Systemic treatment in advanced hepatocellular carcinoma (HCC) refers to the use of medications or therapies that are administered throughout the body to target cancer cells beyond the liver. HCC is the most common type of liver cancer and often presents at an advanced stage, making systemic therapies crucial in managing the disease. One of the main categories of systemic treatment for advanced HCC is targeted therapies. Targeted therapies are designed to selectively inhibit specific molecules or pathways involved in tumor growth, thereby blocking the signals that support cancer cell survival and proliferation. Sorafenib and lenvatinib are examples of targeted therapies that have been approved for the first-line treatment of advanced HCC. They target vascular endothelial growth factor (VEGF) receptors, which play a key role in promoting the growth of new blood vessels necessary for tumor growth. By inhibiting these receptors, these drugs can help slow down tumor growth and improve patient outcomes. In addition to sorafenib and lenvatinib, other targeted therapies have shown promising results in the treatment of advanced HCC. Regorafenib, for instance, is a multi-kinase inhibitor that targets several pathways involved in tumor angiogenesis, cell proliferation, and survival. Cabozantinib is another multi-kinase inhibitor that has been approved as a second-line treatment option for patients who have progressed on or are intolerant to prior systemic therapy. These targeted therapies have demonstrated efficacy in improving overall survival and delaying disease progression in patients with advanced HCC. Another significant advancement in systemic treatment for advanced HCC is the use of immune checkpoint inhibitors. Immunotherapy has revolutionized cancer treatment in recent years, including for HCC. Immune checkpoint inhibitors, such as nivolumab and pembrolizumab, work by blocking proteins that act as checkpoints on immune cells, such as programmed cell death protein 1 (PD-1) or its ligand (PD-L1). By doing so, these drugs help restore and enhance the immune system's ability to recognize and eliminate cancer cells. Checkpoint inhibitors have shown promising results, with some patients experiencing durable responses and improved overall survival.

2. HCC is the most common type of primary liver cancer.
Its incidence has been steadily rising worldwide.
Approximately 70% to 85% of HCC cases are diagnosed at an advanced stage, limiting curative options.
The majority (over 70%) of advanced HCC patients exhibit impaired liver function (Child-Pugh B or C),
complicating treatment.
Prognosis for advanced HCC remains challenging.
3-year overall survival (OS) for advanced HCC is typically below 20%.
The median survival after diagnosis is generally less than 1 year.
Even with systemic therapies, recurrence rates remain significant, often exceeding 70%, necessitating ongoing
research and innovation.

3. Palliative systemic therapy for advanced HCC was limited due to
several factors.
•HCC was considered chemotherapy-refractory due to high
drug resistance gene expression.
•Chemotherapy was poorly tolerated by patients with hepatic
dysfunction.
•Its effectiveness was reduced in patients with significant
cirrhosis, especially those with poor performance status,
ascites, portal vein tumor thrombus, or elevated serum
bilirubin.
With the advent of newer immunotherapy and molecularly
targeted therapy, cytotoxic chemotherapy's role diminished,
leading to its removal from guidelines by NCCN and ESMO.
Nevertheless, chemotherapy is still offered in select cases for
third- or fourth-line therapy when other approved therapies are
not optimal.

4. •Response: Low
response rates
(10% or less).
•Median OS:
Approximately
6-12 months.
2000-2007:
Systemic
Chemotherapy
Era
•Response:
Modest
response rates
(10- 20%).
•Median OS:
Approximately
10.7 months.
2007: Sorafenib
Era
•Response:
Higher
response rates
(approximately
24%).
•Median OS:
Approximately
13.6 months.
2018: Lenvatinib
Approval
•Response:
High response
rates
(approximatel
y 27%).
•Median OS:
Approximately
19.2 months.
2020:
Atezolizumab and
Bevacizumab
Approval
•Response:
Varies with
emerging
treatments
and
combinations.
•Median OS:
Continues to
improve
Ongoing: Advances
in HCC
Management

5.  Disease Stage
- Advanced stage with any of the following:
- Multifocal liver tumors
- Vascular invasion (portal vein thrombosis)
- Extrahepatic spread
 Liver Function
- Child-Pugh class A or B
 Performance Status
- Acceptable performance status
 Comorbidities
- Evaluation of underlying health conditions
 Tumor Characteristics
- Extensive or unresectable tumors
- Tumors located near critical blood vessels or structures
- Portal vein invasion (classified into types I-IV)
 Patient Preferences
- Consideration of treatment goals and quality of life

6. Survival in HCC often depends on liver function more than tumor aggressiveness.
Child-Pugh classification is a commonly used method for assessing liver function, despite not being developed
specifically for HCC.
Various prognostic scoring systems, including ALBI, provide objective liver function assessment and disease stage
classification.
Advanced HCC patients are heterogeneous; some scoring systems may help predict outcomes.
The ALBI score offers a simple, objective, and discriminatory method for liver function assessment.
Prognostic scoring systems aid in selecting treatment candidates but don't predict therapy benefits.
BCLC guidelines recommend assessing liver function beyond conventional Child-Pugh criteria.

7. Copyrights apply
Clinical algorithm for universal screening for hepatitis B virus (HBV) and
management in patients initiating systemic anticancer therapy
Conduct HBsAg, anti- HBc (total Ig or IgG), and
anti –HBs testing before anticancer therapy
Evidence of HBV infection No evidence of HBV infection
Chronic HBV
HBsAg+
Past HBV
HBssAg _ Anti-HBc+
Systemic anticancer therapy
(cytotoxic, immunotherapy, or
targeted therapy)
Hormonal anticancer
therapy alone
Anti-CD20 therapy or
stem cell transplantation
All other systemic anticancer
therapy ( cytotoxic,
immunotherapy, or targeted
therapy)
Check HBV DNA
and ALT at
baseline and
every 6 month
during antiviral
therapy
For chronic HBV:
Consult HBV
specialist, if
available, for
consideration of
long-term
antiviral therapy
For past
HBV :
No further
monitoring
is
necessary.
Check HBV DNA and ALT at
baseline and every 6 MONTH
during antiviral therapy
After anticancer therapy,
monitor ALT for hepatitis flare
after stopping anticancer
therapy
Check HBsAg and ALT every
3 months during anticancer
therapy.
If HBsAg+, then start
antiviral therapy
immediately.
If hepatitis flare , check
HBVDNA. If HBV DNA >1000
IU/ml , start antiviral
therapy immediately>
Consult HBV specialist for co-management, if
available
Start antiviral prophylaxis,
continue at least 12 months
after last anticancer therapy
No antiviral prophylaxis unless
antiviral treatment is needed
independent of anticancer therapy
Start antiviral prophylaxis ,
continue atleast 12 months after
last anticancer therapy
monitoring

8. Screenin
g for
Viral
Hepatiti
s:
Hepatitis B Screening
• Hepatitis B Surface Antigen (HBsAg): Detects
current HBV infection.
• Hepatitis B Core Antibody (anti-HBc): Assesses
prior HBV exposure.
• Hepatitis B Surface Antibody (anti-HBs):
Checks immunity to HBV.
Hepatitis C Screening
• Hepatitis C Antibody (anti-HCV): Detects current or past
HCV infection.
• HCV RNA PCR: Confirms active HCV infection.
Before initiating systemic anticancer therapy, hepatitis B and C screening is
crucial for patient safety and optimizing treatment outcomes.

9. Universal HBV screening for all patients before systemic therapy, including
chemotherapy, immunotherapy, and targeted therapy.
Categorize patients based on HBV status:
• Current HBV infection.
• Prior HBV exposure.
• Immunity to HBV.
Antiviral Prophylaxis
• Consider antiviral prophylaxis for patients at risk of HBV reactivation.
• Preventive antiviral therapy suppresses HBV replication during cancer treatment
Starting Antiviral Treatment:
• Timing and need for antiviral therapy depend on patient-specific factors.
• For hepatitis B, high viral load (often >2,000 IU/mL) is a risk factor for reactivation.
• Antiviral therapy may start before or concurrently with systemic HCC treatment.

10. Predictive Marker Description
Alpha-
Fetoprotein (AFP)
High baseline levels may indicate poorer response. Decrease during treatment
may suggest positive response.
Viral Hepatitis
Status
Presence of viral hepatitis (HBV, HCV) can influence response.
Antiviral therapy may be required for optimal effectiveness.
Liver Function
(Child-Pugh)
Better-preserved liver function (Child-Pugh Class A) correlates with more
favorable response.
Tumor
Biomarkers
Molecular markers and gene mutations may influence targeted therapy
response.
Tumor Response
Assessment
Imaging (MRI, CT) helps predict response.
Tumor shrinkage or stabilization suggests positive response.
Immune Markers PD-L1 expression and immune markers can predict immunotherapy response.
Circulating Tumor
DNA (ctDNA)
Real-time monitoring of genetic changes helps predict response and
resistance mutations.
Underlying Liver
Disease
Patients with viral liver disease may have different responses compared to
those with nonviral liver disease.
NASH may lead to impaired immune surveillance and poorer response to
immunotherapy.
Clinical Factors
General health, performance status, and comorbidities impact treatment

11. Copyrights apply

12. Definition: Pseudoprogression is an unusual response pattern in immunotherapy where
lesions appear larger or new ones emerge on imaging, not due to tumor growth but
immune-mediated changes.
Mechanisms:
• Immune Activation: Immunotherapies boost the immune system, leading to
heightened immune activity in the tumor.
• Lymphocyte Infiltration: Immune cells infiltrate the tumor, causing inflammation and
imaging changes.
• Delayed Response: Immune responses take time to control and eliminate cancer
cells.
Diagnosis:
• Clinical Evaluation: Monitor patient health and performance status.
• Radiographic Assessment: Pseudoprogression may cause temporary lesion changes
before stabilization.
• Time Course: Typically occurs early in treatment.
• Immune-Related Response Criteria: Specialized criteria help differentiate
pseudoprogression from progression.
Importance: Accurate diagnosis ensures appropriate clinical management and treatment
continuation as needed. Specialized criteria aid in recognizing pseudoprogression.

13. Preferred
Option Other Option
Participation
in Clinical
Trial
- Atezolizumab
plus bevacizumab
- Tremelimumab
plus durvalumab
- Monotherapy with
sorafenib or
lenvatinib
- Donafenib or
durvalumab (where
available
•Preferred Option: Participation in Clinical Trial
• Encouraged for exploring new therapeutic
strategies.
•Alternative:
Atezolizumab plus Bevacizumab
• Healthy patients (ECOG PS 0 or 1), Child-Pugh
Class A cirrhosis, no post-transplant recurrence, not
on anticoagulation or with managed esophageal
varices.
Tremelimumab plus Durvalumab
• Considered when bevacizumab is not an option,
taking similar patient criteria into account.
Monotherapy with Sorafenib or Lenvatinib
• For less fit patients, including those with post-
transplant recurrence or contraindications to other
options.
• Considered FDA-approved for first-line therapy.
Donafenib or Durvalumab (where available)
• Alternative options to sorafenib or lenvatinib if

14. Ideal candidates for atezolizumab plus bevacizumab therapy in hepatocellular carcinoma (HCC) typically
exhibit the following characteristics:
•No worse than Child-Pugh Class A cirrhosis.
•Excellent performance status.
•No contraindications to bevacizumab.
•No ongoing therapeutic anticoagulation.
•Management of esophageal varices, if applicable.
•No history of post-liver transplantation recurrence.
Use with precaution in patients with some additional considerations:
•Viral Hepatitis: Careful evaluation in patients with hepatitis B or C to assess liver function and
comorbidities.
•Advanced Liver Disease: Caution when patients have more advanced liver disease, as the use of
sorafenib in those with Child-Pugh Class B disease is limited.
•Patient Preferences: Consider factors like medical history, treatment-related toxicity, treatment goals,
and patient preferences when choosing between lenvatinib and sorafenib.
Contraindications in HCC patients may include:
•Post-Transplant Recurrence:due to the high rate of allograft rejection.
•Recent Myocardial Infarction or Stroke: within the previous three months may not be suitable.
•Therapeutic Anticoagulation: increase the risk of bleeding, may not be candidates for these therapies.

15. Parameter
Atezolizumab +
Bevacizumab Sorafenib
Median Overall Survival (OS) 19.2 months 13.4 months
Overall Response Rate (ORR) 30% 11%
Treatment-Related Grade 3
or 4 AEs (%)
43% 46%
Hypertension (%) Higher Lower
Transaminase Elevation (%) Higher Comparable
Proteinuria (%) Higher Comparable
Diarrhea (%) Higher
Median Time to Deterioration
of Quality of Life
Not estimable 4.2 months
Median Time to Deterioration
of Physical Functioning
13.1 months 5.6 months
Median Time to Deterioration
of Role Functioning
9.1 months 4.3 months
IMBrave 150 trial,
501 previously untreated patients with
advanced unresectable HCC and no
worse than Child-Pugh class A
cirrhosis 2:1 to
Arm 1:-Atezolizumab (1200 mg
intravenous [IV] every 3 wks) plus
Bevacizumab (15 mg/kg IV every 3
wks, after atezolizumab)
Arm 2:- Sorafenib (400 mg twice daily)

16. Outcome STRIDE (Tremelimumab + Durvalumab) Durvalumab Sorafenib
Median Overall Survival (months) 16.43 months 16.56 months 13.77 months
Survival Rates at 18 months (%) 48.7% 47.4% 41.5%
Survival Rates at 24 months (%) 40.5% 39.6% 32.6%
Survival Rates at 36 months (%) 30.7% 24.7% 20.2%
Objective Response Rate (%) 20.1% 17.0% 5.1%
Median Progression-Free Survival 5.4 months 3.8 months 5.6 months
Adverse Events (Grade 3 or 4) (%) 50.5% 37.1% 52.4%
Adverse Events Leading to
Discontinuation (%)
13.7% 8.2% 16.8%
Adverse Events with Outcome of
Death (%)
7.7% 6.7% 7.2%
Immune-Mediated Events Leading to
High-Dose Glucocorticoids (%)
20.1% 9.5% 1.9%
Most Common Immune-Mediated
Events
Hepatic events, diarrhea/colitis,
dermatitis/rash
HIMALAYA Trial: The phase III HIMALAYA trial involved 1171 patients with no worse than Child-Pugh
class A cirrhosis who were ineligible for locoregional therapy. Patients were randomly assigned to one of
three arms:
•Tremelimumab (300 mg) plus durvalumab (1500 mg) followed by durvalumab alone (1500 mg every four
weeks).
•Durvalumab alone (1500 mg every four weeks).
•Sorafenib (400 mg twice daily).

17. •Lenvatinib is indicated for the treatment of unresectable hepatocellular carcinoma
(HCC), which is the most common type of liver cancer.
•It is approved for use as a first-line therapy for patients with unresectable HCC who
have not received prior systemic therapy.
•Lenvatinib received approval for the treatment of unresectable HCC in Japan in
March 2018.
•DOSE
 For patients with a body weight of 60 kg or more, the recommended daily dose is 12 mg.
 For patients with a body weight less than 60 kg, the recommended daily dose is 8 mg.
 It is usually taken orally as a once-daily dose.
Mechanism of Action:
• Lenvatinib is a multi-kinase inhibitor that targets several important signaling pathways.
• It inhibits vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, fibroblast
growth factor receptors (FGFR) 1 to 4, platelet-derived growth factor receptor (PDGFR)
alpha, RET, and KIT.
• These pathways play a crucial role in tumor growth and angiogenesis (formation of new
blood vessels to feed the tumor).

18. REFLECT Trial – Key Outcomes and Toxicities
954 patients with unresectable HCC
compared lenvatinib (12 mg once daily for body weight ≥60 kg, 8 mg daily for <60 kg) vs sorafenib
(400 mg twice daily for all patients)
Parameter Lenvatinib Sorafenib
Overall Survival (OS) Median: 13.6 months Median: 12.3 months
Hazard Ratio (HR): 0.92(95% CI: 0.79-1.06)
Objective Response Rate 24% 9%
Time to Tumor Progression
(TTP)
Median: 7.4 months Median: 3.7 months
Hazard Ratio (HR): 0.66 (95% CI: 0.57-0.77)
Toxicities
Hypertension (Grade 3 or 4) 23% 14%
Hand-Foot Skin Reaction 37% (Any grade) 52% (Any grade)
3% (Grade 3 or worse) 11% (Grade 3 or worse)
Alopecia (Any grade) 25% 3%

19. Parameter
Lenvatinib +
Pembrolizum
ab
Lenvatinib
Alone
Objective
Response
Rate (ORR)
Improved
compared to
Lenvatinib
alone
-
Progression-
Free Survival
(PFS)
Similar rates
(21.2
months)
19 months
Overall
Survival (OS)
Similar rates
(21.2
months)
19 months
Conclusion
Improved
ORR, but not
a standard
1.Randomized phase III LEAP-002 study
LAUNCH Trial Findings
Patient
Population
338 patients
87%
The enrolled patient population had
relatively locally advanced disease (70 %
PVTT, 80 % multifocal, 68 % large tumors)
or extrahepatic disease spread (55 %)
HBV-Related
HCC
Treatment
Lenvatinib (8 or 12
mg daily)
Lenvatinib + "on-
demand" TACE
Median OS 11.5 months 17.8 months
Median PFS 6.4 months 10.6 months
Objective
Response Rate
25% 54%
Grade 3/4
Adverse Events
ALT Elevation: 1.2% ALT Elevation: 17.6%
AST Elevation: 1.8% AST Elevation: 22.9%
Hyperbilirubinemia:
3.0%
Hyperbilirubinemia:
9.4%
Median Duration
of Treatment
5.1 months 8.2 months

20. •Sorafenib received FDA approval for the treatment of unresectable HCC in the United
States in December 2007.
•It has been used as a standard of care and a first-line therapy for HCC.
•Dosing:
• The recommended dose of sorafenib for HCC is typically 400 mg taken orally twice
daily.
• Sorafenib should be taken without food (at least one hour before or two hours after a
meal).
•Mechanism of Action:
• Sorafenib is a multi-kinase inhibitor that targets multiple signalling pathways involved in
tumor growth, angiogenesis (formation of new blood vessels to feed the tumor), and
cancer progression.
• It inhibits several key kinases, including VEGFR (vascular endothelial growth factor
receptor), PDGFR (platelet-derived growth factor receptor), and Raf kinases.

21. SHARP (Sorafenib Hepatocellular Carcinoma Assessment Randomized
Protocol) trial:
Parameter Sorafenib (N=299) Placebo (N=303)
Overall Survival (OS) Median: 10.7 months Median: 7.9 months
Progression-Free Survival (PFS) Median: 5.5 months Median: 2.8 months
Objective Response Rate (ORR) Sorafenib: 2% partial response Placebo: 1% partial response
Disease-Control Rate (DCR) Sorafenib: 43% Placebo: 32%
Treatment-Related Adverse
Events
80% 52%
Grade 3 Drug-Related Adverse
Events
Diarrhea (8%), Hand–foot skin
reaction (8%), Hypertension (2%),
Abdominal pain (2%)
Diarrhea (2%), Hand–foot skin
reaction (<1%)
Serious Adverse Events 52% 54%
Discontinuation of Study Drug
due to Adverse Events
38% 37%
Dose Reductions due to Adverse
Events
26% 7%
Dose Interruptions due to
Adverse Events
44% 30%
Permanent Treatment
Discontinuation due to Adverse
Events
11% 5%

22. Sorafenib's treatment benefits in HCC appear more significant in patients with HCV as the
underlying risk factor.
Analyses of the SHARP trial and an individual patient data meta-analysis support this
observation.
In SHARP, the difference in median OS was most pronounced in HCV-related cirrhosis
patients, while the meta-analysis showed improved survival mainly in those HBV negative
and HCV positive.
Patient Subgroup
Median OS (Sorafenib vs.
Placebo) Survival Benefit
SHARP Trial (Exploratory
Analysis)
HCV-Related Cirrhosis 14 vs. 7.4 months Highest Benefit (6.6 months)
HBV-Related Cirrhosis 9.7 vs. 6.1 months Moderate Benefit(3.6 months)
Alcohol-Related Liver Disease 10.3 vs. 8 months Lower Benefit(2.3 months)
Individual Patient Data Meta-
Analysis
HBV Negative and HCV
Positive
12.6 months (Sorafenib) vs.
10.2 months (Other
Treatments)
Significant Benefit

23. 1.Sorafenib After TACE:
 Limited data support the safety and efficacy of sorafenib after transarterial
chemoembolization (TACE), a procedure that aims to cut off the blood supply to tumors
in the liver.
 While TACE could theoretically limit the delivery of sorafenib to the liver due to the
blood vessel occlusion, some data indicate that sorafenib can still be effective in this
setting.
2.Sorafenib After Liver Transplantation (OLT):
 Sorafenib might be considered as a treatment option in patients with HCC recurrence
following liver transplantation (OLT) who are not suitable for surgical resection or
locoregional treatment.
 In some cases, sorafenib is used in combination with immunosuppressive therapies,
particularly mTOR inhibitors. These are switched from calcineurin inhibitors due to their
potential antiproliferative effect against HCC.
 The largest experience in this context comes from a study of 26 patients. The results
showed a disease control rate of 54%, a median time to progression (TTP) of 6.8
months, and a median overall survival (OS) of 19.3 months.

24. Hypertension,
Renal toxicity,
Arterial thromboembolism,
Bleeding,
Cardiotoxicity,
Thyroid dysfunction,
Hand-foot skin reaction,
Rash,
Pruritus,
Alopecia,
Problems with wound healing,
Potentially fatal hepatotoxicity,
Toxic/metabolic encephalopathy, and
Muscle wasting

25. Study & Treatment Key Findings
Study: KEYNOTE-224 trial
Treatment: Pembrolizumab as first-
line therapy in 51 patients with
advanced HCC
Objective Response Rate (ORR) 16% (all partial responses)
Duration of Response
Median of 16 months (range: 3 to 24+
months)
Progression-Free Survival (PFS) Median duration of 4 months
Overall Survival (OS) Median duration of 17 months
Adverse Events
Common treatment-related adverse
events included diarrhea, fatigue,
hypothyroidism, and myalgias
Safety
One patient experienced immune-
mediated myocarditis and hepatitis,
leading to a fatal outcome

26. Study & Treatment Key Findings
Study: CheckMate 459 trial
Treatment: Nivolumab vs. Sorafenib in 743
previously untreated advanced HCC patients
Objective Response Rate (ORR)
Nivolumab: 15% (with more complete responses,
4%) vs. Sorafenib: 7% (with fewer complete
responses, 1%)
Progression-Free Survival (PFS)
Nivolumab: Median of 3.7 months vs. Sorafenib:
Median of 3.8 months
Overall Survival (OS)
Nivolumab: Median of 16.4 months vs. Sorafenib:
Median of 14.7 months (HR 0.85, 95% CI 0.72-
1.02)
Grade 3 or 4 Serious Adverse
Events
Nivolumab: 12% vs. Sorafenib: 11%
Discontinuation Due to Side Effects
No significant difference between nivolumab and
sorafenib patients

27. Treatment Key Findings
Patients Enrolled 543 patients with advanced or metastatic HCC
Treatment Regimen
Camrelizumab (PD-1 inhibitor) plus Rivoceranib
(Apatinib, antiangiogenic agent targeting VEGFR2) vs.
Sorafenib
Location
Patients from China, Hong Kong, Taiwan, South Korea
(83%) and Europe and the United States (17%)
Progression-Free Survival
(PFS)
Improved with Camrelizumab plus Rivoceranib: Median
5.6 months vs. 3.7 months with Sorafenib (HR 0.52, 95%
CI 0.41-0.65)
Overall Survival (OS)
Improved with Camrelizumab plus Rivoceranib: Median
22 months vs. 15 months with Sorafenib (HR 0.62, 95% CI
0.49-0.80)
Objective Response Rates
Higher with Camrelizumab plus Rivoceranib: 25% vs. 6%
with Sorafenib
Grade ≥3 Toxicity Rates Higher for the combination: 81% vs. 52% with Sorafenib

28. Treatment Combination Trial Name Patient Population Key Findings
Sintilimab + Bevacizumab ORIENT-32 China
Improved OS and
PFS compared to
sorafenib; Available
in China but not
approved in the U.S.
Cabozantinib +
Atezolizumab
COSMIC-312
Systemic therapy-
naïve advanced HCC
Failed to improve OS
and increased
treatment-related
toxicity compared to
sorafenib; Not
recommended as
initial therapy for
advanced HCC.

29. Clinical Indications:
•Disease progression or symptomatic
deterioration during or after first-line
therapy.
•Adequate performance status and
liver function to tolerate second-line
treatment.
Imaging Indications:
•Radiologic evidence of tumor
progression on cross-sectional
imaging (e.g., CT or MRI) that
assesses both tumor viability and
size.
Tumor Marker Indications:
•Serial monitoring of alpha-fetoprotein
(AFP), especially if initially elevated,
can complement imaging findings
and help guide the decision to initiate
second-line therapy.

30. 1. Clinical Trial
2. First-Line
Treatment Second-Line Options
Atezolizumab and
Bevacizumab
1. Sorafenib<br>3. Lenvatinib<br>4. Regorafenib<br>5.
Cabozantinib<br>6. Ramucirumab<br>7. Systemic
chemotherapy (e.g., doxorubicin, gemcitabine, 5-FU)
Sorafenib
1. Immunotherapy (e.g., nivolumab, pembrolizumab)<br>2.
Lenvatinib<br>3. Regorafenib<br>4. Cabozantinib<br>5.
Ramucirumab<br>6. Systemic chemotherapy (e.g.,
doxorubicin, gemcitabine, 5-FU)
Lenvatinib
1. Immunotherapy (e.g., nivolumab, pembrolizumab)<br>2.
Sorafenib<br>3. Regorafenib<br>4. Cabozantinib<br>5.
Ramucirumab<br>6. Systemic chemotherapy (e.g.,
doxorubicin, gemcitabine, 5-FU)

31. CheckMate 040 Trial Outcomes
Nivolumab +
Ipilimumab (Group 1)
Nivolumab +
Ipilimumab (Group 2)
Nivolumab +
Ipilimumab (Group 3)
Combined (All
Groups)
Objective Response Rate (%) 32 -- -- 31
Complete Response (%) 4 -- -- 7
Median OS (months) 22.2 12.5 12.7 --
Median Duration of Response
(months)
22.2 17.5 16.6 --
Disease Control Rate (%) 54 43 49 --
Immune-Mediated A/E (%) 20 -- -- 20
Median Time to Onset of
Immune-Mediated AEs (months)
1.3 -- -- 1.3
High-Dose Glucocorticoids (%) 70 -- -- 70
Common Immune-Mediated AEs
Rash (35%), Adrenal
Insufficiency (18%),
Hypothyroidism/Thyroi
ditis (22%), Colitis (10%),
Pneumonitis (10%),
Infusion-Related
Reactions (8%)
-- -- --
Virologic Breakthrough (HBV) (%) 9 -- -- 9
Virologic Breakthrough (HCV)
10 -- -- 10
The CheckMate 040 trial investigated the efficacy of combined therapy with nivolumab and
ipilimumab in patients with HCC. In this study, 148 sorafenib-treated patients were randomly
assigned to one of three groups receiving different doses and schedules of nivolumab and
ipilimumab. All patients had no worse than Child-Pugh class A cirrhosis.

32. Trial KEYNOTE-240 KEYNOTE-394
Patients 413 patients 413 patients
Median Follow-up Approximately 14 months Median 34 months
Cirrhosis Status Child-Pugh Class A Child-Pugh Class A
Progression/Intolerance Sorafenib
Sorafenib or Oxaliplatin-
based Chemo
Efficacy Measures
Median OS 14 months 15 months
Median PFS 3 months 2.6 months
Objective Response Rate 18% 13%
Complete Responders 6% 2%
Median Duration of
Response
14 months --
Range of Response
Duration
2 to 24+ months --
Grade ≥3 Toxicity Rate -- 14%
table summarizing the key outcomes of the KEYNOTE-240 and KEYNOTE-394 trials,
comparing the efficacy of pembrolizumab to placebo in advanced HCC:

33. Avelumab is an anti-PD-L1 monoclonal antibody approved for various
cancers, including urothelial, renal cell, and Merkel cell carcinoma.
Trial Results (Phase II Trial in Advanced HCC):
•In a study involving 30 patients with advanced hepatocellular carcinoma
(HCC) and no worse than Child-Pugh class A cirrhosis.
•These patients had previously been treated with sorafenib.
•Trial outcomes showed:
• Three partial responses (10 %).
• Nineteen patients (63 %) achieved prolonged stable disease.
• Tumoral overexpression of PD-L1 did not impact treatment response.
•Median time to tumor progression: 4.4 months.
•Median OS: 14.2 months.
•Avelumab treatment was well tolerated with few grade 3 adverse events.
•These results suggest the potential effectiveness of avelumab in advanced
HCC, especially in patients previously treated with sorafenib.

34. Regorafenib is an orally active inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine
kinases.
It is considered an alternative treatment for patients with HCC who have progressed on sorafenib or
immunotherapy and maintain a good PS and adequate liver function.
Regorafenib has been shown to prolong OS in these patients, and it targets kinases involved in
angiogenesis and tumor growth.
Summary of Trial Findings (RESORCE Trial) - Regorafenib in Patients Progressing After
Sorafenib:
Parameter Regorafenib Placebo
Median OS 10.6 months 7.8 months
Objective
Antitumor
Response Rate
11% 4%
Disease Control
Rate (Objective
Response +
Stable Disease)
65% 36%
Grade 3 or 4
Adverse Events
(more often with
Regorafenib)
Hypertension (15%),
Hand-Foot Skin
Reaction (13%),
Fatigue (9%),Diarrhea
(3%)
Hypertension (5%),
Hand-Foot Skin
Reaction (1%),
Fatigue (5%),
Diarrhea (0%)
The RESORCE trial demonstrated that
regorafenib significantly prolonged
median OS, increased objective
antitumor responses, and improved
disease control compared to placebo in
patients with HCC who had radiologic
progression on sorafenib and
maintained good performance status
and liver function.

35. Cabozantinib is a potent inhibitor of several receptor tyrosine kinases, including hepatocyte
growth factor/c-MET, VEGFR-1, VEGFR-2, and VEGFR-3.
It is considered an alternative treatment for patients with HCC who have progressed on
sorafenib and maintain a good performance status and liver function.
Cabozantinib has been shown to prolong OS in these patients, making it a viable option for
second-line treatment after sorafenib or following progression on immunotherapy.
Summary of Trial Findings (CELESTIAL Trial) - Cabozantinib in Previously Treated
Advanced HCC:
Parameter Cabozantinib Placebo
Median OS 10.2 months 8.0 months
Median OS in Patients
with Prior Sorafenib
Only
11.3 months 7.2 months
Grade 3 or 4 Adverse
Events (with
Cabozantinib vs.
Placebo)
Palmar-Plantar
Erythrodysesthesia (17%
vs. 0%), Hypertension
(16% vs. 2%), Increased
Aspartate
Aminotransferase (12%
vs. 7%), Fatigue (10% vs.
4%), Diarrhea (10% vs. 2%)
The CELESTIAL trial demonstrated that
cabozantinib significantly improved
median OS in patients with advanced
HCC who had progressed on sorafenib.
This benefit was more pronounced in
patients who had received sorafenib as
their only prior therapy

36. Ramucirumab: Second Line In HCC
Ramucirumab, a recombinant monoclonal antibody that binds to VEGFR-2, has been evaluated
in several clinical trials for HCC.
While it did not show a significant survival advantage in the overall population in the REACH
trial, an unplanned subset analysis suggested potential survival benefits in patients with a high
initial level of AFP (>400 ng/mL).
Trial Patient Characteristics Treatment Comparison Key Findings
Phase II Trial
Patients with no prior
systemic treatment
Ramucirumab vs. placebo
Objective Response Rate:
10%<br>Median OS: 12
mths
REACH Trial (Phase III)
Advanced HCC after first-
line sorafenib therapy
Ramucirumab vs. placebo
No Significant Survival
Advantage Overall (Median
OS: 9.2 vs. 7.6
months)<br>Potential
Survival Benefit in High AFP
Group (>400 ng/mL):
Median Survival 7.8 vs. 4.2
months
REACH-2 Trial (Phase III)
HCC patients with disease
progression on first-line
sorafenib and high AFP
(≥400 ng/mL)
Ramucirumab vs. placebo
Significant Improvement in
OS with Ramucirumab (8.5
vs. 7.3 months)<br>Higher
Objective Response Rate
and Disease Control Rate
Second-line treatment of

37. •Description: Apatinib is an orally active inhibitor of VEGFR-2 and is
approved for the second-line treatment of advanced gastric cancer in China.
•Trial Summary: In a phase III randomized placebo-controlled trial, 393
patients with advanced HCC, who had failed prior treatment with sorafenib
and oxaliplatin-based chemotherapy and had no worse than Child-Pugh
class A or B (≤7) cirrhosis, were included. The trial aimed to assess the
efficacy of apatinib as a second-line treatment option.
•Key Findings:
• Apatinib improved OS with a median of 8.7 months compared to 6.8 months in
the placebo group.
• It also showed benefits in terms of Progression-Free Survival (PFS).
• The treatment was well-tolerated.

38. Sorafenib —
Nivolumab
GEMOX
Oral capecitabine
PLD in combination with gemcitabine
FOLFOX
Cisplatin plus doxorubicin
Cisplatin, mitoxantrone, and continuous-infusion fluorouracil
Cisplatin, epirubicin, and infusional fluorouracil
Cisplatin, doxorubicin, and capecitabine
Cisplatin plus capecitabine

39. Sorafenib is a targeted therapy used in the treatment of HCC, even in less fit patients with
Child-Pugh class B cirrhosis.
Here are some dosing considerations for sorafenib in these patients:
•Child-Pugh Class B Impairment: Although the manufacturer does not recommend dose
adjustment for Child-Pugh class B impairment, it is advisable to start with reduced-dose
therapy (200 mg twice daily, at least initially) in patients with a total bilirubin 1.5 to 3 times
the upper limit of normal (ULN). The drug should not be administered to patients with
more severe hyperbilirubinemia.
•Standard Dosing with Modification: For other patients with Child-Pugh class B
cirrhosis, standard dosing from the onset is appropriate. However, to enhance early
tolerability, many clinicians initiate all patients (regardless of baseline hepatic function) at
200 mg twice a day and then increase the daily dose in 200 mg increments
approximately every five days, if tolerability is maintained, until the target dose is
reached. This approach has been shown to result in lower rates of adverse events and
drug discontinuation while preserving efficacy.
•Patient Selection: According to consensus-based guidelines from the National
Comprehensive Cancer Network, patients with Child-Pugh class B disease and a total
score greater than 7 may not be ideal candidates for sorafenib. Individualized
assessment and close monitoring are crucial to determine the most suitable treatment
approach for each patient.

40. GEMOX is an active chemotherapy regimen that demonstrates notable efficacy without causing
substantial renal and hepatic toxicity in patients with advanced HCC. Here are the key findings from a
phase II study using GEMOX in this context:
•Study Population: The study involved 32 cirrhotic patients with previously untreated advanced HCC.
Among them, 10 patients had lung metastases, 18 had multifocal liver disease, and the remaining
patients had node-positive disease.
•Treatment Regimen: The GEMOX regimen consisted of gemcitabine (1000 mg/m2) administered
through a fixed dose rate infusion on day 1, followed by oxaliplatin (100 mg/m2) on day 2. This
treatment cycle was repeated every two weeks.
•Toxicities: Grade 3 or 4 toxicities associated with GEMOX included thrombocytopenia (27 percent),
neutropenia (24 percent, with two cases of febrile neutropenia), anaemia (9 percent), and neuropathy
(9 percent). Despite these toxicities, the treatment was generally manageable.
•Clinical Outcomes: The objective response rate to GEMOX was 18 percent, indicating that a portion
of patients experienced tumor shrinkage in response to treatment. An additional 58 percent of
patients had disease stabilization, meaning their tumors did not progress. The median survival for
patients treated with GEMOX was 11.5 months, demonstrating the potential for extended survival
with this regimen.
•Patient Subgroups: Notably, the study observed that GEMOX treatment appeared to be more
effective in patients with non-alcoholic cirrhosis compared to those with alcoholic cirrhosis. The
reasons for this difference in treatment response remain unclear.
GEMOX offers a promising chemotherapy option for patients with advanced HCC and can be
particularly useful in cases where other treatment modalities may not be suitable or effective. It is
essential to consider the potential toxicities and tailor the treatment approach to individual patient
needs and circumstances.

41. FOLFOX, a chemotherapy regimen commonly used in the treatment of
advanced colorectal cancer, was evaluated in an Asian trial involving patients
with advanced or metastatic hepatocellular carcinoma (HCC).
Aspect FOLFOX Doxorubicin
Study Population 371 patients
Underlying Etiology 90% HBV infection
Progression-Free Survival
(PFS)
2.93 months 1.77 months
Overall Survival 6.4 months 4.97 months
Objective Response Rate 8% 3%
Disease Control Rate 52% 32%
Sensory Neuropathy Rate 15% (mostly mild) 0.6% (presumably lower)
Grade 3/4 Toxicities
Comparable between
groups
Comparable between
groups

42. cisplatin-based combination regimens show higher objective response rates
(ORRs), but no clear survival benefit. Various regimens have similar
response rates, such as:
•Cisplatin plus doxorubicin: Response rate 18% and 49% in different studies.
•Cisplatin, mitoxantrone, and continuous-infusion fluorouracil: Objective
response rate 24% and 27%.
•Cisplatin, epirubicin, and infusional fluorouracil: Response rate 15%.
•Cisplatin, doxorubicin, and capecitabine: Response rate 24%.
•Sequential low-dose infusional cisplatin plus infusional fluorouracil:
Response rate 43%.
•Cisplatin plus capecitabine: Response rate 6% and 20% in two studies.

43. 1.
Capecitabine
Monotherap
y
•Reasonable option for less
fit or jaundiced individuals.
•Capecitabine monotherapy
(1000 mg/m2 twice daily for
14 of every 21 days)
associated with a 25%
objective response rate in
one study.
•Better activity seen with a
metronomic capecitabine
schedule in previously
untreated patients.
2.
Fluorouracil
Monotherap
y
•Low response rates as
monotherapy.
•Combination with leucovorin
can increase response rates
(up to 28%).
•Oral fluoropyrimidine
capecitabine is an option.
3. Sorafenib
vs.
Capecitabin
e
•Sorafenib shown to be
superior in a randomized
phase II trial for initial
therapy.
•Inferior median OS (5 vs.
7 months) and median
PFS (4 vs. 6 months) with
capecitabine.
4.
Doxorubicin
, Epirubicin,
Mitoxantron
e
•Single-agent doxorubicin
has modest response rates
(20% or less).
•Slight survival advantage
reported compared to best
supportive care or
nolatrexed.
•Epirubicin and mitoxantrone
have similar efficacy (10-
25% response rate).
•Pegylated liposomal

44. Liver Function Treatment Approach
Child-Pugh Class C
Cirrhosis
Supportive care alone
Poor Functional Status Supportive care alone
Extensive Comorbidity Supportive care alone
•Patients with Child-Pugh class C cirrhosis typically have insufficient liver function to tolerate
systemic therapy.
•Systemic therapy is unlikely to benefit these patients due to their limited survival.
•Example: Median survival times with first-line sorafenib were 8.3 months (Child-Pugh class A),
4.3 months (Child-Pugh class B), and 1.5 months (Child-Pugh class C).

45. Systemic therapy is appropriate for patients with advanced unresectable HCC who are unsuitable
for locoregional therapy and have adequate performance status and underlying liver function.
For patients whose functional status and liver function are adequate Atezolizumab plus
Bevacizumab rather than other systemic agents
For patients who are ineligible for or lack access to Atezolizumab plus Bevacizumab or Durvalumab
plus Tremelimumab, prefer Lenvatinib Over Sorafenib.
Patients progressed on atezolizumab plus bevacizumab or durvalumab plus tremelimumab, Options
include Sorafenib, Lenvatinib, Regorafenib, Cabozantinib, Or Apatinib.
Progressed on or are unable to tolerate sorafenib or lenvatinib, suggest Nivolumab Plus Ipilimumab
Cabozantinib is an option for patients who are intolerant of Sorafenib, Lenvatinib, or Regorafenib
Ramucirumab may be preferred for the subset of patients with a high AFP level (>400 ng/ml).
For less fit patients who have no worse than Child-pugh B7 Cirrhosis, monotherapy with Sorafenib
Or Nivolumab rather than cytotoxic chemotherapy
Supportive care alone is appropriate for those with Child-pugh Class C Cirrhosis, a poor functional
status, or extensive comorbidity.