Chair, Amit Singal, MD, MS, Anthony El-Khoueiry, MD, Ahmed Omar Kaseb, MD, CMQ, and Anjana Pillai, MD, prepared useful Practice Aids pertaining to hepatocellular carcinoma for this CME/MOC activity titled “It Takes a Team for HCC: Improving Outcomes Through Multidisciplinary Collaboration & Modern Therapeutics.” For the full presentation, downloadable Practice Aids, and complete CME/MOC information, and to apply for credit, please visit us at https://bit.ly/3AbNtC5. CME/MOC credit will be available until December 4, 2023.

1. BCLC Staging System for HCC1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/QYD40
Yes
No
Normal Increasedb
HCC
Very early stage (0)
• Single ≤2 cm
• Preserved liver function,a
PS 0
Potential candidate for
liver transplantation
Single
Contraindications to LT
Yesb
1st Treatment
Option
Ablation Resection Ablation Transplant TACE Systemic Therapy BSC
3 mo
>2 y
>2.5 y
>5 y
Expected
Survival
No
≤3 nodules,
each ≤3 cm
Portal pressure,
bilirubin
Extended
liver
transplant
criteria
(size, AFP)
Well-defined
nodules,
preserved
portal flow,
selective
access
Diffuse,
infiltrative,
extensive
bilobar liver
involvement
Early stage (A)
• Single or ≤3 nodules
each ≤3 cm
• Preserved liver function,a
PS 0
Intermediate stage (B)
• Multinodular
• Preserved liver function,a
PS 0
Advanced stage (C)
• Portal invasion and/or
extrahepatic spread
• Preserved liver
function, PS 1-2
Terminal stage (D)
• Any tumor burden
• End-stage liver function,
PS 3-4
To
decide
individualized
treatment
approach
Based
on
tumor
burden,
liver
function,
and
physical
status
Refined
AFP,
ALBI
score,
Child–Pugh,
MELD
Prognosis
Patient
Characterization

2. a
Except for those with tumor burden acceptable for transplant. b
Resection may be considered for single peripheral HCC with adequate remnant liver volume.
1. Reig M et al. J Hepatol. 2022;76:681-693.
BCLC Staging System for HCC1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/QYD40
1st Treatment
Option
Ablation Resection Ablation Transplant TACE
Successful downstaging
Not feasible or failure
TACE
Radioembolization (only for single lesion ≤8 cm)
Systemic Therapy BSC
3 mo
>2 y
>2.5 y
>5 y
Not feasible or failure
Expected
Survival
Treatment
Stage
Migration
primes
lower
priority
options
due
to
non–liver-related
clinical
profile
(age,
comorbidities,
patient
values,
and
availability)
Clinical
Decision-Making
1st Line
• Atezolizumab–bevacizumab/durvalumab–tremelimumab
If not feasible, sorafenib or lenvatinib or durvalumab
3rd Line
• Cabozantinib
2nd Line
• Post sorafenib
Regorafenib
(sorafenib-tolerant)
Cabozantinib
Ramucirumab
(AFP ≥400 ng/mL)
Clinical
trials
Not
feasible
Alternative sequences
could be considered
but they have not
been proved
• Post atezolizumab-bevacizumab
• Post durvalumab-tremelimumab
• Post lenvatinib
Not feasible
Not feasible

3. New Concepts and Emerging Modalities in HCC1-3
Full abbreviations, accreditation, and disclosure information available at PeerView.com/QYD40
Tumor Treating Fields (TTFields) Are an Antimitotic Therapy
New
cell
TTFields
• Living cells contain ions and polar or charged
molecules
• Charged particles and dipoles can be influenced
by electric fields
• TTFields are alternating electric fields that can
disrupt charged particles during mitosis, which
may lead to cell death in dividing cancer cells
but spare quiescent cells
G0
Resting state
G2
Premitosis
G1
Interphase
initiation
S
DNA
synthesis
M
Mitosis
and
cytokinesis
New
cell

4. New Concepts and Emerging Modalities in HCC1-3
Full abbreviations, accreditation, and disclosure information available at PeerView.com/QYD40
1. Gutin PH et al. Am Soc Clin Oncol Educ Book. 2012;32:126-131. 2. Kirson ED et al. Proc Natl Acad Sci USA. 2007;104:10152-10157. 3. https://www.cancernetwork.com/view/novottf-200t-delivery-system-given-a-breakthrough-designation-by-the-fda-for-advanced-liver-cancer.
Non-Invasive, Wearable Device Targeting the Liver
Phase 2 HEPANOVA Trial
TTFields (150 kHz) Concurrent With First-Line Sorafenib for Advanced/Unresectable HCC
• Results showed response
greater than historical control
• Phase 3 RCT being planned with
new SOC: atezolizumab +
bevacizumab
• TTFields + atezolizumab +
bevacizumab granted FDA
breakthrough therapy
designation in advanced HCC3
HCC
N = 25
Until PD per RECIST in the liver
Screening
and baseline
evaluation
TTFields
+ daily
sorafenib
CT/MRI
scan every
12 wk until
PD
Survival
follow-up
• Primary endpoint: overall radiological
response rate
• Secondary endpoints: in-field control
rate, OS
• 27 patients enrolled
• 52% Child-Turcotte-Pugh: 7-8
• Median duration of therapy: 9 weeks

5. Considerations for Selecting and Sequencing
Treatments for Advanced HCC
Full abbreviations, accreditation, and disclosure information available at PeerView.com/QYD40
Current NCCN Guidelines1
All recommendations are category 2A unless otherwise noted
First-Line Systemic Therapy
Subsequent-Line Therapy if Disease Progression
Preferred Regimens
• Atezolizumab + bevacizumab (Child–Pugh A only) (category 1)
Other Recommended Regimens
• Sorafenib (Child–Pugh A [category 1] or B7)
• Lenvatinib (Child–Pugh A only) (category 1)
• Durvalumab
• Pembrolizumab (category 2B)
Useful in Certain Circumstances
• Nivolumab (if ineligible for TKls or other anti-angiogenics)
(Child–Pugh A or B) (category 2B)
Options
• Regorafenib (Child–Pugh A only) (category 1)
• Cabozantinib (Child–Pugh A only) (category 1)
• Ramucirumab (AFP ≥400 ng/mL and Child–Pugh A only) (category 1)
• Lenvatinib (Child–Pugh A only)
• Sorafenib (Child–Pugh A or B7)
Other Recommended Regimens
• Nivolumab + ipilimumab (Child–Pugh A only)
• Pembrolizumab (Child–Pugh A only) (category 2B)
Useful in Certain Circumstances
• Nivolumab (Child–Pugh B only) (category 2B)
• Dostarlimab (for MSI-H/dMMR tumors) (category 2B)
• For RET gene fusion–positive tumors:
– Selpercatinib (category 2B)

6. Considerations for Selecting and Sequencing
Treatments for Advanced HCC
Full abbreviations, accreditation, and disclosure information available at PeerView.com/QYD40
Second-Line
Treatment
and
Beyond
Drug Supporting Evidence
First-Line
Treatment
Dosing
Indication
Atezolizumab +
bevacizumab3
IMbrave150
Atezolizumab 840 mg every 2 weeks, 1,200 mg every 3 weeks, or 1,680 mg every 4 weeks,
administered prior to bevacizumab when given on the same day; bevacizumab 15 mg/kg
every 3 weeks
Sorafenib5-7
SHARP 400 mg orally twice daily without food
Treatment of patients with
unresectable HCC
HIMALAYA
Adult patients with unresectable HCC
Durvalumab+
tremelimumab4
Lenvatinib6
12 mg orally once daily for patients ≥60 kg or 8 mg orally once
daily for patients <60 kg
REFLECT
First-line treatment of patients
with unresectable HCC
Regorafenib7
RESORCE 160 mg orally once daily for the first 21 days of each 28-day cycle after a low-fat meal
Treatment of patients with HCC
who have been previously
treated with sorafenib
Cabozantinib8
CELESTIAL
Treatment of patients with HCC
who have been previously
treated with sorafenib
Ramucirumab9
REACH-2
8 mg/kg every 2 weeks IV administered over 60 minutes; if the first infusion is tolerated,
all subsequent infusions may be administered over 30 minutes
Treament of HCC in patients
who have an AFP ≥400 ng/mL
and have been treated with sorafenib
FDA-Approved Systemic Therapy in HCC2
Treatment of patients with unresectable or
metastatic HCC who have not received prior
systemic therapy
For patients weighing ≥30 kg: durvalumab 1,500 mg + tremelimumab 300 mg as a single
dose at cycle 1/day 1, followed by durvalumab 1,500 mg as a single agent every 4 weeks;
for patients weighing <30 kg: durvalumab 20 mg/kg + tremelimumab 4 mg/kg as a single
dose at cycle 1/day 1, followed by durvalumab 20 mg/kg as a single agent every 4 weeks
60 mg orally once daily; 40 mg orally once daily in pediatric patients with BSA <1.2 m2
;
administer at least 1 hour before or at least 2 hours after eating

7. Considerations for Selecting and Sequencing
Treatments for Advanced HCC
Full abbreviations, accreditation, and disclosure information available at PeerView.com/QYD40
1. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Hepatobiliary Cancers. Version 3.2022. https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. 2. https://www.accessdata.fda.gov/.
3. Finn RS et al. N Engl J Med. 2020;382:1894-1905. 4. Abou-Alfa G et al. 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI 2022). Abstract 379. 5. Llovet JM et al. N Engl J Med. 2008;359:378-390. 6. Kudo M et al. Lancet. 2018;391:1163-1173.
7. Bruix J et al. Lancet. 2017;389:56-66. 8. Abou-Alfa G et al. N Engl J Med. 2018;379:54-63. 9. Zhu AX et al. Lancet Oncol. 2019;20:282-296. 10. El-Khoueiry AB et al. 13th Annual Conference of the International Liver Cancer Association (ILCA 2019). Abstract O-13.
11. Yau T et al. 2019 American Society of Clinical Oncology Annual Meeting (ASCO 2019). Abstract 4012. 12. Keytruda (pembrolizumab) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125514s133lbl.pdf.
Drug Supporting Evidence
Second-Line
Treatment
and
Beyond
Dosing
Indication
Nivolumab 1 mg/kg followed by ipilimumab 3 mg/kg on the same day
every 3 weeks for 4 doses, then nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks
Nivolumab +
ipilimumab10,11
Pembrolizumab12
KEYNOTE-224 200 mg every 3 weeks or 400 mg every 6 weeks
CheckMate -040
Treatment of patients with HCC
who have been previously
treated with sorafenib
Treatment of patients with HCC
who have been previously
treated with sorafenib