Primary liver cancer is the sixth most common cancer and the fourth leading cause of cancer-related deaths worldwide; however, it remains a global health challenge, and its incidence is increasing (1). Hepatocellular carcinoma (HCC) is the leading histological form of primary liver cancer, representing 75–85% of cases (1). Given the tremendous heterogeneity of HCC, the patients’ performance levels, extent of underlying liver cirrhosis, and tumor burden influence the choice of the treatment plan (2). Surgical resection, ablation, and liver transplantation may provide curative potential for early-stage HCC. However, transarterial chemoembolization (TACE) is the main treatment for patients with intermediate-stage and advanced-stage HCC unsuitable for or refused to the curative approaches (3, 4).

Donafenib is a modified form of sorafenib with a trideuterated N-methyl group that enhances its molecular stability and improves its pharmacokinetic properties (5, 6). Simultaneously, the reduction in metabolites improves safety and tolerance. A phase 1 clinical trial of 300 patients evaluated the safety, tolerability, food effects, pharmacodynamics, and pharmacokinetics of donafenib in patients with advanced solid tumors. The oral donafenib was tolerated well, with manageable adverse events (AEs) (6). An open-label, randomized, parallel-controlled, phase II/III clinical study of donafenib as a first-line treatment for advanced HCC (ZGDH3) enrolled 668 patients with advanced HCC and found that overall survival (OS) was significantly longer in the donafenib group than in the sorafenib group (12.1 months vs. 10.3 months). In addition, the AE profiles were similar in both groups, with the sorafenib group being better tolerated than the sorafenib group. Donafenib is also the only monotherapy agent superior to sorafenib in first-line head-to-head studies of advanced HCC (7). Donafenib was first approved in China for treating patients with unresectable HCC (uHCC) who had not previously received systemic treatment (8). Like sorafenib, lenvatinib, and atezolizumab plus bevacizumab, donafenib is recommended as a first-line systemic treatment for patients with uHCC (9).

The first-line systemic therapies sorafinib (10) and lenvatinib (11) have demonstrated low objective response rates (ORRs) and limited benefits for OS. Studies have shown that TACE combined with molecularly targeted drugs has potential synergistic effects that prolong the OS of patients with uHCC (12, 13). The TACTICS (13) and LAUNCH (14) studies demonstrated that concurrent sorafenib and lenvatinib can delay tumor progression following TACE. However, TACE plus sorafenib did not show a significant OS benefit over TACE alone in the TACTICS trial for treating intermediate-stage HCC (15). Kudo et al. (15) demonstrated TACE plus sorafenib significantly improves progression-free survival (PFS) and clinically meaningful OS in patients with a high tumor burden in intermediate-stage HCC.

Currently, molecule-targeted drugs (16, 17) are combined with programmed cell death protein-1 (PD-1) inhibitors to improve PFS and OS in uHCC. TACE could cause an increase in VEGF and PD-L1 expression because of the hypoxic microenvironment after embolization. This effect is the theoretical basis of combining molecularly targeted drugs with PD-1 inhibitors and can be a promising complement to TACE (18). Some studies have focused on combining TACE with PD-1 and tyrosine kinase inhibitors (TKI) to treat uHCC (19, 20). To our knowledge, no similar study has evaluated TACE combined with donafenib and a PD-1 inhibitor to treat uHCC. Therefore, this real-world study explored the safety and efficacy of TACE combined with donafenib and a PD-1 inhibitor compared with donafenib alone in patients with uHCC.

For patients with uHCC at BCLC stage B, TACE is strongly recommended, with the ORR beyond 50% (24). The TACTICS (13) and LAUNCH (14) studies demonstrated that TACE plus sorafenib or lenvatinib achieves greater tumor control rates than TACE alone. In a slight departure from the TACTICS study, LAUNCH included a greater proportion of patients with vascular invasion (71.8%) (15), finding that TACE plus lenvatinib achieved longer mOS (17.8 vs. 11.5 months), longer mPFS (10.6 vs. 6.4 months), and a greater ORR (54.1% vs. 25.0%, P <.001) than lenvatinib alone. TACE plus lenvatinib significantly improved ORR (53.1% vs. 25.0%) and OS (14.5 vs. 10.8 months) compared with plus sorafenib in patients with large tumor burden in BCLC C stage uHCC and with portal vein tumor thrombus (PVTT) (25). Combination therapy can improve outcomes in patients with uHCC and provide deeper and earlier disease control. The effectiveness of sorafenib or lenvatinib may also improve when the tumor burden is relatively low (3, 26, 27). In the retrospective study, TACE+D also improved to 7.9 months mPFS and 13.2 months mOS, demonstrating that donafenib could be a good substitute for sorafenib or lenvatinib in the combination therapy to improve the curative effect of uHCC.

Although the results of single-immune checkpoint inhibitor studies (KEYNOTE-240 and CheckMate 459) (28, 29) for advanced liver cancer have not met near-perfect expectations, their performance in the treatment of advanced liver cancer has been sufficient to focus on combination immunotherapy strategies. The success of the anti-VEGF plus PD-L1 dual blockade regimen in the first-line treatment of advanced hepatocellular carcinoma (IMbrave150 study) (30) marks an important change in the standard of care for advanced HCC. Despite the tumor heterogeneity of hepatocellular carcinoma in China and the West, combination therapy using TKI and PD-1 inhibitors currently shows great advantages for treating uHCC in China. The KEYNOTE-524 study reported that patients with locally advanced unresectable HCC treated with pembrolizumab plus lenvatinib achieved a 46.0% ORR, 9.3 months PFS, and 22 months mOS. The RESCUE study (31) showed that carrilizumab plus apatinib showed good antitumor activity and a manageable safety profile in both the first- and second-line treatment cohorts of patients with advanced HCC. In addition, the proportions of patients in the first- and second-line cohorts receiving interventional therapy were 62.9% and 77.5%, respectively. In addition, the primary endpoints of the LEAP-002 study (32), OS and PFS, did not achieve pre-specified statistical significance; however, subgroup analysis supported the combination regimen, with Finn specifically highlighting the high-risk profile of macrovascular invasion/extrahepatic spread (HR=0.78, 95% CI 0.63–0.95) and elevated alpha-fetoprotein(AFP) status (HR=0.67, 95% CI 0.50–0.90).

Thus, many studies have attempted to identify novel therapeutic strategies, such as TACE combined with TKI and PD-1 inhibitors, to improve the efficacy of uHCC treatment. However, related prospective randomized controlled trials, such as the LEAP-012 trial (NCT04246177) using lenvatinib plus pembrolizumab plus TACE vs. placebo in combination with TACE, have not reached the endpoint (33). In comparison, a prospective single-arm phase II clinical trial (TIDE) (34) of adjuvant tislelizumab plus donafenib in combination with TACE for postsurgical high-risk hepatocellular carcinoma did not meet the study endpoints. Retrospective studies have confirmed the effectiveness of TACE combined with TKI and PD-1 inhibitors for treating uHCC (18, 19). A systematic review of 15 retrospective studies showed that triple therapy with TACE, TKIs, and ICIs would provide a clinical benefit for uHCC in both short- and long-term outcomes without increasing severe AEs (33). The CHANCE001 study (35) results suggest that TACE plus PD-(L)1 blockade and molecule-targeted treatments could significantly improve PFS, OS, and ORR compared to TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice, with an acceptable safety profile.

A single-center retrospective study found TACE combined with apatinib plus camrelizumab improved ORR from 17.3% to 42.9%, DCR from 57.7% to 85.7%, and OS from 13.1 to 24.8 months compared with apatinib plus camrelizumab (36). Another single-center retrospective study found TACE combined camrelizumab and sorafenib/lenvatinib resulted in 52.8% ORR, 81.1% DCR, and 8.5 months PFS (37). In a multicenter retrospective study of 62 patients treated with TACE plus lenvatinib and PD-1 inhibitors (38), 80.6% ORR was and 32 (53.2%) patients successfully converted to resectable HCC.

Donafenib has also been explored for the development of additional combination therapies. At an international conference in 2022, a phase Ib clinical study was the first to report the preliminary efficacy of donafenib combined with TACE and PD-1 inhibitors. The analysis found an 83.3% ORR in 12 patients with BCLC phase B, including three patients with CR (25.0%) and seven patients with PR (58.3%) (39). The donafinib combination therapy had a greater ORR than interventional therapy or drug therapy alone, no new safety risks, and was tolerated well.

In the current study, TACE+DP improved ORR from 41.4% to 50.6%, DCR from 82.8% to 89.2% vs. 82.8%, and PFS from 7.9 to 10.6 months compared with TACE+D. With the similar BCLC staging of tumors in the TACE combined with TKIs and PD-1 groups, we achieved a similar curative effect as Ju et al. (36). TACE combined with TKIs and ICIs may be promising therapeutic strategies for uHCC; their ORRs of 42.9–80.6% are better than the 33.2% ORR found in IMbrave150 (40). In our study, the improved efficacy of patients treated with TACE+DP may be due to the synergistic effects of TACE, donafenib, and PD-1 inhibitors. First, TACE caused tumor cell necrosis, effectively reduced tumor load, and activated immunogenic cell death (41). Second, similar to sorafenib, donafenib inhibits vascular endothelial growth factor and normalizes blood vessels. Finally, normalization of tumor vasculature can prompt immune cells to infiltrate the tumor area and enhance the immunocidal effect (42).

Notably, our subgroup analyses found that TACE+DP treatment was associated with favorable PFS versus TACE+D in patients with a significant tumor burden, such as portal vein invasion Vp3-4, maximum tumor diameter >10 cm, and three or more intrahepatic tumors, supporting the hypothesis that a low tumor burden after TACE might improve the efficacy of donafenib and PD-1 inhibitors. Multivariate analysis showed that patients in the TACE+DP group had independent protective factors for OS. In contrast, extrahepatic metastasis, three or more intrahepatic tumors, portal vein invasion Vp3-4, and a maximum tumor diameter >10 cm were independent risk factors. These results are consistent with previous studies on the risk factors of vascular invasion or extrahepatic metastases on the prognoses of patients with uHCC and suggest that assessing the tumor burden (e.g., number of tumors, distribution) becomes more important with the introduction of immunotherapy for uHCC, determining the timing and combination strategy of treatment with TACEs, TKIs, and ICIs.

The most common AEs of the triple combination modality were fever, abdominal pain, and liver function damage related to TACE (12, 13); hypertension, diarrhea, and HFSR related to TKIs (7, 13) and rash, fatigue, and pruritus related to PD-1 inhibitors (3, 24, 25). TACE combined with TKIs has been reported to increase AEs, including hypertension, HFSR, and diarrhea (26, 37). The most common AEs in the TACE+D group were HFSR, diarrhea, and hypertension, similar to those reported by Qin et al. (7) reported. TACE did not increase the AEs of donafenib because the donafenib dose reductions were applied for 45% of cases in the TACE+DP group and 43% of cases in the TACE+D group. In this study, AEs related to TACE+DP and TACE+D were similar to those reported above. The AEs of donafenib and/or PD-1 inhibitors were mild and manageable and did not lead to donafenib or PD-1 inhibitor interruptions.

The incidence rates of hyperammonemia, hypothyroidism, and RCCEP were greater in the TACE+DP group than in the TACE+D group. The blood–brain barrier can be damaged by the injury of brain endothelial cells by VEGFR receptor inhibitors (43). Hyperammonemia occurred in the TACE+DP group because of increased liver damage caused by the triple combination. Hypothyroidism is a common immune-related AE of PD-1 inhibitors (44). RCCEP is a common skin toxicity caused by camrelizumab that often occurs in patients treated with TACE+DP (45). The rate of RCCEP from TACE+DP treatment was dramatically lower than that of camrelizumab alone (21.5% vs. 66.8%), suggesting that the involvement of the VEGFA/VEGFR-2 signaling pathway in RCCEP pathogenesis (46) can be inhibited by donafenib.

This study had some limitations. First, this retrospective study had selection and indication biases, and the treatment option was determined based on the preference of the attending physician and the patient’s economic situation. Second, three PD-1 inhibitors were used, including camrelizumab, tislelizumab, and toripalimab. The bias of different PD-1 inhibitors was inevitable, and further subgroup studies with more cases for each PD-1 inhibitor should be performed. Third, two patients in the TACE+DP group and one patient in the TACE+D group who received conversion therapy were excluded from the study. Since the number of patients who received conversion therapy was relatively low, we did not perform further analyses. Fourth, the follow-up time was relatively short, and the number of research centers was small. Furthermore, a multicenter, prospective, controlled trial with a large sample size is required to confirm these preliminary results.

In summary, TACE combined with donafenib and a PD-1 inhibitor demonstrated good clinical efficacy, durable antitumor responses, and significantly prolonged PFS and OS in patients with advanced HCC. Good tolerance to these combination therapies will enable further clinical studies. The prognoses of patients with more-advanced HCC are expected to improve through this novel and effective therapeutic strategy.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by The First Affiliated Hospital of Zhengzhou University. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

XD: Methodology, Writing – review & editing. HL: Formal analysis, Writing – original draft. JW: Data curation, Resources, Writing – review & editing. GZ: Data curation, Resources, Writing – review & editing. DK: Formal analysis, Writing – review & editing. YL: Data curation, Resources, Writing – review & editing. XH: Data curation, Resources, Writing – review & editing. CX: Data curation, Resources, Writing – review & editing. YW: Data curation, Resources, Writing – review & editing. MS: Data curation, Resources, Writing – review & editing. XWH: Methodology, Resources, Writing – review & editing. JR: Methodology, Resources, Writing – review & editing.