Safety evaluation of lenvatinib treatment after atezolizumab plus bevacizumab therapy for patients with unresectable liver cancer: A comparison of lenvatinib as 1st‑ or 2nd‑line treatment
- Authors:
- Published online on: May 17, 2024 https://doi.org/10.3892/ol.2024.14464
- Article Number: 330
Abstract
Introduction
The combination of atezolizumab (Atez), a humanized immunoglobulin G1 monoclonal antibody targeting programmed death-ligand 1 (PD-L1), and bevacizumab (BV), a monoclonal antibody that targets vascular endothelial growth factor (VEGF) and inhibits angiogenesis and tumor growth, is the recommended first-line treatment for patients with unresectable hepatocellular carcinoma (HCC) with Child-Pugh A (CP-A) liver function (1–4). Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor, is often used as second-line treatment. LEN targets vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor (FGF) receptors 1 through 4, platelet-derived growth factor receptor α, rearranged during transfection, and stem cell factor receptor. Moreover, LEN also inhibits the formation of vessel-like luminal structures by vascular endothelial cells induced by VEGF and FGF.
Atez is an immune checkpoint inhibitor (ICI) that binds to cell surface PD-L1 and suppresses its function. ICIs produce unique side effects of immune-related adverse events in various organs. These include interstitial lung disease, colitis, hypothyroidism, liver damage, skin rash, vitiligo, hypophysitis, type I diabetes, renal dysfunction, myasthenia gravis, peripheral neuropathy, myositis, and uveitis. Adverse immune events generally occur several months after drug administration; however, the timing of their appearance varies widely. For example, regarding Atez/BV, the onset of thyroid dysfunction was reported to be 93.5 (range 13–419) days in the IMbrave150 study (1). Therefore, the possibility of the influence of secondary treatment on first-line treatment cannot be ruled out. When LEN is selected as a second-line treatment in patients with CP-A liver function, it is important to maintain its safety and continue treatment.
LEN is a standard therapeutic agent for HCC, but the high incidence of adverse events (AEs) is a problematic aspect of LEN treatment (5–8), as these AEs may necessitate treatment discontinuation. The most common any-grade AEs of LEN were hypertension (42%), diarrhea (39%), decreased appetite (34%), decreased weight (31%), and fatigue (30%) during first-line LEN treatment (1st LEN) (6). The incidence of hypothyroidism was 16.4% (6). Regarding the safety of using LEN as a second-line treatment (2nd LEN), Yoo et al (9), Aoki et al (10), and Hiraoka et al (11) reported significant antitumor efficacy with acceptable safety. However, they did not compare the AEs of LEN when used as first- or second-line treatment. Comparing the frequency and appearance of AEs in first- and second-line treatments, will contribute to managing AEs in the 2nd-line treatment.
In this study, we investigated the safety of LEN in second-line therapy by comparing the AEs of LEN in second-line therapy after first-line Atez/BV treatment for unresectable liver cancer, with those of LEN in first-line therapy.
Patients and methods
Patients and evaluations
A total of 53 patients with CP-A unresectable liver cancer treated at the Ogaki Municipal Hospital between April 2018 and September 2023 were retrospectively evaluated. Patients who received Atez/BV as first-line therapy and LEN as second-line therapy or those who received LEN as first-line therapy were included. Patient characteristics, treatment duration, AEs, and relative dose intensity (RDI) were analyzed. Data were analyzed using electronic and pharmacy service records. AEs were evaluated according to the Common Terminology Criteria for Adverse Events, version 5.0 (12), and the most severe grades during chemotherapy were reported. Personal information was protected in the aggregated data. This study was approved by the Institutional Review Board of the Ogaki Municipal Hospital (Ogaki, Japan; approval number: 20220728-17-h). The need for informed consent was waived due to the retrospective nature of the study.
Treatment protocol
Atez was administered intravenously at 1,200 mg for 60 min on the first day. If the first dose was well-tolerated, the duration of the second infusion was shortened to 30 min. BV was administered intravenously at a dose of 15 mg/kg for 90 min on the first day. If no problems were encountered, the durations of the second and third infusions were shortened to 60 and 30 min, respectively. This procedure was repeated every 21 days.
The LEN dose was based on body weight; the initial dose was 12 mg/day for those weighing ≥60 kg and 8 mg/day for those weighing <60 kg. During the 28-day cycle, dose adjustment, including reduction to 8 or 4 mg/day, 4 mg every other day, or interruption, was allowed for LEN treatment based on AEs (6,13). In patients who experienced unacceptable drug-related AEs, the LEN dose was reduced or treatment was interrupted according to the manufacturer's instructions. Dose reduction or temporary interruption of LEN was maintained until the AE severity dropped to grade 1 or 2. In cases where dose reduction was maintained, the reduced doses administered were 20, 14, 10, 8, or 4 mg once daily.
Statistical analysis
To test whether the variances of two populations were equal regarding patient characteristics and RDI the F-test was performed. The Mann-Whitney U test or Fisher's exact probability test was used to compare patient characteristics, AEs, and RDI. The change in AE grade from first line to second line treatment was compared with the Wilcoxon signed-rank test. Kaplan-Meier and log-rank tests were used to compare treatment durations. Differences were considered statistically significant at P<0.05. All analyses were performed using EZR software (version 1.30, Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R software (The R Foundation for Statistical Computing, Vienna, Austria) (14).
Results
Patient characteristics
The 1st LEN and 2nd LEN groups comprised 39 and 13 patients, respectively. Patient characteristics are summarized in Table I. The median age of the patients in the 1st LEN and the 2nd LEN group was 77 (range=58-88) years and 73 (range=64-85) years, respectively. Patients differed significantly in terms of sex and history of transcatheter arterial chemoembolization between the 1st LEN and 2nd LEN groups.
Adverse events
The proportion of patients showing an increase in aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels was greater in the 2nd LEN (76.9%) than in the 1st LEN (46.2%) group (P=0.016). Hypothyroidism was more common in the 2nd LEN (46.2%) than in the 1st LEN (12.8%) group (P=0.011). The major AEs for the 1st LEN and 2nd LEN groups are summarized in Table II. No differences were observed in other AEs between 1st LEN and 2nd LEN groups. The major AEs of 1st-line Atez/BV treatment in patients who were able to transition to LEN as 2nd-line treatment are summarized in Table III.
Hypothyroidism was observed in 30.8% of these patients. In comparison, hypothyroidism was seen in 11.1% (4/36) of all patients who received 1st-line Atez/BV, including the patients who were able to transition to LEN as 2nd-line treatment and those who were not. AEs with an incidence of more than 50% were reduced platelet count (76.9%) and increased AST/ALT (61.5%) in 1st-line Atez/BV treatment in patients who were able to transition to LEN as 2nd-line treatment.
Subgroup analysis of adverse events by sex
Table IV shows subgroup analysis of AEs by sex. In 2nd LEN, hypothyroidism was more common in females (75%) than in males (0%). There were no differences by sex in other AEs.
The effects of lenvatinib treatment on the treatment duration
Fig. 1 shows Kaplan-Meier survival curves of the duration of treatment with LEN for all patients. The median treatment durations for patients in the 1st LEN and 2nd LEN groups were 151.0 [95% confidence interval (CI), 77–303] days, and 128.5 (95% CI, 68–270) days, respectively (log-rank test, P=0.385).
RDI of lenvatinib in the treatment groups
The RDIs of LEN for the 1st LEN and 2nd LEN groups are shown in Fig. 2. The median RDIs in the 1st LEN and 2nd LEN groups were 52.0 and 35.5%, respectively. There was no significant difference in the median RDI between 1st LEN and 2nd LEN (P=0.081).
Grade change of adverse events from first-line atezolizumab plus bevacizumab to second-line lenvatinib
In patients with hypothyroidism or elevated AST/ALT levels with second-line LEN, changes in the grade of AEs from first-line treatment to second-line treatment are shown in Fig. 3. Grade 1 (three patients) and grade 2 (three patients) hypothyroidism was observed with the 2nd LEN. All six patients with hypothyroidism receiving 2nd LEN were women. In these six patients, during the first-line Atez/BV treatment, the AE grade was 0 in four patients and grade 1 in two patients. There was a significant increase in the hypothyroidism grade from Atez/BV as the first-line treatment to 2nd LEN (P=0.025). Grade 1 (seven patients) and grade 3 (two patients) elevated AST/ALT levels were observed in the 2nd LEN. For these nine patients, when receiving Atez/BV as the first-line treatment the AE grade was 0 in one patient, 1 in seven, and 2 in one. The change in the AE grade for increased AST/ALT levels was not significantly different between first-line Atez/BV and 2nd LEN treatment (P=0.427).
Discussion
In this study, the safety of using LEN as second-line treatment was clarified by comparing the AEs of the 2nd LEN administered after the first-line Atez/BV treatment, with the AEs of 1st LEN in patients with unresectable liver cancer. While 2nd LEN may be as effective as 1st LEN, the incidence of hypothyroidism was higher with 2nd LEN compared to 1st LEN.
In this study, when comparing 1st LEN and 2nd LEN, elevated AST/ALT levels and hypothyroidism were more common in the 2nd LEN group. The incidences of hypothyroidism were 12.8% in the 1st LEN and 46.2% in the 2nd LEN groups. Kudo et al reported that the incidence of hypothyroidism when LEN was used as first-line treatment was 16% (6), while Ogushi et al reported that it was 25.4% (7). Thus, for 1st LEN, the incidence rate in this study was similar to or lower than that previously reported.
Lee et al reported the risk of developing hypothyroidism using ICIs (15). The incidence of hypothyroidism in patients who received both an angiogenesis inhibitor (AI) and an ICI was 4.4 times higher than that in patients treated with ICI alone. In other words, they showed a synergistic effect in patients who received multiple doses, which may be associated with thyroid dysfunction. Therefore, when using agents such as AIs in conjunction with ICI treatment, special attention should be paid to treatment-related side effects (15). The timing of onset of adverse immune events caused by ICIs is highly variable (1). Tyrosine kinase inhibitors such as LEN have been reported to cause thyroid dysfunction by acting on the hypothalamic-pituitary-thyroid system (16,17). Therefore, it is predicted that after Atez/BV, LEN will also be expected to exacerbate the incidence of hypothyroidism in patients treated with drugs that are potentially associated with thyroid dysfunction.
In this study, when Atez/BV was used as the 1st-line treatment and LEN as the 2nd-line treatment, the incidence of hypothyroidism in 2nd LEN was 46.2%. According to Finn et al, the incidence of hypothyroidism when Atez/BV was used as the first-line treatment was 10.6% (1). Although not shown in the results, the rate in the present study was 11.1%, which is similar. In other words, in this study, the incidence of hypothyroidism was not high, even when Atez/BV was used as first-line treatment. Furthermore, the incidence during 1st LEN was 12.8 and 46.2% with 2nd LEN, which was high. In contrast, Muto et al (18) reported that when Atez/BV was used as the 1st-line treatment and LEN was used as the 2nd-line treatment, the incidence of hypothyroidism in patients receiving 2nd LEN was 15%. There is a clear difference to the results of this study. However, it should be noted that the number of patients in both studies was small (Muto et al n=20, the current study n=13). Furthermore, in this study, there were differences in sex between patients in the 1st LEN and 2nd LEN groups. In this study, all six patients with hypothyroidism receiving 2nd LEN were women. Hypothyroidism is more common in women than men. Therefore, women receiving treatment with 2nd LEN should be closely monitored for hypothyroidism.
In this study, four of the six patients (66.7%) who had hypothyroidism with 2nd LEN did not have hypothyroidism during the Atez/BV first-line treatment. In addition, one of the two patients with grade 1 hypothyroidism during first-line Atez/BV treatment showed deterioration to grade 2. Thus, hypothyroidism increased with 2nd LEN after first-line Atez/BV treatment. These results suggest that tyrosine kinase inhibitors may cause thyroid dysfunction when the hypothalamus-pituitary-thyroid system is damaged by the synergistic effect from the combined use of angiogenesis inhibitors and ICIs.
The incidence of increased AST/ALT levels was 46.2% with 1st LEN and 76.9% with 2nd LEN. In contrast, eight of the nine patients (88.9%) who had an increase in AST/ALT during 2nd LEN already had an increase in AST/ALT during the first-line Atez/BV treatment. In addition, 3/9 patients (33.3%) showed worsening from the first-line treatment or a new increase in AST/ALT with the 2nd LEN. Thus, no significant increase in AST/ALT levels was observed from first-line Atez/BV treatment to 2nd LEN. Of the 13 patients receiving 2nd LEN, 7 out of 12 patients (58.3%) who discontinued treatment did so due to decreased performance status (results not shown). Therefore, the reason AST/ALT increased more with 2nd LEN than 1st LEN was considered to be the worsening of the patient's condition.
In this study, the treatment duration was similar for both 1st LEN and 2nd LEN, and the RDI was also statistically similar. Therefore, the onset of side effects was not affected by the administration period or RDI.
The limitations of this study include the limited sample size and retrospective nature of the study, which was conducted at a single institution. High hypothyroidism during LEN use after Atez/BV treatment may be due to immune-related factors or anti-VEGF therapy. The onset timing and risk factors for immune-related AEs are not clear, and cases have been reported where they occurred several months after the end of treatment (19). The median (range) first onset of hypothyroidism has been reported as 93.5 (13–419) days, with considerable variation (1,20). Furthermore, it has also been reported that patients with HCC may have a higher incidence of thyroid dysfunction when using both LEN and Atez/BV than those treated with just one of the drugs (21). However, due to the small sample size, a final conclusion could not be drawn. Hypothyroidism may also be influenced by factors other than treatment. Future studies should address these limitations. In particular, it is necessary to examine sex-based differences in incidence and severity. Additionally, durvalumab plus tremelimumab combination therapy and durvalumab monotherapy have been approved in Japan for the treatment of unresectable HCC. It is worth investigating whether similar results will be found when using these ICIs.
In clinical practice, patients receiving LEN as second-line therapy after treatment with Atez/BV are at increased risk of hypothyroidism. However, further research is required to confirm this hypothesis.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The data generated in the present study may be requested from the corresponding author.
Authors' contributions
MK contributed to the study design, collected and provided the data, was the principal author of the report, and is the guarantor of this article. MK and MG confirm the authenticity of all the raw data. ShY, MG, SaY, HT and EU contributed to the study design, reviewed the manuscript, and supervised the drafting of the report and submission process. All authors read and approved the final version of the manuscript.
Ethics approval and consent to participate
The study protocol was approved by the Institutional Review Board of the Ogaki Municipal Hospital (Ogaki, Japan; approval number 20220728-17-h). The requirement for informed consent was waived because of the retrospective study design.
Patient consent for publication
Written informed consent for publication was obtained from each patient.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
|
1st LEN |
first-line LEN treatment |
|
2nd LEN |
second-line LEN treatment |
|
AE |
adverse event |
|
AST/ALT |
aspartate aminotransferase/alanine aminotransferase |
|
Atez/BV |
atezolizumab plus bevacizumab |
|
CI |
confidence interval |
|
CP-A |
Child-Pugh A |
|
FGF |
fibroblast growth factor |
|
HCC |
hepatocellular carcinoma |
|
ICI |
immune checkpoint inhibitor |
|
LEN |
lenvatinib |
|
PD-L1 |
programmed death-ligand 1 |
|
RDI |
relative dose intensity |
|
VEGF |
vascular endothelial growth factor |
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