Lenvatinib continuation versus regorafenib in treating hepatocellular carcinoma after lenvatinib failure

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common cancer globally and the third leading cause of cancer-related death (1). Over 70% of HCC patients are diagnosed at an advanced stage, often with vascular invasion and distant metastasis, by which stage the opportunity for curative treatments has passed (2,3).

Currently, the standard first-line treatments for advanced HCC include immune checkpoint inhibitors (ICIs) combinations such as atezolizumab plus bevacizumab, as well as multi-target tyrosine kinase inhibitors (TKIs), such as sorafenib and lenvatinib (4). Although immunotherapy is currently the best treatment combination, the progression-free survival (PFS) for these treatments ranges from 5.5 to 7.4 months, meaning that over half of the patients require a switch to a second-line treatment after seven months (5-8). For many years, sorafenib was the only first-line option, and second-line therapies, such as regorafenib, cabozantinib, and ramucirumab, were developed based on patients progressing on sorafenib (9-11). Regorafenib, the first established second-line treatment for HCC, demonstrated significant survival benefits after sorafenib failure.

However, following the REFLECT trial, lenvatinib rapidly emerged as a widely adopted option for first-line treatment, due to the limited efficacy of sorafenib and the restrictive insurance coverage for ICIs combinations. Given that lenvatinib and regorafenib share significant target overlap, particularly VEGFR, PDGFR, and KIT, questions arise about regorafenib’s efficacy following lenvatinib failure (12). Most prior studies on this topic have been limited by small sample sizes and single-arm designs, leaving a gap in understanding the optimal second-line treatment after lenvatinib failure (13-15).

This study aimed to compare the efficacy and safety of continuing lenvatinib treatment (LEN-CON group) versus switching to regorafenib (LEN-RG group) as second-line treatments after lenvatinib failure in real-world settings. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-615/rc).

Methods

Study design

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The Third Affiliated Hospital of Sun Yat-sen University (No. IIT-2024-10-034) and the requirement for individual consent for this retrospective analysis was waived. We retrospectively screened the electronic medical records of 871 consecutive HCC patients treated with lenvatinib at The Third Affiliated Hospital of Sun Yat-sen University between January 2019 and October 2021. Patients were included if they met the following criteria: (I) aged 18–75 years; (II) diagnosed with HCC according to European Association for the Study of the Liver guidelines (16); (III) Child-Pugh class A or B; (IV) Eastern Cooperative Oncology Group (ECOG) performance status of 0–1; (V) radiological progression after first-line lenvatinib; and (VI) second-line treatment involving either continued lenvatinib or a switch to regorafenib. The exclusion criteria were as follows: (I) previous targeted therapy other than lenvatinib; (II) monotherapy with immunotherapy as first-line or second-line treatment; (III) concurrent other malignant tumors; and (IV) severe liver or kidney dysfunction or coagulation disorders.

Treatment

The multidisciplinary treatment team determined the treatment strategy. Lenvatinib was dosed at 8 mg daily for patients under 60 kg and 12 mg for those 60 kg and above. Regorafenib was initiated at 120 mg/day and adjusted to 160 mg/day depending on tolerance, administered for 3 weeks of each 4-week cycle. For adverse events (AEs) of grades 1–2, symptomatic treatment was administered without dose adjustment or treatment interruption. In the case of grade 3–4 AEs, doses were appropriately reduced, or treatment was temporarily halted based on the patient’s safety and tolerance. Throughout systemic therapy, the attending physician determined whether to proceed with hepatectomy or local treatments, including transarterial chemoembolization, ablation, and hepatic artery infusion chemotherapy, based on clinical benefit. The treatment course might involve the combination of programmed cell death 1 (PD-1) antibody immunotherapy, but not in an ICI combination regimen, such as atezolizumab plus bevacizumab.

Assessment

Efficacy was assessed every 4–6 weeks using contrast-enhanced multiphasic computed tomography (CT) or magnetic resonance imaging (MRI), with serum biomarkers [alpha-fetoprotein (AFP), liver function, and blood counts] recorded. Overall survival (OS) was defined as the time from lenvatinib initiation to death from any cause or the last follow-up (31 August 2024). Post-progression survival (PPS) was measured from the first occurrence of progressive disease (PD) to death or the last follow-up date. Total progression-free survival (TPFS) was defined as the time from lenvatinib initiation to progression after second-line therapy or last follow-up. Post-second-line PFS was calculated from the first progression to the next progression or last follow-up. PD was assessed according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria by two independent radiologists (17). The following conditions were considered indicative of PD: (I) new intrahepatic lesions or macrovascular invasion; (II) new extrahepatic metastases; and (III) an increase in the sum of the longest diameter of the target lesions by more than 20% compared to the smallest recorded value in the enhanced area. AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Statistical analysis

Data were expressed as mean ± standard deviation (SD), median [interquartile range (IQR)], or number (%). Group comparisons for continuous and categorical variables were performed using the Student’s t-test/Mann-Whitney U test and chi-square/Fisher’s exact test, respectively. Time-to-event endpoints (OS, PPS, TPFS, post-second-line PFS) were estimated by the Kaplan-Meier method and compared via the log-rank test. The Cox proportional hazards model was employed for univariate and multivariate analyses. Variables achieving a significance level of P<0.10 in univariate analysis were entered into the multivariate model using the Forward Likelihood Ratio method. Subgroup analyses were conducted to assess the consistency of treatment effects. The statistical significance for all final analyses was set at a two-sided P<0.05, using the software SPSS 26.0 (IBM Corp., Armonk, NY, USA).

Results

The study included 107 consecutive patients who met the inclusion criteria, with 49 in the LEN-RG group and 58 in the LEN-CON group, as shown in Figure 1. The baseline characteristics of both groups were balanced (Table 1). The majority of patients in both groups were at Barcelona Clinic Liver Cancer stage C when starting lenvatinib treatment, with 40 patients (81.6%) in the LEN-RG group and 42 patients (72.4%) in the LEN-CON group. During treatment, 34 patients (69.4%) in the LEN-RG group and 33 patients (56.9%) in the LEN-CON group were co-treated with PD-1 inhibitors. Notably, due to the majority of patients having benefited from prior treatment, the maximum tumor diameter of patients in the LEN-RG group was 30.0 cm (IQR, 23.0–50.0 cm) at the time of lenvatinib failure, whereas it was 32.5 cm (IQR, 14.0–53.0 cm) in the LEN-CON group. The characteristic radiographic features of patients who continued lenvatinib therapy following treatment failure are demonstrated in Figure 2.

Figure 1 Flowchart of the study. HCC, hepatocellular carcinoma; LEN-CON, lenvatinib continuation group; LEN-RG, lenvatinib-regorafenib group.TKI, tyrosine kinase inhibitor.

Figure 2 Treatment response in two HCC patients continuing lenvatinib after progression. Patient 1: (A) the primary HCC lesion; (B) multiple new intrahepatic metastatic foci following multidisciplinary therapy; (C) marked regression of the metastatic foci with necrotic changes after continuation of lenvatinib therapy. Patient 2: (D) the primary HCC lesion; (E) de novo multifocal intrahepatic metastases under post-resection adjuvant lenvatinib therapy; (F) significant tumor shrinkage and necrotic degeneration upon sustained lenvatinib administration. The red arrows highlight the small tumor nodules identified in the treated group. HCC, hepatocellular carcinoma.

As of 31 August 2024, the median follow-up time was 48.1 months (IQR, 39.3–57.6 months) for the LEN-RG group and 41.1 months (IQR, 37.2–45.3 months) for the LEN-CON group. In the LEN-RG group, 39 patients (79.6%) had died, compared with 34 patients (58.6%) in the LEN-CON group. As shown in Figure 3A, the median OS was 34.4 months [95% confidence interval (CI): 22.4–46.4] in the LEN-CON group and 21.8 months (95% CI: 18.56–25.05) in the LEN-RG group, showing a trend towards better survival in the LEN-CON group [hazard ratio (HR) 0.64, 95% CI: 0.40–1.02, P=0.058]. To further assess PPS, we compared the two groups (Figure 3B). The LEN-CON group had a median PPS of 25.87 months (95% CI: 15.35–36.38), compared to 15.33 months (95% CI: 7.39–23.28) in the LEN-RG group, showing a significant difference (HR 0.58, 95% CI: 0.37–0.93, P=0.019).

Figure 3 Kaplan-Meier curves showing overall survival (A) and post-progression survival (B) of each group. LEN-CON, lenvatinib continuation group; LEN-RG, lenvatinib-regorafenib group.

However, there was no significant difference in TPFS between the LEN-CON and LEN-RG groups [10.86 months (95% CI: 8.00–13.73) vs. 13.63 months (95% CI: 7.10–20.17); HR 1.24, 95% CI: 0.83–1.85, P=0.290, Figure 4A). Similarly, Post-Second-Line PFS showed no significant difference [4.06 months (95% CI: 3.05–5.08) vs. 3.3 months (95% CI: 2.57–4.03); HR 0.96, 95% CI: 0.65–1.44, P=0.858, Figure 4B).

Figure 4 Kaplan-Meier curves showing total PFS (A) and post-second-line PFS (B) of each group. LEN-CON, lenvatinib continuation group; LEN-RG, lenvatinib-regorafenib group; PFS, progression-free survival.

Univariate and multivariate Cox regression analyses of PPS (Table 2) identified several important prognostic factors, including ECOG performance status (HR 1.78, 95% CI: 1.08–2.94; P=0.025), extrahepatic metastasis (HR 4.55, 95% CI: 2.63–7.87, P<0.001), PD-1 combination therapy (HR 2.19, 95% CI: 1.30–3.70; P=0.003), nodule number (HR 5.19, 95% CI: 2.35–11.44; P<0.001), and treatment strategy (HR 0.6, 95% CI: 0.36–1.00, P=0.05). Subgroup analysis (Figure 5) revealed that in patients with ECOG 0, Child-Pugh A, male sex, PD-1 combination therapy, multiple tumors, and AFP ≤400 ng/mL, the LEN-CON group showed clinical benefit in PPS.

Figure 5 Forest plots with subgroup analysis for factors associated with PPS. AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; LEN-CON, lenvatinib continuation group; LEN-RG, lenvatinib-regorafenib group; PD-1, programmed cell death 1; PVTT, portal vein tumor thrombus.

AEs

Table 3 summarizes common AEs, with no treatment-related deaths in either group. Over 30% of patients in both groups experienced AEs such as diarrhea, thrombocytopenia, anemia, elevated aspartate transaminase (AST), elevated alanine transaminase (ALT), hypoalbuminemia, and hand/foot skin reaction, with no significant differences between the groups. However, grade 3–4 AEs, including thrombocytopenia, anemia, elevated AST, and elevated ALT, were more common in the LEN-RG group, with ALT elevation significantly higher than in the LEN-CON group (8.2% vs. 0%, P=0.041).

Discussion

The RESORCE study established regorafenib as the earliest recommended second-line treatment option that significantly improved both OS and PFS compared to placebo after sorafenib. However, these findings were based on data from patients progressing after sorafenib, and it remains unclear whether these results apply to patients failing after lenvatinib, which has become the most widely used first-line therapy. This retrospective study compared the efficacy and safety of lenvatinib continuation versus switching to regorafenib in patients with unresectable HCC who progressed on lenvatinib. Although there was no significant difference in TPFS or post-second-line PFS between the two groups, the LEN-CON group demonstrated a favorable trend in OS and significantly improved patient survival in subsequent survival analysis.

In this study, regorafenib-treated patients had a post-second-line PFS of 3.3 months and a PPS of 14.2 months—seemingly better than the RESORCE trial. However, direct comparisons are not appropriate, as most patients in this study were treated with PD-1 inhibitors, reflecting real-world clinical practice, whereas the RESORCE trial was based on sequential treatment following sorafenib. Currently, multiple studies are exploring second-line therapies after lenvatinib failure (13-15). Hiraoka et al.’s study demonstrated that continuing lenvatinib after progression, compared to switching to other treatments, including regorafenib, can extend OS by approximately 8.4 months (19.6 vs. 11.2 months), suggesting that continuing lenvatinib might be a reasonable therapeutic option after progression (18). However, most of these studies were either small-sample or single-arm trials with more complex confounding factors in the control groups. Although switching to regorafenib may be effective, this study sought to determine whether continuing lenvatinib offers greater benefit to patients.

Sorafenib primarily targets VEGFR, PDGFR, Raf-1, and B-Raf, focusing on anti-angiogenesis and the RAF/MEK/ERK signaling pathway (19). Regorafenib shares VEGFR and PDGFR targets but also inhibits KIT, RET, TIE2, and FGFR1, all of which are crucial for tumor angiogenesis and proliferation (20). This broader target spectrum may explain why regorafenib remains effective as a second-line treatment after sorafenib by inhibiting pathways not targeted by sorafenib. Meanwhile, lenvatinib also targets VEGFR and PDGFR but has a broader profile than regorafenib, including effective inhibition of FGFR, which plays a key role in HCC progression, as well as KIT and RET. The overlapping inhibition of VEGFR and PDGFR by lenvatinib and regorafenib may reduce the therapeutic effect when switching from lenvatinib to regorafenib, as these pathways were already suppressed during lenvatinib treatment. Additionally, regorafenib has weaker inhibitory activity against FGFR, a critical target in HCC treatment for lenvatinib (21). This overlap may contribute to the diminished efficacy observed when switching to regorafenib after lenvatinib.

This study has several limitations. First, although the baseline data were relatively balanced, the inherent selection bias of a retrospective study cannot be avoided. Second, after progression according to mRECIST criteria, individualized treatment decisions were made by the attending physicians, which could have introduced bias. Third, most patients in this study received PD-1 inhibitors in combination with TKIs during treatment, which reflects real-world clinical practice. However, the sample size was limited, and despite conducting further subgroup analyses, there were still many confounding factors. In addition, this was a single-center study conducted in China, where hepatitis B virus (HBV) infection remains the predominant etiology of HCC. Accordingly, the vast majority of patients included had HBV-related HCC, which may restrict the generalizability of our findings to populations in which metabolic dysfunction-associated steatotic liver disease (MASLD) or other etiologies are more prevalent. Nevertheless, we believe that our results provide meaningful preliminary evidence that can inform clinical decision-making in HBV-endemic regions. Future multicenter studies with more diverse patient populations are warranted to further validate and expand upon our findings. Finally, we plan to conduct prospective randomized controlled trials to confirm these results.

Conclusions

Continuing lenvatinib as second-line therapy after failure on lenvatinib may offer sustained survival benefits, with good efficacy and safety in real-world practice. These findings warrant further validation through randomized controlled trials.

Acknowledgments

We would like to express our sincere gratitude to the Department of Interventional Radiology and the Department of Radiology at The Third Affiliated Hospital of Sun Yat-sen University for their support and assistance throughout this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-615/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-615/dss

Funding: This work was supported by the Guangzhou Science and Technology Plan Project (No. 2023A04J0419) and the National Natural Science Foundation Cultivation Project at The Third Affiliated Hospital of Sun Yat-sen University (No. 2022GZRPYQN04).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-615/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The Third Affiliated Hospital of Sun Yat-sen University (No. IIT-2024-10-034) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: J. Jones)