavar->sunitinib
    Adapted from Sablin MP et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
  • 38. MKI Sequencing: Efficacy of Treatment NR=not reached. Adapted from Sablin MP et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL. 22 27 28 33 Average duration, weeks – – 6 (9) 2 (3) Not evaluated (NE), n (%) 8 (36) 5 (23) 17 (25) 10 (15) Progressive disease, n (%) 12 (55) 12 (54) 35 (51) 45 (66) Stable disease, n (%) 2 (9) 5 (23) 10 (15) 11 (16) Partial response, n (%) 17 22 25 26 Median PFS, weeks Nexavar Sunitinib Sunitinib Nexavar 70 NR Median Overall Survival, weeks Su->NEX NEX->Su
  • 39. MKI Sequencing: Efficacy of Nexavar ->S unitinib Adapted from Sablin MP et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL. NE, n PD, n SD, n PR, n Nexavar 2 10 45 11 1 – 1 – 1 (10) 4 (40) 3 (30) 2 (20) 4 (9) 11 (25) 24 (53) 6 (13) – 2 (18) 7 (64) 2 (18) NE n (%) PD n (%) SD n (%) PR n (%) Sunitinib
  • 40. MKI Sequencing: Efficacy of Sunitinib->Nexavar Adapted from Sablin MP et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL. PD, n SD, n PR, n Sunitinib 5 12 5 2 (40) 3 (60) 0 4 (34) 7 (58) 1 (8) 2 (40) 2 (40) 1 (20) PD n (%) SD n (%) PR n (%) Nexavar
  • 41. MKI Sequencing: Conclusions
    • This study supports the sequential administration of Nexavar and sunitinib even though these 2 drugs share the same targets
    • In our study, using Nexavar first appears to be superior with
      • A better PFS for each arm
      • The achievement of PR after PD with sunitinib after Nexavar (20%)
      • A longer duration on therapy (61 vs 49 weeks)
      • A trend toward better survival (to be confirmed)
    • These data will have to be confirmed in prospective studies
    Adapted from Sablin MP et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
  • 42. Phase II Trial of Intrapatient Dose-Escalated-Nexavar in Patients With Metastatic Renal Cell Cancer
  • 43. Dose-Escalated Nexavar for RCC: Study Design
    • 1º endpoints: Safety and toxicity
    • 2º endpoints: RR, PFS, and OS
    Treatment continues until PD or intolerance Target accrual: 44 patients. Response assessed by RECIST every 8 weeks. DLT=dose-limiting toxicities; Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
    • Eligibility
    • Metastatic RCC, component of clear-cell
    • ≤ 1 prior cytokine therapy
    • Adequate PS
    • Adequate pancreatic and cardiac function
    After 4 weeks, patients with no DLT (grade 3 / 4 ) increase dose After 4 weeks, patients with no DLT (grade 3/4) increase dose Nexavar 800 mg po bid Days 57+ Nexavar 400 mg po bid Days 1-28 Nexavar 600 mg po bid Days 29-56
  • 44. Dose-Escalated Nexavar for RCC: Baseline Patient Characteristics Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL. N=44 7 3 3 23 10 Prior radiation therapy 14 38 41 95 20 80 89/11 84/16 Range 43-79 % 1 CC/Papillary 6 2 17 1 18 0 MSKCC Risk Factors 42 Prior nephrectomy 1 CC/Focal Rhabdoid 7 CC/Sarcomatoid 9 Other histology 35 Clear Cell (CC) 39/5 Zubrod PS, (0/1) 37/7 Male/female 50 Median age, years (range) N Characteristics
  • 45. Dose-Escalated Nexavar for RCC: Baseline Patient Characteristics (cont’d) CR=complete response; IL-2=interleukin 2; PR=partial response. Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL. N=44 16 7 ≥ 3 25 59 16/11 43 % 26 1 11 2 Total number of metastatic sites 3/2 Best response to prior systemic CR/PR 1 cG250 1 Interferon 2 RAD001 15 IL-2 19 Prior systemic therapy N Characteristics
  • 46. Dose-Escalated Nexavar for RCC: Intensity of Therapy
    • At 800-mg dose level:
      • 5 patients had dose held between Weeks 2 through 4
      • 3 patients were dose reduced
    • Doses were escalated to 1200 mg in 41 of 44 patients
    • Doses were escalated to 1600 mg in 32 of 41 patients
      • 25 patients maintained dose
      • 7 patients were dose reduced
    • Summary
      • 41 patients were able to receive 1200 or 1600 mg per day of Nexavar
      • 3 patients were unable to be dose escalated
      • Those with early toxicity have difficulty with dose escalation
    Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
  • 47. Dose-Escalated Nexavar for RCC: Best Response by RECIST Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL. 25 20 39 16 (%) 11 9 17 7 No. of Patients Progression defined as ≤4 months Stable disease ≥6 months Partial response Complete response Best Response
  • 48. Dose-Escalated Nexavar for RCC: Incidence of Treatment-Related AEs AEs=adverse events; ALT=alanine aminotransferase; AST=aspartate aminotransferase. Adapted from Amato RJ et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL. — 3 6 — — 2 7 — 3 5 Hypertension Cycle 3 Days 57+ (n=32) Cycle 2 Days 29-56 (n=41) Cycle 1 Days 1-28 (n=44) 1 1 6 — 1 — 3 3 — 5 Amylase/lipase 1 3 9 1 1 1 7 — — 6 ALT/AST 1 — 14 — — — 16 — — 16 Anemia — — 6 — — — 8 — — 4 Anorexia — — 17 — — — 10 — — 4 Alopecia — — 7 — — — 7 1 2 7 Rash — 2 6 — — — 4 1 — 9 Nausea 1 1 13 — — — 11 — 1 9 Fatigue 1 2 21 — 2 4 18 2 2 13 Hand-foot syndrome — 4 16 — — 2 13 1 — 11 Diarrhea 9 8 2 — — 3 10 6 12 — Hypophosphatemia — — — — — — — — — 1 Stomatitis — 1 4 — — 1 4 — — 2 Dry skin — — 18 — — — 8 — — 5 Stomatitis G3 G2 G1 G4 G3 G2 G1 G3 G2 G1 Adverse Events
  • 49. Dose-Escalated Nexavar for RCC: Conclusions
    • Dose-escalated Nexavar was well tolerated when given twice daily by oral administration
    • 93% of patients were able to be dose escalated to either 1200 or 1600 mg per day
    • A high level of antitumor activity was demonstrated by a 55% complete and partial response rate in patients with metastatic RCC
    • Follow-up trials are in progress to verify these data
    Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
  • 50. Sorafenib for mRCC: Tumor Response (TARGET) Pre-Therapy 8 Weeks Post-Therapy Image courtesy of Laura Wood, RN, MSN, OCN.
  • 51. Management of Early-Stage RCC
    • Surgery
      • Partial or radical nephrectomy
      • Open surgery
      • Laparoscopic
      • Cryoablation or radiofrequency ablation
    • Adjuvant Tx
      • No benefit from adjuvant interleukin2 or interferon
      • No benefit from radiation therapy
      • Benefit from adjuvant targeted therapy is unknown
    • Neoadjuvant- investigational
    National Comprehensive Care Network. Clinical Practice Guidelines in Oncology: Kidney Cancer: Version   2. 2006 . Jenkintown, PA: National Comprehensive Cancer Network; 2006. Figure adapted from Urban BA, Fishman EK. Radiographics . 2000;20:197-212 .
  • 52. Predictors of Relapse
    • Prognostic models based on postoperative score:
      • UCLA Integrated Staging System (UISS)
      • Leibovich Model
      • Frank Model (SSIGN)
      • Kattan Model
    • Prognostic Models based on preoperative score:
      • Yaycioglu
      • Cindolo
  • 53. Contributors to Prognosis
    • Pathologic stage
    • Histology
    • Fuhrman Grade
    • Nuclear grade
    • Performance status
    • Necrosis
    • Size
    • Clinical Presentation
  • 54. The UCLA Integrated staging system (UISS) 0 9 1 or more 4 IV V 23 42 0 1 or more 3,4 1-3 IV IV   39 66 1 or more 0 2-4 1,2 III IV III 64 89   1 Any Any 0 1 or more 1,2 3,4 Any Any I I I II III III II 94 96 1,2 I 5Yr 2 Yr. Survival (%) ECOG Fuhrman Grade 1997 TNM Stage (%) UISS Survival
  • 55. Stratify Risk by TNM Stage/Grade Intermediate Risk High Risk Histologic Subtype Clear cell Non-clear cell Performance status Surgery Open vs laparoscopic   Arm B Sorafenib 800mg daily for 1 year Arm C Placebo Daily for 1 year RANDOMIZE Non-Metastatic Kidney Cancer That meets radiologic criteria to be clinically  T1bNany (resectable) M0 disease S U R G E R Y Arm A Sunitinib 50 mg daily for 1 year REGISTRATION1 REGISTRATION2 A.S.S.U.R.E. (ECOG 2805)
  • 56. Objectives
    • Primary Question:
    • Can adjuvant therapy with an oral raf kinase inhibitor/ receptor tyrosine kinase inhibitor (Sorafenib) or pure receptor tyrosine kinase inhibitor (Sunitinib) improve disease-free survival in locally advanced RCC over placebo after surgical resection?
    • Primary endpoint is DFS
  • 57. Secondary Objectives
    • Overall survival
    • Toxicity in the adjuvant setting
    • Prospective collection of tumor and biologic specimens /Correlatives:
      • Measures of angiogenesis
      • Mutational analyses (oncogenes/TSG)
      • Hypermethylation
      • Polymorphisms
  • 58. Nexavar in Adjuvant RCC: MRC SORCE Phase III Trial Nexavar for 1 year, then placebo for 2 years (n=621)
    • 1 º endpoint: Metastasis-free survival
    • 2 º endpoints: RCC-specific survival time, toxicity, QoL, and biomarkers
    (1.5:1.5:1) Randomization (N=1656) High and intermediate risk, resected RCC Nephrectomy Placebo for 3 years (n=414) Nexavar for 3 years (n=621) MRC=Medical Research Council; QoL=quality of life; SORCE=SOrafenib versus placebo in patients with Resected primary renal CEll carcinoma.
  • 59. Developments
    • ECOG BEST Trial (4 arm) of Doublet Targeted therapy (tem/bev vs bev vs sorafenib/bev vs sorafenib/tem
    • Temsirolimus versus sunitinib trial for non clear cell RCC
    • mTKI to mTOR vs mTor to mTKI trial
    • Adjuvant trials SORCE and ASSURE are ongoing
  • 60. Conclusions
    • Surgery remains the most effective therapy for early RCC and plays a role in advanced RCC
    • New molecular targets have been identified which are critical to the pathogenesis of different types of RCC and new targeted therapies are replacing traditional biologic therapies
    • The ultimate role that these agents will play in RCC has yet to be decided
  • 61. Common Treatment related side effects
  • 62. Targeted Therapy: More Questions Than Answers
    • First Line:Should we combine these agents?
      • Sequentially or concurrently?
      • Vertical inhibition or horizontal inhibition?
    • Which Type of Agent should be used first? mTKI or mTor inhibitor?
    • At Progression
      • Dose escalation of mTKI vs other mechanism?
  • 63.
    • Treatment duration-are these agents purely angiostatic?
    • Assessment of Response-
      • Which is more important: RECIST or PFS?
    • Predictors of Response
      • Blood flow/ vascularity
      • histology
      • Imaging- PET/CT, DCE/MRI, CT
    • Role of agents-Adjuvant?, First-line? Before or after cytokines?
    • Exposure to agent- drug levels of sunitinib correlated with response
    • Dose escalation of agent –some patients can tolerate dose escalation at the time of progression
    • How to treat non clear cell and other variants
  • 64. Stratify Risk by TNM Stage/Grade Intermediate Risk High Risk Histologic Subtype Clear cell Non-clear cell Performance status Surgery Open vs laparoscopic   Arm B Sorafenib 800mg daily for 1 year Arm C Placebo Daily for 1 year RANDOMIZE Non-Metastatic Kidney Cancer That meets radiologic criteria to be clinically  T1bNany (resectable) M0 disease S U R G E R Y Arm A Sunitinib 50 mg daily for 1 year REGISTRATION1 REGISTRATION2 A.S.S.U.R.E. (ECOG 2805)