Updates on Renal Cell CancerUpdates on Renal Cell Cancer

Sandy Srinivas.M.DSandy Srinivas.M.DStanford UniversityStanford University

&&David Minor.M.DDavid Minor.M.D

CPMCCPMC

Educational ObjectivesEducational Objectives

Describe the intracellular signaling cascades associated with VEGFR, Describe the intracellular signaling cascades associated with VEGFR, PDGFR, and Ras/Raf kinases in tumor cells and tumor vasculaturePDGFR, and Ras/Raf kinases in tumor cells and tumor vasculature

Discuss Clinical trials and data on SorafenibDiscuss Clinical trials and data on Sorafenib

Discuss the national clinical trial on adjuvant and metastatic disease Discuss the national clinical trial on adjuvant and metastatic disease

Discuss Clinical trials and data on SutentDiscuss Clinical trials and data on Sutent

Role of High dose IL-2Role of High dose IL-2

Describe mTor InhibitorsDescribe mTor Inhibitors

FR=platelet-derived growth factor; RCC=renal cell carcinoma; VEGFR=vascular endothelial growth factor

BHD=Birt-Hogg-Dubé; FH=fumarate hydratase; VHL=von Hippel-Lindau.Modified from Linehan WM et al. J Urol. 2003;170:2163-2172.

Histological ClassificationHistological Classificationof Human Renal Epithelial Neoplasmsof Human Renal Epithelial Neoplasms

RCC

Clear cell

75%

Type

Incidence (%)

Associated mutations VHL

Papillary type 1

5%

c-Met

Papillary type 2

10%

FH

Chromophobe

5%

BHD

Oncocytoma

5%

BHD

American Joint Committee on Cancer (AJCC) American Joint Committee on Cancer (AJCC)

2002 Clinical Staging System2002 Clinical Staging System

Cohen HT, McGovern FJ. N Engl J Med. 2005;353:2477-2490.

Stage Description5-Year Survival

(%)

Stage I T1, N0, M0 95

Stage II T2, N0, M0 88

Stage III T1-2, N1 or T3, N0-1 59

Stage IVT4 (any N or M) orN2 (any T or M) or M1

20

Motzer RJ et al. J Clin Oncol. 2002;20:289-296.

MSKCC Risk Factor Model in MSKCC Risk Factor Model in mRCCmRCC

0 risk factors (n=80 patients)

1 or 2 risk factors (n=269 patients)

3, 4, or 5 risk factors (n=88 patients)

Risk factors associated with worse prognosis

• KPS <80

• Low serum hemoglobin (13 g/dL/11.5 g/dL: M/F)

• High corrected calcium (10 mg/dL)

• High LDH (300 U/L)

• Time from Dx to IFN- <1 yr

Time From Start of IFN- (years)

Pro

po

rtio

n S

urv

ivin

g

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 1614131195436 151210876

MS:20 mo10 mo4 mo

1. Krown SE. Cancer. 1987;59:647-651.2. Muss HB. Semin Oncol. 1988;15:30-34.3. Rosenberg SA et al. JAMA. 1994;271:907-913.

Historical Management Strategies Historical Management Strategies for RCC: Summaryfor RCC: Summary

ChemotherapyChemotherapy

– RCC is highly resistant, <10% ORRRCC is highly resistant, <10% ORR11

IFN-IFN-

– 15% ORR, but responses rarely complete or durable15% ORR, but responses rarely complete or durable22

HD IL-2HD IL-2

– 15% ORR in stage IV patients, only 15% ORR in stage IV patients, only 55% were CR% were CR33

Urgent need for additional options in late-stage RCCUrgent need for additional options in late-stage RCC

Role of VHL in RCC ProgressionRole of VHL in RCC Progression

EGF

PDGF

VEGF

Pericyte

Endothelial cell

Tumor cell

EGF

PDGFVEGF

EGF PDGF

VEGF

HIF-1

VHL

HIF-1

HIF-1HIF-1

RAS

RAF

MEK

ERK

RAS

RAF

MEK

ERK

RAS

RAF

MEK

ERK

ParacrineFunction

ParacrineFunction

AutocrineFunction

Rational Targets in RCC Rational Targets in RCC (cont’d)(cont’d)

EGF

PDGF

VEGF

Pericyte

Endothelial cell

Tumor cell

EGF

PDGFVEGF

EGF PDGF

VEGF

HIF-1

VHL

HIF-1

HIF-1HIF-1

RAS

RAF

MEK

ERK

RAS

RAF

MEK

ERK

RAS

RAF

MEK

ERK

Bevacizumab

Bevacizumab

Bevacizumab

Sunitinib

Sunitinib

Sunitinib

Sunitinib

Sorafenib Sorafenib

Sorafenib

Sorafenib

Sorafenib

Sorafenib

Sorafenib

Bevacizumab for mRCC: Bevacizumab for mRCC: Phase II Study DesignPhase II Study Design

High dose = 10 mg/kg (n=39)

Low dose = 3 mg/kg (n=37)

Placebo (n=40)

Second randomization of placebo group at TTP to low-dose bevacizumab +/- thalidomide.Yang JC et al. N Engl J Med. 2003;349:427-434.

11°° end points: TTP and ORR end points: TTP and ORR

22°° end point: OS end point: OS

Study arms were balanced for demographicsStudy arms were balanced for demographics

mRCC patients (N=116)

ECOG PS <2All patients have

prior therapy (mostly IL-2)

Bevacizumab for mRCC:Bevacizumab for mRCC:Progression-Free SurvivalProgression-Free Survival

100

90

80

70

60

50

40

30

20

10

00 6 12 18 24 30 36

Time (months)

Pat

ien

ts F

ree

of

Tu

mo

r P

rog

ress

ion

(%

)

Adapted from Yang JC et al. N Engl J Med. 2003;349:427-434.

Median PFS (months)

High dose, 10 mg/kg(n=39) 4.8 (P<.001)

Low dose, 3 mg/kg (n=37) 3.0 (P<.041)

Placebo (n=40) 2.5

Partial Response-10%

Bevacizumab + Erlotinib for Bevacizumab + Erlotinib for mRCC: Phase II Study DesignmRCC: Phase II Study Design

Bevacizumab 10 mg/kg IV q 2 wks + erlotinib 150 mg PO qd

Bukowski , Srinivas ASCO 2006

11°° end points: PFS and ORR end points: PFS and ORR

mRCC patients,no prior therapy

(N=104)

Bevacizumab 10 mg/kg IV q 2 wks + placebo 150 mg PO qd

ResultsBevacizumab +Erlotinib Bevacizumab + Placebo

# Patients 51 53ORR (CR+PR) 7(14%) 7(13%)Stable Disease 34(68%) 36(68%)PFS (months) 9.9 8.5 P=0.58

Sorafenib (NexavarSorafenib (Nexavar®®))

Small-molecule receptor TKISmall-molecule receptor TKI11

Inhibits VEGFR-2, VEGFR-3, FLT-3, PDGFR, c-KIT, Raf kinasesInhibits VEGFR-2, VEGFR-3, FLT-3, PDGFR, c-KIT, Raf kinases11

Formulation: 200 mg tabletsFormulation: 200 mg tablets22

Dosing: 2 tablets bid continuous (1 hr ac or 2 hrs pc)Dosing: 2 tablets bid continuous (1 hr ac or 2 hrs pc)22

FDA approved December 20, 2005 for advanced RCCFDA approved December 20, 2005 for advanced RCC33

1. Wilhelm SM et al. Cancer Res. 2004;10:7099-7109.2. Nexavar [package insert]. West Haven, CT: Bayer Pharmaceutical Corporation and Emeryville, CA:

Onyx Pharmaceuticals, Inc.; 2005.3. Food and Drug Administration. FDA approves new treatment for advanced kidney cancer.

Available at: www.fda.gov/bbs/topics/NEWS/2005/NEW01282.html. Accessed January 24, 2006.

NH

NH

OO

O

N

CICF3

NH

CH3

Sorafenib for mRCC: Sorafenib for mRCC: Phase II (RDT) Study DesignPhase II (RDT) Study Design

RDT=randomized discontinuation trial.*May cross over to sorafenib. Ratain MJ et al. Presented at: ASCO; May 13-17, 2005; Orlando FL.

≥25% tumor shrinkage continue sorafenib

Stable patients(-25% to +25%)randomized

>25% tumor growth off-study

11°° end points end points– PFS from day 1PFS from day 1– PFS 12 weeks post-randomization,PFS 12 weeks post-randomization,

tumor response rate, safetytumor response rate, safety

Solid tumors (N=502) mRCC

patients (n=202)

Sorafenib

Placebo*

Median PFS from randomization

Sorafenib=24 weeksPlacebo=6 weeks

P=.0087

Sorafenib for mRCC: Phase II Sorafenib for mRCC: Phase II (RDT) Progression-Free Survival(RDT) Progression-Free Survival

Time From Randomization (days)

Pro

po

rtio

n o

f P

atie

nts

P

rog

ress

ion

-Fre

e1.00

0.75

0.50

0.25

0

12-week period

84 0 100 200 300 400 500

Ratain MJ et al. Presented at: ASCO; May 13-17, 2005; Orlando FL.

Sorafenib (n=33)Placebo (n=32)Censored

Sorafenib for mRCC: Phase II (RDT) Sorafenib for mRCC: Phase II (RDT)

Drug-Related Adverse EventsDrug-Related Adverse Events Any grade

%Grade 3/4

%

Any event 98 48

Cardiovascular 38 25

Hypertension 35 24

Dermatology 90 15

Rash/desquamation 62 2

Hand-foot skin reaction 60 13

Alopecia 50 –

Other 38 –

Dry skin 21 –

Flushing 13 –

Constitutional symptoms 68 6

Fatigue 55 4

Weight loss 24 –Ratain MJ et al. Presented at: ASCO; May 13-17, 2005; Orlando FL.

Sorafenib for mRCC:Sorafenib for mRCC:Phase III Study Design (TARGET)Phase III Study Design (TARGET)

Sorafenib, 400 mg bid (n=451)

11°° end point: OS end point: OS

22°° end points: ORR, PFS, safety, HR-QoL end points: ORR, PFS, safety, HR-QoL

DemographicsDemographics– MSKCC good or intermediate risk patientsMSKCC good or intermediate risk patients– Clear-cell carcinomaClear-cell carcinoma

Unresectable and/or mRCC,

1 prior systemic Tx in last 8 months, ECOG PS 0/1

(N=903*) Placebo (n=452)

*Out of 905 patients randomized by February 15, 2005.Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France.

Sorafenib for mRCC:Sorafenib for mRCC:Response Rate* (TARGET)Response Rate* (TARGET)

Best Response by RECIST

Sorafenib (n=451)n (%)

Placebo (n=452)

n (%)

Complete response 1 (<1) —

Partial response 43 (10) 8 (2)

Stable disease 333 (74) 239 (53)

Progressive disease 56 (12) 167 (37)

Missing 18 (4) 38 (8)

* Investigator assessment. Patients randomized at least 6 weeks before data cut-offof May 31, 2005.

Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France.

Sorafenib for mRCC: Sorafenib for mRCC: Tumor Reduction* (TARGET)Tumor Reduction* (TARGET)

* Investigator assessment. Patients randomized at least 6 weeks before data cut-off of May 31, 2005.Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France.

Sorafenib (n=451)Placebo (n=452)

Tumor Reduction Tumor Reduction

PR (30% or reduction, RECIST).

Ch

an

ge

Fro

m B

as

eli

ne

(%

)*

25% 76%

Ch

an

ge

Fro

m B

as

eli

ne

(%

)*

0

50

100

150

-50

-100

0

50

100

150

-50

-100

PD (20% increase, RECIST);

PFSMedian

(months)Sorafenib

Placebo

5.5

2.8Hazard ratio 0.51

Time From Randomization (months)

Pro

po

rtio

n o

f P

atie

nts

Pro

gre

ssio

n F

ree

0

0.25

0.50

0.75

1.00

0 4 10 202 6 8 12 14 16 18

Sorafenib for mRCC: Sorafenib for mRCC: Progression-Free Survival* (TARGET)Progression-Free Survival* (TARGET)

* Investigator assessment. Independent assessment at planned interim analysis (ASCO 2005) demonstrated doubling of PFS for sorafenib vs placebo (24 vs 12 weeks, P<.000001).Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France.

Censored observation

Placebo (n=452)

Sorafenib (n=451)

Sorafenib for mRCC:Sorafenib for mRCC:Overall Survival* (TARGET)Overall Survival* (TARGET)

OSMedian

(months)Sorafenib

Placebo

Not reached

14.7Hazard ratio (S/P)

0.72

P=.018

Censored observation

Placebo (n=452)

Sorafenib (n=451)

Time From Randomization (months)

Pro

po

rtio

n o

f P

atie

nts

Ove

rall

Su

rviv

al

0

0.25

0.50

0.75

1.00

0 4 10 202 6 8 12 14 16 18

*Interim analysis.Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France.

7

28

13

16

19

6

30

37

43

40

23

19

0 10 20 30 40 50

Hand-foot skinreaction

Fatigue

Diarrhea

Rash/Desquamation

Nausea

Pruritus

Sorafenib for mRCC: Sorafenib for mRCC: Adverse Events Profile (TARGET)Adverse Events Profile (TARGET)

7% grade 4 toxicities in sorafenib-treated patients vs 6% grade 4 toxicities in placebo-treated patients.Nexavar [package insert]. West Haven, CT: Bayer Pharmaceutical Corporation and Emeryville, CA:Onyx Pharmaceuticals, Inc.; 2005.

0

3

6

5

2

0 10 20 30 40 50

Hand-foot skinreaction

Fatigue

Diarrhea

Rash/Desquamation

Nausea

Pruritus

<1<1

<1<1

<1

An

y G

rad

e

Gra

de

3

Placebo (n=452)

Sorafenib (n=451)

Patients (%) Patients (%)

Sorafenib for mRCC: Sorafenib for mRCC: Laboratory Toxicities (TARGET)Laboratory Toxicities (TARGET)

11

13

30

10

49

23

5

45

23

41

18

44

30

12

0 10 20 30 40 50

Hypophosphatemia

Lymphopenia

Elevated lipase

Neutropenia

Anemia

Elevated amylase

Thrombocytopenia

3

7

7

2

4

3

0

13

13

12

5

2

1

1

0 10 20 30 40 50

Hypophosphatemia

Lymphopenia

Elevated lipase

Neutropenia

Anemia

Elevate amylase

Thrombocytopenia

Nexavar [package insert]. West Haven, CT: Bayer Pharmaceutical Corporation and Emeryville, CA: Onyx Pharmaceuticals, Inc.; 2005.

An

y G

rad

e

Gra

de

3

Patients (%) Patients (%)

Placebo (n=452)

Sorafenib (n=451)

TARGETsTARGETsHand–Foot Skin ReactionHand–Foot Skin Reaction

Sorafenib for mRCC: Sorafenib for mRCC: ConclusionConclusion

First MKI approved for treatment of advanced RCCFirst MKI approved for treatment of advanced RCC

– December 20, 2005December 20, 2005

More than doubles PFS compared to placebo More than doubles PFS compared to placebo

Therapeutic response Therapeutic response

– Radiographic response vs disease stabilizationRadiographic response vs disease stabilization

OS survival trend at planned interim analysis (OS survival trend at planned interim analysis (PP<.018)<.018)

Mild to moderate toxicity profileMild to moderate toxicity profile

Response in Treatment naïve Response in Treatment naïve patients(32)patients(32)

PRPR 6(18.8%)6(18.8%)

MRMR 8(25%)8(25%)

SDSD 10(31.3%)10(31.3%)

PDPD 3(9%)3(9%)

UnevalUneval 5(15%)5(15%)

32 of the 202 patients in the RDT had no prior therapy

PFS in this group was 40 weeks -10 months

Overall response of 75%

Escudier ASCO 2006

Phase II Randomized Trial- First LinePhase II Randomized Trial- First Line

Escudier, ASCO 2006

MET RCCCLEAR CELLNO PRIOR RXECOG 0/1

NO BRAIN METSALL MSKCC RISK GROUPS

N=189

REGISTRATION

SORAFENIB400MG BID

IFN-α9 M TIW

SORAFENIB600MG BID

SORAFENIB400MG BID

PROGRESSION

Accrual completed; too few events for results

Randomized phase III trial of Sorafenib: Randomized phase III trial of Sorafenib: Impact of Crossover o survivalImpact of Crossover o survival

OS @ CrossOS @ Cross

overover

OS@6 months OS@6 months Cross overCross over

OS@ 6 mosOS@ 6 mos

Crossover with Crossover with placebo censoredplacebo censored

PlaceboPlacebo 14.714.7 15.915.9 14.314.3

SorafenibSorafenib NRNR 19.319.3 19.319.3

Hazard RatioHazard Ratio 0.720.72 0.770.77 0.740.74

P-valueP-value 0.0180.018 0.0150.015 0.010.01

O-Brien-O-Brien-Flemming SRFlemming SR

0.00050.0005 0.00940.0094 0.00940.0094

Eisen, ASCO 2006

Summary-PFS (months)Summary-PFS (months)

First LineFirst Line Second LineSecond Line

BevazizumabBevazizumab 8.58.5 4.84.8

SorafenibSorafenib 99 5.55.5

ECOG 2805: Adjuvant TrialECOG 2805: Adjuvant Trial

StratifyTNMIntermediate high riskVery high riskHistologic SubtypeClear cellNon-clear cell (except collecting ductor medullary)ECOG Performance Status01SurgeryLaparoscopicOpen

Nephrectomy

Preregister

Group A: (sunitinib) Placebo for Nexavar 400 mg (2 tablets) po bid 6 wks for 9 cycles†; andsunitinib 50 mg (4 capsules)po qd 4 wks followed by rest 2 wks for 9 cycles†

Group B: (Nexavar) Nexavar 400 mg (2 tablets) po bid 6 wks for 9 cycles†; andplacebo for sunitinib 50 mg (4 capsules)po qd 4 wks followed by rest 2 wks for 9 cycles†

Group C: (placebo) Placebo for Nexavar 400 mg (2 tablets) po bid 6 wks for 9 cycles†; andplacebo for sunitinib 50 mg (4 capsules)po qd 4 wks followed by rest 2 wks for 9 cycles†

Randomization

(N=1332)

1° end point: Disease-free survival (DFS)

Nexavar in Adjuvant RCC: Nexavar in Adjuvant RCC: MRC SORCE Phase III TrialMRC SORCE Phase III Trial

11ºº end point: Disease-free survival end point: Disease-free survival

22ºº end points: end points: RCC-specific survival time, toxicity, QOL, and biomarkersRCC-specific survival time, toxicity, QOL, and biomarkers

(1.5:1.5:1) Randomization

(N=1656)

High and

intermediate risk,

resected RCC

Nephrectomy

Preregister

Placebo

for 3 years

(n=414)

Nexavar for 1 yearPlacebo for 2 years

(n=621)

Nexavar

for 3 years

(n=621)