The combination of KN046, a novel bispecific antibody targeting PD-L1 and CTLA-4 immune checkpoints, with lenvatinib has demonstrated promising efficacy as first-line treatment for patients with advanced hepatocellular carcinoma (HCC), according to results from a phase II clinical trial conducted in China.
Treatment Efficacy and Clinical Outcomes
The study enrolled 55 patients with advanced unresectable or metastatic HCC. With a median follow-up of 13.8 months, the combination therapy achieved an objective response rate (ORR) of 45.5% based on RECIST v1.1 criteria. The disease control rate reached 89.1%, with a median progression-free survival (PFS) of 11.0 months. The median overall survival was 16.4 months, with a 12-month survival rate of 60%.
These results compare favorably to historical data from previous immunotherapy combinations in HCC, where ORRs typically ranged from 13% to 30%. The higher response rates suggest potential advantages of using a bispecific antibody approach rather than separate checkpoint inhibitors.
Safety Profile and Tolerability
While the treatment showed meaningful clinical activity, safety monitoring revealed that all patients experienced treatment-related adverse events (TRAEs), with 47.3% experiencing grade ≥3 events. The most common serious TRAEs included:
- Hypertension (12.7%)
- Elevated blood pressure (9.1%)
- Decreased platelet count (5.5%)
- Fatigue (3.6%)
- Elevated liver enzymes (3.6%)
One treatment-related death occurred due to interstitial lung disease. Despite these safety concerns, the adverse event profile appeared manageable and was numerically lower than rates reported in previous dual immunotherapy combinations.
Biomarker Analysis and Patient Selection
The study included comprehensive biomarker analyses using next-generation sequencing of tumor tissue and circulating tumor DNA (ctDNA). Key findings included:
- TP53, TERT, and LRP1B were the most frequently mutated genes at baseline
- CCND1 and FGF19 copy number variations were associated with poorer response
- Early ctDNA clearance correlated with improved survival outcomes
- Patients achieving ctDNA-negative status before the third treatment cycle showed significantly better progression-free and overall survival
Clinical Implications
This innovative approach of combining a bispecific antibody with an antiangiogenic agent represents a potential new treatment strategy for advanced HCC. The study suggests several advantages over traditional dual checkpoint inhibition:
- Single infusion versus multiple separate antibody administrations
- Potentially reduced immune-related toxicity
- Synergistic effects with antiangiogenic therapy
- Promising efficacy in a difficult-to-treat patient population
Study Limitations and Future Directions
The researchers acknowledge several limitations, including:
- Small sample size and lack of control group
- Limited geographic representation (China only)
- High prevalence of viral hepatitis in the study population
- Relatively short follow-up period
A larger phase III trial is warranted to confirm these findings and establish the role of this combination in the treatment landscape for advanced HCC. Additionally, further investigation of ctDNA as a predictive biomarker could help optimize patient selection and monitoring.
The results support further development of bispecific antibody approaches in HCC treatment, particularly when combined with targeted therapies. This strategy could potentially offer a more effective and manageable treatment option for patients with advanced liver cancer.
