Lenvatinib plus transarterial chemoembolization and PD-1 inhibitors as conversion therapies for unresectable intermediate-advanced hepatocellular carcinoma: a phase 2 trial and exploratory biomolecular study

Conversion therapy remains an uncommon strategy for managing unresectable hepatocellular carcinoma (uHCC) due to limited evidence supporting its efficacy. To address this gap, we initiated a prospective phase 2 multicenter trial (NCT04997850) comparing the LEN-TAP regimen, combining lenvatinib, transarterial chemoembolization (TACE), and PD-1 inhibitors, against TACE alone in uHCC patients. The study's primary outcome was salvage liver resection (SLR) rate; secondary measures included objective response rate (ORR), overall survival (OS), event-free survival (EFS), recurrence-free survival (RFS), and safety profile. From October 2020 to November 2021, 142 eligible participants were assigned to LEN-TAP (n = 71) or TACE monotherapy (n = 71). At a median follow-up of 24.2 months, the LEN-TAP cohort exhibited a significantly higher SLR rate (59.2% vs. 18.3%, P < 0.001) and ORR (78.9% vs. 16.9%, P < 0.001). Median OS, EFS, and RFS were also substantially prolonged in the LEN-TAP cohort (not reached vs. 23.0 months, P < 0.001; 20.03 vs. 6.52 months, P < 0.001; 36.6 vs. 19.0 months, P = 0.048). Although grade 3 treatment-related AEs occurred more frequently with LEN-TAP (60.6% vs. 21.1%, P < 0.001), no grade 4 or higher toxicities were observed. Exploratory biomarker assessments via single-cell sequencing and flow cytometry linked elevated levels of circulating HLA-DR⁺CD38⁺CD8⁺ T cells with improved treatment response. These T cells appear to mediate antitumor activity potentially through the CXCR6-PI3K-AKT signaling axis. In summary, the LEN-TAP protocol demonstrates promising efficacy and acceptable tolerability as a conversion therapy in uHCC, with peripheral HLA-DR⁺CD38⁺CD8⁺ T cell abundance serving as a potential predictor of therapeutic benefit.