Research ArticleClinical Studies

Efficacy and Safety of Lenvatinib After Progression on First-line Atezolizumab Plus Bevacizumab Treatment in Advanced Hepatocellular Carcinoma Patients

YEN-HAO CHEN, YEN-YANG CHEN, JING-HOUNG WANG and CHAO-HUNG HUNG
Anticancer Research March 2023, 43 (3) 1377-1384; DOI: https://doi.org/10.21873/anticanres.16286

Abstract

Background/Aim: This study aimed to assess the clinical impact of lenvatinib after disease progression on atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma (HCC). Patients and Methods: A total of 14 patients who received lenvatinib after failure of atezolizumab plus bevacizumab and all patients were classified as having a Barcelona Clinic Liver Cancer stage C. Six patients had macrovascular invasion, and a liver occupation rate of >50% was reported in seven patients. The Kaplan–Meier method was performed to analyze the cumulative survival, while log-rank test was used to detect the differences. The dose of lenvatinib was determined based on body weight. Results: The participants’ responses to lenvatinib treatment were as follows: 21.4% achieved partial response (PR), while 35.7% had a stable disease, with a disease control rate of 57.1%. The median progression-free survival (PFS) and overall survival (OS) were 4.2 months and 8.3 months, respectively; the median PFS and OS were 6.7 months and 10.5 months in the PR group. No significant difference was observed in the median PFS and OS between patients with and without macrovascular invasion or liver occupation rate of >50%. Most of the adverse events (AEs) were categorized as grade 1-2; all patients tolerated the AEs, and no drug-related mortality was reported. Additionally, half of the population underwent subsequent therapy after progression on lenvatinib treatment. Conclusion: Lenvatinib is effective and can be safely used as second-line systemic therapy after progression on atezolizumab plus bevacizumab in patients with advanced HCC in real-world clinical practice.

Key Words:

Hepatocellular carcinoma (HCC) remains one of the most aggressive cancer types and is the second leading cause of cancer-related mortality in Taiwan (1). Systemic therapy is the cornerstone of management for patients with advanced HCC who are not suitable for surgical resection or locoregional therapies, such as radiofrequency ablation or trans-arterial chemoembolization. Based on the SHARP and Asia-Pacific trials, sorafenib provided an overall survival (OS) benefit compared with placebo and was approved as the first and the only systemic therapy for 10 years (2, 3). After that, the REFLECT study showed that lenvatinib is not inferior to sorafenib in terms of OS and had better objective response rate (ORR) and progression-free survival (PFS) compared with sorafenib (4). In a recent study, immunotherapy, especially immune checkpoint inhibitors (ICIs) such as pembrolizumab or nivolumab plus ipilimumab, played an important role in the management of advanced HCC after progression on sorafenib treatment (5-7). However, nivolumab as the first-line treatment did not prolong the OS (primary endpoint) compared with sorafenib as reported in the CheckMate 459 trial (8). Recently, the phase 3 IMbrave150 study revealed that the combination of atezolizumab and bevacizumab is significantly superior to sorafenib in terms of ORR, PFS, and OS and has improved the quality of life in patients with advanced HCC (9). Therefore, atezolizumab plus bevacizumab has been approved and preferred as the first-line systemic therapy against advanced HCC in clinical practice.

There is limited evidence and lack of phase III trials to suggest the standard treatment after progression on atezolizumab plus bevacizumab treatment. Multikinase inhibitors, such as sorafenib or lenvatinib, may be more suitable as they are the preferred first-line systemic therapies prior to the approval of atezolizumab plus bevacizumab treatment. A multinational multicenter retrospective study reported that 49 patients with HCC received subsequent systemic therapy after progression on atezolizumab plus bevacizumab treatment, including lenvatinib, sorafenib, and cabozantinib (10). In this study, a superior PFS was observed in the lenvatinib group compared with that in the sorafenib group (6.1 months versus 2.5 months, p=0.004), but no significant difference was found between these two groups; this finding was similar with the results of the REFLECT trial (4). Another study enrolled 30 patients who were unresponsive to fist-line atezolizumab plus bevacizumab treatment for advanced HCC, of whom 19 were treated with sorafenib and 9 were treated with lenvatinib (11). The ORRs were 11.1% and 0% in the lenvatinib group and sorafenib group, respectively; by contrast, the disease control rates (DCRs) were 47.4% and 22.2% in the sorafenib group and lenvatinib group, respectively. No statistical difference was observed in the PFS between the lenvatinib group and sorafenib group (2.0 months versus 2.6 months). Based on these two studies, the clinical outcome of the lenvatinib group or sorafenib group was not compatible. Owing to the limitation of clinical trials or real-world evidence about the second-line treatment outcome, the current study aimed to investigate the efficacy and safety of lenvatinib after progression on atezolizumab plus bevacizumab treatment in patients with advanced HCC.

Patients and Methods

Patients. Patients with advanced HCC who received atezolizumab plus bevacizumab treatment at Kaohsiung Chang Gung Memorial Hospital from January 2020 to September 2022 were retrospectively reviewed. First, we excluded patients with a history of second primary malignancy or concurrent bile duct cancer. Second, only patients who received at least three cycles of atezolizumab plus bevacizumab treatment and underwent imaging of liver tumors for evaluation of response were included in the study. The diagnosis of HCC was determined based on the pathological findings or results of noninvasive assessment performed according to the American Association for the Study of Liver Disease guidelines (12, 13). The Barcelona Clinic Liver Cancer (BCLC) staging classification was used for disease staging prior to the initiation of lenvatinib treatment (14). Each patient was assessed for at least one measurable lesion. The dynamic computed tomography or magnetic resonance imaging of the liver was used to determine the treatment response in accordance with modified Response Evaluation Criteria in Solid Tumors (mRECIST) by two radiologists without the presence of any clinicopathological data (15). A flowchart of the process in identifying these HCC patients based on the inclusion and exclusion criteria is shown in Figure 1.

Figure 1.
Figure 1.

Flowchart of the process of identifying patients with advanced hepatocellular carcinoma who received lenvatinib after progression on atezolizumab plus bevacizumab treatment.

Treatment. Lenvatinib was prescribed at doses of 12 mg orally once daily for patients with a body weight of ≥60 kg and 8 mg orally once daily for patients with a body weight of <60 kg. Treatment was discontinued if disease progression or intolerable adverse events (AEs) occurred. Each patient underwent blood testing and assessment of AEs every 2–4 weeks at the outpatient department. The AE grade was determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (16).

Statistical analysis. All data in this study were analyzed using the SPSS 19 software (IBM, Armonk, NY, USA). The chi-square test was performed to assess the difference between categorical variables. PFS was defined as the period from the date of lenvatinib initiation to the date of disease progression or death from any cause; OS was defined as the period from the time of lenvatinib initiation to the date of last follow-up or death from any cause. The Kaplan–Meier method was used to analyze the cumulative survival, while the log-rank test was used to detect the differences. The albumin-bilirubin (ALBI) score was calculated according to the levels of serum albumin and total bilirubin using the following formula: ALBI score = [log10 bilirubin (μmol/l) × 0.66] + [albumin (g/l) × −0.085]. The ALBI score was categorized as grade 1 (−2.60 or less), grade 2 (−2.59 to −1.39), or grade 3 (greater than −1.39) (17). A p-value of <0.05 was considered significant.

Ethics statement. The current study was approved by the Institutional Review Board of Chang Gung Medical Foundation (202101199B0) and conducted in accordance with the Declaration of Helsinki. Written informed consent was not necessary owing to the retrospective nature of this study.

Results

Study population. A total of 56 patients with advanced HCC received atezolizumab plus bevacizumab at Kaohsiung Chang Gung Memorial Hospital were identified from January 2020 to September 2022. We excluded 20 patients who continued to receive atezolizumab plus bevacizumab treatment and another nine patients who were unable to undergo subsequent treatment. Patients treated with lenvatinib as a second-line systemic therapy and with Child-Pugh class A were identified, and a total of 14 patients were finally enrolled in the study. The demographic data of these patients were documented at the time of lenvatinib initiation. The median age was 49 years (range=30-80 years); of the total participants, 10 were men and 4 were women. All patients were classified as having BCLC stage C and had an Eastern Cooperative Oncology Group Performance Status score of 0 or 1. Based on the ALBI score, 5 (35.7%) patients had grade 1 and 9 (64.3%) patients had grade 2. Hepatitis B virus infection was detected in 11 (78.6%) patients and hepatitis C virus infection in 2 (14.3%) patients. Six patients had macrovascular invasion, but only one patient developed a thrombosis in the main portal vein. A liver occupation rate of >50% was reported in 7 (50.0%) patients. Most patients underwent hepatectomy before receiving systemic therapy and had extrahepatic spread and lymph node metastasis at the time of lenvatinib administration. The median follow-up period was 6.1 months in all patients. The baseline characteristics of these patients are summarized in Table I.

View this table:
Table I.

Baseline characteristics of 14 patients with advanced hepatocellular carcinoma who received lenvatinib after atezolizumab plus bevacizumab treatment.

Efficacy. The treatment response to atezolizumab plus bevacizumab was assessed according to the RECIST criteria version 1.1 (18): two (14.3%) patients achieved partial response (PR), two (14.3%) patients had a stable disease (SD), and 10 (71.4%) patients developed a progressive disease (PD), with a DCR of 28.6%. On the contrary, the mRECIST criteria were used to determine the response to lenvatinib; results showed that three (21.4%) patients achieved PR, five (35.7%) patients had SD, and six (42.9%) patients developed PD, with a DCR of 57.1%.

In addition, the correlation of response to atezolizumab/bevacizumab and lenvatinib was analyzed. Two patients who responded to atezolizumab plus bevacizumab treatment benefitted from lenvatinib treatment, including one patient who achieved PR and another patient who had SD with a DCR of 100%. Although 10 patients had poor response to atezolizumab plus bevacizumab treatment, two patients who achieved PR and another four patients with SD were treated with lenvatinib, contributing to a DCR of 60%. No significant difference was observed in the ORR between the atezolizumab/bevacizumab group and lenvatinib group (p=0.35). The results of the assessment of treatment response to atezolizumab/bevacizumab and lenvatinib are shown in Table II.

View this table:
Table II.

Anti-cancer treatment responses of 14 hepatocellular carcinoma patients.

The median PFS and OS were 4.2 months and 8.3 months in the entire study population, respectively (Figure 2). Based on the response to lenvatinib, the median PFS was 6.7 months in the PR group, 4.6 months in the SD group, and 4.1 months in the PD group; meanwhile, the median OS times were 10.5 months, 8.3 months, and 3.8 months in the PR, SD, and PD groups, respectively (Figure 3). No significant difference was observed in the median PFS (4.6 months versus 4.2 months) and OS (8.3 months versus 4.9 months) between patients with and without macrovascular invasion; the median PFS (3.1 months versus 2.5 months) and OS (4.6 months versus 4.2 months) between patients with a liver occupation rate of >50% and those with a liver occupation rate of <50% was similar.

Figure 2.
Figure 2.

Kaplan–Meier survival curves of progression-free survival and overall survival in patients with advanced hepatocellular carcinoma who received lenvatinib after progression on atezolizumab plus bevacizumab treatment.

Figure 3.
Figure 3.

Comparison of survival curves of progression-free survival (PFS) and overall survival (OS) among patients with advanced hepatocellular carcinoma who received lenvatinib after failure of atezolizumab plus bevacizumab treatment according to treatment response. (A) PFS and (B) OS. PR: Partial response; SD: stable disease; PD: progressive disease.

Safety. All patients experienced AEs following lenvatinib treatment. The most common AEs were aspartate/alanine aminotransferase increase (92.9%), proteinuria (57.1%), hypertension (50.0%), decreased body weight (42.9%), diarrhea (21.4%), decreased appetite (21.4%), palmar-plantar erythrodysesthesia (21.4%), nausea (21.4%), skin rash (21.4%), and fatigue (14.3%). Most of the AEs were categorized as grade 1-2, while a few of them were categorized as grade 3-4, including hypertension (7.1%) and proteinuria (7.1%). All patients tolerated the AEs caused by lenvatinib treatment, and no drug-related grade 5 AEs were reported. The frequencies of lenvatinib-related AEs are summarized in Table III.

View this table:
Table III.

Incidence of lenvatinib-related adverse events.

Subsequent therapy. Seven (50.0%) patients underwent subsequent therapy after progression on lenvatinib treatment, including targeted therapy, chemotherapy, and ICIs. With regard to targeted therapy, sorafenib, ramucirumab, and cabozantinib were administered to one (7.1%), one (7.1%), and one (7.1%) patient, respectively. With regard to chemotherapy, one (7.1%) patient received FOLFOX (oxaliplatin/leucovorin/fluorouracil) regimen, while another (7.1%) patient received epirubicin. Four patients still continued to receive ICIs after lenvatinib failure: pembrolizumab in two (14.3%) patients, nivolumab in one (7.1%) patient, and nivolumab plus ipilimumab in one (7.1%) patient. The subsequent therapies provided after lenvatinib treatment are shown in Table IV.

View this table:
Table IV.

Subsequent therapy after progression on lenvatinib.

Discussion

HCC is one of the most common primary liver cancer types and remains a challenge due to the high mortality rate. Atezolizumab plus bevacizumab has been approved as first-line systemic therapy for advanced HCC; however, there is lack of phase III trials to confirm the efficacy of subsequent therapy after disease progression while on atezolizumab plus bevacizumab treatment. In the current study, we reported the treatment efficacy and safety profiles of lenvatinib in patients with advanced HCC after failure of atezolizumab plus bevacizumab treatment. The ORR and DCR were 21.4% and 57.1%, respectively, regardless of prior response to atezolizumab plus bevacizumab treatment. The median PFS was 4.2 months in all study patients, and 6.7 months in the PR group treated with lenvatinib; the median OS was 8.3 months in all patients, and 10.5 months in the PR group. No statistical difference was found in the results of the analysis of macrovascular invasion or liver occupation rate of >50%. Most of the lenvatinib-related AEs were grade 1-2, and no drug-related grade 5 AEs were reported. Half of study population received subsequent treatments, including targeted therapy, chemotherapy, and ICIs, after progression while on lenvatinib treatment. In conclusion, our study demonstrated the real-world efficacy and safety of lenvatinib as a second-line systemic therapy after progression while on atezolizumab plus bevacizumab treatment in patients with advanced HCC.

In our study, the ORR and DCR of lenvatinib for advanced HCC were 21.4% and 57.1%, respectively. The REFELCT trial reported that lenvatinib was prescribed as a first-line systemic therapy and demonstrated an ORR of 24% and a DCR of 75.5% (4). The ORR of our study was similar with that reported in the REFLECT trial although the DCR was slightly different; this may be due to the higher percentage of macrovascular invasion (42.9%) and liver occupation rate of >50% (50.0%) reported in our study, which was not included in the REFLECT trial (4). In real-world practice, a multinational, multicenter retrospective study enrolled 19 patients with advanced HCC received lenvatinib after failure of atezolizumab plus bevacizumab treatment and showed an ORR of 15.8% and a DCR of 63.2% (10). On the contrary, another study examined nine patients treated with lenvatinib after progression on atezolizumab plus bevacizumab treatment, and provided an ORR of only 11.1% and a DCR of 22.2%; this result may be associated with the higher percentage (near 30%) of patients with Child-Pugh class B or C (11). In addition, the ORR and DCR of lenvatinib as systemic therapy after progression on sorafenib treatment in our previously published study were 31.2% and 65.6%, respectively; this finding was in agreement with the results of the current study (19).

The median PFS in our study was 4.2 months: 6.7 months in the PR group, 4.6 months in the SD group, and 4.1 months in PD group. The result is a little inferior to the finding of the REFLECT trial (7.4 months). This may be explained as follows. Approximately 7.1% of the study patients developed thrombosis in the main portal vein, while 50.0% had a liver occupation rate of >50%; this may result in poor clinical outcomes. Patients with these variables were excluded in the REFLECT trial (4). Second, lenvatinib was administered as a second-line systemic therapy in our study, but it was regarded as a first-line systemic therapy for treatment-naïve HCC patients in the REFLECT trial; the duration of PFS in the second-line setting was inferior to that of the first-line treatment and was relatively reasonable and acceptable. In addition, Yoo et al. showed that the median PFS was 6.1 months in patients who received lenvatinib after progression on atezolizumab plus bevacizumab treatment in several Asian countries, including Korea, Hong Kong, and Singapore (10). Another Taiwanese study demonstrated that the median PFS was 2.0 months in nine patients treated with lenvatinib after failure of atezolizumab plus bevacizumab treatment (11). As the PFS varied in different studies, a prospective phase III trial may be necessary to validate the real-world findings.

With regard to the OS, the median OS in our study was 8.3 months, while that in the REFLECT trial was 13.6 months (4). The factors that contributed to the worse OS in our study were similar to those that contributed to the poor PFS reported in the studies mentioned above. Another important reason was that the expenses for most systemic therapies provided after progression on lenvatinib treatment were not reimbursed by the national health insurance system in Taiwan, such as regorafenib, cabozantinib, ramucirumab, FOLFOX regimen, or other ICIs; hence, this possibly limited the potential survival benefit from taking these regimens and resulted in the poor prognosis of these patients in Taiwan. On the contrary, the median OS in real-world practice differed; Yoo et al. reported a median OS of 16.6 months, while another study reported a median OS of only 3.8 months (10, 11). Therefore, a prospective phase III trial may be warranted to confirm the real-world evidence.

Lenvatinib has been regarded as a powerful systemic therapy in the management of HCC in clinical practice. However, patients with main portal vein thrombosis or liver occupation rate of >50% were not enrolled in the REFLECT study, resulting in the limited information of efficacy and safety in this population. Shimozato et al. reported the real-world experience of lenvatinib in advanced HCC in Japan, and showed that the ORR was significantly higher in patients who fulfilled the REFLECT inclusion criteria compared to those who did not; in addition, there was no statistical difference in PFS and AEs between these two groups (20). On the other hand, safety is an important issue and how to predict severe AEs may decrease drug interruption, increase tolerability, and improve quality of life. A Japanese study demonstrated that patients with alcohol or nonalcoholic fatty liver disease-related HCC had higher incidence of severe AEs in comparison with those with HCC of other etiologies. Serum zonulin level was found to be an independent factor of severe AEs and showed that more severe AEs were mentioned in patients with high zonulin levels compared to those with low levels (21). With respect to lenvatinib after progression on atezolizumab plus bevacizumab, although there was a lack of phase 3 trial and only limited evidence to support the clinical impact, our study showed the efficacy and safety in advanced HCC. Moreover, Komatsu et al. reported the experience of lenvatinib re-administration after atezolizumab plus bevacizumab and demonstrated that lenvatinib could not only have an anti-tumor effect, but also result in potential liver function deterioration; in addition, the duration of rechallenge with lenvatinib was significantly shorter than that of the first lenvatinib treatment (22).

Our study has several limitations. First, the sample size was relatively small; hence, it was difficult to investigate the impact of different variables, resulting in the difficulty of identifying the prognostic factors. Second, most patients enrolled in our study had poor response to atezolizumab plus bevacizumab treatment, which was contrary to the results of the IMbrave150 trial; this was probable due to the following factors: nearly one-third of the study participants who received atezolizumab plus bevacizumab treatment in our hospital continued this regimen without experiencing disease progression. Third, the follow-up period was not relatively long; hence, there may be some biases in the analysis of the survival outcome. However, to the best of our knowledge, this is one of the few studies that explored the efficacy and safety of lenvatinib in patients who failed to respond to atezolizumab plus bevacizumab treatment in real-world practice.

Conclusion

Our study confirms the efficacy and safety of lenvatinib as a second-line systemic therapy after progression on atezolizumab plus bevacizumab treatment in patients with advanced HCC in real-world clinical practice.

Acknowledgements

The Authors would like to thank the Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital, for providing assistance with the statistical analysis.

Footnotes

  • Authors’ Contributions

    Conceptualization: Y-H Chen; methodology: J-H Wang; formal analysis and investigation: Y-Y Chen; writing – original draft: Y-H Chen; writing – review and editing: Y-H Chen; resources: C-H Hung; supervision: Y-H Chen; validation: Y-H Chen. All the Authors have read and agreed to the published version of the manuscript.

  • Conflicts of Interest

    The Authors have no relevant financial or non-financial interests to disclose.

  • Funding

    This research was funded by the Chang Gung Memorial Hospital (grant number: CORPG8M0521).

  • Received December 14, 2022.
  • Revision received December 22, 2022.
  • Accepted December 23, 2022.

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Efficacy and Safety of Lenvatinib After Progression on First-line Atezolizumab Plus Bevacizumab Treatment in Advanced Hepatocellular Carcinoma Patients
YEN-HAO CHEN, YEN-YANG CHEN, JING-HOUNG WANG, CHAO-HUNG HUNG
Anticancer Research Mar 2023, 43 (3) 1377-1384; DOI: 10.21873/anticanres.16286
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