Editor’s Note: On December 9-10, 2023, the “Huaxia Shanghai Liver Disease Forum and Shanghai Liver Disease Summit” was successfully held, sponsored by the Huaxia Liver Disease Association, organized by the Shanghai “Liver” Magazine, and co-organized by the Shanghai Medical Association Hepatology Subspecialty Branch, Shanghai Physicians Association Infectious Disease Physicians Branch, Shanghai Infectious Disease Clinical Quality Control Center, and the Long Triangle Representative Office of the China Association of Non-Public Medical Institutions. At the conference, Dr.Xiufeng Liu from the Medical Area of the Qinhuai Hospital of the Eastern Theater General Hospital of the People’s Liberation Army provided a detailed interpretation of the “Chinese Expert Consensus on Immunotherapy for Hepatocellular Carcinoma,” which was newly issued in China. This journal has invited Dr.Xiufeng Liu to conduct an in-depth interview to introduce the consensus’s recommendations regarding first-line and subsequent-line treatment options for liver cancer immunotherapy, as well as the assessment of treatment efficacy and other hot topics. The following content summarizes these insights for readers.
“Hepatology Digest”
As the lead author of the “Chinese Expert Consensus on Immunotherapy for Hepatocellular Carcinoma,” could you please start by introducing the main background and objectives behind the creation of this consensus?
Dr. Xiufeng Liu: Certainly, this updated consensus builds upon the 2021 version. It’s widely recognized that from 2021 to 2023, significant progress has been made in the field of immunotherapy for liver cancer in China. We’ve entered the era of Liver Cancer Immunotherapy 2.0, which includes various combinations such as “T+A,” “Double D,” “Double A,” and “Double Immune,” among others. Even combinations like the “Coca-Cola combo,” which had negative results in the LEAP002 study due to study design or statistical issues, have found clinical applications. Overall, liver cancer immunotherapy has made substantial progress in recent years, offering a variety of promising options. However, selecting the right treatment approach for individual patients remains a challenge in clinical practice. Specifically, we need to consider how to optimize selection based on patients’ clinical and molecular characteristics. We must not only focus on achieving the best efficacy but also pay attention to adverse reactions related to combination therapy and identify populations for whom some treatments should be used cautiously or avoided. Additionally, we need to address questions related to the assessment of clinical efficacy and optimize treatment strategies from a comprehensive management perspective. The new consensus was developed in this context and emphasizes its practical value and the accessibility of treatment regimens when interpreting its specific recommendations.
“Hepatology Digest”
As you mentioned, systemic treatment for liver cancer, especially combination therapies based on immune checkpoint inhibitors (ICIs), has become the primary treatment modality for unresectable liver cancer patients. Could you please share the consensus’s recommendations regarding first-line treatment for unresectable liver cancer patients, the key patient populations for various combination regimens, and the specific guidance provided?
Dr.Xiufeng Liu: Regarding treatment selection, our new consensus provides detailed explanations in Recommendations 1, 2, and 3.
Recommendation 1
Combination regimens of immune agents with anti-angiogenic agents, such as Atezolizumab + Bevacizumab/Tislelizumab + IBI305/Carilizumab + Apatinib, can be used as first-line treatment options for unresectable HCC (Evidence Level 2, Recommendation A). The combination of Toripalimab with Lenvatinib can be considered an alternative option (Evidence Level 2, Recommendation B). The combination of Pembrolizumab with Lenvatinib can also be an alternative option (Evidence Level 3, Recommendation C).
As mentioned earlier, the “T+A” regimen, the “Double D” regimen led by Dr. Jia Fan, Dr. Zhenggang Ren, the “Double A” regimen with final results announced at ESMO 2022, and the “Double Immune” regimen from the HIMALAYA study are the four main recommended first-line treatment options.
So, how do we choose among these four options? The general approach has two aspects: first, looking at contraindications to drug use and selecting treatment approaches based on etiology. From the perspective of contraindications to the use of PD-1/PD-L1 inhibitors and tyrosine kinase inhibitors (TKIs), we evaluate treatment options. For example, we assess whether the patient has portal hypertension, a history of recurrent bleeding in the past three months, hepatic encephalopathy, or autoimmune liver disease. From an etiological perspective, we primarily consider whether the patient has non-virus-related liver cancer.
The second aspect is the patient’s liver function. All approved regimens are based on large Phase III clinical studies, which often excluded patients with poor liver function, typically excluding patients beyond BCLC Stage B7. However, in the real world, there is a substantial population of patients with poor liver function. We must consider the patient’s liver function as a crucial reference index when selecting treatment options.
Recommendation 2
For the selection of second-line treatment regimens for liver cancer, after the failure of first-line immunotherapy, it is necessary to differentiate the disease progression pattern and the specific application of first-line regimens. While considering the mechanism of action and evidence of efficacy, as well as safety and tolerability of second-line treatment options, it is recommended to select appropriate new regimens (Expert Consensus Agreement 100%).
Recommendation 3
Various liver cancer guidelines still lack clear recommendations for post-second-line treatment strategies. It is necessary to differentiate disease progression patterns, the composition of first-line and second-line regimens, and, in a multidisciplinary team (MDT) setting, rationally select post-second-line treatment strategies based on the collaborative mechanisms of different liver cancer treatment modalities (Expert Consensus Agreement 100%).
In the new expert consensus, we also discussed second-line and third-line treatments for liver cancer. Regarding post-second-line treatment for liver cancer, this is an area that other guidelines and consensuses have not thoroughly explored. In reality, the new consensus is based on the “Chinese Expert Consensus on Immunotherapy for Hepatocellular Carcinoma Based on Immune Checkpoint Inhibitors (2021 Edition)” and integrates the latest research progress and expert experience to provide detailed clinical application guidelines. Additionally, for issues that currently lack clinical research evidence but are frequently encountered and urgently need to be addressed in clinical practice, the Delphi consensus formation method was used to establish recommendations. It’s worth noting that the Delphi method is a form of inquiry survey that collects expert opinions anonymously through multiple rounds of inquiry, revision, and statistical processing, ultimately summarizing expert opinions as the results.
We elaborated on Recommendations 2 and 3 from the perspectives of drug mechanisms, the patient’s liver function status, and the disease progression pattern, emphasizing the importance of making rational choices for post-second-line treatment strategies within an MDT framework.
“Hepatology Digest”
Could you please introduce the consensus’s recommendations regarding the assessment of immunotherapy’s efficacy? What are the main evaluation criteria? If the disease shows no significant progression, should we continue to observe or opt for second-line treatment? How should we choose the appropriate new regimen?
Dr.Xiufeng Liu: This topic actually involves some very detailed issues in our clinical practice. We are now in the era of targeted immunotherapy for liver cancer, and the modification of the body’s immune microenvironment is a dynamic process during treatment. When we find that the tumor is in a stable state, “stability” can be further divided into two categories: stability with tumor enlargement and stability with tumor shrinkage. We generally use the RECIST 1.1 criteria to assess this. If a patient’s tumor has not increased by less than 20% or has not shrunk by less than 30%, it is still considered stable. In fact, we need to refine the concept of “stability” to a great extent.
Secondly, as mentioned earlier, this assessment is for an isolated lesion. However, if this lesion does not progress or even shrinks but a new lesion develops nearby, it presents a new situation. In the new consensus, we have three scales for evaluating treatment efficacy. RECIST 1.1 criteria are used for the unique target lesion. In addition, we evaluate the overall response, such as immune-related efficacy assessment, which comprehensively assesses the patient’s overall response and any improvements in their overall condition.
Overall, liver cancer treatment involves comprehensive therapy within an MDT framework. Therefore, we cannot measure the efficacy of a particular treatment approach statically or in isolation because patients often receive a combination of systemic therapy, radiation therapy, and other comprehensive treatment modalities at different stages of the disease. Regardless of the criteria used, our goal is to extend the patient’s overall survival as much as possible and provide them with significant clinical benefits.
