new treatment approaches in hepatocellular carcinoma dr. francesco caponigro istituto tumori napoli

New treatment New treatment approachesapproaches

in in HepatocellularHepatocellular

CarcinomaCarcinoma

Dr. Francesco CaponigroDr. Francesco CaponigroIstituto Tumori NapoliIstituto Tumori Napoli

F. Caponigro - Istituto Tumori Napoli

Hepatocellular carcinoma (HCC) is the Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related third leading cause of cancer-related death and the fifth most prevalent death and the fifth most prevalent cancer worldwide with cancer worldwide with > 80% of patients presenting with > 80% of patients presenting with advanced disease.advanced disease.

Late diagnosis and the frequent Late diagnosis and the frequent coexistence of cirrhosis result in a poor coexistence of cirrhosis result in a poor prognosis for patients with HCCprognosis for patients with HCC

Drug-resistance genes such as Drug-resistance genes such as multidrug resistance-1 are common in multidrug resistance-1 are common in liver cells, causing HCC tumors to be liver cells, causing HCC tumors to be inherently chemoresistantinherently chemoresistant


Phase II/III Studies of Systemic Phase II/III Studies of Systemic Treatments in Advanced HCCTreatments in Advanced HCC

TreatmentTreatment Phase of Phase of StudyStudy

Number of Number of PatientsPatients

Overall Overall Response RateResponse Rate

Systemic Systemic ChemotherapyChemotherapy

Doxorubicin as a Doxorubicin as a single agentsingle agent

II/IIIII/III > 1000> 1000 10%-18%10%-18%

Doxorubicin in Doxorubicin in combinationcombination

II/IIIII/III 144144 26%26%

CisplatinCisplatin IIII 4848 10%10%

EpirubicinEpirubicin IIII 6262 11%11%

MitoxantroneMitoxantrone IIII 118118 16%16%

5-FU/paclitaxel/5-FU/paclitaxel/irinotecanirinotecan

II/IIIII/III -- < 10%< 10%

AntiandrogenAntiandrogen IIIIII 376376 < 10%< 10%

InterferonInterferon IIIIII 6060 < 10%< 10%

OctreotideOctreotide IIIIII 6060 < 5%< 5%

SeocalcitolSeocalcitol IIIIII 746746 < 5%< 5%


Sorafenib (BAY 43-9006, Nexavar): a multikinase inhibitor with activity against Raf,

VEGFR-2, VEGFR-3, PDGFR, c-Kit

The turning-point in the The turning-point in the management of management of advancedadvanced HCC HCC


Signaling pathways in HCCSignaling pathways in HCC

Villanueva A et al, Semin Liver Dis 2007

VEGF

EGFR 1.

2.

5.

3.

4.


SORAFENIBSORAFENIBFarmacokineticsFarmacokinetics

Low absorption

T1/2: 24-36 h

Steady state: after 7 days

Time of assumption: 1-2 hours before or after meals

Elimination: mainly as glucuronate


SORAFENIBSORAFENIBSafetySafety Data Data

Sorafenib is well tolerated and grade 3-4 adverse events have been reported in 30%

of cases in phase I studies. The main side effects are:

Skin rash Hand and foot syndrome Diarrhea - nausea Fatigue Hypertension


SORAFENIBClinical studies in HCC

Phase II Study of Sorafenib in non resectable HCC

Abou-Alfa GK, et al. J Clin Oncol 2006



Phase II Study of Sorafenib in non resectable HCC

3/137 pts (2.2%) partial response 8/137 pts (5.8%) minor response 46/137 (33.6%) long-term stable disease (> 16 weeks) Time to progression (TTP) 4.2 months Overall survival 9.2 monthsGrade ¾ toxicity: fatigue (9.5%), diarrhea (8.0%) hand and foot syndrome (5.1%)




Pre-treatment pERK was correlated to TTP

Although Sorafenib activity was really modest, both the manageable toxicity profile and the peculiarity of its

mechanism of action support further trials



PhasePhase III SHARP Trial III SHARP Trial StudyStudy Design Design

Primary endpoints: overall survival, time to Primary endpoints: overall survival, time to symptomatic progression (FHSI8-TSP)symptomatic progression (FHSI8-TSP)

Secondary endpoint: time to progression Secondary endpoint: time to progression (independent review)(independent review)

Stratify by:• Macroscopic vascular invasion (portal vein) and/or extrahepatic spread•ECOG PS•Geographic region

Placebo 2 tablets p.o.b.i.d. continuous dosing

(n = 303)

Sorafenib 400 mg p.o.,b.i.d. continuous dosing

(n = 299)

RANDOMIZE


Phase III SHARP TrialPhase III SHARP TrialBaseline characteristics of Baseline characteristics of

patients patients

CharacteristicsCharacteristics

SorafenSorafenibib

(n=299)(n=299)PlaceboPlacebo(n=303)(n=303)

Age (yr, median)Age (yr, median) 6565 6666

Male/Female (%)Male/Female (%) 87/1387/13 87/1387/13

Region (Europe/N. Region (Europe/N. America/other; %)America/other; %)

88/9/388/9/3 87/10/387/10/3

Etiology (%)Etiology (%)Viral hepatitis (HCV/HBV)Viral hepatitis (HCV/HBV)Alcohol/otherAlcohol/other

29/1929/1926/2626/26

27/1827/1826/2926/29

Llovet JM et al. Presented at: ECCO;September 23-27, 2007; Barcelona, Spain.

Phase III SHARP TrialPhase III SHARP Trial

Baseline characteristics of Baseline characteristics of patients patients

CharacteristicsCharacteristics

SorafenSorafenibib

(n=299(n=299))

PlacebPlaceboo

(n=303(n=303))

Child-Pugh (A/B; %)Child-Pugh (A/B; %) 95/595/5 98/298/2Prior therapies: Surgical Prior therapies: Surgical

resectionresectionLoco-regional therapiesLoco-regional therapies

19%19%39%39%

21%21%41%41%

ECOG PS (%)ECOG PS (%)ECOG 0ECOG 0ECOG 1ECOG 1ECOG 2ECOG 2

5454383888

5454393977

Vascular invasion / Vascular invasion / extrahepatic spreadextrahepatic spread

PresentPresentAbsentAbsent

70703030

70703030

Llovet JM et al. Presented at: ECCO; September 23-27, 2007; Barcelona, Spain.

Llovet JM and Bruix J, BCLC Group, Semin Liver Dis. 1999.


Phase III SHARP TrialPhase III SHARP Trial Efficacy (Intent-to-Treat Efficacy (Intent-to-Treat

Population)Population)SorafenibSorafenib

(n = 299)(n = 299)PlaceboPlacebo

(n = 303)(n = 303)

Median Overall Survival Median Overall Survival (95% CI)(95% CI)

10.7 (9.4-13.3)months 7.9 (6.8-10.7 (9.4-13.3)months 7.9 (6.8-9.1)months9.1)months

HR 0.69; 95% CI, 0.55-0.88; P HR 0.69; 95% CI, 0.55-0.88; P = .00058= .00058

Median Time to Progression Median Time to Progression (95% CI)(95% CI)

5.5 (4.1-6.9)months 2.8 (2.7-5.5 (4.1-6.9)months 2.8 (2.7-3.9)months3.9)months

HR 0.58; 95% CI, 0.44-0.74; P HR 0.58; 95% CI, 0.44-0.74; P = .000007= .000007

ResponseResponse

Complete responseComplete response 00 00

Partial responsePartial response 7 (2%)7 (2%) 2 (< 1%)2 (< 1%)

Stable DiseaseStable Disease 211 (71%)211 (71%) 204 (67%)204 (67%)

Progressive DiseaseProgressive Disease 54 (18%)54 (18%) 73 (24%)73 (24%)

Progression-Free Rate at 4 Progression-Free Rate at 4 MonthsMonths

62%62% 42%42%

Median Duration of Median Duration of TreatmentTreatment

5.3 months5.3 months 4.4 months4.4 months


Su

rviv

al

Pro

bab

ilit

y

Weeks

Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.87)

P=0.00058*

SorafenibMedian: 46.3 weeks (10.7 mo)(95% CI: 40.9, 57.9)

PlaceboMedian: 34.4 weeks (7.9 mo)(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

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 TrialPhase III SHARP TrialOverall survival (Intention-to-Overall survival (Intention-to-

treat)treat)

*O’Brien-Fleming threshold for statistical significance was P=0.0077

Llovet JM et al. Presented at: ECCO;September 23-27, 2007; Barcelona, Spain


PlaceboMedian: 12.3 weeks (2.8 mo)(95% CI: 11.7, 17.1)

SorafenibMedian: 24.0 weeks (5.5 mo) (95% CI: 18.0, 30.0)

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

Pro

bab

ilit

y of

Pro

gre

ssio

n

Hazard ratio (S/P): 0.58 (95% CI: 0.45, 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 TrialPhase III SHARP TrialTime to progression (Independent Time to progression (Independent

central review)central review)

Llovet JM et al. Presented at: ECCO; September 23-27, 2007; Barcelona, Spain.


Phase III SHARP TrialPhase III SHARP TrialExploratory subgroup survival analysisExploratory subgroup survival analysis

Sorafenib benefit

Placebo benefit

Hazard Ratio (95% CI)

ECOG PS 0

ECOG 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

Llovet JM et al. Presented at: ECCO;September 23-27, 2007; Barcelona, Spain.


Phase III SHARP TrialPhase III SHARP TrialAdverse Events (1/2)Adverse Events (1/2)

Sorafenib ( % )Sorafenib ( % )( n = 297 )( n = 297 )

Placebo ( % )Placebo ( % )( n = 302)( n = 302)

Drug-Related Drug-Related Treatment-Treatment-EmergentEmergentSerious Adverse Serious Adverse EventsEvents

13%13% 9%9%

Drug-Related Drug-Related Adverse EventsAdverse Events

AllAll Grade 3Grade 3 AllAll Grade Grade 33

DiarrheaDiarrhea 39%39% 8%8% 11%11% 2%2%

Pain (abdomen)Pain (abdomen) 8%8% 2%2% 3%3% < 1%< 1%

Weight lossWeight loss 9%9% 2%2% < 1%< 1% 0%0%

AnorexiaAnorexia 14%14% < 1%< 1% 3%3% < 1%< 1%


Phase III SHARP TrialPhase III SHARP TrialAdverse Events (2/2)Adverse Events (2/2)

Sorafenib ( % )Sorafenib ( % )( n = 297 )( n = 297 )

Placebo ( % )Placebo ( % )( n = 302)( n = 302)

Drug-Related Drug-Related Adverse EventsAdverse Events

AllAll Grade 3Grade 3 AllAll Grade 3Grade 3

NauseaNausea 11%11% < 1%< 1% 8%8% 1%1%

Hand-foot skin Hand-foot skin reactionreaction

21%21% 8%8% 3%3% < 1%< 1%

VomitingVomiting 5%5% 1%1% 3%3% < 1%< 1%

AlopeciaAlopecia 14%14% 0%0% 2%2% 0%0%

Liver dysfunctionLiver dysfunction < 1%< 1% < 1%< 1% 0%0% 0%0%

BleedingBleeding 7%7% < 1%< 1% 4%4% <1%*<1%*

* Less than 1 % of patients also experienced grade 4 bleeding


Phase III SHARP TrialPhase III SHARP TrialConclusionsConclusions

Sorafenib prolonged median overall survival Sorafenib prolonged median overall survival compared to placebo in patients with advanced compared to placebo in patients with advanced HCC:HCC: Median overall survival: 10.7 months vs. 7.9 monthsMedian overall survival: 10.7 months vs. 7.9 months Hazard ratio 0.69; Hazard ratio 0.69; P = .00058P = .00058 44% increase in median overall survival44% increase in median overall survival

Sorafenib prolonged median time to progression Sorafenib prolonged median time to progression compared to placebo in patients with advanced compared to placebo in patients with advanced HCC: HCC: Median time to progression: 5.5 months vs. 2.8 monthsMedian time to progression: 5.5 months vs. 2.8 months Hazard ratio 0.58; Hazard ratio 0.58; P = .000007P = .000007 73% prolongation in median time to progression73% prolongation in median time to progression

Sorafenib was tolerable, with manageable side effectsSorafenib was tolerable, with manageable side effects Sorafenib is the first systemic therapy to prolong Sorafenib is the first systemic therapy to prolong

survival in patients with HCCsurvival in patients with HCC


Sorafenib + Dox

Placebo + Dox

PRIMARY ENDPOINT Time to Progression (TTP)

SECONDARY ENDPOINT■ Overall Survival (OS)■Time To Symptom Progression (TTSP)■ Quality of life (QoL)

~ 90 pts with advanced HCC

ECOG PS: 0,1,2

Phase II randomized study of Sorafenib + Doxorubicin

versus Doxorubicin + Placebo in HCC

Phase II randomized study of Sorafenib + Doxorubicin

versus Doxorubicin + Placebo in HCC

Randomization 1:1

Abou-Alfa GK et al. Presented at: ECCO; September 23-27, 2007; Barcelona, Spain


Demographics (n=96)Demographics (n=96)DXR/DXR/

sorafenib sorafenib (n=47)(n=47)

DXR/placebo DXR/placebo (n=49)(n=49)

Gender n(%)Gender n(%) MaleMale 31 (66)31 (66) 42 (86)42 (86)

FemaleFemale 16 (34)16 (34) 7 (14)7 (14)

Age (years)Age (years) MeanMean 6363 6262

ECOG n(%) n(%)ECOG n(%) n(%) 00 22 (47)22 (47) 16 (33)16 (33)

11 18 (38)18 (38) 25 (51)25 (51)

2/32/3 4 (8.5)4 (8.5) 4 (8)4 (8)

MissingMissing 4 (8.5)4 (8.5) 4 (8)4 (8)

Child’s Pugh n(%)Child’s Pugh n(%) AA 47 (100)47 (100) 48 (98)48 (98)

BB 0 (0)0 (0) 1 (2)1 (2)

Extrahepatic disease n(%)Extrahepatic disease n(%) YesYes 24(51)24(51) 32 (65)32 (65)

NoNo 23 (49)23 (49) 17 (35)17 (35)

Macroscopic Vascular Macroscopic Vascular Invasion n(%)Invasion n(%)

YesYes 13 (28)13 (28) 16 (33)16 (33)

NoNo 33 (70)33 (70) 32 (65)32 (65)

MissingMissing 1 (2)1 (2) 1 (2)1 (2)DXR=Doxorubicin

Abou-Alfa GK et al. Presented at: ECCO; September 23-27, 2007; Barcelona, Spain.


ResultsResultsDXR/sorafenibDXR/sorafenib

(n=47)(n=47)DXR/DXR/

placeboplacebo

(n=49)(n=49)

TTP (months)TTP (months) 8.68.6 4.84.8

OS (months)OS (months) 13.713.7 6.56.5

PFS (months)PFS (months) 6.96.9 2.82.8

ResponseResponse

(CR+PR) n(%)(CR+PR) n(%)2 (4)2 (4) 1 (2)1 (2)

Stable Disease Stable Disease

(SD) n (%)(SD) n (%)

36 (77)36 (77) 27 (55)27 (55)

Definitive analysis (data from March 2007 cutoff, independent assessment, TTP: 38 events, OS: 50 events, PFS: 70 events) Abou-Alfa GK et al. Presented at:

ECCO; September 23-27, 2007; Barcelona, Spain.


ToxicitiesToxicitiesDXR/sorafenib (n=47)DXR/sorafenib (n=47) DXR/placebo (n=49)DXR/placebo (n=49)

n(%)n(%) All grades All grades Grade 3-4 Grade 3-4 All gradesAll grades Grade 3-4Grade 3-4

FatigueFatigue 35 (75)35 (75) 7 (15)7 (15) 31 (65)31 (65) 7 (15)7 (15)

Abdominal painAbdominal pain 16 (34)16 (34) 5 (10)5 (10) 14 (29)14 (29) 4 (8)4 (8)

NeutropeniaNeutropenia 31 (66)31 (66) 25 (53)25 (53) 29 (60)29 (60) 22 (46)22 (46)

Febrile Febrile Neutropenia Neutropenia

2 (4)2 (4) 2 (4)2 (4) 7 (15)7 (15) 5 (10)5 (10)

DiarrheaDiarrhea 25 (51)25 (51) 5 (11)5 (11) 12 (25)12 (25) 5 (10)5 (10)

Bilirubin Bilirubin 16 (34)16 (34) 5 (11)5 (11) 15 (31)15 (31) 3 (6)3 (6)

Hand footHand foot 14 (30)14 (30) 4 (9)4 (9) 2 (4)2 (4) 0 (0)0 (0)

LV DysfunctionLV Dysfunction 9 (19)9 (19) 1 (2)1 (2) 1 (2)1 (2) 0 (0)0 (0)

HypertensionHypertension 8 (17)8 (17) 0 (0)0 (0) 0 (0)0 (0) 0 (0)0 (0)

NCI-CTC (version 3); NCI-CTC=National Cancer Institute–Common Toxicity Criteria

Abou-Alfa GK et al. Presented at: ECCO;September 23-27, 2007; Barcelona, Spain.


ConclusionsConclusions This randomized phase II study of Doxorubicin This randomized phase II study of Doxorubicin

plus Sorafenib and Doxorubicin plus placebo, plus Sorafenib and Doxorubicin plus placebo, showed encouraging TTP and OS outcome for showed encouraging TTP and OS outcome for the Doxorubicin plus Sorafenib the Doxorubicin plus Sorafenib

This trial supports the growing body of This trial supports the growing body of evidence of the activity of Sorafenib in HCCevidence of the activity of Sorafenib in HCC

Any synergistic role between Sorafenib plus Any synergistic role between Sorafenib plus doxorubicin in HCC needs to be further doxorubicin in HCC needs to be further defineddefined

Abou-Alfa GK et al. Presented at: ECCO; September 23-27, 2007; Barcelona, Spain.


A Phase II Study of Sorafenib Plus A Phase II Study of Sorafenib Plus Tegafur/Uracil for the Treatment of Tegafur/Uracil for the Treatment of

Advanced or Metastatic Advanced or Metastatic Hepatocellular Carcinoma Hepatocellular Carcinoma NCT0046491

9

Ongoing

trial

Unresectable and/or metastatic HCC PS 0-2 ECOG No metastatic brain tumors Prior systemic treatment for HCC

Inclusion criteria

Primary end-point PFSSecondary end-points Toxicity, ORR,

SDR, OS

Tegafur/uracil, which has potential anti-HCC activity (ORR 0-18% ~, in phase II studies) and interesting anti-angiogenesis activity (in several preclinical models), is an ideal candidate drug to improve the efficacy of sorafenib in HCC

Rationale

EnrollmentEnrollment 5050

Start DateStart Date April 2007April 2007

Expected Expected Completion Completion DateDate

December December 20082008

Beyond Sorafenib

NEW POTENTIAL TARGETED THERAPIES

IN HCC


Signaling pathways in HCCSignaling pathways in HCC

Villanueva A et al, Semin Liver Dis 2007

VEGF

EGFR 1.

2.

5.

3.

4.


1. EGFR pathway

EGFR is overexpressed in HCC and is associated with increased cell proliferation and reduced apoptosis

Schmidt CM et al, Biochem Biophys Res Commun 1997Ito Y et al, Br J Cancer 2001


In HepG2 cells, Gefitinib causes:

Inhibition of EGFR by gefitinib induces growth inhibition, apoptosis and cell cycle arrest in human HCC cell lines

Hopfner M et al, J Hepatol 2004

A) time- and dose-dependent growth inhibition

B) dose-dependent accumulation in the G0/G1-phase of the cell cycle.

C) dose-dependently induced caspase-3 activation

A

BC


Phase II Study of Erlotinib in Patients With Advanced

Hepatocellular Cancer (N = 38)

Philip et al, JCO 2005

■ Patients with unresectable or metastatic HCC■ 47% of patients received prior chemotherapy■ Erlotinib given continuously at of 150 mg/day orally■ Primary end-point: proportion of patients progression-free at 6 months

PFS at 6 months: 32% (CI 95%, 18 to 49)

Median OS = 13 months


Erlotinib in Combination With Docetaxel in Advanced

Hepatocellular and Biliary Tract Carcinomas

NCT00532441

Phase II ongoing study Inclusion criteria■ HCC or biliary tract carcinomas, not amenable to curative resection or transplantation■ ≤ 2 prior chemotherapy regimens■ PS 2 ECOG■ Child-Pugh A cirrhosis

Primary end-pointTreatment protocol■ Erlotinib: 150 mg p.o., days 2-7, 9-14,

16-28 q28■ Docetaxel: 30 mg/m2 iv d 1, 8, 15 q28

■ PFS rate at 16 weeks

Secondary end-points■ ORR; d RR; disease control; OS■ Safety and toxicity■ Correlation of response with biomarkers

Key regulator of cell proliferation

2. The mTOR pathway

Rapamycin inhibits HCC growth in vivo

tumor-bearing control animal

−Bjornsti MA et al, Nat Rev Cancer 2004

−Sahin F et al, Clin Cancer Res 2004

−Semela D et al,J Hepatol 2007


A Phase I/II Study of RAD001 in A Phase I/II Study of RAD001 in Advanced Hepatocellular Advanced Hepatocellular

CarcinomaCarcinomaNCT00516165

Ongoing study

Primary end-points■ To determine the maximum tolerated dose

of RAD001 ■ To determine PFS rate at 24 weeks

Inclusion criteria■ Unresectable of metastatic HCC ■ 0-2 prior systemic therapy for HCC■ PS 2 ECOG

RAD001 (Everolimus) is an oral kinase inhibitor that blocks the mTOR, a key component of PI3K/AKT pathway

Enrollment: Enrollment:

4040

Start Date: Start Date: August 2007August 2007


Nuclear -catenin accumulation, a hallmark of the activeted Wnt signaling, has been observed in 33-67% of HCC.

3. The Wnt pathway In the absence of ligand, -catenin is degraded through ubiquitin-proteasome systems after phosphorylation by the APC/AXIN/GSK3b complex.Upon Wnt ligand stimulation, -catenin accumulates in the cytosol and translocates into the nucleus. Intranuclear b-catenin leads to modifications in expression of numerous genes related to cell proliferation, cell cycling, apoptosis, and differentiation (Survivin, c-myc, Cyclin D1, etc).

Moreover, mutations of components of the Wnt pathway ( -catenin, AXIN 1, AXIN 2) have been described in HCC

Breuhahn K et al, Oncogene 2006Miyoshi Y et al, cancer Res 1998Lee HC et al, Front Biosci 2006


4. VEGF Pathway (angiogenesis)

Microvessels stained by anti-CD34 in a tumor section of HCC, with almost no staining in the adjacent non-tumorous liver

DFS after hepatic resection in pts withHCC ≤5 cm stratified into low and high MVD by CD34 immunostaining (P=0.002)

HCCs are highly vascularized tumors and increased levels of VEGF and microvessel density (MVD) have been observed.High VEGF expression has been associated with inferior survival

Poon RT et al, J Clin Oncol 2002

Yamaguchi R et al, Hepatology 1998

Chao Y et al, Ann Surg Oncol 2003


Phase II Trial of Bevacizumab Phase II Trial of Bevacizumab in HCCin HCCNumber of PatientsNumber of Patients

( n = 33)( n = 33)

Patient CharacteristicsPatient Characteristics

AgeAge 31-81 years31-81 years

Gender ( M/F )Gender ( M/F ) 28/528/5

Child-Pugh ( A/B )Child-Pugh ( A/B ) 26/726/7

Tumor stage ( Tumor stage ( uninodular/multinodular )uninodular/multinodular )

5/285/28

Segmental vein invasionSegmental vein invasion 55

Adverse EventsAdverse Events

Transient ischemic accidentTransient ischemic accident 11

Arterial hypertensionArterial hypertension 11

Hepatic arterial thrombosisHepatic arterial thrombosis 11

Gastrointestinal bleedingGastrointestinal bleeding 2*2*

Clinical OutcomeClinical Outcome

ResponseResponse 1 CR, 2 PR1 CR, 2 PR

Stable disease ( 4-24 months )Stable disease ( 4-24 months ) 2121

Median TTPMedian TTP 6.5 months6.5 months* Including 1 death

ASCO Chicago 2007


Phase II Study of Gemcitabine and Oxaliplatin in

Combination With Bevacizumab in Patients With Advanced

Hepatocellular Carcinoma

Zhu AX et al, J Clin Oncol 2006

■ 33 pts, PS 0-1, with unresectable or metastatic HCC were enrolled■ Treatment Protocol: Bevacizumab 10 mg/kg d1 q14

Gemcitabine 100 mg/mq (10 mg/mq/min) d2, d16 q28

Oxaliplatin 85 mg/mq d2, d16 q28Median OS = 9.6 months (95% CI, 8.0 to NA)Median PFS = 5.3 months (95% CI, 3.7 to 8.7)The most common treatment-related G3-G4 toxicities

included leukopenia/neutropenia, transient elevation of aminotransferases, hypertension, and fatigue.

ORR = 20%SD = 27% of pts

GEMOX-B could be safely administered and had moderate antitumor activity for patients with advanced HCC


Bevacizumab and Erlotinib in Inoperable and Metastatic Hepatocellular CarcinomaNCT00287222

Phase II ongoing study

Primary endpointproportion of subjects that remain free of progression at the 27th week following the onset of treatment

Enrollment: Enrollment:

2121

Start Date: Start Date: February February 20062006


General Conclusions (1/2)

1)A majority of HCC patients (>80%) presents with advanced disease and is inelegible for surgical or locoregional therapies

2)At this moment, there is not effective systemic chemotherapy for HCC

3)Understanding the molecular pathway of HCC is crucial to the development of novel therapies

4)The relevant molecular signaling in HCC are: EGFR, VEGFR, AKT/mTOR, Raf/MEK/ERK pathways


5) Sorafenib, inhibiting both cell growth and angiogenesis, is the first agent to improve survival of patients with advanced HCC. This effect establishes Sorafenib as first-line treatment for these pts

6) The next steps include testing Sorafenib earlier in the disease and eventually in combination with other targeted therapies (Bevacizumab, Erlotinib, Sunitinib have all been tested for liver cancer in phase II studies)

7) Until now, experimental therapies for HCC have been compared with placebo. Many patients are reluctant to join clinical trials if they have a 50% chance of receiving a sugar pill. Participation in trials may now increase, with Sorafenib replacing placebo as the standard control

General Conclusions (2/2)


Thanks for your attention

Any Questions?

new treatment approaches in hepatocellular carcinoma dr. francesco caponigro istituto tumori napoli

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j clin oncol

sorafenib bay

ttpalthough sorafenib

bruix j

weeks time

advanced disease

semin liver