Abstract:

Background and purpose: China is a country with high incidence rate and mortality of liver cancer. In 2022, there were approximately 368 000 cases of liver cancer and 317 000 deaths in China. Extending the survival period of liver cancer patients is an urgent issue that we need to address. In recent years, tyrosine kinase inhibitor (TKI) alone or in combination with immune checkpoint inhibitors have achieved good results in the treatment of primary liver cancer. However, most studies did not include the combination of transcatheter arterial chemoembolization (TACE) treatment. We speculate that combining TKI drugs with immune checkpoint inhibitors and TACE therapy may provide greater benefits to liver cancer patients. Therefore, this study aimed to evaluate the short-term efficacy and safety of TACE combined with anlotinib and sintilimab in the treatment of liver cancer. Methods: This study is a single arm phase Ⅱ clinical trial approved by the ethics committee of The Third People’s Hospital of Yibin (ethical approval numbers: 2022009). Inclusion criteria: ① Age 18-70 years; ② Primary liver cancer confirmed by clinical diagnosis or histopathology; ③ Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1; ④ China Liver Cancer Staging (CNLC) stage Ⅱb-Ⅲb; ⑤ Adequate cardiopulmonary function; ⑥ Child-Pugh score ≤8 points; ⑦ At least one measurable tumor lesion according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1. From November 1, 2021 to March 1, 2024, we recruited 61 patients, of whom 39 met the criteria. Firstly, all enrolled patients received TACE treatment. Approximately one week after the initial TACE procedure, 12 mg of anlotinib (adjusted according to tolerance) was administered orally on days 1-14, every 3 weeks; Simultaneously 200 mg of sintilimab was administered intravenously on day 1, every 3 weeks. After completing 2 cycles of treatment, efficacy evaluation was conducted according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) 1.1. The primary observation indicators of the study were objective response rate (ORR), and the secondary observation indicators were median progression-free survival (mPFS), disease control rate (DCR) and safety. Results: The ORR of this study was 76.9%, DCR was 94.9%, and mPFS was 9.2 months (95% CI: 2.317-16.083). 39 cases (100%) had grade 1-2 adverse reactions, 15 cases (38.5%) had grade 3 adverse reactions, 5 cases (12.8%) had grade 4 adverse reactions, and 1 patient died due to upper gastrointestinal bleeding. In the stage mainly treated with TACE combined with TKI and immunotherapy, the incidence of grade 3-4 adverse reactions was higher compared with the stage mainly treated with anlotinib combined with sintilimab. The vast majority of adverse reactions can be recovered through conventional treatment methods. Conclusion: TACE combined with anlotinib and sintilimab has a definite therapeutic effect and overall safety and controllability in the treatment of CNLC stage Ⅱb-Ⅲb liver cancer. This combination therapy may provide a new treatment model for CNLC stage Ⅱb-Ⅲb liver cancer patients. However, further exploration is needed to address the pain, vomiting, decreased appetite, liver function damage, upper gastrointestinal bleeding, and other issues caused by this treatment mode.

Key words: Liver cancer, Transcatheter arterial chemoembolization, Sintilimab, Anlotinib, Targeted-immune combination therapy