Hepatocellular carcinoma (HCC) is a malignancy associated with high morbidity and mortality rates. Conversion therapy provides patients with unresectable HCC (uHCC) the opportunity to undergo radical treatment and achieve long-term survival. Despite accumulating evidence regarding the efficacy of conversion therapy, the optimal treatment approach for such therapy remains uncertain. Lenvatinib (LEN) has shown efficacy and tolerable rates of adverse events (AEs) when applied in combination with immune checkpoint inhibitors (ICIs) or locoregional therapy (LRT) over the past decade. Therefore, the present meta-analysis was performed to systematically assess the safety and efficacy of LEN-based treatment regimens in conversion therapies for uHCC. Data on outcomes, including the conversion rate, objective response rate (ORR), disease control rate (DCR) and AE incidence in patients with uHCC, were collected. A systematic literature search was performed using MEDLINE, Embase, Web of Science and Cochrane Library databases, up to the date of September 1, 2023. In total, 16 studies, encompassing a total of 1,650 cases of uHCC, were included in the final meta-analysis. The pooled conversion rates for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were calculated to be 0.04 (95% CI, 0.00-0.07; I2=77%), 0.23 (95% CI, 0.16-0.30; I2=66%), 0.14 (95% CI, 0.10-0.18; I2=0%) and 0.35 (95% CI, 0.23-0.47; I2=88%), respectively. The pooled ORRs for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were found to be 0.45 (95% CI, 0.23-0.67; I2=96%), 0.49 (95% CI, 0.39-0.60; I2=78%), 0.43 (95% CI, 0.24-0.62; I2=88%) and 0.69 (95% CI, 0.56-0.82; I2=92%), respectively. The pooled DCRs for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were observed to be 0.77 (95% CI, 0.73-0.81; I2=23%), 0.82 (95% CI, 0.69-0.95; I2=90%), 0.67 (95% CI, 0.39-0.94; I2=94%) and 0.87 (95% CI, 0.82-0.93; I2=67%), respectively. The pooled grade ≥3 AEs for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were 0.25 (95% CI, 0.14-0.36; I2=89%), 0.43 (95% CI, 0.34-0.53; I2=23%), 0.42 (95% CI, 0.19-0.66; I2=81%) and 0.35 (95% CI, 0.17-0.54; I2=94%), respectively. These findings suggested that LEN-based combination strategies may confer efficacy and acceptable tolerability for patients with uHCC. In particular, LEN + ICI, with or without LRT, appears to represent a highly effective conversion regimen, with an acceptable conversion rate and well-characterized safety profile.Copyright: © 2024 Li et al.