Jordi Bruix Head, BCLC Group, Liver Unit Hospital Clínic, University of Barcelona New drugs for...

Jordi Bruix

Head, BCLC Group, Liver Unit

Hospital Clínic, University of Barcelona

New drugs for Hepatocellular Carcinoma

Very early stage (0) Single< 2cm.

Portal pressure/ bilirubin

PST >2, Child-Pugh C

Terminal stage (D)

PST 0-2, Child-Pugh A-B

Stage A - C Stage D

Normal

Single 3 nodules <3cm

Associated diseasesIncreased

No Yes

Early stage ( A)Single or 3 nodules < 3cm, PS

0

Intermediate stage ( B)Multinodular, PS 0

Advanced stage (C)Portal invasion, N1,M1, PS 1-2

Portal invasion, N1,M1

No Yes

Stage 0 PST 0, Child-Pugh A

BCLC Staging and Treatment Strategy HCC

Liver Transplantation

(CLT / LDLT)

ChemoembolizationResection PEI/RF

Sympt. Treat. (20%)

Curative Treatments (30%) 50% - 75% at 5 years

Non-curative treatments (50%) 3 year survival 10-40%

Sem Liv Dis 1999 to JNCI 2008

?

Treatment of advanced HCC Phase II/III studies with systemic treatments

Treatments Studies N Objective response

Systemic chemotherapyDoxorubicin as single agent Phase II/III >1000 10-18%Doxorubicin combination (PIAF) Phase II/III 144 26%Cisplatin Phase II 48 10%Epirubicin Phase II 62 11%Mitoxantrone Phase II 118 16%

5-FU,Paclitaxel, iridotecan, gemcitabine Phase II/III .... <10%

Anti-androgen Phase III 376 <10%Interferon Phase III 60 <10%Tamoxifen Phase III >1000 < 5%Octreotide Phase III 60 <5%Seocalcitol Phase III 746 <5%

The hepatocarcinogenic process Signalling pathways: molecular targets for new therapies.

Hanahan. Cell 2000.

Wnt pathway

EGFR pathway

Raf/MAPK pathway

Akt pathway

Jat/Stat pathway

Molecular targeted therapies in HCC

Akt

PI3K

CELL SURVIVALCELL CYCLE

RapamycinmTOR

Translation(5´ TOP)

TRANSLATION(Cap-Dependent)

4E-BP1p70S6

TSC

EGFR VEGFRPDGFR p85

p110

PIP2

PIP3

PTEN

SorafenibIGFR-I

IGFBP3

RAS

RAF

MEK

ERK

PROLIFERATION

Erlotinib

Sorafenib

Bevacizumab

Growth factors receptor pathway

Targets and agents

EGFR: TKI: Erlotinib, Lapatinib

Gefitinib

Ab: Cetuximab

VEGF TKI: Sorafenib

Ab: Bevacizumab

RAF TKI: Sorafenib

mTOR Rapamycin

Proteasome inhibitors Bortezomib

GROWTH FACTORS (EGF, VEGF,

PDGF…)

IGF-1 / IGF-2

Cetuximab

Targeted agents in development for HCC: overview

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

*Sorafenib and sunitinib also have antiproliferative effects through multi-tyrosine kinase inhibition*Sorafenib and sunitinib also have antiproliferative effects through multi-tyrosine kinase inhibition

AgentAnti-angiogenic targets Antiproliferative targets Developmental

statusVEGF 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

Erlotinib: Phase II studies in HCC

Molecular targeted therapies for EGFR pathway

Philip et al. J Clin Oncol 2005

Erlotinib (n=38)

• Characteristics of patients:

Child A/B: 27/11

PST 0/1-2: 10/28

EGFR-1+ in 88%• Treatment : 150 mg/d• Outcomes:

Response rate:

3 PR, 50% SD (3.8 mo)

Toxicity (G3-4): 8 pts.

Median TTP: 3.2 mo

Median survival: 13 mo

Thomas MB, et al. ASCO 2007, JCO 2009

• Patients (n=29) received bevacizumab 10mg/kg every 14 days plus erlotinib 150mg orally daily

• RR (RECIST) in 27

- CR: one patient (4%)

– PR: five patients (19%)

– SD at ≥16 weeks: nine patients (33%)

– SD at 8 weeks: five patients (19%)

• Grade 3–4 toxicities transaminase elevation (1), hyperkalaemia (1), acne (1), diarrhoea (2), proteinuria (2), gastrointestinal bleeding (3), fatigue (4), and hypertension (5).

• Median Survival 19.5 months. (2009 MS 15months)

Erlotinib plus bevacizumab in patients with unresectable advanced HCC

ASCO 2005, JCO 2008

Bevacizumab (5-10 mg/Kg /2 weeks) in HCC: Phase II (n=46)

Molecular targeted therapies for VEGF

Characteristics of patientsAge 21-81Gender (M/F) 38/8Child-Pugh (A/B) 34/12CLIP (0-4) 2/19/15/8/1ECOG (0/1/2) 19/23/2Tumor stage ?

Adverse events (grade 3-4)Transient ischemic accident : 1Arterial hypertension: 7Hepatic arterial thrombosis: 1Hemoperitoneum 1Gastrointestinal bleeding: 5 (1 death)

Clinical OutcomesResponse rate 1CR, 5 PRMedian PFS: 6.9 monthsMedian survival: 12.4 months

Baseline

16 weeks after

Faivre SJ, et al. ASCO 2007, Chicago, IL, USA

Sunitinib in patients with unresectable HCC

• Patients (n=37) received sunitinib 50mg daily for 4 weeks of every 6-week treatment cycle.

• Major (≥50%) tumour necrosis was noted in 46% of patients

• Response (RECIST)– partial response (PR): one patient (3%) – stable disease (SD) >3 months: 13 patients (35%)– SD >6 months: eight patients (22%)

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

– four patients experienced grade 5 toxicity (bleeding, drowsiness, hepatic encephalopathy and renal failure)

RECIST = Response Evaluation Criteria In Solid Tumors; CNS = central nervous system

Treatment of advanced HCC Phase II: sorafenib as a primary treatment of HCC (n=137)

Characteristics of the study– Sorafenib 400mg bid in 28-day cycles in 137 patients with advanced HCC.

– Characteristics: 48% HCV+, TNM Stage III/IV (31%/66%), Child A:72%

– Response WHO: PR: 3 (2.2%), MR: 8 (5.8%), stable disease >4m 33.6%

0 100 200 300 400 500 600 700 8000

0.25

0.50

0.75

1.00

Surv

ival

Dis

trib

utio

n Fu

nctio

n

Time (days from start of study treatment)

0 100 200 300 400 500 600 700 8000

0.25

0.50

0.75

1.00

Surv

ival

Dis

trib

utio

n Fu

nctio

n


Overall survival: 9.2 moTime-to-progression (TTP): 5.5 mo

Abou-Alfa G et al, JCO 2006

0 100 200 300 400 5000

0.25

0.50

0.75

1.00

Sur

viva

l Dis

trib

utio

n Fu

nctio

n


0 100 200 300 400 5000

0.25

0.50

0.75

1.00

Sur

viva

l Dis

trib

utio

n Fu

nctio

n


Sorafenib (n=299)

400mg po bid

continuous dosing

PIs: JM Llovet and J Bruix, S Ricci, V Mazzaferro, P Hilgard, J-L Raoul, S Zeuzem, A Santoro, MS Shan, M Moscovici, Dimitris Voliotis, A Forner, M Schwartz for the SHARP Investigators Study Group

Sorafenib improves survival in hepatocellular carcinoma:Phase III randomized, placebo-controlled trial (SHARP)

Stratification:

* Macroscopic vascular invasion (portal vein) and/or extrahepatic spread

* ECOG PS

* Geographical region

Ran

do

mis

atio

n

N=

602

Placebo (n=303)

2 tablets po bid

continuous dosing

Llovet et al, NEJM 2008

Child-Pugh A : to avoid liver deaths of Child-Pugh B patients obscuring outcome to capture the impact on HCC progression (competing risk)

SorafenibMedian: 10.7 mo (95% CI: 9.4, 13.3)

Su

rviv

al p

rob

abili

ty

Weeks

Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.87). P<0.001*

PlaceboMedian: 7.9 mo(95% CI: 6.8, 9.1)

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 trial

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

Pro

bab

ility

of

pro

gre

ssio

n

546 12 18 24 30 36 42 480 Weeks

SorafenibMedian: 5.5 mo(95% CI: 4.1, 6.9)

PlaceboMedian: 2.8 mo(95% CI:2.7, 3.9)

1.00

0

0.75

0.50

0.25

Patients at risk Sorafenib:

Placebo:299303

Phase III SHARP trialTime to progression (independent central review)


Hazard ratio (S/P): 0.58 (95% CI: 0.45, 0.74) P<0.001

Phase III SHARP trialExploratory subgroup survival analysis

Sorafenib benefit

Placebo benefit

Hazard Ratio (95%CI)

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


Usual comments about SHARP

• SHARP is just informative for HCV European HCC

• There is no attempt for biomarker assessment

• 3 months survival improvement is marginal

• Unknown efficacy in Child-Pugh B

Asian-Pacific sorafenib study

Cheng, et al. ASCO 2008

End points:– Overall survival, time to symptomatic progression (FSHI8-TSP),

time to progression, response (RECIST), and safety– No primary end point defined

Sorafenib400 mg bid

Placebon=76

Eligibility • Advanced HCC• ECOG 0-2• Child-Pugh A• No prior systemic therapy

Stratification • Macroscopic vascular invasion (portal vein) and/or extrahepatic spread

• ECOG PS• Geographic area

RANDOMIZE

n=150

2:1

Overall survivalS

urvi

val p

roba

bilit

y

SorafenibMedian: 6.5 months

(95% CI: 5.6, 7.6)PlaceboMedian: 4.2 months (95% CI: 3.7, 5.5)

HR (S/P): 0.68 95% CI: 0.50, 0.93P=0.014

0.25

0.50

0.75

1.00

00

Months2 4 8 10 12 14 16 20 22

150 134 103 78 53 32 21 15 13 4 1 076 62 41 26 23 15 9 5 4 1 0 0

SorafenibPatients at Risk

Placebo

6 18


Cheng, et al. ASCO 2008

Time to progression

HR (S/P): 0.57 95% CI: 0.42, 0.79P<0.001

SorafenibMedian: 2.8 months(95% CI: 2.6, 3.6)

PlaceboMedian: 1.4 months (95% CI: 1.3, 1.5)

SorafenibPatients at risk

Placebo

0.25

0.50

0.75

1.00

0

Months150 80 38 19 11 8 5 2 1 0 0 076 19 10 8 3 0 0 0 0 0 0 0

Pro

gre

ssio

n-fr

ee

pro

bab

ility

0 2 4 8 10 12 14 16 20 226 18

Adapted from Cheng, et al. ASCO 2008





Terminal stage (D)


Stage A - C Stage D

Normal



No Yes


0




No Yes




(CLT / LDLT)

ChemoembolizationResection PEI/RF Sorafenib

Sharp

Asia

10.7 months

6.5 months

Predictors of Survival

• High c-KIT levels and low HGF and VEGF levels correlated with longer OS in the univariate analysis.

c-Kit VEGF

High HGFMedian OS =6.0 months (n=122)

Low HGFMedian OS =10.8 months (n=366)

Time (Months)

HR = 0.775 (95% CI: 0.620,0.970)P=0.026

High c-KitMedian OS = 10.4 months (n=244)

Low c-KitMedian OS =8.8 months (n=245)

HGF

Time (Months)

HR = 1.780 (95% CI: 1.390,2.280)P<0.001

Time (Months)

HR = 1.530 (95% CI: 1.191,1.965)P<0.001

High VEGFMedian OS =6.2 months (n=122)

Low VEGFMedian OS =10.6 months (n=368)

0

0.25

0.50

0.75

1.00

Su

rviv

al P

rob

abili

ty

0 2 4 6 8 10 12 14 16 18 20 22

0

0.25

0.50

0.75

1.00

Su

rviv

al P

rob

abili

ty

0 2 4 6 8 10 12 14 16 18 20 22

0

0.25

0.50

0.75

1.00

Su

rviv

al P

rob

abili

ty

0 2 4 6 8 10 12 14 16 18 20 22

All patients (univariate analysis)

Llovet et al AASLD 2008

Baseline plasma c-KIT and Sorafenib

• Patients with high c-KIT showed a trend of better survival benefit from sorafenib (interaction P-value=0.081).

Patients with Low* Baseline c-KIT

Su

rviv

al P

rob

abil

ity

HR = 0.90 (95% CI: 0.66, 1.22)

(n=245)

Su

rviv

al P

rob

abil

ity

SorafenibMedian OS = 9.4 months

PlaceboMedian OS = 7.4 months

0

0.25

0.50

0.75

1.00

0 2 4 6 8 10 12 14 16 18 20 22

Patients with High* Baseline c-KIT

HR = 0.58(95% CI: 0.41, 0.81)

(n=244)



0

0.25

0.50

0.75

1.00

mo 0 2 4 6 8 10 12 14 16 18 20 22

Prediction of survival


• Patients with high c-KIT showed a better time to progression with sorafenib (interaction P-value=0.05).

Baseline plasma c-KIT and SorafenibPrediction of time to progression

Patients with High* Baseline c-KIT

Pro

gre

ssio

n

Pro

bab

ilit

y

Time (Months)

1.00

0.75

0.50

0.25

0.00

0 2 4 6 8 1012

SorafenibMedian TTP = 6.7 mo

PlaceboMedian TTP = 2.8 mo

HR = 0.45(95% CI: 0.30, 0.66)

(n=244)

Pro

gre

ssio

n

Pro

bab

ilit

y

Patients with Low* Baseline c-KIT

1.00

0.75

0.50

0.25

0.00

0 2 4 6 8 1012

HR = 0.80 (95% CI: 0.55, 1.17)

(n=245)

SorafenibMedian TTP = 4.1 mo

PlaceboMedian TTP = 3.9 mo

Time (Months)


Patients with Low Baseline HGF

Patients with High Baseline HGF1.00

0.75

0.50

0.25

0

Time (Months)

Su

rviv

al P

rob

abil

ity

HR = 1.10(95% CI: 0.72, 1.67)(n=122)

1.00

0.75

0.50

0.25

0

Time (Months)

Su

rviv

al P

rob

abil

ity

HR = 0.69(95% CI: 0.53, 0.90)(n=366)





0 2 4 6 8 10 12 14 16 18 20 22 0 2 4 6 8 10 12 14 16 18 20 22

Baseline plasma HGF and Sorafenib Effect

• Patients with low HGF showed a trend of better survival benefit from sorafenib (interaction P-value=0.073), but not with TTP (p=0.3)



• SHARP is just informative for HCV + European HCC




Hepatocellular carcinoma (advanced) Survival (3 m)Sorafenib (n=299) vs placebo (n=303)1 0.69 (0.55–0.87)

Colorectal (metastatic) Survival (4.7 m)IFL+ bevacizumab (n=402) vs IFL (n=411) 2 0.66 (NA)

Cetuximab (n=287) vs BSCare (n=285) 3 Survival (1.5 m) 0.77 (0.64–0.92)

Lung cancerPaclitax. + carbo + vs – bevacizumab (n=434 vs n=444) 4 Survival (2 m)

0.79 (0.69–0.93)

Erlotinib (n=488) vs placebo (n=243) 5 Survival (2 m)0.79 (0.58–0.85)

Breast cancer (Advanced (HER2+)Chemotherapy + vs – trastuzumab (n=235 vs n=234) 6 TTP

0.51 (0.39–0.59)

Paclitaxel + vs – bevacizumab (n=347 vs n=326) 7 PFS0.60 (0.51–0.70)

Impact of molecular agents in cancer outcomesEndpoint, absolute gain

HR (95% CI)

Llovet and Bruix, Hepatology 2008

1. Llovet et al NEJM 2008, 2. Hurwitz et al NEJM 2004, 3. Jonkers et al NEJM 2007, 4. Sandler et al NEJM 2006,

5. Shepherd et al NEJM 2005, 6. Slamon et al NEJM 200 7. Miller et al. NEJM 2007

Sorafenib in HCC. Phase I PK:

Non-HCC vs HCC, Non-Japanese vs Japanese; and CPA vs CPB

0

2

4

6

8

10

12

14

16

18

20

Ctr

ou

gh

,ss

(mg

/L)

Advanced Solid Tumor Patients

HCC Patients(CPA)

HCC Patients(CPB)

Non-Japanese with advanced solid tumorsJapanese with advanced solid tumorsNon-Japanese with HCC (CPA)Japanese with HCC (CPA)Non-Japanese with HCC (CPB)Japanese with HCC (CPB)

ss = steady state

• PK equivalent irrespective of ethnicity or Child-Pugh status

Data on file. Bayer HealthCare

Sorafenib for HCC and Child-Pugh B patients

• Child-Pugh B includes a wide range of profile and outcome

• Impact on tumor biology is not modulated by liver function

• PK, Safety and AEs in Child-Pugh B are the same

• Child-Pugh B 7 can be safely treated.

• RCT vs placebo unlikely




Terminal stage (D)


Stage A - C Stage D

Normal



No Yes


0




No Yes




(CLT / LDLT)

ChemoembolizationResection PEI/RF

Sympt. Treat. (20%)

Curative Treatments (30%) 50% - 75% at 5 years

Non-curative treatments (50%) 3 year survival 10-40%

Sem Liv Dis 1999 to JNCI 2008

Sorafenib

Future prospects for Sorafenib

Impact of sorafenib results

• Effective first-line option for advanced HCC available

should be standard first line therapy

• Proves the hope of molecular targeted therapy in HCC

new agents to be investigated in second line/failures

• Opens the path to multipathway blockade

• Evaluation in the adjuvant setting (surgery, ablation, TACE)

Critical issues in combination therapy

• Selection of best partner for sorafenib

• Optimal dosage for efficacy and safety

Underlying cirrhosis: variceal bleeding, renal failure, ascites, encephaloptahy,HBV/HCV flares

• How to define efficacy: RR by RECIST (No meaning), TTP?

• Transition from phase 1 into phase 2. RCT phase 2.

• Target population

Llovet et al, JNCI 2008

Impact of sorafenib results

• Effective first-line option for advanced HCC available

• Proves the hope of molecular targeted therapy in HCC

• Opens the path to multipathway blockade

• Evaluation in the adjuvant setting (surgery, ablation, TACE)

8 weeksrandomise

Stratify:- prior curative tx- geographical region- CP status

Sorafenib 400mg bid

Placebo

RFS

TTR

OSBiomarkers

1:1

Design: double-blind RCT

Resection RFA PEI

• Significant OS benefit in phase III gives rationale to go into adjuvant setting

• Prospective, randomized, double-blind, placebo-controlled, company sponsored phase III study

• Primary endpoint: recurrence-free survival

• Patients: n=1100 (randomised)

• Global trial, significant number of patients from China

• FPFV: August 2008Clinicaltrials.gov

TACE for HCC

Sorafenib as coadjuvant

Trial in the pipeline – SPACE (2009): Target population: Child-Pugh ATechnique: DCBeads End-point: TTP, Survival




Terminal stage (D)


Stage A - C Stage D

Normal



No Yes


0




No Yes




(CLT / LDLT)

ChemoembolizationResection PEI/RF Sorafenib

Combination trial

SPACEAdjuvant trial

STORMAdjuvant trial

Barcelona-Clínic Liver Cancer (BCLC) Group

Liver Unit: J. Bruix, JM. Llovet, A. Forner, M. Reig,, C Rodriguez

Radiology: C. Brú, R. Vilana, Ll. Bianchi, C. Ayuso, J. Rimola,, X. Montañá, I. Real, M. Burrel

Surgery : J. Fuster Pathology : M. Solé Oncology: J. Maurel Nurse: A. Godoy

Oct. 2008

Ad .support

N. Perez

D. Segarra

Laboratory:

L. Boix

A. Villanueva

V. Tovar

C. Alsinet

L. Cabellos

JM. Lopez

J. Peix

H. Cornellà

Jordi Bruix Head, BCLC Group, Liver Unit Hospital Clínic, University of Barcelona New drugs for...

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