Hepatocellular Carcinoma:Progress at last

Alan P. Venook, M.D.

University of California, San Francisco

Sorafenib in HCC

• Sorafenib in HCV patients: subset analysis• Bolondi et al for SHARP

• Doxorubicin +/- sorafenib: randomized ph II• Abou-Alfa et al

RAS

Endothelial cell or Pericyte

Angiogenesis:

PDGF- VEGF

VEGFR-2PDGFR-

Paracrine stimulation

Mitochondria

Apoptosis

Tumor cell

PDGF

VEGF

EGF/HGF

ProliferationSurvival

Mitochondria

EGF/HGF

HIF-2

Autocrine loop

Apoptosis

ERK

RAS

MEK

RAF

Nucleus

ERK

MEK

Sorafenib Targets Both Tumor-Cell Proliferation and Angiogenesis

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

RAF

DifferentiationProliferationMigrationTubule formation

Sorafenib

Sorafenib

Nucleus

Management of Hepatocellular Carcinoma:Sorafenib phase II data

• Child’s A + B, untreated

• 400 mg bid continuous

• N = 137• PR = 2.2%• MR = 5.8%• TTP = 4.2 months• OS = 9.2 months

Abou-Alfa, et al; JCO, 2006

Abou-Alfa et al, JCO, 2007

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

Supported by Bayer HealthCare and Onyx Pharmaceuticals

Phase III SHARP Trial

Stratification:

• Macroscopic vascular invasion and/or extrahepatic spread

• ECOG PS

• Geographical region

Sorafenib (n=299)

400 mg po bid

continuous dosing

Ran

do

miz

atio

n

N=

602

Primary end-points: Overall survival

Time to symptomatic progression (FHSI8-TSP)

Secondary end-points: Time to progression (independent review)

Placebo (n=303)

2 tablets po bid

continuous dosing

Patient characteristics

CharacteristicsSorafenib(n=299)

Placebo(n=303)

• Age (yr, median) 65 66

• Male/Female (%) 87/13 87/13

• Region (Europe/N. America/other; %) 88/9/3 87/10/3

• EtiologyViral hepatitis (HCV/HBV)Alcohol/other

29/1926/26

27/1826/29

• Child-Pugh (A/B; %) 95/5 98/2

• Prior therapies: Surgical resectionLoco-regional

therapies

19%39%

21%41%

SorafenibMedian: 46.3 weeks(95% CI: 40.9, 57.9)

Su

rviv

al P

rob

abili

ty

Weeks

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

PlaceboMedian: 34.4 weeks (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.

0274 241 205 161 108 67 38 12 0Patients at risk

Sorafenib:0276 224 179 126 78 47 25 7 2Placebo:

299303

Overall survival (Intention-to-treat)

Phase III SHARP TrialResponse assessment

FSHI8-TSP: No significant differences between treatment groups (P=0.77).

Sorafenib(n=299)

Placebo(n=303)

Overall responseComplete response (CR)Partial response (PR)

07 (2.3%)

02 (0.7%)

Stable disease (SD) 211(71%) 204 (67%)

Progressive disease 54 (71%) 73 (24%)

Progression-free rate at 4 mo 62% 42%

Duration of treatment (median, weeks) 23 19

Child’s Pugh Score of Liver Cirrhosis

Parameter

Points

1 2 3

Albumin (g/dL) > 3.5 2.8 - 3.5 < 2.8

Bilirubin (mg/dL) < 2 2 - 3 > 3

Ascites Absent Slight Moderate

Encephalopathy None I - II III - IV

PT (INC) < 1. 7 1.8 - 2.3 > 2.3

Score A B C

Points 5 - 6 7 - 9 10 - 15

Pugh, RNH, et al. British Journal of Surgery. 60 (8): 646 -649, 1973

Luigi Bolondi, MD “Alma Mater Studiorum”

University of Bologna, Bologna, Italy

W Caspary, J Bennouna, B Thomson, W Van Steenbergen,F Degos, M Shan, D Voliotis, M Moscovici, J Bruix, for the SHARP

Investigators Study Group

Clinical Benefit of Sorafenib in Hepatitis C Patients With Hepatocellular Carcinoma (HCC): Subgroup Analysis of the Sorafenib HCC Assessment Randomized Protocol (SHARP) Trial

Other

Alcohol

Hepatitis B

Hepatitis C 50%-70%

70%

70%

20%

10%-20%

10%-20%

10%-20%

≤10%

0 20 40 60 80

Cases (%)

Risk Factors for HCC Worldwide

*Excluding Japan. 1. Llovet JM et al. Lancet. 2003;362:1907-1917. 2. Llovet J et al. J Clin Oncol. 2007;25(Suppl 18):LBA1.

% of Patients With Risk Factor in SHARP2

Sorafenib(n=299)

Placebo (n=303)

29 27

19 19

26 26

9 10

Asia/Africa*Europe/N. America

JapanAll

SHARP: OS in Patients With HCVSorafenibMedian: 14.0 mo95% CI: 9.9-N/E*

HR (95% CI): 0.58 (0.37-0.91)

PlaceboMedian: 7.9 mo95% CI: 5.4-9.8

Months From Randomization4 6 8 14 16

Pro

bab

ilit

y o

f S

urv

ival

0

0.25

0.50

0.75

1.00

0

*N/E = not estimable.

2 10 12

SHARP: Summary of Efficacy Measuresby HCV StatusHCV-positive Overall population1

Sorafenib

(n=93)Placebo(n=85)

Sorafenib(n=299)

Placebo(n=303)

DCR (%) 44.1 30.6 43.5 31.6

Med. TTP, mo 7.6 2.8 5.5 2.8

HR (95% CI) 0.44 (0.25-0.76) 0.58 (0.44-0.74)

Med. OS, mo 14.0 7.9 10.7 7.9

HR (95% CI) 0.58 (0.37-0.91) 0.69 (0.55-0.88)

1. Llovet J et al. J Clin Oncol. 2007;25(Suppl 18):LBA1.

Final results of phase II, randomized, double-blind study of sorafenib plus doxorubicin and placebo plus doxorubicin in patients with

advanced hepatocellular carcinoma

Abou-Alfa GK, Johnson P, Knox J, Davidenko I, Lacava J, Leung T, Mori A, Leberre M-A, Voliotis D, and Saltz LB

Memorial Sloan-Kettering Cancer Center, New York, USA, The University of Birmingham, Birmingham, UK, Princess Margaret Hospital, Toronto, Canada, Krasnodar City Oncology Center,

Krasnodar, Russia, Unidad Oncologica de Neuquen, Neuquen, Argentina, Hong Kong Sanatorium & Hospital, Hong Kong, Bayer Healthcare Pharma, Puteaux, France, Bayer HealthCare, France, Bayer

HealthCare, West Haven, USA

Study Design

Doxorubicin total allowed 360 mg/m2 and in approved circumstances 450 mg/m2, after which sorafenib versus placebo can be continued as single agent

Eligibility

Child-Pugh A

ECOG PS: 0, 1, 2

(1:1

) R

and

om

izat

ion

(N~

96)

Period 1 Period 2

Continue until

withdrawal,

PD, or death

6 cycles of:• Doxorubicin 60 mg/m2 IV*

Day 1 in 21-day cycles• Sorafenib 400 mg po bid

6 cycles of:• Doxorubicin 60 mg/m2 IV*

Day 1 in 21-day cycles• Placebo 2 tablets po bid

Placebo2 tablets po

bid

Sorafenib400 mg po

bid

ResultsDXR/sorafenib

(n=47)

DXR/placebo

(n=49)

TTP (months) 8.6 4.8

OS (months) 13.8 6.5

PFS (months) 6.9 2.8

Response

(CR+PR) n(%)

2 (4) 1 (2)

Response (SD) 36 (77) 27 (55)

Definitive analysis (data from March 2007 cutoff, independent assessment, TTP: 38 events, OS: 51 events, PFS: 70 events )

Sorafenib in HCC: Child’s Pugh A

• Subset analysis suggests comparable outcome and toxicity compared to entire cohort

• HCV patients under-represented on this study given the distribution of risk factors worldwide

• These are still high performance HCV / HCC patients

• The sum of the data reinforces the efficacy of sorafenib as a single agent in Child’s-Pugh A patients

Sorafenib / doxorubicin: HCC Child’s A

• Randomized phase II so direct comparison between arms not planned: “exploratory”

• No stratification; under-powered

• LV changes despite low dose total doxorubicin delivered raises issue of synergistic toxicity

Sorafenib / doxorubicin: HCC Child’s A

• Randomized phase II so direct comparison between arms not planned: “exploratory”

• No stratification; under-powered

• LV changes despite low dose total doxorubicin delivered raises issue of synergistic toxicity

• Are these results enough to sway the disbelievers?

Sorafenib / doxorubiNIB: HCC Child’s A

• Randomized phase II so direct comparison between arms not planned: “exploratory”

• No stratification; under-powered

• LV changes despite low dose total doxorubicin delivered raises issue of synergistic toxicity

• Are these results enough to sway the disbelievers?

Sorafenib / doxoruZIMAB: HCC Child’s A

• Randomized phase II so direct comparison between arms not planned: “exploratory”

• No stratification; under-powered

• LV changes despite low dose total doxorubicin delivered raises issue of synergistic toxicity

• Are these results enough to sway the disbelievers?

Sorafenib in HCC: Next questions

• How does sorafenib work?

• Do these findings apply to Child’s-B or C ?

• What is the proper dose of sorafenib in such pts?

• Can it be combined with other agents?

• Might it be active in the “adjuvant” setting?

• Could it be used in conjunction with TACE?

Sorafenib in HCC: Next studies

• Adjuvant after RFA / resection

• Sorafenib +/- erlotinib• Bayer / Onyx

• Sorafenib +/- doxorubicin

• TACE +/- sorafenib• Intergroup

• Other sorafenib combinations

Sorafenib in HCC: Take home message

• Phase II data in HCC is difficult to interpret

• Studies in HCC need to first be done in the most fit patients, then generalized if possible

• These advances, while landmark, are modest and much work needs to be done