Research ArticleClinical Studies
Open Access

Change in Liver Function in Durvalumab Plus Tremelimumab Treatment for Unresectable Hepatocellular Carcinoma

NOBUHARU TAMAKI, NAMI MORI, SHINTARO TAKAKI, KEIJI TSUJI, TOSHIFUMI TADA, SHINICHIRO NAKAMURA, HIRONORI OCHI, TOSHIE MASHIBA, MASAO DOISAKI, HIROYUKI MARUSAWA, HARUHIKO KOBASHI, HIDEKI FUJII, CHIKARA OGAWA, MICHIKO NONOGI, HIROTAKA ARAI, YASUSHI UCHIDA, NAOHITO URAWA, RYOICHI NARITA, TAKEHIRO AKAHANE, MASAHIKO KONDO, YUTAKA YASUI, KAORU TSUCHIYA, NAMIKI IZUMI and MASAYUKI KUROSAKI
Anticancer Research September 2024, 44 (9) 3913-3918; DOI: https://doi.org/10.21873/anticanres.17219

Abstract

Background/Aim: Maintaining liver function throughout the treatment of hepatocellular carcinoma (HCC) is crucial, yet the impact of durvalumab plus tremelimumab (DT) treatment on liver function is not well understood. This multicenter study aimed to examine the changes in liver function during DT treatment. Patients and Methods: This nationwide multicenter study included 80 patients who received DT treatment for unresectable HCC. The primary outcome was changes in albumin-bilirubin (ALBI) scores at baseline, week 8, week 12, and at the time of progressive disease (PD). Results: The median (interquartile range) ALBI scores at baseline, week 8, week 12, and the time of PD were −2.24 (−2.49 to −1.94), −2.13 (−2.51 to −1.86), −2.23 (−2.51 to − 1.77), and −2.06 (−2.53 to −1.72), respectively. No significant differences were observed at 8 weeks (p=0.06), at 12 weeks (p=0.4), and at PD (p=0.8) compared to baseline. Subgroup analyses were conducted for patients with an ALBI grade of 2 at baseline and for those who received DT treatment as a second-line or later treatment. No deterioration in liver function was observed at any time point in both analyses. Conclusion: DT treatment can maintain liver function throughout the treatment period. Maintaining liver function is crucial in managing HCC, and this is an advantage of using DT treatment as a first-line treatment for unresectable HCC.

Key Words:

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, and reducing mortality from HCC remains a significant challenge (1). Chronic viral hepatitis is a major risk factor for HCC. Recently, there has been an increase in HCC cases linked to steatotic liver disease, many of which are detected at an advanced stage due to the absence of regular HCC surveillance (2-4). Systemic therapy is the first-line treatment for unresectable HCC, and several drugs have recently become available for this purpose. Durvalumab plus tremelimumab (DT) treatment is a combination of immune checkpoint inhibitors, recently approved for clinical use and recommended as a first-line treatment in the latest guidelines (5-7).

In the therapeutic decision-making for unresectable HCC, liver function is as important as HCC staging, and systemic therapy is challenging to apply when liver function is compromised (8). Additionally, when HCC becomes progressive disease (PD), a sequential and multidisciplinary approach using various drugs is employed. However, in such cases, it is difficult to initiate second-line treatment if liver function is compromised. Therefore, maintaining good liver function is crucial in the treatment of HCC, alongside achieving a therapeutic effect on the cancer. Although DT treatment is recommended as the first-line treatment for unresectable HCC, its impact on liver function has not been thoroughly investigated. To address this knowledge gap, we conducted a nationwide, multicenter cohort study to examine changes in liver function during DT treatment in patients with unresectable HCC who underwent DT treatment.

Patients and Methods

Study protocol. This is a nationwide multicenter study that included 104 patients who received DT treatment for unresectable HCC from March 2023 to January 2024 across 16 centers within the Japanese Red Cross Liver Study Group. The exclusion criteria were as follows: patients who did not undergo imaging examinations to assess treatment response (n=18) and patients who did not have liver function tests at week 8 of treatment (n=6) were excluded. Ultimately, 80 patients who received DT treatment were included in the analysis. All included patients underwent either computed tomography or magnetic resonance imaging, along with blood tests at week 8, to evaluate treatment response and liver function.

Written informed consent was obtained from all patients before the start of the study. The study protocol was approved by the ethics review committees of Musashino Red Cross Hospital (approval number: 4054), and conformed to the ethical guidelines of the Declaration of Helsinki.

Imaging examination. Imaging examinations were conducted at week 8 of treatment and every 8 weeks thereafter. Treatment response was assessed using the modified Response Evaluation Criteria in Solid Tumors, version 1.1 (mRECIST) (9). The best treatment response and changes in liver function during treatment were evaluated.

Blood tests. Blood tests were conducted following standard protocols at each center. Albumin, bilirubin, and the albumin-bilirubin (ALBI) score were calculated as indices of liver function (10). Liver function was assessed at 8 and 12 weeks of treatment and at the time of PD.

Primary outcome. The primary outcome of the study is the changes in liver function during DT treatment. Changes in liver function from the start of treatment to weeks 8, 12, or at PD were examined. As a subgroup analysis, we also examined changes in liver function in patients with an ALBI grade of 2 at the start of treatment or in those who received DT treatment as a second-line or later treatment.

Statistical analyses. Changes in liver function were examined using the Wilcoxon signed-rank test. Statistical significance was defined as p-values less than 0.05. All statistical analyses were conducted using EZR (Saitama Medical Center, Jichi Medical University, Shimotsuke, Japan), a graphical user interface for R version 3.2.2 (The R Foundation for Statistical Computing, Vienna, Austria).

Results

Patient background. A total of 80 patients undergoing DT treatment were enrolled in the study (Table I). The mean age was 73 years, with an interquartile range (IQR) of 70-78 years, and 70 (88%) of the patients were male. The etiology of chronic liver disease included chronic hepatitis B, chronic hepatitis C, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and cryptogenic disease, affecting 15 (18.8%), 24 (30.0%), 19 (23.8%), 18 (23%), and 4 (5.0%) patients, respectively. DT treatment was initiated as a first-line treatment in 16 (20%) cases and as a second-line or later treatment in 64 (80%) cases. The bilirubin level at the start of treatment was 0.80 mg/dl (IQR=0.58-1.12) and the albumin level was 3.5 g/dl (IQR=3.2-3.8); the ALBI score was −2.24 (−2.48 to −1.94), and the ALBI grade was grade 1 in 16 (20%) and grade 2 in 64 (80.0%). Regarding the best treatment response assessed using imaging modalities, there were two cases with complete responses, 14 with partial responses, 20 with stable disease, and 44 with PD.

View this table:
Table I.

Patient characteristics.

Changes in liver function. We calculated ALBI scores and albumin levels at baseline, week 8, week 12, and at the time of PD. The median (IQR) ALBI scores were −2.24 (−2.49 to −1.94) at baseline, −2.13 (−2.51 to −1.86) at week 8, −2.23 (−2.51 to −1.77) at week 12, and −2.06 (−2.53 to −1.72) at the time of PD (Figure 1A). No significant differences were observed when comparing the scores at 8 weeks (p=0.06), 12 weeks (p=0.4), and at PD (p=0.8) to the baseline scores. Similarly, the median (IQR) albumin levels were 3.5 (3.2 to 3.8) g/dl at baseline, 3.4 (3.1 to 3.8) g/dl at week 8, 3.5 (3.1 to 3.7) g/dl at week 12, and 3.4 (2.9 to 3.8) g/dl at the time of PD (Figure 1B). No significant differences were found in albumin levels at week 8 (p=0.1), week 12 (p=0.3), and PD (p=0.8) compared to baseline.

Figure 1.
Figure 1.

Changes in liver function during durvalumab plus tremelimumab treatment. (A) Changes in albumin-bilirubin (ALBI) score and (B) changes in albumin levels.

Subgroup analysis for changes in liver function. In a subgroup analysis, we examined changes in liver function in patients with a baseline ALBI grade of 2. The median (IQR) ALBI scores at baseline, week 8, week 12, and at the time of PD were −2.15 (−2.35 to −1.84), −2.04 (−2.31 to −1.72), −2.14 (−2.44 to −1.72), and −2.00 (−2.38 to −1.65), respectively (Figure 2A). No significant differences were observed at 8 weeks (p=0.3), 12 weeks (p=0.7), and at PD (p=0.9) compared to baseline. Similarly, another subgroup analysis was conducted on patients who received DT treatment as a second-line or later treatment. The median (IQR) ALBI scores at baseline, week 8, week 12, and at the time of PD were −2.26 (−2.50 to −1.92), −2.19 (−2.48 to −1.88), −2.26 (−2.51 to −1.78), and −2.09 (−2.50 to −1.79), respectively (Figure 2B). No significant differences were observed at 8 weeks (p=0.2), 12 weeks (p=0.6), and at PD (p=0.6) compared to baseline.

Figure 2.
Figure 2.

Subgroup analysis of changes in albumin-bilirubin (ALBI) score during durvalumab plus tremelimumab treatment. (A) Patients with ALBI grade 2 at baseline, and (B) patients who received durvalumab plus tremelimumab treatment in second or later line.

Discussion

Main findings. In this multicenter study, we demonstrated that DT treatment for unresectable HCC did not impair liver function during the treatment period. This beneficial effect was observed even in patients who developed PD. Additionally, a positive impact was also observed in patients with compromised liver function (ALBI grade 2) at baseline or those who received DT treatment in a second-line or later treatment. Maintaining liver function is a critical aspect of treating HCC. Therefore, DT treatment, which does not compromise liver function, may have significant implications for multidisciplinary treatment approaches.

In the context of published literature. In the treatment of HCC, liver function is one of the most important factors determining the treatment strategy (8). If liver function is impaired, it is difficult to introduce various therapies, including systemic therapy. Additionally, as multiple regimens are currently available for unresectable HCC, sequential treatment is commonly used (11-14). However, if liver function deteriorates, it is generally more difficult to progress to the next treatment, although systemic chemotherapy may be effective in some cases (15). Therefore, maintaining good liver function is a crucial issue throughout HCC treatment.

Atezolizumab plus bevacizumab is recommended as a first-line treatment for unresectable HCC, along with DT treatment (16). Many studies reported good therapeutic effects of atezolizumab plus bevacizumab (16, 17). Vascular endothelial growth factor (VEGF) inhibitors are also used as a first-line treatment in cases where immune checkpoint inhibitors are unsuitable (18, 19). During treatment with VEGF inhibitors, proteinuria occurs frequently, and hypoalbuminemia may make it difficult to continue treatment (20). Treatment of immune checkpoint inhibitors have complications including immune-related adverse events or infections, but proteinuria is rarely reported (21). Therefore, proteinuria and hypoalbuminemia are a serious limitation of using VEGF inhibitors. However, as shown in this study, DT treatment did not reduce ALBI scores or albumin levels, and liver function is maintained during DT treatment. Furthermore, liver function is also maintained after PD with DT treatment. This is a major advantage throughout HCC treatment in terms of the continuation of multidisciplinary treatment and highlights the benefits of using DT treatment as a first-line therapy, as well as its therapeutic efficacy.

In clinical trials of DT treatment, the incidence of hypoalbuminemia or proteinuria was low (5, 22). These trials only included patients with good liver function who received DT treatment as first-line therapy. However, in clinical practice, patients with impaired liver function or those who received DT treatment as a later-line therapy were sometimes included (23-25), and the changes in liver function in these patients have not been adequately investigated. The present study showed that liver function was maintained in patients with ALBI grade 2 and in those who received DT treatment as a later-line therapy. Therefore, DT treatment can be administered to patients with more advanced disease compared to those in clinical trials, without worsening liver function.

Strength and limitations. The study is a nationwide, multicenter study. It included patients with reduced liver function or those who received DT treatment as a later-line treatment, consistent with real-world clinical practice. Liver function was maintained in this heterogeneous population. However, a limitation of the study was the short observation period. Future studies are needed to determine the impact on liver function when treatment is continued for longer periods.

Future implications. Atezolizumab plus bevacizumab or DT treatment is recommended as the first-line treatment for unresectable HCC (6, 7). However, there is still no clear evidence to guide the choice between these treatments. Therefore, the selection of a treatment agent depends on the individual patient’s condition. In this decision-making process, the maintenance of liver function during treatment is one of the advantages of DT treatment. Maintaining liver function is one of the most important factors throughout multidisciplinary HCC treatment and is a key rationale for selecting DT treatment as the first-line treatment. However, further clinical data are needed on the use of atezolizumab plus bevacizumab or DT treatment, including their therapeutic efficacy on progression-free survival or overall survival and side effects.

In conclusion, DT treatment can maintain liver function throughout the treatment. Maintaining liver function is crucial in treating HCC, and this is an advantage of using DT treatment as a first-line treatment for unresectable HCC.

Footnotes

  • Authors’ Contributions

    Study concept and design: NT and MK; data collection and interpretation: all Authors; drafting of the manuscript: NT; critical revision of the manuscript: all Authors; statistical analysis: NT; study supervision: NI and MK; obtained funding: NT, YY, and MK. All Authors had access to the study data and reviewed and approved the final manuscript.

  • Conflicts of Interest

    Masayuki Kurosaki and Kaoru Tsuchiya received lecture fees from AstraZeneca. The other Authors have no conflicts of interest to declare related to this study.

  • Funding

    Masayuki Kurosaki receives funding support from Japan Agency for Medical Research and Development (JP24fk0210123, JP24fk0210113) and Japanese Ministry of Health, Labor and Welfare (23HC2001). Nobuharu Tamaki receives funding support from Japan Agency for Medical Research and Development (JP24fk0210111, JP24fk0210104), and Japanese Ministry of Health, Labor and Welfare (23HC2003, 23HC2002). Yutaka Yasui receives funding support from Japan Agency for Medical Research and Development (JP24fk0210126).

  • Received June 28, 2024.
  • Revision received July 13, 2024.
  • Accepted July 15, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Change in Liver Function in Durvalumab Plus Tremelimumab Treatment for Unresectable Hepatocellular Carcinoma
NOBUHARU TAMAKI, NAMI MORI, SHINTARO TAKAKI, KEIJI TSUJI, TOSHIFUMI TADA, SHINICHIRO NAKAMURA, HIRONORI OCHI, TOSHIE MASHIBA, MASAO DOISAKI, HIROYUKI MARUSAWA, HARUHIKO KOBASHI, HIDEKI FUJII, CHIKARA OGAWA, MICHIKO NONOGI, HIROTAKA ARAI, YASUSHI UCHIDA, NAOHITO URAWA, RYOICHI NARITA, TAKEHIRO AKAHANE, MASAHIKO KONDO, YUTAKA YASUI, KAORU TSUCHIYA, NAMIKI IZUMI, MASAYUKI KUROSAKI
Anticancer Research Sep 2024, 44 (9) 3913-3918; DOI: 10.21873/anticanres.17219
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