targeted therapy in hepatocellular carcinoma (hcc)kaim.or.kr/pds/files/hmo/hmo_200807_08.pdf ·...

Development of Molecular Targeted Agents in Hepatocellular carcinoma

영남대학 병원혈액종양내과

이 경 희

Dismal prognosis

More than 80% of patients presents with

advanced or unresectable disease

Supportive care

Stage

OS(%)

1yr 2yrs 3yrs

Intermediate

Advanced

80

29

65

16

50

8

case

55-yrs male, histologically proven HCC, hepatitis B(+),

ECOG PS 1, Child-Pugh score 6, macroscopic portal

vein invasion and regional L/N

Which treatment do you wants?

1. Best supportive care

2. TACE

3. Systemic cytotoxic agent

4. Hormonal therapy

5. Target agents (sorafenib)

Curative treatment for HCC

Orthotopic liver transplantation

Surgical resection

Local destruction (RF, Cryo, Alcohol)

Palliative treatment

Transarterial chemo-embolization

Systemic chemotherapy

INF

Hormonotherapy

Treatments of HCC

Barcelona Clinic Liver Cancer Staging

and Treatment Strategy

Very early

stage (0)

Early

stage (A)

Intermediate

stage (B)

Advanced

stage (C)

Terminal

stage (D)

Liver transplantation Chemoembolization New agentsResection PEI/RF

Symptomatic

treatment

Curative treatments Randomized controlled trials

Extrahepatic disease

YesNo

Associated diseases

YesNo

3 nodules ≤3cm

Increased

Normal

Single HCC

Portal pressure/

bilirubin

HCC

Adapted from Llovet JM, et al, Lancet 2003;362:1907–17

Copyright 2003, with permission from Elsevier

Treatment for Advanced HCC: Systemic

Single-Agent Chemotherapy

Authors,

year Study type Agent(s) n

PR

(%)

CR (%)

Survival

Sciarrino

et al, 1985

Retrospective Doxorubicin 109 9 1 13% at 1 year

Tan et al,

1986

Phase II Epirubicin 13 23 0 11 weeks

Hochster

et al, 1985

Phase II Epirubicin 18 17 0 ND

Pohl et al,

2001

Retrospective Epirubicin 44 7 2 16.2 months*

Yin et al,

2005

Phase II PIAF 26 15 0 6 months

Okada

et al, 1993

Phase II Cisplatin 28 15 0 ND

PR = partial response; CR = complete response


Single-Agent Chemotherapy (cont’d)

Authors,

year Study type Agent(s) n

PR

(%)

CR

(%) Survival

p for

difference

Lai et al,

1988

RCT Doxorubicin

vs

60 N/A N/A 10.6

weeks

0.036

No therapy 46 N/A N/A 7.5

weeks

Yeo et al,

2005

Phase III

RCT

Doxorubicin

vs

94 10.5 0 6.8

months

0.83

PIAF 94 20.9 0 8.7

months

Choi et al,

1998

RCT Doxorubicin

vs

20 6 17 14.4

weeks

ND

5-FU, methotrexate,

cyclophosphamide

+ vincristine

19 N/A N/A 6.5

weeks

PIAF = cisplatin, doxorubicin, 5-fluorouracil (5-FU) and interferon-α (IFN-α)


Combination Chemotherapy

Authors, year Study type Agent(s) n

PR (%) CR

(%)

Median

survival

Morstyn et al,

1983

Phase II Doxorubicin +

streptozotocin

23 9 0 3 months

Falkson et al,

1999

Phase II Doxorubicin +

clofazimine

28 0 0 7 weeks

Ikeda et al, 2005 Phase II 5-FU, mitoxantrone

+ cisplatin

51 27 0 11.6 months

Kim et al, 2006 Phase II Epirubicin,

cisplatin, UFT, and

leucovorin

53 17 0 24.6 weeks

Tanaka et al,

2007

Phase II Epirubicin

emulsified in

lipiodol

20 5 0 12.4 months

UFT = uracil-tegaful

Treatment of Advanced HCC

BCLC and practice guidelines recommend that patients with advanced HCC should be entered into clinical trials1–3

Only supportive care measures are available for patients with terminal stage disease2,3

New molecular agents that selectively target cellular signaling pathways are in development and are being investigated for single-agent therapy of advanced HCC

1. Llovet JM, et al. Lancet 2003;362:1907–17

2. Bruix J and Sherman M. Hepatology 2005;42:1208–36

3. Bruix J, et al. J Hepatol 2001;35:421–30

What’s Next?

Targeted therapies

Immunotherapy

MMG CoA reductase

COX-2 inhibitor

New cytotoxic agent

Targeting the Molecular pathways

Key pathways in hepato-carcinogenesis

Involved in cell proliferation, survival

and angiogenesis

Challenges in assessing the relevant

molecular targets in HCC

Multiple Cellular Signaling Pathways

Implicated in Pathogenesis of HCC

Cell membrane

c-MYC c-JUN

wnt Receptor

BcL-XL

BAD

ERK1/2

MEK1/2

-catenin

GSK3

GBP

DSH

HBx

Akt

mTO

R

Raf

PKC

NF-ҚB

Ras

NF-ҚB

PLC

SH

C

GrB

2

GE

F

PI3K

PTEN

p53

Survival

Transcription/translation

-catenin

HBx

RTK: FGFR

EGFR

IGF-IR

c-MET

Receptor

Adapted from Avila MA, et al. Oncogene 2006;25:3866–84

Mechanisms/

pathways

Molecular

targets

Examples of agents

Wnt/β -catenin

pathway

Wnt

β-catenin

Monoclonal antibody of Wntl and Wnt2

Small molecule inhibitors (e.g. ICG-001)

Cell cycle

regulators

CDKs Flavopiridol

Angiogenic

factors

VEGF

VEGFR

PDGFR

heparanase

Anti-VEGF monoclonal antibody

(Bevacizumab)

Tyrosine kinase inhibitors (e.g. sorafenib,

PTK787,sunitinib)

Tyrosine kinase inhibitors (e.g. sorafenib,

sunitinib)

PI-88

Molecular targets for therapy in hepatocellular carcinoma(I)

Molecular targets for therapy in hepatocellular carcinoma (II)

Mechanisms/

pathways

Molecular

targets

Examples of agents

Growth factors EGFR monoclonal antibody (e.g. cetuximab)

Tyrosine kinase inhibitor (e.g. Gefitinib

and Erlotinib)

Ras/Raf/MEK/

Erk pathway

Ras

Raf

inhibitors of farnesyl transferase

Raf kinase inhibitor (sorafenib)

PI3k/Akt/

mTOR pathway

PI3k

Akt

mTOR

Wortmannin and LY294002

alkylphospholipid perifosine

rapamycin, RAD001

CDKs = Cyclin-dependent kinases; EGFR = epidermal growth factor receptor; mTOR = mammalian target of rapamycin; PI3K = phosphatidylinositol 3-kinase; PDGER = platelet-derived growth factor receptor; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor.

Targeted agents in development for HCC:

overview

Anti-angiogenic targets Antiproliferative targets

Agents VEGF VEGFR PDGFR EGFR Raf mTOR

Bevacizumab

BMS-582664

Cediranib

Erlotinib

Gefitinib

Lapatinib

RAD001

Sorafenib

Sunitinib

Thalidomide

TSU-68

Sources: Trial Trove, ClinicalTrials.gov (NCI), Evaluate Pharma, IMS Knowledge Link, Espicom, IDdB3, BioPharm Insight, MedTrack

In HCC, a net excess of pro-angiogenic factors are secreted, including

– Vascular endothelial growth factor (VEGF)

– Platelet-derived growth factor (PDGF)

– Placental growth factor

– Transforming growth factors α and β

– Basic fibroblast growth factor (FGF)

– Epidermal growth factor (EGF)

– Hepatocyte growth factor

– Angiopoietins

– Interleukin (IL)-4, IL-8

Angiogenesis and HCC

Semela D, Dufour J-F. J Hepatol 2004;41:864–80

Cell membrane

Signaling Pathways for Angiogenesis:

VEGFR and PDGFR in the Vasculature

Semela D, et al. J Hepatol 2004;41:864–80

Clauss M. Semin Thromb Hemost 2000;26:561–69

RTK: VEGFR-1

VEGFR-2

VEGFR-3

PDGFR

c-MYC c-JUN

BcL-XL

BAD

ERK1/2

MEK1/2Akt

mTOR

Raf

PKC

NF-ҚB

NF-ҚB

PLC

SHC

GrB2GEF

PI3K

PTEN

Angiogenesis

HBx

Ras

Cediranib

Bevacizumab

BMS-582664

Sorafenib

Sunitinib

Thalidomide

TSU-68

Site of action

p53

x x

x

x

x

x

x

xx

x

x

Anti-angiogenic Therapies in Development

as Single Agents for HCC

Agent MOA Phase n Inclusion criteria Status Endpoints

Bevacizumab mAb;

VEGFR

antagonist

II 50 HCC not amenable to

curative treatment

Recruiting Disease control

rate, PFS, OS

Bevacizumab mAb;

VEGF-R

antagonist

II 46 Non-metastatic,

unresectable HCC

without main portal

vein invasion

Ongoing PFS, safety

BMS-582664 Multi TKI;

VEGFR-2,

VEGFR-3,

FGFR-1,

FGFR-2

II 100 Advanced

unresectable HCC

Recruiting 6-month PFS,

tumor response,

OS

Cediranib Multi-TKI;

VEGFR-1,

VEGFR-2,

VEGFR-3

II 44 Locally advanced/

metastatic liver

cancer

Recruiting 6-month OS,

tumor response,

safety

Sources: Trial Trove, ClinicalTrials.gov (NCI), Evaluate Pharma, IMS Knowledge Link, Espicom, IDdB3, BioPharm

Insight, MedTrack

MAb = monoclonal antibody; MOA = mechanism of action; TKI = tyrosine kinase inhibitor

OS = overall survival; PFS = progression-free survival

Anti-angiogenic Therapies in Development

as Single Agents for HCC (cont’d)

Agent MOA Phase n Inclusion criteria Status Endpoints

PI-88 Heparanase

inhibitor

II 343 HCC following

resection

Ongoing Recurrence rate,

recurrence-free

survival, OS

Sorafenib Multi-TKI; Raf,

PDGFR-β,

VEGFR-2/3,

KIT, Flt-3

III 602 Advanced HCC Complete OS, TTSP, TTP,

safety versus

placebo1

Sunitinib Multi-TKI;

VEGFR-2,

PDGFR-β, KIT,

Flt-3

II 34 Advanced HCC Recruiting PFS, tumor

response, OS

Thalidomide Glutamic acid

derivative;

VEGF, FGF

inhibitor

III 230 Advanced HCC

with poor liver

reserve

Recruiting OS, tumor

response, safety

TSU-68 Multi-TKI;

VEGFR, PDGF,

FGFR

I/II N/A Unresectable

HCC

Recruiting Safety/feasibility

1. Llovet J. ASCO 2007, Chicago, IL, USA

Sources: Trial Trove, ClinicalTrials.gov (NCI), Evaluate Pharma, IMS Knowledge Link, Espicom, IddB3, BioPharm

Insight, MedTrack. TTSP = time to symptomatic progression; TTP = time to progression

Signaling Pathways for Cell Proliferation

and Survival: Wnt/β-Catenin

Giles RH, et al. Biochim Biophys Acta 2003;1653:1–24. Feitelson MA, et al. Surg Clin N Am 2004;84:339–54

3. De La Coste A, et al. Proc Natl Acad Sci USA. 1998;95:8847–51

Cell membrane

c-MYC c-JUN

RTK: FGFR

EGFR

IGF-IR

c-MET

Receptor

-catenin

Wnt Receptor

BcL-XL

BAD

MEK1/2

PLC

Transcription

GBP

DSH

Ras

NF-ҚB

ERK1/2

NF-ҚB

Raf

p53

PKC

mTOR

PTEN

GSK3

PI3K

-catenin

HBx

Akt

SHC

GrB2GEF


and Survival: PI3K

Cell membrane

p53

c-JUN

wnt Receptor

MEK1/2

Survival

Transcription/translation

PI3

K PTENDSH

GBP

GSK3

-

catenin

NF-ҚB

NF-ҚB

c-MYC

BcL-XL

HBx

mTOR

BAD

Raf

PKC

PLC

-

catenin

ERK1/2

Akt

1. Horie Y, et al. J Clin Invest 2004; 113:

1774–83; 2. Hu T-H, et al. Cancer 2003;

97:1929–40. 3. Anzola M. J Viral Hepat

2004;11:383–93

RTK: FGFR

EGFR

IGF-IR

c-MET

SHC

GrB2GEF

Ras

Site of

action

Erlotinib

Gefitinib

Lapatinib

RAD001

Sorafenib

Sunitinib

x

x x

x

xx

xxx

Receptor


and Survival: Raf/MEK/ERK

Cell Membrane

c-MYC c-JUN

Wnt Receptor

BcL-XL

BAD

ERK1/2

MEK1/2

-

catenin

GSK3

GBP

DSH

AktmTO

R

Raf

PKC

NF-ҚB

Ras

NF-ҚB

PLCPI3K

PTEN

p53

Survival

Transcription/Translation

-

catenin

1. Feitelson MA, et al. Surg Clin N Am 2004;84:339–54

2. Thorgeirsson S, Grisham JW. Nat Genet 2002;31:339–46

3. Wiesenauer CA, et al. J Am Coll Surg 2004;198:410–21

4. Hwang YH, et al. Hepatol Res 2004;29:113–21

RTK: FGFR

EGFR

IGF-IR

c-MET

Receptor

SH

C

GrB

2

GE

F

HBx

x x

x

x

Site of

action

Erlotinib

Gefitinib

Lapatinib

RAD001

Sorafenib

Sunitinib

x

xx

xxx

Antiproliferative Molecular-targeted

Therapies in Development for HCC

Agent MOA Phase n

Inclusion

criteria Status Endpoints

Erlotinib TKI; EGFR

inhibitor

II 80 Unresectable

HCC

Complete PFS, tumor

response,

safety

Gefitinib1 TKI; EGFR

inhibitor

II 31 Unresectable

HCC

Complete Tumor

response,

safety

Lapatinib Dual TKI;

EGFR and

HER-2/neu

II 34 Unresectable

HCC

Ongoing Tumor

response,

OS, safety

1. O’Dwyer PJ, et al. J Clin Oncol 2006; 24(Suppl.):213s (Abstract 4143)

Sources: Trial Trove, ClinicalTrials.gov (NCI), Evaluate Pharma, IMS Knowledge Link, Espicom,

IDdB3, BioPharm Insight, MedTrack; HER-2 = human epidermal growth factor receptor-2

Antiproliferative Molecular-targeted

Therapies in Development for HCC (cont’d)

Agent MOA Phase n

Inclusion


RAD001 Rapamycin

analog; mTOR

inhibitor

I/II 134 Advanced

HCC

Recruiting MTD, disease

control rate

Sorafenib1 Multi-TKI; Raf,

PDGFR-β,

VEGFR-1/2

KIT, Flt-3

III 602 Advanced

HCC

Complete OS, TTSP, TTP,

safety versus

placebo1

Sunitinib Multi-TKI;

VEGFR-2,

PDGFR-β, KIT,

Flt-3

II 34 Advanced

HCC

Recruiting PFS, tumor

response, OS

1. Llovet J. ASCO 2007, Chicago, IL, USA


IDdB3, BioPharm Insight, MedTrack; MTD = maximum tolerated dose

Apoptosis Inducers and Growth Inhibitors

in Development for HCC

Agent MOA Phase n

Inclusion


Arsenic

trioxide

Apoptosis

inducer

II 25 Unresectable

liver cancer

Recruiting Efficacy,

safety

Bortezomib Apoptosis

inducer; 26S

proteasome

inhibitor

II 22 Advanced

HCC

Suspended

2005

Safety, MTD

TAC-101 Retinoid;

inhibits tumor

growth

I/II 18 Advanced

HCC

Ongoing Safety, MTD


IDdB3, BioPharm Insight, MedTrack. MTD = maximum tolerated dose

Study n Efficacy Adverse events

Sorafenib 400mg

b.i.d.1602 OS improved vs placebo (p=0.00058) Grade 3 = diarrhea (8%), hand–foot skin

reaction

Sunitinib 37.5mg

q.d.219 PR=1, SD=8 Grade 3/4 = neutropenia (21%),

lymphopenia (16%), SGOT/SGPT (16%)

Sunitinib 50mg

q.d.337 PR=1, SD=39% Grade 3/4 = thrombocytopenia (43%),

neutropenia (24%), CNS (24%), asthenia

(22%). Dose reduction in 27% pts

Thalidomide4 19 PFS rate at 6 months = 41% Grade 2/3 = constipation (50%),

somnolence (18%)

Cetuximab5 32 27 evaluable, SD (≥8 weeks) 44%,

TTP = 8.0 weeks (22.5 weeks in pts

with SD)

No serious adverse events reported

Bevacizumab6 30 24 evaluable, PR=3, SD=13 including

≥16 weeks in 7 patients)

Six pts withdrew due to variceal

bleeding

Perifisone7 11 HCC pts, 1 PR,

progression free ≥9 months

Grade 2 or higher = diarrhea (49/241),

nausea (44/241), vomiting (28/241),

fatigue (14/241)

Single-Agent Targeted Therapy:

1. Llovet et al. Presented at ASCO 2007; Refs 2–8 from J Clin Oncol 2007;25:

2. Zhu AX, et al. Abs 4637; 3. Faivre SJ , et al. Abs 3546; 4. Fazio N, et al. Abs 15076; 5. Gruenwald V, et al. Abs 4598;

6. Malka D, et al. Abs 4570; 7. Campos LT, et al. Abs 15072

Sorafenib Targets both Tumor-cell

Proliferation and Angiogenesis In Vitro

KIT/Flt-3/

RET

Angiogenesis

Raf

Endothelial cell or pericyte

Nucleus

VEGFR-2PDGFR-β

MEK

Apoptosis

Tumor cell

Proliferation

PDGF

VEGF

EGF

Survival

Wilhelm SM, et al. Cancer Res 2004;64:7099–109

Ras

Nucleus

Ras

ERK

Raf

MEK

Apoptosis

ERK

PDGF-β VEGFParacrine

stimulation

Sorafenib

X X

X X

XX

X

X

Vehicle

Sorafenib 30mg/kg

Sorafenib 100mg/kg

n=5n=5

Tumor cell death assessed by TUNEL assay

Vehicle Sorafenib 30mg/kg Sorafenib 100mg/kg

Me

an

TU

NE

L-p

os

itiv

e

are

a (

%)

10

8

6

4

2

0

*

*

n=5

*p<0.05 versus vehicle by

one-way ANOVA Dunnett’s

multiple comparison test

Sorafenib Induces Cell Death in the

PLC/PRF/5 HCC Xenograft Model

TUNEL = terminal deoxynucleotidyl

transferase biotin-deoxyuridine

5-triphosphate nick end labelling Liu L, et al. Cancer Res 2006;66:11851–8

Phase II Trial Design

Sorafenib

400mg b.i.d.

Eligibility criteria

Inoperable HCC

Child–Pugh A/B status

No previous systemic

therapy

Primary endpoints

• Tumor response

• Safety

137 patients with advanced HCC received continuous sorafenib

400mg b.i.d. in 4-week cycles

Abou-Alfa GK, et al. J Clin Oncol 2006;24:4293–300

Tumor response assessments every two cycles using modified

World Health Organization criteria

Safety assessments (NCI-CTC v2.0)

NCI CTC v2.0 = National Cancer Institute

Common-Toxicity Criteria version 2.0

Phase II Study of Sorafenib in Patients

with Advanced HCC: Tumor Response

Best response n (%)

PR 3 (2.2)

MR 8 (5.8)

SD* 46 (33.6)

PD (by radiologic assessment) 48 (35.0)

Not available for independent review 32 (23.4)

Best response (n=137) based on independent assessment

*To be classified as SD, patients needed to have SD for 16 weeks

MR = minor response


Reproduced with permission from the American Society of Clinical Oncology

Phase II Results: Median TTP

Median TTP (independent assessment)

5.5 months (n=137)

0 100 200 300 400 500

Time from start of study treatment (days)

0

0.25

0.50

0.75

1.00

Su

rviv

al d

istr

ibu

tio

n f

un

cti

on

Median TTP (investigator assessment)

4.2 months (n=137)

0 100 200 300 400 500


0

0.25

0.50

0.75

1.00

Su

rviv

al d

istr

ibu

tio

n f

un

cti

on

600 700 800



Phase II Results: OS

Median OS (investigator assessment)9.2 months (n=137)

0 100 200 300 400 500 600 800

1.00

0.75

0.50

0.25

0

Su

rviv

al

dis

trib

uti

on

fu

ncti

on


700



p=0.00034

TTP according to baseline pERK status (n=33)

0 50 100 150 200 250 300 350 4000

20

40

Pati

en

ts n

ot

pro

gre

ss

ed

(%

)

60

80

100 High (2–4+)

pERK staining

intensity (n=18)

Low (0–1+)

pERK staining

intensity (n=15)

76–100% of

nuclei positive

for pERK

TTP = 178 days

6–25% of

nuclei positive

for pERK

TTP = 46 days

Phase II Biomarkers: TTP According to

Phosphorylated ERK (pERK)

Time (days)

Abou-Alfa G, et al. J Clin Oncol 2006;24:4293–300


Sorafenib Improves Survival in

Hepatocellular Carcinoma:

Results of a Phase III Randomized,

Placebo-Controlled Trial

Josep M Llovet, Sergio Ricci, Vincenzo Mazzaferro, Philip Hilgard,

Jean-Luc Raoul, Stefan Zeuzem, Armando Santoro, Minghua Shan,

Marius Moscovici, Dimitris Voliotis, and Jordi Bruix,

for the SHARP Investigators Study Group

Phase III Trial Design: SHARP

Sorafenib

400mg b.i.d.

n=299

Placebo

n=303

Eligibility criteria

Advanced HCC

Child–Pugh A status

ECOG PS 0–2

Life expectancy

≥12 months

Primary

endpoints

• OS

• TTSP

Secondary endpoints

– TTP

ECOG PS = Eastern Cooperative Oncology

Group Performance Status

Ra

nd

om

izati

on

Llovet JM, et al. ASCO 2007, Chicago, IL, USA

65

87/13

88/9/3

29/1926/26

95/5

1939

66

87/13

87/10/3

27/1826/29

98/2

2141

Sorafenib Placebo

Characteristics (n=299) (n=303)

Age (median, years)

Male/Female (%)

Region (Europe/N America/others) (%)

Etiology (%)Viral Hepatitis (HCV/HBV)Alcohol/other

Child–Pugh (A/B; %)

Prior therapies (%)Surgical resectionLoco-regional therapies

Phase III SHARP Trial: Baseline

Characteristics of Patients

Llovet JM, et al. Presented at ASCO 2007, Chicago, IL, USA

18

82

54

38

8

70

30

17

83

54

39

7

70

30

BCLC stage2 (%)

Stage B (intermediate stage)

Stage C (advanced stage)

ECOG PS (%)

0

1

2

Macroscopic vascular invasion (portal

vein) and/or extrahepatic spread (%)

Present

Absent

1. Llovet JM, et al. Presented at ASCO 2007, Chicago, IL, USA; 2. Llovet JM & Bruix J.

BCLC Group. Semin Liver Dis. 1999

Phase III SHARP Trial: Baseline

Characteristics of Patients1 (cont’d)

Sorafenib Placebo

Characteristics (n=299) (n=303)

0274 241 205 161 108 67 38 12 0

Patients at risk

Sorafenib:

0276 224 179 126 78 47 25 7 2Placebo:

299

303

SorafenibMedian: 46.3 weeks (10.7 months)(95% CI: 40.9–57.9)

Su

rviv

al

pro

bab

ilit

y

Weeks

Hazard ratio (S/P): 0.69 (95% CI: 0.55–0.88)p=0.00058*

PlaceboMedian: 34.4 weeks (7.9 months)(95% CI: 29.4–39.4)

1.00

0

0.75

0.50

0.25

0 808 16 24 32 40 48 56 64 72

*O’Brien–Fleming threshold for statistical significance was p=0.0077

Phase III SHARP Trial: OS

(Intention-to-treat)


SorafenibMedian: 24.0 weeks (5.5 months)(95% CI: 18.0–30.0)

196 126 80 50 28 14 8 2192 101 57 31 12 8 2 1

Pro

gre

ss

ion

-fre

e p

rob

ab

ilit

y

Hazard ratio (S/P): 0.58(95% CI: 0.44–0.74) p=0.000007

546 12 18 24 30 36 42 480Time (Weeks)

PlaceboMedian: 12.3 weeks (2.8 months)(95% CI: 11.7–17.1)

1.00

0

0.75

0.50

0.25

Patients at risk

Sorafenib:Placebo:

299303

Phase III SHARP Trial: TTP

(Independent Central Review)


Phase III SHARP Trial: Response Assessment (RECIST; Independent Review)

Sorafenib

(n=299)

Placebo

(n=303)

Overall response

CR

PR

0

7 (2.3%)

0

2 (0.7%)

SD 211 (71%) 204 (67%)

PD 54 (18%) 73 (24%)

Progression-free rate at 4 months 62% 42%

Duration of treatment (median, weeks) 23 19

Llovet JM, et al. Presented at ASCO 2007

Chicago, IL, USA

RECIST = Response Evaluation Criteria In

Solid Tumors

Phase III SHARP Trial: Exploratory

Sub-group Survival Analysis

Sorafenib benefit Placebo benefit

OS Hazard ratio

ECOG PS 0

ECOG PS 1 & 2

0.5 1.0 1.50.0

Macroscopic vascular invasion

No macroscopic vascular invasion

No macroscopic VI/extrahepatic spread

Macroscopic VI and/or extrahepatic spread

No extrahepatic spread

Extrahepatic spread


Phase III SHARP Trial: Safety Events

Drug-related adverse events (%) All Grade 3–4 All Grade 3–4

Diarrhea 39 8/– 11 2/–

Pain (abdomen) 8 2/– 3 <1/–

Weight loss 9 2/– <1 0/–

Anorexia 14 <1/– 3 <1/–

Nausea 11 <1/– 8 1/–

HFSR 21 8/– 3 <1/–

Vomiting 5 1/– 3 <1/–

Alopecia 14 0/– 2 0/–

Liver dysfunction <1 <1/– 0 0/–

Bleeding 7 <1/– 4 <1/<1

Sorafenib(n=297)

Placebo(n=302)

Treatment-emergent serious adverse events (SAE, %) 52 54

Drug-related treatment-emergent SAE (%) 13 9


Hand–foot skin reaction

Phase III SHARP Trial: Conclusions (cont’d)

Sorafenib is the first systemic therapy to demonstrate

prolonged survival in patients with HCC

Sorafenib may become the new reference standard

for systemic therapy of patients with HCC

Sunitinib is being investigated in different

phase II trials in HCC

Design Country;

clinicaltrials.gov identifier

European/Asian, open-label study of sunitinib in

patients with unresectable HCC

France, Korea;

NCT00247676

Open-label, first-/second-line sunitinib in locally

advanced, unresectable or metastatic HCC

United States;

NCT00361309

Continuous sunitinib treatment in patients with

unresectable HCC

Switzerland; NCT00514228

Sunitinib and chemoembolization in patients with

unresectable HCC

United States;

NCT00524316

Open-label study of sunitinib in patients with

metastatic and/or surgically unresectable HCC

United States;

NCT00495625

Sunitinib and capecitabine for the treatment of

unresectable or metastatic HCC

United States

Open-label study of sunitinib in patients with

metastatic and/or surgically unresectable HCC

Italy, Denmark

www.ClinicalTrials.gov. Accessed December 2007

Phase II study to determine single-agent efficacy and

safety of sunitinib in patients with unresectable HCC

Phase II, European/Asian, open-label study of sunitinib in

patients with unresectable HCC who had not received prior

systemic treatment

Primary endpoints: Objective response rate (defined by RECIST)

Secondary endpoints: Clinical benefit rate (CR + PR + SD),

duration of response, time to tumor progression, overall survival,

exploratory measures of antitumor activity, safety

Faivre et al. Eur J Cancer 2007;5:270 (Abstract 3535)

RECIST=Response Evaluation Criteria in Solid Tumors

Continue as

long as

clinical

benefit

Unresectable

HCC

Sunitinib 50 mg/day

4 weeks on 2 weeks off

Results demonstrate sunitinib activity in

patients with unresectable HCC

Best response, n

(%)

Asia

(n=16)

Europe

(n=21)

Total

(N=37)

CR 0 0 0

PR 1 (6.3) 0 1 (2.7)

SD

>3 months 4 (25.0) 9 (42.9) 13 (35.1)

>6 months 3 (18.8) 5 (23.8) 8 (21.6)

PD 8 (50.0) 5 (23.8) 13 (35.1)

Clinical benefit rate (PR + SD >3 months) was 37.8% (n=14)


Density Density

Prior to sunitinib After sunitinib

Decrease in tumor density, n=26

n (%)

Induction of necrosis, n=21

n (%)

15% 21 (81)* 13 (62)

30% 16 (62) 10 (48)

*Choi criteria

Sunitinib decreases tumor density and 3-

dimensional measurement of tumor necrosis in

unresectable HCC


Phase II study to determine single-agent efficacy

and safety of sunitinib in patients with advanced HCC

Phase II, open-label single-center study of first- and second-line

treatment with sunitinib in patients with advanced HCC

Primary endpoint: PFS of patients with advanced HCC treated

with sunitinib

Secondary endpoints: safety, preliminary efficacy (based on

response rate, duration of response, and OS), exploratory

measures of antitumor activity Zhu et al. AACR-NCI-EORTC 2007 (oral presentation)

Stage 2:

Additional 17 patients

enrolled if >8 patients

achieved PFS >3 months

Stage 1:

Advanced

HCC (N=17)

Sunitinib 37.5 mg/day

4 weeks on

2 weeks off

Median PFS and OS in patients with

advanced HCC

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5

1.00

0.75

0.50

0.25

0

Time (Months)

Median OS = 10 months

(95% CI: 7.5–not estimable)

Zhu et al. AACR-NCI-EORTC 2007 (oral presentation)

1.00

0.75

0.50

0.25

0

Time (Months)

Median PFS = 4 months

(95% CI: 2.8–7.0)

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5

Pro

ba

bil

ity

Sunitinib treatment caused a change in

angiogenic biomarkers: VEGF and soluble

VEGFR2

pg

/ml

0

5000

10000

15000

Day 1 Day 15

pg

/ml

0

400

800

1200

1600

Day 1 Day 15

14/15 patients had a decrease in

sVEGFR2 at day 15

14/18 patients had an increase

in VEGF at day 15

Zhu et al. AACR-NCI-EORTC 2007 (oral presentation)

Summary of Recent Phase II Studies With Epidermal Growth Factor Receptor Inhibitors in Hepatocellular Carcimoma

Study Regimen

No.of

patients RR, %

Median

PFS/TTP,

mo

PFS at 6

mo, %

Median

survival,

mo

Philip2005 Erlotinib 38 9 3.2 32 13

Thomas 2007 Erlotinib 40 0 3.1 28 6.3

O’Dwyer 2006 Gefitinib 31 3 2.8 NR 6.5

Ramanathan 2006 Lapatinib 30 5 2.3 NR 6.2

Zhu 2007 Cetuximab 30 0 1.36 3 9.6

Gruenwald 2007 Cetuximab 32 0 1.87 NR NR

Louafi 2007 Cetuximab-

GEMOX

43 23 4.5 NR 9.2

RR indicates response rate; PFS, progression-free survival; TTP, time to tumor progression;

NR, not reported; GEMOX, gemcitabine and oxaliplatin.

Unresectable

DS : 33/38 (87%)

PR : 9%, SD :

50%

OS : 13 Months

Phase II study of Erlotinib (OSI-774) in patients with advanced HCC

JCO 23:6657-6663, 2005

A phase II open-label study of cetuximab in unresectable HCC

(ASCO 2007, Abs #4598)

GEMOX + Cetuximab

(ASCO 2007, Abs #4594)

Summary of Recent Phase I/II Studies With Bevacizumab-based Regimens in Hepatocellular Carcinoma

Study Regimen No. of patients

RR, % Median PFS/TTP, mo

PFS at 6 mo, %

Median survival, mo

Schwartz 2006 Bevacizumab 25 8 6.5 NR NR

Malka 2007 Bevacizumab 24 12.5 NR NR NR

Zhu 2006 GEMOX-B 33 20 5.3 48 9.6

Sun 2007 CAPEOX-B 30 10 5.4 40 NR

Hsu 2007 Capecitabine-bevacizumab

25 16 4.1 34 10.7

Thomas 2007 Bevacizumab-erlotinib

34 21 9 75(at 4 mo) 19

RR indicates response rate; PFS, progression-free survival; TTP, time to tumor progression; NR, not reported; GEMOX-B, gemcitabine, oxaliplatin, bevacizumab; CAPEOX-B, capecitabine, oxaliplatin, bevacizumab.

Phase II Combination Targeted Therapy:

Study n Efficacy Adverse events

Bevacizumab +

capecitabine1

45 25 patients had 6 months therapy:

ORR = 16%

DCR (ORR + SD) = 60%

Median OS/PFS 10.7/4.1 months

6-month PFS rate = 34%

Grade 3: HFSR (n=2)

Cetuximab +

gemcitabine +

oxaliplatin2

43 35 evaluable patients:

ORR = 23%; DCR = 65%

Grade 4: thrombocytopenia (n=1);

grade 3: thrombocytopenia (21%),

neutropenia (19%), acneiform rash

(19%)

Bevacizumab +

capecitabine +

oxaliplatin3


DCR = 89%

Mean PFS = 5.4 months

6-month PFS rate = 40%

Grade 2–3:

peripheral neuropathy (33%);

hand-foot syndrome reaction (11%)

Bevacizumab +

erlotinib4


CR = 1; PR = 5

SD (16 weeks) = 9

1 early death; grade 3–4:

hypertension (n=5), fatigue (n=4)

and GI bleeding (n=3)

References 1–4 from J Clin Oncol 2007; 25 (Supp):

1. Hsu C, et al. Abstract 15190; 2. Louafi S, et al. Abstract 4594

3. Sun W, et al. Abstract 4574; 4. Thomas MB, et al. Abstract 4567

Ongoing Trials of Molecular-targeted Therapies

in Combination Regimens for HCC

Combination Phase n Inclusion criteria Status Endpoints

Bevacizumab +

capecitabine

II 100 Advanced/

metastatic liver

cancer

In progress PFS rate at 27 weeks

Bevacizumab +

erlotinib

II 21 Unresectable HCC Recruiting PFS rate at 27 weeks,

tumor response rate

Bevacizumab +

erlotinib

II 40 Unresectable HCC Recruiting PFS rate at 16 weeks,

response rate, OS

Bevacizumab +

oxaliplatin +

gemcitabine

II 30 Unresectable HCC In progress TTP, tumor response,

safety

Bortezomib +

doxorubicin

II 40 Unresectable HCC Recruiting Objective response

rate, OS, TTP, safety


IDdB3, BioPharm Insight, MedTrack


in Combination Regimens for HCC (cont’d)

Combination Phase n

Inclusion


Bevacizumab +

dexamethasone

+ floxuridine

II 55 Unresectable

HCC

Initiated Tumor response,

safety

Thalidomide +

UFUR

II 41 Advanced

HCC

Recruiting Tumor response, PFS,

6-month PFS rate, OS

Sorafenib +

UFUR

II 50 Unresectable

and/or

metastatic

HCC

Recruiting PFS, 6-month PFS rate,

tumor response rate,

OS


IDdB3, BioPharm Insight, MedTrack; UFUR = Tegafur/uracil


Combined with Current Modalities

Combination Phase n

Inclusion


Bevacizumab +

TACE

II 30 Unresectable

HCC

Recruiting Neovessel

formation, tumor

progression

Bevacizumab +

TACE

II 40 Unresectable

HCC

Initiated 1-year tumor

response, OS,

safety

Celecoxib +

erlotinib as

adjuvant

I/II 50 Unresectable

HCC

Ongoing OS, disease-free

survival, safety,

MTD

Chemoembolization

+/- bevacizumab

II 30 Unresectable

HCC

Recruiting PFS, safety,

response rate




Combined with Current Modalities (cont’d)

Combination Phase n

Inclusion


PI-88 as

adjuvant to

curative

therapy

III N/A HCC Planned Tumor non-recurrence,

time to recurrence, OS

Gefitinib

adjuvant to

resection

II 40 Resectable

HCC

Recruiting Identification of

biomarkers,

recurrence-free

survival

Thalidomide +

radiotherapy

I/II 19 Locally

advanced

HCC

Recruiting Tolerability, feasibility

Sorafenib +

TACE with

doxorubicin

I N/A Unresectable

HCC

Recruiting MTD, dose-limiting

toxicity



Schematic illustration of potential future trial designs in advanced hepatocellular carcinoma. HCC indicates hepatocellular carcinoma; BSC, best supportive care.

Potential Future Trial Designs in Advanced HCC

A

B

C

Randomized :

1st-line

Randomized :

1st-line

Randomized :

2nd-line

(sorafenib-refractory)

New agent

Sorafenib

New agent + sorafenib

Orngoing sorafenib or BSC

Sorafenib

New agent

Overall Summary

Treatment options in advanced HCC are limited

Pathogenesis of HCC involves multiple signaling

pathways

Sorafenib is the first systemic therapy to demonstrate

prolonged survival in patients with HCC

Sorafenib may become the new reference standard for

systemic therapy of patients with HCC

Future Directions

Developing more effective systemic therapies

To identify key relevant molecular targets for

therapeutic intervention

Understanding of the clinical and molecular

predictors of sorafenib-mediated clinical

benefits and mechanisms of resistance

Examined in the adjuvant setting after RFA,

TACE, surgical resection, liver transplantation

case

55-yrs male, histologically proven HCC, hepatitis B(+),

ECOG PS 1, Child-Pugh A, macroscopic portal vein

invasion and regional L/N

Which treatment do you wants?

1. Best supportive care

2. TACE

3. Systemic cytotoxic agent

4. Hormonal therapy

5. Target agents (sorafenib)

targeted therapy in hepatocellular carcinoma (hcc)kaim.or.kr/pds/files/hmo/hmo_200807_08.pdf ·...

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