Mastering Multidirectional Tactics in HCC: Expert Guidance on Emerging Trends With Systemic Therapy Options Across the Disease Continuum

Chair and Presenter, Univ.-Prof. Dr. Peter R. Galle, Lipika Goyal, MD, MPhil, and Stacey M. Stein, MD, prepared useful Practice Aids pertaining to HCC for this CME/MOC/NCPD/AAPA/IPCE activity titled “Mastering Multidirectional Tactics in HCC: Expert Guidance on Emerging Trends With Systemic Therapy Options Across the Disease Continuum.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/NCPD/AAPA/IPCE information, and to apply for credit, please visit us at https://bit.ly/3z0HMIQ. CME/MOC/NCPD/AAPA/IPCE credit will be available until July 2, 2025.

1. BCLC Staging Algorithm
1

Full abbreviations, accreditation, and disclosure information available at PeerView.com/VXT40 YesNo
Normal Increased
b
HCC
Very early stage (0)
• Single, ≤2 cm
• Preserved liver function,
a
PS 0
Potential candidate for
liver transplantation
Single
Contraindications to LT
Yes
b
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. BCLC Staging Algorithm
1

Full abbreviations, accreditation, and disclosure information available at PeerView.com/VXT40 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 proven
• Post atezolizumab-bevacizumab
• Post durvalumab-tremelimumab
• Post lenvatinib
Not feasible
Not feasible
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.

3. Considerations for Selecting and Sequencing
Treatments for Advanced HCC 
Full abbreviations, accreditation, and disclosure information available at PeerView.com/VXT40 Patient with 
advanced HCC
Contraindications to 
ICI therapy?
Atezo + bev
(EGD and treatment 
of varices required 
within 6 mo)
Durva + treme 
(STRIDE)
Lenvatinib Sorafenib
Single-agent 
PD-1/PD-L1
No, but not ideal candidate for 
combination therapy
No Yes
Patient with 
advanced HCC
1L therapy with 
sorafenib or lenvatinib
1L therapy with atezo + bev,
durva + treme, or single-agent durva
TKI (Nivo + ipi) (Nivo + ipi)Pembrolizumab
Ramucirumab 
(AFP ≥400 ng/mL)
Cabozantinib or 
regorafenib 
Take-Homes for Selection of 1L HCC Therapy
Take-Homes for Selection of 2L HCC Therapy

4. Considerations for Selecting and Sequencing
Treatments for Advanced HCC
Full abbreviations, accreditation, and disclosure information available at PeerView.com/VXT40 1. https://www.accessdata.fda.gov/. 2. Finn RS et al. N Engl J Med. 2020;382:1894-1905. 3. Abou-Alfa G et al. ASCO GI 2022. Abstract 379. 4. Llovet JM et al. N Engl J Med. 2008;359:378-390. 5. Kudo M et al. Lancet. 2018;391:1163-1173. 6. Bruix J et al. Lancet. 2017;389:56-66.
7. Abou-Alfa G et al. N Engl J Med. 2018;379:54-63. 8. Zhu AX et al. Lancet Oncol. 2019;20:282-296. 9. El-Khoueiry AB et al. ILCA 2019. Abstract O-13. 10. Yau T et al. ASCO 2019. Abstract 4012.
11. Keytruda (pembrolizumab) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125514s136lbl.pdf.
FDA-Approved Systemic Therapies in HCC
1

First-Line Treatment Second-Line Treatment and Beyond
Drug
Indication
Atezolizumab +
bevacizumab
2

Treatment of 
patients 
with 
unresectable 
or metastatic 
HCC who 
have not 
received 
prior 
systemic 
therapy
Durvalumab +
tremelimumab
(STRIDE)
3
Adult 
patients 
with 
unresectable 
HCC
Lenvatinib
5
First-line 
treatment of 
patients 
with 
unresectable 
HCC
Regorafenib
6

Treatment of 
patients 
with HCC 
who have 
been 
previously 
treated with 
sorafenib
Cabozantinib
7
Treatment of 
patients 
with HCC 
who have 
been 
previously 
treated with 
sorafenib
Ramucirumab
8
Treatment of 
HCC in 
patients 
who have 
an AFP 
≥400 ng/mL 
and have 
been treated 
with 
sorafenib
Nivolumab +
ipilimumab
9,10
Treatment of 
patients 
with HCC 
who have 
been 
previously 
treated with 
sorafenib
Pembrolizumab
11
Treatment of 
patients 
with HCC 
who have 
been 
previously 
treated with 
sorafenib
Sorafenib
4-6
Supporting
Evidence
IMbrave150 HIMALAYA REFLECT  RESORCE CELESTIAL  REACH-2
CheckMate-
040
KEYNOTE-224SHARP
Treatment of 
patients 
with 
unresectable 
HCC

5. Combining Systemic Therapy and LRT
for BCLC B Stage HCC
Full abbreviations, accreditation, and disclosure information available at PeerView.com/VXT40 All Patients With BCLC B, Intermediate-Stage HCC Are Not Equal
1
≤3 cm
>3-6 cm
Green
Red
Yellow
Good response subgroup to cTACE (within up-to-7 criteria)
Poor response subgroup to cTACE (beyond up-to-7 criteria)
Poor response subgroup to cTACE (beyond up-to-7 criteria, bilobar multifocal tumors)
Huge (>6 cm)
Size
Number
≤3 Nodules
Resection RFA
4-6  Nodules Multiple (7)
>3 Nodules
N0
M0
VP0, Vv0 
Subgroup, easy
to be TACE refractory
TACE- 
unsuitable
patients
Bilobar multifocal tumors
>3 cm
Potential advantages of incorporating systemic therapy earlier include
• Starting efective therapy earlier
• Introducing more efective intervention prior to possible liver decompensation
• Potentially increasing cures

6. Combining Systemic Therapy and LRT
for BCLC B Stage HCC
Full abbreviations, accreditation, and disclosure information available at PeerView.com/VXT40
1. Kudo M. Liver Cancer. 2017;6:177-184. 2. https://clinicaltrials.gov. Trial Agents Primary Endpoint
EMERALD-1
(NCT03778957)
Durvalumab ± bevacizumab + TACE vs TACE + placebo mPFS: 15.0 vs 8.2 mo
EMERALD-3
(NCT05301842)
Durvalumab + tremelimumab + TACE ± lenvatinib vs TACE PFS
LEAP-012
(NCT04246177)
Pembrolizumab + lenvatinib + TACE vs TACE + placebo PFS and OS
DEMAND
(NCT04224636)
Atezolizumab + bevacizumab + TACE 24-mo survival rate
CheckMate -74W
(NCT04340193)
Nivolumab ± ipilimumab + TACE vs TACE + placebo OS and TTP
EMERALD-Y90
(NCT05063565)
Durvalumab + bevacizumab with Y90 TARE PFS
ROWAN
(NCT05063565)
Durvalumab + tremelimumab with Y90 ORR
Select Clinical Trials
2
Rationale for Combining LRT and Systemic Therapy
Intermediate-stage HCC is a heterogeneous entity with variability
in tumor burden, distribution, and underlying liver function
Efcacy of LRT is afected by tumor burden
Risk of missing the opportunity to reach the point of systemic
therapy in cases of liver function deterioration
Systemic therapy has level 1 evidence of improved survival
and high response rates

7. Blue Faery: A Resource for Professionals,
Patients, and Caregivers
Full abbreviations, accreditation, and disclosure information available at PeerView.com/VXT40 Blue Faery: The Adrienne Wilson Liver Cancer Association’s
mission is to prevent, treat, and cure primary liver cancer—
specifically HCC—through research, education, and advocacy. 
Selected resources include
Patient Support Groups
bluefaery.org/liver-cancer-community
Find and Learn About Clinical Trials
bluefaery.org/clinical-trials
Latest Liver Cancer News
bluefaery.org/liver-cancer-news
Visit bluefaery.org for
resources that patients
can use to
 Get the latest information
about their disease
 Connect with other patients
 Participate in clinical trials
And much more
Thank you to
our partners
at Blue Faery!