This retrospective cohort study demonstrated that the combined treatment protocol of HAIC plus camrelizumab and apatinib (TRIPLET) is both safe and feasible. In this study, TRIPLET provided a significant OS benefit compared with camrelizumab and apatinib. CARES-301 trial had revealed camrelizumab combined with apatinib was an effective first-line treatment option for uHCC, while the ORR was only 25% and lack of evidence for patients with high tumor burden [15]. Previously, some triple combination treatment protocols have also been registered and are recruiting eligible patients for enrollment. Beyond LEAP-002, the LEAP-012 trial assessed the safety and efficacy of TACE plus lenvatinib plus pembrolizumab in participants with incurable/non-metastatic HCC compared with TACE alone [17]. In addition, the EMERALD-1 global study aimed to evaluate TACE plus durvalumab plus bevacizumab therapy in patients with locoregional HCC compared with TACE plus durvalumab or TACE alone [18]. In this study, we chose HAIC instead of TACE because the standard operating procedure could be standardized and was technically easy to repeat. Furthermore, HAIC avoids most of the uncertain factors affecting TACE, including the lack of standard medication usage, distinctive operating skills, and different operator habits. Therefore, HAIC-oriented combined therapy has the potential to be popularized with a standard dose regimen.

In this study, the ORR, PFS, and OS of TRIPLET treatment outperformed those of current TKI or ICI monotherapy [19], including lenvatinib (ORR in 18.8% and PFS in 7.4 months) in the REFLECT trial [20], nivolumab (ORR in 15% and PFS in 3.7 months) in the CheckMate 459 trial [21], and pembrolizumab (ORR in 18.3% and PFS in 3.0 months) in the KEYNOTE-240 trial [22]. In addition to its superiority to mono-agent therapies, TRIPLET treatment was considered superior to two-agent combined therapies. Compared with the landmark IMbrave-150 trial, which has changed the first-line recommendation of BCLC guidelines, the results from this TRIPLET treatment showed a median PFS of 12.0 months with an ORR of 67.2% as per mRECIST, which is significantly higher than the ORR of 33.2% as per mRECIST and the median PFS of 6.8 months reported by the IMbrave-150 trial [9]. The advantage of TRIPLET is also evident compared with the KEYNOTE-524, LEAP-002 and ORIENT-32 trial, in which lenvatinib and pembrolizumab, as well as sintilimab and bevacizumab-biosimilar were combined for patients with unresectable HCC. Both the estimated median PFS (KEYNOTE-524: 9.7 months, LEAP-002: 7.4 months, ORIENT-32: 4.6 months) and ORR (KEYNOTE-524: 46.3% per mRECIST, LEAP-002: 40.8%, ORIENT-32: 24.3%) of the above trials were lower than those of TRIPLET treatment [10, 12, 23].

In most cases, the patients with high tumor burden have shorter survival and the main cause of death in HCC is intrahepatic tumor progression. The IMbrave-150 study showed that the mOS of patients with high risk (VP4 portal vein invasion, and/or bile duct invasion and/or tumor occupancy of ≥ 50% of liver) is only 7.6 m, which is far shorter than non-high risk group [11]. Combination with HAIC may reduce the tumor burden and prolong survival. In the treatment decision-making of our study, most patients with high tumor burden were recommended local treatment combination with systematic treatment by MDT based on the Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China (2022 Edition), so the tumor burden and AFP level have not been chosen to perform PSM. Even though the TRIPLET group has the lager tumor burden than C–A group, HAIC combined with camrelizumab and apatinib is still associated with better efficacy.

The survival benefit observed in this study may be due to the synergistic antitumor effects of the chemical agents (HAIC of FOLFOX), antiangiogenic agents, and PD-1 inhibitors. Instead of intravenous chemotherapy, HAIC injects chemical reagents directly into the tumor. Oxaliplatin can induce immunogenic cell death by releasing tumor antigens, transporting CRT to the cell surface, and secreting HMGB1 and ATP [24,25,26]. These molecules related to cell death bind to their respective receptors and support the evolution of tumor-specific CD8+ T cells. Indeed, combined antiangiogenic and anti-PD-1/PD-L1 therapy has been shown to elicit T-cell function and drive tumor cells to activate immune checkpoints, thereby generating greater antitumor immunity than anti-PD-1 treatment alone [13]. In addition, the low dose of apatinib therapy (250 mg daily) used in this study has been proven to induce prolonged vascular normalization, thereby reducing tumor hypoxia and acidosis and improving the anti-cancer activity of infiltrating immune cells [27].

During the median follow-up of 25.2 months, we observed increased ORR in the T group compared with those in the C–A group. However, the DCRs were similar between the two groups. In the T group, PD was observed in 71 patients (34.3%), 60.6% (43/71) of whom showed extrahepatic metastasis (EHM). As a result, we considered EHM in patients to indicate a tendency toward PD because HAIC is highly selective for intrahepatic tumors, and some patients with EHM did not achieve no evidence of disease (NED). However, multivariate analysis using the Cox regression model did not identify EHM as an independent prognostic factor for PFS, possibly because of the small sample size of this study. However, for patients who achieved a CR, the duration of the CR has not been reached, indicating satisfactory efficacy prolongation. One patient, who had evaluated as CR after 2 HAIC circles, died from decompensated liver function-related upper gastrointestinal bleeding after three cycles of TRIPLET treatment and subsequently refusing treatment. We also performed sub-analyses for OS and PFS based on common clinical variables. The results indicated that the patients with HCC who received TRIPLET obtained better tumor control and survival benefit than those who received camrelizumab and apatinib in most clinical variables, including ≤ 65 years old, male, ECOG-PS 0, CTP stage A, > 5 cm tumor diameter, and BCLC stage C. Moreover, radiological features, including pseudo-capsulated and infiltrative, are key indicators for combination therapy selection. Wu et al. also provided evidence that HAIC can obtain better outcomes than TACE for infiltrative HCC.

In terms of safety, the T and C–A groups showed some differences in the frequencies and severity of adverse events. The frequencies of both total AEs and grade 3–4 AEs were higher in the T group than those in the C–A group regardless of PSM. Except abdominal pain, the first and second most common grade 3–4 AEs were elevated AST and thrombocytopenia in the T group, which can be explained by chemotherapy-related liver damage and myelosuppression. Moreover, the increased frequencies of abdominal pain, nausea, vomiting, and diarrhea may be caused by chemotherapy, especially for drug diversion to the gastrointestinal tract or cholecyst. Therefore, we sometimes performed gastroduodenal artery embolization during HAIC to reduce drug diversion. Paradoxically, hypertension was the most frequently occurring AE in the C–A group, which was found to a greater extent than that in the T group. One possible explanation for this is that many patients in the T group were treated with chemotherapy, and the side effects, such as fatigue and anemia, counteracted the hypertension caused by the C–A regimen. Even so, we demonstrate that the safety of the TRIPLET scheme in treating advanced HCC was acceptable and similar to the findings of existing studies [16, 28,29,30,31].

This study has several limitations that warrant discussion. First, as a retrospective study, the patients were consecutively enrolled, which may have introduced patient selection bias, so some baseline characteristics of patients between two group is different. Second, no biomarker analysis was performed to determine the patients who would benefit most from the TRIPLET combination therapy. Third, the mean follow-up duration in TRIPLET group was not long enough.