Atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma: Early clinical experience

Abstract Background Although atezolizumab plus bevacizumab (Atez/bev) treatment has been developed for unresectable hepatocellular carcinoma (u‐HCC), changes in hepatic function during therapy have yet to be reported. Aim This retrospective clinical study aimed to elucidate early responses to Atez/Bev. Methods From September 2020 to April 2021, 171 u‐HCC patients undergoing Atez/Bev treatment were enrolled (BCLC stage A:B:C:D = 5:68:96:2). Of those, 75 had no prior history of systemic treatment. Relative changes in hepatic function and therapeutic response were assessed using albumin‐bilirubin (ALBI) score and Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1, respectively. Results In initial imaging examination findings, objective response rates for early tumor shrinkage and disease control after 6 weeks (ORR‐6W/DCR‐6W) were 10.6%/79.6%. Similar response results were observed in patients with and without a past history of systemic treatment (ORR‐6W/DCR‐6W = 9.7%/77.8% and 12.2%/82.9%), as well as patients in whom Atez/Bev was used as post‐progression treatment following lenvatinib (ORR‐6W/DCR‐6W = 7.7%/79.5%), for which no known effective post‐progression treatment has been established. In 111 patients who underwent a 6‐week observation period, ALBI score was significantly worsened at 3 weeks after introducing Atez/Bev (−2.525 ± 0.419 vs −2.323 ± 0.445, p < .001), but then recovered at 6‐weeks (−2.403 ± 0.452) as compared to 3‐weeks (p = .001). During the observation period, the most common adverse events were appetite loss (all grades) (12.3%), general fatigue/hypertension (all grades) (11.1%, respectively), and urine protein (all grades) (10.5%). Conclusion Atez/Bev might have therapeutic potential not only as first but also later‐line treatment of existing molecular target agents. In addition, this drug combination may have less influence on hepatic function during the early period, as the present patients showed a good initial therapeutic response.

Conclusion: Atez/Bev might have therapeutic potential not only as first but also later-line treatment of existing molecular target agents. In addition, this drug combination may have less influence on hepatic function during the early period, as the present patients showed a good initial therapeutic response.

K E Y W O R D S
albumin-bilirubin score, atezolizumab plus bevacizumab, hepatic function, lenvatinib, unrespectable hepatocellular carcinoma 1 | INTRODUCTION Hepatocellular carcinoma (HCC) is the most commonly encountered primary liver malignancy and sixth most common malignancy worldwide. 1 In addition to curative treatments, such as liver transplantation, 2 surgical resection, 3 and radiofrequency ablation (RFA), 4 and the palliative treatment transcatheter arterial chemoembolization (TACE), 5 systemic therapeutic strategies have been developed for unresectable HCC (u-HCC) cases. 6,7 Following introduction of sorafenib 8 as the initial firstline molecular target agent (MTA) in 2009, approval for lenvatinib 9 as an additional first-line MTA for u-HCC was granted in 2018 in Japan. As for second-line MTA treatments, regorafenib 10 in 2017, ramucirumab 11 in 2019, and cabozantinib 12 in 2020 have received approval. This increase in therapeutic options has improved the prognosis of u-HCC patients. 13 Moreover, atezolizumab plus bevacizumab (Atez/Bev) 14 recently developed in 2020 as a first-line therapy using the combination of an immune-checkpoint inhibitor (ICI) and MTA and is expected to show better therapeutic efficacy for improving prognosis of these patients than previously introduced first-line MTA treatments (sorafenib, lenvatinib). 15 Few reports regarding the influence of hepatic function during the early period of Atez/Bev therapy for u-HCC are available at this time. Moreover, many u-HCC patients continue to receive treatments with existing MTA drugs after approval of Atez/Bev, and there is scant information regarding the therapeutic efficacy of that combination given as later-line therapy when treatment failure is observed in a patient receiving an MTA. In addition, there is no known effective post-progression treatment for patients receiving lenvatinib. 16 This study aimed to evaluate the influence of Atez/Bev on hepatic function as well as early therapeutic response when given not only as a first but also as a later-line treatment in clinical practice.

| MATERIALS AND METHODS
The present findings were obtained in a multicenter analysis of 171 u-HCC patients treated with Atez/Bev from September 2020 to April 2021 at 16 different institutions. Therapeutic response was determined using Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1. 17 The first assessment of therapeutic effect was performed using dynamic CT results obtained at around 6 weeks after introduction of Atez/Bev, whenever possible, and additional dynamic CT examinations were performed as needed depending on the patient condition even before 6 weeks. Findings showing partial response (PR) at around 6 weeks were considered to indicate early tumor shrinkage for the present study (PR-6W).
Patients with a known history of autoimmune disease were not treated with Atez/Bev. In addition, all patients were examined using upper gastrointestinal endoscopy for surveillance of esophageal and gastric varices. When detected or if a high risk of bleeding was present, the patient was treated according to local clinical practice.

| Basal liver disease
For the present study, positive anti-HCV findings were considered to indicate that HCC was due to hepatitis C virus (HCV), whereas HCC due to hepatitis B virus (HBV) was determined when the HBV surface antigen was positive. For patients with a history of alcohol abuse of 60 g/day or more, 18,19 basal liver disease was judged as alcoholic.

| Atez/Bev treatment and adverse event assessment
After obtaining written informed consent from the patient, intravenous Atez/Bev treatment, composed of 1200 mg of atezolizumab plus 15 mg/kg of body weight of bevacizumab, was given every 3 weeks.
Treatment was discontinued following observation of any unacceptable or serious adverse event (AE) or clinical tumor progression.
For assessment of AEs, the National Cancer Institute Common  As for AEs, during the early period of Atez/Bev treatment, appetite loss (any grade) was most frequently observed (12.3%), followed by general fatigue/hypertension (any grade) (11.1%, respectively) and urine protein (any grade) (10.5%) ( the first imaging evaluation, overall survival (OS) was much worse than CR/PR and SD (8.0 months vs not estimated/16.1 months). 34 Thus, the possibility of clinical efficacy with continued Atez/Bev treatment beyond PD should be considered. It will be necessary to establish a treatment strategy in the future that takes into account the initial PD result in patients undergoing Atez/Bev treatment.
Although it is well known that patients receiving sorafenib or lenvatinib show deterioration of hepatic function at 1 month after introducing treatment, both when given as first-line 35,36 and as laterline 37 treatment, another study found no significant deterioration of hepatic function (ALBI score) in ramucirumab, anti-VEGFR-2, and placebo groups during each cycle of treatment. 38 On the other hand, patients in the CheckMate-459 trial who were treated with nivolumab showed small amounts of deterioration and recovery of ALBI score during the early treatment period. 39 Although bevacizumab, an antibody that provides suppression upstream of the VEGFR-2, is given as Although 56.1% of the present cohort were treated with Atez/Bev as later-line treatment, our results indicated a therapeutic response similar to that seen in the IMbrave150 trial. 14  This study has some limitations. Although it was conducted as a multicenter study, the analysis was retrospective, and the observation period was short, making concrete conclusions not possible to obtain.
Additionally, the therapeutic potential of Atez/Bev and determination of its influence on worsening hepatic function as compared to other existing MTA drugs, as well as administration in u-HCC patients with mALBI grade 2b or 3 should be analyzed in the future. Accumulation of greater numbers of patients and a longer observation period will be needed for obtaining definitive conclusions.
In conclusion, Atez/Bev may have a good therapeutic potential when given not only as a first but also as a later-line treatment following

ETHICAL STATEMENT
The Institutional Ethics Committee of our hospital granted approval (IRB No. 30-66). Written informed consent was received from all patients.

DATA AVAILABILITY STATEMENT
The datasets generated during and/or analyzed during the current study are not publicly available. Due to the nature of this research, participants of this study did not agree for their data to be shared publicly, so supporting data is not available.