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Renal Cell Carcinoma A New Standard Of Care

Renal Cell Carcinoma A New Standard Of Care

  1. 1. Renal Cell Carcinoma: A New Standard of Care Roberto Pili M.D. Associate Professor of Oncology and Urology The Sydney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 6th Advancing Cancer Care in the Elderly Conference Taking Aim with Targeted Therapies: Are We Hitting the Right Marks?
  2. 2. Disclosure <ul><li>Research funding: Pfizer, Cephalon, Celgene </li></ul><ul><li>Consultant: Active Biotech, Locus, Novartis, Genentech </li></ul>
  3. 3. Objectives <ul><li>To review the biological and clinical features of renal cell carcinoma </li></ul><ul><li>To summarize the clinical activity & toxicity profiles of antiangiogenesis agents in renal cell carcinoma </li></ul><ul><li>To describe the future development of anti angiogenesis therapies for renal cell carcinoma </li></ul>
  4. 4. Renal Cell Carcinoma <ul><li>In the United States in 2008: </li></ul><ul><ul><li>54,390 estimated new cases of RCC </li></ul></ul><ul><ul><li>13,010 estimated deaths </li></ul></ul><ul><li>Risk factors: </li></ul><ul><ul><li>Male sex (3:2), Cigarette smoking (2:1), Hypertension, Obesity </li></ul></ul><ul><ul><li>Hereditary syndromes (15-40% lifetime risk) </li></ul></ul><ul><li>Incidence: </li></ul><ul><ul><li>Increasing (median age 65 y.o.) </li></ul></ul><ul><li>For mRCC: </li></ul><ul><ul><li>Median survival: 10.9-26.4 months </li></ul></ul><ul><ul><li>20%-30% of patients present with mRCC </li></ul></ul><ul><ul><li>20%-40% of patients will develop mRCC after nephrectomy </li></ul></ul>
  5. 5. Staging of RCC Cohen , NEJM 2005
  6. 6. Histological Classification of Human Renal Epithelial Neoplasms BHD=Birt-Hogg-Dubé; FH=fumarate hydratase; VHL=von Hippel-Lindau. Modified from Linehan WM et al. J Urol . 2003;170:2163-2172. RCC 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
  7. 7. Kinase expression: Genetic Signatures Teh BT, 2006 Clear cell Papillary Chromophobe Oncocytoma Kinome Expression in Renal Tumors C - KIT C - MET - -
  8. 8. Factors Predicting Prognosis in RCC <ul><li>Anatomic </li></ul><ul><li>Tumor size </li></ul><ul><li>Metastasis </li></ul><ul><li>Venous involvement </li></ul><ul><li>Lymph node involvement </li></ul><ul><li>Histologic </li></ul><ul><li>Fuhrman grade </li></ul><ul><li>Morphology </li></ul><ul><li>Microvascular invasion </li></ul><ul><li>Tumor necrosis </li></ul><ul><li>Clinical </li></ul><ul><li>PS </li></ul><ul><li>Cachexia-related symptoms </li></ul><ul><li>Thrombocytosis </li></ul>Shuch BM, et al. Semin Oncol . 2006;33:563-575. PS = performance status.
  9. 9. MSKCC Risk Factor Model in mRCC-IFN days Motzer RJ et al. J Clin Oncol . 2002;20:289-296. <ul><li>Risk factors associated with worse prognosis </li></ul><ul><li>KPS <80 </li></ul><ul><li>Low serum hemoglobin (13 g/dL/11.5 g/dL: M/F) </li></ul><ul><li>High corrected calcium (10 mg/dL) </li></ul><ul><li>High LDH (300 U/L) </li></ul><ul><li>Time from Dx to IFN-  <1 yr </li></ul>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 MS: 20 mo 10 mo 4 mo 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
  10. 10. Targets in RCC Adapted from Brugarolas J NEJM 2007 Bevacizumab VEGF-Trap Vorinostat LBH589 Everolimus Axitinib Pazopanib Everolimus Temsirolimus
  11. 11. Rational Targets in RCC <ul><li>IL-2 </li></ul><ul><li>- immune response FDA approved for RCC 1992 </li></ul><ul><li>Sorafenib FDA approved for RCC 12/05 </li></ul><ul><ul><li>VEGFR, PDGFR, RAF </li></ul></ul><ul><li>Sunitinib FDA approved for RCC 1/06 </li></ul><ul><ul><li>VEGFR, PDGFR </li></ul></ul><ul><li>Temsirolimus - mTor FDA approved for RCC 5/07 </li></ul><ul><li>Everolimus - mTor </li></ul><ul><li>Bevacizumab -VEGF </li></ul><ul><li>VEGF-Trap -VEGF </li></ul><ul><li>Erlotinib - EGFR </li></ul>EGFR=epidermal growth factor receptor.
  12. 12. RCC: Current NCCN Treatment Paradigm National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: kidney cancer. V.1.2008. http://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf. Accessed 01/14/2008. *Category 1 † Selected patients ‡ Category 1 following cytokine therapy and category 2A following TKI § Category 2A following cytokine therapy and category 2B following TKI ¶ Category 2B. CRN = cytoreductive nephrectomy; IL-2 = interleukin-2; NCCN = National Comprehensive Cancer Network; TKI = tyrosine kinase inhibitor. First Line Clinical trial Sunitinib* Temsirolimus (poor prognosis patients)* Bevacizumab + IFN High-dose IL-2 † Sorafenib † Best supportive care Nephrectomy + metastasectomy or CRN (if unresectable, proceed to first-line systemic therapy) Observation or consider adjuvant therapy in a clinical trial Relapse Stage I/II/III Surgical excision Second Line Clinical trial Sorafenib ‡ Sunitinib ‡ Temsirolimus § IFN ¶ High-dose IL-2 ¶ Low-dose IL-2 ± IFN ¶ Bevacizumab ¶ Best supportive care Stage IV (metastatic)
  13. 13. Sorafenib for mRCC: Phase III Study Design (TARGET) Sorafenib, 400 mg bid (n=451) <ul><li>1 ° end point: OS </li></ul><ul><li>2 ° end points: ORR, PFS, safety, HR-QoL </li></ul><ul><li>Demographics </li></ul><ul><ul><li>MSKCC good or intermediate risk patients(57/41) </li></ul></ul><ul><ul><li>Clear-cell carcinoma </li></ul></ul>Unresectable and/or mRCC, 1 prior systemic Tx in last 8 months, ECOG PS 0/1 (N=903*) Placebo (n=452) Escudier, NEJM 2007
  14. 14. Sorafenib for mRCC: Response Rate* (TARGET) Escudier, NEJM 2007 38 (8) 18 (4) Missing 167 (37) 56 (12) Progressive disease 239 (53) 333 (74) Stable disease 8 (2) 43 (10) Partial response — 1 (<1) Complete response Placebo (n=452) n (%) Sorafenib (n=451) n (%) Best Response by RECIST
  15. 15. 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 Placebo (n=452) Sorafenib (n=451) Escudier, NEJM 2007 5.5 2.8 Sorafenib Placebo 0.51 Hazard ratio Median (months) PFS
  16. 16. Sorafenib: Phase III TARGETs— Summary of OS Analysis *At the time of analysis, 216/452 (48%) of patients in the placebo group had crossed over to receive Sorafenib. 1. Escudier B et al. New Engl J Med . 2007;356:125-134. 2. Eisen T et al. Presented at: ASCO 2006 3. Adapted from: Escudier B et al. 2007 <ul><li>In the final OS analysis, 62% of total patient-years of exposure to study drug in the placebo arm corresponded to Sorafenib </li></ul>n/a 0.01 0.74 14.3 months 19.3 months OS 6 Months Post ­ Crossover With Placebo Censored 2 13.5% 30% 39% Increase in OS 17.8 months 19.3 months Not reached Sorafenib med. OS ≤ 0.037 0.0094 0.0005 O’Brien-Fleming stopping boundary 0.146 0.02 0.02 P value 0.88 0.77 0.72 Hazard ratio 15.2 months 15.9 months 14.7 months Placebo median OS Final OS 16 Months Post-Crossover 3 OS 6 Months Post ­ Crossover 1 * OS at Crossover 1
  17. 17. Sorafenib vs IFN-  : Randomized Phase II PFS by Independent Review 97 75 30 16 4 92 57 34 24 7 Sorafenib Interferon Patients at risk Time From Randomization (months) Proportion of Patients Progression-Free 0 15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1.00 0.25 0 0.50 Median PFS Sorafenib=5.7 months Interferon=5.6 months Hazard ratio=0.88 (95% Cl: 0.61-1.27) P value (log-rank test)=0.504 0.75 Sorafenib IFN-  Adapted from Escudier B et al. Presented at: 5th Intl Symposium on TAT; March 8-10, 2007; Amsterdam, The Netherlands.
  18. 18. Sunitinib vs IFN-  for mRCC: Phase III Study Design Sunitinib, 50 mg qd (n=375) <ul><li>1° end point: PFS </li></ul><ul><li>2° end points: RR, OS, safety, patient reported outcomes </li></ul><ul><li>Demographics </li></ul><ul><ul><li>MSKCC good or intermediate risk patients(34/47) </li></ul></ul><ul><ul><li>Clear-cell carcinoma </li></ul></ul>Unresectable and/or mRCC, No prior systemic Tx, ECOG PS 0/1 (N=750) IFN-  (n=375) 4 weeks on, 2 weeks off (4/2) 3 MU tiw, 6 MU tiw, 9 MU tiw Motzer et al , NEJM 2007
  19. 19. Treatment-Related Adverse Events * Greater frequency, P <0.05 Motzer, NEJM 2007 11/<1 * 51 7 51 Fatigue 0 13 5 * 53 Diarrhea 0 29 1 6 Chills <1 2 1 25 Stomatitis <1 16 <1 5 Myalgia 1 3 2 10 Ejection fraction decline <1 1 8 * 24 Hypertension 0 1 5 * 20 Hand-foot syndrome <1 8 0 1 Flu-like symptoms 0 34 1 7 Pyrexia Grade 3/4 Grade 3/4 IFN-  (%) 1 33 All grade 3 44 All grade Sunitinib (%) Nausea Event
  20. 20. First-Line Sunitinib vs IFN- α : PFS and Response Rate PFS = progression-free survival. Motzer RJ, et al. N Engl J Med . 2007;356:115-124. Motzer RJ, et al. 2007 ASCO Annual Meeting; Abstract 5024. P <0.001 Patients at Risk (n) Sunitinib 375 235 90 32 2 IFN- α 375 152 42 18 0 Objective Response Rate (%) Treatment 31% 6% 0 2 4 6 8 10 14 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months PFS Hazard Ratio = 0.42; 95% CI (0.32–0.54); P <0.001 Sunitinib IFN- α 1 3 5 7 9 12 11 13 Sunitinib (n = 375) Median: 11.0 months (95% CI: 10.0-12.0) IFN- α (n = 375) Median: 5.0 months (95% CI: 4.0-6.0) Sunitinib (n = 375) IFN- α (n = 375)
  21. 21. Sunitinib vs IFN-  : Final Overall Survival Figlin RA, et al. 2008 ASCO Annual Meeting; Abstract 5024. Sunitinib (n = 375) Median: 26.4 months (95% CI: 23.0 - 32.9) IFN-  (n = 375) Median: 21.8 months (95% CI: 17.9 - 26.9) Total Death Sunitinib 190 IFN-  200 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Overall Survival Probability Hazard Ratio = 0.821 (95% CI: 0.673 - 1.001) P = 0.051 (Log-rank)
  22. 22. Figlin RA, et al. 2008 ASCO Annual Meeting; Abstract 5024.
  23. 23. Temsirolimus (TEMSR, CCI-779) for mRCC: Phase III Study Design Hudes G et al. Presented at: ASCO; June 2-6, 2006; Atlanta, GA. Hudes G et al. NEJM 2007 IFN-  escalating to 18 MU SC tiw TEMSR 25 mg IV qw TEMSR 15 mg IV qw + IFN-  6 MU tiw Advanced RCC No prior therapy KPS ≥60 (N=626) <ul><li>1 ° end point: OS </li></ul><ul><li>2 ° end points: PFS, TTF, OR, and clinical benefit </li></ul><ul><li>Demographics </li></ul><ul><ul><li>MSKCC poor (~70%) or intermediate risk patients </li></ul></ul><ul><ul><li>Predominately clear-cell carcinoma </li></ul></ul>
  24. 24. Temsirolimus vs IFN-  : Selected Adverse Events Hudes G et al. N Engl J Med . 2007;356:2271-2281. P = 0.02 Stomatitis Anemia Dyspnea Rash Diarrhea Nausea Asthenia Temsirolimus IFN-  Any Grade 3/4 Hyperlipidemia Hyperglycemia Neutropenia 67 NA 78 NA 1 20 0 4 20 45 22 42 3 27 1 14 11 26 2 11 3 14 1 10 Creatinine Increase 3 7 7 12 27 28 47 37 51 All Grades 20 24 6 41 64 All Grades Grade 3/4 Grade 3/4 9 6 4 0 1 2 2 4 11 26 Adverse Event Patients (%)
  25. 25. TEMSR for mRCC: Response Rates Hudes G et al. Presented at: ASCO; June 2-6, 2006; Atlanta, GA. Hudes G et al. NEJM 2007 86 (41) 96 (46) 60 (29) Clinical benefit (CR + PR [SD ≥16 wks]) 24 (11) 19 (9) 15 (7) Objective response (CR + PR) TEMSR + IFN-  (n=210) n (%) TEMSR (n=209) n (%) IFN-  (n=207) n (%) Best response
  26. 26. Temsirolimus vs IFN-  : OS by Treatment Arm Hudes G, et al. N Engl J Med . 2007;356:2271-2281. Copyright © 2007 Massachusetts Medical Society. All rights reserved. Arm 3: Temsirolimus + IFN- α (n = 210) Arm 2: Temsirolimus (n = 209) Arm 1: IFN- α (n = 207) Time From Randomization (months) Probability of Survival 1.00 0.75 0.50 0.25 0.00 0 5 10 15 20 25 30 35 P = 0.008; IFN- α vs temsirolimus P = 0.70; IFN- α vs IFN- α + temsirolimus Patients at Risk (n) IFN- α 207 126 80 42 15 3 0 Temsirolimus 209 159 110 56 19 3 0
  27. 27. Temsirolimus vs IFN- α , Poor-Risk mRCC: Correlation With Survival Histology Clear cell Other 287 129 115 301 Age <65 Years ≥ 65 Years Prognostic Risk Intermediate Poor Subgroup N HR (95% CI) 339 73 Dutcher JP, et al. 2007 ASCO Annual Meeting; Abstract 5033. Temsirolimus Better IFN-α Better 0.0 0.5 1.0 1.5 2.0
  28. 28. AVOREN for mRCC: Phase III Study Design <ul><li>Bevacizumab/placebo 10mg/kg i.v. q2w until progression </li></ul><ul><li>IFN-  2a 9MIU s.c. three times/week (maximum of 52 weeks) (dose reduction allowed) </li></ul><ul><li>Multinational ex-US study: 101 study sites in 18 countries </li></ul><ul><li>Stratification factors: country and Motzer score </li></ul>Escudier, ASCO 2007 Escudier, Lancet 2007 PD = progression of disease; i.v. = intravenous; s.c. = subcutaneous 1:1 IFN- α 2a + placebo (n=322) Advanced RCC No prior therapy KPS ≥60 (N=649) Bevacizumab + IFN- α 2a (n=327)
  29. 29. AVOREN: Selected grade 3/4 adverse events* *Based on safety population Number of patients (%) 13 (3.9) 2 (0.7) Hypertension 4 (1.2) 1 (0.3) Arterial ischemia 5 (1.5) 0 (0) Gastrointestinal perforation 6 (1.8) 2 (0.7) Venous thromboembolism 11 (3.3) 1 (0.3) Hemorrhage 22 (6.5) 0 (0) Proteinuria 76 (23) 46 (15) Fatigue/asthenia/malaise 203 (60) 137 (45) Any grade 3/4 adverse event Bevacizumab + IFN (n=337) IFN + placebo (n=304) Adverse event
  30. 30. AVOREN: Tumor response *Patients with measurable disease only 31 1 30 13 2 11 Overall response rate (%)* Complete response Partial response p<0.0001 13 10 11 7 Median duration of response (months) Median duration of stable disease (months) Bevacizumab + IFN (n=306) IFN + placebo (n=289) Response
  31. 31. AVOREN: Investigator-Assessed PFS Median PFS Bevacizumab + IFN-  2a = 10.2 mo IFN-  2a + placebo = 5.4 mo HR = 0.63, P <0.0001 Probability of Being Progression Free Time (months) 0 6 12 18 24 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 5.4 10.2 Escudier B, et al. Lancet . 2007;370:2103-2111.
  32. 32. AVOREN: PFS Is Maintained With Bevacizumab + Lower-Dose IFN Melichar B, et al. Ann Oncol . 2008 April. [Epub ahead of print.] 0 3 6 9 12 15 18 21 24 Time (months) Bevacizumab + lower-dose IFN = 13.6 months All bevacizumab + IFN patients = 13.5 months Probability of Being Progression Free 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Median PFS
  33. 33. Renal Cell Cancer-Targeted Rx III II III II III III II Phase 31/70 10/ 9/54 10/82 37/84 41/67 PR/ORR 10.2 vs.5.4 4.8 vs. IFN 1 2 649 116 Bevacizumab 3.7 vs. 1.9 vs. IFN I 626 Temsirolimus (poor risk) 5.7 5.5 vs. 2.8 vs. placebo 1 2 189 903 Sorafenib 11 vs. 5 8.2 vs.IFN I 2 750 169 Sunitinib PFS (months) Regimen I/II line N Drug
  34. 34. Efficacy of Sequencing Antiangiogenic Agents in Resistant RCC Stable Disease, % 53 61 40 34 45/48 (n=154/71) *TTP **Patients received both sorafenib and sunitinib 1 . Escudier B, et al. N Engl J Med 2007; 356:125 - 34 2. Rini BI, et al. ASCO 2006; # 4522 3. Rini BI, et al. ASCO 2005; #4509 4. Rini BI, et al. ASCO 2007; # 5032 5. Hutson TE, et al. ASCO 2007; abstract 5031 Sorafenib (Phase III; IFN - Resistant) 1 (n=451) Sunitinib (Ph II: Bevacizumab - Resistant) (n=61) 2 Axitinib (Phase II: IFN - Resistant) (n=52) 3 Axitinib (Phase II; Soraf - /Sunit - Resistant) (n=62) 4 Pazopanib (Phase II; First - Line/Interferon - Resistant) (n=225 ) 5 Median PFS, months 5.5 23.6* NR 7.4/6.1 (n=62/14**) NR ORR, % 10 16 46 21 26/30 (n=154/71)
  35. 35. Everolimus After Progression on VEGFR-TKI: Study Design <ul><li>410 patients randomized between September 2006 and October 2007 </li></ul><ul><li>Second interim analysis cutoff: October 15, 2007, based on 191 PFS events </li></ul><ul><li>Independent Data Monitoring Committee recommended termination of study </li></ul>R A N D O M I Z A T I O N 2:1 Upon Disease Progression Interim Analysis Interim Analysis <ul><li>N = 410 </li></ul><ul><li>Stratification </li></ul><ul><ul><li>Prior VEGFR-TKI: 1 or 2 </li></ul></ul><ul><ul><li>MSKCC risk group: favorable, intermediate, or poor </li></ul></ul>= Final Analysis Everolimus + best supportive care (n = 272) Placebo + best supportive care (n = 138) Motzer RJ, et al. 2008 ASCO; Motzer RJ, Lancet 2008
  36. 36. Everolimus After Progression on VEGFR-TKI: Prior Therapies Motzer RJ, et al. 2008 ASCO ; Motzer RJ, Lancet 2008 10 9 Bevacizumab 44 46 Sunitinib 16 13 Chemotherapy 50 50 Interferon 24 22 Interleukin 2 VEGFR-TKI therapy Placebo (n = 138) % 26 26 Sunitinib and sorafenib Other systemic therapy 30 28 95 31 Radiotherapy 96 Nephrectomy 28 Sorafenib Everolimus (n = 272) % Prior Treatment
  37. 37. Treatment-Related Adverse Events* *≥ 10% of everolimus patients and additional selected AEs. † Significant difference between sum of grade 3/4 events for everolimus and placebo groups ( P < .05) . Motzer R et al. ASCO 2008 1 24 3 37 Asthenia / fatigue 0 3 0 10 Edema peripheral 0 4 0 12 Cough 0 2 3 10 Infections † 0 0 0 0 0 0 0 0 0 Grade 3 4 < 1 25 Rash 2 1 8 Dyspnea 2 1 14 Mucosal inflammation 4 0 12 Vomiting 0 3 8 Pneumonitis † 8 6 3 8 All Grades Placebo %, (n = 135) 1 17 Diarrhea < 1 16 Anorexia 0 15 Nausea 3 Grade 3 40 Stomatitis † All Grades Everolimus %, (n = 269)
  38. 38. Maximum % Change in Target Lesions and Objective Response Rate* − 100% − 75% − 50% − 25% 0% 25% 50% 75% 100% Best Response n (%) PR 3 (1) Stable 171 (63) PD 53 (20) NE 45 (16) Best Response n (%) PR 0 Stable 44 (32) PD 63 (46) NE 31 (22 ) Everolimus Placebo NE = not evaluable * Central Radiology Review
  39. 39. Everolimus vs Placebo: PFS by Central Radiology Review Motzer RJ, et al. 2008 ASCO Annual Meeting; Abstract LBA5026. 100 80 60 40 20 0 0 2 4 6 8 10 12 PFS Probability (%) Everolimus (n = 272) Placebo (n = 138) Hazard ratio = 0.30 95% CI (0.22, 0.40) Log-rank P <0.001 Median PFS Everolimus: 4.0 mo Placebo: 1.9 mo Months
  40. 40. Prospective Trials of Sequential Targeted Agents 1. Rini, et al. J Clin Oncol (in press); 2. Rini, et al. 2007 ASCO Annual Meeting; 3. Sheppard, et al. 2008 ASCO Annual Meeting; 4. Motzer, et al. 2008 ASCO Annual Meeting. OR = overall response; TS = tumor shrinkage. 4.0 months 3.8 months 7.4 months 7.1 months PFS 1/50 410 Phase 3: RAD001 vs placebo in TKI-refractory RAD001 4 480 Phase 3: Temsirolimus vs sorafenib in patients previously treated with sunitinib Temsirolimus 540 Phase 3: Axitinib vs sorafenib in previously treated patients Axitinib 3/38 26 each Phase 2: Bevacizumab-or sunitinib-refractory Sorafenib 3 23/55 62 Phase 2: Sorafenib-refractory Axitinib 2 23/75 62 Phase 2: Bevacizumab-refractory Sunitinib 1 OR/TS (%) N Population Agent
  41. 41. RCC Therapies 2008 * MSKCC risk status. Adapted from Atkins M ASCO 2006 Clinical trial Prior mTOR inhibitor IL-2 (selected pts) Bevacizumab +/- IFN-  Clinical trial (Everolimus) Prior VEGFr-TKI Sorafenib/Sunitinib Prior cytokine Previously treated Temsirolimus Poor risk* Clinical trial Sunitinib Good or intermediate risk* Treatment- naive Treatment Setting
  42. 42. Issues in Sequencing Anti-Angiogenesis Agents in RCC <ul><li>Why do we still observe responses after sequencing anti VEGF agents? </li></ul><ul><li>- Do some drugs have better PK profile? Interpatient PK variability? </li></ul><ul><li>- Is it due to OFF VEGF target mechanisms? </li></ul><ul><li>- Is the target VEGF always inhibited? </li></ul><ul><li>Does the sequence affect toxicity? </li></ul><ul><li>What are the mechanisms of resistance to anti VEGF therapies? </li></ul>
  43. 43. BMDCs CAFs SDF1  Bone marrow derived cells (i.e myeliod suppressive cells) Cancer associated fibroblasts Adapted from Casanovas O Cancer Cell 2005 Osteopontin Potential Mechanism of Resistance to VEGF Inhibitors SDF1  <ul><ul><li>MMP9 </li></ul></ul>1 Oromi A et al Cell 2005 3 Du R Cancer Cell 2008 2 Ebos JM et al PNAS 2007 <ul><ul><li>PDGF </li></ul></ul>
  44. 44. RCC Microenvironment is Responsible for Tumor Response/Resistance to RTKIs Hammers H et al AACR 2008 Tumor volume Sunitinib resistant disease
  45. 45. Tumor Size Combination Strategies: Sequential Approach 0 2 4 6 8 10 12 Month Anti-VEGF w/wo HIF-1  Inhibitor RTK = receptor tyrosine kinase VEGF dependence 7 6 5 4 3 2 1 0 RTKI
  46. 46. Sequential Approach: Phase II Study of VEGF Trap in Metastatic RCC (ECOG 4805) <ul><li>Eligibility Criteria </li></ul><ul><li>Confirmed clear cell RCC </li></ul><ul><li>Measurable metastatic disease </li></ul><ul><li>Prior TKI treatment </li></ul>VEGF Trap 4 mg IV d1-15 (N=120*) Primary end points: PFS Secondary end points: ORR,SD, duration of response, , safety RANDOM I Z A T I ON VEGF Trap 1 mg IV d1-15 Crossover allowed <ul><li>Stratification </li></ul><ul><li>Low vs intermediate vs high risk (Motzer criteria) </li></ul><ul><li>Prior cytokine : yes vs no </li></ul><ul><li>Prior nephrectomy: yes vs no </li></ul>
  47. 47. Tumor Size Month RTKI + HIF-1  Inhibitor Delay TTP Combination Strategies: Concomitant Approach VEGF dependence HIF-1  dependence 7 6 5 4 3 2 1 0 0 2 4 6 8 10 12 RTKI
  48. 48. Phase II Study of Bevacizumab, Sorafenib, and Temsirolimus in mRCC (ECOG 2804 “BeST” Trial): Study Design <ul><li>Eligibility Criteria </li></ul><ul><li>Confirmed clear cell RCC </li></ul><ul><li>Measurable metastatic disease </li></ul><ul><li><25% of any other histology (papillary, chromophobe, or oncocytic) </li></ul><ul><li>Primary or metastatic lesion </li></ul><ul><li>Not curable by standard radiotherapy or surgery </li></ul><ul><li>Prior nephrectomy </li></ul>Bevacizumab IV over 30-90 min d1-15 + Temsirolimus IV over 30 min d1, d8, d15, d22 Bevacizumab IV over 30-90 min d1-15 Primary end point: PFS * Expected enrollment. At: http://www.clinicaltrials.gov . (N=360*) + Sorafenib bid PO, d1-28 Bevacizumab IV over 30-90 min d1-15 RANDOM I Z A T I ON + Sorafenib PO bid, d1-28 Temsirolimus IV over 30 min d1, d8, d15, d22
  49. 49. Toxicities in RCC Patients Receiving RTKIs <ul><li>Most common: </li></ul><ul><ul><li>Fatigue </li></ul></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>Hand-foot syndrome </li></ul></ul><ul><ul><li>Diarrhea </li></ul></ul><ul><li>Rarer but potentially mores serious: </li></ul><ul><ul><li>Cardiac events </li></ul></ul><ul><ul><li>Hypothyroidism </li></ul></ul><ul><ul><li>Thromboembolic events </li></ul></ul><ul><ul><li>Bleeding </li></ul></ul><ul><li>To date no validated predictors </li></ul><ul><li>No clear linear association with pharmacokinetics </li></ul><ul><li>Limiting factor in combination strategies </li></ul>
  50. 50. Kinase Dendrogram KINASE INHIBITION CLINICAL EFFICACY ? Adapted from Fabian et al, Nature Biotech 2006 TOXICITY ? VATALANIB SORAFENIB SUNITINIB
  51. 51. Predictors of Toxicity with RTKIs <ul><li>Pharmacogenomics: Single nucleotide polymorphism (SNPs) may correlate with sunitinib treatment-related toxicity *- larger study needed </li></ul><ul><li>Some SNPs may be associated with tissue restricted toxicity (i.e. creatine kinase and cardiac toxicity) </li></ul><ul><li>Correlation of SNPs, toxicity and pharmacokinetcs to be assessed </li></ul><ul><li>Awaiting for analysis from E2805 adjuvant study </li></ul><ul><li>Is age a predictor factor? </li></ul>* Faber PW et al ASCO 2008 abstract #5009
  52. 52. Probability of Severe Toxicity from Sunitinib in Older Adults van der Veldt AAM British Journal of Cancer (2008) 99(2), 259 – 265
  53. 53. Clinical Development of Antiangiogenesis in RCC 1 For advanced disease Neoadjuvant therapy Adjuvant therapy IL-2, IFN- α Other immunotherapy strategies <ul><li>Targeted agents </li></ul><ul><li>VEGF inhibitors </li></ul><ul><li>mTOR inhibitors </li></ul><ul><li>Others (ie, HDAC inhibitors) </li></ul><ul><li>Chemotherapy? </li></ul><ul><li>Capecitabine </li></ul><ul><li>Gemcitabine </li></ul><ul><li>Others </li></ul>2 Optimizing dose and schedule to overcome resistance? VEGF inhibitor mTOR inhibitor 3 Combination strategies HDAC = histone deacetylase.
  54. 54. RCC: Role for Palliative Nephrectomy 1) EORTC: N CR PR Survival (mo) Nx + IFN 42 12 7 17 IFN 43 2 6 7 p=0.03 2) SWOG: N CR PR Survival (mo) Nx + IFN 120 0 3 11.1 IFN 121 0 3 8.1 p=0.05 Two randomized trials: IFN Nx + IFN 1 Mickisch, Lancet 358, 2001; 2 Flanigan, NEJM 345, 2001 .
  55. 55. n=444 n=444 n=444 Treatment repeats every 6 weeks for up to 9 courses in the absence of disease progression or unacceptable toxicity Sunitinib 50 mg PO qd for 4 of 6 wk + Sorafenib placebo for 6 wk Sorafenib 400 mg PO bid for 6 wk + Sunitinib malate placebo for 6 wk Placebo for sunitinib malate and sorafenib for 6 wk ASSURE Trial (ECOG 2805) Primary end point: Disease-free survival Secondary end points: OS, safety, analysis of molecular markers N=1332* <ul><li>Eligibility Criteria </li></ul><ul><li>pT1b, G3-4; pT2-4; N+ disease, no metastatic disease </li></ul><ul><li>Confirmed clear cell or non–clear cell RCC </li></ul><ul><li>Intermediate high–risk or very high–risk disease </li></ul><ul><li>Prior radical or partial nephrectomy </li></ul>RANDOM I Z A T I ON
  56. 56. Future Directions for Individualized Treatments for RCC <ul><li>Predict tumor behavior by molecular signatures </li></ul><ul><ul><li>Patient prognosis </li></ul></ul><ul><li>Stratify patients into risk categories by clinical/molecular parameters </li></ul><ul><ul><li>Predict disease recurrence and cancer-related death </li></ul></ul><ul><li>Select treatment approach and predict response </li></ul><ul><ul><li>Based on the target expression </li></ul></ul><ul><ul><li>Minimize unnecessary exposure to treatment toxicity </li></ul></ul>Adapted from Eppert JT, et al. BJU Int . 2007;99:1208-1211.
  57. 57. <ul><li>Individualizing treatment; attention for possible age-related effects on PK and PD in older adults </li></ul><ul><li>Optimal duration of treatment and timing for changing treatments </li></ul><ul><li>Selecting treatment for patients with comorbid conditions </li></ul><ul><li>Integration of molecular targeted therapies with surgery </li></ul>Future Directions for Individualized Treatments for RCC
  58. 58. Conclusions <ul><li>The treatment of patients with metastatic RCC continues to evolve with several drugs already FDA approved </li></ul><ul><li>Preclinical and clinical trials will determine the most effective dosing schemes, optimal sequencing, and treatment combinations </li></ul><ul><li>The goal remains individualized treatments to optimize patient outcomes </li></ul>

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