A novel combination therapy involving envafolimab, lenvatinib, and transcatheter arterial chemoembolization (TACE) has shown promising results in patients with unresectable hepatocellular carcinoma (uHCC). The study, published in Nature, highlights the potential of this combination to improve outcomes in a challenging patient population.
The trial enrolled 38 patients with uHCC, assessing the safety and efficacy of the combined treatment approach. The median age of patients was 55.5 years, with the majority being male (81.6%) and having BCLC stage C disease (55.3%). All patients had Child-Pugh class A liver function.
Efficacy Outcomes
The objective response rate (ORR) per RECIST 1.1 was 50% (95% CI: 32.9–67.1%), meeting the primary endpoint of the study. The disease control rate (DCR) was 83.3% (95% CI: 67.2–93.6%). According to modified RECIST (mRECIST), the ORR and DCR were both 83.3% (95% CI: 67.2–93.6%).
The median progression-free survival (mPFS) was 7.58 months (95% CI: 5.1 to 16.1) per RECIST 1.1 or mRECIST. The median overall survival (mOS) was 19.9 months (95% CI: 18.2 to NA), with a 1-year OS rate of 88.9% (95% CI: 79.2–99.8%).
Surgical Conversion and Pathological Response
Following conversion therapy, 17 patients were deemed suitable for surgery, resulting in a surgical conversion rate of 47.2%. Sixteen patients underwent surgery, achieving an R0 resection rate of 100%. A major pathological response (MPR) was observed in 56.3% of patients, with a pathologic complete response (pCR) in 31.3%. The 1-year disease-free survival (DFS) rate was 56.2% (95% CI: 36.5–86.7%). Patients with pCR had significantly better 1-year DFS compared to those without pCR (100% vs 36.4%; p<0.05).
Safety Profile
The combination therapy was associated with treatment-related adverse events (TRAEs) in 97.4% of patients, with grade ≥3 TRAEs reported in 52.6%. The most common grade 3 or worse TRAEs were increased aspartate aminotransferase (AST) (34.2%), increased alanine aminotransferase (ALT) (18.4%), and decreased platelet count (15.8%). One patient (2.6%) experienced a serious adverse event (SAE; gastrointestinal bleeding) requiring treatment discontinuation. No treatment-related deaths occurred.
Impact on Tumor Microenvironment
Immunohistochemistry analysis revealed significant improvements in the immune environment of patients who achieved a partial response (PR). The therapy increased CD4+ T cells, CD8+ T cells, NK cells, dendritic cells (DC), and macrophage populations. Conversely, tumor-associated neutrophils decreased. The analysis also indicated a potential increase in tertiary lymphoid structures (TLS) within the tissues after treatment.
Cellular Neighborhood Analysis
Cellular neighborhood (CN) analysis confirmed that the combination therapy improved the immune microenvironment in PR patients. The resident macrophage-enriched CNs showed a significant difference between pre-treatment PR and progressive disease (PD) patients, highlighting the predictive potential of this CN for patient response.
