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Sunitinib (Sutent) for Renal Cell Cancer

Sunitinib (Sutent) for Renal Cell Cancer. Blocking VEGF in Kidney Cancer is like Blocking Estrogen in Breast Cancer. Blocking VEGF in Kidney Cancer is like Blocking Estrogen in Breast Cancer Anti-VEGF agents have somewhat similar toxicities

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Sunitinib (Sutent) for Renal Cell Cancer

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  1. Sunitinib (Sutent)for Renal Cell Cancer Blocking VEGF in Kidney Cancer is like Blocking Estrogen in Breast Cancer

  2. Blocking VEGF in Kidney Cancer is like Blocking Estrogen in Breast Cancer • Anti-VEGF agents have somewhat similar toxicities • High-Dose Interleukin-2 can cure some patients with metastatic kidney cancer

  3. T.E., 50 yr old male c kidney cancer • July 2004 Nephrectomy clear cell cancer venous margin + • December 2004 Partial excision tumor in vena cava • February 2005 Brain metastases Rx cyberknife • April 2005 Liver, lung metastases Rx Subcu IL-2---PD • August 2005 Rx sorafenib --PD • October 2005 GI bleeding bowel invasion Rx weekly transfusion • December 2005 Rx sunitinib 50mg/day • April 2006 Grade 2-3 Hand-foot syndrome dose 37mg/day • June 2006 CT’s show 47% recist PR in lung mets leaves town for 3000 mile motocycle trip

  4. Sunitinib Mechanism of Action in RCC Loss of VHL protein function ↑VEGF ↑PDGF VEGF PDGF VEGFR PDGFR Pericyte/fibroblast/ vascular smooth muscle Vascular endothelial cell Sunitinib Vascular permeability Cell survival, proliferation, migration Vascular formation, maturation RCC pathogenesis and progression

  5. Phase 3 Randomized Trial of Sunitinib malate (SU11248) versus Interferon-alfa as First-line Systemic Therapy for Patients with Metastatic Renal Cell Carcinoma RJ Motzer, TE Hutson, P Tomczak, MD Michaelson, RM Bukowski, O Rixe, S Oudard, ST Kim, CM Baum, RA Figlin and the SU11248 Study Group Supported by Pfizer Inc.

  6. Randomization Scheme R A N D O M I Z A T I O N • N=750 • Stratification Factors: • LDH >1.5 vs. 1.5 x ULN • ECOG PS 0 vs. 1 • Presence vs. absence of nephrectomy Sunitinib (n=375) IFN- (n=375)

  7. Patient Characteristics

  8. Best Response by RECIST (Independent Central Review) ** Sunitinib vs. IFN-: p <0.000001 * 88 patients not yet assessed by central review;

  9. 1.0 Sunitinib (n=375) Median: 11 months 0.9 (95% CI: 10, 12) IFN- (n=375) 0.8 Median: 5 months (95% CI: 4, 6) 0.7 0.6 Progression Free Survival Probability 0.5 0.4 0.3 0.2 Hazard Ratio = 0.415 (95% CI: 0.320, 0.539) 0.1 p < 0.00001 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time (Months) Progression-free Survival(Independent Central Review) No. at Risk Sunitinib: 235 90 32 2 No. at Risk IFN-: 152 42 18 0

  10. Sunitinib (n=375) Median not reached 1.0 IFN- (n=375) Median not reached 0.9 0.8 0.7 0.6 Overall Survival Probability 0.5 0.4 0.3 0.2 Hazard Ratio = 0.65 95% CI (0.449, 0.942) 0.1 p = 0.0219* 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Time (Months) Overall Survival * The nominal level of significance for this pre-planned analysis was p <0.0031 No. at Risk Sunitinib: 341 190 84 15 1 No. at Risk IFN-: 296 162 66 10 0

  11. Laboratory Abnormalities

  12. Treatment-Related Adverse Events

  13. Sunitinib Dermatological Toxicity

  14. Outcome Summary * Sunitinib versus IFN-: p <0.000001

  15. Unusual Side effects of Sunitinib (sutent) • Hand-foot syndrome with skin blisters or ulcers • Hypothyroidism and adrenal insufficiency • Decreased cardiac function?? • Hypertension • Pulmonary hemorrhage seen in lung cancer patients • Hypophosphatemia

  16. High-dose IL-2 at California Pacific: 5 of 50 patients in 10 years

  17. Renal cell cancer Age < 65 P.S 0--1.5 Brain metastases if resected Motivated patient Clear cell renal cell Age <55 P.S. 0--0.5 No brain metastses Very motivated patient Clinical trials if available Indications for high-dose IL-2before January 2006 after January

  18. TEMSR ± IFN 3-Arm Phase III Study Overall Survival Temsirolimus vs IFN 1.00 0.75 Arm 2: Temsirolimus Probability of survival 0.50 Arm 1: IFN 0.25 Arm 3: IFN + temsirolimus 0 0 5 10 15 20 25 30 35 Time from randomization (months) Adapted from:Hudes G et al. Presented at: ASCO; June 2-6, 2006; Atlanta, GA.

  19. Sorafenib given BID Sorafenib probably less toxic Dispensed via mail-order pharmacies only Onyx/Bayer pharmaceuticals In trial in combinations Sunitinib given daily 4 weeks on, 2 weeks off Sunitinib probably more potent but more toxic with fatigue and mild hematologic toxicity Dispensed via local pharmacies Sugen/Pfizer pharmaceuticals In trial in combinations Sorafenib (Nexavar) and Sunitinib (Sutent):Differences

  20. Blocking VEGF in Kidney Cancer is like Blocking Estrogen in Breast Cancer • Anti-VEGF agents have somewhat similar toxicities • High-Dose Interleukin-2 can cure some patients with metastatic kidney cancer

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