In the treatment landscape of Hepatocellular Carcinoma (HCC), first-line systemic therapy is undergoing significant changes.

The long-standing first-line paradigm centered on Sorafenib is being gradually replaced by combination strategies involving immunotherapy and multi-target tyrosine kinase inhibitors (TKIs).

In this article, Hong Kong DengYueMed reviews current clinical practice to systematically outline the decision-making logic for first-line HCC treatment, with a focus on the differences between immunotherapy-based combinations and traditional targeted monotherapy.

Which Patients Should Receive First-Line Systemic Therapy?

It is important to clarify that first-line systemic therapy is not initiated immediately upon diagnosis in all liver cancer patients. Rather, it applies to those who are not candidates for surgical resection or are no longer suitable for locoregional therapies.

Typical candidates include:

● Patients with unresectable HCC or limited benefit from surgery

● Presence of multifocal disease, portal vein tumor thrombosis (PVTT), or extrahepatic metastases

● Patients who have failed or are no longer suitable for locoregional treatments such as TACE

● Preserved liver function (Child–Pugh A, selected B7)

● Performance status ECOG 0–1

These patients are generally within the “therapeutic window,” where liver function is still adequate and tumor burden is defined—making this a critical stage that influences long-term survival outcomes.

Current Landscape of First-Line Treatment for HCC

According to international and Chinese guidelines, first-line systemic therapy for HCC can be broadly categorized into three main approaches:

1. Immunotherapy + Anti-angiogenic Combination (Preferred Option)

Representative regimens include:

●       Atezolizumab +      Bevacizumab

● Other PD-1/PD-L1 inhibitors combined with anti-angiogenic agents

Key features:

● Significantly improved overall survival compared with traditional targeted therapy

● Higher objective response rate (ORR)

● Potential for conversion therapy in some patients

Important considerations: Prior to initiating this regimen, the risk of gastrointestinal bleeding must be carefully assessed, particularly the presence of esophageal or gastric varices.

For patients with high-risk varices, appropriate endoscopic evaluation and management are recommended before treatment to reduce bleeding risk.

2. Dual Immunotherapy

Representative regimen:

●       Durvalumab + Tremelimumab (STRIDE regimen)

Key features:

● Does not rely on anti-angiogenic agents

● Suitable for patients with high bleeding risk

● Demonstrates sustained long-term survival benefit

Risk considerations: This regimen may lead to immune-related adverse events (irAEs), requiring close monitoring and timely management.

In addition, due to CTLA-4 pathway involvement, toxicity may be more pronounced, posing higher demands on patient tolerance and clinical management.

3. Targeted Therapy Monotherapy

Includes:

●       Sorafenib

●       Lenvatinib

●       Donafenib

Key features:

● Well-established clinical experience and predictable safety profile

● Can be combined with locoregional therapies such as TACE, radiotherapy, and ablation

● Remains a core option for patients who are not candidates for immunotherapy

Clinical positioning: Not necessarily the most aggressive approach, but often the most balanced and stable option.

Why Is “Immunotherapy + Targeted Therapy” Increasingly Preferred?

1. Superior Survival Outcomes

Clinical studies of Atezo + Bev have shown:

● Significant improvement in overall survival (OS)

● Higher tumor response rates

● A clear “long-tail” effect in survival curves

This indicates that some patients may achieve long-term survival, rather than just incremental median survival benefits.

2. Synergistic Mechanism of Action

The rationale for combination therapy lies in tumor microenvironment modulation and immune activation:

● Anti-angiogenic therapy reduces tumor blood supply and improves the tumor microenvironment

● Immunotherapy activates T-cell–mediated tumor recognition and destruction

Together, these mechanisms create a synergistic anti-tumor effect.

Not All Patients Are Suitable for Immunotherapy-Based Combinations

In clinical decision-making, safety is as important as efficacy. Key limiting factors include:

1. Bleeding Risk (Critical Factor)

Particularly relevant for anti-angiogenic therapy:

● Esophageal or gastric varices

● Recent gastrointestinal bleeding

● Untreated high-risk lesions

Management strategies:

● Endoscopic evaluation and preventive intervention

● Switching to non-anti-angiogenic immunotherapy regimens

● Using targeted monotherapy instead

2. Autoimmune Diseases or Organ Transplant History

Immunotherapy may lead to:

● Exacerbation of pre-existing autoimmune conditions

● Risk of transplant rejection

Such patients are generally not suitable for immunotherapy.

3. Liver Function Determines Treatment Intensity

Child–Pugh classification remains central:

● Class A: standard window for systemic therapy

● Class B (especially ≥B7): requires caution

● Class C: supportive care is usually preferred

The poorer the liver function, the more limited the treatment intensity.

Targeted Therapy Remains Indispensable

Despite the rise of immunotherapy combinations, targeted agents still play an important role.

1. Sorafenib: A Stable Option

Advantages:

● Most extensive clinical experience

● Manageable safety profile

Suitable for:

● Elderly patients or those with multiple comorbidities

● Patients not eligible for immunotherapy or anti-angiogenic therapy

2. Lenvatinib: Strong Tumor Control

Advantages:

● Rapid onset of action

● Higher tumor response rate

Suitable for:

● Patients with high tumor burden

● Those requiring rapid disease control

3. Donafenib: A New-Generation Chinese TKI

Characteristics:

● Demonstrated improved survival compared with sorafenib

● Supported by domestic clinical data

● Distinct adverse event profile

Suitable for: Patients unsuitable for or delaying immunotherapy

Conclusion: The Core of First-Line Treatment Has Shifted

The management of HCC has moved beyond the “monotherapy era” into a “strategy-driven era.”

In summary:

● When feasible and safe, immunotherapy combined with anti-angiogenic or targeted therapy should be considered first-line

● When immunotherapy is not suitable, targeted therapy remains a reliable foundation

● Long-term outcomes depend not on a single drug, but on the overall treatment strategy