HCC: what s new?

HCC: what s new
Ashraf Omar
Prof of Hepatology and
Endemic Medicine
Cairo University
Secretary General of ESLC

Agenda: AASLD 2016
I. Is There an Increased Risk of Cancer After
Taking Direct-Acting Antiviral Medication?
II. Genetic associatiation with HCC
development after HCV eradication
III. Oral zinc supplementation and risk of
hepatocellular carcinoma development
IV. Regorafenib a New systemic therapy.
V. Immunotherapy

Abstract #175
The impact of sustained virological response to
HCV infection on long term risk of hepatocellular
carcinoma: The BC Hepatitis Testers Cohort
Naveed Z. Janjua 1,2 , Mei Y. Chong 1 , Margot E. Kuo 1 ,
Amanda Yu 1 , Hasina Samji 1 , Zahid Butt 1,2 , Maria Alvarez 1 , Darrel Cook 1 ,
Jason Wong 1,2 , Ryan Woods 3 , Mark Tyndall 1,2 , Morris Sherman 4 ,
Eric M. Yoshida 2 , Mel Krajden 1,2 ;
1. BC Centre for Disease Control,Vancouver, BC, Canada;
2. University of British Columbia, Vancouver, BC, Canada;
3. BC Cancer Agency, Vancouver, BC, Canada;
4. Medicine, University of Toronto, Toronto, ON, Canada
4

Background
• The risk of hepatocellular carcinoma(HCC) post HCV cure is
not well-established for the North American population.
• We assessed the effect of sustained virologic
response(SVR) on the risk of HCC among a large population
based cohort in Canada.
Janjua N, et al. Abstract #175, AASLD 2016.
13
5

Methods
• Cohort includes ~1.5 million individuals tested for HCV
between 1990–2013, linked with data on medical visits,
hospitalizations, cancers, prescription drugs and mortality.
• Patients who received IFN based treatments were followed
from the end of last treatment to HCC occurrence, death or
December 31, 2012.
• Examined HCC risk among those who did and did not
achieve SVR using cumulative incidence function and
multivariable Cox proportional hazard models.
• 8147 patients initiated treatment and 57% achieved SVR.
• Median follow up: 5.6 yr (range: 0.5-12.9)
Janjua N, et al. Abstract #175, AASLD 2016.
6

SVR Substantially Reduces, But Does Not
Eliminate, the Risk of HCC
• HCC incidence rate (IR) was
1.1/1000 person-yr (PY) in
the SVR and 7.2/1000 PY in
the no-SVR groups.
• The IR was higher among
those with cirrhosis at
treatment (SVR: 6.4, no-
SVR: 21.0/1000 PY).
• In those with SVR, cirrhosis
(HR=3.16), older age (50-59
yr: HR=4.73; 60+yr:
HR=5.44 vs. ≤49 yr), and
being male (HR=3.3) were
associated with higher HCC
risk.
Janjua N, et al. Abstract #175, AASLD 2016.
7

SVR Substantially Reduces, But Does Not
Eliminate, the Risk of HCC
• HCC incidence rate (IR) was
1.1/1000 person-yr (PY) in
the SVR and 7.2/1000 PY in
the no-SVR groups.
• The IR was higher among
those with cirrhosis at
treatment (SVR: 6.4, no-
SVR: 21.0/1000 PY).
• In those with SVR, cirrhosis
(HR=3.16), older age (50-59
yr: HR=4.73; 60+yr:
HR=5.44 vs. ≤49 yr), and
being male (HR=3.3) were
associated with higher HCC
risk.
Is There an Increased Risk of
Cancer After Taking Direct-Acting
Antiviral Medication?
Janjua N, et al. Abstract #175, AASLD 2016.
8

Potential explanation

Potential explanation

Conclusion
• Incidence of d novo HCC is higher than expected after DAAs
• No significant reduction of HCC incidence following DAA
therapy in short term follow up
• If DAA – therapy started shortly after treatment of HCC risk
recurrence may be increased.
• No pharmacological prevention of HCC even with successful
antiviral therapy
• It is mandatory that patients treated with DAAs with
advanced liver disease should continue to be monitored for
HCC.

NEED
• LONG TERM FOLLOWUP AFTER SVR
• REAL WORLD REGISTRIES
• MECHANISMS

Abstarct # LB-21
• Genome-wide association study identifies a TLL1
variant associated with development of hepatocellular
carcinoma after eradication of hepatitis C virus
• Y. Tanaka, K. Matsuura, Department of Virology & Liver Unit, Nagoya City
University Graduate School of Medical Sciences, Nagoya, JAPAN|K. Matsuura,
Department of Gastroenterology and Metabolism, Nagoya City University
Graduate School of Medical Sciences, Nagoya, JAPAN|H. Sawai, K. Tokunaga,
Department of Human Genetics, Graduate School of Medicine, The University of
Tokyo, Tokyo, JAPAN|K. Ikeo, Center for Information Biology, National Institute
of Genetics, Mishima, JAPAN|A. Komori, Clinical Research Center, National
Nagasaki Medical Center, Omura, JAPAN|H. Yoshiji, Third Department of
Internal Medicine, Nara Medical University, Kashihara, JAPAN|N. Sakamoto,
Department of Internal Medicine, Hokkaido University Graduate School of
Medicine, Sapporo, JAPAN|Y. Asahina, Department of Gastroenterology and
Hepatology, Tokyo Medical and Dental University, Tokyo, JAPAN|M. Kurosaki,
Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital,
Musashino, JAPAN|N. Kawada, Department of Hepatology, Graduate School of
Medicine, Osaka City University, Osaka, JAPAN|M. Honda, Department of
Gastroenterology, Kanazawa University Graduate School of Medicine,
Kanazawa, JAPAN|

Bakground & Aim
• The risk of developing hepatocellular carcinoma (HCC) is
not completely abrogated after eradication of hepatitis C
virus (HCV) by anti-viral agents.
• Aimed is to identify host genetic variation associated with
the development of HCC after SVR in chronic HCV patients.

Methods
456 Japanese patients who achieved SVR by interferonbased
therapy and either developed HCC at ≥ 1 year after the
end of treatment (EOT) (n=123) or did not develop HCC for ≥
5 years after the EOT (n=333), and conducted GWAS in these
two groups. then carried out a replication analysis of 79
candidate single nucleotide polymorphisms (SNPs) in an
independent set consisting of 130 HCC and 356 non-HCC
patients.

Results
• SNP rs17047200, located within the intron of TLL1 on chromosome 4,
showed a strong association with developing HCC at a genome-wide
level of significance when the results of the GWAS and the replication
cohort were combined (odds ratio = 2.37, P = 2.66 × 10-8).
• The cumulative incidence of HCC up to 10 years after the EOT was
significantly higher in patients with rs17047200 AT/TT
.
• Multivariate analysis showed that rs17047200 AT/TT was an
independent risk factor for developing HCC (hazard ratio = 1.86, P =
0.002) in addition to male gender, older age, lower platelet count and
albumin level, and higher post-treatment α-fetoprotein level
• Combining the rs17047200 genotype with other factors ,propose
different prediction models for HCC development in patients with mild or
advanced hepatic fibrosis.

Conclusion
• TLL1 may contribute to HCC development mainly via
hepatic fibrogenesis, and suggest that genetic testing for the
TLL1 SNP would be useful for implementing personalized
surveillance of HCC after SVR has been achieved

174. Oral zinc supplementation improves liver
function and decreases the risk of hepatocellular
carcinoma development
Atsushi Hosui ; Naoki Hiramatsu Gastroenterology and
Hepatology, Osaka-Rosai Hospital, Sakai, Osaka, JAPAN|

Backgrounds and Aim
• Zinc plays a pivotal role in various zinc enzymes, resulting in
maintenance of liver function and decrease of reactive
oxygen species. Patients with chronic liver diseases (CLD)
have usually lower concentration of zinc, which decreases
along with progression of liver fibrosis whether zinc
supplementation improves liver function and the risk of
hepatocellular carcinoma (HCC) development

Patients and Methods
• Two hundred forty patients with CLD who had received zinc
preparation (Zn group: 192 cases) at least for 6 months, or
never received (no treatment group: 48 cases) were
retrospectively analyzed in this study.
• Zn group was divided into 4 groups by Zn concentration at 6
months after the start of Zn treatment
• (less than 50 μg/dl (G1), 50-69 μg/dl (G2), 70-89 μg/dl
(G3), and not less than 90 μg/dl (G4)).
• Liver function and the number of event (death, development
of liver cancer, and appearance of liver failure) were
evaluated at least every 6 months.
• The Log-rank test was used to assess the cumulative
incidence rates of event and HCC development

Results
• The mean follow-up period was 47.2±23.2 months.
• Liver function significantly deteriorated in the no treatment group
while no significant change was observed in the Zn group .
• The cumulative incidence rates of events at 3 years were 31.8%
in the no treatment group, vs 11.9% in the Zn group.
• The incidence rate of HCC at 3 years was lower in the Zn group
(7.9%) than in the no treatment group (25.4%).
• HCC was significantly suppressed in patients with Zn
concentration ≧70 μg/dl (G3/G4 groups).

Conclusion
• Zn concentration can be related with the progression of liver
disease and HCC development in patients with CLD.
• Oral zinc supplementation was suggested to be effective for
maintenance of liver function and suppression for HCC
development

NEW SYSTEMIC THERAPTY

Regorafenib
• Oral multi-kinase inhibitor which targets angiogenic, stromal
and oncogenic receptor tyrosine kinase (RTK).
• Shows anti-angiogenic activity due to its dual targeted
VEGFR2-TIE2 tyrosine kinase inhibition.
• Since 2009 it was studied as a potential treatment option in
multiple tumor types.
• By 2015 it had 2 US approvals for advanced cancers.

RESORCE: Regorafenib in HCC After
Progression on Sorafenib
• Phase III, randomized, double-blind trial
Pts with BCLC stage
B or C HCC;
documented PD on
sorafenib ≥ 20 days
at ≥ 400 mg/day;
Child-Pugh A liver
function;
ECOG PS 0-1
(N = 573)
Randomized 2:1
Regorafenib + BSC
160 mg PO daily Wks 1-3
(n = 379)
Placebo + BSC
PO daily Wks 1-3
(n = 194)
4-wk cycles
• Primary endpoint: OS (ITT) Secondary endpoints: PFS,
TTP, RR, DCR
All pts treated
until PD,
death, or
unacceptable
toxicity
Bruix J, et al. ESMO GI 2016. Abstract LBA-03.

RESORCE: Efficacy
Endpoint
Regorafenib
(n = 379)
*HR 0.44; 95% CI: 0.36-0.55; P < .001; † P = .005
Placebo
(n = 194)
Median OS, mos 10.6 7.8
Median PFS,
mos
3.1 1.5
Median TTP 3.2* 1.5*
ORR, % 10.6 † 4.1 †
• 38% reduction in risk of death (HR: 0.62; 95% CI: 0.50-0.78;
P < .001)
• 54% reduction in risk of progression or death (HR: 0.46;
95% CI: 0.37-0.56; P < .001)
• DCR (CR + PR + SD): 65.2% vs 36.1% (P < .001)
Bruix J, et al. ESMO GI 2016. Abstract LBA-03

RESORCE: Safety
AE, %
Regorafenib
(n = 379)
Placebo
(n = 194)
Any ≥ grade 3 AE 79.7 58.5
Hypertension 15.2 4.7
Hand–foot syndrome 12.6 0.5
Fatigue 9.1 4.7
Diarrhea 3.2 0
Dose modifications due
to AEs
Deaths occurring ≤ 30
days after last dose
68.2 31.1
13.4 19.7
Bruix J, et al. ESMO GI 2016. Abstract LBA-03
Slide credit: clinicaloptions.com

Immunotherapy in HCC

IMMUNE SYSTEM FUNCTION AND IMMUNE
RESPONSE
Nonspecific
First line of defense
WBCs (natural
killer cells,
neutrophils)
Activation of
adaptive response
Identify and destroy foreign or abnormal cells in the body
Innate Immunity
Macrophage
Natural
killer cell
Complement
protein
Dendritic cell
Basophil
Eosinophil
Neutrophil
Mast cell
Adaptive Immunity
λδ T-cell
Natural
killer T-cell
Granulocytes
B-cell
Antibodies
CD4+
T-cell
T-cell
CD8+
T-cell
Specific
Adapts specifically
to diverse stimuli
B-cell antibody
production
T-cell stimulation
Memory functions
Immune surveillance:
Involves both innate and adaptive immune mechanisms
Goal of immunotherapy for cancer: to “educate and liberate” underlying anticancer
immune responses
Janeway CA Jr, et al. Immunobiology: the immune system in health and
disease. 2001.

Discovery of
dendritic cell
HISTORY OF CANCER IMMUNOTHERAPY:
KEY MILESTONES
Tumor-specific
monoclonal Abs
Adoptive T-cell
immunotherapy
IFN-α as adjuvant
therapy for melanoma
BCG
approved
for bladder
cancer
Discovery of checkpoint
inhibitors
First immunotherapy
approved for prostate
cancer (sipuleucel-T)
Pembrolizumab and
nivolumab approved for
advanced melanoma
Atezolizumab approved
for advanced UC and
metastatic NSCLC
Nivolumab
approved for
RCC
Nivolumab
approved for
HL
1970s 1980s 1990s 2000s 2011 2014 2015
2016
Immune component
to spontaneous
regressions in
melanoma
IL-2 approved
for RCC and
melanoma (US)
First tumor-associated antigen
cloned (MAGE-1)
First checkpoint
inhibitor (ipilimumab)
approved for advanced
melanoma
Nivolumab
approved for
NSCLC
Pembrolizumab
approved for
PD-L1+ NSCLC
Pembrolizumab
approved for
HNSCC
References in slidenotes.

Abstract # LB-10.
Nivolumab (Nivo) in Patients (Pts) With
Advanced Hepatocellular Carcinoma
(HCC): the CheckMate 040 Study
• Melero, B. Sangro, Clinica Universidad de Navarra, Pamplona,
SPAIN|T. Yau, W. Yeo, Chinese University of Hong Kong, Hong Kong,
CHINA|C. Hsu, National Taiwan University Hospital, Taipei, TAIWAN|M.
Kudo, Kinki University School of Medicine, Osaka, JAPAN|T.S. Crocenzi,
Providence Cancer Center, Portland, Oregon, UNITED STATES|T. Kim,
Seoul National University Hospital, Seoul, KOREA (THE REPUBLIC
OF)|S. Choo, National Cancer Center, Singapore, SINGAPORE|J.
Trojan, Goethe University, Frankfurt, GERMANY|T. Meyer, Royal Free
Hospital, London, UNITED KINGDOM|T. Welling, University of Michigan
School of Medicine, Ann Arbor, Michigan, UNITED STATES|A. Chopra,
Johns Hopkins Singapore International Medical Centre, Singapore,
SINGAPORE|J. Anderson, C. Delacruz, L. Lang, J. Neely, H. Tang,
Bristol-Myers Squibb, Princeton, New Jersey, UNITED STATES|A.B. El-
Khoueiry, University of Southern California Norris Comprehensive
Cancer Center, Los Angeles, California, UNITED STATES|

Background
• For pts with advanced HCC, standard-of-care therapy with
sorafenib has limited benefit and those who progress have
few effective treatment options.
• Nivo is a fully human IgG4 monoclonal antibody inhibitor of
the programmed death-1 (PD-1) receptor that provides
survival benefit in multiple malignancies.
• Safety, tolerability, and preliminary efficacy of nivo in pts with
advanced HCC in the CheckMate 040 trial

CHECKMATE-040: ASSESSING NIVOLUMAB IN
PTS WITH ADVANCED HCC
Phase I/II dose escalation study in advanced HCC
Uninfected pts:
sorafenib
progressors
(n = 58)
sorafenib naive
(n = 51)
HCV-infected
pts (n = 51)
HBV-infected
pts (n = 51)
3 + 3 Dose-Escalation Phase
Nivolumab 0.1-10 mg/kg
Q2W for up to 2 yrs
(n = 23)
Nivolumab 0.3-10 mg/kg
Q2W for up to 2 yrs
(n = 10)
Nivolumab 0.1-10 mg/kg
Q2W for up to 2 yrs
(n = 15)
Expansion Phase
Nivolumab 3 mg/kg
Q2W for up to 2 yrs
(n = 112)
Nivolumab 3 mg/kg
Q2W for up to 2 yrs
(n = 51)
Nivolumab 3 mg/kg
Q2W for up to 2 yrs
(n = 51)
El Khoueiry A, et al. ASCO 2016. Abstract 4012.
Sangro, et al. ASCO 2016. Abstract 4078.

Proportion Surviving
NIVOLUMAB IN HCC (CHECKMATE-040): OS BY
PRIOR SORAFENIB IN ESCALATION COHORT
OS similar among sorafenib-naive and sorafenib-treated
pts
1.0
0.8
0.6
0.4
Group Died/Treated Median (95% CI)
Sorafenib naive 7/11 14.1 (3.2-28.6)
Sorafenib treated 22/37 15.0 (5.0-18.9)
0.2
0
Naive Treate
d
0 3 6 9 12 15 18 21 24 27 30 33
Mos Since First Dose
El Khoueiry A, et al. ASCO 2016. Abstract 4012.

CHECKMATE-459: NIVOLUMAB VS SORAFENIB AS
FIRST-LINE TREATMENT IN ADVANCED HCC
Advanced HCC; no
prior systemic
therapy; not eligible
for/progressed after
locoregional
therapy; C-P A;
ECOG PS 0-1
(planned N = 726)
Randomized, open-label, multicenter phase III trial
Stratified by etiology, vascular invasion and/or
extrahepatic spread, and geography
Nivolumab
30 min IV Q2W
Sorafenib
PO BID
All pts treated
until PD,
unacceptable
toxicity, or
withdrawal of
consent
*Nonviral HCC, HBV-HCC (HBV infection resolved or controlled),
or HCV-HCC (resolved or active HCV infection)
Primary endpoint: time to progression, OS
Secondary endpoints: ORR, PFS, PD-L1 expression
Sangro B, et al. ASCO 2016. Abstract TPS4147.
ClinicalTrials.gov. NCT02576509.

• Conclusions:
• Nivo had a manageable safety profile and provided durable
responses in pts with advanced HCC irrespective of infection
status.
• OS was encouraging
• Notable disease stabilization was observed.
• Limited antiviral activity was reported in HCV or HBV
infected pts.
• Results support continued investigation of Nivo in advanced
HCC

Thank
You
abdelazizashraf@hotmail.com