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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

Epidemiology of HCC

• Fifth most common cancer globally1

• Over 600,000 new cases of liver cancer are diagnosed globally each year1

– Eastern Asia: 370,0001 – Japan: 40,0001

– Europe: 32,0002

– United States: 19,0003

• HCC is the third leading cause of cancer-related mortality,1 and is the leading cause of death in cirrhotic patients

• The incidence of HCC is increasing globally4

• Available systemic therapies have no proven survival advantage

1. International Agency for Cancer Research. GLOBOCAN 2002. Available at: http://www-dep.iarc.fr. Accessed April 23, 2007.2. International Agency for Cancer Research. EUCAN 1998. Available at: http://www-dep.iarc.fr/eucan/eucan.htm. Accessed

April 26, 2007; 3. Jemal A et al. CA Cancer J Clin. 2007;57:43-66; 4. Bosch XF et al. Clin Liver Dis. 2005;9:191-211.

Llovet JM, & Bruix J, BCLC. Lancet, 2003

End StageAdvanced StageIntermediate StageEarly Stage

Surgical TreatmentsLocal Ablation New AgentsTACE

HCC

(30%)Potentially curative treatments

5-yr survival: 50-70%

(50-60%)Randomized trials

median survival if untreated: 6-16 mo

(10%)BSC

survival <3 mo

Rationale HCC treatment schedule

Sorafenib in HCC: Rationale

• Raf kinase is overexpressed and activated in HCC1

• RAF/MEK/ERK signaling pathway is implicated in liver tumorigenesis1-3

• Sorafenib, approved in advanced RCC, is the only approved inhibitor of Raf kinase4

• Sorafenib is a multikinase inhibitor of RAF, VEGFR, and other kinases3

• Sorafenib induces apoptosis in HCC xenograft models4

• Sorafenib was active in a Phase II trial of patients with advanced HCC and Child-Pugh class A and B liver function status5

1. Hwang et al. Hepatol Res. 2. Calvisi et al, Gastroenterology 2006 3. Villanueva et al. Sem Liv Dis 2007 4. Liu et al. Cancer Res. 2006 5. Abou-Alfa et al. J Clin Oncol. 2006.

RAS

Endothelial cell or Pericyte

Angiogenesis:

PDGF- VEGF

VEGFR-2PDGFR-

Paracrine stimulation

Mitochondria

Apoptosis

Tumor cell

PDGFVEGF

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

Phase III SHARP TrialStudy design

Stratification:

• Macroscopic vascular invasion and/or extrahepatic spread

• ECOG PS

• Geographical region

Sorafenib (n=299)400 mg po bid

continuous dosingR

ando

miz

atio

nN

=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

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Phase III SHARP TrialStudy design

Design • International, multicentre Phase III study• Inclusion criteria:

Histology-proven HCCAdvanced HCC At least 1 measurable untreated lesion ECOG 0-2Child-Pugh A class No prior systemic treatment

Randomization • Double-blind sorafenib 400 mg bid vs placebo;

ratio 1:1• Accrual: March 2005 to April 2006

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Phase III SHARP TrialStudy design

Treatment schedule• Sorafenib 400 mg bid continuous dosing until:

– Both radiologic progression and FHSI8-TSP were achieved – Any adverse event requiring discontinuation

Statistical methods• Intention-to-treat analysis• Sample size: N=560 patients (424 OS events)

– Overall alpha for trial maintained at =0.025 (one-sided)

• Overall survival assessment =0.02 (one-sided)– Two interim analyses planned using O’Brien-Fleming spending function– 90% power to detect a 40% improvement: 7 months → 9.7 months

• TTSP assessment (FHSI8-TSP) =0.005 (one-sided)– Single analysis performed at time of final survival analysis

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Phase III SHARP TrialSummary of trial conduct

2nd Interim analysis OS Events: 321 deaths Date: Oct 17th, 2006

Sorafenib (n=299) Placebo (n=303)

902 patients with HCC screened

602 pts randomized

Consent withdrawn: 8%Death: 4%Adverse events: 5%Protocol deviations: 83%

2 did not receive treatment 1 did not receive treatment

DMC recomendaciónStop RCT

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Baseline characteristics of patients

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%

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Baseline characteristics of patients

CharacteristicsSorafenib(n=299)

Placebo(n=303)

• BCLC stage (%)Stage BStage C

1882

1783

• ECOG PS (%)ECOG 0ECOG 1ECOG 2

54388

54397

• Vascular invasion / extrahepatic spreadPresentAbsent

7030

7030

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

Surv

ival

Pro

babi

lity

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

Phase III SHARP TrialOverall survival (Intention-to-treat)

PlaceboMedian: 12.3 weeks(95% CI: 11.7, 17.1)

SorafenibMedian: 24.0 weeks(95% CI: 18.0, 30.0)

0196 126 80 50 28 14 8 20192 101 57 31 12 8 2 1

Pro

babi

lity

of P

rogr

essi

on

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

546 12 18 24 30 36 42 480 Weeks

1.00

0

0.75

0.50

0.25

Patients at risk Sorafenib:

Placebo:299303

Phase III SHARP TrialTime to progression (Independent central review)

Phase III SHARP TrialResponse assessment (RECIST; Independent review)

Time to symptom progression (FSHI8-TSP)

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

Phase III SHARP TrialExploratory subgroup analysis

Sorafenib benefit Placebo benefit

Hazard Ratio

ECOG PS 0ECOG PS 1 & 2

Macroscopic vascular invasionNo macroscopic vascular invasion

No macroscopic VI/extrahepatic spread

Macroscopic VI/extrahepatic spread

No extrahepatic spread

Extrahepatic spread

0.5 1.0 1.50.0

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Safety events

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

Diarrhea 39 8 11 2Pain (abdomen) 8 2 3 <1Weight loss 9 2 <1 0Anorexia 14 <1 3 <1Nausea 11 <1 8 1Hand-foot skin reaction 21 8 3 <1Vomiting 5 1 3 <1Alpecia 14 0 2 0Liver dysfunction <1 <1 0 0Bleeding 7 <1 4 <1/<1

Sorafenib(n=297)

Placebo(n=302)

• Treatment-emergent serious adverse events (SAE, %) 52 54• Drug-related adverse events (%) 13 9

Phase III SHARP TrialConclusions

• Sorafenib prolonged overall survival vs placebo in advanced HCC

Median OS, 46 weeks vs 34 weeksHR 0.69, P=0.0005844% increase in overall survival

• Sorafenib prolonged time to progression vs placebo Median TTP, 24 weeks vs 12 weeks HR 0.58, P=0.00000773% prolongation in time to progression

• Sorafenib was well-tolerated with manageable side effects

Phase III SHARP TrialConclusions

• Sorafenib is the first systemic therapy to prolong survival in HCC patients

• Sorafenib is the new reference standard for systemic therapy of HCC patients

SHARP trial acknowledgments

Argentina: Maria Guadalupe Pallota, Juan Jose Zarba, Marcelo SilvaBrazil: Carlos Barrios, Andre Cosme de OliveiraChile: Jorge Martinez-Castillo, Claudia Gamargo GarateMexico: Laura Estela Cisnero Garza, Jesus Miguel Lazaro LeonPeru: Jorge Leon, Adelina Lozano

Belgium: Ivan Borbath, Jean-Luc Van Laethem, Hans Van Vlierberghe, Jacques De Greve, Werner Van SteenbergenBulgaria: Iskren Kotzev, Dimitar Takov, Konstantin TchernevFrance: Michel Beaugrand, Jaafar Bennouna, Jean-Pierre Bronowicki, Françoise Degos, Sophie Dominguez, Jean-Didier Grange, Patrick Hillon, Jean-Luc Raoul, Jean-François Seitz, Jean-Frédéric BlancGermany: Hubert Blum, Wolfgang Caspary, Peter Buggisch, Reiner Wiest, Mathias Dollinger, Guido Gerken, Burkhard Göke, Michael Gregor, Tim Greten, Dieter Häussinger, Peter Galle, Johann Scherübl, Roland Schmid, Ulrich Spengler, Gerhard Treiber, Stefan Zeuzem, Max ScheulenGreece: Constantin Arvanitakis, Georgios Germanidis, Ioannis Katsos, Israel: Salomon Stemmer, Arie Figer, Ron Epelbaum

Canada: Morris Sherman, Charles Olweny, Kelly Burak, Rakesh Goel, Mang Ma, Peter MetrakosUnited States: Carolyn Britten, Nashat Gabrail, Philip Gold, Peter Kennedy, Jorge Marrero, Alex Befeler, Thomas Boyer, Douglas Heuman, Samuel So, Josep Llovet, Alvaro Koch, Michael Schilsky, Rise Stribling, Alec Goldenberg, Thomas Byrne, Stuart Gordon, Jonathan Schwartz, Brian Carr, Guadalupe Garcia-Tsao

Australia: Michael Boyer, Benjamin Thomson, Howard Gurney, Stephen Riordan, Niall Tebbutt, Andrew StricklandNew Zealand: Edward Gane, Anne O'Donnell

Italy: Dino Amadori, Francesco Cognetti, Antonio Craxi, Fabio Farinati, Cesare Gridelli, Luigi Bolondi, Angelo Sangiovanni, Andrea Martoni, Camillo Porta, Armando Santoro, Franco Trevisani, Vincenzo Mazzaferro, Sergio RicciPoland: Jacek Jassem, Grazyna Rydzewska, Andrzej Szawlowski, Piotr TomczakRomania: Stefan Curescu, Lucian Miron, Florinel BadulescuRussia: Eskender Topuzov, Alexei Chzhao, Vladislav Novozhenov, Pavel Bogomolov, Valery KubyshkinSpain: Jordi Bruix, Javier Bustamante Schneider, José Luís Montero Alvarez, Moises Diago, Cristina Grávalos, Luís Ruíz del Arbol, Bruno Sangro, Ricard Solá, Josep Tabernero, Sonia PascualSwitzerland: Beat Muellhaupt, Arnaud RothUnited Kingdom: Tim Meyer, T. R. Jeffry Evans, Stephen Falk, Helen Reeves, Paul RossThe patients

and their families