Comparison of Efficacy between Lenvatinib and Bevacizumab in Combination of Immune Checkpoint Inhibitor and Interventional Triple Therapy in Chinese Advanced Hepatocellular Carcinoma: The CLEAP 2302 Study

Zhaolong Pan; Dongming Liu; Junbo Cao; Linlin Fu; Xihao Zhang; Xiaodong Zhu; Yangxun Pan; Jianwei Liu; Chuangye Han; Renan Jin; Shunli Shen; Xiaoyun Zhang; Hongzhi Liu; Xiaobo Yang; Kuan Hu; Xiaoyi Shi; Dongxu Wang; Yang Zhao; Jianhong Zhong; Bangde Xiang; Shanzhi Gu; Tao Li; Shuijun Zhang; Ledu Zhou; Haitao Zhao; Yongyi Zeng; Tianfu Wen; Ming Kuang; Xiao Liang; Tao Peng; Kui Wang; Li Xu; Huikai Li; Tianqiang Song; Huichuan Sun; Wei Zhang; China Liver Cancer Study Group Young Investigators (CLEAP)

doi:10.1159/000545545

Comparison of Efficacy between Lenvatinib and Bevacizumab in Combination of Immune Checkpoint Inhibitor and Interventional Triple Therapy in Chinese Advanced Hepatocellular Carcinoma: The CLEAP 2302 Study

Liver Cancer. 2025 Apr 3:1-19. doi: 10.1159/000545545. Online ahead of print.

Authors

Zhaolong Pan^{1

2

3}, Dongming Liu^{1

2

3}, Junbo Cao^{1

2

3}, Linlin Fu^{1

2

3}, Xihao Zhang^{1

2

3}, Xiaodong Zhu⁴, Yangxun Pan⁵, Jianwei Liu⁶, Chuangye Han⁷, Renan Jin⁸, Shunli Shen⁹, Xiaoyun Zhang¹⁰, Hongzhi Liu¹¹, Xiaobo Yang¹², Kuan Hu¹³, Xiaoyi Shi¹⁴, Dongxu Wang¹⁵, Yang Zhao¹⁶, Jianhong Zhong¹⁷, Bangde Xiang¹⁷, Shanzhi Gu¹⁶, Tao Li¹⁵, Shuijun Zhang¹⁴, Ledu Zhou¹³, Haitao Zhao¹², Yongyi Zeng¹¹, Tianfu Wen¹⁰, Ming Kuang⁹, Xiao Liang⁸, Tao Peng⁷, Kui Wang⁶, Li Xu⁵, Huikai Li^{1

2

3}, Tianqiang Song^{1

2

3}, Huichuan Sun⁴, Wei Zhang^{1

2

3}; China Liver Cancer Study Group Young Investigators (CLEAP)

Affiliations

¹ Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China.
² Tianjin's Clinical Research Center for Cancer, Tianjin, China.
³ Tianjin Key Laboratory of Digestive Cancer, Tianjin, China.
⁴ Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China.
⁵ Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Sun Yat-Sen University, Guangzhou, China.
⁶ Department of Hepatic Surgery II, The Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
⁷ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
⁸ Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Institute of Minimally Invasive Surgery, Zhejiang University, Hangzhou, China.
⁹ Department of Hepatic Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
¹⁰ Department of Liver Surgery, West China Hospital of Sichuan University, Chengdu, China.
¹¹ Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China.
¹² Department of Hepatobiliary Surgery, Peking Union Hospital, Chinese Academy of Medical Sciences, Beijing, China.
¹³ Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha, China.
¹⁴ Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
¹⁵ Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China.
¹⁶ Department of Interventional Therapy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
¹⁷ Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China.

Abstract

Background: The conversion therapy for advanced hepatocellular carcinoma (HCC) shows promise with a triple therapy approach that combines interventional therapy, immune checkpoint inhibitors, and molecular targeted therapy (primarily small-molecule TKIs and the large-molecule bevacizumab). This combination has achieved the highest objective response rates (ORR) along with acceptable safety profiles. The aim of this study was to compare the clinical efficacy of lenvatinib versus bevacizumab, when combined with immune checkpoint inhibitors and interventional triple therapy, as first-line treatments for Chinese patients with unresectable HCC (uHCC).

Method: This retrospective multicenter study involved 371 consecutive patients from 21 centers in China, observed between April 2017 and December 2023. The study focused on patients with uHCC at Chinese liver cancer stages IIb to IIIb (Barcelona Clinic Liver Cancer stage B or C) who received lenvatinib or bevacizumab combined with anti-PD-1/L1 and interventional therapy (including TACE and/or HAIC) as first-line treatment. Of the 371 patients, 258 received lenvatinib-based triple therapy, while 113 received bevacizumab-based triple therapy. The primary endpoints were overall survival (OS) and progression-free survival (PFS). To balance baseline clinical characteristics, propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were applied. Subgroup analysis was also performed based on different clinicopathological characteristics of the enrolled uHCC patients.

Results: The median OS in the lenvatinib group was significantly longer than in the bevacizumab group, both before (36.0 vs. 27.9 months; hazard ratio [HR]: 0.536; 95% confidence interval [CI]: 0.344-0.835; p = 0.0016) and after PSM (HR: 0.524; 95% CI: 0.305-0.900; p = 0.01), as well as after IPTW (HR: 0.549; 95% CI: 0.331-0.908; p = 0.01). Before adjustment, PFS in the lenvatinib group was also significantly longer than in the bevacizumab group (20.0 vs. 12.1 months; HR: 0.649; 95% CI: 0.457-0.922; p = 0.0078). However, after PSM (HR: 0.808; 95% CI: 0.535-1.222; p = 0.33) and IPTW, there was no significant difference in PFS between the two groups. Multivariate analysis showed that lenvatinib-based triple therapy was independently associated with improved OS compared to bevacizumab-based triple therapy. Subgroup analysis indicated that patients with age ≤65 years, no history of hepatitis B virus infection, Barcelona Clinic Liver Cancer stage C (BCLC-C), ALT levels ≤40 U/L, platelets ≥100 × 10⁹/L, or log 10 AFP ≥1.40 benefited more from lenvatinib-based triple therapy.

Conclusion: Lenvatinib-based triple therapy tends to prolong OS compared to bevacizumab, although the PFS was similar between the two groups. Patients aged ≤65 years, without a history of hepatitis B virus infection, with BCLC-C stage, ALT ≤40 U/L, platelets ≥100 × 10⁹/L, or log 10 AFP ≥1.40 are likely to benefit more from lenvatinib-based triple therapy.

Keywords: Bevacizumab; Conversion therapy; Lenvatinib; Overall survival; Unresectable hepatocellular carcinoma.

Plain language summary

This study explores the effectiveness of two different treatments for advanced liver cancer, known as hepatocellular carcinoma (HCC), in patients who cannot have surgery. The treatments tested combined immune therapy with two drugs: lenvatinib and bevacizumab. These drugs work by targeting different aspects of cancer growth. Lenvatinib is a small molecule that blocks blood vessel growth, while bevacizumab is a larger molecule that also prevents the tumor from getting the nutrients it needs to grow. The research involved 371 patients from 21 hospitals in China, who received treatment between 2017 and 2020. The study compared how well lenvatinib and bevacizumab worked when combined with other therapies, like immune checkpoint inhibitors and interventional treatments (procedures used to treat cancer without surgery). Results showed that both treatments were effective, but the study aimed to determine which one was better in terms of survival and other health outcomes for patients with advanced HCC. The study’s findings could help doctors choose the most effective first-line treatment for these patients in the future.