Richard S. Finn, MD, Robin K. (Katie) Kelley, MD, and Amit Singal, MD, MS, prepared useful practice aids pertaining to the management of hepatocellular carcinoma for this CME/MOC activity titled "Developing a Therapeutic Game Plan for the Management of Hepatocellular Carcinoma: Expert Insights From the Patient CaseBook." For the full presentation, monograph, complete CME/MOC information, and to apply for credit, please visit us at PeerView.com/BXY865. CME/MOC credit will be available until March 5, 2020.

1. Considerations for Selecting and Sequencing Treatments for Advanced HCCa
a
Phase 3 level of evidence for all listed agents. b
Real-world effectiveness data in extended populations, including in patients with Child–Pugh B cirrhosis, are available. c
Combination regimen is not FDA approved for this indication. d
Dose studied in phase 2 trial.
AFP: alpha-fetoprotein; ECOG: Eastern Cooperative Oncology Group; HCC: hepatocellular carcinoma; HFSR: hand-foot skin reaction; mRECIST: modified Response Evaluation Criteria In Solid Tumors; ORR: overall response rate.
1. Llovet JM et al. NEnglJMed. 2008;359:378-390. 2. Kudo M et al. Lancet. 2018;391:1163-1173. 3. Cheng A-L et al. AnnOncol. 2019;30(suppl 9): Abstract LBA3. 4. Bruix J et al. Lancet. 2017;389:56-66. 5. Abou-Alfa GK et al. NEnglJMed. 2018;379:54-63. 6. Zhu AX et al. LancetOncol. 2019;20:282-296.
7. Opdivo (nivolumab) Prescribing Information. https://packageinserts.bms.com/pi/pi_opdivo.pdf. Accessed December 20, 2019. 8. Keytruda (pembrolizumab) Prescribing Information. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. Accessed December 20, 2019.
PRACTICE AID
Access the activity, “Developing a Therapeutic Game Plan for the Management of Hepatocellular Carcinoma:
Expert Insights From the Patient CaseBook,” at PeerView.com/BXY40
Regorafenib
Tolerated sorafenib but
with radiographic progression
Improved OS
Similar to AE profiles
of other TKIs (eg, sorafenib)
Orally once daily for
3 wk with a 1-wk holiday
Cabozantinib
Intolerant to sorafenib or with
radiographic progression; additional
line of systemic therapy allowed
Improved OS
Similar to AE profiles
of other TKIs (eg, sorafenib)
Orally once daily
Ramucirumab
Intolerant to sorafenib or with
radiographic progression; patients
with AFP ≥400 ng/mL
Improved OS
Well tolerated with low
rates of dose reductions
or discontinuations
IV infusion every 2 wk
Nivolumab
Progressed on or intolerant
to sorafenib; Child–Pugh A cirrhosis
ORR (mRECIST) = 18.2%
Grade 3/4 AST, ALT, and
bilirubin levels; immune-
mediated hepatitis
240 mg every 2 wk or
480 mg every 4 wkd
Pembrolizumab
Progressed on or intolerant to
sorafenib; Child–Pugh A cirrhosis
ORR (RECIST) = 17%
Increased ascites and
immune-mediated hepatitis;
elevated AST, ALT, and
bilirubin levels
200 mg every 3 wkd
Child–Pugh A cirrhosis, ECOG 0-1,
unresectable HCC with no
prior systemic therapy
Improved survival compared
with placebob Increased HFSR
Orally twice daily;
should be taken 1-2 h
removed from food
Lenvatinib
Child–Pugh A cirrhosis, ECOG 0-1,
unresectable HCC with no prior systemic
therapy; excluded: patients with >50%
liver involvement, main portal vein tumor
thrombus, and bile duct invasion
Noninferior OS compared with
sorafenib; improved objective
responses and time to
progression compared with
sorafenib
Increased hypertension,
proteinuria, and anorexia
Orally once daily; can be
taken ± food
Atezolizumab +
bevacizumabc
Child–Pugh A cirrhosis, ECOG PS 0-1,
≥1 measurable untreated lesion,
no prior systemic therapy for HCC
Improved OS and PFS
compared with sorafenib
Increased hypertension
Atezolizumab 1,200 mg IV
/ bevacizumab 15 mg/kg IV
on d 1 of each 21-d cycle
Sorafenib
FirstLine1-3SecondLine4-8
EfficacyAgent Patient Population AEs Dosing

2. Access the activity, “Developing a Therapeutic Game Plan for the Management of Hepatocellular
Carcinoma: Expert Insights From the Patient CaseBook,” at PeerView.com/BXY40
Selected Ongoing Clinical Trials in HCC1
PRACTICE AID
Immunotherapeutic Agents
HIMALAYAa
(NCT03298451)
IMbrave150
(NCT03434379)
3
3
Durvalumab ± tremelimumab
vs sorafenib
Atezolizumab + bevacizumab
vs sorafenib
First-LineAdvancedHCC
COSMIC-312
(NCT03755791)
LEAP-002
(NCT03713593)
3
3
Cabozantinib ± atezolizumab
vs sorafenib
Pembrolizumab + lenvatinib vs
placebo + lenvatinib
NCT03412773a Tislelizumab (BGB-A317)
vs sorafenib 3
CheckMate -9DX
(NCT03383458)
KEYNOTE-937
(NCT03867084)
3
3Nivolumab (adjuvant) vs placebo
Pembrolizumab (adjuvant)
vs placebo
Resectedor
LocallyAdvancedHCC
EMERALD-1
(NCT03778957)
EMERALD-2
(NCT03847428)
3
3
Durvalumab ± bevacizumab
+ TACE vs placebo + TACE
Durvalumab ± bevacizumab
vs placebo
IMbrave050
(NCT04102098)
Atezolizumab plus bevacizumab
(adjuvant) vs active surveillance
3
NCT03916627 Cemiplimab 2
CheckMate -9DW
(NCT04039607) 3
Nivolumab + ipilimumab vs
sorafenib or lenvatinib
NCT03638141 2
TACE + durvalumab +
tremelimumab
Intermediate
HCC
IMMUTACE (NCT03572582) 2Nivolumab + TACE
NCT03347292 1Regorafenib + pembrolizumab
Trial Name Trial Arms Phase
NCT03841201 2Nivolumab + lenvatinib

3. Access the activity, “Developing a Therapeutic Game Plan for the Management of Hepatocellular
Carcinoma: Expert Insights From the Patient CaseBook,” at PeerView.com/BXY40
Selected Ongoing Clinical Trials in HCC1
PRACTICE AID
a
Active, not recruiting.
HCC: hepatocellular carcinoma; SBRT: stereotactic body radiation therapy; TACE: transarterial chemoembolization; TTFields: tumor treating fields.
1. https://clinicaltrials.gov. Accessed January 13, 2020.
Other Treatment Modalities and Strategies
ResectedorLocally
AdvancedHCC
NCT02762266 SBRT vs TACE 3
NCT02182687 SBRT vs TACE 2
Trial Name Trial Arms Phase
Intermediateand
AdvancedHCC
NCT01730937 SBRT + sorafenib vs sorafenib 3
HEPANOVA
(NCT03606590)
TTFields + sorafenib 2

4. Clinical Monitoring Recommendations for Advanced HCC Treatments1
Access the activity, “Developing a Therapeutic Game Plan for the Management of Hepatocellular Carcinoma:
Expert Insights From the Patient CaseBook,” at PeerView.com/BXY40
PRACTICE AID
Complete Blood Count (CBC)
Comprehensive Metabolic Panel
• Sorafenib: B/L, every 2 wk for 2 mo,
then mo
• Lenvatinib: B/L, every 2 wk for 2 mo,
then mo
• Regorafenib: B/L, every 2 wk for 2 mo, then mo
• Cabozantinib: B/L, every 2 wk for 2 mo, then mo
• Ramucirumab: Every 2 wk
• Nivolumab: B/L, every 2-4 wk during Tx
• Pembrolizumab: B/L and every 3 wk during Tx
Thyroid-Stimulating Hormone
Sorafenib: B/L, then every 2-3 mo
Lenvatinib: B/L, then mo
Regorafenib: B/L, then every 2-3 mo
Cabozantinib: B/L, then every 2-3 mo
Ramucirumab: —
Nivolumab: B/L, every 4-6 wk on Tx, every 6-12 wk
after Tx
Pembrolizumab: B/L, every 4-6 wk on Tx, every
6-12 wk after Tx
Clinical Evaluation While on Therapy
• Sorafenib: Every 1-2 wk for 6 wk, then mo
• Lenvatinib: Every 1-2 wk for 6 wk, then mo
• Regorafenib: Every 1-2 wk for 6 wk, then mo
• Cabozantinib: Every 1-2 wk for 6 wk, then mo
• Ramucirumab: Every 2-4 wk
• Nivolumab: Every 2-4 wk
• Pembrolizumab: Every 3-6 wk
• Sorafenib: B/L, at 2 wk, then mo
• Lenvatinib: B/L, at 2 wk, then mo
• Regorafenib: B/L, at 2 wk, then mo
• Cabozantinib: B/L, at 2 wk, then mo
• Ramucirumab: Every 2 wk
• Nivolumab: Every 2-4 wk
• Pembrolizumab: Every 3 wk

5. Clinical Monitoring Recommendations for Advanced HCC Treatments1
a
Use caution about applicability of data, because these agents, except for nivolumab, have not formally been tested in patients with Child–Pugh B scores.
B/L: baseline.
1. Grieb BC et al. AmSocClinOncolEducBook. 2019;39:248-260.
Access the activity, “Developing a Therapeutic Game Plan for the Management of Hepatocellular Carcinoma:
Expert Insights From the Patient CaseBook,” at PeerView.com/BXY40
PRACTICE AID
Dose Adjustment in Child–Pugh Ba
Urinalysis Electrocardiogram (ECG)
Blood Pressure
• Sorafenib: Every 1-2 wk for up to 8 wk, then mo
• Lenvatinib: Every 1-2 wk for up to 8 wk,
then mo
• Regorafenib: Every 1-2 wk for 6 wk, then mo
• Cabozantinib: Every 1-2 wk for up to
8 wk, then mo
• Ramucirumab: Every 2 wk
• Nivolumab: —
• Pembrolizumab: —
• Sorafenib: Regularly
• Lenvatinib: Regularly
• Regorafenib: Regularly
• Cabozantinib: Regularly
• Ramucirumab: Regularly
• Nivolumab: —
• Pembrolizumab: —
• Sorafenib: B/L, 2-4 wk after start,
then every 3 mo
• Lenvatinib: B/L, 2-4 wk after start,
then every 3 mo
• Regorafenib: B/L, 2-4 wk after start, then
every 3 mo
• Cabozantinib: B/L, 2-4 wk after start, then
every 3 mo
• Ramucirumab: B/L, 2-4 wk after start, then
every 3 mo
• Nivolumab and pembrolizumab: —
• Sorafenib: None
• Lenvatinib: 8 mg daily
• Regorafenib: No dose adjustment
for bilirubin ≤3 ULN
• Cabozantinib: Dose reduce with caution
• Ramucirumab: Not indicated;
increased hepatic toxicity
• Nivolumab: None
• Pembrolizumab: No data

6. Therapeutic Options in HCC: A Patient Casebook for Physicians
PRACTICE AID
Access the activity, “Developing a Therapeutic Game Plan for the Management of Hepatocellular Carcinoma:
Expert Insights From the Patient CaseBook,” at PeerView.com/BXY40
HCC in Cirrhotic Liver1
Solitary
2-3 nodules
3 cm
tnalpsnarT
candidate
Resection
No Yes No
tnalpsnarT Ablation Chemoembolization Systemic therapyAblation BSC
Optimal surgical
candidate
Yes
Very early stage (0)
Single <2 cm
Preserved liver function
PS 0
Early stage (A)
3-2roelgniS
nodules <3 cm
Preserved liver function
PS 0
Intermediate stage (B)
,raludonitluM
unresectable
Preserved liver function
PS 0
Advanced stage (C)
Portal invasion/
extrahepatic spread
Preserved liver function
PS 1-2
Terminal stage (D)
Not transplantable
egats-dnE
liver function
PS 3-4
HCC Patient Cases

7. Therapeutic Options in HCC: A Patient Casebook for Physicians
PRACTICE AID
Access the activity, “Developing a Therapeutic Game Plan for the Management of Hepatocellular Carcinoma:
Expert Insights From the Patient CaseBook,” at PeerView.com/BXY40
Case 1
Therapy
Considerations
for Early-Stage
HCC
Clinical
Presentation
and Testing
Early-Stage (BCLC A) HCC2-11
• 32-year-old man with chronic HBV, on tenofovir, and with compensated cirrhosis
• Undergoing HCC surveillance and found to have liver mass
• MRI shows 3.5-cm LR-5 lesion in segment VI
• Child–Pugh A: Bili 0.7, Alb 4.0, INR 1.0
• PLT: 217
• ECOG 0
• Patient undergoes robotic liver resection without complication
• Returns to clinic, at which time, you reinforce risk of recurrence and need for
continued surveillance
• Recurrence: 70%-80% at 5 years
• No proven adjuvant therapy to decrease HCC recurrence
• Ongoing phase 3 trials are testing adjuvant immunotherapy monotherapy and
combinations (eg, CheckMate -9DX, KEYNOTE-937, EMERALD-2,
IMbrave050)

8. Therapeutic Options in HCC: A Patient Casebook for Physicians
PRACTICE AID
Access the activity, “Developing a Therapeutic Game Plan for the Management of Hepatocellular Carcinoma:
Expert Insights From the Patient CaseBook,” at PeerView.com/BXY40
Case 2
Therapy
Considerations
for Intermediate-
Stage HCC
Clinical
Presentation
and Testing
Intermediate-Stage (BCLC B) HCC12-13
• AASLD guidance: TACE (level 1 evidence)
• Suboptimal long-term survival, particularly in patients with larger tumor burden;
offers opportunity for combinations with systemic therapies
• Ongoing trials are testing immunotherapy in combination with LRT (eg, phase 3
trial EMERALD-1)
• Consideration of transition to systemic therapy is important if patient fails TACE
multiple times
• 64-year-old man with NASH and compensated cirrhosis
• Found to have incidental liver mass on imaging
• MRI shows 6.5-cm LR-5 lesion with two satellite nodules
• No vascular invasion and no metastatic disease
• Child–Pugh A: Bili 0.9, Alb 3.7, INR 1.0
• ECOG 0

9. Therapeutic Options in HCC: A Patient Casebook for Physicians
PRACTICE AID
Access the activity, “Developing a Therapeutic Game Plan for the Management of Hepatocellular Carcinoma:
Expert Insights From the Patient CaseBook,” at PeerView.com/BXY40
Case 3
Appropriate
First-Line
Options
for Newly
Diagnosed
Advanced HCC
Clinical
Presentation
and Testing
Newly Diagnosed Advanced (BCLC C) HCC14-20
• 59-year-old man with NASH cirrhosis
• Child–Pugh A; AFP 178 ng/mL
• No ascites or encephalopathy
• ECOG-PS 0
• Previously treated with two rounds of TACE
• Follow-up MRI shows multifocal HCC (LR-5) with three lesions, largest 6.5 cm,
with invasion into the right portal vein
• Sorafenib
• Lenvatinib
• Emerging option: atezolizumab/bevacizumab (IMbrave150 results)
• Phase 3 clinical trials
Checkpoint inhibitor + TKI (ie, LEAP-002, COSMIC-312)
PD-1/L1 inhibitor + CTLA-4 inhibitor (ie, CheckMate -9DW,
HIMALAYA)

10. Therapeutic Options in HCC: A Patient Casebook for Physicians
PRACTICE AID
Access the activity, “Developing a Therapeutic Game Plan for the Management of Hepatocellular Carcinoma:
Expert Insights From the Patient CaseBook,” at PeerView.com/BXY40
Case 4
Selecting a
Second-Line
Targeted
Therapy
Option
Clinical
Presentation
and Testing
Previously Treated Advanced (BCLC C) HCC21-23
• Consider AE profile, AFP levels, liver
function, comorbidities, and prior
treatment history
Regorafenib
Did not receive prior sorafenib
Ramucirumab
AFP levels <400 ng/mL
Cabozantinib
Allowed up to two lines of prior therapy
Favorable data in patients with HBV
• 54-year-old Asian woman with chronic HBV on entecavir with undetectable viral load
• Treated with TACE for a 6-cm right lobe liver tumor 6 months ago
• MRI now shows enlarging 8-cm right lobe tumor, HCC (LR-5), with two satellite lesions
and new right branch portal vein tumor thrombus
• Child–Pugh A; ECOG-PS 0; AFP level 142 ng/mL
• Started on lenvatinib 12 mg daily
Required dose reduction to 8 mg/d for fatigue and HTN
Demonstrated initial tumor regression on restaging imaging for 6 months
Developed lung metastases after 6 months; AFP has risen to 233 ng/mL

11. Therapeutic Options in HCC: A Patient Casebook for Physicians
PRACTICE AID
Access the activity, “Developing a Therapeutic Game Plan for the Management of Hepatocellular Carcinoma:
Expert Insights From the Patient CaseBook,” at PeerView.com/BXY40
Case 5
Clinical
Presentation
and Testing
Previously Treated Advanced (BCLC C) HCC
• 69-year-old man with chronic HCV was treated and cured with direct-acting
antiviral therapy 2 years ago
• He then presents to his PMD with right upper quadrant pain
• He was found to have an 8-cm mass and satellite lesions in the right lobe; he
was hypervascular with delayed washout, and he has right portal vein thrombosis
• Hb 12.3; MCV 90; PLT 95; bili 1.8; Alb 3.1; Cr 0.9; AFP 78 ng/mL
• History: HCV, T2DM, HTN
• No ascites; no encephalopathy; PS 1
• Staging: no extrahepatic disease; BCLC C
• Started on sorafenib 400 mg twice daily; dose reduced to 400 mg daily after
3 weeks because of fatigue, weight loss, and anorexia
• Continued for 2 months but developed worsening pain and rising AFP, prompting
restaging imaging
Tumors found on the left lobe, and the right lobe masses are larger
Extension of PVT

12. Therapeutic Options in HCC: A Patient Casebook for Physicians
AFP: alpha-fetoprotein; Alb: albumin; BCLC: Barcelona Clinic Liver Cancer staging system; Bili: bilirubin; Cr: creatinine; ECOG-PS: Eastern Cooperative Oncology Group performance status; Hb: hemoglobin; HTN: hypertension; INR: international normalized ratio;
MCV: mean corpuscular volume; NASH: nonalcoholic steatohepatitis; PLT: platelets; PMD: primary medical doctor; T2DM: type 2 diabetes mellitus; TACE: transarterial chemoembolization; TKI: tyrosine kinase inhibitor
1. Galle PR et al. J Hepatol. 2018;69:182-236. 2. Ikai I et al. Cancer. 2004;101:796-802. 3. Vauthey JN et al. J Clin Oncol. 2002;20:1527-1536. 4. Shi M et al. Ann Surg. 2007;245:36-43. 5. Katz SC et al. Ann Surg. 2009;249:617-623. 6. Tabrizian P et al. Ann Surg. 2015;261:947-855. 7. Bruix J et al.
Lancet Oncol. 2015;16:1344-1354. 8. https://clinicaltrials.gov/ct2/show/NCT03383458. Accessed January 23, 2020. 9. https://clinicaltrials.gov/ct2/show/NCT03867084. Accessed January 23, 2020. 10. https://clinicaltrials.gov/ct2/show/NCT03847428. Accessed January 23, 2020.
11. https://clinicaltrials.gov/ct2/show/NCT04102098. Accessed January 23, 2020. 12. Marrero JA et al. Hepatology. 2018;68:723-750. 13. https://clinicaltrials.gov/ct2/show/NCT03778957. Accessed January 23, 2020. 14. Llovet JM et al. N Engl J Med. 2008;359:378-390. 15. Kudo M et al.
Lancet. 2018;391:1163-1173. 16. Cheng A-L et al. ESMO Asia 2019. Abstract LBA3. 17. https://clinicaltrials.gov/ct2/show/NCT03713593. Accessed January 23, 2020. 18. https://clinicaltrials.gov/ct2/show/NCT03755791. Accessed January 23, 2020. 19. https://clinicaltrials.gov/ct2/show/
NCT04039607. Accessed January 23, 2020. 20. https://clinicaltrials.gov/ct2/show/NCT03298451. Accessed January 23, 2020. 21. Bruix J et al. Lancet. 2017;389:56-66. 22. Abou-Alfa G et al. N Engl J Med. 2018;379:54-63. 23. Zhu AX et al. Lancet Oncol. 2019;20:282-296.
24. El-Khoueiry AB et al. Lancet. 2017;389:2492-2502. 25. Zhu AX et al. Lancet Oncol. 2018;19:940-952.
PRACTICE AID
Access the activity, “Developing a Therapeutic Game Plan for the Management of Hepatocellular Carcinoma:
Expert Insights From the Patient CaseBook,” at PeerView.com/BXY40
Case 5
Consider
Checkpoint
Inhibitor
Immunotherapy
as Second- or
Third-Line
Therapy
Previously Treated Advanced (BCLC C) HCC (Cont’d)24,25
When to consider checkpoint inhibitor therapy as a treatment option:
• Patients who have not received immunotherapy in first line
• If rapid progression and/or intolerance to TKI first-line therapy
• If increasing degrees of hepatic dysfunction
Prospective cohort and retrospective case series show acceptable
safety and efficacy of nivolumab in patients with Child–Pugh B HCC
• If contraindications to antiangiogenic therapy (eg, nonhealing wounds,
active venous thromboembolism, bleeding complications)