Renal Cell Carcinoma Diagnosis And Management

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  • Clues to the pathogenesis of RCC have been identified through study of von Hippel Lindau (VHL) syndrome, an autosomal dominant disorder with inherited susceptibility to clear-cell RCC and other tumors. VHL syndrome is associated with overexpression of various growth factors that have been linked with tumorigenesis, including VEGF and PDGF. In VHL syndrome, VHL gene inactivation due to gene mutation or methylation leads to defective VHL protein function. VHL protein normally earmarks another protein called hypoxia inducible factor-1  (HIF-1  ) for metabolic degradation, so loss of VHL protein function leads to an accumulation of HIF-1  HIF-  forms a complex with HIF-  that regulates gene transcription, including the genes encoding VEGF, PDGF, and TGF-  . Hence, accumulation of HIF-  in VHL syndrome leads to overexpression of VEGF, PDGF, and TGF-  Patients with VHL syndrome have a lifetime risk of RCC that approaches 50% Reference Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol . 2005;23:1028-1043.
  • Multiple receptor tyrosine kinases (RTKs) have been implicated in different cancers. Activation of RTKs triggers signaling cascades within the cells that are associated with processes important for cancer development or progression. 1-3 RTKs are transmembrane receptors. The intracellular domains are associated with tyrosine kinase activity (i.e., ability to transfer a phosphate group from ATP to tyrosine residues of various proteins). RTKs are commonly involved in cellular growth and other processes associated with cancer development or progression 4 Normally, ligand binding is required to activate the receptor. Ligand binding causes the RTK to dimerize with a similar RTK (see the various RTK pairs in the figure), which leads to kinase activation 4 The receptor or receptor pair is usually the first site of phosphorylation (autophosphorylation, as shown in the figure, the little circles linked with the intracellular domain). The resulting signal cascades within the cell modify gene expression and promote processes involved in tumor development: cell differentiation and proliferation, cell survival by inhibiting apoptosis, cell adhesion and invasion (processes involved in tumor metastasis), and (for certain cells) angiogenesis (development of new blood vessels) 4 Some tumors are associated with mutated RTKs that are activated independently of ligand binding. These receptors are said to be constitutively active. Gastrointestinal stromal tumor(GIST) is an example of a tumor associated with mutated and constitutively active RTKs (KIT and PDGFR) linked with tumor development 5 Angiogenesis is involved in the progression of most solid tumors. Two types of vascular cells, associated with two distinct RTKs, work together to promote tumor-related angiogenesis: VEGFRs on vascular endothelial cells and PDGFRs on pericytes (upper right of figure). Overexpression of ligands for these RTKs may promote tumor progression, as appears to be the case with RCC 1,6 References Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor–targeted therapy in renal cell carcinoma. J Clin Oncol. 2005;23:1028-1043. Duensing A, Heinrich MC, Fletcher CDM, Fletcher JA. Biology of gastrointestinal stromal tumors: KIT mutations and beyond. Cancer Invest . 2004;22:106-116. Marmor MD, Skaria KB, Yarden Y. Signal transduction and oncogenesis by ErbB/HER receptors. Int J Radiat Oncol Biol Phys. 2004;58:903-913. Tibes R, Trent J, Kurzrock R. Tyrosine kinase inhibitors and the dawn of molecular cancer therapeutics. Annu Rev Pharmacol Toxicol . 2005;45:357-384. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol . 2004;22:3813-3825. Bergers G, Song S. The role of pericytes in blood-vessel formation and maintenance. Neuro-Oncology . 2005;7:452-464.
  • Sunitinib inhibits the kinase activity of multiple RTKs associated with cancer, including isoforms of VEGFR, isoforms of PDGFR, KIT, wild-type and mutated FLT, and RET 1-4 Angiogenesis is a key process involved in the progression of most solid tumors. VEGFRs (particularly VEGFR-2) and PDGFRs (particularly PDGFR-  ) are important for tumor-related angiogenesis 5 RCC is a highly vascular tumor where inhibition of angiogenesis is thought to be an important therapeutic strategy 6 Mutated forms of KIT and PDGFR-  , resulting in receptors with constitutive or ligand-independent kinase activity, have been implicated in GIST 7 References Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res . 2003;9:327-337. Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor  in preclinical models of human small cell lung cancer. Mol Cancer Ther . 2003;2:471-478. O’Farrell A-M, Abrams TJ, Yeun HA, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood . 2003;101:3597-3605. Data on file. Pfizer Inc, New York, NY. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth an angiogenesis. J Clin Oncol . 2005;23(5):1011-1027. Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor–targeted therapy in renal cell carcinoma. J Clin Oncol . 2005;23:1028-1043. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol . 2004;22:3813-3825.
  • In preclinical studies, treatment with sunitinib demonstrated both direct antitumor and antiangiogenic effects through inhibition of RTKs on tumors and vascular cells, respectively. RTKs on two types of vascular cells work together to promote tumor-related angiogenesis, namely VEGFRs on vascular endothelial cells and PDGFR-  on supportive pericytes (bottom right) 1,2 Sunitinib demonstrated antiangiogenic activity by inhibiting PDGF receptors on pericytes and VEGF receptors on endothelial cells in preclinical studies 3,4 Sunitinib demonstrated direct antiproliferative activity by inhibiting PDGF and KIT receptors on tumor cells in preclinical studies 4,5 References Bergers G, Song S. The role of pericytes in blood-vessel formation and maintenance. Neuro-Oncology . 2005;7:452-464. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol . 2005;23:1011-1027. Erber R, Thurnher A, Katsen AD, et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J . 2004;18:338-340. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest . 2003;111:1287-1295. Abrams TJ. Lee LB, Murray LJ Pryer, NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor ß in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003;2:471-478.
  • BCG, Bacillus Calmette-Guérin; VEGF, vascular endothelial growth factor.
  • UISS, UCLA integrated staging system.
  • CWG, Cytokine Working Group
  • DCE-MRI, dynamic contrast-enhanced magnetic resonance imaging .
  • KPS, Karnofsky Performance Status
  • Renal Cell Carcinoma Diagnosis And Management

    1. 1. Renal Cell Carcinoma Diagnosis & Management Raúl H. Morales - Borges, MD, FICPS, FIACATH Chairman of the Board of Trustees and Lecturer of Pathology, Immunology & Genetics San Juan Bautista School of Medicine Medical Director of The Ashford Institute of Hematology & Oncology Attending Physician and Consultant Ashford Presbyterian Community Hospital
    2. 2. Disclosures <ul><li>Investments: None </li></ul><ul><li>Speaker Bureau: </li></ul><ul><ul><li>Pfizer Caribbean </li></ul></ul><ul><ul><li>Sanofi Aventis </li></ul></ul><ul><ul><li>Astra Zeneca </li></ul></ul><ul><li>Consultant: </li></ul><ul><ul><li>Astra Zeneca Glaxo SmithKline </li></ul></ul><ul><ul><li>Sanofi Aventis Merck </li></ul></ul>
    3. 3. TOPICS TO BE DISCUSSED <ul><li>Overview: Epidemiology, Pathology, and Pathogenesis of Rena Cell Carcinoma (RCC) </li></ul><ul><li>Clinical manifestations, evaluation, and staging of RCC </li></ul><ul><li>Prognosis and Treatment of RCC </li></ul><ul><li>Targeted therapies for RCC </li></ul>
    4. 4. INTRODUCTION <ul><li>Renal cell carcinoma (RCC) has increased its incidence at a rate of 2% per year on the last 65 years as well as its mortality on the last 2 decades. </li></ul><ul><li>Partial Surgery is the new option for localized tumors. 20% to 40% of the operated tumors will develop metastases in a future and will require additional therapy. </li></ul><ul><li>RCC are resistant to chemotherapy and radiotherapy. Hormones doesn’t work too. </li></ul><ul><li>New target therapy agents are available with great responses & survival benefits. </li></ul>
    5. 5. Overview of RCC Epidemiology Pathology Pathogenesis
    6. 6. Epidemiology <ul><li>RCC is the responsible of 2% - 3% of all malignancies in the adults. </li></ul><ul><li>The incidence peak age is: 60 – 80 years old. </li></ul><ul><li>Men : Women ratio of 2:1 </li></ul><ul><li>Incidence & Mortality are rising in African Americans. </li></ul><ul><li>51190 new cases & 12890 deaths on 2007 with 54390 cases and 13010 deaths on 2008 in USA. </li></ul><ul><li>5-year survival rate of 65% by 1995-2000. . </li></ul>
    7. 7. <ul><li>RCC affects more than 150,000 people annually worldwide, resulting in 78,000 deaths each year. </li></ul><ul><li>An individual with positive family history of RCC have a 2.5-fold greater chance for developing renal cancer during their life time. </li></ul><ul><li>Patients with a family history comprise about 4% of all cases of RCC. </li></ul>
    8. 8. Pathology Clear cell (non-papillary) carcinoma is the most common.
    9. 12. Pathogenesis A number of environmental, hormonal, cellular, and genetic factors have been studied as possible causes of RCC.
    10. 13. Etiology <ul><li>Tobacco </li></ul><ul><li>Obesity </li></ul><ul><li>Chronic arterial hypertension </li></ul><ul><li>Diabetes mellitus </li></ul><ul><li>End-Stage Renal Disease on hemodialysis </li></ul><ul><li>High fat, high protein diet, fried food, red meat </li></ul><ul><li>Use of phenacetin chronically as analgesics </li></ul><ul><li>Amphetamines </li></ul><ul><li>Petroleum products </li></ul><ul><li>Cadmiun </li></ul><ul><li>Asbestos </li></ul><ul><li>Aromatic hydrocarbons </li></ul>
    11. 14. <ul><li>Smoking: 30% in men, 24% in women. </li></ul><ul><li>Obesity: Increased BMI is related with RCC, but more favorable prognosis. </li></ul>
    12. 16. Familiar type RCC & von Hippel Lindau <ul><li>Suppressor gene in the short arm of chromosome 3 as autosomic dominant. </li></ul><ul><li>1 in 30,000 births. </li></ul><ul><li>Age of early symptoms: 26.3 years old. </li></ul><ul><li>Penetrance age of 60 years old. </li></ul><ul><li>RCC: bilateral low staging. </li></ul><ul><li>Associated features: retinal angiomas, cerebelar & spinal cord hemagioblastomas, cysts and/or angiomas of solid organs, pheochromocytomas. </li></ul>
    13. 20. Birt-Hogg-Dubé Syndrome <ul><li>Rare autosomal dominant </li></ul><ul><li>Gene located at the short arm of the chromosome 17 </li></ul><ul><li>Chromophobe RCC with low metastatic potential </li></ul><ul><li>Fibrofolliculomas trichodiscomas (benign hamartomas of the hair follicule), pulmonary cysts, spontaneous pneumothorax </li></ul>
    14. 22. Clinical Manifestations Evaluation and Staging Of RCC
    15. 23. Clinical Presentation <ul><li>Small tumors as incidental findings </li></ul><ul><li>Hematuria </li></ul><ul><li>Abdominal pain </li></ul><ul><li>Palpable abdominal mass </li></ul><ul><li>Paraneoplastic syndrome: </li></ul><ul><ul><li>Bone pain </li></ul></ul><ul><ul><li>Hypercalcemia </li></ul></ul><ul><ul><li>Fever </li></ul></ul><ul><ul><li>Weight loss </li></ul></ul><ul><ul><li>Polycythemia </li></ul></ul><ul><ul><li>Neuromyopathy </li></ul></ul><ul><ul><li>Amyloidosis </li></ul></ul>
    16. 25. <ul><li>30% presented with metastatic disease, 25% with locally advanced disease, and 45% with localized disease. </li></ul><ul><li>75% of metastatic disease presents with pulmonary lesions, 36% to soft tissues, 20% to the bones, 18% to the liver, 8% to the skin, and 8% to the CNS. </li></ul>
    17. 26. Diagnostic tests <ul><li>History & Physical Exam </li></ul><ul><li>Laboratory: CBC, CMP, LDH, ESR, U/A </li></ul><ul><li>CXR, Abdomino-pelvic CT Scan </li></ul><ul><li>MRI if IVC thrombosis suspected </li></ul><ul><li>Bone scan if bone metastases suspected </li></ul><ul><li>PET/CT is controversial </li></ul>
    18. 33. Prognosis and Treatment of RCC
    19. 34. Prognostic factors <ul><li>Symptomatic presentation </li></ul><ul><li>Weight loss </li></ul><ul><li>Poor performance status </li></ul><ul><li>ESR > 30 mm/hr </li></ul><ul><li>Anemia </li></ul><ul><li>Elevated alkaline phosphatase </li></ul><ul><li>Tumor size, positive margins, liver & lung metastases, Sarcomatoid tumors </li></ul>
    20. 38. Surgery in RCC <ul><li>We are moving from Radical nephrectomy to partial nephrectomy using laparoscopy. </li></ul><ul><li>We can minimize positive margins in partial nephrectomy using: </li></ul><ul><ul><li>Intraoperative sonography </li></ul></ul><ul><ul><li>Use of cold scissors for parenchymal transection </li></ul></ul><ul><ul><li>Hilum control to avoid vascular leak (bleeding). </li></ul></ul>
    21. 39. <ul><li>The first nephrectomy was performed on June 4 th of 1861. Since then, there have been significant advances in surgical techniques. </li></ul><ul><li>The most common procedure today for treatment of localized renal carcinoma > 4 cm is radical nephrectomy. </li></ul><ul><li>Laparoscopic nephrectomy has become the standard of care for management of most renal tumors not amenable to nephron-sparing surgery. </li></ul>
    22. 40. <ul><li>At present, lymphadenectomy is a safe adjunct to radical nephrectomy and is primarily used for staging. </li></ul><ul><li>Cytoreductive nephrectomy in metastatic RCC is controversial, but depends on the selection of the patient due to insignificant benefit and short term survival. </li></ul>
    23. 41. Angioinfarction <ul><li>Embolization of the renal artery: only for palliation. No definitive benefit. </li></ul>
    24. 42. Chemotherapy <ul><li>NO ROLE !!!!! </li></ul><ul><li>Combination of Vinblatine + Toremifene/ Verapamil/ Nifedipime/ Cyclosporin ????? Due to inhibition of p-glycoprotein which is the responsible for chemo-resistance. </li></ul>
    25. 43. <ul><li>4% SPONTANEOUS REGRESSION RATE. </li></ul><ul><li>IL-2 & IFN-alpha 2a and 2b alone or in combinations: poor response rates. </li></ul><ul><li>TIL’s, LAK cells, and Dendritic cell therapies: very complex and expensive with low response rates. </li></ul>IMMUNOTHERAPY
    26. 44. Targeted Therapies for RCC
    27. 45. New Class of Agents Used in RCC: Tyrosine Kinase Inhibitors (TKI’s) <ul><li>Sorafenib : Approved by FDA in Dec. 2005 </li></ul><ul><li>Sunitinib : Approved by FDA in Jan. 2006 </li></ul><ul><li>Temsirolimus : Approved in May 2007 </li></ul>
    28. 49. Long-term toxicity of TKI’s <ul><li>HYPOTHYROIDISM </li></ul><ul><li>MYELOSUPPRESSION </li></ul><ul><li>FATIGUE </li></ul><ul><li>B.k Vakkalanka et al: Abstract 16045; ASCO 2008 </li></ul>
    29. 50. Adjuvant Therapy
    30. 51. Adjuvant Therapy: Rationale <ul><li>Patients with recurrent disease following nephrectomy have micrometastatic disease at the time of surgery </li></ul><ul><li>There is a 35%-65% recurrence rate* with locally aggressive tumors </li></ul><ul><li>Use of effective therapy may reduce the risk of relapse </li></ul>Lam JS, et al. BJU Int. 2005;96:483-488. * Depending on pathologic stage.
    31. 52. Adjuvant Therapy <ul><li>To date, all adjuvant therapy trials have failed to demonstrate DFS or OS advantage </li></ul><ul><ul><li>High-dose (HD) IL-2 </li></ul></ul><ul><ul><li>Interferon </li></ul></ul><ul><ul><li>Autologous tumor cells + BCG vaccine </li></ul></ul><ul><ul><li>Vitespen (HSPPC-96) vaccine </li></ul></ul><ul><li>Given the risk/benefit profile, no adjuvant treatment is appropriate outside clinical trial </li></ul><ul><li>VHL mutation (and thus VEGF production) is an early oncogenic event in RCC </li></ul><ul><ul><li>Radiation therapy </li></ul></ul><ul><ul><li>Megestrol acetate </li></ul></ul>
    32. 53. ASSURE Trial (Intergroup Sponsored by ECOG) <ul><li>Eligibility: nonmetastatic kidney cancer </li></ul><ul><ul><li>Disease  T1b N any (resectable) M0 by radiologic criteria </li></ul></ul><ul><li>Primary endpoint: DFS </li></ul>Nephrectomy Patients with nonmetastatic kidney cancer Disease stage II-IV (N = 1332) Stratification by UISS stage (II-V) and histologic subtype (clear cell or nonclear cell) Sunitinib 50 mg daily for 4 of 6 wks Sorafenib 800 mg daily continuously Placebo daily continuously Available through www.CTSU.org 1 year
    33. 54. SORCE (MRC Adjuvant trial) <ul><li>Eligibility </li></ul><ul><ul><li>No evidence of residual disease after RCC resection </li></ul></ul><ul><ul><li>Leibovich prognostic score 3-8 (high or intermediate risk of metastatic RCC or death) postsurgery </li></ul></ul><ul><ul><li>≥ 4 weeks and ≤ 4 months since surgery </li></ul></ul><ul><li>Endpoints </li></ul><ul><ul><li>Primary: metastasis-free survival </li></ul></ul><ul><ul><li>Secondary: DFS, toxicity, genomics </li></ul></ul>Patients with high- and intermediate-risk resected RCC (Planned N = 1420) Placebo 3 years Sorafenib Sorafenib Placebo 1 year
    34. 55. ARISER Study <ul><li>Eligibility </li></ul><ul><ul><li>Clear-cell RCC, no metastasis, ECOG status 0 </li></ul></ul><ul><ul><li>RCC patients at high-risk of recurrence* </li></ul></ul><ul><li>Primary endpoints: DFS, OS </li></ul>cG250 (WX-G250) IV over 15 minutes once weekly Placebo IV over 15 minutes once weekly Patients with clear-cell nonmetastatic RCC (N = 600+) * T3b/T3c/T4 N0/XM0; All T stages N+M0; T1b/T2 N0/XM0 with G ≥ 3 and MVI or T3a N0/XM0 with G ≥ 3 Nephrectomy 24 weeks
    35. 56. Neoadjuvant Trials <ul><li>Phase II </li></ul><ul><ul><li>Neoadjuvant sunitinib: Cleveland Clinic Foundation </li></ul></ul><ul><ul><ul><li>For patients with “unresectable” primary renal tumors (with or without metastases) </li></ul></ul></ul><ul><ul><li>Neoadjuvant RAD-001 (mTOR inhibitor): UCLA </li></ul></ul>
    36. 57. Metastatic RCC: Frontline/Monotherapy
    37. 58. CALGB 90206: Interferon alfa-2b ± Bevacizumab in Advanced RCC <ul><li>Endpoints </li></ul><ul><ul><li>Primary: OS </li></ul></ul><ul><ul><li>Secondary: TTP, ORR, toxicity </li></ul></ul><ul><li>Follow-up </li></ul><ul><ul><li>Every 3 months for 2 years </li></ul></ul><ul><ul><li>Annual thereafter (up to 10 years from study entry) </li></ul></ul>Interferon alfa-2b 9 MU SC 3 times weekly (n = 350) Interferon alfa-2b 9 MU SC 3 times weekly + Bevacizumab 10 mg/kg IV Days 1 and 15, every 28 days (n = 350) Patients with untreated, metastatic or unresectable clear-cell RCC (N = 700) Stratified for nephrectomy status and MSKCC risk group
    38. 59. <ul><li>Primary endpoint </li></ul><ul><ul><li>OS (improvement from 13-17 months) </li></ul></ul>European Phase III Trial of IFN/Bevacizumab in RCC (BO17705) Patients with metastatic clear cell RCC, status post nephrectomy (N = 638) Interferon alfa-2a 9 MU 3 times weekly for up to 52 weeks + Placebo every 2 weeks until disease progression Interferon alfa-2a 9 MU 3 times weekly for up to 52 weeks + Bevacizumab 10 mg/kg every 2 weeks until disease progression
    39. 60. <ul><li>Randomized, open-label, multicenter trial </li></ul><ul><ul><li>100 Sites (US, Canada, Europe, Australia, Brazil) </li></ul></ul>Phase III Trial of Sunitinib vs Interferon alfa in Metastatic RCC Patients with metastatic clear cell RCC (N = 690) Sunitinib orally administered daily (4 of every 6 weeks) (n = 345) Interferon alfa administered 3 times weekly (n = 345) <ul><li>Endpoints </li></ul><ul><ul><li>Primary: PFS </li></ul></ul><ul><ul><li>Secondary: TTP, OS, RR, QoL, safety, cost-effectiveness </li></ul></ul>
    40. 61. <ul><li>Phase II trial </li></ul><ul><li>111 patients </li></ul><ul><li>RR: 7% </li></ul><ul><li>TTP: 5.8 months </li></ul><ul><li>OS: 15 months </li></ul><ul><li>Toxicity: rash, fatigue, mucositis, nausea </li></ul>CCI-779: mTOR inhibitor ASK1 Cap-dependent translation 0 2 Schematic from Bjornsti and Houghton Nat Rev Cancer 4L335-348 (2004) Atkins J, et al. J Clin Oncol. 2004;22:909-918. ATP Amino acids Protein stability Phosphatidic acid TOR Mitochondria Transcription-factor translocation Apoptosis S6K1 Translation ribosomal proteins eIF4E Ribosome biogenesis Nutritional-stress response Growth/survival factors Nucleus 4E-BP1 Plasma membrane Cytoplasm
    41. 62. <ul><li>International phase III randomized trial </li></ul><ul><li>Endpoints </li></ul><ul><ul><li>Primary: OS </li></ul></ul><ul><ul><li>Secondary: Safety, PFS, RR, health outcomes </li></ul></ul>Temsirolimus (CCI-779) + Interferon alfa in Advanced RCC 1. Motzer RJ, et al. J Clin Oncol. 2002;20:289-296. CCI-779 IV 25 mg weekly CCI-779 15 mg IV weekly + Interferon alfa 6 MU SC TIW Interferon alfa SC up to 18 MU TIW as tolerated Patients with previously untreated advanced RCC Poor risk criteria [1] (Planned N = 600)
    42. 63. CA IX and Response to Interleukin-2 (IL-2) Therapy in RCC * Including all CRs. Bui MH, et al. Clin Cancer Res. 2003;9:802-811. Atkins M, et al. Clin Cancer Res. 2005;11:3714-3721. 51 80 Nonresponders with high CA IX 78 91 Responders with high CA IX 24 14 Response in low CA IX 51 27* Response in high CA IX 62 77 No of metastatic pts with > 85% CA IX Boston, % (N = 66) UCLA, % (N = 83) Outcome
    43. 64. HD IL-2 “Select” Trial: Study Design rIL-2 600,000 IU/kg q8h by 15-min infusion rIL-2 600,000 or q8h by 15-min infusion Rest 9 days 5 days 5 days <ul><li>Eligibility </li></ul><ul><ul><li>Measurable metastatic RCC; all histologic subtypes </li></ul></ul><ul><ul><li>Consented to provide tumor blocks </li></ul></ul><ul><ul><li>No prior systemic therapy </li></ul></ul><ul><ul><li>Candidate for HD IL-2 </li></ul></ul><ul><ul><li>ECOG PS 0-1 and good organ function </li></ul></ul>Maximum 3 courses per patient. Responses independently audited.
    44. 65. Metastatic RCC: Determining Clinical Cross-Resistance to VEGF-Targeted Agents
    45. 66. Approach to Tyrosine Kinase Inhibitor (TKI) – Resistant Disease KDR HIF VEGF mTOR inhibitor (temsirolimus, CCI-779) Bevacizumab Sorafenib, sunitinib, AG13736 O 2 <ul><li>Hypothesis </li></ul><ul><ul><li>Resistance to 1 TKI will be mediated by pathways sensitive to inhibition by another TKI </li></ul></ul><ul><ul><li>Varying response rates and toxicity profiles suggest some differences between TKIs </li></ul></ul>
    46. 67. <ul><li>Sunitinib in bevacizumab-refractory RCC </li></ul><ul><ul><li>VEGF-R (and other targets like PDGF) after VEGF ligand inhibition </li></ul></ul><ul><ul><li>ASCO 2006: definite activity, data to be presented </li></ul></ul><ul><ul><li>Sorafenib in sunitinib or bevacizumab-refractory RCC </li></ul></ul><ul><ul><ul><li>Multitargeted agent, plus Raf kinase inhibition </li></ul></ul></ul><ul><li>AG013736 in sorafenib-refractory RCC </li></ul><ul><ul><li>More potent VEGFR inhibition </li></ul></ul><ul><li>All 3 are standard clinical trials </li></ul><ul><ul><li>No insights into mechanisms of resistance, etc, are possible </li></ul></ul>A  B Trials
    47. 68. 6-Arm Randomized Phase II Trial (E9805): Sunitinib Failures Patients failing sunitinib Sunitinib daily Arm A Arm B Sunitinib + Bevacizumab Arm C Change to Sorafenib
    48. 69. 6-Arm Randomized Phase II Trial (E9805): Sorafenib Failures Patients failing sorafenib Increase Sorafenib dose Sorafenib + Bevacizumab Arm D Arm E Arm F Change to Sunitinib Arm D Arm D Arm E
    49. 70. Metastatic RCC: Combinations
    50. 71. Phase I and II Combination Studies <ul><li>Sorafenib + bevacizumab </li></ul><ul><li>Sunitinib + bevacizumab </li></ul><ul><li>CCI-779 + bevacizumab </li></ul><ul><li>CCI-779 + sorafenib </li></ul><ul><li>AMG386 (anti-Ang2/Tie2) + bevacizumab, TKI </li></ul><ul><li>HD IL-2 + bevacizumab (Phase II CWG study) </li></ul>
    51. 72. ECOG “BEST” Trial Bevacizumab 10 mg/kg IV every 2 weeks (Days 1 and 15) Patients with advanced RCC (N = 360*) Bevacizumab 10 mg/kg IV every 2 weeks (Days 1 and 15) Sorafenib 400 mg PO twice daily *Accrual goal. † Arm to be added when phase II doses are available from ongoing phase I trials. Bevacizumab 10 mg/kg IV every 2 weeks (Days 1 and 15) and Temsirolimus 25 mg IV weekly (Days 1, 8, 15 and 22) Sorafenib PO twice daily and Temsirolimus IV weekly (Days 1, 8, 15 and 22) † <ul><li>Randomized phase II study </li></ul><ul><li>Endpoints </li></ul><ul><ul><li>Primary: PFS </li></ul></ul><ul><ul><li>Secondary: ORR, OS, correlates (DCE-MRI, biomarkers) </li></ul></ul>Stratified by prior therapy (prior cytokine/vaccine or no prior cytokine) and Motzer risk category (low, intermediate, or high)
    52. 73. Patients with clear cell RCC (N = 499)* 1 year Phase III Renal EFFECT Trial *Initial, nonrandomized dose-finding study for sunitinib and interferon-alfa2b in first 25 patients at 4 sites <ul><li>Primary endpoint: improvement in TTP from 8-12 months; 85% power (hazard ratio = 0.67); 222 events required. </li></ul><ul><li>1 year of follow-up after end of treatment </li></ul>Sunitinib, 50 mg/d orally, 4 weeks on 2 weeks off (n = 149) Sunitinib, daily , 4 weeks on 2 weeks off , plus Interferon alfa-2b every 3 weeks (n = 149) Sunitinib 35 mg/d orally for 6 weeks (n = 149)
    53. 74. Conclusions <ul><li>VEGF and other targeted therapies </li></ul><ul><ul><li>Robust activity in metastatic RCC </li></ul></ul><ul><ul><li>Cornerstone of future therapy </li></ul></ul><ul><li>Currently under investigation </li></ul><ul><ul><li>Value in earlier stages of disease </li></ul></ul><ul><ul><li>Clinical cross-resistance </li></ul></ul><ul><ul><li>Optimal sequencing/combination </li></ul></ul><ul><li>Clinical trials </li></ul><ul><ul><li>Participation mandatory for benefit of all </li></ul></ul>
    54. 75. Thank You THANK YOU !!!

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