New Drugs in HCC

Dr Sandeep

Historically
Single Agents
Irinotecan
Gemcitabine
Doxorubicin
Studies demonstrated low response rates with little to no clinical
efficacy
Combination
combination of cisplatin, interferon, doxorubicin and 5-fluorouracil
(PIAF)
response (10 % for doxorubicin vs. 21 % for PIAF) survival (6.8 vs.
8.6 months)

Newer Agents

Antiangogenic
Drugs

Tyrosine Kinase
Inhibitors
Sorafenib
Sunitinib,
Brivanib
Linifanib
Erlotinib
Regorafenib
Lenvatinib
Other Drugs Refametinib,
Bevacizumab, Ramucirumab
es

Microenvironment signaling

MET inhibitors
mTorInhibitors
Inhibitor of FGFR4- BLU554
TGF Beta Inhibitor -Galunisertib

Immune Modulators
CTLA4inhibitors
PD1inhibitors
Oncolyticviruse

cmet

 TKI
Others
Antiangiogenic
Drugs

Sorafenib
oral multi-kinase and angiogenesis inhibitor
B-Raf and Raf-1

Microenvironment
Sig

Mtor
MET
FGFR4
TGF

Inhibits several other receptor tyrosine kinases

involved in angiogenesis
VEGFR 2, PDGFR, c-Kit receptors, and p38
signaling pathways.

Immune
Modulators

CTLA4
PD1
Viruses

Sorafenib

SHARP TRIAL
602 patients with advanced hepatocellular carcinoma who had not
received previous systemic treatment to receive either sorafenib (at
a dose of 400 mg twice daily) or placebo.
Median overall survival was 10.7 months in the sorafenib group and
7.9 months in the placebo group.
Time to Radiological progression 5.5 vs 2.8
In patients with advanced hepatocellular carcinoma, median
survival and the time to radiologic progression were nearly 3
months longer for patients treated with sorafenib than for those
given placebo.

Pan-Asian Trial
Similar eligibility and criteria to the SHARP trial completed in an
Asia-Pacific population.

sorafenib improved both median overall survival (6.5 vs. 4.2

months, p = 0.014) and median TTP (2.8 vs. 1.4 months,p =
0.0005) compared to placebo alone.

STORM TRIAL
Adjuvant sorafenib for hepatocellular carcinoma after resection or
ablation.

No difference in median recurrence-free survival between the two

groups (333 months in the sorafenib group vs 337 months in the
placebo group)

GIDEONTrial
GlobalInvestigationoftherapeuticDEcisionsinhepatocellular
carcinomaandOfitstreatmentwithsorafeNib

Confirmed safety in both Child A and B classes

 TKI
Others
Antiangiogenic
Drugs

Microenvironment
Sig

Immune
Modulators

Mtor
MET
FGFR4
TGF

CTLA4
PD1
Viruses

Sunitinib
Multikinase inhibitor
Demonstrated modest efficacy and significant
adverse events in two separate single arm phase
II trials
Phase III clinical trial comparing sunitinib to
sorafenib in patients with advanced HCC
Median OS for sunitinib of 7.9 months vs. 10.2
months in the sorafenib arm
Adverse events occurred in 82 % of sunitinib
vs. 74 % of sorafenib patients
Terminated early due to adverse effects

 TKI
Others
Antiangiogenic
Drugs

Microenvironment
Sig

Immune
Modulators

Mtor
MET
FGFR4
TGF

CTLA4
PD1
Viruses

Brivanib
Tyrosine kinase inhibitor, with dual inhibition of
fibroblast growth factor (FGF) and vascular
endothelial growth factor (VEGF)
Demonstrated activity against advanced HCC in
a single arm phase II clinical trial
Failed to achieve its endpoint in the subsequent
randomized phase III clinical trial (brivanib, 9.5
months, vs. sorafenib, 9.9 months)

Linifanib

TKI
Others
Antiangiogenic
Drugs

Microenvironment
Sig

Immune
Modulators

Mtor
MET
FGFR4
TGF

CTLA4
PD1
Viruses

Inhibitor of VEGF and PDGFR

Demonstrated marginal efficacy in a single

arm phase II clinical trial in advanced HCC
In Phase III trial failed to meet the primary
endpoint of median OS when compared to
sorafenib alone (9.1 months vs. 9.8 months)

 TKI
Others
Antiangiogenic
Drugs

Erlotinib
Inhibitor of EGFR

Microenvironment
Sig

Mtor
MET
FGFR4
TGF

Demonstrated marginal efficacy in two

single arm phase II trials with median OS of
10 and 13 months
720 pts were randomized in a phase III
clinical trial to sorafenib alone or sorafenib
plus erlotinib.

Immune
Modulators

CTLA4
PD1
Viruses

Median OS was not statistically different

between the two groups (9.5 vs. 8.5
months,).

 TKI
Others
Antiangiogenic
Drugs

Microenvironment
Sig

Immune
Modulators

Mtor
MET
FGFR4
TGF

CTLA4
PD1
Viruses

Regorafenib
Diphenylurea multikinase inhibitor of VEGFR1-3, c-KIT, tyrosine kinase with
immunoglobulin-like and EGF-like domains-2,
platelet-derived growthFactor receptor 2,
Fibroblast growth factor receptor-1,
RET, RAF-1, BRAF and p38 mitogen-activated
protein kinase (MAPK)
Approved for the treatment of metastatic
colorectal cancer and metastatic GIST
A small single-arm Phase II study in HCC patients
who progressed on sorafenib showed a signal for
activity
Phase III trial (RESORCE) of regorafenib in
patients who progressed under sorafenib

 TKI
Others
Antiangiogenic
Drugs

Microenvironment
Sig

Mtor
MET
FGFR4
TGF

Lenvatinib
Multitargeted TKI of the VEGFRs 1, 2 and 3,
FGFRs 1 through 4, PDGFRa, RET and KIT
signaling networks.
Effective in Thyroid malignancies
Early trials in HCC

Immune
Modulators

CTLA4
PD1
Viruses

 TKI
Others
Antiangiogenic
Drugs

Other Antiangiogenesis
Drugs
Refametinib

Allosteric inhibitor of MEK1/2

Microenvironment
Sig

Immune
Modulators

Mtor
MET
FGFR4
TGF

CTLA4
PD1
Viruses

Thalidomide Immune modulator + Oral VEGF

inhibitor

Bevacizumab
TKI
Others

Humanised monoclonal antibody against VEGF

Antiangiogenic
Drugs

Tried alone or in combination with erlotinib

Microenvironment
Sig

Immune
Modulators

Mtor
MET
FGFR4
TGF

CTLA4
PD1
Viruses

Results promising in Phase 2 trials. High incidence

of adverse effects preventing clinical use.

 TKI
Others
Antiangiogenic
Drugs

Microenvironment
Sig

Immune
Modulators

Mtor
MET
FGFR4
TGF

CTLA4
PD1
Viruses

Ramucirumab
Ramucirumab is a monoclonal antibody targeting
the VEGFR 2
Useful in metastatic gastric cancer
Phase III study (REACH) comparing ramucirumab to
placebo in patients after failure to sorafenib
Median overall survival 9.2 months for
ramucirumab versus 7.6 months for placebo
No statistically significant difference
AFP >400 ng/ml (n = 250) the overall survival was
significantly longer for the patients treated with
ramucirumab (7.8 vs 4.2)

Agents Altering
Microenvironment Signaling

Antiangiogenic
Drugs

Microenvironment
Sig

Immune
Modulators

TKI
Others

Everolimus
mTOR inhibitor

mTor
MET
FGFR4
TGF

CTLA4
PD1
Viruses

EVOLVE Trial
After failure of sorafenib treatment
,patients were randomly assigned to
treatment with or placebo.
No survival benefit(7.6 vs 7.3 months)

MET inhibitors
MET is the receptor for hepatocyte growth
factor
HGF is the predominant factors involved in
liver regeneration and wound healing.
Frequently dysregulated and activated in
several cancers including HCC.
MET activation favors migration, and
vascular invasion as well as tumor
angiogenesis.
MET overexpression is found in 25-- 87% of
HCC patients

Antiangiogenic
Drugs

TKI
Others

MET inhibitors
Tivantinib
Cabozantinib

Microenvironment
Sig

Immune
Modulators

Mtor
MET
FGFR4
TGF

CTLA4
PD1
Viruses

Antiangiogenic
Drugs

TKI
Others

Tivantinib
non-ATP competitive MET inhibitor

Microenvironment
Sig

Immune
Modulators

Mtor
MET
FGFR4
TGF

CTLA4
PD1
Viruses

Could improve the survival in comparison to

placebo in a Phase II randomized controlled
trial.
Patients with high MET expression had a
substantial benefit from tivantinib.(7.2 vs 3.8)
Phase III trial investigating tivantinib is
currently recruiting

Antiangiogenic
Drugs

TKI
Others

Cabozantinib
Cabozantinib is a receptor TKI with activity
against MET,VEGFR2, FLT3, c-KIT and RET.

Microenvironment
Sig

Mtor
MET
FGFR4
TGF

Approved in refractory medullary thyroid cancer.

Investigated in HCC patients in a Phase II clinical
trial
Phase 2 trials Promising

Immune
Modulators

CTLA4
PD1
Viruses

 TKI
FGFR4
Inhibitor
Others

Antiangiogenic
Drugs

BLU-554 Selective, Potent inhibitor of

FGFR4
Microenvironment
Sig

Immune
Modulators

Mtor
MET
FGFR4
TGF

CTLA4
PD1
Viruses

Phase 1 Trials ongoing

 TKI
Others

Galunisertib

Antiangiogenic
Drugs

TGFR1 Kinase Inhibitor

Phase 1 Trials ongoing

Microenvironme
ntSig

Immune
Modulators

Mtor
MET
FGFR4
TGF

CTLA4
PD1
Viruses

ImmuneModulators

 TKI
Others
Antiangiogenic
Drugs

Tremelimumab
CTLA-4 antibody

Microenvironment
Sig

ImmuneModulators

Mtor
MET
FGFR4
TGF

CTLA4
PD1
Viruses

Investigated in a Phase Ib trial in HCC

This trial enrolled 21 patients with HCC
and chronic hepatitis C virus infection
Partial response rate was 17.6% and
disease control rate was 76.4%.
Another Pilot study in combination with TACE
or RFA ongoing
Ipilimumab

Antiangiogenic
Drugs

Microenvironment
Sig

TKI
Others

Mtor
MET
FGFR4
TGF

Nivolumab
Fully human

Immune
Modulators

CTLA4
PD1
Viruses

IgG4 anti-PD-1
monoclonal antibody
Restores T cell immunity against
tumour cells
Currently, a Phase I/II trial with
nivolumab in advanced HCC is
recruiting patients

Pembrolizumab

Antiangiogenic
Drugs

Microenvironment
Sig

Immune
Modulators

TKI
Others

Mtor
MET
FGFR4
TGF

CTLA4
PD1
Viruses

Oncolytic viruse
Promising class of drugs that preferentially
replicate in cancer cells as well as finally kill the
malign cells.
Several OVs have been investigated in Phase I
and II trials
JX-594 also known as Pexa-Vec
(pexastimogene 60 devacirepvec)
dl1520 (ONYX-015) or H101 (Oncorine)
VSV-hIFN-b

JX-594
vaccinia virus (Wyeth vaccine strain)
Disruption of the viral thymidine kinase (TK) gene for cancer
selectivity and insertion of human granulocyte-macrophage colonystimulating factor (hGM-CSF) and b-galactosidase transgenes for
immune stimulation and replication assessment, respectively.
Phase II clinical trial JX-594 was administered in two doses of with
low-dose and high-dose JX-594
Overall survival 14.1 months for the high-dose group compared
to 6.7 months in the low-dose group.

LocoregionalTherapy

TACEwithDrug-ElutingBeads
Embolicmicrospheresthathavetheabilitytoactivelysequesterdoxorubicin
andreleaseitinacontrolledandsustainedfashion.
Lesssystemicleakhighlocalconcentrationofthedrugandtheantitumoral
efcacy
High-dosedoxorubicincanbeusedevenwithbaselinerisks
PRECISIONVphase2RCT
Rateoftumorprogressionat12monthswassignicantlylowerinthedrug-elutingbeadarmthan
intheblandembolizationarm(46%versus78%,P-0.002)

Hepatic Artery Infusion Chemotherapy

TreatadvancedHCCpatientswithvascularinvasion,multipleintrahepaticlesions,or
both.

DeliveryofhighdosesofdrugsdirectlytothehypervascularHCC

Implantableportsystem

5FUandcisplatinmostcommonlyused

Kimetalhaicvstace
ObjectiveresponseratewasbetterwithHAIC(16.7%vs.0%;p=0.030).
Theoswaslongerwithhaic(mediansurvival193daysvs.119days;p=0.026)

Yttrium-90 Radioembolization
Microspherescontaining90Yareinjectedthroughthehepaticartery,-becometrappedatthe
precapillarylevel
Selectivelyemithigher-doseradiationtotheHCC
90Yisapurebeta-emitter,andgenerateshigh-energyradiationwithashorthalf-life(2.67days),
Shorttissuepenetration(mean,2.5mm;maximum,11mm)
Microspheres25-35Micron(100-500microninTACE)
Ensurethattheliverparenchymaexposuredoesnotexceed70gy,whileatleast120gymust
accumulatewithinthetumortodeliveradose-dependenttumoricidaleffect

Pre Treatment Evaluation

1.Pretreatment angiography is carried out in order to detect the vascular
anatomy and the tumor feeding vessels.
2. 99mTc labeled macroaggregated albumin scintigraphy
Exclusion
1. uncorrectable flow to the gastrointestinal tract
2. lung shunting >20% (resin microspheres) or estimated radiation doses to
the lungs >30 Gy (with a single administration) or 50 Gy (with multiple
administrations);
3. significant extrahepatic disease.
4.Tumor volume should not exceed 50% of the total liver volume

 Assess response after 3 months

Side Effects
fatigue (54%61%),
mild-to-moderate abdominal pain (23%56%), nausea and vomiting (20%32%),
fever (3%12%)
lymphopenia
Radiation-induced gastroduodenal ulcerations and pancreatitis
radioembolization-induced liver disease (REILD) - jaundice, mild ascites in the
absence of tumor progression or bile duct obstruction, a marked increase in
bilirubin and alkaline phosphatase 8-12 weeks later. Form of sinusoidal obs
syndrome

RCT TACE vs TARE

99 patients with HCC received a single dose of 90Y, and 691
patients who had similar treatment criteria received repetitive,
cisplatin-based TACE
overall survival was slightly better in the 90Y group compared with
the TACE group (median survival, 11.5 months versus 8.5 months).
The study had a selection bias Re-analysis showed no significant
difference

Cancer.2010 Mar 1;116(5):1305-14. doi: 10.1002/cncr.24884.

TARE vs Sorafenib
Only one retrospective has compared the outcomes of two groups
of patients treated with TARE and sorafenib. -- Pts with portal vein
thrombosis
The median os of the sorafenib arm was 13.1 months (95% CI:
1.225.9) and of the TARE arm 11.2 months (95% CI: 6.7
15.7;p=0.392),
Only in the TARE arm two patients were fully downstaged to LT
Gramenzi A, Golfieri R, Mosconi C, et al. Yttrium-90 radioembolization versus sorafenib for intermediate-locally
advanced hepatocellular carcinoma: a cohort study with propensity score analysis. Liver Int. Epub April 22,
2014.

Summarising
Sorafenib still is the only FDA approved drug.
Regorafenib could be useful in Sorafenib resistant HCC.
Resorce Trial
Ramucirumab could be useful in cases with high AFP.
REACH Trial
TACE with Drug-Eluting Beads Better than TACE in Phase 2
trials
No clinical evidence to suggest TARE over TACE/Sorafenib
at present

Quiz
1.Which of the following is primarily an antiangiogenic drug?
A.Sorafenib
B. Nivolumab
C. Everolimus
d. Tremelimumab

2.Resorce Trial is associated with which drug?

A.Sorafenib
B.Sunitinib
C. Regorafenib
D. Nivolumab

3.Which of the following is a phase 4 Trial?

a.Sharp Trial
b. Pan-Asian Trial
c.Storm Trial
d.Gideon Trial

4.Which of the following is an absolute contraindication for

Y90 Radio embolisation?
a.Partial Portal Vein Thrombosis
b.Child B Cirrhosis
c.Hepatopulmonary shunt >20%
d.Tumour >5cm

5.Which of the following is the least common side effect of

sorafenib?
a.Hand foot mouth Disease
b.Rash
c.Diarrhea
d.Liver Failure

Thank You