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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
Vascularpermeability
Cell survival, proliferation, migration
Vascularformation, maturation
Loss of VHL protein function
VEGF PDGF VEGFR PDGFR
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 GroupSupported 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
RANDOMIZATION
Sunitinib(n=375)
IFN-(n=375)
Patient Characteristics
CharacteristicsSunitinib (n=375)
IFN- (n=375)
Median age 62 59
ECOG PS 0/1 (%) 62/38 61/39
Prior nephrectomy (%) 91 89
Prior radiation therapy (%) 14 14
Sites of disease involvement (%)
Lung 78 80
Liver 26 24
Bone 30 30
Best Response by RECIST (Independent Central Review)
Response Sunitinib IFN-
Pts with measurable disease at baseline* (n)
335 327
Overall response**Complete response
Partial response
103 (31%)
0
103
20 (6%)
0
20
Stable disease 160 (48%) 160 (49%)
Progressive disease or
not evaluable
72 (21%) 147 (45%)
** Sunitinib vs. IFN-: p <0.000001* 88 patients not yet assessed by central review;
Progression-free Survival(Independent Central Review)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Time (Months)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
gre
ssio
n F
ree
Su
rviv
al P
rob
abili
ty Sunitinib (n=375) Median: 11 months (95% CI: 10, 12)IFN- (n=375) Median: 5 months (95% CI: 4, 6)
Hazard Ratio = 0.415(95% CI: 0.320, 0.539)p < 0.00001
No. at Risk Sunitinib: 235 90 32 2No. at Risk IFN-: 152 42 18 0
Overall Survival
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Time (Months)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Ove
rall
Su
rviv
al P
rob
abili
ty
Sunitinib (n=375)Median not reachedIFN- (n=375)Median not reached
Hazard Ratio = 0.6595% CI (0.449, 0.942)p = 0.0219*
No. at Risk Sunitinib: 341 190 84 15 1No. at Risk IFN-: 296 162 66 10 0
* The nominal level of significance for this pre-planned analysis was p <0.0031
Laboratory Abnormalities
Sunitinib (%) IFN- (%)
EventAll
gradeGrade 3/4 All grade
Grade 3/4
Neutropenia 72 11/1 46 7
Anemia 71 3/<1 64 4/<1
Thrombocytopenia 65 8 21 0
Lymphopenia 59 12 63 22
Hyperlipasemia 52 13/3 43 5/1
Hypophosphatemia 36 4/<1 32 6
Hyperamylasemia 31 4/1 28 2/<1
Treatment-Related Adverse Events
Event
Sunitinib (%) IFN- (%)
All grade Grade 3/4 All grade Grade 3/4
Fatigue 51 7 51 11/<1
Diarrhea 53 5 13 0
Nausea 44 3 33 1
Stomatitis 25 1 2 <1
Hypertension 24 8 1 <1
Dermatitis/HFS 20 5 1 0
Ejection fraction decline 10 2 3 1
Pyrexia 7 1 34 0
Chills 6 1 29 0
Myalgia 5 <1 16 <1
Flu-like symptoms 1 0 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
Investigator31% (26, 36)
37% (32, 42)
6% (4, 9)
9% (6, 12)
Safety Acceptable Acceptable
Patient-reported Outcomes Superior -* Sunitinib versus IFN-: p <0.000001
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 therapy Disease-free since
8 46 7/97 Brain,bone,
Liver,adrenal
5 Craniotomy, adrenalectomies
2000
14 32 11/98 Brain,bone,
liver
8 craniotomy 1999
26 54 3/01 Bone 2 Radiation 2003
37 63 9/02 Lung, liver 8 Thoracotomy 2003
40 57 1/03 Lung 5 2003
Indications for high-dose IL-2before January 2006 after January
• 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
Overall Survival Temsirolimus vs IFN
TEMSR ± IFN 3-Arm Phase III Study
0 5 10 15 20 25 30 350
1.00
0.75
0.50
0.25
Time from randomization (months)
Pro
bab
ilit
y o
f su
rviv
al
Arm 1: IFN
Arm 3: IFN + temsirolimus
Arm 2: Temsirolimus
ParameterIFN
Arm1TEMSRArm 2
TEMSR + IFNArm 3
n 207 209 210
Comparisons Arm 2: Arm 1 Arm3: Arm 1
Stratified log-rank P 0.0069 0.6912
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