This multinational, multicenter, retrospective analysis of patients with recurrent HCC after LT demonstrated that lenvatinib showed an ORR of 20.0% and median PFS and OS of 7.6 and 14.5 months, respectively. Our findings on the efficacy and safety of lenvatinib in patients with LT were comparable to those of the pivotal phase 3 REFLECT trial (ORR per RECIST v1.1 of 18.8%, median PFS of 7.4 months, and median OS of 13.6 months), which excluded patients with prior LT , and with previous real-world studies [12–15]. Our findings validate the clinical relevance of lenvatinib in patients with recurrent HCC following LT.
Although immune checkpoint inhibitors are now regarded as key components of the management of patients with advanced HCC [16–18], patients with prior LT may not benefit because of the risk of allograft rejection . Therefore, targeted agents, mainly MKIs, should be the mainstay of 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 well demonstrated.
As sorafenib is the only systemic therapy approved for unresectable or metastatic HCC, most studies of systemic therapy in patients with recurrent HCC after LT have included sorafenib [20–24], although most of them 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 achieving CR and PR was 0% (range, 0–11.7%) and 4.8% (range, 0–26.7%), respectively . 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 the current study, although a direct comparison between our results for lenvatinib and those for sorafenib in previous studies was not possible. Further studies are necessary to define the optimal first-line therapy in patients with recurrent HCC following LT.
Previous studies have shown that baseline liver function classified by ALBI grade is associated with the efficacy of lenvatinib in non-LT patients with unresectable or metastatic HCC . Consistent with these results, a lower ALBI grade was significantly associated with better OS and marginally related with better PFS with lenvatinib in our study population. As multiple targeted agents become available for the management of HCC, it may be important to provide timely initiation of these drugs prior to the deterioration of liver function, even in patients with prior LT, considering that repeated TACE may induce the deterioration of liver function [26–27]. Meanwhile, 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 . Large multicenter studies are needed to define the relevant immunosuppressive regimens in combination with anti-cancer agents for recurrent HCC after LT.
The safety profiles of lenvatinib in patients with prior LT were consistent with the results of the REFLECT trial and other real-world studies of lenvatinib in non-LT HCC patients [8, 12, 28]. Although multiple immunosuppressants were used simultaneously with lenvatinib, there was no new safety signal observed for lenvatinib in the current study. There were discrepancies in the pattern of AEs between different ethnicities (more frequent hematological AEs in Asian patients and anorexia in Caucasian patients), but it is not clear whether these were due to ethnicity-related differences in the pharmacokinetics of lenvatinib.
Our study was limited by its retrospective design, which is subject to unintentional biases. 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 did include a diverse range of ethnic groups from multiple countries under various patterns of clinical practice.
In conclusion, lenvatinib showed consistent efficacy and toxicity in patients with recurrent HCC following LT compared to those of 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.