Research ArticleClinical Studies
Open Access

Efficacy of Lenvatinib and Atezolizumab Bevacizumab Combination Therapy in Patients With Combined Hepatocellular-cholangiocarcinoma

NORIKAZU TANABE, ISSEI SAEKI, KENJI YAMAOKA, TOMOKAZU KAWAOKA, TETSU TOMONARI, JOJI TANI, TAKESHI TERASHIMA, YUSUKE KAWAMURA, SHIRO OKA, TETSUJI TAKAYAMA, HIDEKI KOBARA, TARO YAMASHITA, NORIO AKUTA, TAKAHIRO YAMASAKI and TARO TAKAMI
Anticancer Research March 2025, 45 (3) 1117-1125; DOI: https://doi.org/10.21873/anticanres.17499

Abstract

Background/Aim: Surgical resection remains the only curative treatment for combined hepatocellular-cholangiocarcinoma; however, systemic therapy is the primary treatment option for unresectable cases. This multicenter retrospective study aimed to assess the efficacy of systemic therapy for unresectable combined hepatocellular-cholangiocarcinoma.

Patients and Methods: Twenty-one patients with histologically confirmed or clinically diagnosed combined hepatocellular-cholangiocarcinoma who received systemic therapy were included. First-line regimens consisted of lenvatinib (n=14) and atezolizumab plus bevacizumab (n=7) and their therapeutic efficacy was evaluated.

Results: The objective response and disease control rates were 42.9% and 92.9% for lenvatinib, and 14.3% and 100% for atezolizumab plus bevacizumab, respectively. Median overall survival for all treatments was 14.9 months and median progression-free survival was 6.5 months. By regimen, median overall and progression-free survival was 14.9 and 6.1 months for lenvatinib, and “not reached” and 7.9 months for atezolizumab plus bevacizumab, respectively.

Conclusion: Lenvatinib and atezolizumab plus bevacizumab exhibited potential activity in patients with combined hepatocellular-cholangiocarcinoma.

Keywords:

Introduction

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a type of primary liver cancer (PLC) that exhibits both hepatocellular and cholangiocyte differentiation within the same tumor, along with migratory features (1). cHCC-CCA is a rare subtype, estimated to represent 2-5% of PLC cases worldwide according to the World Health Organization in 2019 (2). In Japan, cHCC-CCA accounts for 1.3% of PLC cases (3). Radiological diagnosis of cHCC-CCA depends on the proportion of hepatocellular carcinoma (HCC) and cholangio-carcinoma (CCA) components. However, the concordance between radiological and histological diagnoses is reported to be low (4). Consequently, cHCC-CCA is typically diagnosed via surgical resection or histological examination of a biopsy. The prognosis for cHCC-CCA is generally similar to that of CCA and worse than HCC (5). Although surgical resection remains the only curative treatment, systemic therapy is the primary treatment option for unresectable cases. However, currently, no standard regimen is available for cHCC-CCA (6). This study aimed to evaluate the therapeutic efficacy of systemic therapy for cHCC-CCA by analyzing cases from six tertiary hospitals in Japan.

Patients and Methods

Patients. Twenty-one patients with histologically confirmed or clinically diagnosed cHCC-CCA who received systemic therapy were enrolled in this study between April 2016 and December 2022. The study protocol was approved by the Ethics Review Committee of Yamaguchi University Hospital (2023-055) and was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. Informed consent was not required due to the retrospective study design.

Systemic therapy regimens. Regimen selection was determined by the treating physician and included secondary and subsequent treatments. All patients continued treatment until clinical or radiological disease progression or the occurrence of intolerable adverse events.

Clinical outcomes. Treatment response was assessed using the response evaluation criteria in solid tumors (RECIST) 1.1 (7). The objective response rate (ORR) was defined as the percentage of patients achieving complete response (CR) or partial response (PR). The disease control rate was defined as the percentage of patients achieving CR, PR, or stable disease (SD).

Statistical analysis. Data are expressed as median and interquartile range. Overall survival (OS) was defined as the time from the start of drug treatment to the date of death from any cause. Patients lost to follow-up were censored at the date of the last visit. Progression-free survival (PFS) was defined as the time from initiation of first-line therapy to radiological tumor progression or death from any cause. All analyses were performed using the JMP software package version 16.0 (SAS Institute, Cary, NC, USA).

Results

Patient characteristics. cHCC-CCA was diagnosed histologically in 15 cases and clinically in six cases. The etiology of cHCC-CCA was attributed to hepatitis B virus in five patients (23.8%), hepatitis C virus in two patients (9.5%), and non-viral causes in 14 patients (66.7%). The modified albumin-bilirubin score (ALBI) grades were 1, 2a, and 2b in seven (33.3%), seven (33.3%) and seven (33.3%) patients, respectively. According to the Barcelona Clinic Liver Cancer staging system (8), two patients had stage A, seven had stage B, and 12 had stage C disease. Nine patients (45.0%) had extrahepatic spread. Regarding tumor markers, the median levels of alpha-fetoprotein (AFP), des-gamma-carboxy-prothrombin (DCP), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) were 13.5 ng/ml, 65.0 mAU/ml, 3.6 ng/ml, and 91.0 U/ml, respectively. Both HCC tumor markers (AFP or DCP) and CCA tumor markers (CEA or CA19-9) were within reference limits in three patients (14.3%). HCC tumor markers were elevated in three patients (14.3%), CCA tumor markers were elevated in three patients (14.3%) and both were elevated in 12 patients (57.1%) (Table I).

View this table:
Table I.

Patient characteristics.

Clinical course. Four patients had primary onset, while 17 had recurrence. As initial treatment, liver resection was performed in eight patients, radiofrequency ablation in three patients, transarterial chemoembolization in three patients, hepatic arterial infusion chemotherapy in one patient, and others in two patients. Initial systemic therapy regimens comprised lenvatinib (LEN) in 14 patients and atezolizumab plus bevacizumab (Atezo/Bev) in seven patients. No patient was treated according to the CCA regimen, such as gemcitabine plus cisplatin (Gem/Cis). Second-line treatment for patients treated with LEN was Atezo/Bev in three patients and sorafenib in two patients, while the others transitioned to best supportive care; no second-line treatment transitions were observed for patients treated with Atezo/Bev, with two patients in progress and the others transitioning to best supportive care (Figure 1).

Figure 1.
Figure 1.

Sankey diagram of treatment sequences from first-line. LEN, Lenvatinib; Atezo/Bev, atezolizumab/bevacizumab; BSC, best supportive care.

Tumor response. The best anti-tumor responses to first-line treatment according to RECIST 1.1 were CR in 0/21 patients (0%), PR in 7/21 (33.3%), SD in 13/21 (62.0%), and PD in 1/21 (4.8%). The ORR was 33.3%, and the disease control rate was 95.2% (Table II). The responses to LEN were CR in 0/14 patients (0%), PR in 6/14 (42.9%), SD in 7/14 (50.0%), and PD in 1/14 (7.1%), whereas the responses to Atezo/Bev were CR in 0/7 (0%), PR in 1/7 (14.3%), SD in 6/7 (85.7%), and PD in 0/7 (0%). Atezo/Bev was administered in 10 patients in all treatment lines, and the best anti-tumor effect was CR in 0/10 patients (0%), PR in 4/10 (40%), SD in 6/10 (60%), and PD in 0/10 (0%).

View this table:
Table II.

The best treatment response based on RECIST 1.1.

Survival time. The median OS for all patients was 14.9 months [95% confidence interval (CI)=9.7-19.3], and median PFS was 6.5 months (95%CI=4.9-10.8) (Figure 2). In the regimen-specific analysis, median OS and PFS were 14.9 months (95%CI=6.6-17.5) and 6.1 months (95%CI=2.5-10.8) for LEN, and “not reached” (95%CI=8.7-not evaluated) and 7.9 months (95%CI=3.2-12.5) for Atezo/Bev.

Figure 2.
Figure 2.

The Kaplan–Meier curve for (A) overall survival and (B) progression-free survival of all patients.

Discussion

This study evaluated the therapeutic efficacy of systemic therapy for cHCC-CCA by analyzing cases from six hospitals in Japan. In this study, either the HCC regimen LEN or Atezo/Bev was selected as first-line treatment for cHCC-CCA treatment in all patients. Moreover, the HCC regimen was selected regardless of imaging findings in patients with elevated HCC tumor markers (AFP or DCP). The HCC regimen was selected in the three patients with elevated CCA tumor markers (CEA or CA19-9) only because the imaging findings were suggestive of HCC (enhance in the arterial phase).

LEN previously demonstrated non-inferiority to sorafenib in OS for HCC in the REFLECT trial (9). Similarly, Atezo/Bev demonstrated significant OS improvement over sorafenib for unresectable HCC in the IMbrave150 trial (10) and is now widely used as standard therapy. Additionally, the TOPAZ-1 trial for advanced biliary tract cancer revealed that adding the immune checkpoint inhibitor (ICI) durvalumab to the standard Gem/Cis regimen significantly prolonged OS (12.8 vs. 11.5 months) and PFS (7.2 vs. 5.7 months) (11, 12). However, at the time of this study, ICIs were not available for CCA and cytotoxic antineoplastics were the treatment of choice. Gem/Cis plus durvalumab and Gem/Cis plus pembrolizumab are now first-line treatments for biliary tract cancer.

Although the efficacy of LEN or Atezo/Bev in cHCC-CCA has been reported in case studies (13-16), this study represents the first small-cohort analysis for LEN. Previous reports on systemic therapy for cHCC-CCA have shown varied outcomes (Table III). In case-control studies, the Gem-based regimen (Gem plus platinum or 5FU) showed an ORR of 5.6-28.6%, and PFS and OS of 3.0-9.0 and 11.5-16.2 months, respectively. In contrast, sorafenib showed a low ORR (0-10.0%), poor PFS (1.6-4.8 months), and poor OS (3.5-10.7 months) (17-20). Whereas studies comparing cytotoxic agents and tyrosine kinase inhibitors (mainly sorafenib) showed ORRs of 8-21.6% and 3-10.0%, respectively. That survival benefit was reported to be similar (PFS: 2.9-4.1 vs. 2.8-4.2, and OS: 10.6-15.5 vs. 5.3-10.7 months) (20-22). In contrast, this study demonstrated that treatment outcomes with LEN and Atezo/Bev for cHCC-CCA were superior those previously reported. Nivolumab plus LEN has shown poor efficacy in biliary tract cancer (23). Additionally, many patients in this study had either elevated HCC tumor markers or imaging findings suggestive of HCC and may have been better treated according to HCC.

View this table:
Table III.

Overview of first-line systemic therapy for combined hepatocellular-cholangiocarcinoma.

cHCC-CCA has been treated with CCA-based therapies with good results. Although LEN and ICIs have emerged as treatments for HCC, their efficacy in cHCC-CCA is unknown. LEN did not show an OS advantage over sorafenib in the REFLECT trial for HCC; however, our results suggest better outcomes for patients with cHCC-CCA compared to previous sorafenib studies. LEN’s inhibition of unique targets, such as fibroblast growth factor receptor, may contribute to its efficacy (24, 25). Recently, molecular target agents and ICIs have shown promise in treating CCA (26). Regarding Atezo/Bev in unresectable cHCC-CCA, Satake et al. reported PR in three of six patients, although the three patients discontinued treatment due to adverse events (14). Moreover, a few recent studies have assessed the effect of ICIs for cHCC-CCA (15, 16). Given the small number of cases in this study, it remains unclear whether adverse events are more common in cHCC-CCA. However, the favorable outcomes in this study suggest that Atezo/Bev may be a viable option for treating cHCC-CAA. A clinical study is currently underway in Japan (jRCTs031220099) to evaluate this. The OS in this study compared favorably with that in previous reports, suggesting that effective treatments, such as LEN and Atezo/Bev, may improve survival outcomes.

Study limitations. First, the small sample size limits the generalizability of the findings. However, as shown in Table III, the efficacy of systemic therapies for cHCC-CCA has not been extensively updated, making these outcomes with LEN and Atezo/Bev significant. Second, some patients were diagnosed clinically rather than histologically, although majority of the patients in this cohort had histological confirmation. The dominant component and clinicopathologic characteristics of cHCC-CCA have been reported to be associated with recurrence and prognosis (27). In the analysis limited to patients with histologically diagnosed cHCC-CCA, the ORR was 40.0% (Table IV), median OS was 14.9 months (95%CI=6.6-19.3), and median PFS was 8.9 (95%CI=2.5-15.4) (Figure 3). For LEN and Atezo/Bev, the ORR was 41.7% and 33.3%, median OS was 11.6 months (95%CI=2.8-19.3) and “not reached”, and median PFS was 6.1 (95%CI=2.3-15.4) and 12.5 months (95%CI=not evaluated), respectively. Third, regimen selection was biased toward HCC due to the retrospective nature of the study, and treatment decisions were at the discretion of the treating physicians. Nevertheless, to the best of our knowledge, this is the first report on the efficacy and prognostic value of LEN and Atezo/Bev in cHCC-CAA. Further studies, including other ICIs, are warranted.

View this table:
Table IV.

The best treatment response based on RECIST 1.1. of the patients with pathological diagnosis.

Figure 3.
Figure 3.

The Kaplan–Meier curve for (A) overall survival and (B) progression-free survival of the patients with pathological diagnosis.

Conclusion

LEN and Atezo/Bev demonstrated potential efficacy in the treatment of cHCC-CCA.

Acknowledgements

The Authors would like to thank all collaborators who participated in this study.

Footnotes

  • Authors’ Contributions

    Conceptualization: Norikazu Tanabe and Issei Saeki; Methodology: Norikazu Tanabe and Issei Saeki; Formal analysis and investigation: Norikazu Tanabe and Issei Saeki; Data curation, Norikazu Tanabe, Issei Saeki, Tomokazu Kawaoka, Tetsu Tomonari, Joji Tani, Takeshi Terashima, and Yusuke Kawamura; Writing – original drafting: Norikazu Tanabe; Writing – Review and Editing: Issei Saeki and Takahiro Yamasaki; Supervision: Shiro Oka, Tetsuji Takayama, Hideki Kobara, Taro Yamashita, Norio Akuta, and Taro Takami. All Authors approved the final version of the manuscript.

  • Conflicts of Interest

    Issei Saeki: Lecture fees from Eisai Co. Ltd., Chugai Pharmaceutical Co., Ltd., and AstraZeneca. Tomokazu Kawaoka: Lecture fees from Chugai Pharmaceutical Co. Joji Tani: Lecture fees from AstraZeneca. Takeshi Terashima: Lecture fees from Eisai Co. Ltd., Chugai Pharmaceutical Co., Ltd., and AstraZeneca. Yusuke Kawamura: Lecture fees from Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd., AstraZeneca PLC., TERUMO CORPORATION, and Boston Scientific Japan. K.K. Taro Takami: Lecture fees from Eisai Co. Ltd., Chugai Pharmaceutical Co., Ltd., and AstraZeneca. The remaining Authors have no conflicts of interest to declare in relation to this study.

  • Funding

    This research received no external funding.

  • Received January 30, 2025.
  • Revision received February 15, 2025.
  • Accepted February 17, 2025.

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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Efficacy of Lenvatinib and Atezolizumab Bevacizumab Combination Therapy in Patients With Combined Hepatocellular-cholangiocarcinoma
NORIKAZU TANABE, ISSEI SAEKI, KENJI YAMAOKA, TOMOKAZU KAWAOKA, TETSU TOMONARI, JOJI TANI, TAKESHI TERASHIMA, YUSUKE KAWAMURA, SHIRO OKA, TETSUJI TAKAYAMA, HIDEKI KOBARA, TARO YAMASHITA, NORIO AKUTA, TAKAHIRO YAMASAKI, TARO TAKAMI
Anticancer Research Mar 2025, 45 (3) 1117-1125; DOI: 10.21873/anticanres.17499
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