locoregional treatment of unresectable HCC · GIDEON: The Largest Global Observational Study...

Thierry de Baere

Institut Gustave Roussy - VILLEJUIF - FRANCE

locoregional treatment of unresectable HCC

Nom du module

T. de Baere Disclosure of interest :

Grants/research supports: Galil; Terumo

Honoraria / consultation fees: AstraZenecca,

Boston sceintific, Eisai, GE Healthcare,

Guerbet, Janssen , MSD, Terumo.

Sponsored speaker’s bureau : Terumo,

Guerbet, SIRTEX, Boston sceintific

GIDEON: The Largest Global Observational Study

Completed in HCC (n = 3,202)

%AP

n=928

EU

n=1113

LA

n=90

USA

n=563

Japan

n=508

Overall

N=3202

All LRTs 67.2 43.5 27.8 49.4 84.4 57.5

TACE 60.3 33.1 13.3 37.1 71.3 47.2

Conventional

TACE (Lipiodol) *90.2 59.2 83.3 40.7 82.3 73.9

DEB-TACE * 2.9 36.1 16.7 39.7 1.7 15.9

Surgical treatment 24.2 15.5 5.6 9.4 43.3 21.1

Ablation 15.5 20.2 17.8 12.6 50.0 22.2

* For patients who received TACE: n=1511; AP=560, EU=368, LA=12, USA=209, Japan=362;

AP, Asia-Pacific; LA, Latin America; LRTs, Loco-Regional Therapies

Pre-Sorafenib Therapy for HCC by Geographical Region

Lencioni R et al. Int J Clin Pract 2014;68:609-617

(Journal of Hepatology 2018)

ESMO Guidelines for HCC - 2019

100 patients HCC < 5 cm

Microsatellites at pathology

46/100 (46%)

Mean dist tumor/satellites : 9.9 mm

TTumor < 2.5 cm

No satellites farther than 5 mm

Excepted one tumor.

Sasaki A et al. Cancer 2005;103:299-306

Ablation

local efficacy according to tumor size

• HCC complete necrosis

– Smaller than 3 cm 90%

– 3.1 to 5 cm 61%

– Greater than 5 cm 23 %

– 2cm or smaller 97.2 %

Livraghi, Radiology, 2000

2.5/3 cm 4/5 cm

Livraghi, Radiology 1999

RF ablation local efficacy :

Livraghi T, Hepatology 2007

Huang J et al. Ann Surg 2010;252:903-912

● 230 patients, 94% Child A, within Milan criteria

● Single ≤ 5 cm, up to 3 ≤ 3 cm

Feng K et al. J Hepatol 2012;57:794-802

● 168 patients, 49% Child A

● Up to 2 HCC tumors ≤ 4

cm

p = 0.342

Pompili M et al. J Hepatol 2013;59:89-97

729 consecutive single HCC <3 cm treated with surgey (n=302) or RFA (n=427)

(Peng ZW; JCO 2013. 31 426-432)

HCC : d < 7 cm (single), or n<3 & <3cm

TACE-RFA (n=94) Vs RFA (n=95)

OS : (HR=0.525; 95% CI = 0.335-0.822; P = .002 )

DFS : (HR=0.575; 95% CI = 0.374-0.897; P = .009)

OS : treatment (HR=1.87), tum. Size (HR=1.73), tum. number (HR=2.49)

Combined treatment are doing better ?

Location >>>> central vs peripheral

ESMO Guidelines for HCC - 2019

In case of long-anticipated waiting time (> 3 months), resection, local ablation or

TACE to minimise the risk of tumour progression / ‘bridge’ to transplant [III, B]

Technical recommendations on TACE from expert groups

CHINA

TAIWAN

EUROPE

AND US

INTER

NATIONAL cTACE

cTACE

DEB-

TACE

DEB-

TACE

de Baere T, et al.

Cardiovasc Intervent Radiol 2016;39:334-343

China manual for clinical practice for transarterial

chemoembolization treatment of hepatocellular carcinoma

(2018 edition)

Lencioni R, et al.

Cardiovasc Intervent Radiol 2012;35:980-985

Chang PY, et al.

Liver Cancer 2018;7:312-322

cTACE, conventional transarterial chemoembolisation; `

DEB-TACE, drug-eluting bead-transarterial chemoembolisation

Conventionallipiodol-based TACE is the standard

of care for patients with intermediate HCC,

although using DEB-TACE is an option to

minimis esystemic side effects of chemotherapy

[I, C]

Discontinue after complete response @ mRECIST

At least 2 TACE treatment before changing treatment

44% to 65% of non responders to the 1st course of TACE

demonstrated response after the 2nd course of TACE 1,2

Usually, 2 subsequent TACE 2 to 8 weeks apart are performed

• Indication for subsequent TACE

• treatment tolerance

• treatment efficacy

• need for subsequent treatment, until complete response

1. Georgiades C. Radiology 2012; 265:115-23

2. Choi J. J Hepatol 2014; 60:1212-8

Indication new TACE

• New progression in a treated location that previously responded

• New tumor foci in a non treated part of the liver

• Treatment schedule : Large Unilobar Tumors

Even if unilobar, two sessions 2-4 weeks apart

Patients with more than 50% liver replacement should be carefully

evaluated with multidisciplinary team experts in the field

• Treatment schedule : Bilobar Tumors

Separate treatment sessions for both hepatic lobes 4-8 wks apart

CT and clinical evaluation in between looking for possible complications and tolerance that

might require a longer time interval between sessions.

Liver enzymes returned to baseline before next treatment session is recommended

Treatment strategy with TACE

(Raoul JL. Cancer Treatment Reviews 72 (2019) 28–36)

STATE: selection for transarterial chemoembolization treatment; HAP: hepatoma arterial-embolisation prognostic;

ART: Assessment for Retreatment; ABCR: Alpha- foeto Protein, BCLC, Child-Pugh, Response.

Outside clinical trials, the use of therapeutic algorithms based on prognostic

scores of unknown predictive values is currently not recommended for the

selection of candidates to initial and repeated TACE [III, A]

Unresectable

early stage

Within the Milan criteria

(bridging therapy)

TACE(More evidence for cTACE)

Liver transplantation

Intermediate stage

Out of the Milan criteria

TACE

Response

In Milan criteria

1st TACE Systemic treatment

Advanced stage

Worsening liver function or

PS

2nd TACECE-CT or CE-MRI

No objective

response

Objective

response

TACE

on-demand

EHS, PVT, PD in treated area

worsening in CP or PS

New lesionsTACE or

cTACE + RFA

Scores to be

validated

Scores to be

validated

Segmental PVTT

(systemic treatment not feasible)

More evidence for cTACE

Strong evidence

Further trials required

cTACE + RFA

(Kudo M. Lancet Gastroenterol Hepatol 2018; 3: 37-46)

Median OS in patients with vascular invasion

- 13.3 months (orantinib group) / 16 months (placebo group)

Median OS in patient without vascular invasion

- 31·4 months (orantinib group) / 34·8 months (placebo group)

cTACE : lipiodol + anti-tumour drugs and embolisation materials

cTACE

Photomicrographs of doxorubicin loaded microspheres

Scale bars = 200µm

LifePearl DC Bead

Hepasphere

Tandem

(J Vasc Interv Radiol 2016. 27:1425-31)

36

37

38

39

40

41

0 0,5 1 1,5 2

Do

xo

rub

icin

Loa

de

d (

mg

/mL

bea

d)

Time (hr)

LifePearl (N=5)

DC Bead (N=5)

Tandem (N=5)

Hepasphere (N=4)

LIFEPEARL ANTHRACYCLIN REGISTRY IN SELECTIVE CHEMO-EMBOLIZATION

OF PATIENTS WITH UNRESECTABLEHEPATOCELLULAR CARCINOMA

Thierry de Baere1, Gontran Verset², Boris Guiu³, Maxime Ronot4 , Patrick Chevallier5, Géraldine Sergent6, Pierre Goffette7

Liver and Biliary damages

idarubicin (N=36)

doxorubicin (N=149)

Biloma 2.8% (1/36) 5.4% (8/149)

Portal vein thrombosis

2.8% (1/36) 6.0% (9/149)

Portal vein branch narrowing

0 1.3% (2/149)

Bile duct dilation 2.8% (1/36) 5.4% (8/149)

Global Hepatic damages

(Biloma, Portal vein thrombosis, Portal vein branch narrowing, Bile

duct dilation)

8.3% (3/36) 18.1% (27/149)

Bevacizumab/Avastin

Beyond chemotherapyFuture of drug delivery

PLGA nanoparticles

Study population

•Confirmed HCC

•Unsuitable for curative

therapy,

e.g. surgical resection,

ablation, transplantation

•Disease amenable to TACE

•No extrahepatic disease

•Child-Pugh A to B7

•ECOG 0 or 1

•Exclude Vp3 and Vp4

•Exclude patients with

clinically significant

cardiovascular disease or

history of arterioembolic

event

Primary endpoint:

PFS for Arm A versus

Arm C (BICR)

Secondary

endpoints:

PFS for Arm B versus

Arm C (BICR), OS,

PROs

Other endpoints:

Safety,

immunogenicity, PK

EMERALD-1 (locoregional HCC)Phase 3, randomised, double-blind, placebo-controlled study (recruiting)

Arm C

TACE + placebo

Arm A

TACE + durvalumab

Arm B

TACE + durvalumab +

bevacizumab

R

BICR, blinded independent central review; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; OS, overall survival; PFS,

progression-free survival; PK, pharmacokinetics; PROs, patient-reported outcomes; TACE, transarterial chemoembolisation

http://clinicaltrials.gov/ct2/show/NCT03778957

N=600

http://clinicaltrials.gov/ct2/show/NCT03778957

Investigator-initiated studies – IO

plus TACEShort title

(NCT number)

Country

Phase

(status)Design / population HCC type Regimen

IMMUTACE

(NCT03572582)

Germany

Phase 2

(recruiting)

Estimated enrolment: N=49

(single-arm, open-label)

Key inclusion criteria:

•Confirmed intermediate-stage HCC

•Not eligible for resection or local ablation

•No prior treatment with TACE

•No prior systemic therapy

Primary endpoint: ORR

• Child-Pugh Class A

• Multinodular or large,

solitary HCC

• Tumour burden <50%

of liver volume

• TACE in combination with

nivolumab

• 4-week cycles from the

starting date of TACE

• Second TACE repeated on

Day 1 of cycle 3

• Nivolumab (240 mg IV

q2w) started 2–3 days

after first TACE, until PD

(up to 2 years)

PETAL

(NCT03397654)

United Kingdom

Phase 1/2

(recruiting)




•Confirmed HCC

•Not eligible for resection or local ablation

•No extrahepatic metastasis

•No prior treatment with TACE or

systemic therapy for HCC

Primary endpoint: safety and tolerability

• Child-Pugh score <7

• ≥1 unidimensional

lesion measurable by

CT scan or MRI based

on mRECIST criteria

• TACE using doxorubicin

solution (60 mg dose) and

gelatin sponge particles

• Pembrolizumab (200 mg

q3w) 30 or 45 days after

TACE for up to 1 year

CT, computed tomography; HCC, hepatocellular carcinoma; IO, immuno-oncology; IV, intravenous; MRI, magnetic resonance imaging; ORR, objective response rate; PD,

disease progression; q2w, every 2 weeks;

q3w, every 3 weeks; TACE, transarterial chemoembolisationCourtesy of R Lencionni

https://clinicaltrials.gov/ct2/show/NCT03572582




(NCT number)

Country

Phase


Nivolumab with

deb-TACE in

patients with liver

cancer

(NCT03143270)

United States

Early

Phase 1

(recruiting

for >1 year)


(non-randomised, open-label)


•Confirmed HCC

•Not amenable to curative surgery or

transplant

•Amenable to deb-TACE to treat all sites

of disease in one session

•No vascular invasion or extrahepatic

spread

•No prior embolisation and / or ablation

•No prior immunotherapy

Primary endpoint: safety


• Measurable disease

per RECIST v1.1

• BCLC stage B

• Deb-TACE on Day 0 (±5

days) for all cohorts

Cohort 1:


q2w) will be administered 2

weeks after deb-TACE for

up to 1 year

Cohort 2:


q2w) starting 4 weeks prior

to

deb-TACE (Week -4) for up

to

1 year

• No nivolumab on the day of

deb-TACE

Cohort 3:


q2w) starting 4 weeks prior

to

deb-TACE (Week -4) and

continue for up to 1 yearBCLC, Barcelona Clinic Liver Cancer; deb-TACE, Drug-eluting bead TACE; HCC, hepatocellular carcinoma; IO, immuno-oncology; IV, intravenous;

q2w, every 2 weeks;

TACE, transarterial chemoembolisationCourtesy of R Lencionni




(NCT number)

Country

Phase


Durvalumab and

tremelimumab

following

deb-TACE in

patients with

intermediate

HCC

(NCT03638141)

United States

Phase 2

(not yet

recruiting)


(non-randomised, open-label)


•New diagnosis of intermediate HCC

•Disease amenable to deb-TACE

•No concurrent anticancer therapy or

therapy received ≤30 days prior

to study

Primary endpoint: ORR (mRECIST)


• No diffuse HCC,

vascular invasion or

extrahepatic disease

• Main portal vein

thrombosis present

on imaging

• Four doses of

durvalumab (1500 mg

IV q4w) starting at Week

2

• At Week 15, patients

with CR will receive 9

doses of durvalumab

(1500 mg

IV q4w)

Cohort A:

• Single dose of

tremelimumab (300 mg

IV) at Week 2

Cohort B:

• Four doses of

tremelimumab (75 mg

IV q4w) starting at Week

2

CR, complete response; deb-TACE, Drug-eluting bead TACE; HCC, hepatocellular carcinoma; IO, immuno-oncology; IV, intravenous; ORR, objective

response rate; q4w, every 4 weeks; TACE, transarterial chemoembolisation

Courtesy of R Lencionni


Left radioembolization Right radioembolization

Right radioembolization

microspheres

fibrosed hepatic parenchyma

viable ADK

Fibrosis &

chronic inflammation

hepatic parenchyma

m-spheres & fibrosis

dense fibrosis

residual tumor

Sharma RA et al. J Clin Oncol 2007; 25: 1099–1106.

1000 Gy100 Gy

PS-018 | Role of 99mTc-Macroaggregated Albumin SPECT/CT based dosimetry in predicting survival and tumor response of patients with locally advanced and

inoperable HCC treated by SIRT with yttrium-90 resin microspheres, a cohort from SARAH study

Anne-Laure Hermann1, Arnaud Dieudonné2, Ronot Maxime1, Sanchez Manuel2, Pereira Helena3, Chatellier Gilles3, Castera Laurent4, Lebtahi Rachida5, Valerie Vilgrain1, Sarah Trial Group6

1 Hôpital Beaujon, Radiology, Clichy, France; 2 Hôpital Beaujon, Nuclear Medicine, Clichy, France; 3 Hôpital Européen Georges Pompidou, URC-Biostatistical Unit, Paris Cedex 15, France; 4 Hôpital Beaujon, Hepatology, Clichy, France; 2 Hôpital Beaujon, Nuclear Medicine, Clichy, France; 6 Hôpital Beaujon,

Radiology, Paris, France

5.8 months [95%CI 4.47–6.67] with 0 predictor

33.9 months [95%CI 9.46–NA] with 3 predictors

Variable HR 95% CI p

Tumour burden (%)

(> 25% vs. ≤ 25%) 1.85 1.15 – 2.97 0.0108

ALBI grade (A2 vs. A1) 1.91 1.15 – 3.20 0.0133

Tumour-absorbed dose

(< 100 Gy vs. ≥ 100 Gy) 2.70 1.72 – 4.25 < 0.0001

Courtesy of Maxime Ront

• Personalyzed dosimetry approch (PDA) vs standard dosimetry approach (SDA)

• Specific inclusion criteria : 1 tumor larger than 7 cm / Hepatic > 30%

Interim analysis of the multi-center randomized

phase 2 in advanced HCC (DOSISPHERE)

PDA :

> 205 Gy (If possible > 250-30 ) to the tumor,

Normal perfused liver Dose < 120 Gy

SDA :

120±20 Gy to the perfused liver

• Mean tumor dose (TD) was 324±131Gy (PDA) vs 221±110Gy (SDA), p=0.01.

TD = 329±145Gy for responders vs 225±110Gy for non responers p<10-3.

RRindex lesion : 71.4% (PDA) vs only 35.7% (SDA), p=0.007

Trial primary endpoint reached

Radioembolization : is it right or left ?

SIRT is not recommended as first line therapy for

patients in intermediate or advanced stage [I,E]

2 mois 4 mois 7 mois

Left radioembolization … to the right liver

7 mois

(Garlipp B, de Baere T, Seidensticker M. Hepatology 2014.59:1864-1873)

26 matched pairs

PVE : 61.5 ± 39 % after 33 [24-56] days

RE : 29 ± 28 % after 46 [27-79] days (p<0.001)

JHEP 2014

33 patients had surgery

17/33 (52%) Complete pathologic necrosis

16/33 (48%) Pathologic necrosis > 90%

Baseline Demographics (n=102)


plus SIRT / TAREShort title

(NCT number)

Country

Phase


NASIR-HCC

(NCT03380130)

Spain

Phase 2

(recruiting

for >1 year)




•Confirmed HCC

•Patients with fibrolamellar carcinoma are

not excluded

•No history of hepatic encephalopathy


Primary endpoint: safety

• Preserved liver

function (without

cirrhosis or with

compensated cirrhosis

in Child-Pugh Class

A)

• Cirrhosis absent,

non-viral or due to

hepatitis C or B virus

infection

• SIRT will be performed in

a single session using SIR-

Spheres resin

microspheres

• After 3 weeks, nivolumab

(240 mg IV q2w) will be

initiated for 8 cycles or

until PD

Y90

radioembolisation

with nivolumab in

Asians with HCC

(NCT03033446)

Singapore

Phase 2

(recruiting

for >2

years)




•Confirmed HCC

•Not suitable for resection or liver

transplant

•No prior Y90 radioembolisation therapy


Primary endpoint: ORR



with target lesion in

liver

(≤1 lesion >20 mm

with conventional

techniques or as >10

mm with spiral CT

scan)

• Y90 dose based on BSA

and size of liver tumour

• Dose modifications

required for percent lung

shunting between 10 and

20% on the Tc-99MMA

scan

• 21 days after

radioembolisation,

nivolumab (240 mg IV

q2w) administered over 30

minsBSA, body surface area; CT, computed tomography; HCC, hepatocellular carcinoma; IO, immuno-oncology; IV, intravenous; ORR, objective response rate; PD, disease

progression;

q2w, every 2 weeks; SIRT, selective internal radiation therapy; TARE, transarterial radioembolisation Courtesy of R Lencionni





(NCT number)

Country

Phase


Nivolumab and

Y90 in patients

with advanced

liver cancer

(NCT02837029)

United States

Phase 1

(recruiting

for >2

years)




•Confirmed advanced HCC

•Not eligible for resection or liver

transplant


Primary endpoint: MTD

• Child-Pugh Class A or

B

• ≥1 measurable lesion

using RECIST

guidelines

• Y90 glass microsphere

• Nivolumab administered

4 weeks after Y90, over

30–60 mins on Days 1 and

15

• Course repeated every

28 days (until PD or

unacceptable toxicity)

Nivolumab and

Y90 in patients

with liver cancer

undergoing

surgical resection

(NCT03812562)

United States

Early

Phase 1

(recruiting)




•Confirmed HCC

•Eligible for resection based on preserved

hepatic function and lack of clinically

significant portal hypertension


•No chemotherapy or radiotherapy ≤28

days prior to registration

Primary endpoint: Recurrence rate

• Child-Pugh Class A or

B


per RECIST v1.1

• Y90 glass microspheres

• Nivolumab administered

within 1–2 weeks after

Y90, over

30 mins on Day 1

• Treatment repeated q2w

for up to 4 doses (until PD

or unacceptable toxicity)

• If adequate FLR and at

least SD, patients will

undergo resection within 2

weeks of last dose of

nivolumab

FLR, future liver remnant; HCC, hepatocellular carcinoma; IO, immuno-oncology; MTD, maximum tolerated dose; PD, disease progression; q2w, every 2 weeks; SD, stable

disease; SIRT, selective internal radiation therapy; TARE, transarterial radioembolisationCourtesy of R Lencionni





(NCT number)

Country

Phase


Y90, ipilimumab

and nivolumab

for uveal

melanoma with

liver metastases

(NCT02913417)

United States

Phase 1/2

(recruiting

for

>2 years)




•Confirmed metastatic uveal melanoma

•Liver metastasis

•≤1 prior systemic therapy

•No prior ipilimumab or CTLA-4

inhibitor

•No CNS metastases

Primary endpoint: safety and

tolerability


by RECIST

• Liver tumour

volume ≤50%

• Y90 given by injection

into the hepatic artery in

two treatments, one for

each lobe

• Four doses of concurrent

ipilimumab (3 mg/kg

q3w) and nivolumab (1

mg/kg q3w) 3–5 weeks

after Y90

• After 4 cycles,

nivolumab

(3 mg/kg q2w) given

until PD or up to 3 years

CNS, central nervous system; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; HCC, hepatocellular carcinoma; IO, immuno-oncology; PD,

disease progression; q2w, every 2 weeks; q3w, every 3 weeks; SIRT, selective internal radiation therapy; TARE, transarterial radioembolisation

Courtesy of R Lencionni


locoregional treatment of unresectable HCC · GIDEON: The Largest Global Observational Study...

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