Targeted Approach to Renal Cell Carcinoma Therapy

Robert J. Motzer MD,

Memorial Sloan-Kettering Cancer Center

Targeted Approach to RCC Therapy

Background • 38,000 cases/year in U.S.• High proportion develop

metastases• Lack of effective systemic

therapy• Low proportion of long term

survivors for advanced RCC• Drug discovery is of the

highest priority

JCO:18,1928,2000

Metastatic Renal Cell Carcinoma

Survival by Systemic Treatment at MSKCC

Renal Cell Carcinoma Approved Drugs

rIL-2 High-dose Bolus in U.S.Number

Patients 255

Partial response 11%

Complete response 4%

Median response duration 23 mo

(1-50) JCO 14: 2410

NCI: High Dose vs Low Dose vs Subcutaneous IL-2No Improvement in Median Survival for High-dose

Interleukin-2 vs Interferon-alpha vs Combination

*p=0.55, NEJM 338:1272

Category IL2 IFN-α IL2 + IFN-αPatients 138 147 140

Response 8% 8% 21%

Med Survival 12 mo 13 mo 17 mo*

Toxic Deaths 9% 1% 6%

Months from randomization

% S

urv

ival

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 6 12 18 24 30 36 42 48

MPA

IFN

IL2

IFN + IL2

Median 14.9 months [11.7 - 19.2]

Median 15.2 months [12.8 - 19.9]

Median 15.3 months [13.3 - 20.0]

Median 16.8 months [14.0 - 18.9]

Phase III Immunotherapy Trial for RCC by Negrier et al

Randomized Trial Showing Role of Cytoreductive Nephrectomy Before Interferon-α

Median Survival (mos)No Nephrectomy Nephrectomy

(n=123) (n=123)

All Patients 8.1 12.5

Performance Status1 12.8 17.4

>1 4.8 6.9

MetastasesLung only 10.3 14.3Other 6.3 10.2

NEJM 345:1655

Survival by MSKCC Risk Group (JCO 17:2530)

Unmet Need: Assessing New Therapies for RCCProgression-Free Survival for 2nd-line Therapy

Response to Cytokines by Histology

Cell Type Responsive

Clear Cell (>85% of cases) Yes

Sarcomatoid variant Yes (Less)

Papillary No

Collecting duct No

Medullary No

Chromophobe No

Origin, Classification, GeneticsRenal Cell Carcinoma

VHL Gene In Renal Cell CarcinomaMutations in Sporadic Clear Cell

Nat Genet 7:85-90,1994

Role Of Vhl In Ubiquitination Of Hif-1αααα

VHL GeneMutation VHL Complex

Disrupted

VHL Protein

HIF1-α,α,α,α, HIF2-ααααAccumulation

VEGF TGF-α,

Angiogenesis Endothelial stabilization Autocrine GrowthStimulation

PDGF

Targeted Approach to RCC TherapyDrugs and Targets

ββββ pVHL HIF=αααα

VEGF TGFααααPDGF

VEGF-receptor EGFRPDGF-receptor

Sunitinib, Sorafenib Sunitinib, Sorafenib

Bevacizumab

Temsirolimus(CCI-779)

Target Approach to RCC TherapyBevacizumab in RCC : Phase II Trial

Yang JC et al. NEJM 349(5), 2003

RANDOMIZE

BEVACIZUMAB (3 MG/KG) Q 2 WEEKS (n=37)

PR 0/37, TTP 3.0 m¹, OS 15.1 m

PLACEBO Q 2 WEEKS (n=40)

PR 0/40, TTP 2.5 m, OS 13.0 m

BEVACIZUMAB (10 MG/KG) Q 2 WEEKS (n=39)

PR 4/39, TTP 4.8 m², OS 15.5 m

PDTreatment-refractory, metastatic RCC - clear cell Ca

¹vs placebo p=0.041²vs placebo p=0.001

Randomized Phase 2 Trial of Randomized Phase 2 Trial of BevacizumabBevacizumab vs. vs. Placebo :Major Responses Placebo :Major Responses (NEJM 349:427)(NEJM 349:427)

NN CRCR PRPR RRRR

PlaceboPlacebo 40 0 0 0%40 0 0 0%

HighHigh--Dose Ab 39 0 4* 10%Dose Ab 39 0 4* 10%

LowLow--Dose Ab 37 0 0 0%Dose Ab 37 0 0 0%

*Durations 39+, 15, 9, 6 months*Durations 39+, 15, 9, 6 months

High-Dose Bevacizumab vs. PlaceboProgression-free Survival (NEJM 349:427)(NEJM 349:427)

Phase II Trial of Bevacizumab + Erlotinib in Metastatic RCC: Response Rates

36 (61)SD/minor response†

13 (22)PR

8 (14)PD

2 (3)CR

No. of Patients (%)Response (N=59*)

*59/63 evaluable patients were included in the response analysis.†13 patients (22%) had minor responses.

Spigel et al. ASCO, 2005. Abstract 4540 and poster presentation.

Subjects withuntreated

metastatic renal cell carcinoma;

first-line(n = 100)

Arm 1: Bevacizumab + Elotinib x 12 months

Arm 2: Bevacizumab + placebo x 12 months

Phase II Randomized Trial : Bevacizumab +Erlotinib in RCC

� Primary endpoints: PFS and RR� Bevacizumab dose = 10 mg / kg IV q 2 wks� Erlotinib dose = 150 mg p.o. q d� Study closed 11/04 - 104 patients randomized� Genentech press release (10/18/05) - “preliminary results from the randomized

phase II trial … in renal cell carcinoma.” PFS similar in both arms.No additional trials of the combination in RCC are planned.

Bevacizumab + IFNαααα : Phase 3 Trials in Renal Cell Carcinoma

Patient Population : Metastatic Clear Cell Ca

CALGB 90206

N = 700 patients

BO17705 (Roche)

N = 638

IFNαααα 9.0 MU TIW

IFNαααα 9.0 MU TIW

+

Bevacizumab10 mg/kg d1,15

IFNαααα 9.0 MU TIW

+Placebo

d 1, 15, etc

Randomize Randomize

Studies powered to detect ↑ median survival : 13.0 → 17.0 mos

– Designed as a C-RAF-targeted agent� Also inhibits wild-type and mutant B-RAF

– Recently demonstrated to inhibit other targets

� VEGFR-2, PDGFR-b, FLT-3 and c-KIT

N

CF3

Cl

NH

NH

OO

NH

O

CH 3

BAY 43-9006 (Sorafenib)

BAY 43-9006 (sorafenib) Study 100391 Trial Schema for Patients with Advanced

Refractory Solid Tumors

* May cross over to BAY 43-9006

12 Week Induction

>-25% to <25%Randomized

≥≥≥≥ 25% Shrinkage Continue BAY 43-9006

Open Label

≥≥≥≥ 25% GrowthOff study

BAY 43-9006

Placebo*

Tumor Assessment

Baseline 12 weeks 24 weeks

Ratain MJ et al. ASCO 2004: Presentation 4501.

BAY 43-9006 (sorafenib) Study 100391 RCC Bidimensional Tumor Measurements* at Week 12:

Change from Baseline in Target Lesions (n=89)

-100

-80

-60

-40

-20

0

20

40

60

80

100

120

% C

han

ge

in T

um

or

Mea

sure

men

t

Number of Patients

> 25% Growth

< 25% to >-25% Change

>-25% to -49% Shrinkage

> -50% Shrinkage

7

45** 24 13

* Investigator assessed

* * 7 of 45 patients not randomized

Ratain MJ et al. ASCO 2004: Presentation 4501.

0.00

0.25

0.50

0.75

1.00

Pro

po

rtio

n o

f p

atie

nts

pro

gre

ssio

n f

ree

0 100 200 300 400 500

Days from randomization

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

Median progression-free survival from randomization:Placebo = 6 weeksSorafenib = 24 weeksp = 0.0087

12-weekrun-in period

-84

Rationale for Study: Clinical

Ratain MJ et al. ASCO 2005, Orlando, FL Escudier B et al. Oral presentation, ECCO 13, Nov 3, 2005

Sorafenib: TARGETsStudy Design

Sorafenib400 mg bid

Placebo

Major endpoints• Survival (alpha=0.04) • PFS (alpha=0.01)

(1:1) Randomization

n~905

Stratification

• Motzer criteria

• Country

Eligibility criteria• Histologically/cytologically

confirmed, unresectable and/or metastatic disease

• Clear-cell histology

• Measurable disease

• Failed one prior systemic therapy in last 8 months

• ECOG PS 0 or 1

• Good organ function• No brain metastasis

• Poor risk Motzer group excluded

Complete Response 1 (<1%) 0 (0%)

Partial Response 43 (10%) 8 (2%)

Stable Disease 333 (74%) 239 (53%)

Progressive Disease 56 (12%) 167 (37%)

Missing 18 (4%) 38 (8%)

TARGETsObjective Responses by Investigator Assessment

*Patients randomized at least 6 weeks before data cut-off of May 31, 2005

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

Best Response (RECIST)

TARGETsMaximum Percent Reduction in Tumor Measurement*

*Independently assessed measurements available for 574 patients (January 28, 2005 data cut-off)

0

50

100

150

-50

-100

-150

Per

cen

tag

e ch

ang

e fr

om

bas

elin

e

Placebo

25%

*Investigator assessed measurements

Sorafenib

76%

Escudier B et al. Oral presentation, ECCO 13, Nov 3, 2005

Pro

po

rtio

n o

f p

atie

nts

pro

gre

ssio

n f

ree

0

0.25

0.50

0.75

1.00

Time from randomization (months)0 4 10 202 6 8 12 14 16 18

Censored observation

Placebo

Sorafenib

Median PFS

Sorafenib = 5.5 months

Placebo = 2.8 months

Hazard ratio (S/P) = 0.51

TARGETsProgression-Free Survival Benefit*

*Based on investigator assessment

TARGETsPlanned Interim Analysis of Overall Survival*

*Results are from a planned interim analysis as per protocol (220 events) and are considered preliminary**Threshold for significance of interim analysis was p<0.0005

Time from randomization (months)0 4 10 202 6 8 12 14 16 18

0

0.25

0.50

0.75

1.00

Ove

rall

surv

ival

Censored observation

Placebo

Sorafenib

Median OSPlacebo = 14.7 months

Sorafenib = Not reached

Hazard ratio (S/P) = 0.72

p-value = 0.018**

TARGETsIncidence of Grade 3/4 Treatment-Emergent Adverse

Events* in ≥2% patientsSorafenib (n=451) Placebo (n=451)

Any grade Grades 3/4 Grades 3/4Any grade

Diarrhea 195 (43%) 11 (2%) 58 (13%) 3 (1%)

Hypertension 76 (17%) 16 (4%) 8 (2%) 2 (<1%)

Fatigue 165 (37%) 22 (5%) 125 (28%) 16 (4%)

Hand–foot skin reaction 134 (30%) 25 (6%) 30 (7%) –

Decreased hemoglobin 34 (8%) 12 (3%) 33 (7%) 20 (4%)

Tumor pain 29 (6%) 13 (3%) 24 (5%) 8 (2%)Bone pain 34 (8%) 3 (1%) 35 (8%) 15 (3%)

Dyspnea 65 (14%) 16 (4%) 52 (12%) 11 (2%)

*NCI-CTC Version 3.0 Escudier B et al. Oral presentation, ECCO 13, Nov 3, 2005

TARGETsHand–Foot Skin Reaction

Escudier B et al. Oral presentation, ECCO 13, Nov 3, 2005

Sorafenib : Phase 2 Trial in Untreated RCC Patients

Study schema :

Sorafenib

400 mg bid

INFαααα2a9 MIU TIW

Randomize*

DiseaseProgression

Sorafenib600 mg bid

Sorafenib400 mg bid

Primary

Endpoint :

PFS

Secondary

Endpoints:

DCR, RR, PK,

Resp. Duration,

PRO’s* Stratification - MSK criteria

Integration of Novel Agents in Therapy of Metastatic RCC

Sorafenib

Monotherapy :

Untreated Pts.

StandardCytokineRegimen (s) :IL-2, IFNα

Targeted Agents :1) TKI’s2) VEGF inhibitors3) EGFR inhibitors4) mTOR inhibitors5) Others

Chemotherapy:1) 5-FU2) Capecitabine3) Gemzar4) Others

Unique Settings:1) CNS mets2) Renal/hepatic

dysfunction3) Others

Adjuvant Therapy Neoadjuvant Setting

SU11248- Multi-targeted T-K Inhibitor from Pfizer,

Inc.

• Oxindole TK inhibitor• Orally bioavailable small

molecule• Selective multi-target

inhibition of:– PDGFR– VEGFR– KIT– FLT3

• Antitumor and antiangiogenicactivity

• Long plasma half-life ≈ 40 hours

• Active metabolite

NH

O

NH

F

H3C

CH3

NH

O

N

CH3

CH3

Phase II Evaluation of Sunitinib in mRCC

Sunitinib

Two independent, single-arm, multicenter, phase II trials (trial 014: N=63; trial 1006: N=106)

Patients with advanced disease and failure of prior cytokine therapy

Continuesunitinibtreatment unless progression or intolerability

4 weeks on, 2 week off (4/2)

50 mg/day*

SunitinibDosing schedule Sunitinib

*Dose reduction permitted (to 37.5 mg/day and then to 25 mg/day)

Objective Response to Sunitinib in Patients with mRCC

35 (33)

24 (23)

46 (44)1 (1)

45 (43)

Study 1006*(N=105)

56 (33)21 (33)PD, SD <3 months or not evaluable

41 (24)17 (27)SD ≥3 months

71 (42)1 (1)

70 (42)

25 (40)0

25 (40)

Overall responseCRPR

Pooled analysis(N=168)

Study 014(N=63)Response, n (%)

*Study ongoing

-100

-80

-60

-40

-20

0

20

40

Trial 1: Maximum % Reduction of Target Lesions According to RECIST Criteria by Patient

Subcarinal LN Resolved Subcarinal LN Lung Nodule

Renal Mass

Trial 2: Tumor Assessment Over Time Target Lesions for Patients with PR or

CR

-100

-80

-60

-40

-20

0

20

40

60

80

100

1 2 3 4 5 6 7 8

Cycle

Per

cent

Cha

nge

from

Bas

elin

e (%

)

Progression-free Survival Trials 1 and 2 Combined

Pro

po

rtio

n o

f p

atie

nts

p

rog

ress

ion

fre

e

Sunitinib therapy (months)

0 5 10 15 20 25 30

1.00.90.80.70.60.50.40.30.20.1

0

Median PFSTrial 1: 8.7 monthsTrial 2: 8.1 months

Combined: 8.2 months(95% CI: 7.8, 10.4)

Treatment-Related Adverse Events

16562103Hypertension

Trial 2Trial 2Trial 2Grade 3 Total

Incidence (%)

4

7

5

0

3

11

2

2

2

3

3

11Trial 1

3

8

9

13

17

17

9

6

17

16

21

27Trial 1

Grade 2

7

15

14

13

20

28

11

8

19

19

24

38Trial 1

LVEF decline

Dermatitis

Stomatitis

Nausea

Diarrhea

FatigueEvent

SU11248 Hand-foot Syndrome

SU11248: Change in Color of Hair on Treatment

Phase 3 Trial of SU11248 versus Interferon-α in First-Line Treatment for Metastatic RCC

• Randomized, Open-Label, Multicenter Trial (100 Sites: US, Canada, Europe, Australia, and Brazil)

• Endpoints: progression-free survival, overall survival, and response rate

1:1Randomization

N=690

SU11248: orally administered daily (Schedule 4/2)

IFN-αααα: administered TIW

Additional Trials with SU11248 for RCC

• SU11248 in bevacizumab-refractory RCC

• “ with gefitinib in RCC

• “ in continuous dosing schedule for RCC

• “ plus interferon in RCC (planned)

• “ plus bevacizumab in RCC (planned)

• “ as adjuvant therapy (under discussion)

• “ with gemcitabine (phase I)

• “ with capecitabine (phase I)

Renal EFFECT Study• Randomized, Open-Label, Multicenter Trial

(60 Sites: US)

• Primary endpoint: time to progression

• Secondary endpoints: response rate, overall survival, QOL by FACT-renal (MSKCC)

• Stratified by MSKCC prognostic criteria

1:1:1Randomization

N=474Sunitinib 4/2 Schedule

Sutent 4/2 Schedule + Interferon-αααα

Sunitinib continuous dose schedule

Growth factors promote angiogenesis by mTOR dependent upregulation of HIF-1αααα

RTK

PIP3

PI3KpY

Membrane

AKT

mTOR CCI-779

Tumor Angiogenesis

Amino acid

Translation & Stability of HIF-1αααα transcript

VEGF gene expression

Targeted Approach to RCC TherapyCCI-779 in Heavily Pretreated RCCn Heavily Pretreated RCC

Number

Patients 111

Partial Response 7%

PR, MR, Stable>24wks 51%

Median Time to Progression 5.8 mo

Median Survival 15 mo

J Clin Oncol 22:909-918; 2004

Targeted Approach to RCC Therapy Phase III Trial Design for CCI-779 304-WW:

CCI-779 25 mg IV q Wk

CCI-779 15 mg IV q Wk+ IFNαααα 6 MU s.c. TIWk

IFNαααα escalating as tolerated to 18 MU s.c. TIWk

RANDOMIZE

Advanced RCC First-line Rx High-risk PtsN = 600Sites ~165

Event-driven analyses with one interim analysisNumber of subjects: 600 (200 per arm)

Primary endpoint: Survival

Vertical Combinations-Targeting of VEGF at multiple levels

HIF

VEGF

KDR

CCI-779, 17-AAG, RAD001

Bevacizumab

BAY 43-9006,SU11248

Targeted Therapy for Renal Cell Carcinoma

Conclusions• Sorafinib, Sunitinib, Bevacizumab and CCI-779 show

activity in second-line therapy.

• Randomized phase 3 pivotal trials are comparing targeted therapy to interferon in first-line therapy.

• Future trials are dependent on the outcome of these pivotal trials, and will include new combinations and comparisons of targeted agents.

• Studies of tumor biology to identify markers of response are a priority.

Trials To Watch

In developmentECOGE2804 - 6 arm combination trial

PlannedPfizerPhase III SU11248 +/- IFN

AccruingMSKCCSU11248 plus Iressa

Just openedVand/PennDF/HCC

Bevacizumab + BAY 43-9006

In DevelopmentNCISU11248 vs BAY 43-9006 vs Placebo as Adjuvant

AccruingBayerPhase II BAY 43-9006 vs IFN

completedWyethPhase III CCI-779 + IFN vs IFN vs CCI

Completed/accruing

US/EuropePhase III bevacizumab + IFN vs IFN

CompletedPfizerPhase III SU 11248 vs IFN

StatusGroupRegimen

Q&A