Editor’s Note: Primary hepatocellular carcinoma (HCC) is a prevalent malignant tumor, and combining systemic therapy, immunotherapy, and regional local treatment is guiding HCC clinical treatment to new heights. At the recent 18th International Liver Cancer Association (ILCA) Annual Meeting, Dr. Tao Peng from the Hepatobiliary Surgery Department of The First Affiliated Hospital of Guangxi Medical University shared findings from a preliminary clinical trial targeting multinodular HCC. This study explored the use of cadonilimab (Cadonilimab) combined with the FOLFOX regimen via hepatic artery infusion chemotherapy (HAIC) as a neoadjuvant treatment, aimed at providing a more effective treatment strategy for resectable multinodular HCC patients. Oncology Frontier invited Dr. Tao Peng to discuss the main findings and clinical significance of the study.Oncology Frontier：Can you provide background and rationale for selecting cadonilimab combined with FOLFOX-HAIC as a neoadjuvant treatment for early multinodular HCC? What potential advantages does this combination therapy offer compared to monotherapy?
Dr. Tao Peng: This study primarily addresses a specific type of primary HCC—multinodular HCC, focusing on Chinese clinical classifications Ib and IIa with multiple nodules. We selected cadonilimab, a bispecific PD1/CTLA4-targeting antibody that has shown promising results in first-line treatment of advanced HCC, and applied it in a neoadjuvant setting for relatively early-stage HCC patients. FOLFOX-HAIC has also demonstrated clinical benefits in both conversion therapy for advanced HCC and as adjuvant therapy for patients with high-risk factors. Thus, we combined cadonilimab with FOLFOX-HAIC to investigate their combined effects in early multinodular HCC.
To explore which treatment pathway is most effective, our clinical research includes three plans: monotherapy with cadonilimab, combination therapy of cadonilimab and HAIC, and HAIC monotherapy. This design allows for a comprehensive evaluation of the efficacy of different treatment pathways, establishing a solid scientific basis for selecting the optimal clinical treatment.
Oncology Frontier： What are the primary findings of this study, and what clinical implications do they hold?
Dr. Tao Peng: Primary HCC is a highly prevalent malignancy, ranking sixth in global incidence and third in mortality. In China, it ranks fourth in incidence and second in mortality. In Guangxi, both incidence and mortality of primary HCC exceed those of lung cancer, making it the leading malignancy. At The First Affiliated Hospital of Guangxi Medical University, the proportion of patients eligible for curative resection or liver transplantation is below 40%, with approximately 30% presenting at mid to late stages despite being operable, highlighting low resection rates and high recurrence. Data shows that even after resection, the five-year recurrence rate can reach 50% or more, with national five-year survival rates for primary HCC at only 12-14%.
Given the high proportion of advanced cases, low resection rates, high postoperative recurrence, and poor long-term survival, there is an urgent need for multidimensional treatment strategies. Multinodular HCC is particularly prone to recurrence after resection, with few clinical trials focusing on this subtype. Thus, we designed this clinical study to address an unmet clinical need.
Among the three treatment groups in our study, the combination therapy group of cadonilimab and HAIC showed the highest rate of major pathological response (MPR), defined as ≤50% residual viable tumor. This finding suggests that the combination of systemic immunotherapy and regional interventional therapy may offer greater benefits for multinodular HCC patients. In terms of safety, the adverse event rate among all patients remained within a controllable range. Although the study is ongoing, we observed notable heterogeneity in the response of multiple HCC nodules to combination therapy, with some nodules undergoing complete necrosis while others remained unaffected. This finding highlights the need to address the high heterogeneity of primary HCC in treatment approaches.
Oncology Frontier： Based on current results, what are the future research directions for cadonilimab combined with FOLFOX-HAIC as a neoadjuvant therapy?
Dr. Tao Peng: This study is an initial exploratory clinical trial (pilot study) to provide insights into treating multinodular HCC. We aim to recruit 45 patients, with only about ten remaining to meet our target. Additional data on MPR and one-year recurrence-free survival (RFS) will be analyzed as we move forward.
The preliminary results prompt us to consider optimizing combination therapy further, including adjustments in systemic medications and local interventional methods. Our planned future studies, based on these early indicators, will involve multi-center, large-sample research to validate and refine our current approach, ensuring a more accurate evaluation of efficacy and developing more precise and effective strategies for multinodular HCC.
Oncology Frontier： In HCC treatment, immune-based combination therapies are a major trend in research. How do you see the future of immunotherapy combined with HAIC evolving, and could it potentially become a new standard for HCC treatment?
Dr. Tao Peng: This is an excellent question. Combination therapies have become an irreversible trend, both globally and in major medical centers across China. Numerous clinical research designs focus on combining systemic therapies and exploring optimal combinations for maximum patient benefit. However, in primary HCC treatment, simply stacking treatments for longer durations (two, three years, or more) may not be the final approach, as it increases complexity, adverse events, and economic burden.
Instead, our focus should be on identifying new immunotherapy targets, achieving better responses, and increasing disease control rates (DCR). Furthermore, with the development of multi-omics and AI technology, we are equipped to manage complex cases better. These advancements, particularly the integration of AI and multi-omics, offer potential solutions to the high heterogeneity of multinodular HCC, overcoming current clinical challenges.
In conclusion, I believe future combination therapy should focus on three areas: acknowledging and addressing the downsides of combination therapy, exploring new immunotherapy targets, and utilizing AI and multi-omics to tackle the high heterogeneity of multinodular HCC. These directions will guide us towards more precise and effective primary HCC treatments.
Dr. Tao Peng
- Chief Physician, Second-Tier Professor, Doctoral Supervisor
- Chief of General Surgery and Hepatobiliary Surgery at The First Affiliated Hospital of Guangxi Medical University
- Lead of the National Clinical Key Specialty in Oncology at The First Affiliated Hospital of Guangxi Medical University
- Educational Background: Medical degree from Peking University, Doctorate from West China Medical University, Postdoctoral research at Columbia University and NIH-NCI in the USA
Professional Affiliations:
- Committee Member, Hepatobiliary Disease Specialty Committee, China International Healthcare Promotion Association
- Committee Member, Liver Surgery Professional Committee, Chinese Medical Doctor Association Surgery Branch
- Chairman, Oncology Branch, Guangxi Medical Association
- Director, Organ Transplant Quality Control Center, Guangxi
- Associate Member, American Association for Cancer Research (AACR)
- Guest Reviewer for journals such as Liver International, Annals of Surgery, Toxins, and Food and Chemical Toxicology
Research:
- Principal Investigator on more than ten projects, including National Science Foundation and New Century Excellent Talents projects from the Ministry of Education
- Published over 100 SCI-indexed research papers in journals such as Gut, Annals of Surgery, Human Genetics, Annals of Surgical Oncology, Carcinogenesis, and Cancer Letters
- Recipient of three provincial-level second prizes for scientific and technological advancement
