HCC First- and Second-Line Treatment Updates: What’s New in Current Guidelines

To further improve the standardization of diagnosis and treatment for primary liver cancer, the newly released 2026 guideline introduces important HCC first- and second-line treatment updates, particularly in systemic therapy.

The Medical Administration Department of the National Health Commission of the People’s Republic of China officially released the Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2026 Edition) on April 9.

The guideline introduces important updates in systemic therapy, particularly in first-line treatment strategies: 🔽

• Immunotherapy-based combination therapy has become the standard first-line approach
• Dual immunotherapy regimens have formally entered mainstream clinical options
• Chinese innovative drugs have been fully incorporated into the core treatment system

✨ As a Hong Kong–based pharmaceutical distributor, DengYueMed monitors oncology developments, with a focus on liver cancer treatment and drug availability.

Systemic Therapy for HCC

1. Clinical Role and Target Population of Systemic Therapy

Because most patients with hepatocellular carcinoma (HCC) have underlying liver diseases (such as viral hepatitis and cirrhosis) and present with subtle early symptoms, only about 20%–30% are eligible for curative treatments at diagnosis.

Therefore, systemic therapy plays an irreplaceable role in intermediate and advanced HCC. It not only prolongs survival but also serves dual purposes: disease control and conversion therapy.

In addition, in certain cases, systemic therapy can be combined with transarterial interventions, forming a “local + systemic” strategy to improve treatment depth. This reflects an important direction in HCC systemic therapy updates.

2. Components and Key Management Points of Systemic Therapy

Systemic therapy is not limited to the use of antitumor drugs, but rather represents a comprehensive management system. Its core remains antitumor treatment, including:

• Molecular targeted therapies
• Immune checkpoint inhibitors
• Chemotherapy regimens

At the same time, antiviral therapy, hepatoprotective treatment, and complication management run throughout the entire treatment process. Among these, the importance of antiviral therapy is further emphasized in the new guideline.

👉 For patients with HBV-related HCC, high-barrier nucleos(t)ide analogs such as Entecavir or Tenofovir disoproxil fumarate should be initiated early to suppress viral replication, preserve liver function, and improve tolerance to systemic therapy.

👉 For patients with HCV-related HCC, direct-acting antivirals (DAAs) can improve the liver environment and are recommended by guidelines such as the National Comprehensive Cancer Network and the European Association for the Study of the Liver.

HCC First-Line Treatment Updates

1. Changes in First-Line Treatment Strategy

First-line treatment applies to patients with unresectable or metastatic HCC who have not previously received systemic therapy.

Unlike previous strategies dominated by targeted monotherapy such as Sorafenib or Lenvatinib, the 2026 guideline clearly proposes that immunotherapy-based combination regimens have significant efficacy advantages and have become the preferred recommended options.

This is a core highlight of the HCC first- and second-line treatment updates.

This shift is based on multiple Phase III clinical trials, which consistently show that immunotherapy combinations outperform traditional monotherapy in:

• Overall survival (OS)
• Progression-free survival (PFS)
• Objective response rate (ORR)

2. Composition of First-Line Treatment Regimens

Current first-line treatment mainly revolves around two types of immunotherapy-based combination strategies, which are central to first-line immunotherapy HCC treatment trends.

(1) Immune Checkpoint Inhibitor + Anti-Angiogenic Therapy

This type of regimen works through dual mechanisms:

On one hand, anti-angiogenic agents (such as Bevacizumab) can improve tumor vascular structure and the immune microenvironment. On the other hand, immune checkpoint inhibitors activate T-cell-mediated antitumor responses, achieving synergistic effects.

Representative regimens include: 👇

• Atezolizumab + Bevacizumab
• Apatinib + Camrelizumab
• Sintilimab + bevacizumab biosimilar

At the same time, the 2026 guideline adds multiple China-led combination regimens, such as: 👇

• Toripalimab + Bevacizumab
• Anlotinib + Penpulimab
• Finotonlimab + Bevacizumab

These combinations have demonstrated clear survival benefits in Phase III studies, highlighting the rapid development of Chinese innovative drugs within HCC first-line treatment updates.

(2) Dual Immunotherapy (New Addition)

The new guideline includes dual immunotherapy regimens for the first time: 👇

• Nivolumab + Ipilimumab

This regimen enhances tumor recognition and clearance by simultaneously blocking different immune suppression pathways.

In the CheckMate-9DW study, this combination increased median overall survival to 23.7 months and showed potential advantages in long-term survival, suggesting that some patients may achieve durable benefits.

3. Evidence Supporting Newly Added Regimens

Multiple Phase III studies provide strong evidence for these additions, further strengthening HCC first- and second-line treatment updates:

1. Nivolumab + Ipilimumab significantly reduces mortality risk and improves long-term survival
2. Penpulimab + Bevacizumab shows superiority over Sorafenib in OS and PFS
3. Toripalimab + Bevacizumab demonstrates stable survival benefits in the HEPATORCH study
4. Anlotinib combined with immunotherapy shows strong disease progression control

✅ These data collectively indicate that immunotherapy combination strategies are gradually replacing traditional targeted monotherapy and becoming the core pathway in first-line HCC treatment.

4. Treatment Selection and Safety Management

In real-world clinical practice, the selection of first-line treatment regimens should comprehensively consider multiple factors, including liver function reserve (Child-Pugh classification), tumor burden, bleeding risk, and drug accessibility.

Based on these factors, individualized treatment strategies are essential to improve efficacy and reduce risks. This is a key aspect of HCC first- and second-line treatment updates in clinical implementation.

In terms of safety, immune-related adverse events (irAEs) remain a major concern, including immune-related hepatitis, endocrine disorders, and pneumonitis.

Risk assessment should be conducted before treatment and continuous monitoring is required during therapy.

At the same time, before using Bevacizumab or its biosimilars, endoscopic evaluation of esophageal and gastric varices should be performed to reduce bleeding risk.

For patients with high bleeding risk or Child-Pugh class C liver function, such therapies should be avoided.

HCC Second-Line Treatment Updates

1. Current Standard Treatment Options

Current second-line treatment recommendations are mainly based on Phase III evidence following failure of Sorafenib or systemic chemotherapy.

Commonly used drugs include:

• Regorafenib
• Apatinib
• Ramucirumab (for AFP ≥400 μg/L patients)
• Pembrolizumab

In addition,:

• Camrelizumab
• Tislelizumab

can also be used in patients who fail first-line therapy.

Overall, this part of the recommendation remains largely consistent with the 2024 guideline, which is an important observation in second-line HCC treatment options updates.

2. Challenges of Second-Line Therapy in the Immunotherapy Era

With the widespread use of immunotherapy combinations in first-line treatment, traditional second-line pathways based on Sorafenib failure are being redefined.

Currently, there is still a lack of high-level evidence for standard treatment after immunotherapy failure, which has become a major challenge in clinical practice and a key issue in HCC first- and second-line treatment updates.

At present, clinicians usually make strategic treatment decisions based on prior treatment history and patterns of disease progression, for example, by avoiding the reuse of drugs with the same mechanism and prioritizing therapies that the patient has not previously been exposed to.

This area still requires further research for optimization.

Summary and Future Trends in HCC Treatment

In the long term, HCC treatment is moving toward greater precision and multidimensional integration:

With continuous accumulation of clinical evidence, treatment pathways will continue to be optimized, and the 2026 guideline represents a key milestone in this transformation of HCC first- and second-line treatment updates.

In this context, drug accessibility and supply stability are becoming increasingly important. China pharmaceutical wholesaler DengYueMed will continue to monitor HCC first- and second-line treatment updates, providing stable drug supply and up-to-date information support for the global market.

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