At an industry-sponsored symposium during the International Liver Cancer Association (ILCA) 2025 Annual Conference, Dr Krittiya Korphaisarn of Mahidol University, Bangkok, Thailand, reviewed systemic therapy for advanced hepatocellular carcinoma (HCC), focusing on lenvatinib as a second-line (2L) option following immunotherapy (IO). Professor Joseph Llovet of the University of Barcelona, Barcelona, Spain, and Tisch Cancer Institute at Mount Sinai, New York, US, and Professor Masatoshi Kudo of the Kindai University, Osaka, Japan, discussed the integration of systemic and locoregional treatments for intermediate HCC to optimize outcomes through multidisciplinary care.
1L systemic therapy for advanced HCC
For patients with advanced HCC with good liver function (Child-Pugh A) and an Eastern Cooperative Oncology Group performance status of 0–1, immune checkpoint inhibitor (ICI)–based combinations such as atezolizumab + bevacizumab (A + B) or tremelimumab + durvalumab (T + D) are the preferred first-line (1L) systemic therapies. The tyrosine kinase inhibitors (TKIs), lenvatinib or sorafenib, offer suitable alternative for patients with contraindications to ICIs, with lenvatinib often favoured due to higher objective response rates (ORRs) and longer progression-free survival (PFS), while overall survival (OS) is comparable between the two. Furthermore, OS with lenvatinib alone was found to be comparable with lenvatinib + pembrolizumab in the LEAP002 study. [JAMA Oncol 2024;10:395-404; J Hep Rep 2025;7:101571; Ann Oncol 2025;36;491-506; Lancet Oncol 2023;24:1399-1410]
Subsequent-line systemic treatment
Optimal treatment sequencing after progression on 1L systemic therapy remains uncertain. Although guidelines list several 2L and later-line options, no head-to-head trials exist to inform the best sequence. Decisions are therefore individualized based on prior therapy, comorbidities, tumour biology, and anticipated tolerability. [JAMA Oncol 2024;10:395-404; J Hep Rep 2025;7:101571; Ann Oncol 2025;36;491-506; NCCN Clinical Practice Guidelines in Oncology, Hepatocellular Carcinoma, version 2.2025]
“Randomized placebo-controlled trials evaluating VEGF receptor [VEGFR]–targeted therapies [regorafenib, cabozantinib, and ramucirumab] demonstrated median OS of 8.5–10.6 months post-sorafenib,” noted Korphaisarn. “These findings highlight the important role of VEGF-directed therapy in the 2L treatment landscape.” [Lancet 2017;389:56-66; N Engl J Med 2018;379:54-63; Lancet Oncol 2019;20:282-296]
“However, phase III comparative data following 1L IO remain limited,” she continued. “Emerging real-world [RW] evidence, mostly from patients treated with A + B, suggests meaningful clinical activity with 2L TKIs.”
A large retrospective RW study of 1,141 patients with advanced HCC across five Asia-Pacific countries evaluated outcomes after progression on 1L A + B. Among the 629 patients receiving subsequent therapy, sorafenib (53.9 percent) and lenvatinib (25.6 percent) were the most commonly used 2L agents. [Liver Cancer 2025;14:127-141]
Lenvatinib was associated with significantly longer median PFS (4.0 vs 2.3 months; hazard ratio [HR], 0.53; 95 percent confidence interval [CI], 0.43–0.67; p<0.0001) and median OS (8.0 vs 6.3 months; HR, 0.75; 95 percent CI, 0.59– 0.96; p=0.023) compared with sorafenib. (Figure) The PFS benefit remained statistically significant after propensity score (PS) matching (p=0.0001). [Liver Cancer 2025;14:127-141]
A Korean phase II, single-arm study (n=50) provided the first prospective clinical evidence for 2L lenvatinib after A + B, reporting a median PFS of 5.4 months, median OS of 9.8 months, and an 82 percent disease control rate. [J Hepatol 2025;doi: 10.1016/j.jhep.2025.08.020]
“IMbrave 251, an ongoing phase III randomized trial evaluating atezolizumab plus either lenvatinib or sorafenib vs TKI monotherapy after prior A + B, will be key to informing future standard 2L treatment,” noted Korphaisarn.
Lenvatinib: A rational 2L option after A + B
Lenvatinib inhibits multiple protumour pathways (VEGFR 1–3, FGFR 1–4, PDGFRα, as well as RET and KIT), producing broader antiangiogenic and antiproliferative effect than bevacizumab, which selectively targets VEGF-A. These mechanistic differences support its potential efficacy after PD-L1/VEGF-directed therapy such as A + B. [J Hematol Oncol 2024;17:130; Nat Rev Drug Discov 2004;3:391-400]
RW evidence indicates retained sensitivity to TKIs following progression on IO therapy, as reflected by meaningful disease control with subsequent TKI treatment. [Cancers (Basel) 2024;16:2813]
“Overall, lenvatinib appears biologically rational, clinically effective, and feasible as a 2L therapy after A + B in advanced HCC,” summarized Korphaisarn.
Systemic + locoregional therapies for intermediate HCC
Transarterial chemoembolization (TACE) has been the standard of care for intermediate-stage (Barcelona Liver Clinic Cancer [BCLC] stage B) HCC for more than two decades. [JHEP Rep 2025;7:101571; Hepatology 2023;78:1922-1965]
More recently, combining TACE or other locoregional therapies with systemic ICIs or antiangiogenic agents has emerged as a promising strategy for enhancing treatment efficacy. [Nat Rev Gastroenterol Hepatol 2021;18:293-313; Nat Rev Clin Oncol 2022;19:151-172]
“Three randomized, double-blind phase III trials — LEAP012 [lenvatinib + pembrolizumab + TACE vs TACE], EMERALD-1 [durvalumab + bevacizumab (D + B) + TACE vs TACE], and TALENTACE [A + B + TACE vs TACE] — have investigated the efficacy and safety of combined systemic and locoregional therapies in patients with unresectable HCC. All three trials met their PFS or TACE-PFS primary endpoints,” explained Llovet. “OS results are pending or immature for EMERALD-1 and TALENTACE, and LEAP012 did not show OS superiority at interim analysis.” [Lancet 2025;405:203-215; Lancet 2025;405:216-232; Dong J, et al, ESMO 2025, abstract LBA2]
“ESMO guidelines now list TACE combined with systemic agents, such as lenvatinib + pembrolizumab or D + B, as possible treatment options for BCLC-B HCC. Furthermore, based on LEAP012’s Chinese subgroup results, the lenvatinib + pembrolizumab + TACE regimen has received regulatory approval in China for unresectable nonmetastatic HCC,” noted Llovet. [Ann Oncol 2025;36;491-506; www.eisai.com/news/2025/pdf/ enews202551pdf.pdf]
Optimizing outcomes with systemic and/or locoregional therapies
Patient selection for TACE
Intermediate HCC is a heterogeneous disease, and TACE suitability depends on tumour burden and liver function. Patients with limited tumour burden (BCLC-B1: within the up-to-7 criteria) derive the best outcomes from TACE, whereas those with high tumour burden (BCLC-B2: outside the up-to-7 criteria) or impaired liver function are considered TACE-unsuitable. [Gastroenterology 2016;150:835-853; Dig Dis 2017;35:589-597]
“Survival benefit from TACE is closely tied to achieving meaningful tumour response while preserving liver function. However, repeated TACE can lead to hepatic deterioration,” noted Kudo. [Oncology 2014;87:22-31; Dig Dis 2017;35:602-610]
Anti-VEGF therapy enhances TACE efficacy
Anti-VEGF agents such as lenvatinib can normalize tumour vasculature, reduce interstitial pressure, and enhance intratumoural drug delivery, thereby potentially improving the effectiveness of subsequent TACE.* [Liver Cancer 2019;8:299-311; Med Oncol 2021;38:60]
In a proof-of-concept study, upfront lenvatinib followed by TACE in BCLC-B2 (TACE-unsuitable) patients significantly improved ORR (p<0.001), PFS (p<0.001) and OS (p<0.01), while maintaining liver function vs TACE alone. [Cancers (Basel) 2019;11:1084]
“In patients with bilobar multifocal HCC, only palliative TACE is typically feasible, but this is associated with limited efficacy and deterioration of liver function. TACE-induced hypoxia may also promote recurrence or new lesion formation. Administering lenvatinib before TACE provides antitumour effects, normalizes tumour vasculature, and allows for more effective superselective TACE. Lenvatinib additionally suppresses hypoxia-inducible cytokines, helping to preserve liver function and limit recurrence,” explained Kudo. [Liver Cancer 2019;8:299-311]
The multicentre, phase II, single-arm TACTICS-L study (n=62) in Japan evaluated the efficacy and safety of lenvatinib + TACE (upfront lenvatinib followed by TACE, with concurrent lenvatinib and on-demand TACE administration). [Liver Cancer 2023;13:99-112]
“Lenvatinib + TACE achieved a high complete response [CR] rate of 67.7 percent as best response, with consistent benefit both within and beyond the up-to-7 criteria — each subgroup achieved a CR rate >50 percent,” remarked Kudo. “Notably, efficacy was also seen in TACE-resistant macroscopic pathological types, including simple nodular with extranodular growth, multinodular, and infiltrative tumours. Moreover, the systemic upfront strategy produced durable high-quality CR compared with TACE alone [as shown in the TACTICS trial].” [Liver Cancer 2023;13:99-112; Liver Cancer 2023;12:395-404]
Importance of curative conversion
Another proof-of-concept study evaluated the value of curative conversion therapy using A + B followed by locoregional therapy including resection, ablation, or superselective TACE (ABC conversion), for improving CR rate with/without drug-free status in 110 TACE-unsuitable intermediate HCC patients. Clinical CR was achieved in 35 percent of patients (n=38/110), and 23 percent (n=25/110) attained drug-free status. Moreover, patients who underwent curative conversion had better PFS and OS compared with those who did not. [Liver Cancer 2023;12:321-338]
“The results showed that intentional curative conversion during/after A + B can enable clinical CR and/or drug-free status, including in some initial nonresponders. A + B alone is often not enough to achieve CR, because patients with partial response or stable disease will progress sooner or later,” noted Kudo. “The study found that a substantial proportion of patients who were eligible and underwent locoregional therapy after 1L A + B attained clinical CR with/without drug-free status [n=35/110], of which 15 had received TACE or lenvatinib + TACE.”
Lenvatinib + TACE vs A + B as 1L therapy
A retrospective RW study compared lenvatinib + TACE vs A + B as 1L treatment for intermediate HCC beyond the up-to-7 criteria. After PS matching, PFS and OS were similar between the two groups. However, ORR was significantly higher with lenvatinib + TACE (88.9 vs 47.3 percent; p=0.001). (Table) [J Gastroenterol Hepatol 2025;40:2060-2067]
Summary
Lenvatinib’s role in the management of unresectable HCC is expanding, particularly as a 2L option after IO and as a key component of systemic-locoregional combination strategies. RW and early prospective data demonstrate meaningful clinical activity with lenvatinib following A + B and reveal improved survival vs sorafenib. Additionally, lenvatinib + TACE is emerging as a versatile, high-response strategy for TACE-unsuitable intermediate HCC, which provides enhanced tumour control while preserving liver function.
*These findings are primarily based on experiments in animal models.
The above editorial is for medical education purpose supported by Eisai (HK) Co. Ltd.
