Angiogenesis Targeted Therapiesin Renal Cell Carcinoma

John S. Lam, MD

Department of Urology

David Geffen School of MedicineUniversity of California-Los Angeles

Patient Case

• CC: Abdominal pain

• VS: T 99.6, BP 146/90, HR 102

• Assessment:

– Excessive fatigue in recent weeks

History

• History of present illness (HPI):– 62-year-old female presents with abdominal pain associated with

night sweats, early satiety, and 10 pound weight loss over the past3 months

– Eastern Cooperative Oncology Group (ECOG) score = 0

– Patient is taking no medications

– Patient has no known drug allergies

– Social history: married, denies use of tobacco and recreationaldrugs, social ETOH

– Family history includes a father with a history of prostate cancer

– ROS: otherwise normal

Physical Examination

• Physical Examination– Alert and Oriented x 3

– Well-built, well-nourished

– HEENT: WNL

– Neck: supple, no lymphadenopathy

– CV: S1, S2 present, no murmurs

– Pulmonary: bilateral clear to auscultation

– GI: soft, non-tender, non-distended, palpable right upper quadrantabdominal mass

– GU: WNL

– Extremities: warm without clubbing, cyanosis, edema

– Neuro: grossly intact

Laboratory Evaluation

• Laboratory evaluation– WBC of 8,400/cu mm, hematocrit of 29.2 g/dL, and platelet

count of 154,000/cu mm

– Electrolytes were within normal limits. Blood urea nitrogen was22 mg/dL, and creatinine was 0.9 mg/dL

– Liver enzymes, alkaline phosphatase, albumin, and total bilirubinwere within normal limits

– Urinalysis: 2+ blood, 20 RBC, 2 WBC

Imaging and Diagnosis

• Imaging– Abdominal CT:

• A 9.5-cm-by-7.5-cm lobulated, enhancing soft tissue mass withextension into the renal vein

• The mass displaced the right kidney medially

• Enlarged retroperitoneal lymph nodes

– Chest CT: pulmonary metastases

– Bone Scan: negative

– MRI brain: negative

• Biopsy: clear cell RCC

Patient Case

Patient Case

Lung nodule

Patient Case

Patient Case

• Pathology– Clear cell RCC

– Fuhrman grade 3

– Size: 10 cm

– Renal vein involvement

– Margin negative

– 25% tumor necrosis

– Collecting system involvement

– CA IX: 95% positive

– Lymph nodes negative

– pT3b N0 M1

Multitargeted Approaches in mRCC:Sunitinib (SU11248)

• Small-molecule receptor tyrosine kinase inhibitor

• Inhibits all VEGFRs, PDGFR-A, PDGFR-B, c-KIT, and FLT-3

• Oral administration

• Both antitumor and antiangiogenic activity

• FDA approved January 26, 2006 for treatment of advanced RCC

FGFR-1=fibroblast growth factor receptor; FLT-3=FMS-like kinase 3.

F

H3C

O

O

CH3

CH3

CH3

NH

NH

NH

N

10PDGFR

15VEGFR-1

10VEGFR-2

10c-Kit

880FGFR-1

8900EGFR

IC50 nMReceptors

Sunitinib (SU11248) for Renal Cell Carcinoma:Rationale for Receptor Targeted Therapy

Substrate

Substrate

PSubstrate

Substrate

P

Endothelial (Tumor) CellMembrane

Tumor Vasculature Development and Proliferation

VEGFR

Clear Cell CarcinomaPDGF &VEGF

Binds to hypoxiaregulated region onVEGF and PDGF genes

StabilizesHIF-1

MutantVHL

KP

PP

PP

KP

SU11248

PDGFR

R1R1

VEGF PDGF

KP

K

PP

P

SU11248

R2 R2

X X

X

X X• Endothelial cell

proliferation• Pericyte proliferation• Tumor proliferation

Phase II Evaluation of Sunitinibin mRCC

Sunitinib

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

Patients withadvanced diseaseand failure of priorcytokine therapy

Continuesunitinibtreatment unlessprogression orintolerability

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)

Sunitinib in mRCC:Hand-Foot Syndrome

3%12%Hand-foot syndrome

Grade 3All grades

Patient Case

Lung nodule

Efficacy of Sunitinib in Phase II Trial as2nd-line Therapy After Cytokine Progression

(N=105)*

34%43% PR

0%1% CR

8.3 months8.1 monthsMedian PFS

29%22%Stable disease≥3 months

34%44%Overall response

Independentcentral review

Investigatorassessment

CR=complete response; PR=partial response; PFS=progression-free survival

Motzer RJ, et al. JAMA 2006;295:2516-24

Sunitinib (SU11248) for RCC: Trial 1 Maximum % Reduction of Target Lesions by Patient

% change from baseline

Partial responders by RECIST

SD/PD patients

-100

-80

-60

-40

-20

0

20

40

Duration of ResponseTrials 1 and 2

Pro

port

ion

of P

atie

nts

Pro

gres

sion

Fre

e

Sunitinib Therapy (months)

0 5 10 15 20 25 30

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Median TTP trial 1: 8.7 monthsMedian PFS trial 2: 8.1 months

Pooled analysis: 8.2 months(95% CI: 7.8, 10.4)

Motzer RJ, et al. JAMA 2006;295:2516-24

Objective Response to Sunitinibin Patients with mRCC

36 (34)

23 (22)

46 (44)1 (1)

45 (43)

Study 1006*(N=105)

57 (34)21 (33)PD, SD <3 months or notevaluable

40 (24)17 (27)SD ≥3 months

71 (42)1 (1)

70 (42)

25 (40)0

25 (40)

Overall responseCR

PR

Pooled analysis

(N=168)

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

*Study ongoing

Motzer RJ, et al. JAMA 2006;295:2516-24

Progression-Free Survival by ResponseTrials 1 and 2

5.5–8.2

7.9

40

SD ≥3 months

1.2–2.310.9–24.295% CI

2.114.8Median PFS (months)

57 71Patients (n)

SD <3 months, PDor NEResponder

SD=stable disease, PD=progressivedisease, NE = not evaluable,PFS=progression-free survival

Motzer RJ, et al. JAMA 2006;295:2516-24

Treatment-related Adverse Events

7 8 7 0* 8 0*Hand-foot syndrome

1013 0 31010Vomiting

1616 1 01516Dyspepsia

813 6 210 3Hypertension

Trial 2Trial 2Trial 2

Grade 3 Total

Incidence (%)

1

5

0

3

11

0

2

3

3

11

Trial 1

11

8

13

17

17

6

17

16

21

27

Trial 1

Grade 2

12

13

13

20

28

6

19

19

24

38

Trial 1

Anorexia

Stomatitis

Nausea

Diarrhea

Fatigue

Event

* Hand–foot syndrome initially classified as dermatitis, rash or neurotoxicity before being recognized as a unique toxicity

Original Article

Sunitinib versus Interferon Alfa inMetastatic Renal-Cell Carcinoma

Robert J. Motzer, M.D., Thomas E. Hutson, D.O., Pharm.D., Piotr Tomczak, M.D., M.Dror Michaelson, M.D., Ph.D., Ronald M. Bukowski, M.D., Olivier Rixe, M.D., Ph.D.,Stéphane Oudard, M.D., Ph.D., Sylvie Negrier, M.D., Ph.D., Cezary Szczylik, M.D.,

Ph.D., Sindy T. Kim, B.S., Isan Chen, M.D., Paul W. Bycott, Dr.P.H., Charles M.Baum, M.D., Ph.D., and Robert A. Figlin, M.D.

N Engl J MedVolume 356(2):115-124

January 11, 2007

Phase III Trial of Sunitinib vs. Interferon-αin First-Line Treatment for mRCC

• 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=750

Sunitinib: orally administered daily(schedule 4/2)

IFN-α: administered TIW

Phase III Trial: Best Response by RECIST Investigator Assessment

127 (34%)61 (16%)Progressive disease/Not evaluable

373374Pts with measurable disease at baseline (n)

213 (57%)176 (47%)Stable disease

33 (9%)0

33

137 (37%)1

136

Objective response*Complete responsePartial response

IFN-αSunitinibResponse

*Sunitinib vs. IFN-α: P <0.000001

Phase III Trial: Best Response by RECISTIndependent Central Review

147 (45%)72 (21%)Progressive disease/

Not evaluable

327335Pts with measurable disease at baseline* (n)

160 (49%)160 (48%)Stable disease

20 (6%)0

20

103 (31%)0

103

Objective response**Complete responsePartial response

IFN-αSunitinibResponse

*88 patients not yet assessed by central review

**Sunitinib vs. IFN-α: P <0.000001

Phase III Trial: Progression-Free SurvivalIndependent Central Review

No. at Risk Sunitinib: 235 90 32 2No. at Risk IFN-α: 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

gres

sion

Fre

e S

urvi

val P

roba

bilit

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

IFN-α Median: 5 months(95% CI: 4–6)

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

Phase III: Subgroup AnalysisProgression-Free Survival*

*Independent Central Review

IFN-α benefitSunitinib benefit

Hazard ratio (95% CI)

Baseline factor

0.0 0.5 1.0 1.5

Sunitinib vs. IFN-α treatment effect,without adjusting for risk factors

N

Prior nephrectomy 673

Absence of prior nephrectomy 77

LDH ≤1.5xULN 716

LDH >1.5xULN 34

Time since diagnosis ≥1 year 344

Time since diagnosis <1 year 391

Hgb <LLN 219

Hgb ≥LLN 515

Serum corrected Ca ≤10 mg/dL 688

Serum corrected Ca >10 mg/dL 46

ECOG=0 456

ECOG=1 294

750

Phase III Study: Progression-Free Survival byMSKCC Risk Status*

*Motzer et al. JCO 2002;20:289-296; Excludes 17 pts from IFN-α with missing data

Independent Central Review

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

Time (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

abili

ty

Sunitinib (n=143)Median not reached

IFN-α (n=121)

Median: 8 months

(95% CI: 7–NA)

Hazard Ratio=0.371(95% CI: 0.214–0.643)

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

Time (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

abili

ty

Sunitinib (n=209)Median: 11 months(95% CI: 11–11)

IFN-α (n=212)Median: 4 months(95% CI: 3–4)

Hazard Ratio=0.388(95% CI: 0.281–0.537)

MSKCC Risk Factors: 0 (Favorable)

MSKCC Risk Factors: 1-2(Intermediate)

Phase III Study: Treatment-Related Adverse Events

11/<1*51751Fatigue

0135*53Diarrhea

0291 6Chills

<1 2125Stomatitis

<116<1 5Myalgia

1 3210Ejection fraction decline

<1 18*24Hypertension

0 15*20Hand-foot syndrome

<1 80 1Flu-like symptoms

0341 7Pyrexia

Grade 3/4Grade 3/4

IFN-α (%)

133

All grade

344

All grade

Sunitinib (%)

Nausea

Event

* Greater frequency, P <0.05

Phase III Study: Outcome Summary

—AcceptableSafety

—SuperiorPatient-reported outcomes

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

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

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

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

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

Median Progression-free survival*, mos (95% CI) Independent review Investigator

IFN-αSunitinib

* Sunitinib vs. IFN-α: P <0.000001

Targeted Therapy for RCCConclusions

• Sunitinib shows activity in second-line therapy

• Randomized phase III pivotal trial of sunitinibshow benefit over interferon in first-linetherapy

• Future trials will include new combinationsand comparisons of targeted agents

• Studies of tumor biology to identify markers ofresponse are a priority