Update on Evolving Therapies for Advanced Kidney Cancer

Nancy A. Dawson M.D.Professor of Medicine

Director, Genitourinary Oncology ProgramLombardi Comprehensive Cancer Center

Washington, DC

Case Study

• 51 yo male presented with headaches, confusion 4/04 MRI- 4 cm frontal mass/1.1 cm occipital mass. Resection frontal mass 4/04. Path – c/w renal cell carcinoma.

• CT chest/abdomen- numerous lung nodules, 8 cm R renal mass

• Whole brain XRT. Gamma knife to occipital mass. R nephrectomy- clear cell carcinoma

Case Study continued• Rx interferon 6/04-12/05 with slow growth of

lung nodules. Initial mild flu symptoms, resolved after 2 months

• 11/05 –two new lesions R occipital lobe, occasional flashing lights. Rx gamma knife

• 1/06 Nexavar 400mg bid started• 3/06 Severe fatigue, diarrhea, hand-foot

syndrome, hypertension requiring initiation of antihypertensive therapy.

• Nexavar decreased to 400mg qAM /200mg qPM with improvement

Case Study continued

• 7/06 Cyberknife to new brain lesion• 4/07 Near resolution all lung nodules. Pulseless

left arm. Nexavar held for subclavian artery bypass graft.

• 5/07 Nexavar X 1 month, poorly tolerated and stopped.

• 7/07 Solitary residual lung nodule resected (clear cell carcinoma). Acute coronary syndrome-emergent stents L main/RCA

Case Study continued

• 7/08 L common iliac artery stent placed• 8/08 Cyberknife to two new brain lesions• 1/09 Patient has been off all systemic therapy

since 6/07. No active cancer. Working full time. STILL SMOKING. Scheduled for stent of L axillary artery, bilateral carotid endarterectomies on 1/30/09

Educational Objectives

• Review pathophsiology of kidney cancer• Review rationale for targetted therapy• Review role of immunotherapy, surgery,

radiotherapy and targetted therapy in the management of metastatic renal cell carcinoma (mRCC)

• Review new targetted agents for mRCC in development

Renal Cell Carcinoma

• Approximately 51,190 new cases diagnosed in US and 12,890 deaths in 2007. Worldwide, 95,000 death annually.

• Kidney cancer has increased by 38% from 1974 to 1990

• About 30% cases present with unresectable disease.

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

Histological Classificationof Human Renal Cancers

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

Clear cell RCC is characterized by VHL gene inactivation

: selected series

Author VHL gene methylation

Herman, 1994 19% (5/26)

Clifford, 1998 15% (7/45)

Kondo, 2002 5.4% (11/202)

Brauch, 2000 7% (10/151)

Total 8% (33/424)

Author VHLgene mutation

Gnarra, 1994 57% (56/98)

Gallou, 1999 56% (73/130)

Brauch, 2000 45% (68/151)

Shuin, 1994&Kondo, 2002

51% (104/202)

Schraml, 2002 34% (38/113)

Total 49% (339/694)

Treatment for mRCC• Surgery: the only modality that appears to

offer cure in RCC.• Radiation: palliative for metastases.• Chemotherapy: low response rate (<10%)• Immunotherapy: 20-30% response,5%

durable CRs with high dose IL-2• Targetted Therapy: Prolonged PFS/OS!!

Solitary metastases• Series N 5yr OS

• Middleton, 1967 59 34%• Skinner, 1971 41 29%• Toli, 1975 19 35%• Kavolius, 1998 94 52%*

* Versus 29% for multiple

Solitary metastases• Site N=94 5yr OS

• Lung 50 54%• LNs 15 63%• Brain 11 18%• Bone 5 40%• Soft tissue 5 75%

Kavolius JP et al JCO 16: 2261, 1998

Interferon

• Meta-analysis on 1600 patients treated with IFN.• Response rate: 15%, CR: 2%• Response duration 6-10 months.• Longer response in patients with good performance

status and non-bulky pulmonary metastases.• Dosage: 3-20x106 units daily, no apparent dose-

response relationship.

Negrier S et al NEJM 338 1272-1278 1998

IL-2 for mRCC: ResponseHD IL-2(720,000 IU/kg)

LD IL-2(72,000 IU/kg)

SC IL-2(250,000 IU/kg d1-

5, 125,000 IU/kg

5x/wk)

Evaluable 96 92 93

CR 6% 1% 2%

PR 15% 10% 8%

Major RR 21% 11% 10%

Yang J et al. J Clin Oncol. 2003;21:3127-3132.

IL-2 for mRCC: SurvivalP

rop

ort

ion

Su

rviv

al

Survival Time (months)

0120

1.0

0.8

0.6

0.4

0.2

24 36 48 60 72 84 96 108 120 132

Comparison P value

HD vs LD

HD vs SC

.38

.34

LD IL-2 (Fail/Total 69/92)

HD IL-2 (Fail/Total 66/95)

SC IL-2 (Fail/Total 73/92)

Yang J et al. J Clin Oncol. 2003;21:3127-3132.

Common Toxicities AssociatedWith Cytokine Therapy

• HD IL-2

– Hypotension

– Capillary leak

– Neurologic

– Hematologic

– Pulmonary

– Renal/electrolytes

– Cardiac

• IFN-α– Constitutional– Neurologic– Hematologic

• IL-2 + IFN-α– Constitutional– Gastrointestinal

McDermott DF et al. J Clin Oncol. 2005;23:133-141.

β pVHL HIF=α

VEGFR EGFRPDGFR

Sunitinib, Sorafenib, AG-013736

Sorafenib

Bevacizumab

RAF

Erlotinib

Kaelin WG. Nat Rev Cancer. 2002;2:673-682.

RCC:Targets of Single Agents

VEGF TGF-αPDGF

RAF

Sorafenib

TemsorilimusEverolimus

Kim KJ, et al. Nature. 1993;362:841-844.Gordon MS, et al. J Clin Oncol. 2001;19:843-850.

Bevacizumab (Avastin)

• Humanized monoclonal anti-VEGF antibody• Binds and neutralizes all biologically active

forms of VEGF• Inhibits angiogenesis in experimental models• Inhibits human xenograft tumor growth in vivo

but not in vitro

Bevacizumab in RCC

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

RANDOMIZE

BEVACIZUMAB (3 MG/KG) Q 2 WEEKS

(n=37)

PLACEBO Q 2 WEEKS

(n=40)

BEVACIZUMAB (10 MG/KG) Q 2 WEEKS

(n=39)

PD

Treatment-refractory, metastatic RCC

% o

f Pa

tien

ts F

ree

of P

rog

ress

ion

Time to Progression100

80

60

40

20

00 6 12 18 24

Months from On-Study Date

30 36 0 6 12 18 24 30 36

Low-dosePlacebo

High-dosePlacebo

p < 0.001p =0.041

AVOREN: An International Phase III Trial of Interferon Alpha-2a or Interferon Alpha-2a Plus

Bevacizumab in Advanced Renal Carcinoma

RANDOMIZE

IFN-alpha-2a

IFN-alpha-2a +

Bevacizumab 10 mg/kg IV

q 2 weeks

STRATIFY

UNTREATED, ADVANCED RCC; N=649

• 12/06 Planned interim analysis showed improved PFS for the combination, DSMB recommended unblinding of study and all patients offered Avastin

AVOREN

Escudier ASCO June 2008

Placebo BevacizumabInterferon Interferon P-value HR

Response rate 13% 31% <0.0001

PFS (months) 5.4 10.2 <0.0001 0.63

OS (months) 19.8 NR p<.027 0.75

CALGB 90206: A Randomized Phase III Trial of Interferon Alpha-2b or Interferon Alpha-2b Plus

Bevacizumab in Advanced Renal Carcinoma

RANDOMIZE

IFNA 9 MU TIW

IFNA 9 MU TIW +

Bevacizumab 10 mg/kg IV

q d1 and d15

STRATIFY

UNTREATED, METASTATIC CLEAR CELL

RCC

• Patients will be stratified for nephrectomy status and Motzer risk group (0, 1-2 or 3+ risk factors).

CALGB 90206

ASCO GU Symposium 2/08

Placebo BevacizumabInterferon Interferon P-value

Response rate 13.1% 25.5% <0.0001

(95%CI,9.5-17.3) (95%CI, 20.9-30.6)

TTP (months) 5.2 8.5 <0.0001

(95%CI, 3.1-5.6) (95%CI,7.5-9.7)

OS (months) NR NR

CALGB 90206Toxicity

DSMB review 6/22/2007

Placebo Bevacizumab Interferon Interferon

Hypertension 0% 9%

Anorexia 8% 17%

Fatigue 28% 35%

Proteinuria 0% 13%

Riedl B, et al. Proc Am Soc Clin Oncol. 2001;20:83a.

Wilhelm S, et al. Cancer Res. 2004;64:7099–7109.

Sorafenib (Nexavar)

• Sorafenib selectively inhibits B-RAF, VEGFR-2, VEGFR-3, PDGFR-β, FLT-3, and c-KIT

• Originally identified through inhibitory effects on RAF-1, a serine-threonine kinase

• Inhibits angiogenesis in experimental models• Inhibits growth of human renal cell carcinoma

xenografts

>25% Tumor

shrinkage

-25% to +25%Tumor

stabilization

>25%Tumor growth

Sorafenib12-weekrun-in

Continuesorafenib

Continue sorafenib12 weeks

Placebo12 weeks

Off study

16 (50%) SD at

24 weeks

6 (18%) SD at

24 weeks

SD = Stable Disease Ratain MJ, et al. ASCO 2005, abstract 4544.

Randomized Discontinuation Trial:Patient Outcome

Randomized Discontinuation Trial:

Progression-Free Survival (PFS)

Ratain MJ, et al. ASCO 2005, abstract 4544.

0.00

0.25

0.50

0.75

1.00

Su

rviv

al D

istr

ibu

tio

n

Fu

nct

ion

–84 0 50 100 150 200 250 300 35012 -week

run -in period Days from Randomization

450400

Median PFS from randomization:

Placebo = 6 weeks

Sorafenib = 24 weeks

p = 0.0087

Sorafenib (n=32)

Placebo (n=33)

Censored

SorafenibSorafenib400 mg bid400 mg bid Major end points

• Survival (α=0.04)

• PFS (α=0.01)

Escudier B, et al. NEJM 2007;356:125-134.

Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGETs):Study Design and Objectives

PlaceboPlacebo

(1:1) Randomization

N=903

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 MSKCC group excluded

Stratification• MSKCC criteria

• Country

Objective Responses by Investigator Assessment

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

Sorafenib (n=451)*

Placebo (n=452)*

Complete Response (CR) 1 (<1) 0 (0)

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

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

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

Missing 18 (4) 38 (8)

Best Response (RECIST)

Number of Patients (%)

Escudier B, et al. NEJM, 2007;356:15-134..

TARGETsProgression-Free Survival Benefit*

* Based on investigator assessment

Pro

po

rtio

n o

f P

atie

nts

Pro

gre

ssio

n-F

ree

Time from Randomization (Months)

0

0.25

0.50

0.75

1.00

0 4 10 202 6 8 12 14 16 18

Sorafenib

Censored observation

Placebo

Median PFS

Sorafenib = 5.5 months

Placebo = 2.8 months

Hazard ratio (S/P) = 0.51

Escudier B, et al. Presented at: ECCO 13 – the European Cancer Conference, October 30-November 3, 2005; Paris, France. abstract 794.

TARGETsMedian Overall Survival

Escudier B, et al. NEJM, 2007;356:15-134.

Time from randomization (months)

0 5 10 2515 200

0.25

0.50

0.75

1.00

Su

rviv

al d

istr

ibu

tio

n f

un

ctio

n

Median OS

Placebo = 15.9 months

Sorafenib = 19.3 months

Hazard ratio = 0.77 (95% CI: 0.63, 0.95)

p-value = 0.02

Incidence of Treatment-Emergent Adverse Events* in ≥2% patients

Sorafenib (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 3.0Escudier B, et al. Presented at: ECCO 13 – the European Cancer Conference, October 30-November 3, 2005; Paris, France. abstract 794.

Grade 3 Hand-foot syndrome Improved to Grade 1

Hand-Foot Syndrome

*Sorafenib 400 mg bid.

Image courtesy of Laura Wood, RN, MSN, OCN.

Sunitinib (Sutent)

• Oxindole TK inhibitor • Orally bioavailable small

molecule• Selective multitarget

inhibition of:– PDGF-R– VEGF-R– Kit– Flt-3

• Plasma half-life ≈ 40 hours

NH

O

NH

F

H3C

CH3

NH

O

N

CH3

CH3

Mendel et al. Clin Cancer Res 9, 2003

Sunitinib Phase 2 Studies: Best Response by RECIST

* 1 patient with change in cancer diagnosis excluded from analysis

Motzer RJ, et al. Presented at: 4th International Kidney Cancer Symposium of the Kidney Cancer Association, October 21-23, 2005; Chicago, IL.

Response Trial 1 N (%)

Trial 2* N (%)

Patients 63 105

Overall response (OR) 25 (40) 46 (44)

Complete response (CR) 0 1 (1)

Partial response (PR) 25 (40) 45 (43)

Stable disease (SD) > 3 mos 17 (27) 24 (23)

Progression, SD < 3 mos, or not evaluable

21 (33) 35 (33)

Progression-Free Survival Trials 1 and 2 Combined

Sunitinib Therapy (Months)

Pro

po

rtio

n o

f P

atie

nts

Pro

gre

ssio

n-F

ree 1.0

0.8

0.7

0.6

0.5

0

0 9 15 18 24

0.9

0.3

0.2

0.1

0.4

3 6 12 21

Median PFS: Trial 1: 8.7 monthsTrial 2: 8.1 months

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

27

Motzer RJ, et al. Presented at: 4th International Kidney Cancer Symposium of the Kidney Cancer Association, October 21-23, 2005; Chicago, IL.

Sunitinib Phase 2 Studies: Treatment-Related Adverse Events

Incidence (%)Grade 2 Grade 3

Adverse Event Trial 1 Trial 2 Trial 1 Trial 2

Fatigue 27 17 11 11

Diarrhea 21 17 3 3 Nausea 16 13 3 0 Stomatitis 17 9 2 5

Dermatitis 6 8 2 7

LVEF Decline 9 3 2 4

Hypertension 3 10 2 6

Motzer RJ, et al. Presented at: 4th International Kidney Cancer Symposium of the Kidney Cancer Association, October 21-23, 2005; Chicago, IL.

Phase III trial of IFNA vs Sunitinib

Untreated, metastatic RCC (n=750)

Sunitinib(50 mg/day x4weeks q 6 weeks)

IFNA 9 MU TIW

Response rate 8% (P<0.001) 39%

PFS (months) 5 (P<0.001) 11

OS (months) 21.8 p=0.051 26.4

*Motzer R et al. NEJM 2007;356:115-124, Figlin ASCO 2008

*

0 3 6 9 12 15 18 21 24 27 30 33 36

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=193) Median 28.1 months (95% CI: 19.5 - NA)IFN-α (n=162) Median 14.1 months (95% CI: 9.7 - 21.1)

Hazard Ratio = 0.647(95% CI: 0.483 - 0.870)p =0.0033 (Log-rank)

Figlin et al. ASCO 2008. Abstract 5024.

Sunitinib vs. Interferon in First-Line Treatment of mRCC: OS

(Patients Received No Post-Study Treatments)

Biomarker Analysis and Final Efficacy and Safety Results of a Phase II Renal Cell Carcinoma Trial With Pazopanib

(GW786034), a Multi-Kinase Angiogenesis Inhibitor

TE Hutson,1 ID Davis,2 JH Machiels,3 PL de Souza,4 K Baker,5 L McCann,5 W Bordogna,5 JP Hodge,5 R Westlund,5

L Pandite,5 RA Figlin6

1Baylor-Sammons/Texas Oncology PA, Dallas, TX, USA; 2Austin Hospital, Melbourne, VIC, Australia; 3Centre du Cancer, Cliniques Universitaires St.-Luc, Brussels, Belgium; 4Cancer Center, St. George Hospital, Sydney, NSW, Australia; 5GlaxoSmithKline, Research Triangle Park, NC, USA; 6City of Hope National

Medical Center, Duarte, CA, USA

Original Study Design (N = 225)

IDMC Recommendations at the Interim Analysis• Based on robust clinical activity observed in the first 60 patients enrolled

– Randomization was discontinued– Patients on placebo were crossed over to pazopanib– The study continued as an open-label, single-arm study

CR = Complete response; PR = Partial response; SD = Stable disease; PD = Progressive disease; IDMC = Independent data monitoring committee.

Treatment12 weeks pazopanib 800 mg once daily

orally

CR/PR Continue pazopanib

SD

PD

RANDOMIZE

Pazopanib

Placebo

Maximum Decrease in Target Lesion Diameters: Independent Review

*Patients with non-target new lesions at the same time point as the recorded maximum decrease in sum of the longest diameters for target lesions.

Progression-Free Survival:Randomized Comparison (n = 55)

Independent Review

When the randomized phase was stopped because of IDMC recommendation, patients crossing over to open-label pazopanib were not censored.

Investigator-Assessed Treatment-Related AEs (> 10% of Patients)

Patients, n (%)(N = 225)

Any grade Grade 3 Grade 4*

Patients with any treatment-related AE, n (%)† 215 (96) 77 (34) 16 (7)

Diarrhea 133 (59) 9 (4) 0 (0)

Hair color changes 96 (43) 0 (0) 0 (0)

Hypertension 90 (40) 19 (8) 0 (0)

Nausea 83 (37) 1 (<1) 0 (0)

Fatigue 83 (37) 9 (4) 0 (0)

Dysgeusia 52 (23) 0 (0) 0 (0)

Anorexia 39 (17) 2 (<1) 0 (0)

Vomiting 33 (15) 1 (<1) 0 (0)

Alanine aminotransferase (ALT) 30 (13) 12 (5) 2 (<1)

Aspartate aminotransferase (AST) 26 (12) 7 (3) 2 (<1)

Rash 28 (12) 2 (<1) 0 (0)

Hand-foot syndrome 28 (12) 4 (2) 0 (0)

Abdominal pain 22 (10) 4 (2) 0 (0)

Alopecia (hair thinning) 23 (10) 0 (0) 0 (0)AE = Adverse event.*Two grade 5 drug-related AEs: large bowel perforation and dyspnea.†Safety data are presented on all 225 patients with a median exposure of 36 weeks (0.30 to 130 weeks); AEs led to treatment discontinuation in 15% of patients.

No Correlation Demonstrated Between VHL Status and Clinical Response

Best response assessment, n (%)

Evaluable patients*(N = 78)

Methylation or mutation(n = 70)

Wild-type (n = 8)

Complete response 1 (1) – 1 (13)

Partial response 31 (40) 29 (41) 2 (25)

Stable disease 31 (40) 28 (40) 3 (38)

Progressive disease 7 (9) 6 (9) 1 (13)

Not evaluable 8 (10) 7 (10) 1 (13)

VHL mutations or methylation found in 70 patients (90% of 78 assessed). Literature: VHL mutations ~47% to 70%.

• VHL mutations were located in Exons 1, 2, and 3 in 40%, 37%, and 23% of patients, respectively

• Types of mutations included frameshifts (48%), missense (30%), nonsense/stop (9%), splices (9%), and inframe deletions or insertions (4%)

• All except for 1 missense mutation occurred in evolutionarily conserved regions and all occurred in a domain of the protein critical for VHL function (a and b domain)

• Therefore, all amino acid changes may have a functional impact on the protein

*Patients for whom PGX data were available.

Axitinib in Cytokine-Refractory mRCC: Trial Design

• Primary end point: Response rate

• Secondary end points: Duration of response, TTP, OS, safety

Patients with mRCC (refractory to cytokine)

N=52

Axitinib:5 mg, bid, q4wks

Assess

Rini et al. Lancet Oncology 2007;8:975-84.

Single-Agent Axitinib in Cytokine-Refractory RCC Maximum Reduction in Target Lesions (ORR = 44%)

Rini et al. Lancet Oncology 2007;8:975-84.

Max

imu

m r

edu

tio

n in

tar

get

lesi

on

s

-100

-80

-60

-40

-20

0

20

Excludes 4 patients without a post-baseline scan

0

0.25

0.50

0.75

1.00

0 3 6 9 12 15 18 21 24 27 30 33

Cytokine-Refractory RCC Time to Progression (Median = 15.7 months)

N=50, excludes 12 patients without a post-baseline scan due to study withdrawal (Discontinued due to adverse events or withdrawal of consent) B.I. Rini,1 G. Wilding,2 G. Hudes,3 W.M. Stadler,4 S. Kim,5 J.C. Tarazi,5 P.W. Bycott,5 K.F. Liau,5 J.P. Dutcher6

Time (months)

Tim

e-to

-pro

gre

ssio

n p

rob

abili

ty

mTOR Inhibitors in the Treatment of Renal Cell

Cancer

mTOR Is a Novel Cancer Target

• mTOR is an intracellular serine-threonine kinase activated by mutations in cancer

• mTOR is downstream of growth factor and nutrient signalling

• mTOR is a central regulator of protein synthesis

• Everolimus and Temsorilimus are amultifunctional inhibitors of:

– cell growth and proliferation

– angiogenesis

– cancer cell metabolism (bioenergetics)

Nutrients Growth Factors

IGF, EGF, VEGF etc

PI3KPI3K

glucose, amino acids, etc

Mutations in cancer

AKTAKT

S6k eif-4e

Protein Synthesis

Growth &Proliferation

Cell Metabolism

Angiogenesis

Podsypanina K, et al. PNAS. 2001;98:10320-10325.

Licun W, et al. Cancer Res. 2005;65:2825-2831.

Temsorilimus(CCI-779, Torisel)

• Water-soluble ester of sirolimus• Novel mammalian target of rapamycin

(mTOR) kinase inhibitor• Exhibits immunosuppressive and anti-tumor

activity• Reduces tumor growth in PTEN +/- mice

Phase III Study of Temsirolimus and IFN in Advanced RCC: Study Design

Eligibility Criteria

• Histologically confirmed, measurable (RECIST) advanced (stage IV or recurrent) RCC

• No prior systemic therapy

• Karnofsky PS ≥60

• Fasting serum cholesterol ≤350 mg/dL, triglycerides ≤400 mg/dL

• Minimum of 3 poor-risk features required*

(n=207)

(n=209)

(n=210)

IFN escalating to 18 MU SC tiw

Temsirolimus25 mg IV qw

+Temsirolimus

15 mgIV qw

IFN 6 MU SC tiw

Primary end point: OS

Hudes et al. N Engl J Med. 2007;356:2271.

(N=626)

*Risk Factors• LDH >1.5 × ULN• Hgb <LLN• Corrected calcium >10 mg/dL• Time from diagnosis to first treatment <1 y• Karnofsky PS 60-70• Multiple organ sites of metastasis

RANDOMIZATION

Lam JS, et al. J Urol. 2005;173:1853-1862.

Pro

po

rtio

n S

urv

ivin

g

Years Following Systemic Therapy

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Risk factors are:• no prior nephrectomy• KPS < 80• low HGB• high corrected calcium• high LDH

0 risk factors (164 patients, 30 alive)

1 or 2 risk factors (348 patients, 23 alive)3, 4, or 5 risk factors (144 patients, 1 alive)

Survival by the Memorial Sloan-Kettering Cancer Center Risk Factor Model

Phase III Study of Temsirolimus and IFN in Advanced RCC: OS by Treatment Arm

Hudes et al. N Engl J Med. 2007;356:2271.

nMedian OS

(mo)

IFN 207 7.3

Temsirolimus 209 10.9

Temsirolimus + IFN 210 8.4

0

0.25

0.50

0.75

1.00

0 5 10 15 20 25 30 35Months

Pro

po

rtio

n s

urv

ivin

g

P=0.008 P=0.70

RAD001

Phase 2 in Metastatic RCC (Amato)

• Single-arm, 2-stage design, RAD001 10 mg/d orally (28-day cycle)– 41 patients

• Primary end point: TTP– Secondary end point: RR (RECIST, q 12 wks); OS

• Results: - 12/37 PR (32%), 14 SD (38%) > 6 months duration- PFS 11.17+ (2.00-31.53+) months - Overall survival 24.17+ months

Jac ASCO 2007, #5107

Progression Free Survival

0 10 20 30 400

25

50

75

100

Time (Months)

Perc

en

t P

rog

ressio

n F

ree

N=37

Median = 11.17+( 2.00 – 31.53+) Months

RAD001 Phase 2 in Metastatic RCC (Amato)

Jac ASCO 2007, #5107

Overall Survival

0 10 20 30 400

25

50

75

100

Time (Months)

Percen

t su

rviv

al

Median = 24.17 + Months

N = 39

RAD001 Phase 2 in Metastatic RCC (Amato)

Jac ASCO 2007, #5107

Non-Hematologic Adverse Events

0 10 20 30 40

Population (Percent)

Diarrhea

Nausea

Rash

Stomatitis

Anorexia

Vomiting

Pneumonitis

G3

G2

G1

RAD001 Phase 2 in Metastatic RCC (Amato)

Jac ASCO 2007, #5107

60

Late-Breaking Abstract # 5026

RECORD-1: RAD001 (Everolimus) + Best Supportive Care (BSC) vs BSC + Placebo in Pts With Metastatic RCC After Progression

on VEGFr-TKI Therapy

R. Motzer, B. Escudier, S. Oudard, C. Porta, T. Hutson, S. Bracarda, R. Figlin, J. Thompson,

V. Grünwald, N. Hollaender, G. Urbanowitz, A. Kay, A. Ravaud, for the RECORD-1 Study Group

Supported by Novartis Pharmaceuticals

Key Eligibility Criteria

• Metastatic RCC with clear cell component

• Measurable disease

• Progressive disease on or within 6 mos of treatment with sunitinib, sorafenib, or both

• Prior bevacizumab and cytokines permitted

• Adequate performance status, blood counts and serum chemistry

Study Conduct

• 410 patients randomized September 2006 and October 2007

• Second interim analysis cut-off: October 15, 2007, based on 191 PFS events

• Independent Data Monitoring Committee recommended termination of study

RRAANNDDOOMMIIZZAATTIIOONN

2:12:1

Placebo + BSC(n = 138)(n = 138)

Upon Disease Progression

Interim analysis

Interim analysis

N = 410

Stratification

• Prior VEGFrTKI: 1 or 2

• MSKCC risk group: favorable, intermediate,

or poor

=Finalanalysis

Everolimus + BSC(n = 272)(n = 272)

Progression-Free Survival by Treatment Central Radiology Review

Patients at Risk Everolimus 272 132 47 8 2 0 0 Placebo 138 32 4 1 0 0 0

100

80

60

40

20

0

0 2 4 6 8 10 12

Pro

bab

ility

, %

Hazard ratio = 0.30 95% CI [0.22, 0.40]

Median PFSEverolimus: 4.0 moPlacebo: 1.9 mo

P value < 0.001 Everolimus (n = 272) Placebo (n = 138)

Months

Subgroup Analysis of Progression-Free Survival Central Radiology Review

1. Motzer et al. J Clin Oncol. 2004;22:454-463.

HR NCentral Review 0.30 410Investigator Review 0.31 410MSKCC RiskFavorable 0.35 118Intermediate 0.25 231Poor 0.39 61Prior TxSorafenib Only 0.29 119Sunitinib Only 0.30 184Both 0.28 107Age< 65 yrs 0.32 259≥ 65 yrs 0.29 151SexMale 0.29 317Female 0.36 93RegionU.S. & Canada 0.24 130Europe 0.37 251Japan & Australia 0.10 29

0 0.4 1.0 1.4

Hazard Ratio

Everolimus benefit Placebo benefit

1.20.80.60.2

1

−100%

−75%

−50%

−25%

0%

25%

50%

75%

100%

Best Response n (%)

PR 3 (1) Stable 171 (63) PD 53 (20) NE 45 (16)

Best Response n (%)

PR 0 Stable 44 (32) PD 63 (46) NE 31 (22)

Maximum % Change in Target Lesions and Objective Response Rate*Everolimus Placebo

NE = not evaluable

* Central Radiology Review

Treatment-Related Adverse Events*

Everolimus%, (n = 269)

Placebo%, (n = 135)

All Grades Grade 3 All Grades Grade 3

Stomatitis† 40 3 8 0

Asthenia / fatigue 37 3 24 1

Rash 25 < 1 4 0

Diarrhea 17 1 3 0

Anorexia 16 < 1 6 0

Nausea 15 0 8 0

Mucosal inflammation 14 1 2 0

Vomiting 12 0 4 0

Cough 12 0 4 0

Edema peripheral 10 0 3 0

Infections† 10 3 2 0

Pneumonitis† 8 3 0 0

Dyspnea 8 1 2 0

*≥ 10% of everolimus patients and additional selected AEs.†Significant difference between sum of grade 3/4 events for everolimus and placebo groups (P < .05) .

Overall Survival by Treatment

Hazard ratio = 0.8395% CI [0.50, 1.37]

Median OSEverolimus: not reachedPlacebo: 8.8 mo

Log rank P value = 0.233 Everolimus (n = 272)Placebo (n = 138)

81% of pts with PD on placebo crossed-over to everolimus

100

80

60

40

20

0

0 2 4 6 8 10 12

Pro

bab

ility

, %

MonthsPatients at Risk Everolimus 272 229 126 61 9 1 0 Placebo 138 111 62 25 9 1 0

Outcome Summary

End Point Everolimus Placebo

Median PFS, mo (95% CI) 4.0 (3.7, 5.5) 1.9 (1.8,1.9)

Hazard ratio (95% CI) 0.30 (0.22, 0.40)

6 Month PFS 26% 2%

Benefit across all subgroups

MSKCC risk1 Yes —

Prior VEGFr-TKI Yes —

Secondary end points

Safety Acceptable —

Patient-reported outcomes Acceptable —

1. Motzer et al. J Clin Oncol. 2004;22:454-463

Adjuvant Immunotherapy

• Two large randomized clinical trials of interferon vs placebo and IL-2 vs placebo in high risk resected disease failed to show a survival benefit to adjuvant immunotherapy

Intergroup Adjuvant TrialArms/Regimens:Patients minimum 6 weeks post radical nephrectomy will be randomized to receive Arm A Nexavar 400mg po BID versus Arm B

Sutent 50 mg qd for 28days q 6weeks vs Arm C placebo, All for 12 months

StratifyDisease Stage: II T2 Grade 3,4III T1,N1, M0T2,N1,M0T3aN0-1, M0T3bN0-1,M0T3cN0-1,M0IV T4 anyN M0

AnyT, N2,M0Histologic SubtypeClear cellNon-clear cell 

Arm A Sorafenib (Nexavar)

Arm C Placebo

Randomize

Arm B Sunitinib (Sutent)

Standards for RCC Therapy by Phase III Trial

ASCO 2008

Setting Phase III

Treatment- naive

Good or intermediate risk*

Sunitinib

Bevacizumab + IFN-α

Poor risk* TemsirolimusSunitinib

Previously treated

Prior cytokine Sorafenib

Prior VEGFr-TKI Everolimus

Prior mTOR inhibitor

*MSKCC risk status.