More Related Content Similar to Renal Cell Carcinoma A New Standard Of Care Similar to Renal Cell Carcinoma A New Standard Of Care (20) More from fondas vakalis (20) 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? 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. Kinase expression: Genetic Signatures Teh BT, 2006 Clear cell Papillary Chromophobe Oncocytoma Kinome Expression in Renal Tumors C - KIT C - MET - - 10. Targets in RCC Adapted from Brugarolas J NEJM 2007 Bevacizumab VEGF-Trap Vorinostat LBH589 Everolimus Axitinib Pazopanib Everolimus Temsirolimus 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) 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. 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 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. 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. 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. 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) 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. 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. 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. 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 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. 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. 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. 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. 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. 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) 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. 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. 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. 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. 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. 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 44. RCC Microenvironment is Responsible for Tumor Response/Resistance to RTKIs Hammers H et al AACR 2008 Tumor volume Sunitinib resistant disease 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 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 50. Kinase Dendrogram KINASE INHIBITION CLINICAL EFFICACY ? Adapted from Fabian et al, Nature Biotech 2006 TOXICITY ? VATALANIB SORAFENIB SUNITINIB 52. Probability of Severe Toxicity from Sunitinib in Older Adults van der Veldt AAM British Journal of Cancer (2008) 99(2), 259 – 265 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 .
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