A novel bifunctional antibody, QL1706, is showing promise in the first-line treatment of locally advanced or metastatic hepatocellular carcinoma (HCC), according to results from a Phase II study presented at ESMO. The study, led by Dr. Shu and colleagues, explores the potential of QL1706, a combination of anti-PD-1 IgG4 and anti-CTLA-4 IgG1 antibodies, in improving outcomes for HCC patients. This is a significant development in a field that has seen substantial progress with combination therapies involving immune checkpoint blockade, offering more durable tumor responses and improved overall survival rates.
Rationale for Bifunctional Antibody Approach
The rationale behind QL1706 lies in the need to balance efficacy and toxicity in HCC treatment. While combination therapies, such as PD-1 inhibitors with anti-VEGF agents or dual-immune checkpoint blockade, have shown benefit, they often come with increased immune-related adverse events. QL1706 is designed with a shorter elimination half-life for the anti-CTLA-4 component, aiming to reduce exposure and potentially lower the risk of these adverse events, making it a more attractive option for combination regimens.
Study Design and Patient Population
The adaptive, open-label Phase II/III study enrolled 120 patients with locally advanced or metastatic HCC across four arms: a control arm of sintilimab and bevacizumab, QL1706 plus CAPOX chemotherapy, QL1706 with CAPOX and bevacizumab, and QL1706 and bevacizumab alone. A notable aspect of the patient population was that almost 30% were intermediate stage, with the majority having Child-Pugh A disease, indicating well-preserved liver function. This may not fully represent the typical HCC patient population seen in Europe or the United States, where underlying cirrhosis and coexisting liver diseases are more prevalent.
Efficacy and Safety Results
Initial activity results presented at ESMO demonstrated numerically higher response rates in all QL1706-containing arms compared to the control arm, with response rates approaching 35-36% versus 20% in the control arm. The QL1706 arms also showed numerically higher median progression-free survival. Based on improvements in six-month progression-free survival and disease control rate, the investigators selected the arm containing chemotherapy with bevacizumab and QL1706 to move forward to evaluation versus the control arm in a Phase III randomized study.
Treatment-related adverse events were similar across all arms, with a possible trend toward more treatment delays in the QL1706-containing arms. However, detailed results on immune-related adverse events were not presented, leaving uncertainty about whether the bifunctional antibody approach truly reduces toxicity compared to standard checkpoint inhibitor blockade.
Implications and Future Directions
While the results are encouraging, several questions remain. The relevance of these findings to patients with more significant underlying liver dysfunction needs to be further explored. Additionally, the necessity and tolerability of chemotherapy in a triplet regimen are uncertain. Nevertheless, the study suggests that bifunctional antibodies like QL1706 may facilitate the development of triplet combinations with potentially reduced toxicity in HCC treatment.
