There has been some progress in systemic treatment with novel targeted drugs in phase III studies for advanced HCC. These advancements in targeted therapeutics represent promising developments in the treatment of HCC, offering options for both first-line and second-line interventions and potential improvements in adjuvant therapy to help prevent cancer recurrence. The use of targeted drugs in the adjuvant setting indicates ongoing efforts to explore new treatment approaches beyond initial cancer management phases.
4.2. Immunotherapy
Atezolizumab and bevacizumab have shown effectiveness as first-line therapies in advanced HCC. Research into tumor immunology has deepened our understanding of the tumor microenvironment (TME) in HCC [
34] The roles and operative mechanisms of immune cells, such as PD-1, CTLA-4, and CD28, in the TME have been elucidated. PD-1 binding to its ligand leads to T cell exhaustion and reduces IFN-γ T cell secretion. CTLA-4 and CD28 mediate immunosuppression by competing for the B7 protein and disrupting the CD28 signal transduction pathway. Various immune checkpoints, including PD-1, PD-L1, and CTLA-4, have been identified in HCC [
35] Clinical trials have been conducted to investigate the biological behavior of these immune checkpoints.
Nivolumab, pembrolizumab, and the combination of nivolumab plus ipilimumab have received FDA approval for the treatment of HCC. Despite the success of immune checkpoint inhibitors (ICIs), there are challenges, including low response rates and side effects. To address the limitations of ICI treatment, researchers are exploring combination therapies.
In a phase 2 trial [
36] assessing the safety and tolerability of perioperative immunotherapy in resectable HCC, 30 patients were enrolled, and 27 of them were randomly assigned to receive either nivolumab alone or nivolumab in combination with ipilimumab. The trial found that the incidence of grade 3-4 adverse events was higher in the group receiving nivolumab combined with ipilimumab than in the group receiving nivolumab alone. Grades 3 and 4 adverse events indicate more severe side effects that may require medical intervention or management. Thus, the combination therapy of nivolumab and ipilimumab led to a higher occurrence of significant adverse events, potentially indicating increased treatment-related toxicity compared to nivolumab monotherapy. However, it is important to consider that adverse events are a known risk with immunotherapy, and these treatments’ overall safety and tolerability profile should be evaluated in the context of potential clinical benefits and further research. Notably, this trial was conducted in a small patient population, necessitating more extensive studies to better understand the safety and efficacy of perioperative immunotherapy in resectable HCC. Additionally, when determining the most appropriate treatment approach, individual patient characteristics and the specific risks and benefits for each patient should be considered. The most common treatment-related adverse events were increased alanine aminotransferase and aspartate aminotransferase. No surgery delays occurred due to grade 3 or worse adverse events. Perioperative nivolumab alone and nivolumab plus ipilimumab were deemed safe and feasible for patients with resectable hepatocellular carcinoma. Estimated median progression-free survival (PFS) was longer in the nivolumab plus ipilimumab group compared to nivolumab alone (19.53 months vs. 9.4 months, HR: 0·99, 95% CI: 0·31–2·54).
Patients at high risk of recurrence, characterized by factors such as increased tumor burden, large or multifocal neoplasms, poor differentiation, and MVI, are likely to benefit the most from adjuvant therapy with ICIs.
The IMbrave050 study [
37], is a significant, global, open-label, phase 3 trial that enrolled adult patients with high-risk surgically resected or ablated HCC from various regions worldwide. The study recruited participants from 134 hospitals and medical centers spanning 26 countries across four WHO regions: the European, American, South-East Asian, and Western Pacific regions.
Patients in the study were randomly assigned in a 1:1 ratio through an interactive voice-web response system, utilizing permuted blocks with a block size of 4. They were allocated to receive either intravenous 1200 mg of atezolizumab in combination with 15 mg/kg of bevacizumab every 3 weeks for 17 cycles (equivalent to 12 months) or to undergo active surveillance without treatment.
The primary endpoint of the Imbrave050 study was RFS, as assessed by an independent review facility in the intention-to-treat population. This primary endpoint aimed to evaluate the efficacy of atezolizumab and bevacizumab combination therapy in preventing disease recurrence in patients with high-risk surgically resected or ablated HCC compared to those on active surveillance. The adjuvant treatment combining atezolizumab with bevacizumab demonstrated a significant improvement in RFS compared to active surveillance in the study. Patients receiving adjuvant atezolizumab plus bevacizumab showed a median RFS that was not evaluable (NE), with a 95% CI ranging from 22.1 to NE, as opposed to the active surveillance group, which also had a median RFS of NE and a 95% CI from 21.4 to NE. The hazard ratio was reported as 0.72, with an adjusted 95% CI of 0.53–0.98, and the statistical significance level was P = 0.012.
In terms of safety outcomes, grades 3 and 4 adverse events were more commonly observed in patients who received atezolizumab plus bevacizumab, with 136 out of 332 patients (41%)affected, compared to 44 out of 330 patients (13%) in the active surveillance group. Grade 5 adverse events, which represent severe events leading to death, were reported in six patients (2%, two of whom were related to treatment) in the atezolizumab plus bevacizumab group and one patient (<1%) in the active surveillance group.
Furthermore, the discontinuation of both atezolizumab and bevacizumab due to adverse events was necessary for 29 patients (9%). Managing adverse events and monitoring patient safety remain significant considerations in the utilization of adjuvant atezolizumab plus bevacizumab therapy despite the observed efficacy benefits in improving RFS.
Patients with liver cancer who are candidates for embolization often face high rates of disease progression or recurrence without early access to effective systemic therapies. The EMERALD-1 trial represents a significant advancement in this field. It is a worldwide phase III clinical trial that employed a randomized, double-blind, placebo-controlled approach across multiple centers to evaluate the efficacy of Imfinzi combined with TACE as an initial treatment. This was followed by continued Imfinzi with or without bevacizumab until disease progression, compared to TACE alone, in 616 patients with unresectable HCC suitable for embolization. The study was conducted at 157 medical facilities in 18 countries, including North America, Australia, Europe, South America, and Asia. The primary goal of the trial was to assess PFS in patients receiving Imfinzi and TACE with bevacizumab versus those receiving TACE alone, with secondary endpoints including PFS for patients receiving Imfinzi and TACE, OS, patient-reported outcomes, and objective response rates. Notably, the EMERALD-1 trial stands out as the inaugural global phase III trial, demonstrating enhanced clinical outcomes by combining systemic therapy with TACE to treat liver cancer. It has reported encouraging results, indicating that durvalumab, when combined with TACE and bevacizumab, significantly and meaningfully enhances the primary endpoint of PFS compared to TACE alone in patients diagnosed with HCC suitable for embolization. As the trial progresses, it continues to monitor the secondary endpoint of OS. These findings regarding durvalumab in conjunction with bevacizumab could potentially revolutionize the management of this complex disease, which typically has an unfavorable prognosis, as they mark the first instance where the addition of an immunotherapy combination to TACE has led to a notable improvement in PFS.
Furthermore, an extensive clinical development program is ongoing, which includes investigating the use of Imfinzi in combination with bevacizumab in adjuvant HCC (EMERALD-2) and in combination with tremelimumab, lenvatinib, and TACE for patients eligible for embolization due to HCC (EMERALD-3).
Several ongoing clinical trials are investigating the efficacy of ICIs in the adjuvant setting after loco-regional treatment for HCC, including KEYNOTE-937 (NCT03867084), CHECKMATE 9DX (NCT03383458), and EMERALD-2 (NCT03847428).
Table 2 and
Table 3 illustrate the ongoing clinical trials of adjuvant ICI therapy for early-stage and intermediate-stage HCC, respectively.