This lecture was part of an educational course performed by the IATTGI group this August in Buenos Aires and describes novel targets and novel drugs in hepatocellular carcinoma.

1. Tumor microenvironment in HCC:
new targets, biomarkers, and new drugs
Eric Raymond MD, PhD
Chair of Medical Oncology
@ Groupe Hospitalier Paris Saint-Joseph
France
eraymond@hpsj.fr
XI CURSO DE ENTRENAMIENTO INTENSIVO
PARA EL MANEJO INTERDISCIPLINARIO DE LOS TUMORES DIGESTIVOS
Organizado por el Intergrupo Argentino para el Tratamiento
de los Tumores Gastro-Intestinales

2. HCC is a worldwide medical need
• ~850,000 cases/per year
• ~800,000 deaths/year

3. Hepatocellular carcinoma
• A Two faced disease:
– Underlying liver diseases create the conditions for
carcinogenesis (cirrhosis, fibrosis, steatosis, HBV-HCV
infection, hemochromatosis, etc…) and have their own
natural history of evolution
– A carcinoma that has a low propensity to spread to other
organs and thus offer opportunity for local therapy
• A double vascularization
– HCC is primarily vascularize through the hepatic artery
– Unlike most other organs, the liver has a dual
vascularization, arterial obliteration being potentially
compensated by the portal vein vascularization

4. 1. Vogelstein B et al. Science. 2013;339:1546-1558. 2. Schulze K et al. Nat Genet. 2015;47:505-511.
Genome Sequencing in HCC (N = 250)
•
•
•
•
•
•
•
•
•
•
Telomerase maintenance: 60%
Cell-cycle gene: 49%
Wnt-B–catenin: 54%
Epigenetic modifier: 32%
Akt/mTOR: 51%
MAPK: 43%
Signaling Pathways (Other):
NOTCH: 30%
TGF-beta: 17%
MET: 50%
IGF signaling: 15% (IGF2 epi-driver)
2. Schulze K et al. Nat Genet. 2015;47:505-511. 2. Villanueva A et al. Gastrotenterology. 2012;143:1660-1669.
3. Coulouarn C et al. Hepatology. 2008;47:2059-2067.
Landscape of Mutations in HCC
Signaling Pathways (Mut)

5. Characteristics of Hepatocellular Carcinoma
Microenvironment
• Likely to vary according to the type of tumor carcinogenesis
– Alcohol
– Viral hepatitis B/C induced inflammation
– NASH
– Others
• Likely to be influenced by focal hypoxia
– Tumor angiogenesis being genuine or induced by sorafenib
– Induction of mesenchymal differentiation
– Induction of lactic acid metabolism
– Facilitate the occurrences of specific oncogenic mutations
• Associated with local immunosuppression
– Inhibition of T-cell functions (PD1/PDL1, CTLA4)
‘Epigenetic’ changes may be focal accounting for tumor heterogeneity and drift occurring
over time facilitating resistance to single agent therapy, pledging for combinations

6. Cellular & Molecular Components of the
Hepatocellular Carcinoma Microenvironment
Endothelial cells
Pericytes
VEGFR-PDGFR
T cells (CD4-Treg)
CD4:PD1-CTLA4-CD28
Treg: CD73-CD39
Dendritic cells
PDL1-PD1-MSH II-CD80/86
Tumor associated macrophages
CXCR4-TGFβR
Tumor cells
TGFβR-MET-PDL1
Fibroblasts
FGFR
TGFβ HGF
FGF19 IL8 IL10
SDF1/CXCL12

7. Cell-cell and cell-stroma interplay sustaining fibrosis
and inducing hepatocyte transformation.
HSC, hepatic stellate cell; CAF, cancer activated fibroblast; EMT, epithelial-to-mesenchymal transition
Transl Gastroenterol Hepatol 2018;3:24
Cancer cell

8. VEGFR & PDGFR as Anti-angiogenic
Targets for Hepatocellular Carcinoma
New Targets and New Agents in Hepatocellular Carcinoma
Endothelial cells
Pericytes
VEGFR-PDGFR
XI CURSO DE ENTRENAMIENTO INTENSIVO
PARA EL MANEJO INTERDISCIPLINARIO DE LOS TUMORES DIGESTIVOS
Organizado por el Intergrupo Argentino para el Tratamiento
de los Tumores Gastro-Intestinales

9. HGF & c-MET Inhibition in
Hepatocellular Carcinoma
New Targets and New Agents in Hepatocellular Carcinoma
Hepatocytes
Tumor cells
TGFβR-MET-PDL1
XI CURSO DE ENTRENAMIENTO INTENSIVO
PARA EL MANEJO INTERDISCIPLINARIO DE LOS TUMORES DIGESTIVOS
Organizado por el Intergrupo Argentino para el Tratamiento
de los Tumores Gastro-Intestinales

10. mRNA overexpression
Protein overexpression
Gene amplification
Mutation
Chronic liver inflammation (viral – others)
Fibroblasts and fibrosis
Local immunosupression
Genuine Hypoxia
Treatment induced hypoxia
(embolization, anti-angiogenic)
Epigenetic changes associated with HGF/c-MET activation
HGF stimulation of
hepatocytes and
hepatocarcinoma cells
harboring c-MET
Bouattour et al. Hepatology 2017, in press

11. c-MET inhibitors in late stage drug
development
METIV-HCC – Tivantinib – phase 3 trial
CELESTIAL – Cabozantinib – phase 3 trial
• First generation
• Specificity ?
Bouattour et al. Hepatology 2017, in press

12. Tivantinib Placebo
MedianOS,mo 8.4 9.1
Patients 226 114
Events 180 94
HR(95%CI) 0.97(0.75-1.25);P=.81
Tivantinib - METIV Trial: Overall Survival
1. Rimassa L et al. ASCO Annual Meeting. 2017. Abstract 4000.

13. Inhibition of c-MET With Tepotinib

14. Tolerability and Activity of Second-Line Tepotinib, a Potent and Highly
Selective c-Met Inhibitor, in Patients with Advanced Hepatocellular
Carcinoma Previously Treated with Sorafenib
30
10
-10
-20
-40
-50
-60
Bestrelativechangeinsum
oflongestdiameter
inbaseline(%)
Tepotinib 300 mg
Dose level
Tepotinib 500 mg
20
0
-30
Abstract No. 238
Faivre et al. World GI 2016
CT after 2 cycles showed objective
response by RECIST (-48%)
PET scan after 2 cycles showed significant
decrease of size and metabolic activity

15. FGF19 & FGFR4 as Targets in
Hepatocellular Carcinoma
New Targets and New Agents in Hepatocellular Carcinoma
Tumor cells
TGFβR-MET-PDL1
Fibroblasts
FGFR
XI CURSO DE ENTRENAMIENTO INTENSIVO
PARA EL MANEJO INTERDISCIPLINARIO DE LOS TUMORES DIGESTIVOS
Organizado por el Intergrupo Argentino para el Tratamiento
de los Tumores Gastro-Intestinales

16. Inhibition of FGF19/FGFR4 Activation
With BLU-554

18. Baseline Week 16
0 8 16 24 32
-26% SD -44% PR -45% PR PD
Week
Baseline
IHC+
FISH-
Radiographic response in post-sorafenib, non-viral HCC
Kim R et al. ILCA 2017

19. *4 confirmed responses
IHC-positivity enriches for radiographic tumor
reduction and response
Kim R et al. ILCA 2017

20. PD1 & PDL1 as Targets for
Hepatocellular Carcinoma
New Targets and New Agents in Hepatocellular Carcinoma
T cells (CD4-Treg)
CD4:PD1-CTLA4-CD28
Treg: CD73-CD39
Dendritic cells
PDL1-PD1-MSH II-CD80/86
Tumor cells
TGFβR-MET-PDL1

21. Around 30% of HCCs belong to the "immune class,"
with high levels of immune cell infiltration
Clin Cancer Res; 25(7) April 1, 2019

22. MHC
PD-L1
PD-1
PD-1
T-cell
receptor
PD-L2
T cell
NFκB
Other
PI3K
Tumor cell
IFNγ
IFNγR
Shp-2
Nivolumab
Immune Checkpoint Inhibition by Nivolumab
• Nivolumab is a fully human IgG4 anti-PD-1 monoclonal antibody that selectively blocks
the interaction between PD-1 and PD-L1/PD-L2,1 restoring T-cell immune activity
directed against the tumor cell
1. Topalian SL, et al. N Engl J Med. 2012;366:2443-2454

23. 1. El-Khoueiry AB et al. Lancet. 2017. pii: S0140-6736(17)31046-2.
Nivolumab in Patients With Advanced HCC
CheckMate 209-040
A Phase 1/2 Trial of Safety and Antitumor Activity of Nivolumab
September 22, 2017

24. • 58-year-old white male with HCV-infected HCC, ECOG 0, Child-Pugh A5
• Progressed on sorafenib
CA209-040: Durable Partial Response to Nivolumab
Week 12 Week 48Baseline
Arterial
Venous
+ +
+
+
+
+
+
+
+
+
Anthony B. El-Khoueiry et al. ASCO 2015

25. CA209-040: Activity
Activity reported across subgroups
Median OS: around 14 months irrespective of prior
sorafenib treatment
AE> grade 3: 1% - Well tolerated
Summary
1. El-Khoueiry AB et al. Lancet. 2017. S0140-6736(17)31046-2.

27. Zhu AX et al, ASCO GI 2018
Immunotherapy in HCC: what do we know?
Activity according to disease etiology
Sangro B et al, Lancet 2017

28. Sangro B et al, Lancet 2017
Immunotherapy in HCC: what do we know?
Activity according to PD-L1 expression
PD-L1 ≥ 1%
(20-25%)
PD-L1<1%
(75-80%)
RR 26-28% 12-19%
DCR 25-67% 63-70%

29. Immunotherapy has demonstrated activity in phase
I-II trials (2L++)
Lancet. 2017 Apr 20. [Epub
ahead of print]
Presented By Andrew Zhu at 2018 Gastrointestinal
Cancers Symposium

30. Adjuvant First line Second line
Overall Survival (OS)
Early stages Advanced stages
SURGERY/ABLATION Ongoing phase 3 of immunotherapy in HCC
according to disease setting
CheckMate-9DX
(nivolumab versus
placebo)
CheckMate-459
(nivolumab versus
sorafenib)
KEYNOTE-240
(pembrolizumab
versus placebo)NCT03412773
(tislelizumab versus
sorafenib)
HIMALAYA
(durvalumab+/trem
elimumab versus
sorafenib)
Relapse-free survival (RFS) Negative phase III trials

31. Other immune-based approaches in development
for advanced HCC
Compounds Target(s) #Patients ORR
Atezolizumab +
bevacicumab
Stein S ASCO 2018
PD-L1 + VEGF 23 65% (n = 15)
Pembrolizumab +
lenvatinib
Ikeda M ASCO 2018
PD-L1 + VEGFR 26 42% unconfirmed
27% confirmed
Atezolizumab + bevacicumab versus sorafenib alone Phase 3/1L (NCT#03434379)
Lancet Oncology - VOLUME 20, ISSUE 5, P711-718, MAY 01, 2019
FDA Grants Breakthrough Designation to Pembrolizumab & Lenvatinib Times-23 juil. 2019
(https://www.targetedonc.com/news/pembrolizumablenvatinib-combo-gets-fda-breakthrough-
designation-for-newly-diagnosed-unresectable-hcc)

32. New Targets and New Agents in Hepatocellular Carcinoma
Sorafenib
(1st line)
Regorafenib
(2nd line)
Tumor
angiogenesis
Galunisertib
(TGFβ-RI)
Tepotinib
(c-MET)
BLU-554
(FGF19/FGFR4)
Microenvironment signaling
Nivolumab
Pembrolizumab
(PD-L1)
Ipilimumab
Tremelimumab
(CTLA4)
Immune stroma
ç Combinations è

33. Conclusions
• Various components of tumor microenvironment
could be used as targets to control tumor growth in
hepatocellular carcinoma
• Inhibition of tumor angiogenesis, microenvironment
signaling and local immunosuppression appear as
promising options for tumor growth control
• Combination therapies normalizing the
microenvironment offer promise for optimal control
of hepatocellular carcinogenesis

34. Thanks for your attention