Breakthrough Triple-Therapy Shows Promise in Advanced Liver Cancer Treatment

What Promising Strategies Are Emerging for Advanced HCC?

Shanghai Henlius Biopharmaceuticals has reported promising results from a phase II clinical trial evaluating a three-pronged approach for advanced hepatocellular carcinoma (HCC). The combination of serplulimab (PD-1 inhibitor), HLX04 (bevacizumab biosimilar), and hepatic arterial infusion chemotherapy (HAIC) with FOLFOX demonstrated an objective response rate of 53.1% in untreated patients with BCLC stage C liver cancer.

The single-center, observational study enrolled 32 patients with untreated advanced HCC at Tianjin Cancer Hospital Airport Hospital between August 2023 and September 2024. Patients received intravenous serplulimab (4.5 mg/kg) and HLX04 (15.0 mg/kg), alongside FOLFOX chemotherapy delivered through hepatic arterial infusion every three weeks. The primary endpoint was objective response rate (ORR), with secondary endpoints including disease control rate (DCR), progression-free survival (PFS), and safety. The patient population was predominantly male (81.2%) with a median age of 62 years, and notably, 68.8% had HBV infection—reflecting the typical epidemiology of HCC in China, where the disease burden is particularly high. Most patients (87.5%) completed at least three treatment cycles, with a subset experiencing significant tumor reduction that enabled subsequent surgical intervention. The study revealed that patients with a single lesion had a significantly higher ORR than those with multiple lesions (100% vs. 44.4%), suggesting that lesion number could be an important consideration for patient selection. Additionally, patients who received three or more treatment cycles showed substantially better responses (60.7% ORR) compared to those with fewer cycles, indicating a potential dose-response relationship that could inform treatment duration strategies in future studies.

What Do the Trial Results and Expert Insights Reveal?

The study builds on previous research exploring immunotherapy-antiangiogenic combinations for advanced HCC, including the landmark IMbrave150 trial that established the atezolizumab-bevacizumab combination as a standard of care. Dr. Li Wei, principal investigator from Tianjin Cancer Hospital, noted: "What's particularly encouraging is that five patients with stage IB to IIIA liver cancer achieved sufficient tumor reduction after three to four treatment cycles to undergo partial hepatectomy, potentially converting unresectable disease to surgical candidates." This finding suggests the regimen could serve as a downstaging approach for select patients, offering a pathway to more definitive treatment. The trial's results compare favorably to previous phase II studies of serplulimab with HLX04 alone, which showed an ORR of 29.3%. The addition of HAIC-FOLFOX appears to significantly boost response rates, supporting the rationale for the triple combination approach. The observed 6-month PFS rate of 89.9% also indicates durable disease control in most patients, though longer follow-up will be needed to determine the true survival benefit of this approach. Adverse events were consistent with the known safety profiles of the individual components, with the most common grade III or higher adverse events including decreased lymphocyte count (18.8%), elevated γ-glutamyltransferase (18.8%), and increased aspartate aminotransferase (15.6%).

How Does the Triple Combination Compare in a Competitive Landscape?

The triple combination strategy being evaluated by Henlius enters an increasingly competitive landscape for advanced HCC treatment. Several global pharmaceutical companies, including Roche/Genentech, Merck, and BeiGene, are pursuing similar combination approaches involving PD-1/PD-L1 inhibitors with anti-angiogenic agents. What distinguishes this approach is the addition of regional chemotherapy through HAIC, which may offer improved local disease control while potentially enhancing immunotherapy responses through immunogenic cell death. The Chinese pharmaceutical sector has shown particular interest in HAIC-based approaches for HCC, given the high disease burden in the region and the expertise in interventional techniques at specialized centers. Analysts from CSPC Securities noted: "The combination of regional chemotherapy with systemic immunotherapy represents a rational approach to target both local and distant disease, potentially addressing multiple resistance mechanisms." While the global standard of care for first-line unresectable HCC has shifted toward atezolizumab plus bevacizumab following the IMbrave150 trial, there remains significant interest in identifying more effective combinations, particularly for patients with more advanced disease or those who progress on first-line therapy.

What Next Steps Could Transform HCC Treatment?

Looking ahead, Shanghai Henlius plans to initiate a larger, randomized phase III trial to confirm these findings and potentially position this triple combination as a new standard for advanced HCC. The company is also exploring biomarker analyses to identify patient subgroups most likely to benefit from this approach. The downstaging potential observed in this trial may open new treatment paradigms where combination therapy serves as a bridge to surgery for selected patients. Industry experts suggest that if confirmed in larger studies, this approach could significantly impact treatment guidelines for advanced HCC, particularly in regions with high HBV-related HCC prevalence. The company has not yet disclosed specific timelines for the phase III program but indicated that discussions with regulatory authorities are ongoing. The trial results were presented at a recent liver cancer symposium in Shanghai and are expected to be published in a peer-reviewed journal in the coming months.

The disease control rate (DCR) reached an impressive 90.6% in the study, with 17 patients achieving partial response and 12 showing stable disease. This high DCR underscores the potential of the triple combination to effectively manage the disease burden in patients with advanced HCC. The safety profile revealed manageable toxicity with most adverse events related to abnormal liver function and myelosuppression. Importantly, only 2 of 32 patients experienced adverse events that led to temporary suspension of HAIC treatment, with no permanent discontinuations due to toxicity, suggesting the regimen is generally well-tolerated despite its intensity.

Industry Context: This study reflects the ongoing shift in liver cancer treatment toward multi-modal approaches that combine local and systemic therapies. The high incidence of HCC in China has made it a strategic focus for domestic pharmaceutical companies seeking to address a significant unmet need. The integration of regional chemotherapy with immunotherapy and anti-angiogenic agents represents a logical evolution in treatment strategy, potentially offering improved outcomes compared to either approach alone. However, the complexity and cost of triple-therapy regimens raise questions about accessibility and implementation in resource-limited settings, particularly given that HCC disproportionately affects regions with developing healthcare infrastructure.

Summary

A phase II clinical trial conducted at Tianjin Cancer Hospital Airport Hospital has shown promising results for treating advanced hepatocellular carcinoma (HCC) using a triple-therapy approach. The study combined serplulimab (PD-1 inhibitor), HLX04 (bevacizumab biosimilar), and FOLFOX chemotherapy via hepatic arterial infusion, achieving a 53.1% objective response rate. The trial enrolled 32 patients, predominantly male with HBV infection, and demonstrated a 90.6% disease control rate. Notably, five patients achieved sufficient tumor reduction to undergo surgery. The treatment showed better results in patients with single lesions and those who completed three or more treatment cycles. The safety profile was manageable, with minimal treatment discontinuations, positioning this approach as a potential new standard for advanced HCC treatment, particularly in regions with high HBV-related HCC prevalence.