Adjuvant Therapy Combining Donafenib and Sintilimab Enhances Recurrence-Free Survival in Hepatocellular Carcinoma Patients With High-Risk Recurrence Factors After Radical Resection: A Retrospective Cohort Study

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death and the sixth in incidence globally. Curative resection is a main treatment for HCC patients, yet the 5-year post-radical resection tumor recurrence rate remains up to 70%. Most high-risk recurrence patients may experience early recurrence within 2 years and have a poor prognosis [1]. Notably, there's still a lack of standardized postoperative treatment globally. A recent study, IMbrave050, found that the postoperative adjuvant use of the combination of bevacizumab and atezolizumab did not extend recurrence-free survival (RFS) when compared to surveillance [2]. Combinations of tyrosine kinase inhibitors (TKIs) and PD-1 inhibitors have shown promise in unresectable HCC, with the efficacy of adjuvant treatment postradical resection yet to be confirmed. Donafenib, a novel TKI, has demonstrated survival benefits over sorafenib in unresectable HCC. Additionally, several studies of donafenib combined with PD-1 inhibitors have shown promising results for unresectable HCC because of synergistic antitumor effects [3, 4]. This retrospective study aims to evaluate the efficacy and safety of adjuvant donafenib combined with PD-1inhibitor sintilimab in preventing tumor recurrence in HCC patients with high-risk recurrence factors (HRRF).

This retrospective study involved patients who underwent radical resection from June 2019 to February 2023. Informed consent was waived due to the retrospective nature of the study. The study adhered to the Helsinki Declaration and was approved by the ethics committee of Chinese PLA General Hospital (Approval no. S2023-737-01). Eligible patients were ≥ 18 years old and had HRRF, including tumor size ≥ 5 cm, tumor number ≥ 2, macrovascular invasion (invasion of portal and hepatic veins), presence of microvascular invasion (MVI), and satellite nodules. Patients receiving adjuvant donafenib (0.1 g twice daily orally) and sintilimab (200 mg every 3 weeks intravenously) initiated treatment 4–8 weeks postsurgery for up to 1 year or until HCC recurrence or serious adverse events. To balance confounding factors, we utilized a 1:1 propensity score matching (PSM) analysis with a caliper width of 0.02, which considered variables such as sex, age, Eastern Co-operative Oncology Group Performance Status, Barcelona Clinic Liver Cancer (BCLC) stage, Child-Pugh score, HBV, tumor diameter, tumor number, macrovascular invasion, MVI, satellite nodules, alpha-fetoprotein (AFP), and tumor differentiation. Imaging was conducted every 12 weeks during the first 2 years and then every 24 weeks until disease recurrence. The outcomes included RFS, overall survival (OS) and safety.

From June 2019 to February 2023, we collected 260 HCC patients with HRRF after radical resection. A total of 101 patients met the inclusion criteria and were ultimately included in the study. The treatment group consisted of 34 patients who received a combination of donafenib and sintilimab, while the group without postoperative adjuvant treatment (control group) comprised 67 patients. After PSM, 52 patients were included in the study (Figure 1A). Baseline characteristics before and after PSM matching are in Supporting Information: Table S1. The median follow-up was 17.7 months in the treatment group and 11.5 months in the control group (p = 0.116). After PSM, 8 patients in the treatment group and 13 patients in the control group experienced recurrence or death (Figure 1B). The median RFS in the treatment group was not estimable (NE) (95% confidence interval [CI]: 13.4–NE), while it was 11.1 months (95% CI: 8.3–NE) in the control group (hazard ratio [HR] = 0.339 [95% CI = 0.138–0.835], p = 0.014, Figure 1C). Notably, in the control group, four patients experienced recurrence within 4 months after surgery. The RFS rates of the treatment group at 9, 12, and 18 months were significantly superior to those of the control group (Supporting Information: Table S2). Neither group reached the median OS (p = 0.720, Figure 1C). The 18-month OS rates of the patients in two groups were 82.6% and 62.7%, respectively, and the treatment tended to prolong the OS.

We performed an additional analysis focusing on patients characterized by the presence of at least two HRRF. RFS was significantly longer with the treatment group than with the control group (median, 14.7 months [95% CI: 12.2–NE] vs. 8.3 months [95% CI: 5.1–NE]; HR = 0.365 [95% CI = 0.136–0.977]; p = 0.037, Supporting Information: Figure S1A). The median OS in the treatment group was NE (95% CI: 12.2–NE), while it was 14.4 (95% CI: 14.4–NE) months in the control group (HR = 0.724 [95% CI = 0.119–4.390], p = 0.720, Supporting Information: Figure S1B).

Multivariate analysis identified adjuvant therapy (HR = 0.373, p = 0.035) and BCLC stage (HR = 4.225, p = 0.026) as independent predictors significantly associated with RFS (Supporting Information: Table S3). Subgroup analysis showed that the treatment group consistently outperformed the control group in the following subgroups: male (HR = 0.316, p = 0.018), Child Pugh 5 (HR = 0.316, p = 0.026), AFP < 400 ng/mL (HR = 0.143, p = 0.005), BCLC stage C (HR = 0.274, p = 0.017), single tumor (HR = 0.285, p = 0.020), tumor diameter ≥ 5 cm (HR = 0.184, p = 0.001), no macrovascular invasion (HR = 0.231, p = 0.014), and no tumor satellites (HR = 0.271, p = 0.023). (Figure 1D).

Before PSM, no patients in the therapy group terminated the regimen due to an adverse event. In the therapy group, there were no deaths related to treatment, a treatment emergent adverse event (TEAE) of any grade occurred in 12 patients (35.3%). The most common Grade 3 TEAE was rash (two patients, 5.9%). No adverse events of Grade 4 or 5 occurred (Supporting Information: Table S4).

In this study, we observed that donafenib combined with sintilimab significantly improve RFS in high-risk HCC patients following radical resection. In both univariate and multivariate analyses, we identified adjuvant donafenib-sintilimab as a prognostic factor for RFS. Although OS did not show a significant difference, we believe that longer follow-up may reveal the OS benefit of this adjuvant regimen. This study was conducted specifically in Chinese patients, and while the results are applicable within this population, the applicability to other populations may vary.

High-risk HCC patients post-radical resection harbor residual micro-metastases that often lead to recurrence. The combination of TKIs and PD-1 inhibitors may synergistically target these residual foci. Additionally, tumor recurrence is influenced by factors such as decreased cytotoxic T-cell infiltration, immune checkpoint upregulation, and immune-suppressive cell accumulation. The immunosuppressive liver tumor microenvironment may be modulated by antiangiogenic therapies.

Evidence suggests surgery benefits selected advanced HCC patients, and Asian guidelines endorse it as a first-line option for such patients [5]. In our study, patients had a relatively late tumor stage, with 53.8% being BCLC C, yet they still received surgical treatment. Subgroup analysis revealed that these patients had a better prognosis after postoperative adjuvant therapy, without severe adverse reactions.

In conclusion, adjuvant treatment with donafenib and sintilimab significantly improved RFS in Chinese HCC patients with HRRF post-radical resection compared to active surveillance. The adverse events were manageable, enhancing the confidence in adjuvant therapy. However, this study's limitations include its retrospective, single-center design and small sample size. A planned multicenter, randomized, controlled, prospective trial aims to further validate the efficacy of donafenib combined with sintilimab in improving RFS for HCC patients with HRRF.

Hanchuan Shen: data curation, formal analysis, investigation, methodology, software, visualization, writing–original draft. Bing Liu: data curation, formal analysis, investigation, methodology, software, visualization, writing–original draft. Hangyu Zhang: data curation, writing–review and editing. Yang Liu: data curation, project administration, supervision, writing–review and editing. Chenggang Li: conceptualization, project administration, supervision, writing-review and editing. All authors have read and approved the final manuscript.

The study was approved and the informed consent for this retrospective analysis was waived by the ethics committee of Chinese PLA General Hosptial, (Approval no. S2023-737-01). The study adheres to the Declaration of Helsinki.

The authors declare no conflicts of interest.