TARGETED THERAPIES FOR HEPATOCELLULAR CARCINOMA

Universitätsklinik für Innere Medizin IIIKlin. Abtl. für Gastroenterologie und Hepatologie

Christian Müller

TARGETED THERAPIES FOR HEPATOCELLULAR CARCINOMA

Universitätsklinik für Innere Medizin IIIKlin. Abtl. für Gastroenterologie und Hepatologie

Christian Müller

HEPATOCELLULAR CARCINOMA

INCIDENCE

rising incidence

worldwide most frequent malignancy

Austria 9 / 100.000 2% of all tumors

0 10 20 30 40 50age-adjusted incidence rates

Northern Europe

Australia

Southern Asia

South America

North America

Northern Africa

Western Europe

Western Asia

Estern Europe

Central America

The Caribbean

Southern Europe

South-Eastern Asia

Pacific Islands

Eastern Africa

Southern Africa

Western Africa

Central Africa

Eastern Asia

Bosch et al. Sem.Liv.Dis. 1999; 19: 271-285.

HEPATOCELLULAR CARCINOMAETIOLOGY OF LIVER DISEASE

Anti-HCV+ 94 38%HBsAg+ 28 11%ALCOHOLIC 86 35%HEMOCHROMATOSIS 10 4%PBC 2 1%CRYPTOGENIC 29 12%

38%

11%

35%

4%1%12%

alcoholic

Anti-HCV +

HBsAg +

hemochromatosis

PBCcryptogenic

HCC

STAGE 0Very early

1 HCC < 2 cmCHILD A PST 0

STAGE AEarly

1 HCC < 5 cm or <3 HCC < 3 cmCHILD A/B PST 0

STAGE BIntermediate

MultinodularCHILD A/B PST 0

STAGE CAdvanced

Portal Invasion, N1,M1CHILD A/B PST 1-2

STAGE DTerminal

Portal Invasion M1,N1CHILD C,PST >2

BCLC HCC STAGING AND TREATMENT

Portal Pressure / Bilirubin

Associated Diseases

Resection LTX PEI / RFA

normal

increased

no yes

TACE Sorafenib

Potentially Curative Treatment5-year survival 50-70%

Palliative Treatment – RCTMedian survival (untreated) 5-16 mo

SupportiveTreatment

Survival < 3 mo

SORAFENIB IN HCC TREATMENT - RATIONALE

RAF kinase overexpressed and activated in HCC

RAF / MEK / ERK signaling pathway implicated in liver

tumorigenesis

Sorafenib is a multikinase inhibitor of RAF, VEGFR, and

other kinases

Sorafenib induces apoptosis in HCC xenograft models

Sorafenib active in Phase II trial of patients with

advanced HCC and CHILD A / B liver function

Hwang et al. Hepatol Res 2004;29:113-121Calvisi et al. Gastroenterology 2006;130:1117-1128Villanueva et al. Semin Liv Dis 2007; 27:55-76Liu et al. Cancer Res 2006; 66:11851-11858Abou-Alfa et al. J Clin Oncol 2006; 24: 4293-4300

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

Nucleus

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

PHASE III SHARP TRIALSORAFENIB TREATMENT FOR HCC

STUDY DESIGN

PRIMARY END-POINT: OVERALL SURVIVALTIME TO SYMPTOMATIC PROGRESSION

SECONDARY END-POINTS: TIME TO PROGRESSION

Stratification:

Macroscopic vascular invasion and / or

extrahepatic spread

ECOG PS

Geographic region Rand

omiz

atio

n

n =

602

Sorafenib (n=299)400 mg po bid

Continous dosing

Placebo (n=303)2 tablets po bid

Continous dosing

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

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 TRIALSORAFENIB TREATMENT FOR HCC

OVERALL SURVIVAL

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

SorafenibMedian: 24.0 weeks(95% CI: 18.0, 30.0)PlaceboMedian: 12.3 weeks(95% CI: 11.7, 17.1)

1.00

0

0.75

0.50

0.25

Patients at risk Sorafenib:

Placebo:299303

PHASE III SHARP TRIALSORAFENIB TREATMENT FOR HCC

TIME TO PROGRESSION

PHASE III SHARP TRIALSORAFENIB TREATMENT FOR HCC

Baseline characteristics of patientsCharacteristics Sorafenib Placebo

(n=299) (n=303)

Age (vears,median) 65 66Male / Female (%) 87 / 13 87 / 13Region (Europe / N.America / others;%) 88 / 9 / 3 87 / 10 / 3Etiology (%)

HCV / HBV 29 / 19 27 / 18Alcohol / other 26 / 26 26 / 29

Child (A / B; %) 95 / 5 98 / 2Prior Therapies (%):

Resection 19 21PAI / RFA / TACE 39 41

BCLC stage (%) Stage B 18 17Stage C 82 83

ECOG PS (%)ECOG 0 54 54ECOG 1 38 39ECOG 2 8 7

Vascular Invasion /Extrahepatic spread (%) 70 70

PHASE III SHARP TRIALSORAFENIB TREATMENT FOR HCC

Safety eventsSorafenib Placebo

(n=299) (n=303)

Serious adverse events (SAE;%) 52 54

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/-Hand-foot skin reaction 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 plus doxorubicin in patients with advanced HCCO

S (%

pts

)

Time from randomisation (mo)0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

Median OS (Phase II)Doxorubicin + sorafenib: 13.7 months(95% CI: 10.4–can not be estimated)

100

75

50

25

0

Doxorubicin + placebo: 6.5 months (95% CI: 4.9–9.5)HR=0.45; p=0.0049

Censored treatment

Abou-Alfa GK. ECCO 2007

OVERALL SURVIVAL

HCC

STAGE 0Very early

1 HCC < 2 cmCHILD A PST 0

STAGE AEarly

1 HCC < 5 cm or <3 HCC < 3 cmCHILD A/B PST 0

STAGE BIntermediate

MultinodularCHILD A/B PST 0

STAGE CAdvanced

Portal Invasion, N1,M1CHILD A/B PST 1-2

STAGE DTerminal

Portal Invasion M1,N1CHILD C,PST >2

BCLC HCC STAGING AND TREATMENT

Portal Pressure / Bilirubin

Associated Diseases

Resection LTX PEI / RFA

normal

increased

no yes

TACE New Agents

Potentially Curative Treatment5-year survival 50-70%

Palliative Treatment – RCTMedian survival (untreated) 5-16 mo

SupportiveTreatment

Survival < 3 mo

Targeted agents in development for HCC

AgentAnti-angiogenic targets Antiproliferative targets Developmental status

VEGF VEGFR PDGFR EGFR Raf mTOR

Bevacizumab ● Phase II ongoing

Brivanib ● Phase II recruiting

Cediranib ● Phase II recruiting

Erlotinib ● Phase II complete

Gefitinib ● Phase II complete

Cetuximab ●Lapatinib ● Phase II ongoing

RAD001 ● Phase I/II recruiting

Sorafenib* ● ● ● Phase III complete

Sunitinib* ● ● Phase II ongoing

Thalidomide ● Phase III recruiting

TSU-68 ● ● Phase I/II recruiting

Phase II complete

Faivre SJ, et al. ASCO 2007

Sunitinib in patients with unresectable HCC

• Patients (n=37) sunitinib 50mg daily for 4 weeks, 2 weeks pause• Major (≥50%) tumour necrosis: 46% of patients• Response (RECIST)

– PR: 1 pt (3%) – SD >3 months: 13 pts (35%)– SD >6 months: 8 pts (22%)

• Grade 3–4 toxicities:thrombocytopenia (43%)neutropenia (24%) CNS symptoms (24%) asthenia (22%) haemorrhage (14%)

Grade 5 toxicity (bleeding, drowsiness, hepatic encephalopathy and renal failure)

Grade 1–2 skin toxicity frequently reportedDose reductions: 27% of patients

• 38 pts erlotinib 150mg daily • Median OS: 13 months• PFS: 3 months• Grade 3–4 Aes: 61% of patients (skin rash [13%], diarrhoea [8%] and fatigue [8%])

Erlotinib in patients with advanced HCC

Philip PA. J Clin Oncol 2005;23:6657–63

100

80

60

40

20

00 3 6 9 12 15 18 21 24 27 30

Follow-up (months)

Pati

ents

(%

)

OSPFS

Summary

• Several targeted agents, either alone or in combination with other therapies, have shown promising efficacy and tolerability in phase II trials of patients with advanced HCC

• Randomised, phase III trials, with sorafenib as an active comparator, will be required to optimise targeted therapy of HCC in the future

• Sorafenib standard treatment in advanced HCC (BCLC stage C) and well preserved liver function (Child A). Prolongs TTP and survival (Phase III study)

Studies with other targeted therapeutic agents in advanced HCC

• Thalidomide

• Cetuximab (Erbitux; EGFR-Ak)

• Bevacizumab (Avastin; VEGF-AK) Bevacizumab + Erlotinib

Bevacizumab + Capecitabine

• Perifosine (Akt- Inhibitor)

• Erlotinib (Terceva; EGFR Thyrosinkinase-Inhibitor)

• Gefitinib (Iressa; EGFR Thyrosinkinase-Inhibitor)

• Lapatinib (Tyverb; EGFR Thyrosinkinase-Inhibitor)

• 32 pts cetuximab 400 mg / m2 loading dose +

250 mg / m2 i.v. weekly

• 27 pts evaluable for tumour response– SD ≥8 weeks: 12 pts (44.4%)

• Median time to progression (TTP): 8 weeks – median TTP in pts with SD ≥8 weeks: 22.5 weeks

• No treatment-related severe AEs noted