Abstract
Background/Aim: The current study evaluated the efficacy and toxicity of atezolizumab plus bevacizumab in patients with advanced-stage hepatocellular carcinoma in a real-world setting. Patients and Methods: This retrospective study enrolled 23 patients. The primary endpoint was progression-free survival (PFS). Antitumor responses 6 weeks after initiation of atezolizumab plus bevacizumab were assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and the modified RECIST (mRECIST). The Common Terminology Criteria for Adverse Events version 5.0 was used to evaluate the severity of adverse events. Relative changes in hepatic function and nutritional status were investigated. Results: The median PFS was 119 days. The objective response rate (ORR) and disease control rate (DCR) at 6 weeks based on RECIST were 21.7% and 60.9%, respectively. The ORR and DCR based on mRECIST were 26.1% and 69.6%, respectively. The group with hepatitis B/C-related HCC had a higher ORR based on mRECIST than the non-hepatitis B and C-related group. Patients with Barcelona Clinic Liver Cancer (BCLC) stage A and B disease had a higher DCR based on RECIST than those with BCLC stage C disease. The incidence rates of any grade and grade ≥3 adverse events were 65.2% and 21.7%, respectively. The albumin–bilirubin and Child–Pugh scores, neutrophil-to-lymphocyte ratio and skeletal muscle index did not significantly worsen within 6 weeks after treatment initiation. Conclusion: Atezolizumab plus bevacizumab is effective and safe and can help achieve complete remission in patients with advanced-stage hepatocellular carcinoma in a real-world setting. Nevertheless, large-scale studies must be conducted to validate its outcomes in this patient group.
Recent clinical trials have evaluated the effect of systemic chemotherapy in patients with advanced-stage hepatocellular carcinoma (HCC) (1). Atezolizumab (a programmed death ligand 1 inhibitor) plus bevacizumab (a monoclonal antibody targeting vascular endothelial growth factor (VEGF) is the first-line therapy for unresectable HCC based on the fourth version of Clinical Practice Guidelines for Hepatocellular Carcinoma revised by the Japan Society of Hepatology (2). Prior to the approval of this combination therapy, lenvatinib or sorafenib was the standard first-line systemic therapy for advanced HCC according to the 2017 Clinical Practice Guidelines for HCC by the Japan Society of Hepatology (2). Several patients with advanced HCC continued to receive molecularly targeted agents (MTAs) including lenvatinib and sorafenib after the approval of atezolizumab plus bevacizumab as a later-line therapy (3, 4). Regorafenib, ramucirumab and cabozantinib were approved as second-line MTA treatment for HCC in 2017, 2019 and 2020 (5), respectively. These medications then improved the prognosis of patients with advanced HCC (6, 7). Systemic chemotherapy is not well tolerated by patients with HCC who have deteriorating liver function. However, there are no data on the use of atezolizumab plus bevacizumab in patients with advanced HCC after resistance to MTAs in a real-world setting. Furthermore, only a few studies have focused on the effect of this combination on hepatic function reserve during the early period treatment in patients with advanced HCC (8). The current study aimed to investigate the safety and efficacy of atezolizumab plus bevacizumab against HCC in a real-world setting.
Patients and Methods
The current study included 26 patients with advanced HCC treated with atezolizumab plus bevacizumab at a single centre from September 2020 to September 2021. Of 26 patients, three who did not receive the third cycle of atezolizumab plus bevacizumab due to adverse events (AEs) which led to treatment withdrawal were excluded. Atezolizumab plus bevacizumab was continually administered until the development of progressive disease and unmanageable AEs or if a patient wanted to discontinue the therapy at their own discretion. The inclusion criterion was age >20 years with a baseline Eastern Cooperative Oncology Group performance status score of 0 or 1. The objective response rate (ORR) and disease control rate (DCR) were evaluated via dynamic computed tomography scan using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at approximately 6 weeks after treatment initiation (9). Subsequently, therapeutic response was determined with the modified RECIST (m RECIST) (10). Patients with a history of autoimmune disease were not treated with atezolizumab plus bevacizumab. In addition, all patients underwent upper gastrointestinal endoscopy to assess oesophageal and gastric varices. When varices were detected or there was a high risk for bleeding, the patients underwent endoscopic variceal ligation. The Child–Pugh (11), albumin–bilirubin (ALBI) score (12, 13) and the modified ALBI grade (14) were utilised to assess liver function reserve. Grade 2 ALBI was classified into mALBI 2a and 2b, with a cut-off score of −2.27. All procedures involving human participants were approved by the Medical Ethics Committee of Nara Medical University (Nara-med: 03-0142 date: 15 July 2020), and the study was performed according to the Declaration of Helsinki. All patients provided informed consent.
HCC diagnosis and treatment. HCC was diagnosed based on high levels of tumour markers including alpha-fetoprotein and des-gamma-carboxy pro-thrombin, and dynamic computed tomography scan and magnetic resonance imaging findings (15, 16). Tumour progression was assessed based on the Barcelona Clinic Liver Cancer (BCLC) staging classification (17) and tumour, node, metastasis staging for HCC by the 2021 Liver Cancer Study Group of Japan, sixth edition (revised version) (18).
Adverse events. Patients underwent laboratory tests and physical examinations every 3 weeks to assess their tolerance to atezolizumab plus bevacizumab. Data on Eastern Cooperative Oncology Group-performance states score, vital signs, physical findings and laboratory test and urinalysis results were obtained. AE grades were based on the Common Terminology Criteria for Adverse Events version 5.0 (19). When patients developed a severe AE, grade ≥3, or were unable to tolerate AEs, treatment was discontinued according to the manufacturer’s instructions until the condition before starting treatment or recovery of AEs to grade ≤1 was achieved.
Statistical analysis. Data are expressed as the median and range. Qualitative data comprised categorical variables in a contingency table. The baseline characteristics between groups were compared using the Mann–Whitney U-test. The chi-square tests were used to identify factors associated with treatment response. The Kaplan–Meier plots of medians with 95% confidence intervals (CIs) were used to estimate PFS based on RECIST version 1.1. The censored date was defined as the date of the last follow-up. Moreover, the censored date was defined as the date of the last radiological assessment without disease progression. All statistical analyses were conducted using the Statistical Package for the Social Sciences version 25 (IBM, Armonk, NY, the USA). Values of p<0.05 were considered statistically significant.
Results
Characteristics of patients. This retrospective study enrolled 23 patients. Table I summarizes the clinical characteristics of the study patients. The median age of the patients was 72 years, and 18 (78.3%) were men. Hepatitis C was the most common aetiology of HCC (n=5, 21.7%), followed by alcohol-related liver disease (n=7, 30.4%). Twenty (87.0%) patients had Child–Pugh class A disease. BCLC stage A was observed in one patient, stage B in 10 and stage C in 12. Seven (30.4%) patients presented with treatment-naïve HCC. Atezolizumab plus bevacizumab was used as the initial systemic treatment in 12 (52.2%) patients. Sorafenib had been previously used in four patients, lenvatinib in 11, regorafenib in two and ramucirumab in three. The median PFS was 119 (95% confidence interval=65-225) days (Figure 1). None of the patients required discontinuation of atezolizumab plus bevacizumab therapy during the observation period.
Characteristics of patients with hepatocellular carcinoma treated with atezolizumab and bevacizumab (n=23).
Kaplan–Meier analysis of progression-free survival in 23 patients treated with atezolizumab plus bevacizumab. The median progression-free survival was 119 days (95% confidence interval=65-225 days).
Therapeutic efficacy of atezolizumab plus bevacizumab. The median PFS was 119 (95% confidence interval=65-225) days (Figure 2). At the initial imaging evaluation performed at 6 weeks after the start of treatment, complete response (CR) was not observed in any of the patients. At the time of writing, partial response as early tumour shrinkage was noted in five (21.7%) patients, stable disease in nine (39.1%) and progressive disease (PD) in nine (39.1%); at 6 weeks the ORR was 21.7% and DCR 60.8% based on RECIST 1.1 (Table II). CR was not observed in any of the patients. At the time of writing, partial response, early tumour shrinkage was found in six (26.1%) patients, stable disease in 10 (43.5%) and PD in seven (30.4%); at b weeks ORR was 26.1% and DCR 69.6% based on the mRECIST criteria. The group with hepatitis B/C-related HCC had a higher 6-week ORR based on mRECIST than the non-hepatitis B and C-related group (p=0.051). Patients with stage A and B BCLC had a higher 6-week DCR based on RECIST 1.1. than those with stage C BCLC (p=0.09) (Table III). No significant differences in 6-week ORR or DCR by Child–Pugh grade, modified ALBI, prior therapy or prior systemic therapy were noted.
Relative changes in Child–Pugh score (A) and modified albumin-bilirubin (ALBI) grade (B) in patients treated with atezolizumab plus bevacizumab. None of the alterations were significant.
Response to initial treatment at 6 weeks by Response Evaluation Criteria for Solid Tumors (RECIST v1.1) and modified (m)RECIST criteria.
Factors associated with treatment response in patients with hepatocellular carcinoma treated with atezolizumab and bevacizumab.
Relative change in hepatic function at 6 weeks after atezolizumab plus bevacizumab initiation. Figure 2 shows the mALBI grade and Child–Pugh score at baseline and at 3 and 6 weeks after starting atezolizumab plus bevacizumab treatment. The proportion of patients with Child–Pugh class A scores at those time points were 87.0%, 91.3% and 91.3%, respectively (Figure 2A). The rates of mALBI grade 1/2a were 34.8%/34.8% (69.6%), 40.9%/18.2% (59.1%) and 47.8%/13.0% (60.8%) at these times, respectively (Figure 2B). The ALBI score did not worsen significantly within 6 weeks after atezolizumab plus bevacizumab initiation (Figure 3A). In the 23 patients who underwent the 6-week examination (Figure 3B), changes in the ALBI score were relatively similar at baseline (p=0.280), 3 weeks (p=0.180) and 6 weeks (p=0.666) in those who received atezolizumab plus bevacizumab as first-line systemic therapy (n=11) or as a later-line treatment (n=12) (Figure 3C). In addition, there were no significant differences in terms of ALBI score between patients with prior therapy (n=16) and those without (n=7) at baseline (p=0.786), 3 weeks (p=0.236) and 6 weeks (p=0.467) (Figure 3D). Furthermore, there were no significant differences in terms of ALBI score between patients without PD (n=14) and those with PD (n=9) at baseline (p=0.803), 3 weeks p=0.629) and 6 weeks (p=0.969) (Figure 3E). Changes in Child–Pugh score, neutrophil-to-lymphocyte ratio and skeletal mass index did not significantly worsen within 6 weeks after atezolizumab plus bevacizumab initiation (Figure 4).
Relative changes in albumin-bilirubin (ALBI) score in the whole patient cohort (A), and according to modified ALBI grade (B), line of atezolizumab plus bevacizumab therapy (first-line vs. later) (C), receipt of previous therapy (D) and therapeutic response by Response Evaluation Criteria for Solid Tumors (E). PD: Progressive disease. None of the alterations were significant.
Relative changes in Child–Pugh score (A), skeletal muscle index (SMI) (B) and neutrophil-lymphocyte ratio (NLR) (C). None of the alterations were significant.
AEs. Table IV lists the atezolizumab plus bevacizumab-related AEs. In the early period of treatment, the overall incidences rates of any grade and grade 3 or higher drug-related AEs were 65.2% (n=15) and 21.7% (n=5), respectively. Proteinuria (grade 3 or higher) (8.7%) was the most common atezolizumab plus bevacizumab-related serious AE, followed by hypertension (4.3%), anaemia (4.3%), pruritus (4.3%), leg oedema (4.3%), skin rash (4.3%), adrenal dysfunction (4.3%) and diarrhoea (4.3%) (Table IV). Interruption of atezolizumab plus bevacizumab therapy was not observed during the treatment period.
Frequency of adverse events during treatment with atezolizumab plus bevacizumab.
Discussion
In the IMbrave150 trial, 18 (5.5%) and 33 (10.2%) patients with HCC treated with atezolizumab plus bevacizumab presented CR according to RECIST and mRECIST, respectively (3). The IMbrave 150 study showed slightly lower DCR and ORR at 6 weeks than our study. However, the ORR improved after treatment (3, 20). Kuzuya et al. showed that one patient (4.3%) achieved CR at 6 weeks according to mRECIST (21). Consistent with the study by Hiraoka et al., none of the patients achieved CR based on either RECIST or mRECIST (8). However, it is possible that the present results show that recovery and deterioration of ALBI score were similar to those noted in the CheckMate-459 trial (22).
Several studies have revealed the deterioration of liver function in the early period after the initiation of systemic therapy including lenvatinib and sorafenib (23, 24). The relative dose intensity of early-phase MTA treatment reflects the treatment response. Hence, improvement in grade 1 or 2a mALBI after MTA initiation is an important factor in obtaining better therapeutic outcomes in patients with advanced HCC who receive MTA treatment in clinical settings (25). patients in the hepatitis B/C-related HCC group were more likely to have a better 6-week ORR based on mRECIST than those in the non-hepatitis B and C-related HCC group. The causes for differences in therapeutic responses remain unclear. However, this might be attributed to the fact that the group with hepatitis B/C-related HCC had larger and fewer lesions than the second group. However, studies with a larger sample size should be performed to validate the results of the current research.
In the IMbrave150 trial, the incidence rate of serious AEs was 56.5% in the atezolizumab plus bevacizumab-treated group (3). In the IMbrave150 trial, the incidence rates of serious AEs which led to interruption or withdrawal of any trial drug were 49.5% and 15.5%, respectively, in the atezolizumab plus bevacizumab-treated group (3). In our study, the incidence of serious AEs within 6 weeks was low at 21.7% (5/23); high-grade (grade 3 or 4) proteinuria had the highest incidence (7.8%). Furthermore, none of the patients experienced treatment discontinuation during the first 6 weeks of treatment in the current cohort. A longer observation is required for assessing the association between atezolizumab plus bevacizumab therapy and the incidence of serious AEs.
The hepatic function reserve of patients with HCC worsened at 7 months of lenvatinib and sorafenib as the first-line (23, 24) and later (26) treatment. The results of the REACH and REACH-2 trials have shown no significant deterioration in the ALBI score of patients with HCC treated with ramucirumab, a fully humanised IgG monoclonal antibody to VEGF receptor 2 during the treatment course (27). In contrast, El-Khoueiry et al. revealed that the ALBI score of patients treated with nivolumab decreased (28). Therefore, atezolizumab plus bevacizumab treatment might be expected to have a negative impact on hepatic function reserve, such as that observed in patients receiving nivolumab, during the early period after treatment initiation, even if bevacizumab is a humanised monoclonal antibody targeting VEGFA (22). In this study, the ALBI score of the patients slightly decreased at 3 weeks after treatment initiation. However, the ALBI score reflects the recovery of liver function during the early treatment period. Decline might be caused by temporary low-grade AEs associated with digestive disorders such as diarrhoea and appetite loss in the early period of atezolizumab plus bevacizumab therapy. Despite the safety and tolerability of this combination therapy, patients with advanced HCC should be closely monitored due to potential AEs.
The current study had several limitations. Firstly, it was retrospective in nature, and a non-randomised design was used. Secondly, the sample size was small, and the observation period was 175 days. Therefore, future large-scale prospective studies should be performed.
In conclusion, in a real-world setting, combination therapy with atezolizumab plus bevacizumab may be effective and safe and can help achieve complete remission in patients with HCC, including those whose disease is refractory to lenvatinib. Nevertheless, further studies must be conducted to validate the therapeutic benefits of atezolizumab plus bevacizumab in this patient group.
Acknowledgements
The Authors would like to thank Ms Nakai for collecting laboratory data and Enago for English editing and proofreading the article.
Footnotes
Authors’ Contributions
Conceptualisation: TN and HT; methodology: YF; software: KM; validation: ME and YT; formal analysis: TI; investigation: AM; resources: HT; data curation: YF; writing – original draft preparation: ST; writing – review and editing: TN and HT; visualisation: TA and HK; supervision: KK; project administration: KK; funding acquisition: NN. All Authors read and agreed to the published version of the article.
Conflicts of Interest
The Authors declare no conflicts of interest.
- Received July 29, 2022.
- Revision received August 29, 2022.
- Accepted August 31, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
