esmo e-learning advances in hepatocellular carcinoma · reprinted from the lancet oncol, 2015, 16...
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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: [email protected]; European Association
for the Study of the Liver. J Hepatol. 2018 Jul;69(1):182-236
THANK YOU!