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