ADVANCES INHEPATOCELLULAR CARCINOMA

Professor Tim Meyer

UCL Cancer Institute and Royal Free Hospital,

London, UK

OUTLINE

Introduction

◆ Epidemiology

◆ Prognostication

◆ Staging and treatment algorithm

Systemic therapy

Combining TACE with systemic therapy

The role of SIRT

Conclusions

EPIDEMIOLOGY

Liver cancer is the second most common cause of cancer related mortality

1. Reprinted by permission from Springer Nature, Nat Rev Clin Oncol, Advances in targeted therapies for hepatocellular carcinoma in the genomic era, Llovet JM, et al. Copyright 2015;

2. Cancer Research UK, https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/liver-cancer/mortality#heading-Three, Accessed May 2019.

HCC – A global health problem

1990-2009

……and an increasing one

PROGNOSIS

80-90% patients have background chronic liver disease

1. Liver Function

2. Tumour Factors

3. Performance status

Prognosis determined by:

PROGNOSIS

Liver function

Child-Pugh Score

1. Bilirubin

2. Albumin

3. INR

4. Ascites

5. Encephalopathy

Johnson PJ, et al. J Clin Oncol, 33(6), 2015:550–8. Reprinted with permission. © 2015. American Society of Clinical Oncology. All rights reserved.

PROGNOSIS

Liver function

ALBI Score

◆ Bilirubin

◆ Albumin

Johnson PJ, et al. J Clin Oncol, 33(6), 2015:550–8. Reprinted with permission. © 2015. American Society of Clinical Oncology. All rights reserved.

PROGNOSIS

Tumour

Tumour

1. Size

2. Number

3. Vascular Invasion

4. Metastatic disease

5. AFP

6. Differentiation

Main trunk

3rd order branch

1st order branch(RPV)

2nd order branch

Contralateral 1st

order branch (LPV)

Tumour

Vp1Tumour

Vp2

Vp3

and/or

Vp4

LPV, left portal vein; RPV, right portal veinKudo M, et al. Dig Dis 2011;29:339–64; Costentin CE, et al. Liver Cancer 2017;6:360–74.

3rd order branch

1st order branch(RPV)

2nd order branch

Contralateral 1st

order branch (LPV)

Tumour

Main trunk

3rd order branch

1st order branch(RPV)

2nd order branch

Contralateral 1st

order branch (LPV)

Tumour

Main trunk

3rd order branch

1st order branch(RPV)

2nd order branch

Contralateral 1st order branch

(LPV)

Tumour

Classification for HCC with portal vein tumour thrombosis

PROGNOSIS

BCLC Algorithm

Reprinted from J Hepatol, 69(1), EASL, EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma, 182–236, Copyright 2018, with permission from Elsevier.

PROGNOSIS

BCLC and other prognostic systems

Many other prognostic staging systems

◆ TNM

◆ OKUDA

◆ CLIP

◆ CUPI

◆ JIS

Hsu CY, et al. Sci Reports 2017;7(1):7914. Reproduced under a Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0/.

SYSTEMIC THERAPY

Sorafenib as the first standard of care for advanced disease

Median Overall Survival

S = 10.7 months, P = 7.9 months

HR 0.69 (95% CI 0.55 to 0.87 ; p<0.001

Median Overall Survival

S = 6.5 months, P = 4.2 months

HR 0.68 (95% CI 0.5-0.93; p=0.014)

Sorafenib = multi-kinase inhibitor targeting Raf-1, B-Raf, VEGFR 1,2,3, PDGFβ, RET, KIT

1. From N Engl J Med 2008; Llovet JM, et al. Sorafenib in Advanced Hepatocellular Carcinoma,359 (4):378-390. Copyright © 2008. Massachusetts Medical Society.

Reprinted with permission from Massachusetts Medical Society.

2. Reprinted from The Lancet Oncology, 10(1), Cheng AL, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-

controlled trial, 25-34. Copyright 2009, with permission from Elsevier.

TOXICITY AND TOLERABILITY OF SORAFENIB

Most common Drug-Related Adverse Events (%)

Adverse event

Sorafenib Placebo P value

Any Grade Grade 3/4 Any Grade Grade 3/4 Any Grade

Overall 80 52

Diarrhoea 39 8 11 2 <0.001

Hand foot skin reaction 21 8 3 1 <0.001

Anorexia 14 <1 3 1 <0.001

Alopecia 14 0 2 0 <0.001

Weight loss 9 2 1 0 <0.001

For sorafenib

◆ Median duration 5.3 months

◆ 76% received at least 80% planed daily dose

◆ 11% permanently discontinued due to AEs

Llovet JM, et al. N Engl J Med 2008; 359:378-390. Cheng AL, et al. Lancet Oncol. 2009;10(1):25-34.

SORAFENIB

Limited activity in Child Pugh B and C

Median OS 9.5 vs. 4.6 months

1. Reprinted from Clin Oncol, 2017, 29(4), King J, et al. Sorafenib for the Treatment of Advanced Hepatocellular Cancer – a UK Audit; 256-262; Copyright 2017, with permission from Elsevier. 2. Reprinted from J Hepatol 2016,

65(6), Marrero JA, et al. Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: The GIDEON study:1140-1147. Copyright 2016, with permission from Elsevier.

SORAFENIB

Predictive factors

1. Extrahepatic spread (EHS) 2. Hepatitis C Virus (HCV)

3. Neutrophil to lymphocyte ratio (NLR)

EHS present EHS absent HCV Present HCV Absent

NLR ⩽ medianNLR > median

4. Tumour Burden

TB present TB absent

Bruix J, et al. J Hepatol 2017, 67 (5), 999-1008 Published under the terms of the Creative Commons Attribution-NonCommercial-No Derivatives License (CC BY NC ND). https://creativecommons.org/licenses/by-nc-nd/3.0/

SORAFENIB AS ADJUVANT THERAPY

No benefit following surgery – STORM Trial

Reprinted from The Lancet Oncol, 2015, 16 (13), Bruix J, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial, 1344-135.

Copyright 2015, with permission from Elsevier.

SORAFENIB

Summary

Response rates < 2%

2-3 month increase in median OS

Child A with good PS

Associated toxicity

More effective in patients with HCV and no EHD

Not effective as adjuvant therapy

◆ Surgery or RFA (STORM)

◆ TACE (TACE 2 and SPACE)

MANY FAILED PHASE III TRIALS

First line: Sorafenib control

Phase n

OS (m)

HR (p)Sorafenib Exp Arm

Brivanib1 III 1,155 9.9 9.5 1.06 (0.31)

Sunitinib2 III 1,074 10.2 7.9 1.3 (0.0014)

Sorafenib +

Erlotinib3 III 720 8.5 9.5 0.92 (0.2)

Linifanib4 III 1,035 9.8 9.1 1.046 (0.52)

Sorafenib +

Doxorubicin5 III 256 10.5 8.9 1.06 (0.24)

1. Johnson PJ, et al. J Clin Oncol 2013;31(28):3517-24. 2. Cheng AL, et al. J Clin Oncol 2013;31(32):4067-75. 3. Zhu AX, et al. J Clin Oncol 2015;33(6):559-66. 4. Cainap C, et al. J Clin Oncol 2015;33(2):172-9.

5. Abou-Alpha GK, ASCO 2016.

MANY FAILED PHASE III TRIALS

Second Line – Placebo control

Drug Phase n

OS (m)

HR (p)Placebo Exp Arm

Brivanib1 III 395 8.2 9.4 0.89 (0.33)

Everolimus2 III 546 7.3 7.6 1.05 (0.68)

Ramucirumab3 III 565 7.6 9.2 0.86 (0.13)

Tivantinib4 III 340 8.4 9.1 0.97 (0.81)

ADI-PEG5 III 635 7.4 7.8 1.022 (0.88)

Codrituzumab6 II 185 10.0 8.7 0.96 (0.82)

1. Llovet J, et al. J Clin Oncol 2013;31(28):3509-16. 2. Zhu AX et al JAMA 2014;312(1):57-67. 3. Zhu AX, et al. Lancet Oncol 2015;16(7):859-870. 4. Ramassa L, et al. Lancet Oncol 2018,

5. Abou-Alfa GK, et al. Ann Oncol 2018;29(6):1402-1408. 6. Abou-Alfa GK, et al. J Hepatol 2016;65(2): 289-95.

PROGRESS

First line

Lenvatinib

Second line

Regorafenib

Cabozantinib

Ramucirumab

Randomised Trials Approved based on Phase II Trials

Second line

Nivolumab

Pembrolizumab

PROGRESS

First Line – Lenvatinib (REFLECT Trial)

Inhibits

◆ VEGFR 1-3

◆ FGFR 1-4

◆ PDGFRα

◆ RET

◆ KIT

Kudo M, et al. Lancet 2018, 391 (10126): 1163-1173.

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

Patients with unresectable HCC

(N=954)

◆ No prior systemic therapy for

unresectable HCC

◆ ≥1 measurable target lesion

based on 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 portal

vein were excluded

Lenvatinib (n=478)

8 mg (BW <60 kg) or

12 mg (BW ≥60 kg) once daily

Sorafenib (n=476)

400 mg twice daily

R

(2:1)

Primary endpoint:

◆ OS

Secondary endpoints:

◆ PFS

◆ TTP

◆ ORR

◆ Quality of life

◆ PK lenvatinib

exposure parameters

LENVATINIB

Met primary endpoint for non-inferiority

Reprinted from The Lancet, 391(10126), Kudo M, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial;1163-1173. Copyright

2018, with permission from Elsevier.

LENVATINIB

Most frequent TEAEs (≥15%)

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)

Diarrhea 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 (6) 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)

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)

LENVATINIB

Key points

First positive trial in front-line : non-inferior to sorafenib

Mainly AP population

Excluded main PVI and less 50% liver involvement

Improved secondary endpoints

Different toxicity profile

PROGRESS

Second line trials – Regorafenib (RESORCE Trial)

Cell free assayRegorafenib

IC50 (nM)

Sorafenib

IC50 (nM)

RET 1.5 5.9

RAF-1 2.5 6

VEGR2 4.2 90

KIT 7 68

VEGFR1 13 9

PDGFR β 22 57

BRAF 28 22

FGFR1 202 580

TIE2 311

Wilhelm SM, et al. Clin Canc Res 2004,64(19); Wilhelm SM, et al. Int J Canc 2011,129(1):245-55; Plaza-Menacho I, et al. J Biol Chem 2007,282(40):29230-40.

RESORCE TRIAL

Design

Patients (n=573)

◆ Treated with sorafenib ≥ 20

days at ≥ 400 mg/day

◆ Radiological progression

◆ CPA and PS 1

◆ Randomised 2:1 Regorafenib

160mg OD 3/4 weeks vs.

Placebo

◆ Stratified by: region, ECOG PS,

macrovascular invasion,

extrahepatic spread, AFP

Regorafenib

Placebo

R

2:1

Patients progressed

on Sorafenib

Child-Pugh A

PS <2

Primary endpoint

◆ Overall Survival

Secondary endpoints

◆ PFS

◆ TTP

◆ Response (RECIST 1.1 and mRECIST)

RESORCE TRIAL

Endpoints

Reprinted from The Lancet 2017, 389 (10064), Bruix J, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3

trial; 56-66. Copyright 2017, with permission from Elsevier.

Dose modification due to AEs; 68.2% vs. 31.1%

RESORCE TRIAL

Key points

First positive trial in second-line

Efficacy only demonstrated in sorafenib tolerant patients

No toxicity data in sorafenib intolerant patients

Bruix J, et al. Lancet 2017, 389 (10064): 56-66.

PROGRESS

Second line trials – Cabozantinib (CELESTIAL Trial)

• Inhibits tyrosine kinases including VEGF receptors, MET, and AXL

• VEGF, MET, and AXL promote tumour progression and angiogenesis

• MET and AXL are associated with resistance to VEGFR-targeted therapy

• Elevated expression of VEGF, MET, or AXL is associated with poor prognosis in HCC

Abou-Alfa GK, et al. N Engl J Med 2018; 379:54-63.

CELESTIAL TRIAL

Endpoints

From N Engl J Med, Abou-Alfa GK, et al. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma, 379(1):54-63. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission from

Massachusetts Medical Society.

CELESTIAL TRIAL

Keypoints

Second positive post-sorafenib trial

Included

◆ Sorafenib intolerant patients

◆ Included >1 line prior therapy

Biomarkers outstanding ? relevance of MET

Abou-Alfa GK, et al. N Engl J Med 2018; 379:54-63.

PROGRESS

Second line trials – Ramucirumab - REACH Trial

Reprinted from The Lancet Oncol, 16(7), Zhu AX, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a

randomised, double-blind, multicentre, phase 3 trial, 859-870. Copyright 2015, with permission from Elsevier.

Ramucirumab

Placebo

R

1:1

565 Patients progressed

on Sorafenib

Child-Pugh A

PS <2

Negative trial but benefit for AFP ≥400 ng/ml subgroup

Ramucirumab = recombinant IgG1 monoclonal antibody and

VEGF receptor-2 antagonist

PROGRESS

Second line trials – Ramucirumab REACH 2 Trial

Reprinted from The Lancet Oncol, 20(2), Zhu AX, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind,

placebo-controlled, phase 3 trial, 282-296, Copyright 2019, with permission from Elsevier.

First positive biomarker-selected trial

Ramucirumab

Placebo

R

1:2

292 Patients progressed

on Sorafenib

Child-Pugh A

PS <2

AFP ≥400 ng/ml

PROGRESS

Immunotherapy

Reprinted by permission from Springer Nature, Nature, Signatures of mutational processes in human cancer, Alexandrov LB, et al. Copyright 2013.

IMMUNOTHERAPY

CHECKMATE 040 – Phase I/II trial of Nivolumab

Design

Key inclusion criteria

◆ Histologically confirmed HCC

◆ Pre and post-sorafenib cohorts

◆ ECOG PS <2

◆ HBV viral lode <100 IU/ml and on

antiviral therapy

◆ Active or history of autoimmune disease

◆ Dose escalation Child Pugh A and B7

◆ Dose expansion Child Pugh A

Reprinted from The Lancet, 389(10088), El-Khoueiry AB, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial;

2492-2502. Copyright 2017, with permission from Elsevier.

IMMUNOTHERAPY

CHECKMATE 040 – Phase I/II trial of Nivolumab

Overall response rate in dose expansion = 20% (RECIST 1.1)

Objective responses were observed in nine (26%) of 34 patients with PD-L1 expression on at least 1% of tumour cells (95% CI 13–44) and

in 26 (19%) of 140 patients with PD-L1 on less than 1% of tumour cells (95% CI 13–26).

1. Reprinted from The Lancet, 389(10088), El-Khoueiry AB, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion

trial; 2492-2502. Copyright 2017, with permission from Elsevier.

90 63 2112 1815 3324 3027 4536 4239 48

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0

Median OS (95% CI), mo = NR (NE–NE)

Median OS (95% CI), mo = 15.15 (13.2–18.8)

Median OS (95% CI), mo = 13.4 (10.35–15.15)

Pro

babi

lity

of s

urvi

val

Responders (n=22)

No responders (n=132

All patients (N=154)

NIVOLUMAB

Keypoints

El-Khoueiry AB, et al. Lancet 2017, 389 (10088):2492-2502.

• 20% response rate

• PD-L1 not predictive

• 15 month mOS in second-line

• FDA approved for second-line therapy

• Not considered by EMA pending phase III data

• Results of CheckMate 459 awaited: First line Sorafenib vs Nivolumab

IMMUNOTHERAPY

KEYNOTE-224 Phase II trial of Pembrolizumab

Key inclusion criteria

◆ Histologically confirmed HCC

◆ Progression post-sorafenib

◆ ECOG PS <2

Response rate RECIST 1.1

◆ Complete response 1%

◆ Partial Response 16%

◆ Stable Disease 44%

◆ Progressive Disease 33%

◆ ‘Combined PD-L1

Reprinted from Lancet Oncol 19(7), Zhu AX, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial; 940-952.

Copyright 2018, with permission from Elsevier.

◆ HBV viral lode <100 IU/ml and on antiviral therapy

◆ Active or history of autoimmune disease

◆ Child Pugh A

KEYNOTE-224

Endpoints

Reprinted from Lancet Oncol 19(7), Zhu AX, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial; 940-952.

Copyright 2018, with permission from Elsevier.

PFS 4.9 months (95% CI 3.4–7.2) OS 12.9 months (95% CI 3.4–7.2)

PEMBROLIZUMAB

KEYNOTE 240 – 2nd line Phase III trial of Pembrolizumab versus BSC

0 4 8 1 2 1 6 2 0 2 4 2 8 3 2

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

T i m e ( m o n t h s )

Ov

er

all S

ur

viv

al (

%)

N o . a t r i s k

2 7 8 2 3 7 1 9 0 1 5 2 1 1 0 5 7 1 6 1 0

1 3 5 1 1 3 8 4 6 5 4 2 2 3 8 1 0

M e d i a n ( 9 5 % C I )

1 3 . 9 m o ( 1 1 . 6 - 1 6 . 0 )

1 0 . 6 m o ( 8 . 3 - 1 3 . 5 )

Events HR (95% CI) P

Pembrolizumab 183 0.781 (0.611-0.998) 0.0238

Placebo 101

Finn RS, et al. J Clin Oncol 37, 2019 (15_suppl; abstr 4004). Presented at ASCO 2019. By permission of Prof Finn.

COMBINATIONS

Atezolizumab and bevacizumab - Phase 1b

Pishvaian MJ, ESMO 2018. Courtesy of Prof Pishvaian.

COMBINATIONS

Pembrolizumab and lenvatinib

Ikeda M, et al. ASCO Annual Meeting 2018. By permission of Eisai CO Ltd and Prof Ikeda Masafumi.

42% RR mRECIST

SYSTEMIC THERAPY

Summary

First Line

◆ Sorafenib

◆ Lenvatinib

Second Line (post-sorafenib)

◆ Regorafenib in sorafenib tolerant patients

◆ Cabozantinib

◆ Ramucirumab in patients with AFP>400

◆ Nivolumab and Pembrolizumab have high response rate and encouraging survival but results of RTC trials

awaited

◆ Combinations have promising response rates and RCT ongoing

SYSTEMIC THERAPY

Practice changing clinical research

2008-2017

Sorafenib 10 years

2018

Lenvatinib

Regorafenib

Cabozantinib

Ramicirumab

Nivolumab

Pembrolizumab

Sorafenib 11 m

Sorafenib and second-line therapy 26m

BSC 8 m

TACE AND SYSTEMIC THERAPY COMBINATIONS

TACE 2

Primary

◆ PFS

Secondary

◆ Overall survival

◆ Time to progression

◆ Toxicity-NCI CTCAE v4

◆ QOL - EORTC QLQ-C30 v3, QLQ-

HCC18, EQ-5D

◆ Response – RECIST 1.0

◆ Health economic

◆ Number of TACE procedures in 12 months

Meyer T, et al. Lancet Gastro Hep 2017, 2(8):565-575.

TACE 2

Endpoints

Meyer T, et al. Lancet Gastro Hep 2017, 2(8): 565-575. Published under the terms of the Creative Commons Attribution-NonCommercial-No Derivatives License (CC BY NC ND).

SPACE TRIAL

Also TACE +/- Sorafenib

Reprinted from J Hepatol, 64(5), Lencioni R, et al. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: The SPACE trial, 1090–8, Copyright 2016, with permission from Elsevier.

ORIENTAL TRIAL

TACE +/- Orantinib

Reprinted from The Lancet Gastro Hep, 3(1), Kudo M, et al. Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised,

double-blind, placebo-controlled, multicentre, phase 3 study; 37-46. Copyright 2018, with permission from Elsevier.

BRISK-TA

TACE +/- Brivanib

Kudo M, et al. Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: A randomized phase III trial. Hepatology 2014;60(5):1697–707. © 2014 by the American Association for

the Study of Liver Diseases.

TACE AND SYSTEMIC THERAPY COMBINATIONS

Summary

Four large phase III trials combining TACE with anti-angiogenic TKIs – all negative

Need to consider a different combination strategy

Ongoing trials with TACE and Immunotherapy

SELECTIVE INTERNAL RADIOTHERAPY (SIRT)

SARAH trial (France)

Primary endpoint: Overall survival

Powered for superiority to detect 4 month

improvement in median OS

SIRT Sorafenib HR

ITT OS 8.0 9.9 1·15 [95% CI 0·94-1·41] p=0·18

PP OS 9.9 9.9 0·99 [95% CI 0·79–1·24]

ITT Response rate 19% 12%

ITT intention to treat; PP per protocol.

Reprinted from The Lancet Oncol, 18(12), Vilgrain V, et al. Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced

and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial; 1624-1636. Copyright 2017, with permission from Elsevier.

Sorafenib

400 mg BD

SIRT 90Y-loaded resin

microspheres

R

1:1

467 patients

ECOG PS 0/1

Child Pugh A or B7

BCLC C or not suitable

for surgery/ablation or

refractory to TACE

SIRT

SIRveNIB Trial (Asia Pacific)

Stratified by centre and portal vein thrombosis

Primary endpoint: Overall survival

Powered for superiority with HR 0.67

SIRT % Sorafenib %

Response rate 16.5 1.7

AEs Grade 3 28 51

SAEs 21 35

Chow PKH, et al. J Clin Oncol, 36(19), 2018:1913-1921. Reprinted with permission. © 2018 American Society of Clinical Oncology. All rights reserved.

Sorafenib

400 mg BD

SIRT 90Y-loaded resin

microspheres

R

1:1

360 patients

ECOG PS 0/1

Child Pugh A or B7

BCLC C or not suitable

for

Surgery/ablation or

refractory to TACE

SIRT COMBINED WITH SORAFENIB

SORAMIC Trial

Presented at EASL 2018 (publication pending) OutcomeSIRT +

Sorafenib Sorafenib HR

ITT Median OS (m) 12.1 11.51.067 95% CI, 0.82-1.25;

p=0.95

PP Median OS (m) 14.1 (n=114) 11.1 n=1740.86; 95% CI, 0.67–1.11;

p=0.25

AEs ≥ Grade 3 72.3% 68.5

Result of TS103 (STOP-HCC) trial awaited

https://clinicaltrials.gov/ct2/show/NCT01556490

Ricke J, et al. J Hepatol 2018;69(5). Abstract LBO-005.

Sorafenib

400 mg BD

SIRT 90Y-loaded resin

microspheres

+

Sorafenib 400 mg BD

R

1:1

424 patients

Advanced HCC not

suitable for TACE

ITT intention to treat; PP per protocol.

SELECTIVE INTERNAL RADIOTHERAPY

Conclusion

Three randomised trials of SIRT all failed to meet the primary endpoint of superiority to sorafenib alone

Tolerability and response are encouraging

Questions remain around

◆ The need for dosimetry to improve outcomes

◆ The optimal patient group

◆ The high rate of patients in ITT group that fail to receive allocated SIRT therapy

The place of SIRT in the treatment of HCC remains to be determined

CHALLENGES FOR THE FUTURE

Determining optimal sequence or combination therapy

Defining predictive biomarkers of response to checkpoint inhibitors

Developing effective adjuvant systemic therapy for locoregional and surgical intervention

Defining the role of SIRT

Revising endpoints to meet the demands of recent therapeutic advances

RECENT GUIDELINES

ESMO: Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Vogel A,

Cervantes A, Chau I, Daniele B, Llovet J, Meyer T, Nault JC, Neumann U, Ricke J, Sangro B, Schirmacher P,

Verslype C, Zech CJ, Arnold D, Martinelli E; ESMO Guidelines Committee. Ann Oncol. 2018 Oct

1;29(Supplement_4):iv238-iv255

EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma.

European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association

for the Study of the Liver. J Hepatol. 2018 Jul;69(1):182-236

THANK YOU!