54,390 estimated new cases of RCC 13,010 estimated deaths. Incidence is increasing 2.0% per year

(1)

1

Advanced Renal Cell Carcinoma

Individualizing Treatment Selection

in the Era of Targeted Therapy

2

Renal Cell Carcinoma

¾

In the United States in 2008:

–

54,390 estimated new cases of RCC

–

13,010 estimated deaths

¾

Median age at onset: 65 years

¾

Incidence is increasing 2.0% per year

¾

For mRCC:

–

Median survival: 10.9-26.4 months

–

20%-30% of patients present with mRCC

–

20%-40% of patients will develop mRCC after nephrectomy

National Cancer Institute. Renal Cell Cancer Treatment (PDQ®). Available at http://www.cancer.gov/

cancertopics/pdq/treatment/renalcell/HealthProfessional/page2. Accessed July 16, 2008; Lam JS, et al. J Clin Oncol. 2006;24:5565-5575; SEER Stat Fact Sheets-Cancer of Kidney and Renal Pelvis. Available at: http://seer.cancer.gov/statfacts/html/kdrp. Accessed July 16, 2008; Figlin RA, et al. 2008 ASCO Annual Meeting; Abstract 5024; Hudes G, et al. N Engl J Med. 2007;356:2271-2281.

(2)

3

RCC: Histologic Subtypes

Linehan WM, et al. J Urol. 2003;170:2163-2172. Copyright American Urological Association 2003.

Type

Frequency

Gene

Clear cell

75%

VHL

Papillary type 1

5%

c-Met

Papillary type 2

10%

FH

Chromophobe

5%

BHD

Oncocytoma

5%

BHD

c-MET = hepatocyte growth factor receptor; BHD = Birt-Hogg-Dubé; FH = fumarate hydratase; VHL = von Hippel Lindau.

4

VHL Protein:

Normal and Aberrant Function

VHL Protein:

Normal and Aberrant Function

Rini BI, et al. J Clin Oncol. 2005;23:1028-1043. Reprinted with permission from the American Society of Clinical Oncology. HIF = hypoxia-inducible factor; hp = hydroxyproline; PDGF = platelet-derived growth factor; VEGF = vascular

endothelial growth factor.

Hypoxia or Abnormal

VHL Protein Function

Induction of hypoxia-inducible genes (eg, VEGF, PDGF) Constitutively expressed HIFα

translocates into the nucleus VHL Protein

HIFα

HIFα HIFβ Proteasome

Normoxia and Normal

VHL Protein Function

Ubiquitin attachment HIFα degradation VHL Protein hp

HIFα

(3)

5

Signaling Pathways and

Selective Inhibitors

Signaling Pathways and

Selective Inhibitors

Rini BI, et al. J Clin Oncol. 2005;23:1028-1043, modified with permission from the American Society of Clinical Oncology; Patel PH, et al. Br J Cancer. 2006;94:614-619; Motzer RJ, et al. J Clin Oncol. 2006;24:5601-5608; Phung TL, et al. Cancer Cell. 2006;10:159-170.

Vascular

permeability

Sorafenib

Bevacizumab

Akt PI3-K MAPK Raf MEK Erk

VEGFR-2

P P P P

EC

survival

EC

migration

EC

proliferation

VEGF VEGF

Sorafenib

Sunitinib

EC

Sorafenib

Akt PI3-K Raf MEK Erk

Growth factor

receptor

P P P P

Sorafenib

Sunitinib

mTOR

Tumor

proliferation

↑ HIF1α expression

Temsirolimus

Everolimus

Growth Factor

(eg, PDGF, TGFα, EGF)

Tumor Cell

EC = endothelial cell; EGF = epidermal growth factor; Erk = extracellular receptor kinase; MAPK = mitogen-activated protein kinase; MEK = mitogen and extracellular kinase; PI3-K = phosphoinositide 3-kinase; TGF = transforming growth factor.

mTOR

Temsirolimus

Everolimus

6

mTOR = mammalian target of rapamycin; PTEN = phosphatase and tensin homolog. Atkins MB. ASCO 2006 Plenary session; Patel PH, et al. Br J Cancer. 2006;94:614-619; Motzer RJ. J Clin Oncol. 2006;24:5601-5608.

PI3-K

Akt

PTEN

S6K

4E-BP1

Translation

Extracellular

membrane

Growth Factors

Temsirolimus, everolimus

Cell division

Cell proliferation

Angiogenesis

PI3-K/Akt

activation

PTEN

loss

mTOR

mTOR Pathway

(4)

7

RCC Staging: Rationale

¾

Predict tumor behavior

–

Patient prognosis

¾

Stratify patients into risk categories

–

Predict disease recurrence and cancer-related death

¾

Select treatment approach

–

Choose therapy based on the expression of the target by

the tumor

–

Predict response to therapy

–

Minimize unnecessary exposure to treatment toxicity

¾

Inclusion criteria for clinical trials

Leppert JT, et al. BJU Int. 2007;99:1208-1211.

8

Factors Predicting Prognosis in RCC

Anatomic

¾

Tumor size

¾

Metastasis

¾

Venous

involvement

¾

Lymph node

involvement

Histologic

¾

Fuhrman grade

¾

Morphology

¾

Microvascular

invasion

¾

Tumor necrosis

Clinical

¾

PS

¾

Cachexia-related

symptoms

¾

Thrombocytosis

Shuch BM, et al. Semin Oncol. 2006;33:563-575. PS = performance status.

(5)

9

Poor Risk Factors in Advanced

Untreated RCC: MSKCC and CCF Criteria

Poor Risk Factors in Advanced

Untreated RCC: MSKCC and CCF Criteria

Motzer RJ, et al. J Clin Oncol. 2002;20:289-296; Motzer RJ, et al. J Clin Oncol. 2004;22:454-463; Mekhail TM, et al. J Clin Oncol. 2005;23:832-841.

>10.0 mg/dL

Corrected serum

calcium

Yes

Prior radiotherapy

<LLR

Hemoglobin

>1.5 x ULR

LDH

CCF Criteria 2005

Yes

Presence of hepatic,

lung, or retroperitoneal

lymph node metastases

<12 months

Time from diagnosis to

treatment with IFN-α

<80%

KPS

<LLR

Hemoglobin

>1.5 x ULR

LDH

MSKCC Criteria 2002

>10.0 mg/dL

Corrected serum

calcium

<12 months

Time from diagnosis to

treatment with IFN-α

CCF = Cleveland Clinic Foundation; IFN = interferon; KPS = Karnofsky PS; LDH = lactate dehydrogenase; LLR = lower limit of laboratory’s reference range; MSKCC = Memorial Sloan-Kettering Cancer Center; ULR = upper limit of laboratory’s reference range.

10

Number of Risk Factors and RCC Prognosis

¾

0 risk factor = favorable risk

¾

1-2 risk factors = intermediate risk

¾

≥3 risk factors = poor risk

(6)

11

RCC: Current NCCN Treatment Paradigm

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: kidney cancer. V.1.2008. http://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf. Accessed 01/14/2008. *Category 1

†_{Selected patients}

‡_{Category 1 following cytokine therapy and category 2A following TKI} §_{Category 2A following cytokine therapy and category 2B following TKI} ¶_{Category 2B.}

CRN = cytoreductive nephrectomy; IL-2 = interleukin-2; NCCN = National Comprehensive Cancer Network; TKI = tyrosine kinase inhibitor.

First Line

Clinical trial

Sunitinib*

Temsirolimus

(poor prognosis

patients)*

Bevacizumab + IFN

High-dose IL-2

†

Sorafenib

†

Best supportive care

Nephrectomy +

metastasectomy or

CRN

(if unresectable,

proceed to first-line

systemic therapy)

Observation or consider adjuvant

therapy in a clinical trial

Relapse

Stage I/II/III

Surgical

_excision

Second Line

Clinical trial

Sorafenib

‡

Sunitinib

‡

Temsirolimus

§

IFN

¶

High-dose IL-2

¶

Low-dose IL-2 ± IFN

¶

Bevacizumab

¶

Best supportive care

Stage IV

(metastatic)

12

RCC: Challenges and Innovations

¾

Cytokine-based therapy insufficient for mRCC

–

IFN-α

• Response rate: ~15% (CR: 2%)

• Response duration: 6-7 months

–

High-dose IL-2

• Response rate: ~15% (CR: 7%)

• Response duration: 54 months

• Toxic, expensive, limited accessibility

¾

Prognostic and predictive factors

–

Risk stratification

–

Individualized therapy

¾

Better understanding of RCC biology is leading to the

development of new therapeutics

Patel PH, et al. Br J Cancer. 2006;94:614-619; Atkins MB, et al. Clin Cancer Res. 2004;10:6342s-6346s; Leppert JT, et al. BJU Int. 2007;99:1208-1211.

(7)

13

First-Line Therapy in Metastatic RCC

14

Sunitinib vs IFN-

α: Study Design

Sunitinib vs IFN-

α: Study Design

N = 750

Eligibility Criteria

Clear cell histology

No prior

systemic treatment

ECOG PS 0 or 1

Measurable disease

R

A

N

D

O

M

I

Z

A

T

I

O

N

Sunitinib

50 mg PO QD

Schedule 4/2

(n = 375)

IFN-

α

9 MU SC tiw

(n = 375)

(8)

15

First-Line Sunitinib vs IFN-α: PFS and Response

Rate by Independent Central Review

First-Line Sunitinib vs IFN-α: PFS and Response

Rate by Independent Central Review

PFS = progression-free survival.

Motzer RJ, et al. N Engl J Med. 2007;356:115-124. Motzer RJ, et al. 2007 ASCO Annual Meeting; Abstract 5024.

0 5 10 15 20 25 30 35 Sunitinib IFN-α O b je ct ive Re sp o n se Ra te ( % ) Treatment

31%

6%

0 2 4 6 8 10 14 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Months PFS Hazard Ratio = 0.42; 95% CI (0.32–0.54); P<0.001 Sunitinib IFN-α 1 3 5 7 9 11 12 13 Sunitinib (n = 375) Median: 11.0 months (95% CI: 10.0-12.0) IFN-α (n = 375) Median: 5.0 months (95% CI: 4.0-6.0) Sunitinib (n = 375) IFN-α (n = 375) P<0.001 Patients at Risk (n) Sunitinib 375 235 90 32 2 IFN-α 375 152 42 18 0 16

Sunitinib vs IFN-

α: Final Overall Survival

Sunitinib vs IFN-

α: Final Overall Survival

Sunitinib (n = 375)

Median: 26.4 months

(95% CI: 23.0 - 32.9)

IFN-α (n = 375)

Median: 21.8 months

(95% CI: 17.9 - 26.9)

Total Death

Sunitinib 190

IFN-

α

200 Total Death

Sunitinib 190

IFN-α

200

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 Ov

er

al

l S

u

rv

ival Probability

Hazard Ratio = 0.821

(95% CI: 0.673 - 1.001)

P

= 0.051 (Log-rank)

(9)

17

First-Line Sunitinib vs IFN-α:

Treatment-Related AEs

First-Line Sunitinib vs IFN-α:

Treatment-Related AEs

Motzer RJ, et al. N Engl J Med. 2007;356:115-124.

Patients (%)

0

34

1

7 Pyrexia

1

3

2

10 Ejection Fraction

Decline

0

1

5

20 Hand-Foot

Syndrome

1

8

24 Hypertension

1

2

1

25 Stomatitis

1

33

3

44 Nausea

0

12

5

53 Diarrhea

12

51

7

51 Fatigue

Grade 3/4

Grades

All

Grades

Event

IFN-α (n = 375)

Sunitinib (n = 375)

18

Sorafenib vs Interferon First-Line:

Phase 2 Results

Sorafenib vs Interferon First-Line:

Phase 2 Results

Progres

sion

Progres

sion

N = 65 with PD

N = 56 with PD

¾

5% OR

¾

68% with tumor

shrinkage

¾

PFS 5.7 months

¾

9% OR

¾

39% with tumor

shrinakge

¾

PFS 5.6 months

Adapted from Szczylik C, et al. 2007 ASCO Annual Meeting; Abstract 5025.

PD = disease progression; OR = objective response (complete + partial response); MU = million unit.

Sorafenib

400 mg po bid

(n = 97)

IFN

9 MU tiw

(n = 92)

(10)

19

N = 626

Eligibility Criteria

Phase 3 Trial: Temsirolimus vs IFN-α in

First-Line Treatment of Poor-Risk mRCC

Phase 3 Trial: Temsirolimus vs IFN-α in

First-Line Treatment of Poor-Risk mRCC

Hudes G, et al. N Engl J Med. 2007;356:2271-2281.

¾

Previously untreated mRCC

¾

Poor prognosis (≥3 predictors of

poor risk):

• LDH >1.5 × ULN

• Hemoglobin <LLN

• Corrected calcium >10 mg/dL

• Diagnosis to first treatment <1 year

• KPS 60-70

• Multiple organ sites of metastasis

Temsirolimus 25 mg IV weekly

(n = 209)

IFN-α escalating to 18 MU SC tiw

(n = 207)

Temsirolimus 15 mg IV weekly +

IFN-α 6 MU SC tiw

(n = 210)

LLN = lower limit of normal; ULN = upper limit of normal; OS = overall survival.

¾

Randomized, international multicenter trial

¾

All histologies included

¾

Primary end point: OS

¾

Treatment continued until PD, toxicity, or symptom deterioration

20

First-Line Temsirolimus vs IFN-

α:

OS by Treatment Arm

First-Line Temsirolimus vs IFN-

α:

OS by Treatment Arm

Arm 3: Temsirolimus + IFN-α

(n = 210)

Arm 2: Temsirolimus (n = 209)

Arm 1: IFN-α (n = 207)

Time From Randomization (months)

Pr obab ilit y of Sur vi val 1.00 0.75 0.50 0.25 0.00 0 5 10 15 20 25 30 35

P

= 0.008; IFN-α vs temsirolimus

P

= 0.70; IFN-α vs IFN-α + temsirolimus

Patients at Risk (n)

IFN-α 207 126 80 42 15 3 0

(11)

21

Temsirolimus vs IFN-α in First-Line, Poor-Risk

mRCC: Correlation With Survival

Temsirolimus vs IFN-α in First-Line, Poor-Risk

mRCC: Correlation With Survival

Histology Clear cell Other 287 129 115 301 Age <65 Years ≥65 Years Prognostic Risk Intermediate Poor Subgroup N HR (95% CI) 339 73

Dutcher JP, et al. 2007 ASCO Annual Meeting; Abstract 5033.

0.0 0.5 1.0 1.5 2.0

Temsirolimus Better IFN-α Better

22

First-Line Temsirolimus vs IFN-

α:

Selected Adverse Events

First-Line Temsirolimus vs IFN-

α:

Selected Adverse Events

Hudes G et al. N Engl J Med. 2007;356:2271-2281.

Stomatitis

Anemia

Dyspnea

Rash

Diarrhea

Nausea

Asthenia

Temsirolimus

IFN-

α

Any Grade 3/4

Hyperlipidemia

Hyperglycemia

Neutropenia

67 NA

78 NA

1

20

0

4

20

45

22

42

3

27

1

14

11

26

2

11

3

14

1

10 Creatinine Increase

3

7

12

27

28

47

37

51

All Grades

20

24

6

41

64

All Grades Grade 3/4 Grade 3/4

9

6

4

0

1

2

4

11

26 Adverse Event

Patients (%)

P= 0.02

(12)

23

AVOREN: Study Design

¾

End Points

–

Primary: OS

–

Secondary: PFS, time to progression, time to failure, relapse rate, safety

IFN-α + bevacizumab

10 mg/kg IV q 2w until

progression

(n = 327)

IFN-α 9 MU SC tiw (maximum

52 weeks; dose reduction

allowed) + placebo

(n = 322)

N = 649

Eligibility Criteria

Nephrectomized patients

with advanced RCC

Stratification:

Country

MSKCC risk group

1:1

Escudier B, et al. Lancet. 2007;370:2103-2111.

24

Median PFS

Bevacizumab + IFN-

α 2a = 10.2 mo

IFN-

α 2a + placebo = 5.4 mo

HR = 0.63, P<0.0001

Probabil

it

y o

f Being

Progression

Fre

e

AVOREN: Investigator-Assessed PFS

Time (months)

0

6

12

18

24

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

5.4

10.2

(13)

25

AVOREN: PFS Is Maintained With

Bevacizumab + Lower-Dose IFN

AVOREN: PFS Is Maintained With

Bevacizumab + Lower-Dose IFN

Melichar B, et al. Ann Oncol. 2008 April. [Epub ahead of print.]

0

3

6

9

12

15

18

21

24 Time (months)

Bevacizumab + lower-dose IFN = 13.6 months

All bevacizumab + IFN patients = 13.5 months

Probabil

it

y o

f Being

Progression

Fre

e

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0 Median PFS

26

Bevacizumab + IFN: PFS Benefit Observed in

All Subgroups

Bevacizumab + IFN: PFS Benefit Observed in

All Subgroups

0.2 0.5 1 2 5

Total (n)

HR

Baseline Risk Factor

HR

All patients 649 0.63

CL_CR

Low 191 0.65

High/normal 131 0.60

VEGF levels above median

No 191 0.45 Yes 191 0.67 MSKCC risk score Favorable 180 0.60 Intermediate 363 0.55 Poor 54 0.81 RCC histology Clear cell 564 0.64 Mixed 85 0.53

(14)

27

Bevacizumab + IFN: AEs in Total Study

Population

Bevacizumab + IFN: AEs in Total Study

Population

1

2

3

4

7

22 Grades 3/4

Patients (%)

All Grades

Grades 3/4

All Grades

<1

0

1 <1

<1

2

0

15

1

23

3

12

33

26

7

18

65 Bevacizumab + IFN

(n = 337)

<1

0

16 <1

10

9

7

3

55 IFN + Placebo

(n = 304)

ATE

GI perforation

Headache

Venous thromboembolism

Depression

Bleeding

Hypertension

Neutropenia

Proteinuria

Fatigue/asthenia

Event

Escudier B, et al. Lancet. 2007;370:2103-2111.

GI = gastrointestinal; ATE = arterial thromboembolic event.

28

Prospective Trials of Targeted Agents in

Untreated Patients With RCC

Prospective Trials of Targeted Agents in

Untreated Patients With RCC

NA Phase 3: Sunitinib vs pazopanib

Sunitinib

360 Phase 2: RAD001 + bevacizumab vs IFN + bevacizumab RAD001 + Bevacizumab 5.5 months 10.2 months 5.7 months 11 months

PFS

31/70 649

Phase 3: Nephrectomized patients with advanced RCC Bevacizumab + IFN3 8.6/NA 626 Phase 3: Temsirolimus vs temsirolimus + IFN in untreated patients with poor prognosis mRCC Temsirolimus4

800 Phase 3: Bevacizumab + temsirolimus vs bevacizumab + IFN-α

Bevacizumab/ Temsirolimus

5/68 189

Phase 2: Sorafenib vs IFN in untreated patients

Sorafenib2

31/NA 750

Phase 3: Untreated patients with ECOG PS of 0 or 1 Sunitinib1

OR/TS

(%)

N

Population

Agent

1. Motzer RJ, et al. N Engl J Med. 2007;356:115-124. 2. Szczylik C, et al. 2007 ASCO Annual Meeting; Abstract 5025; 3. Escudier B, et al. Lancet. 2007;370:2103-2111; 4. Hudes G, et al. N Engl J Med. 2007;356:2271-2281.

(15)

29

Second-Line Therapy in Metastatic RCC

30

Everolimus After Progression on

VEGFR-TKI: Study Design

Everolimus After Progression on

VEGFR-TKI: Study Design

•410 patients randomized between September 2006 and October 2007

•Second interim analysis cutoff: October 15, 2007, based on 191 PFS events

•Independent Data Monitoring Committee recommended termination of study

R

A

N

D

O

M

I

Z

A

T

I

O

N

2:1

Upon Disease Progression

Interim

Analysis

Interim

Analysis

N = 410

Stratification

¾

Prior VEGFR-TKI:

1 or 2

¾

MSKCC risk

group: favorable,

intermediate,

or poor

N = 410

Stratification

¾

Prior VEGFR-TKI:

1 or 2

¾

MSKCC risk

group: favorable,

intermediate,

or poor

=

_Analysis

Final

Everolimus + best

supportive care

(n = 272)

Placebo + best

supportive care

(n = 138)

(16)

31

Everolimus After Progression on

VEGFR-TKI: Prior Therapies

Everolimus After Progression on

VEGFR-TKI: Prior Therapies

10

9 Bevacizumab

44

46 Sunitinib

16

13 Chemotherapy

50

50 Interferon

24

22 Interleukin 2

VEGFR-TKI therapy

Placebo

(n = 138)

%

26

26 Sunitinib and sorafenib

Other systemic therapy

30

28

95

31 Radiotherapy

96 Nephrectomy

28 Sorafenib

Everolimus

(n = 272)

%

Prior Treatment

Motzer RJ, et al. 2008 ASCO Annual Meeting; Abstract LBA5026.

32

Everolimus vs Placebo:

PFS by Central Radiology Review

Everolimus vs Placebo:

PFS by Central Radiology Review

Motzer RJ, et al. 2008 ASCO Annual Meeting; Abstract LBA5026.

100

80

60

40

20

0

2

4

6

8

10

12 PFS Probabil

it

y

(%

)

Everolimus (n = 272)

Placebo (n = 138)

Hazard ratio = 0.30

95% CI (0.22, 0.40)

Log-rank P<0.001

Median PFS

Everolimus: 4.0 mo

Placebo: 1.9 mo

Months

(17)

33

Everolimus vs Placebo:

Treatment-Related Adverse Events

Everolimus vs Placebo:

Treatment-Related Adverse Events

1

24

3

37 Asthenia/fatigue

0

3

0

10 Peripheral edema

0

4

0

12 Cough

0

2

3

10 Infections

*

0

0 Grade 3

4 <1

25 Rash

2

1

8 Dyspnea

2

1

14 Mucosal inflammation

0

3

8 Pneumonitis

*

8

3

8 All

Grades

Placebo (n = 135)

(%)

1

17 Diarrhea

0

15 Nausea

3 Grade 3

40 Stomatitis

*

All

Grades

Everolimus (n = 269)

(%)

*Significant difference between sum of grade 3/4 events for everolimus and placebo groups (P<.05). Motzer RJ, et al. 2008 ASCO Annual Meeting; Abstract LBA5026.

34

Sequential TKIs in Advanced RCC

¾

Data from

retrospective

reviews suggests activity to

second agent

¾

No obvious correlation of response to first TKI with response to

second TKI

¾

Giving TKIs in sequence is feasible, safe, and has some

antitumor effect

Sablin M, et al. 2007 ASCO Annual Meeting; Abstract 5038.

Sunitinib → Sorafenib

Sorafenib → Sunitinib

Sequence

55%

9%

14 51%

15%

51 SD

OR

Patients (n)

(18)

35

Sunitinib in Patients With Bevacizumab-Refractory

mRCC: Best Response by RECIST

Sunitinib in Patients With Bevacizumab-Refractory

mRCC: Best Response by RECIST

95% CI (13%, 36%)

8

10

5

6 No Response

Progression

Indeterminate/Missing

59

52

36

32 Stable Disease

No. With Tumor Shrinkage

23

14 Partial Response

%

No.

(N = 61)

George D, et al. 2007 ASCO Annual Meeting; Abstract 5035.

36

High-Dose IL-2 for TKI Failures

¾

Retrospective analysis of 16 patients previously treated with a TKI

¾

All 16 patients assumed they could get IL-2 therapy after treatment with

anti-VEGF therapy

¾

Median number of doses for cycle 1 was 18/28 (64%)

¾

Toxicities that prevented further Rx

–

Bullous pemphigoid

–

Irreversible cardiomyopathy

–

Myocarditis and severe angina

–

Sudden fatal cardiac arrest

–

Hypotension and bowel ischemia

¾

Incidence of severe (grade 3-5) cardiac toxicities in patients with prior TKI

was 50% (compared with 8.5% in Cytokine Working Group Phase 3 trial)

¾

No objective responses seen

Schwarzberg T, et al. Abstract presented at the International Society for Biological Therapy of Cancer. November 1-4, 2007. Boston, MA.

(19)

37

TARGET: Phase 3 Trial of Sorafenib in

Patients With Cytokine-Refractory mRCC

TARGET: Phase 3 Trial of Sorafenib in

Patients With Cytokine-Refractory mRCC

¾

Phase 3 randomized, double-blind, multicenter trial

¾

Treatment continued until PD or toxicity

¾

Primary end point: OS

¾

Secondary end point: PFS

Escudier B, et al. N Engl J Med. 2007;356:125-134.

Placebo

(N = 452)

Sorafenib

400 mg bid

(N = 451)

N = 903

Eligibility Criteria

¾

Clear-cell histology

¾

Prior systemic therapy

¾

MSKCC prognostic score

(low or intermediate)

38

Proportion

of

Pa

tie

n

ts

Pro

g

ressio

n

Free

0

0.25

0.50

0.75

1.00 Time From Randomization (months)

0

2

4

6

8

10

12

14

16

18

20 Sorafenib in Patients With

Cytokine-Refractory mRCC: Investigator-Assessed PFS

Sorafenib in Patients With

Cytokine-Refractory mRCC: Investigator-Assessed PFS

5.5

2.8 Sorafenib (n = 451)

Placebo (n = 452)

0.51 Hazard ratio (S/P)

Median (months)

PFS*

Censored observation

Placebo

Sorafenib

*PFS based on investigator assessment.

Escudier B, et al. Paper presented at: The European Cancer Conference; October 30-November 3, 2005; Paris, France.

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39

Sorafenib in Patients With

Cytokine-Refractory mRCC: Final Results

Sorafenib in Patients With

Cytokine-Refractory mRCC: Final Results

Bukowski RM, et al. 2007 ASCO Annual Meeting; Abstract 5023.

TARGET Final OS Analysis:

16 Months Post-Crossover,

Intent-to-Treat

TARGET Preplanned Secondary

Analysis: OS for

Patients on Placebo, Censored*

561 events.

*Nonsignificance; O’Brien–Fleming threshold for statistical significance α = 0.037. 100 75 50 25 0 20 24 28 32 36 16 0 4 8 12 Sorafenib = 17.8 months Placebo = 15.2 months HR (sorafenib/placebo) = 0.88 95% CI: 0.74–1.04 P = 0.146* OS (% p at ie n ts )

¾ Placebo patients, median duration of therapy

–Placebo exposure = 12.0 weeks

–Sorafenib exposure = 40.1 weeks

100 75 50 25 0 40 0 4 8 12 16 20 24 28 32 36 Sorafenib = 17.8 months Placebo = 14.3 months HR (sorafenib/placebo) = 0.78 95% CI: 0.62–0.97 P = 0.0287† OS (% p at ie n ts )

*Censored at 30 June 2005, approx. start of crossover.

†Statisticvally significant; O’Brien–Fleming threshold for statistical significance α = 0.037.

40

Sorafenib in Patients With

Cytokine-Refractory mRCC: Best Response by RECIST

Sorafenib in Patients With

Cytokine-Refractory mRCC: Best Response by RECIST

38 (8)

18 (4)

Not evaluated

8 (2)

43 (10)

Partial response

167 (37)

279 (62)

Disease control rate

†

167 (37)

56 (12)

Progressive disease

239 (53)

333 (74)

Stable disease*

0 (0)

1 (<1)

Complete response

Placebo (n = 452)

n (%)

Sorafenib (n = 451)

n (%)

*Stable disease = disease that remained unchanged for ≥28 days.

†_{The sum of patients with a complete response, partial response, and stable disease for at least 2 cycles.}

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41

Second-Line Sorafenib in mRCC:

Treatment-Related AEs

Second-Line Sorafenib in mRCC:

Treatment-Related AEs

Patients (%)

0.76

1.00

0.06 <0.001

0.37

0.41

0.001 P

Value

(Grade

3/4)

<1

16

1

40 Rash/Desquamati

on

0

7

6

30 Hand Foot Skin

Reaction

1

19 <1

23 Nausea

1

12

1

16 Vomiting

1

13

2

43 Diarrhea

4

28

5

37 Fatigue

<1

2

4

17 Hypertension

Grade

3/4

Any

Grade

3/4

Any

Grade

Placebo

(N = 451)

Sorafenib

(N = 451)

Adverse Event

AE = adverse event.

Escudier B, et al. N Engl J Med. 2007;356:125-134.

42

RCC Treatment Algorithm: 2008

Clinical trial

mTOR

*

Clinical trial

Everolimus

VEGFR

*

Sunitinib

Bevacizumab

Sorafenib

Cytokine

*

Previously treated

Sunitinib

Clinical trial

Temsirolimus

Poor risk

High-dose IL-2

Sorafenib

Clinical trial

Observation

Sunitinib

Bevacizumab + IFN

Good or

intermediate risk

Untreated

Other Options

(≥ level 2)

Therapy

(level 1)

Patients

Setting

*Patients who failed prior therapy.

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43

Prospective Trials of Sequential

Targeted Agents

Prospective Trials of Sequential

Targeted Agents

4.0 months 3.8 months 7.4 months 7.1 months

PFS

1/50 410

Phase 3: RAD001 vs placebo in TKI-refractory

RAD0014

480 Phase 3: Temsirolimus vs

sorafenib in patients previously treated with sunitinib

Temsirolimus

540 Phase 3: Axitinib vs sorafenib in previously treated patients Axitinib 3/38 26 each Phase 2: Bevacizumab-or sunitinib-refractory Sorafenib3 23/55 62 Phase 2: Sorafenib-refractory Axitinib2 23/75 62 Phase 2: Bevacizumab-refractory Sunitinib1

OR/TS

(%)

N

Population

Agent

1. Rini, et al. J Clin Oncol (in press); 2. Rini, et al. 2007 ASCO Annual Meeting; 3. Sheppard, et al. 2008 ASCO Annual Meeting; 4. Motzer, et al. 2008 ASCO Annual Meeting.