sunitinib (sutent) for renal cell cancer blocking vegf in kidney cancer is like blocking estrogen in...

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