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 High-Dose Interleukin-2 can cure some patients with metastatic kidney cancer
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
Sunitinib Mechanism of Action in RCC RCC pathogenesis and progression ↑ VEGF ↑ PDGF Vascular permeability Cell survival, proliferation, migration Vascular formation, maturation Loss of VHL protein function VEGFPDGF VEGFRPDGFR Vascular endothelial cell Pericyte/fibroblast/ vascular smooth muscle Sunitinib
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.
Randomization Scheme N=750 Stratification Factors: LDH >1.5 vs. 1.5 x ULN ECOG PS 0 vs. 1 Presence vs. absence of nephrectomy RANDOMIZATIONRANDOMIZATION Sunitinib (n=375) IFN- (n=375)
Patient Characteristics Characteristics Sunitinib (n=375) IFN- (n=375) Median age ECOG PS 0/1 (%) 62/38 61/39 Prior nephrectomy (%) Prior radiation therapy (%) 14 Sites of disease involvement (%) Lung Liver Bone 30
Best Response by RECIST (Independent Central Review) ResponseSunitinib IFN- Pts with measurable disease at baseline* (n) Overall response** Complete response Partial response 103 (31%) (6%) 0 20 Stable disease160 (48%)160 (49%) Progressive disease or not evaluable 72 (21%)147 (45%) ** Sunitinib vs. IFN- : p < * 88 patients not yet assessed by central review;
Progression-free Survival (Independent Central Review) No. at Risk Sunitinib: No. at Risk IFN- :
Overall Survival No. at Risk Sunitinib: No. at Risk IFN- : * The nominal level of significance for this pre-planned analysis was p <0.0031
Laboratory Abnormalities Sunitinib (%) IFN- (%) Event All grade Grade 3/4All grade Grade 3/4 Neutropenia7211/1467 Anemia71 3/<1644/<1 Thrombocytopenia Lymphopenia Hyperlipasemia5213/3435/1 Hypophosphatemia364/<1326 Hyperamylasemia31 4/1282/<1
Treatment-Related Adverse Events Event Sunitinib (%) IFN- (%) All gradeGrade 3/4All gradeGrade 3/4 Fatigue517 11/<1 Diarrhea Nausea Stomatitis251 2<1 Hypertension248 1<1 Dermatitis/HFS Ejection fraction decline Pyrexia Chills Myalgia 5<116<1 Flu-like symptoms 10 8<1
Sunitinib Dermatological Toxicity
Outcome Summary Sunitinib IFN- Median Progression-free Survival* (95% C.I.) Independent Review Investigator 11 mos (10, 12) 11 mos (8, 14) 5 mos (4, 6) 4 mos (4, 5) Overall response* (95% C.I.) Independent Review Investigator 31% (26, 36) 37% (32, 42) 6% (4, 9) 9% (6, 12) SafetyAcceptable Patient-reported OutcomesSuperior- * Sunitinib versus IFN- : p <
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
High-dose IL-2 at California Pacific: 5 of 50 patients in 10 years Patient number age Date Rx Sites of disease # of IL-2 Other therapyDisease -free since 8467/97Brain,bone, Liver,adrenal 5 Craniotomy, adrenalectomies /98Brain,bone, liver 8craniotomy /01Bone2Radiation /02Lung, liver8Thoracotomy /03Lung52003
Indications for high-dose IL-2 before January 2006 after January Renal cell cancer Age < 65 P.S Brain metastases if resected Motivated patient Clear cell renal cell Age <55 P.S No brain metastses Very motivated patient Clinical trials if available
Overall Survival Temsirolimus vs IFN TEMSR ± IFN 3-Arm Phase III Study Time from randomization (months) Probability of survival Arm 1: IFN Arm 3: IFN + temsirolimus Arm 2: Temsirolimus Parameter IFN Arm1 TEMSR Arm 2 TEMSR + IFN Arm 3 n ComparisonsArm 2: Arm 1Arm3: Arm 1 Stratified log-rank P Adapted from: Hudes G et al. Presented at: ASCO; June 2-6, 2006; Atlanta, GA.
Sorafenib (Nexavar) and Sunitinib (Sutent): Differences 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
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