MEET THE EXPERTS...MEET THE EXPERTS: THE CHANGING LANDSCAPE OF HCC TREATMENT Professor Arndt Vogel MD, Professor Riad Salem MD, Professor Richard Finn MD & Professor Masatoshi Kudo

MEET THE EXPERTS:

THE CHANGING LANDSCAPE

OF HCC TREATMENT Professor Arndt Vogel MD, Professor Riad Salem MD,

Professor Richard Finn MD & Professor Masatoshi Kudo MD

This event is sponsored and organised by Eisai whose products will be

discussed. Prescribing information for lenvatinib is available on the

last slide and at this meeting.

September 2019 GL-LENB-19-00046

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Welcome and introduction

Time Duration Presentation title Speaker

12:15 10 minsAssessing response in advanced liver cancer – does response matter?

What does the previous data suggest?Prof Vogel

12:25 15 minsHow do we measure response and how does this affect clinical

decisions?Prof Salem

12:40 20 mins What does the latest data show about how meaningful response is? Prof Finn

13:00 25 minsResponse and its impact on survival – identifying the right patient

(stage B & C)Prof Kudo

13:25 20 mins Audience question and answer session Q & A

Assessing response in advanced liver cancer

– does response matter?

What does the previous data suggest?ARNDT VOGEL

Served as consultant, received speakers’ honoraria and/or travel expenses from:

Disclosures

• Amgen

• AstraZeneca

• Bayer

• Baxalta/Shire

• BMS

• Lilly

• MSD

• Roche

• Sanofi Aventis

• Eisai

EMA approval status subject to change

Current first-line approvals for sorafenib and lenvatinib, and second-line approvals for nivolumab,

regorafenib, cabozantinib, ramucirumab and pembrolizumab as of September 2019

Treatment of HCC: ESMO clinical practice guidelines 2018

Vogel et al. ESMO CPG 2018, Annals of Oncology

BCLC 0-A

Resectiona

LTX

[III, A]

Ablationa

[III, A]

TACE [I, B]

SBRTC

BrachytherapyC

SIRTC

[III, C]

BCLC D

BSC

[III, A]

SIRT

[III, C]C

BCLC B

LTX

Resection

[III, A]

TACEa

[I, A]

Systemic

therapy

[I, A]

TACE failure/

refractoriness

BCLC C

Sorafeniba

[I, A]

Lenvatiniba

[I, A]

Nivolumabb,c

[III, C]

Regorafeniba [I, A]

Cabozantinibb [I, A]

Ramucirumabb [I, A]

Nivolumabb [III, B]

Pembrolizumabb [III, B]

Does response matter in HCC?

• In respect to local therapies

• In respect to systemic therapies

- Data in RCC (drugs with similar MOA)

- Data in HCC

What do we know?

950 patients screened, 70% ≥2 tumours, ∼5 cm,

Median: 2.8 treatments

17.9 (BSC!) vs 28.7 months

Evidence for TACE

Phase III study

Llovet et al., Lancet 2002.

Lencioni et al. Hepatology 2016.

Systematic review of 101 studies (n=10,108)

Patients treated with lipiodol TACE

Real life

mOS: 19.4 months

How to measure response in HCC

Jung et al. Journal of Hepatology 2013

WHO RECIST EASL mRECIST

International collaboration: GO-TREAT HCC

• 4621 HCC patients

treated with TACE,

19 centres in 11 countries

• Clinical parameters

at baseline (pre-TACE)

• mRECIST response

after 1st TACE

(post-TACE)

T. Labeur/ Vogel/ Johnson; GO-TREAT HCC consortium @ILCA 2018

Random split

GO-TREAT HCC dataset (N=4261)

The rest (n=3428)Xijing, china (n=786)

External validation (East)

Freiburg, Germany (n=407)

External validation (West)

Internal validation set

(n=1714)

Training set

(n=1714)

N=2688

N=748

N=1714

N=748

0

.25

.5.7

5

1

0 20 40 60Survival (months)

CR PR SD PD

Survival by mRECIST response

508

CR: 36.02

(32.80, 40.33)

653

PR: 21.32

(20.20, 22.96)

674

SD: 13.88

(11.88, 15.00)

504

PD: 6.97

(6.09, 7.93)

Overall survival according to mRECIST following TACE:

Response matters!

T. Labeur/ Vogel/ Johnson; GO-TREAT HCC consortium @ILCA 2018

mRECIST

EASL

Prognostic relevance of objective response in TACE

according to EASL criteria and mRECIST

Vincenzi et al. PlosOne 2015

A literature-based meta-analysis

Best predictor for OS: CR @1st TACE?

Kim BK et al. Journal of Hepatology 2015

Best predictor for OS: 6-months sustained response?

Zhang et al. JAMA Network Open 2018

2403 patients treated with cTACE in China

RCC: objective response predicts survival

Grünwald et al. European Urology 2015

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 10 20 30 40 50 60

Surv

ival pro

babilit

y

Time (months)

Median OS (m)

–100% to –60% (n=283) 54.53

–60% to –30% (n=547) 26.38

–30% to 0% (n=1155) 16.56

0% to +20% (n=390) 10.36

≥20% (n=156) 7.33

No post-baseline scan (n=218) 1.97

2749 patients treated in phase II and III with TKI, mTOR inhibitor and/or interferon

RCC: objective response predicts survival

Grünwald et al. European Urology 2015

First-line therapy

n=1759

Second-line therapy

n=990

Time (months)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 10 20 30 40 50 60

Su

rviv

al

pro

ba

bil

ity

–100% to –60% (n=208)

–60% to –30% (n=336)

–30% to 0% (n=708)

0% to +20% (n=247)

≥20% (n=101)

No post-baseline scan (n=159)

Time (months)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 10 20 30 40 50 60

Surv

ival pro

babilit

y

–100% to –60% (n=75)

–60% to –30% (n=211)

–30% to 0% (n=447)

0% to +20% (n=143)

≥20% (n=55)

No post-baseline scan (n=59)

2749 patients treated in phase II and III with TKI, mTOR inhibitor and/or interferon

Objective response by mRECIST and RECIST as an independent

prognostic factor in HCC in 2nd line

Meyer et al. Liver International 2017

Nintedanib is not an approved drug in 2L HCC

Nintedanib vs sorafenib

RECISTmRECIST

Objective response by mRECIST as an independent prognostic

factor in HCC in 2nd line

Lencioni et al. Journal of Hepatology 2017

Brivanib is not an approved drug in 2L HCC

BRISK-PS (brivanib)

Univariate analysis Multivariate analysis

HR [95% CI] p value HR [95% CI] p value

Distant metastasis 1.27 [0.96―1.67] 0.094 1.37 [1.05―1.78] 0.019

Macrovascular invasion 1.77 [1.33―2.34] <0.001 1.54 [1.19―1.99] 0.001

Nodal metastasis 1.52 [1.17―1.99] 0.002 1.36 [1.07―1.73] 0.013

AFP >200 ng/ml 2.02 [1.55―2.62] <0.001 1.99 [1.56―2.54] <0.001

Albumin >median 0.58 [0.45―0.75] <0.001 0.65 [0.51―0.83] 0.001

Bilirubin >median 2.32 [1.78―3.03] <0.001 2.24 [1.73―2.89] <0.001

Objective response mRECIST 0.28 [0.14―0.54] <0.001 0.48 [0.26―0.91] 0.025

Take home

Response matters in HCC

Response should be evaluated by mRECIST or EASL

- R. Salem

Correlation between response and survival has first been established

for local therapies

Low response rates did so far not allow definite correlation for systemic

therapies - Prof. Finn & Prof. Kudo

HOW DO WE MEASURE RESPONSE

AND HOW DOES THIS AFFECT

CLINICAL DECISIONS IN HCC?Riad Salem MD MBA FSIR

Professor of Radiology, Medicine and Surgery

Vice-Chair, Image-Guided Therapy

Chief, Vascular and Interventional Radiology

Robert H Lurie Comprehensive Cancer Center

Northwestern University

Chicago, Illinois

Consultant

Disclosures

• BTG UK Ltd

• Boston Scientific

• BMS

• Dova

Scientific advisory board

• BTG UK Ltd

• Cook

• Eisai

• Exelixis

Scientific advisory board

• BTG UK Ltd

Outline

Differentiating

RECIST 1.1

and mRECIST

1

Investigator review

and central review

differences -

Why are outcomes

different?

2

Making clinical

decisions based

on imaging

3

Technical requirements: quality control

LIRADS 2018

State-of-the-art

CT/MR

1

Contrast-enhanced

2

Pre contrast

(if prior LRT-lipiodol,

Ca), arterial, portal,

delayed phases

3

Compare images

from same modality,

same patient

anatomic plane

4

POINT 1

Differentiating RECIST 1.1

and mRECIST

Competing methods of assessing response

1. Uni-dimensional

- Response Evaluation Criteria

in Solid Tumours (RECIST)

2. Bi-dimensional

- World Health Organization (WHO)

3. Volumetric

4. European Association for the Study

of the Liver (2D EASL, mRECIST)

5. European Association for the Study

of the Liver (3D EASL)

6. Functional Diffusion-Weighted (DW)

MR Imaging (ADC)

• EASL (necrosis)

- Guidelines measure change in the amount of enhancing

(viable) tissue only

• Tissue viability (necrosis)

- Assumes enhancement is tumour

- Did not describe methods to measure necrosis

- Qualitative observation

Bruix et al J Hep 2001

New response evaluation criteria in solid tumours:

Revised RECIST guideline (version 1.1)

Eisenhauer et al Eur J Cancer 2009

Number of

tumours

required to

assess response

decreased to:

Maximum of 5

Maximum 2/organ

Modified RECIST (mRECIST) assessment for hepatocellular carcinoma

Reviews and clarifies imaging methodology:

• New lesions

• Portal vein thrombosis non measurable

• LN >2 cm (malignant)

• Pleural effusions/ascites

• Retrospective adjudication of extrahepatic metastases

Lencioni and Llovet Semin Liver Dis 2010

mRECIST versus RECIST v1.1

Eisenhauer et al Eur J Cancer 2009. Lencioni et al Sem Liv Dis 2010

mRECIST RECIST v1.1

Complete responseDisappearance of any intratumoral arterial

enhancement in all target lesionsDisappearance of all target lesions

Partial response

Decrease of ≥30% in the sum of diameters of

viable (enhancement in the arterial phase)

target lesions, taking as reference the baseline

sum of the diameters of target lesions

Decrease of ≥30% in the sum of diameters of

target lesions, taking as reference the baseline

sum of the diameters of target lesions

Progressive disease

Increase of ≥20% in the sum of the diameters of

viable (enhancing) target lesions, taking as

reference the smallest sum of the diameters of

viable (enhancing) target lesions recorded since

treatment started

Increase of ≥20% in the sum of the diameters of

target lesions, taking as reference the smallest

sum of the diameters of target lesions recorded

since treatment started

Edeline et al Cancer 2011Edeline et al Cancer 2011

Figure 1. These images illustrate evaluation according to Response

Evaluation Criteria in Solid Tumours (RECIST) and modified RECIST

(mRECIST) in a voluminous lesion that had central necrosis before

treatment and discontinuous peripheral enhancement after treatment.

(A,B) These images illustrate RECIST measurement (arrows) of the lesion

(A) before treatment and (B) after treatment. (C,D) mRECIST

measurement of the same lesion is shown (C) before treatment and (D)

after treatment. Note that mRECIST measurements (arrow) were not

taken at the same level as RECIST measurements to ensure that the

greatest dimension of continuous enhancement was measured.

A B

C D

Patterns of progression: enhancement-mRECIST

Patterns of progression: portal vein thrombosis

POINT 2

Investigator review and

central review differences

Why are outcomes different?

Site versus central review

Site review

• No protocol training

• May not be liver MR/CT specialised

• MD possibly biased

• Aware of clinical circumstance

• Prospectively performed

• Influenced by patient care

• Affects treatment decisions

Central Review

• Protocol training + charter

• Specialist in liver MR/CT

• Competency is tested

• No MD bias

• Blinded to clinical circumstance

• Retrospectively performed

• Intended for statistical analyses and temporally unrelated to patient care

• Per patient discordance in treatment-response finding

• Reader reviews all patient scans

• 2nd, 3rd reader→ adjudication

Central review

• Protocol training + charter

• Specialist in liver MR/CT

• Competency is tested

• No MD bias

• Blinded to clinical circumstance

• Retrospectively performed

• Intended for statistical analyses and temporally unrelated to patient care

• Per patient discordance in treatment-response finding

• Reader reviews all patient scans

• 2nd, 3rd reader→ adjudication

NORMAL READER

VARIABILITY

ADJUDICATION

A

B

POINT 3

Making clinical decisions

based on imaging

Response matters!

Response versus non response:

Interpret with caution

1. Survival analyses by simple R vs NR biases responders

→ Misinterpretation that response provides survival benefit

2. Guarantee-time bias

→ Better biology patients live longer and show R

→ Worse biology live insufficient time to show R, hence NR

3. Two methods to correct for this bias

→ Landmark - most commonly used

→ Mantel-Byar

Anderson et al JCO 1983

Landmark analyses

Evaluates survival by tumour response1

Addresses guarantee-time bias via the selection of fixed time points after

treatment onset2

Patients at the landmark time points are stratified by best response and survival

analyses are performed3

Patients who die before the landmark time point are excluded4

Multivariate Cox regression models with OR as a time-dependent covariate

- Adjusts OS outcome corrected for confounding factors (liver function, burden) 5

Northwestern University Multidisciplinary Collaborative Project

Memon et al Gastroenterology 2011

• 1818 CT/MRI scans performed on 463 patients

• Staged by Child-Pugh, BCLC, UNOS

Total patients undergoing transarterial therapy

for HCC

N=463

IMAGING

• Response

• Time-to-progression (size, necrosis, PVT)

SURVIVAL

• Censored

• Intention-to-treat

ANALYSES

• Biomarker lesion

• AFP as a prognosticator

• TACE vs Y90

Radiographic response to locoregional therapy in hepatocellular

carcinoma predicts patient survival times

Memon et al Gastroenterology 2011, Lencioni et al JHEP 2017, Meyer et al Liv Int 2017, Kudo et al ASCO 2018

Guarantee/immortal-time bias

Survival analysis by response status STATISTICAL METHOD WHO EASL

Child

Pugh ≤B7

Landmark

R

vs

NR

(SD+PD)

6-month 12-month 6-month 12-month

R NR R NR R NR R NR

N 15 90 20 54 42 63 25 49

Survivala 31.6 13.7 36.4 11.1 24.6 13.2 36.4 9.7

P value .0694 .0004 .002 <.0001

DC

(R+SD)

vs

PD

R SD PD R SD PD R SD PD R SD PD

N 15 46 44 20 10 44 42 28 35 25 8 41

Survivala 31.6 21 10.6 36.4 19.2 10.4 24.6 14 10.1 36.4 11.2 9.7

P value .0008 .0004 .002 .0001

R NR R NR R NR R NR

6-month risk of death following the

landmark

1/15

(6.6)

14/90

(15.5)

0/20

(0)

17/54

(31.5)

2/42

(4.7)

13/63

(20.6)

1/25

(4)

16/49

(32.7)

Chi-square 0.141 6.492 3.970 6.147

P value .707 .010 .0463 .0132

First author [ref.], year Agents (study design) ORR (mRECIST). % (n/total n)

Median OS, months

HR (95% CI) P valueResponder

(CR + PR)

Nonresponder

(SD + PD)

Lencioni [6], 2017brivanib

(phase 3 RCT)11.5 (26/226) 14.3 9.4

0.31

(0.16―0.60)<0.001

Meyer [7], 2017nintedanib + sorafenib

(phase 2 RCT)15.6 (28/180) 16.7 10.9

0.544

(0.335―0.881)0.0122

Kudo [8], 2018sorafenib

(phase 3 RCT)18.8 (18/96) 27.2 8.9 N/A <0.001

Radiographic response to locoregional therapy in hepatocellular

carcinoma predicts patient survival times

Memon et al Gastroenterology 2011. Riaz et al HEP 2018

Survival analysis by response status STATISTICAL METHOD WHO EASL

Child

Pugh ≤B7

Landmark

R

vs

NR

(SD+PD)

6-month 12-month 6-month 12-month

R NR R NR R NR RNR

N 15 90 20 54 42 63 25 49

Survivala 31.6 13.7 36.4 11.1 24.6 13.2 36.4 9.7

P value .0694 .0004 .002 <.0001

DC

(R+SD)

vs

PD

R SD PD R SD PD R SD PD R SD PD

N 15 46 44 20 10 44 42 28 35 25 8 41

Survivala 31.6 21 10.6 36.4 19.2 10.4 24.6 14 10.1 36.4 11.2 9.7

P value .0008 .0004 .002 .0001

R NR R NR R NR R NR

6-months risk of death following the

landmark

1/15

(6.6)

14/90

(15.5)

0/20

(0)

17/54

(31.5)

2/42

(4.7)

13/63

(20.6)

1/25

(4)

16/49

(32.7)

Chi-square 0.141 6.492 3.970 6.147

P value .707 .010 .0463 .0132

Few landmark analyses in BCLC B

Kudo et al ASCO GI 2019

Landmark analyses for OS by OR in overall

REFLECT population

• Time-dependent analysis

• Landmark analyses confirm responders > non responders

Kudo et al ASCO GI 2019.

Landmark KM curve as function of

tumour response at 2 months





Why does response matter? Related to PFS

Time since start of treatment

Tum

our

load a

t base

line

Tumour nadir

Lethal tumour load

- 30%

OS

PFS +20% from nadir

For any

given PFS,

highest RR yields

lowest tumour

burden

Phase 2 study of lenvatinib in patients with advanced

hepatocellular carcinoma

CR by mRECIST in uHCC after lenvatinib

Ikeda et al J Gasteroenterol 2018

Baseline Timepoint 2 Timepoint 5

Lenvatinib-treated patient

Lencioni R. Presented at AASLD-ETC, Atlanta, March 22-23, 2019

Conclusions

• Standardising imaging technique (CT/MR)

• mRECIST favoured over RECIST 1.1 in HCC

• Site vs central read will show differences

• Landmark analyses critical when assessing R vs NR survival

• For any given PFS, better RR beneficial for patient

• Potential area of research for systemic agents with high RR

- Downstaging to resection

- Downstaging to transplantation

- Combining with LRTs

WHAT DOES THE LATEST DATA

TELL US SHOW ABOUT HOW

MEANINGFUL RESPONSE IS?Richard S. Finn, MD

Professor of Clinical Medicine

Division of Hematology/Oncology

Director, Signal Transduction and Therapeutics Program

Jonsson Comprehensive Cancer Center at UCLA

Geffen School of Medicine at UCLA

Served as a consultant for:

Disclosures

• AstraZeneca

• Bayer

• BMS

• CStone

• Eisai

• Eli Lilly

• Novartis

• Pfizer

• Merck

• Roche/Genentech

Barcelona Clinic Liver Cancer (BCLC)

staging and treatment strategy1

1. Forner F et al. Lancet 2018;391:1301-1314.

Potential candidate

for liver transplantationSolitary

Up to 3 nodules

(≤3cm)

No Yes

Ablation Reservation Transplantation Ablation Chemoembolisation Systemic therapy

Best supportive care

Effective treatments with impact on survival

>5 years >2-5 years >1 year 3 months

SU

RV

IVA

L

TR

EA

TM

EN

TPR

OG

NO

SIS

Hepatocellular carcinoma

Very early stage (O)

Single ≤2cm

Preserved liver function,

ECOG PS 0

Very early stage (A)

Single or up to 3 nodules ≤3cm


ECOG PS 0

Intermediate stage (B)

Multinodular


ECOG PS 0

Intermediate stage (C)

Portal invasion

Extrahepatic spread


ECOG PS 1-2

Terminal stage (D)

End-stage liver function,

ECOG PS 3-4

Yes Portal pressure bilirubin No

Normal IncreasedAssociated

diseases

The problem with size criteria after locoregional therapy

EASL CR

mRECIST CR

RECIST SD

WHO SD

Imaging response

Size criteria Enhancement criteria

WHO RECIST EASL mRECIST

Bi-dimensional Uni-dimensional Bi-dimensional Uni-dimensional

Objective

response

No

objective

response

HR (95% CI) HR (95% CI)

Total 847 510 0.39 (0.26, 0.61)

Gilmore (2011) 48 35 0.56 (0.35, 0.90)

Prajapati (2013) 63 57 0.40 (0.19, 0.84)

Li (2013) 38 26 0.49 (0.27, 0.89)

Kim (2013) 210 82 0.46 (0.32, 0.65)

Jung (2013) 62 36 0.27 (0.15, 0.48)

Kim (2014) 250 118 0.15 (0.09, 0.23)

Choi (2014) 176 156 0.71 (0.50, 1.01)

0,01 1 100

Favours objective response Favours no objective response

Objective response predicts OS in locoregional therapy

EASL guidelines recommend that objective response measured by mRECIST predicts survival in

patients receiving locoregional therapies

Vincenzi B, et al. PLoS One 2015;10:e0133488.

Kudo et al Dig Dis 2011

Definition of TACE failure/refractoriness (JSH criteria)

Intrahepatic lesion

i. Two or more consecutive insufficient responses of the treated tumour

(viable lesion >50%) even after changing the chemotherapeutic agents and/or

reanalysis of the feeding artery seen on response evaluation CT/MRI at 1―3

months after having adequately performed selective TACE

ii. Two or more consecutive progressions in the liver (tumour number increases

as compared to tumour number before the previous TACE procedure) even after

having changed the chemotherapeutic agents and/or reanalysis of the feeding

artery seen on response evaluation CT/MRI at 1―3 months after having

adequately performed selective TACE

Kudo et al Dig Dis 2011

Phase III SHARP trial: overall survival

(intent-to-treat population)

Llovet JM et al. N Engl J Med. 2008; 359:378-390.

Phase III SHARP trial: time to tumour progression

(independent review)


Phase III SHARP trial: best response by RECIST

(independent review)

*The level of response was measured according to RECIST (Response Evaluation Criteria in Solid Tumors) by independent

radiologic review.


sorafenib

n=299

%

Placebo

n=303

%

Level of response*

Complete response 0 0

Partial response 2 1

Stable disease 71 67

Progression-free rate at 4 mo 62 42

Univariate analysis Multivariate analysis

HR [95% CI] p value HR [95% CI] p value

Distant metastasis 1.27 [0.96―1.67] 0.094 1.37 [1.05―1.78] 0.019

Macrovascular invasion 1.77 [1.33―2.34] <0.001 1.54 [1.19―1.99] 0.001

Nodal metastasis 1.52 [1.17―1.99] 0.002 1.36 [1.07―1.73] 0.013

AFP >200ng/ml 2.02 [1.55―2.62] <0.001 1.99 [1.56―2.54] <0.001

Albumin >median1 0.58 [0.45―0.75] <0.001 0.65 [0.51―0.83] 0.001

Bilirubin >median2 2.32 [1.78―3.03] <0.001 2.24 [1.73―2.89] <0.001

Objective response mRECIST 0.28 [0.14―0.54] <0.001 0.48 [0.26―0.91] 0.025

Tumour shrinkage/necrosis contributes to prolonging OS (RCT)

Meyer T et al.: Liver Int 2017; 37: 1047-1055. Lencioni R et al.: J Hepatol 2017; 66: 1166-1172. Kudo M, et al. Lancet Gastroenterol Hepatol 2018

Responder analysis in systemic therapy (mRECIST)

ORR by mRECIST predicts overall survival

ORR=15.6％ ORR=11.5％ ORR=18％

Variables not associated with OS in univariate analysis (p value .0.10) were reason for sorafenib discontinuation, ECOG PS score, region, age, sex, race, and risk factors.1 3.59 g/dl2 0.98 mg/dl

nintedanib vs

sorafenib

brivanib

brivanib

EASL clinical practice guidelineObjective response in systemic therapies

J Hepatol. 2018 Apr 5. pii: S0168-8278(18)30215-0

REFLECT study schema

BCLC, Barcelona Clinic Liver Cancer; BW; body weight; ECOG PS, Eastern Cooperative Oncology Group Performance

Status; EHS, extrahepatic spread; MPVI, macroscopic portal vein invasion; mRECIST, modified Response Evaluation

Criteria In Solid Tumors; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PK,

pharmacokinetic; RECIST, Response Evaluation Criteria in Solid Tumors; TTP, time to progression.

Kudo M et al. Lancet 2018

sorafenib (n=476)

400 mg twice daily

Stratification

• Region: (Asia-Pacific or Western)

• MPVI and/or EHS:(yes or no)

• ECOG PS: (0 or 1)

• Body weight:(<60 kg or ≥60 kg)

Lenvatinib (n=478)

8 mg (BW <60 kg)

or

12 mg (BW≥ 60 kg)

once daily

Patients with unresectable HCC (N = 954)

• No prior systemic therapy for unresectable HCC

• ≥1 measurable target lesion per mRECIST

• BCLC stage B or C

• Child-Pugh A

• ECOG PS ≤ 1

• Adequate organ function

• Patients with ≥50% liver occupation, clear bile duct invasion, or portal vein invasion at the main portalvein were excluded

Ra

nd

om

isa

tio

n1

:1

Primary endpoint:

• OS

Secondary endpoints:

• PFS

• TTP

• ORR

• Quality of life

• PK lenvatinib exposure parameters

Tumour assessments were performed according to mRECIST by the investigator

Global, randomised, open-label, phase 3 non-inferiority study

Patient characteristics

Characteristic CategoryLenvatinib

(n=478)

Sorafenib

(n=476)

Mean age (years) 61.3 61.2

Sex, n (%)Male

Female

405 (85)

73 (15)

401 (84)

75 (16)

Region, n (%)Western

Asia-Pacific

157 (33)

321 (67)

157 (33)

319 (67)

Body weight (kg), n (%)<60

≥60

153 (32)

325 (68)

146 (31)

330 (69)

ECOG PS, n (%)0

1

304 (64)

174 (36)

301 (63)

175 (37)

MVI, EHS, or both, n (%)Yes

No

329 (69)

149 (31)

336 (71)

140 (29)

Child-Pugh class, n (%)A

B

475 (99)

3 (1)

471 (99)

5 (1)

BCLC stage, n (%)B (intermediate stage)

C (advanced stage)

104 (22)

374 (78)

92 (19)

384 (81)


Patient characteristics (continued)

AFP, alpha-fetoprotein.


Characteristic CategoryLenvatinib

(n=478)

Sorafenib

(n=476)

Involved disease sites per patient, n (%)

1

2

≥3

207 (43)

167 (35)

103 (22)

207 (44)

183 (38)

86 (18)

Aetiology of chronic liver disease, n (%)

Hepatitis B

Hepatitis C

Alcohol

Other

Unknown

251 (53)

91 (19)

36 (8)

38 (8)

62 (13)

228 (48)

126 (27)

21 (4)

32 (7)

69 (15)

Baseline AFP level group (ng/mL), n (%)<200

≥200

255 (53)

222 (46)

286 (60)

187 (39)

Median baseline AFP level (ng/mL) 133.1 71.2

Concomitant systemic antiviral therapy for hepatitis B, n (%) 162 (34) 148 (31)

Kudo M, Finn RS, Qin S et al. Lancet 2018

REFLECT study

Primary endpoint: Kaplan-Meier estimate of OS


REFLECT study

Secondary endpoint: Kaplan-Meier estimate of PFS by mRECIST


ParametermRECIST by

investigator

mRECIST by

independent review

RECIST v1.1 by

independent review

Lenvatinib (n=478)

ORR, n (%) 115 (24.1) 194 (40.6) 90 (18.8)

95% CI 20.2–27.9 36.2–45.0 15.3–22.3

Odds ratio (95%CI)a 3.13 (2.15–4.56) 5.01 (3.59–7.01) 3.34 (2.17–5.14)

BOR, n (%)

Complete response 6 (1) 10 (2) 2 (<1)

Partial response 109 (23) 184 (38) 88 (18)

Stable disease 246 (51) 159 (33) 258 (54)

Durable stable diseaseb 167 (35) 84 (18) 163 (34)

Progressive disease 71 (15) 79 (17) 84 (18)

Not evaluable/unknown 46 (10) 46 (10) 46 (10)

Tumour assessments: lenvatinib

aLenvatinib vs sorafenib.bStable disease lasting ≥23 weeks.

BOR, best overall response; CI, confidence interval; mRECIST, modified

Response Evaluation Criteria in Solid Tumours; ORR, objective response rate.

ParametermRECIST by

investigator

mRECIST by

independent review

RECIST v1.1 by

independent review

Sorafenib (n=476)

ORR, n (%) 44 (9.2) 59 (12.4) 31 (6.5)

95% CI 6.6–11.8 9.4–15.4 4.3–8.7

BOR, n (%)

Complete response 2 (<1) 4 (1) 1 (<1)

Partial response 42 (9) 55 (12) 30 (6)

Stable disease 244 (51) 219 (46) 250 (53)

Durable stable diseaseb 139 (29) 90 (19) 118 (25)

Progressive disease 147 (31) 152 (32) 152 (32)

Not evaluable/unknown 41 (9) 46 (10) 43 (9)

Tumour assessments: sorafenib

aLenvatinib vs sorafenib.bStable disease lasting ≥23 weeks.

BOR, best overall response; CI, confidence interval; mRECIST, modified

Response Evaluation Criteria in Solid Tumours; ORR, objective response rate.

OS by OR for the overall REFLECT population (post-hoc)

Kudo M et al. ASCO GI 2019

Landmark analyses for OS by OR in the overall

REFLECT population (post-hoc)


CI, confidence interval; HR, hazard ratio; KM, Kaplan-Meier; OR, objective response; OS, overall survival.







Multivariate analysis of factors associated with OS (post-hoc)

Only factors selected by the stepwise selection method are displayed in the table. Factors not selected include age, sex, region, extrahepatic spread,

extrahepatic spread or both, ECOG PS, bodyweight, antiviral therapy for HBV or HCV, etiology HCV, etiology alcohol, underlying cirrhosis, and BCLC staging.

AFP, α-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HBV,

hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; OS, overall survival.


ParameterMultivariate analysis

HR [95% CI] P-value

Baseline AFP (ng/mL) (<200 vs ≥200) 0.564 [0.483–0.659] <0.0001

Objective response (yes vs no) 0.611 [0.490–0.762] <0.0001

Prior procedure for HCC (yes vs no) 0.844 [0.723–0.986] 0.0323

Treatment (lenvatinib vs sorafenib) 0.855 [0.734–0.996] 0.0439

Aetiology HBV (yes vs no) 1.199 [1.031–1.395] 0.0185

Macroscopic portal vein invasion (yes vs no) 1.366 [1.141–1.636] 0.0007

Number of tumour sites at baseline (2 vs 1) 1.400 [1.180–1.662] <0.0001

Involved tumour site - liver (yes vs no) 1.675 [1.203–2.332] 0.0022

Number of tumour sites at baseline (≥ 3 vs 1) 2.024 [1.659–2.469] <0.0001

SAFETY

Duration of treatment


Lenvatinib

(n=476)

Sorafenib

(n=475)

Median duration of treatment (months) 5.7 3.7

Starting dose Patient <60 kg

8 mg QD

Patient ≥60 kg

12 mg QD 400 mg BD

Mean dose intensity 7.0 mg 10.5 mg 663.8 mg

Patients who received the planned starting

dose 88% 88% 83%

TEAE, treatment-emergent adverse event.

Kudo M et al. Lancet. 2018;391:1163-1173.

Summary of adverse events

• Treatment-related fatal adverse events in the lenvatinib arm included hepatic

failure (n=3), cerebral haemorrhage (n=3), respiratory failure (n=2)

• Treatment-related fatal adverse events in the sorafenib arm included tumour

haemorrhage, ischemic stroke, respiratory failure, sudden death (n=1 each)

TEAE, treatment-emergent adverse event.

Kudo M et al. Lancet. 2018;391:1163-1173.

When adjusted

by duration of treatment,

the adverse event rate

(episodes/patient-year)

for lenvatinib was

18.9 vs 19.7

for sorafenib

ParameterLenvatinib

(n=476)

Sorafenib

(n=475)

TEAEs 470 (99) 472 (99)

Treatment-related 447 (94) 452 (95)

TEAEs grade ≥3 357 (75) 316 (67)


Serious adverse events 205 (43) 144 (30)


Treatment-related fatal adverse

events11 (2) 4 (1)

Adverse event, n (%) Lenvatinib (n=476) Sorafenib (n=475)

Any grade Grade ≥3 Any grade Grade ≥3

Hypertension 201 (42) 111 (23) 144 (30) 68 (14)

Diarrhoea 184 (39) 20 (4) 220 (46) 20 (4)

Decreased appetite 162 (34) 22 (5) 127 (27) 6 (1)

Decreased weight 147 (31) 36 (8) 106 (22) 14 (3)

Fatigue 141 (30) 18 (4) 119 (25) 17 (4)

Palmar-plantar erythrodysesthesia 128 (27) 14 (3) 249 (52) 54 (11)

Proteinuria 117 (25) 27 (6) 54 (11) 8 (2)

Dysphonia 113 (24) 1 (0) 57 (12) 0 (0)

Nausea 93 (20) 4 (1) 68 (14) 4 (1)

Decreased platelet count 87 (18) 26 (5) 58 (12) 16 (3)

Abdominal pain 81 (17) 8 (2) 87 (18) 13 (3)

Hypothyroidism 78 (16) 0 (0) 8 (2) 0 (0)

Vomiting 77 (16) 6 (1) 36 (8) 5 (1)

Constipation 76 (16) 3 (1) 52 (11) 0 (0)

Increased blood bilirubin 71 (15) 31 (7) 63 (13) 23 (5)

Elevated aspartate aminotransferase 65 (14) 24 (5) 80 (17) 38 (8)

Rash 46 (10) 0 (0) 76 (16) 2 (0)

Alopecia 14 (3) 0 (N/A) 119 (25) 0 (N/A)

REFLECT study

Most frequent TEAEs (≥15%)


Dose reductions and interruptions

Kudo M, Finn RS, Qin S et al. Lancet 2018

Lenvatinib Sorafenib


REFLECT: adverse events and outcome

Sung M, et al ASCO GI 2019, poster presentation.

Diarrhoea Hypertension

Hypothyroidism Proteinuria

Lenvatinib: REFLECT study

• Lenvatinib is an oral multikinase inhibitor

that targets VEGFR(1–3), FGFR(1–4),

PDGFRα, RET and KIT1–4

• There have been 4 failed phase 3 trials in

front-line HCC in the past 10 years5–8

• In a global, randomised, open-label

phase 3 non-inferiority study, lenvatinib

was non-inferior to sorafenib for OS, and

significantly improved the secondary

endpoints of PFS, TTP and ORR in patients

with untreated advanced HCC9

HCC, hepatocellular carcinoma; FGFR, fibroblast growth factor receptor; ORR, overall response rate; OS, overall

survival; PDGFR, platelet-derived growth factor receptor; PFS, progression-free survival; TTP, time to progression;

VEGFR, vascular endothelial growth factor receptor

1. Matsui et al. Int J Cancer 2008;122:664-71; 2. Matsui et al. Clin Cancer Res 2008;14:5459-65; 3. Tohyama et al. J

Thyroid Res 2014;2014:638747; 4. Yamamoto et al. Vasc Cell 2014;6:18; 5. Cheng et al. J Clin Oncol 2013; 31: 4067-

75; 6. Johnson et al. J Clin Oncol 2013; 31: 3517-24; 7. Cainap et al. J Clin Oncol 2015; 33: 172-9; 8. Zhu et al. J Clin

Oncol 2015; 33: 559-66; 9. Kudo M et al. Lancet. 2018;391:1163-1173. 10. Kudo M. Liver Cancer 2018;7:1–19.

In vitro kinase inhibitory profiles10

IC50 (nmol/L) Lenvatinib Sorafenib

VEGFR1 4.7 21

VEGFR2 3.0 21

VEGFR3 2.3 16

FGFR1 61 340

FGFR2 27 150

FGFR3 52 340

FGFR4 43 3400

RET 6.4 15

KIT 85 140

PDGFRα 29 1.6

PDGFRβ 160 27

BRAF 8700 310

RAF1 1600 46

LEN vs SOR in first-line uHCC: pharmacodynamic biomarkers

• In a global, randomised, open-label,

phase 3 study (N=954), LEN was

determined to be noninferior to SOR

for OS, and significantly improved

PFS, TTP and ORR in uHCC1

• In a biomarker analysis

(LEN, n=279; SOR, n=128), both LEN

and SOR were found to increase

VEGF levels, but only LEN increased

FGF19 and FGF23 levels, and

decreased ANG-2 levels

• These data are hypotheses

generating

*P < 0.05 vs baseline; †P < 0.01 vs baseline; ‡P < 0.0001 vs baseline; §P < 0.05 between LEN and SOR arms.

ANG-2, angiopoietin-2; C#D#, Cycle # Day #; FGF, fibroblast growth factor; LEN, lenvatinib; OS, overall survival; PFS, progression-free survival;

SOR, sorafenib; TTP, time to progression; uHCC, unresectable hepatocellular carcinoma; VEGF, vascular endothelial growth factor.

Finn et al ESMO 2018


Median percentage change from baseline in blood serum

biomarker levels in REFLECT (biomarker analysis set)

Pharmacodynamic changes and response

• In the LEN arm, patients who

achieved objective response

(complete or partial responses)

had greater magnitudes of

increase from baseline in FGF19

(55% vs 18%; P=0.014) and FGF23

levels (48% vs 16%; P=0.002) vs

patients who did not achieve an

objective response

• These data are hypotheses

generating

Median percentage changes of biomarker levels at Cycle 4 Day 1 from baseline are shown at the top of each box plot.

Figures exclude outliers outside the y-axis range: VEGF (LEN CR/PR, n = 4; LEN non-CR/PR, n = 7; SOR CR/PR, n = 3; SOR

non-CR/PR, n = 4); ANG-2 (LEN non-CR/PR, n = 2; SOR non-CR/PR, n = 1); FGF19 (LEN CR/PR, n = 6; LEN non-CR/PR, n = 5; SOR

non-CR/PR, n = 2); FGF23 (LEN CR/PR, n = 1; LEN non-CR/PR, n = 1). All other groups had 0 outliers.

ANG-2, angiopoietin-2; CR, complete response; FGF, fibroblast growth factor; LEN, lenvatinib; PR, partial response; SOR,

sorafenib; VEGF, vascular endothelial growth factor.



Percentage change of pharmacodynamic biomarker levels at

cycle 4 day 1 from baseline and association with objective response

CHECKMATE-040 (nivolumab): overall survival by best overall response

Not approved by EMA

*Best overall response was unable to be determined in 8 patients.

BOR, best overall response; CI, confidence internal; OS, overall survival; mo, month; NE, not estimable;

NR, not reached.

El-Khoueiry AB et al. Oral presentation at 2018 Gastrointestinal Cancer Symposium. Abstract 475.

OS rate (95% CI), %

Complete/partial

response

n=22

Stable

disease

n=65

Progressive

disease

n=59

12-month 100 (100–100) 67 (55–77) 41 (28–53)

18-month 100 (100–100) 45 (33–57) 26 (15–38)

KEYNOTE-224: phase 2 Study of Pembrolizumab

in previously treated HCC

Median DOR not reached, objective response: 17%

Not approved by EMA

Zhu AX et al. Lancet Oncol. 2018;19:940-952.

Phase 1b study: lenvatinib plus pembrolizumab in unresectable HCC

Not approved by EMAaAcute respiratory distress syndrome (n = 1); intestinal perforation (n = 1); bacterial peritonitis (n = 1). bTwo TEAEs leading to discontinuation (acute respiratory distress syndrome and acute respiratory failure)

were reported in the same patient. cPatients with postevaluable tumor assessment. dZero CR confirmed. eSeven PR confirmed

Ikeda M et al. ASCO 2018. Abstract 4076.

Parameter, n (%)

LEN + PEM

Part 1

(n=6)

Part 2

(n=24)

Overall

(N=30)

TEAEs

Treatment-related TEAEs

TEAEs ≥ grade 3

6 (100.00)

6 (100.00)

5 (83.3)

24 (100.00)

22 (91.7)

13 (54.2)

30 (100.00)

28 (93.3)

18 (60.0)

Serious AEs

Fatal AEsa

2 (33.3)

0

6 (25.0)

3 (12.5)

8 (26.7)

3 (10.0)

Dose modifications

LEN or PEM dose

interruptions due to TEAES

LEN dose reductions due to

TEAEs

Discontinuation of LEN or

PEM due to TEAE(s)b

5 (83.3)

5 (83.3)

0

13 (54.2)

13 (54.2)

5 (20.8)

18 (60.0)

18 (60.0)

5 (16.7)

LEN + PEM

Part 1

(n=6)

Part 2

(n=24)

Overall

(N=30)

BOR, n (%)

CRd

PRe

SD

PD

0

4 (66.7)

2 (33.3)

0

1 (5.0)

6 (30.0)

13 (65.0)

0

1 (3.8)

10 (38.5)

15 (57.7)

0

ORR (including unconfirmed

responses), n (%)

95% CI

4 (66.7)

22.3-95.7

7 (35.0)

15.4-59.4

11 (42.3)

23.4-63.1

ORR (excluding unconfirmed

responses), n %

95% CI

3 (50.0)

11.8-88.2

4 (20.0)

5.7-43.7

7 (26.9)

11.6-47.8

Summary of TEAEs:

safety analysis set

Summary of tumor response:

investigator assessment by mRECIST; efficacy analysis setc

Atezolizumab plus bevacizumab in advanced HCC:

safety and response summary

Not approved by EMAaFour patients were unevaluable. bRegion data from one patient are missing.cBaseline AFP data from five patients are missing. dEHS and MVI baseline data from two patients are missing.

Pishvaian MJ et al. ESMO 2018. Abstract LBA26.

Grade 3/4 TRAEs (≥5% of pts), n (%) N=68

Hypertension 8 (12)

ORR

Overall, n (%)a

CR

PR

23/68 (34)

1/68 (1)

22/68 (32)

SD 30/68 (44)

PD 11/68 (16)

By region, n/n (%)b

Asia excluding Japan

Japan/USA

12/37 (32)

10/30 (33)

By aetiology, n/n (%)

HBV

HCV

Nonviral

11/33 (33)

10/22 (46)

2/13 (15)

By baseline AFP, n/n (%)c

<400 ng/mL

≥400 ng/mL

12/38 (32)

11/25 (44)

By EHS and/or MVI, n/n (%)d

Yes

No

18/57 (32)

4/9 (44)

• Any grade TRAEs occurred in 49 patients (72%)

• No grade 5 TRAEs

• Immune-related AEs required systemic corticosteroids

occurred in 4 patients (6%)

• DOR (range) NR mo (1.6–22.0+)

• mPFS (95% CI) 14.9 mo (8.1–NE)

HCC treatments recommended in EASL guidelines 2018

Llovet JM et al. Nat Rev Clin Oncol 2018 Jul 30. doi:

10.1038/s41571-018-0073-4. [Epub ahead of print]

EASL Clinical Practice Guidelines: Management of

hepatocellular carcinoma. J Hepatol 2018;69:182–236.

Sorafenib or Lenvatinib (first line)

Regorafenib, cabozantinib, or ramucirumab (AFP >400 ng/ml) second line

Chemoembolization

• Radiofrequency ablation • Percutaneous ethanol injection

(for tumours <2 cm in diameter)

LT or LDLT according to the Milan criteria

Nivolumab* Resection

Downstaging to Milan criteria

Microwave ablation

LT or LDLT extended to patients with downstaging to within Milan criteria

Resection in non-cirrhotic liver

Neoadjuvant locoregional therapies whilst on waiting list for LT

Strong Strong

Negative PositiveRecommendation

Weak

Low

Moderate

High

Level of evidence

Adjuvant therapy after resection or ablation

Chemotherapy

Other molecularly targeted therapies

90Y-radioembolization (first line)

Hormonal compounds

90Y-radioembolization (BCLC B)

External beam radiation

*Approval in US only, currently unlicensed in the UK

AASLD Guidance HCC 2018

Merrero JA et al Hepatology 2018;68:723–750.

Barcelona Stage

Level of evidence

1 Resection TACE

Sorafenib (1L)

Lenvatinib (1L)

Regorafenib (2L)

Cabozantinib (2L)

2RFA

MWA

Resection,

OLT, RAF, MWA,

TARE, TACE, SBRT

TARE

Downsize OLTnivolumab (2L)

OLT

BSC

3 Hepatology TARE

Stage 0 Stage A Stage B Stage C Stage D

*

*Regulatory applications submitted, currently unlicensed in the UK†Approval in US only, currently unlicensed in the UK

†

Conclusions

• The significance of objective response in HCC trials has been evolving

- WHO RECIST EASL mRECIST

• Increasing data suggests that response is associated with better outcomes

- mRECIST in LRT and with systemic therapies

- The lack of an objective response does not rule out benefit

• In the future, use of biomarkers may help select patients that benefit

• Ongoing prospective studies will provide further insight into these assessment tools

REAL WORLD EXPERIENCE ON

RESPONSE AND SAFETY DATA

AND IMPLICATIONS

Masatoshi Kudo, MD, PhD

Professor and Chairman,

Department of Gastroenterology and Hepatology

Kindai University Faculty of Medicine

MSD-EASL-International Liver Congress Symposium, 13 April, 2019

Served as consultant/advisor, given sponsored lectures and received research funding for:

Disclosures

• Bayer

• BMS

• Ono

• Eisai

• BeiGene

• MSD

• Roche

• AstraZeneca

• Otsuka

• Takeda

• Taiho

• Sumitomo Dainippon

• Daiichi Sankyo

• Abbvie

• Astellas Pharma

Real-world

experience

of lenvatinib

2

Identifying

the right patients

and the right timing

1

Outline

Identifying the right patients and the right timing

• BCLC C advanced HCC

excluding main bile duct and main

portal vein invasion and high tumour

burden (patients with >50% liver

occupation)

• BCLC B intermediate stage HCC

with TACE failure


in TACE unsuitable patients

Identifying the right patient

Main inclusion and exclusion criteria from the REFLECT trial1

BCLC: Barcelona Clinic Liver Cancer, ECOG PS: Eastern Cooperative Oncology Group Performance Status, mRECIST: modified Response

Evaluation Criteria In Solid Tumours, uHCC: unresectable hepatocellular carcinoma.

1. Kudo M et al. Lancet 2018;391:1163-1173.

• ≥50% liver occupation

• Invasion of bile duct or main portal vein

Reasons:

- Poor prognosis that could compromise the

survival data

- sorafenib is not recommended for HCC

patients with portal invasion at the main portal

branch (Vp4) in Japanese guidelines so inclusion

would compromise the comparator arm

• Previous systemic therapy for HCC

EXCLUSIONx• uHCC

• ≥1 target lesions by mRECIST

• BCLC B or C

• Child-Pugh A

• ECOG PS 0 or 1

• Adequate blood pressure, full blood count, INR

and adequate liver, renal and pancreatic

function

INCLUSION

Japan Overall

AEs, %Lenvatinib

(n=81)Sorafenib

(n=87)Lenvatinib

(n=476)Sorafenib(n=475)

Subjects with any TEAEs 77.8% 75.9% 75.0% 66.5%

Hypertension 34.6% 26.4% 23.3% 14.3%

Decreased weight 11.1% 0% 7.6% 2.9%

Proteinuria 8.6% 1.1% 5.7% 1.7%

Decreased platelet count 7.4% 10.3% 5.5% 3.4%

Aspartate aminotransferase increased 2.5% 6.9% 5.0% 8.0%

Decreased appetite 9.9% 0% 4.6% 1.3%

Diarrhoea 3.7% 2.3% 4.2% 4.2%

Fatigue 1.2% 4.6% 3.8% 3.6%

Palmar-plantar erythrodysesthesia syndrome 7.4% 17.2% 2.9% 11.4%

Most frequent treatment-related AEs (≥ grade 3)



excluding main bile duct and main

portal vein invasion and high tumour

burden (patients with >50% liver

occupation)


with TACE failure



Intermediate stage End stage

Advanced stage End stage

OS

†

Death

OS

Intermediate stage

Switch to targeted agents BSC

†

Death

1 2 3 4 5 6 7 8 9

1 2 3 4 5 6

Treatment strategy of intermediate stage HCC

Kudo M et al. Oncology 2014;87:22–31

Point of TACE failure

Consensus:At the time of TACE failure, switching to targeted agents from TACE will prolong the

overall survival as revealed by 2 retrospective studies and OPTIMIS study



excluding main bile duct and main portal

vein invasion and high tumour burden

(patients with >50% liver occupation)


with TACE failure



<3 nodules 4-6 nodules Multiple（≧7）

<3ｃｍResection・

RFA

>3cm -6 cm

Huge

（>6 cm）

NumberSize

N0

M0

VP0,Vv0>3 nodules

>3cm

green

pink

good response subgroup to cTACE (within up-to-7 criteria)

poor response subgroup to cTACE (beyond up-to-7 criteria)

yellow poor response subgroup to cTACE (beyond up-to-7, Bilobar multifocal tumors)

Bilobar multifocal tumors

Subgroup; easy to

be TACE

refractory

TACE

unsuitable

patients

Heterogeneity and treatment strategy of

intermediate stage HCC (Kinki Criteria)

Question

What treatment

strategy is adequate for

this population, TACE

or targeted agent?

In order to address to this

question, we performed

retrospective study

comparing the treatment

benefit with lenvatinib to

TACE in intermediate stage

HCC over up-to-7 criteria

(TACE unsuitable patient

population) with

preserved liver function

Retrospective propensity score-matched study

Kudo M, et al. Cancers (Basel) 2019;11:1084

Lenvatinib

(n=37)

TACE

(n=176)

Excluded (n=466)

• Substage B1 and B3 (n=424)

• Child-Pugh B or C (n=42)

Imaging intermediate stage HCC patients who received

lenvatinib or TACE as an initial treatment

(n=642)

Lenvatinib

(n=30)

TACE

(n=60)

Intermediate stage HCC over up-to-7 criteria with Child-Pugh A liver function

Propensity

score-matched

Lenvatinib

n=30 (%)

TACE

n=60 (%)P value

ORR 22 (73.3%) 20 (33.3%) P<0.001

DCR 30 (100%) 32 (53.3%)

CR 2 4

PR 20 16

SD 8 12

PD 0 26

NE 0 2

Response rate (propensity score matched)


Progression Free Survival (propensity score matched)


Overall survival (propensity score matched)


TACE LEN or SOR

Intermediate stage

TACE TKI-2

OS

Advanced - Terminal stage

BSC

BSC

TACE TACE

LEN or SOR

TKI-1(LEN or SOR)

Early stage

Lenvatinib TKI-2 TKI-3 BSC

BSC

Subgroup; easy

to be TACE

refractoryTACE unsuitable cases

Point of TACE Refractory

Point of switching to systemic therapy

For this population, systemic therapy may be first treatment option

followed by on-demand superselective TACE when necessary.

Sorafenib TKI-2 TKI-3 BSC

Treatment strategy of intermediate stage HCC

Kudo M, Liver Cancer 2018

Treatment strategy of bilobar multifocal

intermediate stage HCC (TACE unsuitable HCC)

Kudo M, Liver Cancer 2018

Sorafenib-regorafenib

sequenceLong OS(26M),low response rate

Preservation of liver function

LenvatinibSimilar RR with TACE (ORR=40%)


TACE＋sorafenibGood PFS (PFS=25.2M)


TACEResponse rate (ORR=40%)

Impairs Liver functionX

Immunotherapy ? Low RR, durable(ORR=15-20%)


SELECTED PATIENTS

Outline

Real world

experience

of lenvatinib

2

Identifying

the right patients

and the right timing

1

Thank you very much for your

kind attention.

Osaka Castle Japan

MEET THE EXPERTS:

THE CHANGING LANDSCAPE OF

HCC TREATMENT Audience Q&A

PRESCRIBING INFORMATION

Lenvima®▼ (lenvatinib)Please refer to the Summary of Product Characteristics (SPC) before prescribing.

Presentation: 4mg and 10mg hard capsules. Indication: Monotherapy treatment of

adult patients with advanced or unresectable hepatocellular carcinoma (HCC) who

have received no prior systemic therapy. Dose and administration: For oral use.

Should be initiated and supervised by a health care professional experienced in the

use of anticancer therapies. 8 mg once daily for patients with a body weight of < 60 kg

and 12 mg once daily for patients with a body weight of ≥ 60 kg at about the same

time each day, with or without food. Swallow the capsules whole with water or

dissolve in water or apple juice without breaking or crushing - see SPC for guidelines.

If dose missed, and it cannot be taken within 12 hours, skip dose and take next dose

at normal time. Continue treatment as long as clinical benefit observed or

unacceptable toxicity occurs. Initiate medical management for nausea, vomiting, and

diarrhoea prior to interruption or dose reduction. Actively treat GI toxicity to reduce

risk of renal impairment or failure. Dose adjustment: Dose adjustments are based

only on toxicities observed and not on body weight changes during treatment. Mild to

moderate adverse reactions (e.g., Grade 1 or 2) generally do not warrant interruption

of lenvatinib, unless intolerable despite optimal management. For persistent and

intolerable Grade 2 or Grade 3 toxicities, upon resolution to Grade 0-1 or baseline,

resume treatment at a reduced dose of lenvatinib. No dose adjustment required for

first occurrence of haematologic toxicity or proteinuria. For ≥60 kg body weight: First

occurrence 8mg/day; second occurrence 4 mg/day; third occurrence 4 mg every other

day. For <60 kg body weight: First occurrence 4 mg/day; second occurrence 4mg

every other day; third occurrence discontinue. Discontinue treatment in case of life-

threatening reactions (e.g., Grade 4) except if laboratory abnormality judged to be

non-life-threatening, then manage as Grade 3. Special populations: Patients ≥75

years, of white race or female sex or those with worse baseline hepatic impairment

(ChildPugh A score of 6 compared to score of 5) appear to have reduced tolerability

to lenvatinib. Patients with hypertension: Control blood pressure prior to treatment

and monitor regularly during treatment. Patients with hepatic impairment: No dose

adjustment of starting dose required for HCC patients with mild hepatic impairment

(Child-Pugh A). No dosing recommendation is available for patients with HCC and

moderate hepatic impairment (Child-Pugh B). Not recommended for HCC patients

with severe hepatic impairment (Child-Pugh C). Patients with renal impairment: No

dose adjustments are required in patients with mild or moderate renal impairment. No

dosing recommendation is available for patients with HCC and severe renal

impairment. Elderly population: No adjustment of starting dose is required. Paediatric

population: No data in children aged 2 to <18 years. Do not use in children <2 years

due to safety concerns identified in animal studies. Race: No adjustment of starting

dose is required. Contra-Indications: Hypersensitivity to active substance or any of

the excipients. Breast-feeding. Special warnings and precautions: Control blood

pressure prior to treatment with lenvatinib and, if patients are known to be

hypertensive, control with stable dose of antihypertensive therapy for at least 1 week

prior to treatment with lenvatinib. Monitor blood pressure after 1 week of treatment

with lenvatinib, then every 2 weeks for the first 2 months and monthly thereafter.

When necessary, manage hypertension as recommended in SPC. Monitor urine

protein regularly. Interrupt, adjust or discontinue dose if urine dipstick proteinuria ≥2+.

Discontinue in the event of nephrotic syndrome. Closely monitor overall safety in

patients with mild or moderate hepatic impairment. Monitor liver function tests before

starting treatment, then every 2 weeks for the first 2 months and monthly thereafter

during treatment. Monitor patients for worsening liver function including hepatic

encephalopathy. In the case of hepatotoxicity, renal impairment, renal failure, signs or

symptoms of PRES, bleeding, gastrointestinal perforation or fistula, dose

interruptions, adjustments, or discontinuation may be necessary. Discontinue

lenvatinib in the event of persistence of Grade 4 diarrhoea despite medical

management. Monitor for clinical symptoms or signs of cardiac decompensation, as

dose interruptions, adjustments or discontinuation may be necessary. Use lenvatinib

with caution in patients who have had an arterial thromboembolism within the

previous 6 months. Discontinue following an arterial thrombotic event. Women of

childbearing potential must use highly effective contraception while taking lenvatinib

and for one month after stopping treatment. Screen for and treat oesophageal varices

in patients with liver cirrhosis before initiating lenvatinib. Do not start lenvatinib in

patients with fistulae to avoid worsening and discontinue permanently in patients with

oesophageal or tracheobronchial tract involvement and any Grade 4 fistula. Monitor

ECGs at baseline and periodically during treatment in all patients particularly those

with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, and

those taking medicinal products known to prolong the QT interval, including Class Ia

and III antiarrhythmics. Withhold lenvatinib in QT interval prolongation greater than

500 ms. Resume lenvatinib at a reduced dose when QTc prolongation is resolved to <

480 ms or baseline. Monitor and correct electrolyte abnormalities before starting

treatment. Monitor electrolytes during treatment. Monitor blood calcium levels at least

monthly and replace calcium as necessary during treatment. Interrupt or adjust

lenvatinib dose as necessary depending on severity, presence of ECG changes, and

persistence of hypocalcaemia. Monitor thyroid function before initiation of, and

periodically throughout, treatment with lenvatinib. Monitor TSH levels regularly and

adjust thyroid hormone administration as required. Consider temporary interruption of

lenvatinib in patients undergoing major surgical procedures. Use with caution in

elderly or Asian patients due to reduced tolerability to lenvatinib. Consider washout

between lenvatinib and other anti-cancer treatment due to potential risk for additive

toxicities. Drug Interactions: No significant drug-drug interaction expected between

lenvatinib and CYP3A4/ Pgp substrates. Cannot exclude risk that lenvatinib could

induce CYP3A4 or Pgp. Administer CYP3A4 substrates known to have a narrow

therapeutic index with caution. Unknown if lenvatinib reduces effectiveness of

hormonal contraceptives. Women using oral hormonal contraceptives should add a

barrier method. Pregnancy: Do not use during pregnancy unless clearly necessary.

Women of childbearing potential should avoid becoming pregnant and use highly

effective contraception during and for at least one month after treatment. Lactation:

Unknown if excreted in human milk. A risk to newborns or infants cannot be excluded;

contraindicated during breast-feeding. Fertility: Fertility effects in humans are

unknown. Effects on ability to drive and use machines: Use caution when driving

or operating machines if experiencing fatigue and/or dizziness. Undesirable effects:

Consult the SPC for information on all side effects. The adverse reactions

presented in this section are based on the combined safety data of differentiated

thyroid cancer and HCC patients. Very common ( 1/10): Urinary tract infection,

Thrombocytopenia, Leukopenia, Neutropenia, Hypothyroidism, Hypocalcaemia,

Hypokalaemia, Decreased weight, Decreased appetite, Insomnia, Dizziness,

Headache, Dysgeusia, Haemorrhage, Hypertension, Hypotension, Dysphonia,

Diarrhoea, Gastrointestinal and abdominal pains, Vomiting, Nausea, Oral

inflammation, Oral pain, Constipation, Dyspepsia, Dry mouth, Increased blood

bilirubin, Hypoalbuminaemia, Increased alanine aminotransferase, Increased

aspartate aminotransferase, Palmar- plantar erythrodysaesthesia syndrome, Rash,

Alopecia, Back pain, Arthralgia, Myalgia, Pain in extremity, Musculoskeletal pain,

Proteinuria, Fatigue, Asthenia, Peripheral oedema. Common (≥1/100 to <1/10):

Lymphopenia, Increased blood thyroid stimulating hormone, Dehydration,

Hypomagnesaemia, Hypercholesterolaemia, Cerebrovascular accident, Myocardial

infarction, Cardiac failure, Prolonged electrocardiogram QT, Decreased ejection

fraction, Pulmonary embolism, Anal fistula, Flatulence, Increased lipase, Increased

amylase, Hepatic failure, Hepatic encephalopathy, Increased blood alkaline

phosphatase, Hepatic function abnormal, Increased gamma-glutamyltransferase,

Cholecystitis, Hyperkeratosis, Renal failure cases, Renal impairment, Increased blood

creatinine, Increased blood urea, Malaise. Uncommon (≥1/1,000 to <1/100): Perineal

abscess, Splenic infarction, Posterior reversible encephalopathy syndrome,

Monoparesis, Transient ischaemic attack, Aortic dissection, Pneumothorax,

Pancreatitis, Hepatocellular damage/hepatitis, Nephrotic syndrome, Impaired healing.

Frequency not known (cannot be estimated from the available data): Non-

gastrointestinal fistula. Overdose: No specific antidote. In case of suspected

overdose, lenvatinib should be withheld and appropriate supportive care given as

required. Legal Category: POM Cost: UK NHS list price: 4mg capsules pack of 30:

£1,437.00; 10mg capsules pack of 30: £1,437.00 Marketing authorisation (MA)

number: 4mg capsules: EU/1/15/1002/001; 10mg capsules: EU/1/15/1002/002 MA

holder: Eisai GmbH Further information from: Eisai Ltd., Mosquito Way, Hatfield,

Hertfordshire, AL10 9SN, United Kingdom Date of preparation: April 2019

Adverse events should be reported. Reporting forms and

information can be found at www.mhra.gov.uk/yellowcard or

search for the MHRA Yellow Card in the Google Play

or Apple App Store, or Ireland: www.hpra.ie.

Adverse events should also be reported to Eisai Ltd on

+44 (0)845 676 1400/ +44 (0)208 600 1400

or [email protected]

UK-LENA-19-00141

Date of Preparation: April 2019

http://www.mhra.gov.uk/yellowcard

http://www.hpra.ie/

mailto:[email protected]

mailto:[email protected]

Documents

MEET THE EXPERTS...MEET THE EXPERTS: THE CHANGING LANDSCAPE OF HCC TREATMENT Professor Arndt Vogel MD, Professor Riad Salem MD, Professor Richard Finn MD & Professor Masatoshi Kudo