Efficacy and safety of lenvatinib in patients with recurrent hepatocellular carcinoma after liver transplantation

Abstract Introduction Lenvatinib is approved for the treatment of patients with metastatic or recurrent hepatocellular carcinoma (HCC); however, clinical outcomes of lenvatinib therapy in patients with post‐liver transplantation (LT) HCC recurrence remain unclear. We investigated the efficacy and safety of lenvatinib in patients with post‐LT HCC recurrence. Methods This multinational, multicenter, retrospective study included 45 patients with recurrent HCC after LT who received lenvatinib at six institutions in three countries (Korea, Italy, and Hong Kong) from June 2017 to October 2021. Results At the time of lenvatinib initiation, 95.6% (n = 43) of patients had Child–Pugh A status, and 35 (77.8%) and 10 (22.2%) participants were classified as having albumin–bilirubin (ALBI) grades 1 and 2, respectively. The objective response rate was 20.0%. With a median follow‐up duration of 12.9 months (95% confidence interval [CI]: 11.2–14.7), the median progression‐free survival and overall survival (OS) were 7.6 (95% CI: 5.3–9.8) months, and 14.5 (95% CI: 0.8–28.2) months, respectively. Patients with ALBI grade 1 showed significantly better OS (52.3 months, [95% CI: not assessable]) than patients with ALBI grade 2 (11.1 months [95% CI: 0.0–30.4 months], p = 0.003). The most common adverse events were hypertension (n = 25, 55.6%), fatigue (n = 17, 37.8%), and anorexia (n = 14, 31.1%). Conclusion Lenvatinib showed consistent efficacy and toxicity profiles in patients with post‐LT HCC recurrence that were comparable to those reported from previous studies among non‐LT HCC patients. The baseline ALBI grade correlated with better OS in post‐LT lenvatinib‐treated patients.


| INTRODUCTION
Worldwide, hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related mortality. 1 HCC is an extremely heterogenous disease, and the selection of the treatment strategy may vary, based on tumor burden, the degree of underlying liver cirrhosis, and the patient's performance status. Surgical resection, liver transplantation (LT), and locoregional therapies, such as radiofrequency ablation (RFA), are all potentially curative therapeutic modalities for patients with early-stage HCC. 2 LT offers the possibility of curing both the tumor and underlying liver diseases, including cirrhosis. However, post-LT HCC recurrence has been reported in 10%-18% of patients, and the median interval from LT to HCC recurrence is 12-13 months. [3][4][5] Based on the recurrence pattern in patients with post-LT HCC recurrence, local therapies such as RFA, transarterial chemoembolization (TACE), and surgical resection may be considered. Systemic therapy should be considered in patients with extrahepatic metastasis or for those whose tumors may be refractory to local therapy. 5 For more than a decade, sorafenib -an oral multikinase inhibitor (MKI) -was the only systemic drug that was available for patients with post-LT HCC recurrence. Moreover, most of the small retrospective studies that evaluated the outcomes of sorafenib treatment have shown variable clinical outcomes, with 1-year overall survival (OS) rates of 18%-90%. 6,7 Lenvatinib is an MKI for vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor receptors 1-4, PDGFRα, RET, and KIT. In a phase 3, multicenter, randomized trial (REFLECT), as compared with sorafenib, lenvatinib demonstrated non-inferior OS and statistically significant improvements in progression-free survival (PFS), time to progression, and the objective response rate (ORR). 8 Based on the abovementioned data, lenvatinib was approved as a first-line standard therapy for unresectable or metastatic HCC. However, patients with prior LT were excluded from prospective studies of lenvatinib. [8][9][10] As only a limited number of studies, with most including <15 patients, have been reported, [11][12][13][14] further investigation is required to assess the efficacy and safety of lenvatinib in patients with post-LT HCC recurrence. Therefore, we conducted a multinational, multicenter, retrospective study of lenvatinib in patients with post-LT HCC recurrence.

| Patients
Patients who were treated with lenvatinib for post-LT HCC recurrence from June 2017 to October 2021 were identified from six centers in three countries (Korea, Italy, and Hong Kong). Clinical and laboratory data were retrospectively obtained by reviewing the electronic medical records. This study was approved by the institutional review board of each participating center and was performed in accordance with the ethical standards specified in the institutional research guidelines and the principles evinced in the Declaration of Helsinki.
Conclusion: Lenvatinib showed consistent efficacy and toxicity profiles in patients with post-LT HCC recurrence that were comparable to those reported from previous studies among non-LT HCC patients. The baseline ALBI grade correlated with better OS in post-LT lenvatinib-treated patients.

K E Y W O R D S
Albumin-bilirubin grade, chemotherapy, hepatocellular carcinoma, lenvatinib, liver transplantation was described in the REFLECT trial (12 or 8 mg/day for patients with body weight ≥60 or <60 kg, respectively). 8 Dose modification (to 8 or 4 mg/day) at the initiation or during the lenvatinib treatment course was allowed at the discretion of the attending physicians.
Patients underwent computed tomography or magnetic resonance imaging every 6-8 weeks for the assessment of the tumor status. The investigators from various institutions graded the tumor response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). All treatment-related adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

| Statistical analysis
The ORR and disease control rate (DCR) were evaluated according to the RECIST v1.1. PFS was defined as the interval from the initiation of lenvatinib to the date of disease progression or death, whichever occurred first. OS was defined as the time from the initiation of lenvatinib to death from any cause. The time to response (TTR) was defined as the interval between the initiation of lenvatinib and the best response. Survival outcomes were estimated using the Kaplan-Meier method. A two-sided p-value <0.05 was considered statistically significant. All statistical analyses were performed using the Statistical Package for the Social Sciences version 23.0 (IBM).

| Patient characteristics
A total of 45 patients who received lenvatinib for post-LT recurrent HCC were included in this analysis. The baseline patient characteristics are summarized in Table 1. The median age was 59 years (range, 20-87 years), and the majority of the study population (n = 43, 95.6%) was male. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. The most common HCC etiology was hepatitis B (n = 25, 55.6%), followed by hepatitis C (n = 11, 24.4%) and alcohol consumption (n = 4, 8.9%).
Most patients (n = 42, 93.3%) received lenvatinib as the first-line therapy. Three patients (6.7%) received lenvatinib as a second-line therapy after progression on firstline sorafenib. The median interval between LT and the initiation of lenvatinib therapy was 28.1 months (range, 4.2-231.9 months), and the starting dose of lenvatinib was 12 mg/day for 29 patients (64.4%) and 8 mg/day for the remaining 15 patients (33.3%). Seven patients with a body weight > 60 kg received a reduced starting dose of lenvatinib, and the commonest reasons for the dose down-titration were decreased renal (n = 2) and hepatic (n = 1) function and tumor bleeding (n = 1). At the data cutoff point (December 9, 2021), 13 (28.9%) patients were receiving lenvatinib treatment (1.0+ to 20.0+ months), and the median duration of lenvatinib treatment was 6.6 months (range, 0.1-20.0 months). Tumor progression was the commonest reason for the discontinuation of lenvatinib (28 of 35, 80.0%). Seventeen patients died, and the cause of death for all of these patients was HCC progression.
AEs that occurred in >5% of patients are listed in Table 3. The majority (n = 44, 97.8%) of patients experienced an AE. Hypertension (n = 25, 55.6%) was the most frequent AE, followed by fatigue (n = 17, 37.8%), and liver enzyme elevation (n = 17, 37.8%). The most common grade 3-4 AEs were hypertension (n = 9, 20.0%) and neutropenia (n = 4, 8.9%). Four (8.9%) patients discontinued lenvatinib due to AEs (n = 2, grade 3 hypertension; n = 1, grade 3 proteinuria; n = 1, grade 3 fatigue). Although immune checkpoint inhibitors are now considered key treatment components in the management of patients with advanced HCC, [19][20][21] patients with prior LT may not benefit from the abovementioned therapy because of the risk of allograft rejection. 22 Therefore, F I G U R E 1 Kaplan-Meier curves of (A) PFS and (B) OS following lenvatinib therapy in patients with recurrent hepatocellular carcinoma after liver transplantation. CI, confidence interval; OS, overall survival; PFS, progression-free survival. targeted agents, mainly MKIs, should be the mainstay for managing patients with unresectable or metastatic HCC following LT. However, as patients with prior LT have been excluded from previous prospective randomized trials of currently approved agents for unresectable or metastatic HCC, an optimal strategy for systemic therapy in patients with recurrent HCC following LT has not been established.

| DISCUSSION
As sorafenib is the only systemic therapy that has been approved for unresectable or metastatic HCC, most studies of systemic therapy in patients with recurrent HCC after LT have included sorafenib [23][24][25][26][27] ; however, most of the abovementioned studies had small sample sizes (n = 5-50). In a previous meta-analysis of sorafenib for patients with recurrent HCC after LT, the median OS was 10.5 months (range, 5-21.3 months) and the median percentage of patients who achieved CR and PR was 0% (range, 0%-11.7%) and 4.8% (range, 0%-26.7%), respectively. 6 Our findings suggest that lenvatinib may have better efficacy outcomes than sorafenib, as the ORR was 20% and the median OS was 14.5 months in our study, although a direct comparison between our results for lenvatinib and those that were reported for sorafenib in previous studies was not feasible. Further studies are necessary to define the optimal first-line therapy in patients with post-LT HCC recurrence.
Previous studies have shown that baseline liver function, as classified by the ALBI grade, is associated with the efficacy of lenvatinib in non-LT patients with unresectable or metastatic HCC. 28 Consistent with these results, a lower ALBI grade was significantly associated with better OS and was marginally related with better PFS with lenvatinib therapy in our study population. As multiple targeted agents become available for the management of HCC, it may be important to facilitate timely initiation of these drugs prior to the deterioration of liver function, even in patients with a prior LT, because repeated TACE may induce deterioration of liver function. 29,30 Nonetheless, immunosuppressants were not associated with the efficacy of lenvatinib against recurrent HCC following LT, although a previous study for combination of sorafenib and mTOR inhibitors, including EVE, showed favorable survival outcomes. 27 There were four cases in which the TAC dose was adjusted. The TAC dose was increased only in one participant due to the decreased FK level during lenvatinib therapy. Of the other three patients who had their TAC dose reduced during lenvatinib treatment, one patient reduced the TAC dose and discontinued EVE due to proteinuria. However, none of the patients had graft rejection. Large multicenter studies are needed to define the relevant immunosuppressive regimens in combination with anticancer agents for post-LT HCC recurrence.

T A B L E 3 Adverse events during lenvatinib treatment
It is relevant to mention the limitations of our study, including the retrospective design, which is subject to unintentional biases. As almost all of the participants (95.6%) were male, this imbalance in the sex distribution may limit the generalizability of the results. Although the current analysis was based on the largest sample size for patients with prior LT, multivariate analysis to define the prognostic factors could not be performed because of insufficient statistical power. However, we included a diverse range of ethnic groups from multiple countries under various patterns of clinical practice.

| CONCLUSIONS
In conclusion, lenvatinib showed consistent efficacy and toxicity patterns in patients with post-LT HCC recurrence compared to those identified in the pivotal phase 3 REFLECT trial, which excluded patients with prior LT. Better liver function (ALBI grade 1) at the time of lenvatinib initiation correlated with better survival outcomes.

FUNDING INFORMATION
This research received no specific grant from any public, commercial, or not-for-profit funding agency.