Highlight
- Lenvatinib showed a median progression-free survival of 5.4 months in patients with advanced hepatocellular carcinoma (HCC) after progression on first-line atezolizumab plus bevacizumab (atezo-bev), surpassing the prespecified primary endpoint.
- The objective response rate was 14.0%, with a high disease control rate of 82.0% and a median duration of response of 9.4 months, indicating durable clinical benefit.
- The safety profile of lenvatinib was consistent with prior studies, with manageable toxicity including diarrhea, hypothyroidism, and anorexia; grade ≥3 adverse events occurred in 46% of patients.
- This multicenter, prospective study provides the first robust clinical evidence supporting lenvatinib as a viable second-line treatment option post-atezo-bev failure in unresectable HCC.
Study Background
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with limited curative options for unresectable disease. The advent of immunotherapy combined with antiangiogenic agents, notably the combination of atezolizumab (an anti-PD-L1 monoclonal antibody) plus bevacizumab (an anti-VEGF monoclonal antibody), has established a new standard first-line therapy, improving survival outcomes in unresectable HCC (uHCC). Despite this advancement, disease progression is almost inevitable, and optimal therapeutic strategies following progression on atezo-bev are not well-defined.
Second-line treatments after failure of atezo-bev lack prospective evidence, and approved agents in pre-immunotherapy eras (such as sorafenib or regorafenib) have unknown efficacy and safety in this setting. Lenvatinib, a potent multikinase inhibitor targeting VEGF receptors and other kinases involved in tumor angiogenesis and proliferation, has demonstrated non-inferiority to sorafenib in first-line HCC treatment but its role post-atezo-bev progression had remained unclear.
This clinical gap underlines the urgent need for prospective studies evaluating systemic treatments after progression on immune checkpoint inhibitor and antiangiogenic combination therapy.
Study Design
This investigator-initiated, multicenter, phase II, single-arm trial (KCSG HB23-04) enrolled 50 patients with unresectable HCC who exhibited radiologic progression on first-line atezolizumab plus bevacizumab. Recruitment occurred across 13 centers between August 2023 and May 2024.
Key inclusion criteria included confirmed diagnosis of uHCC, documented disease progression after atezo-bev, adequate organ function, and Eastern Cooperative Oncology Group (ECOG) performance status generally 0–1. Patients received lenvatinib dosed at 12 mg daily for body weight ≥60 kg or 8 mg daily for <60 kg, administered orally until disease progression or unacceptable toxicity.
The study's primary endpoint was progression-free survival (PFS) assessed by RECIST 1.1 criteria. Secondary endpoints encompassed overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and treatment-related safety.
Key Findings
Patient median age was 66 years, with 72% presenting viral-related HCC (mostly hepatitis B or C infection). The median time to progression on prior atezo-bev therapy was 6.5 months.
At a median follow-up of 12.6 months, lenvatinib yielded a median PFS of 5.4 months (95% confidence interval [CI] 4.2 to 7.1 months), exceeding the prespecified target of >4.5 months. The median OS reached 9.8 months (95% CI 8.1 months to not reached). The ORR was 14.0%, including partial responses; meanwhile, the DCR was impressively high at 82.0%, demonstrating disease stabilization benefit. Responders exhibited a median duration of response of 9.4 months.
Subgroup analyses found survival outcomes correlated with achieving tumor response on lenvatinib but not significantly influenced by HCC etiology or duration of response to first-line atezo-bev.
Regarding safety, common adverse events (AEs) included diarrhea (42%), hypothyroidism (32%), and anorexia (30%). Grade 3 or higher AEs occurred in 46% of patients, consistent with the known safety profile of lenvatinib. No new safety signals emerged. Toxicities were generally manageable with dose modifications and supportive care.
Expert Commentary
This prospective multicenter study is pivotal in defining the therapeutic landscape post-atezo-bev failure in uHCC. While regimens combining immune checkpoint inhibitors with VEGF-directed therapies have reshaped first-line management, few data have directly informed subsequent therapy choices. Lenvatinib’s performance here, demonstrating clinically meaningful PFS, durable responses, and a safety profile aligned with prior studies, supports its integration into second-line practice.
Although the study was single-arm and non-comparative, the multicenter design and clearly defined endpoints enhance the validity of findings. The relatively short median PFS on prior atezo-bev suggests that lenvatinib may offer additional benefit even in ostensibly aggressive disease. The lack of effect modification by HCC etiology broadens applicability across viral and non-viral disease.
Future research should evaluate combination approaches, potential sequencing strategies, and biomarkers predictive of response to optimize post-immunotherapy treatment selection. Additionally, comparative trials against alternative second-line agents would solidify standard of care.
Conclusion
The KCSG HB23-04 trial provides the first prospective evidence supporting lenvatinib as an effective and tolerable second-line option for patients with advanced unresectable HCC after progression on first-line atezolizumab plus bevacizumab. By meeting the primary endpoint for PFS and demonstrating encouraging overall survival and response outcomes, lenvatinib emerges as a valuable therapeutic strategy in a clinical scenario with limited evidence-based options. Its manageable safety profile facilitates clinical adoption. This study importantly guides clinicians managing HCC in integrating lenvatinib into treatment algorithms post-immunotherapy failure and sets the stage for future trials to optimize sequential therapy paradigms.
Funding and Clinical Trial Registration
The trial was investigator-initiated and conducted across multiple centers in South Korea. Clinical trial registration number: NCT06138769.
References
Kim HD, Sym SJ, Chon HJ, Kim M, Kang JH, Ryoo BY, Lee CK, Hong J, Ryu H, Bae WK, Kim H, Kim H, Kim JW, Kim TY, Yoo C. Multicenter phase II trial of lenvatinib in patients with advanced hepatocellular carcinoma after progression on first-line atezolizumab plus bevacizumab. J Hepatol. 2025 Sep 4:S0168-8278(25)02457-2. doi: 10.1016/j.jhep.2025.08.020. Epub ahead of print. PMID: 41038766.
