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Identifying And Improving Outcomes In The High Risk Patient With Renal Cell Carcinoma

Identifying And Improving Outcomes In The High Risk Patient With Renal Cell Carcinoma. Ronald M. Bukowski, MD Director Experimental Therapeutics Cleveland Clinic Taussig Cancer Center. Metastatic RCC : Patient Subsets. Metastatic RCC : Histology Clear vs Nonclear Cell. CNS Metastases.

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Identifying And Improving Outcomes In The High Risk Patient With Renal Cell Carcinoma

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  1. Identifying And Improving Outcomes In The High Risk PatientWith Renal Cell Carcinoma Ronald M. Bukowski, MD Director Experimental Therapeutics Cleveland Clinic Taussig Cancer Center

  2. Metastatic RCC : Patient Subsets Metastatic RCC : Histology Clear vs Nonclear Cell CNS Metastases Absent CNS Metastases Nonclear Cell CA Clear Cell Ca Untreated Systemic Therapy Status Prognostic Factors : Good/Intermediate Poor (10-20%) Refractory, intolerant

  3. Prognostic Models in Advanced RCC • RCC - variable natural history • Difficult to interpret and compare clinical trials • Identification of a reliable, validated prognostic model: • Help optimize patient selection for treatment strategy • Aid in the interpretation of clinical trials. • Will determine the extent to which therapy impacts the natural history of the disease

  4. Risk Groups No. of Factors 2-Yr Survival % Good 0 45 Intermediate 1-2 17 Poor  3 3 Risk Groups for Advanced RCC: MSK • Pretreatment features associated with shorter survival • Low Karnofsky performance status (< 80%) • High lactate dehydrogenase level (> 1.5 x ULN) • Hemoglobin level < LLN • High corrected serum calcium • Absence of nephrectomy (DFI < 1 year) Motzer RJ, et al. JCO 1999;17:2530

  5. GR (18%) 29. 6 months IR (62%) 13.8 months GR (19%) 28. 6 months PR (20%) 4.9 months IR (70%) 14.6 months PR (11%) 4.5 months Prognostic Factor Models: Advanced Renal Cell Carcinoma CCF Patients MSK Patients Mekhail T et al, JCO, 2005; Motzer et al, JCO, 2002

  6. Prognostic Factors: Refractory RCC Patients • Two reports investigating factors associated with outcome in therapy refractory RCC patients : Motzer et alBou Merhi et al Time Period 1975-2002 1987-2002 No. Patients 251 85 Med. OS 10.2 mos 16.5 mos Prior Cytokine Rx 50% 100% Prognostic Fx Hgb < LLN Corrected Ca++> 10.0 mg/dL KPS < 80% Alk PO4 < 120 U/L

  7. Prognostic Factors:Refractory Patients • Patient groups - all failed front line therapy • Prognostic groups defined : Median OS (mos) Motzer et alBou Merhi et al No. Fx (1990-2002) (1987-2002) No. Patients 137 85 Good Risk 0 22.4 42.3 Intermediate Risk 1 11.9 14.9 Poor Risk 2-3 5.4 5.8 Motzer et al, JCO, 2004, 22:454; Bou Merhi et al, Proc ASCO, 2003, 22:411

  8. Prognostic Factors in Patients Treated with VEGF Targeted Therapy • Data base at CCF examined - 130 patients treated between 10/03 to 1/06 identified • PFS utilized as endpoint • 124 patients with data available for analysis : • Multivariate analysis identified 6 clinical factors significantly associated with  PFS : - Time from Dx < 1 yr- Lymphs < 1.1 K/ml - Platelets > 300k-  3 Met. sites - ANC > 4.5 K/ml- Serum Ca <8.5 or >10.5 Bevacizumab (9%) Sunitinib (50%) AG-013736 (6%) Sorafenib (35%)

  9. PFS in Patients Receiving VEGF Targeted Therapy : Risk Groups % P r o g r e s s i o n F r e e 0-2 Poor Prog. Factors (n=94) >2 Poor Prog. Factors (n=30) Med PFS 17.6 mos Med PFS 4.0 mos Months

  10. RCC : Poor Risk Patients • Clinical criteria to define a poor risk population (previously treated vs untreated) are available • Use in a clinical trial setting and/or to determine therapy is reasonable • Validation and development of an International risk classification is underway • It is unclear whether this group of patients can be defined biologically, eg,  Akt levels

  11. Levels of Phospho-AKT and Survival :RCC

  12. Activity Novel Agents in High Risk Patient Subsets • Limited data available • Clinical trials which included this subset : • Phase 2 randomized trial temsirolimus • Prospective phase 3 temsirolimus trial in high risk patients • Phase 3 sunitinib vs IFN trial : subset of patients with poor prognosis • Compassionate use protocols : sunitinib, sorafenib

  13. CCI-779 : Phase 2 Trial • Mechanism of Action • Rapamycin analog that blocks activity of mTOR • Inhibition of signaling pathways regulated by p70 s6 kinase- G1 cell cycle arrest • Interruption of PI3-Kinase and Akt signaling • Clinical Investigation • Randomized, double blind phase II trial of weekly IV CCI-779 in refractory stage IV RCC • Doses - 25 mg, 75 mg, 250 mg • Toxicity: hyperlipidemia, hyperglycemia, nail bed changes, pruritic rash, thrombocytopenia, stomatitis

  14. CCI-779 Efficacy:Prognostic Factor Analysis Patient Med 95%Med 95% Med 95% GroupN (%) SurvCIN (%)SurvCIN (%)SurvCI CCI-779*8 (8)23.817.7,48 (46)22.516.9,49 (47)8.27.0, (n = 105)27.1 25.710.1 IFN†7929.620.9,271 (62)13.812.4,87 (20)4.94.3, (n = 437)(18)37.815.96.3 Good Intermediate Poor *Atkins et al, Proc JCO 22:909, 2004 †Motzer et al JCO 20: 289-296, 2002

  15. CCI-779: ? Activity in Poor Prognosis Patients • Conclusions : • Active in refractory RCC • Efficacy parameters are not dose related • Particular efficacy seen in patients with poor prognostic factors--? Relationship to elevated pAKT, low PTEN • Critique : • Lack of comparator group • Definition of poor risk incorrect - use of criteria for treatment naïve patients vs previously treated patients • 91% of patients previously treated, predominantly IL-2

  16. Global ARCC Trial of Temsirolimus in First-line, Poor-Risk RCC Poor-Risk Features for Eligibility** • Minimum of 3 poor-risk features required: • 1. LDH > 1.5 X upper limit of normal 2. Hemoglobin < lower limit of normal 3. Corrected calcium > 10 mg/dL 4. Time from diagnosis to first treatment < 1 yr 5. Karnofsky Performance Status 60-70 6. Multiple organ sites of metastasis ** Hudes et al: J Clin Oncol 24, 18S, 930s, LBA4

  17. Phase III Trial Temsirolimus ± Interferon • 1° end point: OS • 2° end points: PFS (investigator assessment, independent read), TTF, OR, clinical benefit (CR + PR + [SD  16 wks]) • Eligibility criteria: • Advanced RCC • No prior systemic therapy • Karnofsky performance status 60 • Measurable disease (RECIST) • Adequate bone marrow, renal, and hepatic function • Fasting serum cholesterol 350 mg/dL, triglycerides 400 mg/dL • At least 3 of 6 poor-risk IFN: escalating to 18 MU SC tiw Days 1 2 3 4 5 6 7 . . . IFN IFN IFN 1 2 3 4 5 6 7 . . . Days TEMSR: 25mg IV qw (1:1:1)Randomization(N=626) CCI TEMSR: 15 mg IV QW + IFN: 6 MU tiw 1 2 3 4 5 6 7 . . . Days CCI IFN IFN IFN Adapted from: Hudes G et al. Presented at: ASCO; June 2-6, 2006; Atlanta, GA.

  18. Overall Survival Parameter IFNArm1 TEMSRArm 2 TEMSR + IFNArm 3 1.00 n 207 209 210 Comparisons Arm 2: Arm 1 Arm3: Arm 1 Stratified log-rank P 0.0069 0.6912 0.75 Arm 2: Temsirolimus 0.50 Probability of survival Arm 1: IFN 0.25 Arm 3: IFN + temsirolimus 0 0 10 15 20 25 30 35 5 Time from randomization (months) Adapted from: Hudes G et al. Presented at: ASCO; June 2-6, 2006

  19. Activity of Sunitinib in Poor Risk Patients • Phase 3 trial compared sunitinib vs IFN • Patient entry not restricted to good/intermediate risk patients • In both arms 6-7% of patients were poor risk utilizing MSK criteria • Utilizing criteria employed in CCI-779 phase 3 trial, 21% of patients are poor risk

  20. Phase 3 Trial Sunitinib:Patient Characteristics Characteristics Sunitinib (n=375) IFN- (n=375) Sites of disease involvement (%)LungLiverBone 782630 802430 MSKCC risk factors1(%)0 (favorable)1-2 (intermediate)3 (poor) 38566 34597 1Motzeretal.JCO2002;20:289-296;Excludes17ptsfromIFN-αwithmissingdata

  21. Progression-Free Survival by Modified MSKCC Risk Status* (Independent Central Review) MSKCC Risk Factors: ≥3 (Poor) 1.0 Sunitinib (n=77) 0.9 Median: 10 months (95% CI: 4–11) 0.8 IFN- (n=81) Median: 2 months 0.7 (95% CI: 1–2) 0.6 Progression Free Survival Probability 0.5 0.4 0.3 0.2 Hazard Ratio = 0.394 0.1 (95% CI: 0.244–0.635) P <0.0001 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (Months) * Motzer et al. JCO 2002 and 1 additional risk factor (multiple metastatic sites); Excludes 17 pts from IFN- with missing data

  22. Conclusions : Poor Risk RCC • Clinically defined subset of RCC patients • Limited survival • Risk factors and definitions are variable • In the untreated poor risk patient, therapy may be associated with significant improvements in OS and PFS • It is unclear whether this subset of patients can be defined biologically

  23. Progression-Free Survival Parameter IFNArm1 TEMSRArm 2 TEMSR + IFNArm 3 1.00 n 207 209 210 Median PFS (mos) 1.9 3.7 3.7 0.75 Comparisons Arm 2: Arm 1 Arm3: Arm 1 Stratified log-rank P 0.0001 0.0019 progression­free survival 0.50 Arm 2: Temsirolimus Arm 3: IFN + Temsirolimus 0.25 Arm 1: IFN 0 5 10 15 20 25 30 35 0 Time to PD or death (months) Adapted from: Hudes G et al. Presented at: ASCO; June 2-6, 2006

  24. Phase 3 Trial of Sunitinib vs IFN: Randomization Scheme R A N D O M I Z A T I O N Sunitinib (N=375) N=750 Stratification Factors • LDH 1.5 vs >1.5xULN • ECOG PS 0 vs 1 • Presence vs Absence of Nephrectomy IFN- (N=375)

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