Metastatic Renal Cell Carcinoma What’s Hot In The Treatment Of Renal Cell Carcinoma And Is There Hope?

Cora N. Sternberg, MD, FACP

Chairman, Department of Medical OncologySan Camillo and Forlanini Hospitals

Rome, Italy

Metastatic Kidney Cancer: Options

• Interferon- for good risk patients until recently

• HD-IL-2 for intermediate and good risk patients.

–Limited availability

–Intensive treatment

–Of value (long lasting CR) for a small group of patients

–Patient selection required

• Poor risk patients: no proven therapeutic options until recently

• Second line: no proven therapeutic options until recently

Treatment of Metastatic Kidney Cancer

• Has our perception of RCC been changed with the advent of new drugs?

• Can we commute a death sentence to a chronic disease that patients can learn to live with?

• How have traditional criteria to measure response with cytotoxics led us astray?

• Can we afford these expensive promising new treatments?

Mancuso and Sternberg, BJU Int. Jun 2005Mancuso and Sternberg, Can J Urol. Feb 2005

Von Hippel-Lindau Suppressor Gene Inactivated in > 75% Sporadic RCC

pVHL HIF=

VEGFangiogenesis

TGFaPDGF

periocytes

KDR EGFRPDGFR

degradation of hypoxia inducibleSuppressor gene

Sunitinib, SorafenibAG13736,Vatalanib

Sunitinib, SorafenibImatinib

Sunitinib, SorafenibCCI-779

Bevacizumab,VEGF TRAP

Regulated by hypoxia; NoHIF1-breakdown

autocrine growth factors

mTOR inhib, HSP 90 inhib

Critical Cofactor in the Ubiquitin Ligase Complex

VEGF-B

VEGF-A

VEGF-E

VEGF-C

VEGF-D

Bevacizumab binds VEGF A

• The vascular endothelial growth factor (VEGF) family are critical tumor secreted signaling molecules that stimulate angiogenesis and lymphangiogenesis

• There are five members of the VEGF family (VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E)

The VEGF Family Are Critical Tumor-Secreted Angiogenic Factors

Time to ProgressionHigh-Dose Ab vs. Placebo

Yang, NEJM 2003

4.8 mos

2.5 mos

(RR= 10%)

Survival Update

Yang, NEJM 2003

CALGB 90206: Randomized Phase III Trial of IFNα or IFNα + Bevacizumab in Advanced RCC (n=700)

IFNα 9MU TIW

IFNα 9MU TIW + Bevacizumab 10 mg/KG

D1 and D15

VS

RANDOMI ZE

1° Endpoint: Survival, 89% Power to Detect Improvement in OS of 13 to 17 mos

No prior Rx

Stratify Motzer Score

Europe: Randomized Phase III Trial of IFNα or IFNα + Bevacizumab in Advanced RCC (n=638)

IFNα 9MU TIW + placebo

IFNα 9MU TIW + Bevacizumab 10 mg/KG D1 and D15

VS

RANDOMI

ZE

1° Endpoint: Survival, 80% Power to Detect Improvement in OS of 13 to 17 mos

NephrectomyClear Cell

> 50%

Sunitinib Mechanism of Action in RCC

Inhibition of RCC pathogenesis and progression

↑ VEGF ↑ PDGF

Vascularpermeability

Cell survival, proliferation, migration

Vascularformation, maturation

Loss of VHL Protein Function

VEGFR PDGFRVEGF PDGFPDGF

Vascular Endothelial CellPericyte/Fibroblast/

Vascular Smooth Muscle

Sunitinib

Best Response By RECIST

ResponseTrial 1n (%)

Trial 2n (%)

Patients 63 106

Overall response Complete response Partial response

25 (40) 0

25 (40)

44 (42) 1 (1)

43 (41)

Stable disease (SD) 3 months 18 (28) 22 (21)

Progression, SD <3 months 16 (25) 33 (31)

Not evaluable 4 (6) 7 (7)

Motzer R ,J Clin Oncol. 2006 Jan 1;24(1):16-24 Motzer R, JAMA. 2006 Jun 7;295(21):2516-24

Two Types of Response Observed

Week32

1-Shrinkage 2-Central Necrosis

Week0

Week12

Phase 3 Randomized Trial of Sunitinib malate (SU11248) versus Interferon-alfa as First-line Systemic Therapy for

Patients with Metastatic Renal Cell Carcinoma

N=750

Stratification Factors

● LDH 1.5 vs >1.5xULN

● ECOG PS 0 vs 1

● Presence vs Absence of Nephrectomy

RANDOMIZATION

Sunitinib(N=375)

IFN-(N=375)

90% power to detect a 35% improvement in median PFS from 20 weeks to 27 weeks (4.6 months to 6.2 months; 2-sided unstratified log-rank test; significance level 0.05)

Pre-planned analysis of primary endpoint PFS

Motzer R, ASCO 2006

Outcome Summary

Sunitinib IFN-

Median Progression-freeSurvival*, mos (95% CI) Independent Review Investigator

11 (10-12)11 (8-14)

5 (4-6)4 (4-5)

Objective response*, % (95% CI) Independent Review Investigator

31 (26-36)37 (32-42)

6 (4-9)9 (6-12)

Safety Acceptable —

Patient-reported Outcomes Superior —

*Sunitinib vs IFN-: P <0.000001

No. at Risk Sunitinib: 235 90 32 2No. at Risk IFN-: 152 42 18 0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14Time (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

ab

ilit

y

SunitinibMedian: 11 months(95% CI: 10–12)

IFN- Median: 5 months(95% CI: 4–6)

Hazard Ratio = 0.415(95% CI: 0.320–0.539)P <0.000001

(Independent Central Review)

Progression-Free Survival

No. at Risk Sunitinib: 341 190 84 15 1No. at Risk IFN-: 296 162 66 10 0

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

abil

ity

Sunitinib (n=375)Median not reached

IFN- (N=375)Median not reached

Hazard Ratio = 0.65(95% CI: 0.449–0.942)P = 0.0219*

*The observed p-value did not meet the pre-specified level of significance for this interim analysis

Overall Survival

Laboratory Abnormalities

Sunitinib (%) IFN- (%)

Event All grade Grade 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*

Hypophosphatemia 36 4/<1 32 6

Hyperamylasemia 31 4/1* 28 2/<1

* Greater frequency, P <0.05

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

Hand-foot syndrome 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* Greater frequency, P <0.05

Motzer R, ASCO 2006

Conclusions

•Sunitinib is a new reference standard for the first-line treatment of RCC

•Mechanism-directed RCC therapy based on tumor-specific molecular features is validated

•Sunitinib is a new treatment option providing hope for patients with RCC

Global ARCC Trial

A Phase 3, Randomized, 3-Arm Study of Temsirolimus (TEMSR) or Interferon-Alpha (IFN) or the Combination of TEMSR + IFN in the Treatment

of First-Line, Poor-Risk Patients With Advanced Renal Cell Carcinoma

G Hudes, M Carducci, P Tomczak, J Dutcher, R Figlin, A Kapoor, E Staroslawska, T O’Toole,

S Kong, and L Moore

2006 ASCO Presentation

Temsirolimus: Mechanism of Action

PI-3 KinasePI-3 Kinase

AAktkt

mTOR

PTENPTEN

S6KS6K 4EBP14EBP1

HIF-1, HIF-2overexpression

PTENLoss

TranslationTranslation

PI-3K/AKTActivation

cMycoverexpression

extracellularmembrane

Cyclin D1Cyclin D1overexpressionoverexpression

TemsirolimusTemsirolimus

GrowthGrowth FFactorsactors

• 626 patients with advanced metastatic RCC with poor-risk features

• 209 sites (26 countries)

Stratificationby:

Geographic Regions:• WEU + AU + CA (22%)• US (30%)• EEU + Other (48%)

Nephrectomy:• Yes (67%)• No (33%)

Global ARCC Trial

RANDOMIZE

IFN: escalating to 18 MU SC TIW

TEMSR: 25 mg IV QW

TEMSR: 15 mg IV QW

+ IFN: 6 MU TIW

n = 207

n = 209

n = 210

Phase 3 Study of TEMSR and IFN in Advanced RCC

Overall Survival by Treatment Arm

Arm 3: IFN + Temsirolimus

Arm 2: Temsirolimus

Arm 1: IFN

Time from Randomization, Months

Pro

bab

ilit

y o

f S

urv

ival

Parameter IFN Arm 1

TEMSR Arm 2

TEMSR + IFN Arm 3

n 207 209 210

Comparisons Arm 2:Arm 1 Arm 3:Arm 1

Stratified Log-Rank p 0.0069 0.6912

IFNArm 1n=207

TEMSRArm 2n=209

TEMSR + IFNArm 3n=210

Deaths, n 149 141 152

Median Survival, months(95% CI)

7.3(6.1 - 8.9)

10.9(8.6 - 12.7)

8.4(6.6 - 10.2)

Arm 2: Arm 1 Arm 3: Arm 1

Increase inMedian Survival 49% 15%

Hazard Ratio

(95% CI)

0.73

(0.57 - 0.92)

0.95

(0.76 - 1.2)

Stratified Log-Rank p 0.0069* 0.6912

Overall Survival by Treatment Arm

*O’Brien-Fleming boundary for significance = 0.0155

Global ARCC Trial

•This is the first study to demonstrate a

statistically significant improvement in

survival in advanced poor-risk RCC patients

•The results of this global phase 3 trial

demonstrate that mTOR is an important

therapeutic target in RCC

Global ARCC Trial

Ras

P P

P P

GF

Raf kinase

MEKP

ERKP

NucleusNucleus

BAY 43-9006

Sorafenib (BAY 43-9006)

Potent inhib c-RAF Other targets: - VEGFR-2 - VEGFR-3- FLT-3- PDGFR - c-kit

Inhibits survival of tumor cells Targets proliferation + angiogenesis

* 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, ASCO 2005

Eisen T, Br J Cancer. 2006 Sep 4;95(5):581-6

Sorafenib (BAY 43-9006)Randomized Discontinuation Trial Schema (n=202)

Sorafenib400 mg bidSorafenib

400 mg bid

PlaceboPlacebo

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

Escudier, ASCO and ECCO 2005

Treatment Approaches in RCC Global Evaluation Trial

TARGETs: Pretreated Patients Study Design

*Independently assessed measurements available for 574 patients

Placebo Sorafenib

74%20%

Max

imum

Per

cent

Red

uctio

n in

Tum

or M

easu

rem

ent

-100

-80

-60

-40

-20

0

20

40

60

80

100

Patient number

50 100 150 200

250

Patient number

50

100 150 200 250

Maximum Percent Reduction in Tumor Measurement*

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

*Based on investigator assessment Escudier, ECCO, October 2005

5.5 mos2.8 mos

TARGETsProgression-Free Survival Benefit

*At 367 events, Nov. 30, 2005**O’Brien-Fleming stopping boundary for significance was p<0.0094

Time from randomization ( months)0 5 10 2515 20

0

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 = 0.015**

Of 367 events, a total of 122 deaths were reported

in the low-risk and 245 in the intermediate-risk groups

Eisen T, ASCO 2006

Overall Survival Analysis 6 Months Post-crossover*

Pazopanib Preclinical Summary

•Potent Multi-target tyrosine kinase inhibitor

•Selectively inhibits

•VEGFR-1, 2 and 3

•PDGFR- and -

•c-kit

•IC50 of 10, 30, 47, 71, 84 and 74 nM

respectively (high affinity for all receptors)

Pazopanib 800mg qd

Matching Placebo

RANDOMIZE

1° Endpoint PFS, 2° survival and RR

2:12:1

Pazopanib Phase III Trial (VEG105192) Design (n=350)

EligibilityPrior cytokines*

StratificationECOG PS 0 vs 1Prior nephrectomy

Adjuvant Therapy

• ASSURE trial (n=1,332) Intergroup ECOG. After nephrectomy patients are stratified by UISS stage (II-V) and histologic subtype (clear cell or nonclear cell) among 3 arms to 1 year of adjuvant sunitinib, sorafenib or placebo. The primary endpoint is disease free survival.

• SOURCE trial (n = 1,420), MRC. After nephrectomy, patients with high- and intermediate-risk RCC will be randomized to 3 years of sorafenib, 1 year of sorafenib and 2 years of placebo, or 3 years of placebo. The primary endpoint is metastases free survival.

Unaddressed Questions

•Is any one agent better than the other?–Are they cross-resistant?–Are the studied doses/schedules optimal?

•Can combination therapy improve outcome?•Can novel imaging modalities identify

“benefiting” patients?•What is the role of these agents in the

adjuvant setting?

•What is the role of these agents in non-clear cell RCC?

What’s Hot in the Treatment of Renal Cell Carcinoma and is there Hope?

•Oral VEGFR/PDGFR and mTOR inhibitors are extremely active in clear cell RCC

•They are much better tolerated than IFN or IL2 but there is toxicity associated with these agents

•These agents have changes how we treat this disease

•Complete responses are extremely rare and

the vast majority of patients eventually progress

• Strong rationale for targeting multiple pathways Strong rationale for targeting multiple pathways

particularly angiogenesis in patients with particularly angiogenesis in patients with

advanced RCCadvanced RCC

• Novel signal transduction inhibitors have Novel signal transduction inhibitors have

demonstrated an increase in PFS in 1demonstrated an increase in PFS in 1stst and 2 and 2ndnd line line

and an increase in survival in poor risk therapy and an increase in survival in poor risk therapy

naive patients naive patients

• Some of these agents have been recently Some of these agents have been recently

approved and others are still awaiting trial results approved and others are still awaiting trial results

• They are defining a new standard of care They are defining a new standard of care

What’s Hot in the Treatment of Renal Cell Carcinoma and is there Hope?