Abstract
Background/Aim: The combination of atezolizumab plus bevacizumab (Atz/Bev) has become widely used as a first-line therapy for advanced hepatocellular carcinoma (HCC). However, for post-Atz/Bev therapy, evidence on the outcomes of molecular targeted agents, such as lenvatinib, is limited. The present study aimed to assess the clinical effectiveness of lenvatinib on advanced HCC in patients who had previously undergone Atz/Bev treatment. Patients and Methods: Twenty patients with HCC, who received lenvatinib after Atz/Bev treatment, were enrolled in the study. In particular, we examined the impact of adverse events (AEs), such as anorexia and general fatigue. During the treatment, lenvatinib dosages were adjusted or temporarily discontinued in response to AEs. Treatment outcomes were retrospectively evaluated. Results: The objective response rate (ORR) and disease control rate (DCR) for lenvatinib treatment were 25.0% and 95.0%, respectively, according to the Response Evaluation Criteria in Solid Tumors. The median progression-free survival (PFS) was 6.0 months, and the median overall survival (OS) was 10.5 months. Eleven patients experienced anorexia or fatigue, leading to a reduction in the dose of lenvatinib but not to a significant difference in the time to drug discontinuation. Importantly, there were no significant differences between the 11 anorexia/fatigue-suffering patients and the nine other patients with regard to PFS and OS. Conclusion: Lenvatinib can be efficacious and safe for treating advanced HCC patients previously treated with Atz/Bev, and AEs such as anorexia and general fatigue can be effectively managed without losing lenvatinib’s therapeutic benefits.
- Atezolizumab/bevacizumab
- lenvatinib
- hepatocellular carcinoma
- liver function
- post-progression treatment
- adverse event
- anorexia
- general fatigue
After 2020, based on the positive results of the IMbrave150 trial, the combination of atezolizumab plus bevacizumab (Atz/Bev) became widely used in clinical practice as a first-line therapy for patients with advanced hepatocellular carcinoma (HCC) (1, 2). Atezolizumab and bevacizumab are antibodies that bind/inhibit PD-L1, an immune checkpoint protein, and VEGF, a growth factor, respectively. In 2022, the combination of durvalumab and tremelimumab (Dur/Tre) was also approved for use in the first-line setting (3). Durvalumab and tremelimumab are antibodies that bind/inhibit the immune checkpoint proteins PD-L1 and CTLA-4, respectively. In cases where disease progression is observed following treatment with Atz/Bev or Dur/Tre, five molecular targeted agents (MTAs), namely sorafenib, regorafenib, lenvatinib, ramucirumab and cabozantinib, can be used as second-line therapy for patients diagnosed with advanced HCC (4). The American Association for the Study of the Liver Diseases (AASLD) guidelines weakly recommend sorafenib and lenvatinib as second-line therapy, and indeed these two drugs are frequently used in clinical practice (5). However, evidence on the outcomes of these MTAs as second-line therapy is limited.
Lenvatinib is a tyrosine kinase inhibitor (TKI) that selectively targets multiple receptors involved in cell growth and angiogenesis, such as vascular endothelial growth factor receptors (VEGFR) 1-3, fibroblast growth factor receptors (FGFR) 1-4 and other associated receptors (6, 7). By blocking these pathways, lenvatinib can effectively inhibit tumor progression (8, 9). In 2018, results from the REFLECT trial demonstrated non-inferiority of lenvatinib compared to sorafenib in patients with unresectable HCC (10). As a result, lenvatinib was adopted as a first-line treatment along with sorafenib, although the current first-line treatment has shifted toward using Atz/Bev or Dur/Tre (5, 11). By suppressing VEGF signaling (12), lenvatinib inhibits angiogenesis within tumors and thereby normalizes the vasculature (13). This normalization process facilitates the infiltration of immune cells, such as cytotoxic T cells, into the tumor (14, 15). Therefore, in drug therapy for HCC, lenvatinib is expected to interact synergistically with immune checkpoint inhibitors (ICIs) that have durable effects (16-18).
In clinical practice, lenvatinib is often given to patients who have previously received Atz/Bev, although there is limited data on its efficacy and safety (19-22). Therefore, the purpose of the present study was to evaluate the clinical efficacy of lenvatinib in patients with advanced HCC previously treated with Atz/Bev in real-world clinical practice. We also focused on the management of AEs such as fatigue or anorexia and their impact on the prognosis, as previous studies reported that general fatigue and anorexia led to an early discontinuation of lenvatinib and poor prognosis (23, 24).
Patients and Methods
Patients. From 25 patients with HCC who received lenvatinib after Atz/Bev at our institution from February 2021 to May 2023, after excluding 5 patients who were rechallenged with lenvatinib, 20 patients were enrolled in this study to retrospectively evaluate treatment outcomes. All study protocols were approved by the ethics committee at Fujita Health University School of Medicine and were conducted in accordance with the 1975 Declaration of Helsinki (approval no. HM17-152). Written informed consent for lenvatinib treatment was obtained from each patient, but informed consent was not required for participation in this study because of the retrospective design.
Lenvatinib dosage, assessment of adverse events and changes in liver function. The initial dose of lenvatinib recommended by the manufacturer is 12 mg/day for patients weighing 60 kg or more and 8 mg/day for patients weighing less than 60 kg. However, some patients received lower doses based on their condition, as determined from previous experiences with lenvatinib. The relative dose intensity (RDI) of lenvatinib was calculated as a percentage of the recommended starting dose. Adverse events (AEs) were evaluated using the Common Terminology Criteria for Adverse Events version 5.0. In case of a drug-related AE, the dose was adjusted or temporarily discontinued until the symptoms improved to grade 1 or 2, following the manufacturer’s guidelines. However, for the AEs of anorexia and fatigue, lenvatinib was reduced or discontinued prior to grade 3, based on the initial experience that in these cases unaltered continuation was more likely to cause deterioration in the hepatic reserve. Lenvatinib treatment continued until an unacceptable or severe AE occurred or clinical tumor progression was observed. To assess changes in liver function, Albumin-bilirubin (ALBI) scores (25) were determined at baseline, week 1, week 2, week 4 and week 6.
Evaluation of antitumor response. Anti-tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) (26) and modified RECIST (mRECIST) (27). Four-phase (non-enhanced, late arterial, portal venous, balanced) contrast-enhanced CT scans were performed at baseline and 6 weeks after lenvatinib administration, and every 4 to 10 weeks according to a predetermined schedule.
Statistical analysis. Statistical analysis was performed using Easy R (EZR) (28) version 1.61 (Saitama Medical Center, Jichi Medical University, Omiya, Japan). Progression-free survival (PFS), overall survival (OS), and Lenvatinib treatment duration were evaluated using the Kaplan–Meier method, and differences in survival were evaluated using the log-rank test. Factors with p<0.05 were considered significant.
Results
Baseline characteristics. Table I shows the baseline characteristics of the 20 patients with HCC at the start of lenvatinib treatment. The patients had a median age of 70 years (range=42-86 years). Among them, 17 patients (85.0%) were male, 14 (70.0%) had non-viral HCC, and 14 (70.0%) were at Barcelona Clinic Liver Cancer stage C. The median alpha-fetoprotein (AFP) level was 171 ng/ml (range=2.7-282,878 ng/ml). Regarding the Child-Pugh score, 12 patients had a score of 5, four patients had a score of 6, three patients had a score of 7, and one patient had a score of 9. In ECOG-PS, 12 patients (60.0%) had a score of 0. Lenvatinib was administered as second-line therapy in 19 patients and as third-line therapy in 1 patient. In addition, 9 patients (45.0%) started lenvatinib at doses that were lower than the recommended dose.
Baseline characteristics at initiation of lenvatinib treatment.
Efficacy. The best anti-tumor responses with lenvatinib based on RECIST or mRECIST in all 20 patients are summarized in Table II. According to RECIST, these included a complete response (CR) in zero patients, a partial response (PR) in five patients, stable disease (SD) in 14 patients, disease progression (PD) in zero patients and not evaluable (NE) in one patient. The objective response rate (ORR) was 25.0% and the disease control rate (DCR) was 95.0%. According to mRECIST, the responses were zero CR, 12 PR, seven SD, zero PD and one NE, while the ORR was 60.0% and the DCR was 95.0%. Of the 13 patients with baseline AFP ≥10 ng/ml, 10 (76.9%) had AFP levels lower than baseline at six weeks and eight (61.5%) had AFP levels below 80% (Table III). The median progression free survival (PFS) for all 20 patients was 6.0 months (range=3.0-37.8 months) (Figure 1A), and there was no significant difference in median PFS when stratified by ALBI grade (Figure 1B) or Child Pugh score (Figure 1C). The median overall survival (OS) for all 20 patients was 10.5 months (range=16.9-NR) (Figure 2A); the median OS was significantly longer in the ALBI grade 1/2a group (NR, range=7.2 months-NR) than in the 2b/c group (8.9 months, range=1.6-NR, p<0.018) (Figure 2B). The Child-Pugh A group (NR, range=7.2 months-NR) had a significantly longer median OS than the B group (6.7 months, range=1.6-NR, p<0.019) (Figure 2C). Table IV shows baseline factors associated with PFS and OS. There were no significant baseline factors associated with PFS according to univariate analysis. Univariate analysis found that prognostic factors associated with favorable OS were Child-Pugh class A and ALBI grade 1/2a.
Best antitumor response to lenvatinib according to Response Evaluation Criteria in Solid Tumors (RECIST) and Modified Response Evaluation Criteria in Solid Tumors (mRECIST).
Alfa-fetoprotein (AFP) ratio at 2 and 6 weeks after starting lenvatinib treatment (only for patients with baseline AFP >10 ng/ml, n=13).
Cumulative progression-free survival stratified by albumin-bilirubin grade or Child-Pugh score. (A) Cumulative progression-free survival (PFS) in all patients, (B) cumulative PFS in the albumin-bilirubin (ALBI) grade 1/2a and ALBI grade 2b/3 groups, and (C) cumulative PFS in the Child-Pugh A and Child-Pugh B groups.
Cumulative overall survival stratified by albumin-bilirubin grade or Child-Pugh score. (A) Cumulative overall survival (OS) in all patients, (B) cumulative OS in the albumin-bilirubin (ALBI) grade 1/2a and ALBI grade 2b/3 groups, and (C) cumulative OS in the Child-Pugh A and Child-Pugh B groups. NR: Not reached.
Univariate analyses of baseline factors associated with progression-free survival (PFS) and overall survival (OS).
Safety and tolerability. AEs that occurred within six weeks after initiation of lenvatinib and their gradings are listed in Table V. The most common AEs of all grades in all 20 patients were proteinuria (40.0%), anorexia (40.0%), general fatigue (40.0%) and hand-foot syndrome (35.0%), with grade 3 anorexia and grade 3 general fatigue each occurring in one patient. Anorexia or fatigue, of any grade, were found in 11 patients. These 11 patients did not show significant differences in any of the background factors compared to the 9 patients without fatigue or anorexia (Table VI).
Adverse events within 6 weeks of lenvatinib administration (total n=20).
Baseline characteristics at initiation of lenvatinib treatment (in patients with anorexia or fatigue and patients with none of these adverse events).
The median time to lenvatinib dose reduction was 14 days (range=7-14 days) (Figure 3A), and the median duration of lenvatinib treatment was six months (range=2.9-7.8 months) (Figure 3B). The median time to lenvatinib dose reduction in the group with anorexia or fatigue was 14 days (range=7-14 days), which was significantly shorter than the median of 28 days (range=7-NR) in the group without either of the two AEs (Figure 4A). In contrast, there was no significant difference in the time to drug discontinuation between the two groups (Figure 4B), and neither in PFS (Figure 5A) nor OS (Figure 5B).
Time to reduction or discontinuation of lenvatinib. (A) Cumulative time to dose reduction of lenvatinib in all patients, and (B) Cumulative time to discontinuation of lenvatinib in all patients.
Time to reduction or discontinuation of Lenvatinib stratified by the presence of fatigue/anorexia. (A) Cumulative time to dose reduction of lenvatinib in patients with adverse events (AEs) of anorexia or fatigue and patients with none of these AEs, and (B) Cumulative time to discontinuation of lenvatinib in patients with AEs of anorexia or fatigue and patients with none of these AEs.
Progression-free survival and overall survival stratified by the presence of fatigue/anorexia. (A) Cumulative progression-free survival (PFS) in patients with adverse events (AEs) of anorexia or fatigue and patients with none of these AEs, and (B) Cumulative overall survival (OS) in patients with AEs of anorexia or fatigue and patients with none of these AEs.
The median RDI of lenvatinib up to six weeks in 20 patients was 53.35% (range=19.4-100%). The median RDI was 50.4% (range=19.4-77.8%) in the group with anorexia/fatigue and 57.1% (range=27.8-100%) in the group without either of the two AEs (p=0.879).
The development of the ALBI score within 6 weeks was assessed in all 20 patients. In the group with anorexia or general fatigue, there was a trend toward worsening of the ALBI score early in the treatment period, but the difference was not significant (Figure 6).
Change in albumin-bilirubin scores by the presence of fatigue/anorexia. Changes in albumin–bilirubin (ALBI) scores within 6 weeks after lenvatinib initiation in patients with adverse events (AEs) of anorexia or fatigue and patients with none of these AEs.
Discussion
To the best of our knowledge, there have only been a few reports evaluating the efficacy and safety of lenvatinib in patients previously treated with Atz/Bev in real-world clinical practice (19-21). Recently, Hiraoka et al. (22) reported on lenvatinib treatment in 101 patients previously treated with Atz/Bev, which has been the largest study so far. The results showed a median PFS of 4.4 months, a median OS of 13.6 months, mRECIST ORR and DCR of 23.9% and 70.4%, respectively, and RECIST ORR and DCR of 15.4% and 66.2%, respectively (22). The main findings of that report (22), and of the others reports available to date (19-21), are compared with our present findings in Table VII. In comparison, the antitumor response rates observed in the present study were favorable. A significant contributor to this favorable outcome in our group of patients may have been the good baseline hepatic reserve, with 75% of patients having a Child-Pugh score of 5. Ueshima et al. previously reported that baseline liver function was closely associated with ORR, frequency of AEs and duration of treatment in lenvatinib therapy (29). We found that a Child-Pugh score of 5 and an ALBI grade of 1 were predictive of an extended treatment with lenvatinib and an improved outcome (Figure 2). Consequently, when transitioning to second-line therapy, it would be important to recognize a suboptimal efficacy of the first-line therapy early on and to initiate the second-line therapy prior to deterioration of the hepatic reserve.
Reports on lenvatinib treatment outcome after Atz/Bev.
Patients in the present study were closely monitored from early during their lenvatinib therapy, and their AEs were comprehensively evaluated. It is well known that various AEs during MTA treatment often require dose reduction or discontinuation (30-32). Particularly if using an MTA as second-line or later-line therapy, attention to AEs is crucial because pre-existing AEs from the previous therapy may exacerbate the situation (33). In HCC patients, special attention should be given to anorexia and general fatigue as they tend to lead to a deterioration of liver function (23). In the present study, patients who developed anorexia and general fatigue received early dose reductions of lenvatinib (Figure 4A). This resulted in only one patient experiencing grade 3 AEs, and an absence of significant differences between the anorexia/fatigue group and the non-anorexia/fatigue group in ALBI score (Table VI), time to discontinuation (Figure 4B), PFS and OS (Figure 5). Thus, by adequately monitoring patients and matching the dose of lenvatinib, AEs could be safely managed, and the results suggest that this enables even advanced HCC patients with symptoms of anorexia or fatigue to experience a normal level of benefits from lenvatinib treatment.
The desired effects of ICIs (e.g., atezolizumab or bevacizumab) on the immune system tend to be long-lasting, and, after treatment of HCC patients with ICIs, favorable effects have been reported for the use of the anti-VEGFR-2 monoclonal antibody ramucirumab or the multi-kinase inhibitor cabozantinib (an MTA) as second-line therapies (34-36). Our results are in line with these findings, and support the possibility of a favorable pseudo-combination therapy effect when administering agents that inhibit other cellular signaling pathways to patients who earlier received immunotherapy (37).
A real-world clinical study that tested lenvatinib as a first-line therapy against advanced HCC, reported mRECIST ORR and DCR of 50.0% and 90.0%, respectively (31). Hence, the results of the present study (mRECIST ORR 60%, DCR 95%) indicate that if lenvatinib is used as a second-line therapy in HCC patients previously treated with Atz/Bev, it can induce an antitumor response that is similar or better than that if lenvatinib is used as a first-line therapy. We hypothesize that this favorable comparison derives from the above-mentioned pseudo-combination therapy effect. Significantly, the median 0-6 week RDI in the present study was 55.35%, which is lower than the previously reported 79.1% for lenvatinib as a first-line therapy (38). Regardless of the low RDI, we found a good antitumor response, which indicates that early dose reduction of lenvatinib to manage AEs such as anorexia and fatigue allows treatment to continue without compromising efficacy.
The HIMARAYA trial authorized the use of a combination therapy consisting of durvalumab and tremelimumab (3), thereby further highlighting the importance of ICIs in the treatment of HCC. Consequently, MTAs, including lenvatinib will be increasingly employed in the second line and subsequent lines of therapy. Considering the enduring effects of ICIs post-treatment, administering MTAs after ICIs may require distinct precautions compared to their first-line use. We hope that further accumulation of information will contribute to the development of more effective management strategies of MTA treatment.
Although this study provides pivotal insights into the management and outcomes of the use of lenvatinib subsequent to the failure of Atz/Bev in real-world clinical practice, it is essential to acknowledge several limitations of this study. First, a retrospective nonrandomized design was employed, conducted solely at a single center. Second, the study cohort exhibited heterogeneity concerning factors impacting efficacy and safety, including liver function, lenvatinib treatment line, and lenvatinib dosage. Third, the sample size was small, and the observation period was relatively short for a clinical study. Therefore, additional prospective studies including larger patient cohorts and longer observation periods are imperative to validate and substantiate the findings of this study.
Conclusion
Lenvatinib shows promising therapeutic efficacy and safety in patients with advanced HCC who have received prior treatment with Atz/Bev. It is crucial to effectively manage the occurrence of AEs, particularly anorexia and general fatigue. Our data suggests that this is possible, at least to a large extent, without losing the therapeutic benefits of lenvatinib. However, additional research is needed to confirm and validate these observations in larger numbers of patients.
Acknowledgements
The Authors thank the Office of Research Administration of Fujita Health University for manuscript proofreading.
Footnotes
Authors’ Contributions
Hisanori Muto (H.M.) and Teiji Kuzuya (T.K.) have contributed equally to this work. Conceptualization: T.K and H.M.; Methodology: T.K. and H.M.; Formal analysis and investigation: T.K., H.M. and N.K.; Data curation: H.M., T.K., N.K., E.O., K.F., M.N., Y.N., R.M., T.S., S.H. and Y.K.; Writing – original draft preparation: H.M.; Writing – review and editing: T.K.; Super-vision: Y.H. All Authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
Teiji Kuzuya received lecture fees from Eisai, Eli Lilly Japan, Takeda Pharmaceutical, AstraZeneca, and Chugai Pharmaceutical. All the other Authors declare no competing interests.
- Received July 30, 2023.
- Revision received September 4, 2023.
- Accepted September 5, 2023.
- Copyright © 2023 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
