Current landscape and future directions for systemic treatments of hepatocellular carcinoma

Systemic treatment is the optimal approach for patients with advanced or intermediate-stage hepatocellular carcinoma (HCC) with contraindications or refractoriness to locoregional treatments^[1]. The aim of systemic treatment is to prolong survival and delay clinical deterioration. Until 2008, no systemic therapy provided meaningful clinical benefit. In the past, studies that evaluated the role of conventional chemotherapy, mainly doxorubicin or combinations of platinum agents, resulted in significant toxicities, without a clear demonstration of efficacy^[2].

In the early 2000s, there were advances in the knowledge of the molecular mechanisms that drive hepatocarcinogenesis, such as the hyperactivation of intracellular signaling pathways of protein kinases and angiogenesis^[3]. This knowledge has boosted the development of molecular target drugs that inhibit receptors and mediators of these signaling pathways, which have been translated into clinical studies that included patients with advanced HCC.

Sorafenib, a multikinase inhibitor, was the first systemic agent to demonstrate a survival benefit in patients with unresectable HCC based on two placebo-controlled trials^[4,5]. It is important to highlight that this drug increased survival without causing a significant reduction in tumor burden. The radiological response rate, however, remains low, ranging from only 2% to 3%. In addition, some adverse events such as fatigue, hand-foot reaction, diarrhea and arterial hypertension indicate the need for strict follow-up during treatment with this drug^[4,5].

In 2016, regorafenib (a tyrosine kinase inhibitor against VEGFR1-3, PDGFR, KIT RET, and RAF) showed a significant increase in survival after progression with sorafenib, with a median survival of 10.6 months in the regorafenib arm versus 7.8 months for placebo^[6]. An exploratory analysis showed that the sorafenib-regorafenib sequence reached a median survival of 26 months, which reflects a significant advance in the treatment of patients with advanced HCC^[7].

Between 2016 and 2019, other drugs were introduced for the management of HCC after the results of prospective randomized studies. Lenvatinib, another tyrosine kinase inhibitor, demonstrated non-inferiority to sorafenib in the first-line setting and was incorporated as an option in this scenario^[8]. Cabozantinib, a tyrosine kinase inhibitor against VEGFR, MET and AXL, increased the survival of patients with advanced HCC after progression to sorafenib and became a second-line option^[9]. Finally, ramucirumab, a monoclonal antibody against VEGFR-2, was associated with better survival in patients with AFP ≥ 400 ng/mL^[10]. Besides the imaginary targets, there may be a general mechanism of action of tyrosine-kinase inhibitors aimed at blocking a wide spectrum of pathways, which remain underexplored but can be addressed in the setting of a personalized approach^[11].

As of 2020, immunotherapeutic agents have also been incorporated into the management of advanced HCC. The phase III study IMBRAVE150 included patients with advanced HCC to receive the combination of atezolizumab (a PD-L1 inhibitor) with bevacizumab (a VEGF inhibitor) or sorafenib. The study demonstrated a significant increase in overall survival, with a median survival of 19.2 months for the experimental arm and 13.4 months for the control arm^[12]. In 2022, another combination of immunotherapeutic agents demonstrated a benefit in overall survival in a phase III study with patients with advanced HCC. In this study, patients who received the combination of durvalumab (a PD-L1 inhibitor) and tremelimumab (a CTLA-4 inhibitor) had better median survival (16.4 months) compared to patients who received sorafenib (13.8 months)^[13]. Therefore, combinations of immunotherapeutic agents have become the standard choice in the first line of patients with advanced HCC.

The alternatives of systemic therapies for HCC are rapidly evolving and clinical decisions are challenging. In order to offer guidance on the selection of first-line and subsequent second-line systemic therapies, the American Association for the Study of Liver Diseases (AASLD) recently released recommendations, which are summarized in Table 1^[14].

Several questions remain open in regard to the applicability of systemic treatment for HCC, most notably the use in earlier stages aimed at preventing recurrence and the safety in populations underrepresented in pivotal trials, such as patients with liver dysfunction or prior transplantation.

The pivotal trials restricted the inclusion of Child-Pugh A patients, while there is limited available data on the use of systemic treatment in patients with liver dysfunction. A recent real-world study with 202 patients, including 48 patients with Child-Pugh B treated with atezolizumab and bevacizumab, showed that these patients had comparable rates of treatment-related adverse events to Child-Pugh A, and a median overall survival of 6.7 months versus 16.8 months for Child-Pugh A patients^[15]. A meta-analysis evaluated different studies of immunotherapy in patients with liver dysfunction and observed a median survival of 6.05 months, but concluded that the high heterogeneity across studies reflects the incapacity of the current evidence to support the indication of immunotherapy in HCC patients with relevant liver dysfunction^[16].

Global real-world data reported that sorafenib is safe in Child-Pugh B patients, but survival outcomes are worse compared to Child-Pugh A^[17]. Additionally, an Italian multicentric randomized trial was designed to explore the benefit of sorafenib in Child-B7-9 patients. The trial was planned to include 320 patients, but only 35 patients were enrolled. Although not statistically powered, a median overall survival of 3.5 months was observed^[18].

Solid organ transplantation is a formal contraindication to immunotherapy because of its potential risk of inducing allograft rejection, and therefore this subgroup was also excluded from the pivotal trials. Although small series have reported cases of transplanted patients safely treated with immune checkpoint inhibitors, the standard systemic therapy for these patients is still based on tyrosine kinase inhibitors^[19].

The use of systemic treatment in early stages is currently under active research. Adjuvant treatment with atezolizumab plus bevacizumab has been shown to delay recurrence after surgery or ablation in patients at high risk of recurrence, but no positive impact on survival has been demonstrated^[20]. In intermediate stage (BCLC-B) HCC, systemic treatment is preferable for patients with high tumor burden. In a propensity-matched study, lenvatinib was shown to provide better survival and lower liver alteration compared to transarterial chemoembolization, in patients with BCLC-B and beyond up-to-seven criteria^[21]. In addition, several trials are testing combinations of immune checkpoint inhibitors plus transarterial treatments such as transarterial chemoembolization or radioembolization. The rationale for this approach is to harness the immune boost provided by tumor cell death with local treatments and to optimize systemic antitumor activity with immune checkpoint inhibitors.

Finally, the achievements in the management of advanced HCC in recent years were remarkable. A clear survival benefit has been seen with the incorporation of immunotherapy and novel targeted therapies. Optimal sequences remain to be defined, while clinical practice should be tailored by the risk of adverse events and the use of drugs that proved survival benefits in prospective trials [Figure 1]. Future directions will explore how to broaden new strategies in orphan conditions and how to integrate different modalities into HCC treatment algorithms.

Figure 1. Treatment strategy for HCC with systemic therapies. BCLC: Barcelona clinic liver cancer; ECOG: eastern cooperative oncology group; HCC: hepatocellular carcinoma; AFP: alpha-fetoprotein.