Real‐world experiences of atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma in Hong Kong

The IMbrave150 trial established atezolizumab–bevacizumab as the new standard of care for hepatocellular carcinoma (HCC). However, evidence on its applications in real‐world patients is limited. We report the efficacy and safety of atezolizumab–bevacizumab in a Chinese cohort of HCC patients ineligible for clinical trials.


| INTRODUC TI ON
The introduction of immune checkpoint inhibitors (ICIs) represents a paradigm shift in managing a variety of cancers, having shown superior survival benefits to traditional chemotherapy across different tumour types.Atezolizumab is a programmed death-ligand 1 (PD-L1) antibody that blocks the PD-1/PD-L1 axis.The IMbrave150 clinical trial is a phase III clinical trial comparing the combination regimen of atezolizumab and anti-VEGF agent bevacizumab to sorafenib as the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). 1 Patients treated with atezolizumab-bevacizumab had improvement in both primary endpoints, the overall survival (OS) and progression-free survival (PFS), compared with sorafenib.
The combination of atezolizumab and bevacizumab has thus been approved by the United States Food and Drug Administration and the European Medicines Agency as the first-line treatment for unresectable HCC. 2,3e 2022 update of the Barcelona Clinic Liver Cancer (BCLC) treatment algorithm recommended the use of either atezolizumab-bevacizumab or durvalumab-tremelimumab in the firstline treatment of advanced stage HCC. 4 Alternatively, if patients are unsuitable for combination therapies, sorafenib, lenvatinib or durvalumab monotherapy could be used. 4Camrelizumab-apatinib also showed favourable results in both first-line and second-line settings in the RESCUE phase II trial. 5A network meta-analysis of Phase III trials comparing first-line systemic treatments for HCC has found that out of 14 different regimens, atezolizumab-bevacizumab offered one of the highest reductions in the mortality risk when compared to sorafenib. 6In Hong Kong, atezolizumab-bevacizumab or lenvatinib are more commonly prescribed for advanced HCC.
For novel treatments, clinical trial data do not sufficiently reflect real-world experiences, as the regimen is prescribed to a more general population who may not fulfil the stringent eligibility criteria of clinical trials.Real-world experiences compliment randomized clinical trial data in filling knowledge gaps and guiding practice where trial data are not easily available. 7For example, HCC patients with suboptimal hepatic function (Child-Pugh B) may be started on systemic therapy despite lack of clinical trial data.Therefore, this study aims to provide real-world experiences of the safety and efficacy of atezolizumab-bevacizumab for patients with in advanced HCC.

| Study design and population
This was a retrospective study to evaluate the safety and efficacy of

| Data collection and statistical analyses
Eligible patients were identified from the chemotherapy database in the hospital.Baseline patient data were extracted from electronic medical records.Clinical characteristics include sex, age, Eastern Cooperative Oncology Group (ECOG) performance status, prior treatment and disease stage.HCC-specific characteristics included liver function, aetiologies, tumour burden, extrahepatic disease and vascular invasion.Disease stage was classified by the BCLC system.
Baseline liver function was stratified by Child-Pugh score.Adverse events deemed related to atezolizumab-bevacizumab were recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Tumour response was assessed by computed tomography or magnetic resonance imaging in all but two patients.Best response was classified according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.The objective response rate (ORR) was defined as the proportion of patients with partial response (PR) or complete response (CR).The disease control rate (DCR) was defined as the proportion of patients with stable disease (SD), PR, or CR.While regular scanning was not performed, our departmental protocol necessitates assessment of radiological response every 6-10 weeks.
Radiological response was not assessed in two patients, due to suboptimal clinical condition.
Kaplan-Meier analysis was used to estimate OS and PFS with 95% confidence interval (95% CI) given.OS was defined as the period from initiation of treatment until the last follow-up or death.
PFS was defined as the period from initiation of treatment until the last follow-up, disease progression or death.Patients were followed up until January 2022.For baseline patient characteristics, categorical variables were presented as counts with percentages, and continuous variables were presented as median with range.

Key points
The combination regimen of atezolizumab and bevacizumab has prolonged survival time compared with sorafenib in patients with late-stage liver cancer in the IMbrave150 clinical trial.However, real-world patients often have different characteristics from patients enrolled in clinical trials.We examined 13 patients with late-stage liver cancer treated with atezolizumab-bevacizumab in Hong Kong.We showed that use of the combination regimen provided comparable survival time to that reported in clinical trials.

| Toxicity
Adverse events of any grade regardless of causality were reported by 11 patients (84.6%).No grade 5 events were reported (Table 3).
The most common grade 3 or 4 event was hypertension (30.8%), a finding consistent with the known safety profile of bevacizumab.
There were no patients who discontinued treatment due to adverse events.Adverse events leading to dose modification or interruption occurred in 2 (15.4%) patients.All events involved dosage reduction or interruption of bevacizumab.There were no dosage modifications of atezolizumab.No patients discontinued treatment due to adverse events.

| DISCUSS ION
Our study is the first retrospective study to report on the real-world efficacy and safety of atezolizumab-bevacizumab in Hong Kong.
Our analysis revealed similar safety profiles and comparable efficacy to previous landmark clinical trials, despite a more heterogeneous patient cohort.
In the IMbrave150 trial, only 69% (501/725) of screened patients were included in the intention-to-treat analysis, 1 reflecting a lack of high-quality evidence for atezolizumab-bevacizumab in a significant proportion of HCC patients.Our study cohort provides evidence for the efficacy of atezolizumab-bevacizumab in patients who would have been excluded from IMbrave150, namely Child-Pugh B or C patients, and patients who have received previous systemic treatment.Despite including patients with unfavourable clinical characteristics, median OS and PFS in our study were similar to that reported by the IMbrave150 trial (mOS: 18.6 vs. 19.2 months; mPFS: 9.3 vs. 6.8 months). 1 Survival rate at 6 months was 76%, comparable to 84.8% survival achieved in the trial. 1 In addition, the results of our study are comparable to those of other recent real-world studies on the use of atezolizumab-bevacizumab as first-line treatment for HCC, [8][9][10] and to studies including patients receiving atezolizumab-bevacizumab in the post-first-line setting. 11e efficacy of atezolizumab-bevacizumab in our cohort may be attributed to the predominantly Asian patient cohort.Recent randomized clinical trials suggested a greater survival benefit for ICIs among Asian populations.KEYNOTE-394, powered to investigate the efficacy of second-line pembrolizumab versus placebo with best supportive care in Asian patients with HCC in five countries, reported significantly improved OS, PFS and ORR in the pembrolizumab group, 12 standing in contrast with the negative results of KEYNOTE-240, which explored a similar research question in a 27-country global cohort. 13Similarly, a pre-specified subgroup analysis in CheckMate 249 revealed an OS benefit favouring nivolumab for HCC within patients from Asian countries, which was not seen in the overall study cohort. 14e large proportion of HBV-related HCC may also account for the efficacy of atezolizumab-bevacizumab in our cohort.
There is accumulating evidence supporting viral aetiology as a favourable predictor for ICI response in HCC. 15 A meta-analysis of three randomized controlled trials for ICIs in advanced HCC (IMbrave150, CheckMate459, KEYNOTE-240) showed that the survival benefits brought by ICIs were largely associated with HBV-related HCC and HCV-related HCC patients, while non-viral HCC patients did not enjoy a benefit from ICIs. 16These results may be explained by pre-clinical evidence of aberrant T-cell activation in non-alcoholic steatohepatitis (NASH) and subsequent impairment to immune surveillance, which resulted in a lack of response to ICIs in NASH-related HCC. 16Another possible factor that may account for the efficacy of atezolizumab-bevacizumab in our cohort is the significant proportion of patients that have received prior immunotherapy (46.2%), which consisted of either nivolumab or pembrolizumab.A recent study has demonstrated the benefit of ICI rechallenge in HCC patients, even in patients with progressive disease as their best overall response during their first ICI treatment. 17 Adverse events reported were largely consistent with earlier studies, and no bleeding-related adverse events were documented in our study, despite a poorer baseline liver function in our cohort.
With prior assessment of gastrointestinal varices and proper management, risks of bleeding related to bevacizumab remain low.Upper endoscopy should hence be performed in all patients before atezolizumab-bevacizumab treatment. 18We have provided evidence for the safety and potential of using atezolizumab-bevacizumab in patients with suboptimal liver function.
This study is a single-centre retrospective study, with limitations inherent to its retrospective design.Information retrieved may be incomplete as some tests are not routine in the clinical setting.Given the retrospective nature of this study, selection biases may be present.As radiological response was not assessed at regular intervals, PFS and tumour response may not be accurately evaluated.A limited TA B L E 3 Treatment-related adverse events.
atezolizumab-bevacizumab at the Department of Clinical Oncology in the Prince of Wales Hospital between February 2019 and August 2021.Findings are reported in accordance with the STROBE guidelines for observational studies.Inclusion criteria included the use of atezolizumab-bevacizumab for treatment of HCC and the administration of at least one cycle of treatment.Patients were excluded if there are incomplete data in the record or if atezolizumab-bevacizumab was administered as part of a clinical trial.Upper endoscopy was routinely performed for screening and treatment of oesophageal or gastric varices up to 3 months before administration of atezolizumab-bevacizumab.All patients were treated with the regimen till disease progression, intolerable toxicity or death.Ethical approval was obtained from the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (Reference number: 2021.605).
Data collection was done by two authors (D.C.Y.Y. and B.L.H.C.) and verified by a third author (A.C.F.W.) under supervision of the corresponding author (S.L.C.).Statistical analyses were conducted using SPSS (version 26.0., IBM Corp).Statistical significance was defined as a p-value of 0.05.

1 |
Patients' characteristicsA total of 13 patients underwent atezolizumab-bevacizumab therapy.Baseline characteristics of the patients are presented in Table1.Among the 13 patients with advanced HCC included in the study, the median age was 64.0 years old (range, 41.0-79.0),with 11 males (84.6%).Most patients (84.6%) had hepatitis B virus (HBV) infection.Nine patients received prior treatment before starting atezolizumab-bevacizumab treatment.Prior treatment regimens of individual patients are detailed in Table S1.There were seven patients with Child-Pugh A liver disease, five patients with Child-Pugh B and one patient with Child-Pugh C. Most patients had the latestage disease, with 46.2% with vascular invasion at baseline.

F I G U R E 1
Kaplan-Meier analyses of (A) progression-free survival and (B) overall survival of hepatocellular carcinoma (HCC) patients receiving atezolizumab-bevacizumab.TA B L E 2Response rates to atezolizumab-bevacizumab among the cohort.