Systemic Therapies for Hepatocellular Carcinoma: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Albert Morales.

Clinical treatment of Hepatocellular carcinoma (HCC) in initial stages includes surgical therapies, resection or tumor ablation, transplantation and transarterial chemoembolization (TACE). In advanced HCC, useful systemic therapies were not available for patients until 2007, when sorafenib was approved. After years without major therapeutic improvements and with increasing incidence, finally advances are arriving for hepatocellular carcinoma (HCC)HCC treatment. Novel drugs and Sorafenib is no longer the only systemic therapy for patients, and novel combinations are already working in clinical trials, reaching  hospitals to help in HCC. Accumulating data demonstrate that etiology and the HCC microenvironment have a major influence on tumor growth and immune control. The improved knowledge of the specific molecular mechanisms involved is expected to provide evidence-based information critical for clinical management.

  • Hepatocellular carcinoma (HCC)
  • Atezolizumab
  • Sorafenib
  • Therapies
  • multikinase inhiitors

1. First-Line Therapies

1.1. Atezolizumab-Bevacizumab (Atezo-Bev)

Atezolizumab and bevacizumab combination is the first treatment superior to sorafenib demonstrating prolonged overall survival (67.2% vs. 54.6%; hazard ratio [HR] 0.58) and progression-free survival (6.8 months vs. 4.3 months; HR 0.59) [1]. The success of IMbrave 150 clinical trial has changed the paradigm of hepatocellular carcinoma (HCC) treatment, and atezo-bev has become the recommended systemic therapy if no contraindications are present [2].
Atezolizumab (Tecentriq) is a humanized IgG1 monoclonal antibody that targets PD-L1 to prevent its binding with PD-1 and B7-1 receptors, thus reversing T-cell suppression [3]. Bevacizumab (Avastin) is a monoclonal antibody that targets vascular endothelial growth factor (VEGF), inhibiting angiogenesis and tumor growth [4]. Anti-VEGF therapy also enhances anti-PD-1/PD-L1 activity by reducing VEGF-mediated immunosuppression and promoting T-cell infiltration in tumors [5]. Of note, other immune checkpoint inhibitors [6],[7], as well as atezolizumab [8], in monotherapy, did not reach better outcome in HCC patients, highlighting the synergistic efficacy of immunotherapy and anti-angiogenic combination.
Regarding adverse effects, hypertension and increased AST or ALT are grade 3 or 4 adverse events frequently observed after atezo–bev treatment. Moreover, bleeding, a life-threatening risk for cirrhotic patients, is a common reaction to bevacizumab. In this sense, risk of bleeding, comorbidities such as arterial hypertension and cardiovascular disease, and prior autoimmune conditions may become limiting parameters for the indication of atezo-bev. If the patient has contraindications to atezo-bev, alternative therapies should be considered, such as sorafenib or lenvatinib.
Another immune-based therapy that will likely be included in the first line soon is the tremelimumab/durvalumab combination. Although the peer review data have not yet been published, a significant survival benefit over sorafenib has been announced in the HIMALAYA phase III trial. Once the study data are fully available, changes in clinical decision-making are expected in such a setting, although these are now difficult to foresee.

1.2. Sorafenib

Sorafenib (Nexavar) is a small molecule that inhibits the phosphorylation of up to 40 tyrosine kinases, including VEGFR1, 2 and 3, PDGFRβ, KIT, and RET. This tyrosine kinase inhibitor (TKI) also suppresses Raf kinase isoforms, such as wild-type Raf1, B-Raf, and mutant b-raf V600E. Sorafenib displayed anti-proliferative, anti-angiogenic, and pro-apoptotic properties in HCC cell lines [9], anti-tumor activity in tumor xenograft nude mice [10], and anti-metastatic effect in preventing postsurgical recurrence in an orthotopic mouse model [11]. The efficacy of sorafenib possibly lays in its capacity to target both tumor cells and their microenvironment. As an example, it has been described that sorafenib also had an impact on HSCs proliferation by the suppression of α-SMA and PDGF-related pathways, which decreased HCC cell viability [12]. However, a high dose of sorafenib has been described as promoting immunosuppression through the induction of PD-1 expression in infiltrating immune cells in a murine HCC model [13]; whether this could affect patients, particularly those under immunotherapy, is an aspect that deserves to be studied.
Sorafenib was the first compound that demonstrated survival benefit in HCC in a phase 3, double-blind trial versus placebo (SHARP trial). The median overall survival for patients in the sorafenib arm was 10.7 months compared to 7.9 months in the control group (HR 0.69, 95% confidence interval 0.55–0.87, p < 0.001) [14]. In a parallel trial conducted in the Asian-Pacific population, sorafenib showed a similar survival benefit [15]. The most common adverse effects are diarrhea (8–9% patients) and a hand–foot skin reaction (8–16% patients). Sorafenib has been recommended as the standard systemic therapy for HCC in the first line setting in patients with well-preserved liver function (Child–Pugh A or early B class), with advanced tumors, BCLC-C, or tumors that progressed after loco-regional therapies [16]. The appearance of dermatologic reactions has been linked to better survival following sorafenib administration [17].
Among the molecular mechanisms responsible for sorafenib effectivity in HCC cells is the activation of programmed cell death, apoptosis, provoked by the downregulation of myeloid cell leukemia sequence 1 (MCL-1) expression, an anti-apoptotic member of the BCL-2 family [18]. Recent data have shown that the mitochondrial link with sorafenib activity is more profound. Sorafenib induces mitochondrial reactive oxygen species (ROS), depletes mitochondrial membrane potential, and induces changes in the BCL-2/MCL-1 ratio [19],[20]. In fact, continuous sorafenib exposure altered the levels of anti-apoptotic BCL-2 proteins allowing HCC cell death escape. In contrast, surviving cells are sensitized against BH3-mimetics, inhibitors of specific BCL-2 proteins such as navitoclax [20]. Sorafenib has also been described as involved in the autophagy pathway. The administration of autophagy inhibitors, such as chloroquine or pemetrexed, improved sorafenib efficacy in tumor cells and nude mice hepatoma tumors [21]. Additionally, MCL-1 downregulation was found to disrupt the MCL-1:Beclin 1 complex and induce autophagic cell death in HCC cell lines [22]. In fact, as a consequence of the mitochondrial damage induced by sorafenib, mitophagy is also activated by a triggering mechanism that involves mitochondrial ROS production [23], allowing sorafenib activity to be modulated by antioxidant administration [24]. Acquired drug resistance, which reduces sorafenib effectiveness in patients, may depend on these or other mechanisms. HCC is highly heterogeneous, within the tumor and among individuals, and this influences disease progression, classification, prognosis, and, naturally, cellular susceptibility to drug resistance. In this sense, long-term exposure to sorafenib of hepatoma cells provoked the acquisition of chemoresistance, as well as EMT features [25],[26]. Hypoxia has been described to be involved in sorafenib resistance due to HIF-1α and NF-κB activation [27]. Moreover, M2 macrophages have been found to participate in sorafenib resistance by the release of HGF [28].

1.3. Lenvatinib

Lenvatinib (Lenvima) is an inhibitor of VEGFRs, RET, KIT, PDGFRα, and FGFR1-FGFR4 [29]. It also displayed anti-angiogenic properties and anti-FGFRs activity in hepatoma cells and xenografts [30],[31]. Lenvatinib has been described to exert an immunomodulatory effect through the increase of CD8+ T cell population while diminishing macrophages and monocytes populations in HCC cells [32].
In a phase 3 clinical trial, lenvatinib showed to be non-inferior to sorafenib in terms of overall survival. Hypertension, diarrhea, or a decrease in appetite or weight were among the most common adverse events [33]. In a small group of patients, the levels of AFP were found to decrease in the next two weeks following treatment, suggesting that AFP levels could be predictive of patients’ response [34]. Furthermore, circulating FGF-19 and Ang-2 have been proposed as predictors of clinical response to lenvatinib in HCC patients [35],[36], as well as an early tumor shrinkage [37]. However, like sorafenib, HCC has been described as displaying resistance against lenvatinib. The HGF/c-MET signaling activation was identified as one mechanism of lenvatinib tolerance [38].

2. Second-Line Therapies

2.1. Regorafenib

Regorafenib (Stivarga) is a multikinase inhibitor (MKI) against VEGFR-2, VEGFR-3, KIT, RET, wild-type, and mutant (V600E) B-Raf, PDGFR, FGFR1, angiopoietin 1 receptor (TIE2), RET, and p-38-alpha. Its inhibitory profile is slightly different from sorafenib, since regorafenib has stronger potency targeting VEGFR and TIE2, KIT, and RET [39]. Like sorafenib, regorafenib inhibits angiogenesis, oncogenesis, and tumor microenvironment. Regorafenib was shown to block cell growth and invasion in hepatoma cell lines [40]. This MKI also targeted MAPK pathway, induced caspase cleavage and activated the autophagic pathway [41],[42], and mitophagy as a consequence of its mitochondrial activity [24]. In fact, regorafenib alteration of mitochondrial proteins such as BCL-xL is related to regorafenib resistance, pointing to BH3 mimetics for combined therapies [43]. Moreover, both intrinsic and extrinsic apoptotic pathways were activated by regorafenib [44]. The treatment with regorafenib provoked a decrease in the expression of metastasis-related proteins in HCC cells[45]. Regorafenib was demonstrated to block EMT activation and overcome the acquired resistance to sorafenib [46].
The RESORCE trial was the first phase 3 clinical trial that showed that patients who progressed on sorafenib benefited from oral regorafenib administration versus placebo in a second line setting [47]. Median survival was 10.6 months for the regorafenib arm, while 7.8 months for the control group (HR 0.63; 95% 0.50–0.79; p < 0.0001). Manageable adverse events consisted of a hand–foot skin reaction, hypertension, and fatigue. Additional analyses of the RESORCE trial have suggested that the administration of regorafenib following sorafenib may extend survival [48].

2.2. Cabozantinib

Cabozantinib (Cometriq, Cabometyx) is a small molecule with tyrosine kinase inhibitory prolife against VEGFR-2, RET, KIT, FLT-3, TIE2, and AXL. Cabozantinib differs from sorafenib and regorafenib in that it is capable to also block c-Met [49]. Cabozantinib has demonstrated anti-tumor activity in HCC cells by inhibiting tumor growth, angiogenesis, invasion, and migration. It also reduced the number of HCC metastatic nodules in the lungs and liver in mice [50]. In a phase two clinical trial, cabozantinib demonstrated effectivity in HCC patients[51]. Those promising results led to the conduction of a phase 3 clinical trial in patients who progressed after sorafenib treatment. Cabozantinib increased overall survival (10.2 months) compared to placebo (8.0 months, HR 0.76; 95% CI, 0.63–0.92; p = 0.005). The most frequent side effects were palmar-plantar erythrodysesthesia, hypertension, increase AST, fatigue, and diarrhea [52].

2.3. Nivolumab

Nivolumab (Opdivo) is a human monoclonal antibody that targets programmed cell death protein 1 (PD-1). It is an immune checkpoint inhibitor, since nivolumab impedes the signaling that blocks T cell anti-tumor activity [53]. A phase 1/2 dose escalation study performed with advanced HCC with or without previous sorafenib treatment showed the potential of nivolumab for the treatment of HCC (CheckMate 040 trial) [54]. A further analysis of the CheckMate 040 trial highlighted that some inflammatory biomarkers trended with improved survival and an anti-tumor immune response [55]. Nevertheless, a subset of patients with hyperprogressive disease (HPD) was identified after nivolumab treatment in HCC patients [56]. Furthermore, administration of nivolumab plus ipilimumab, which targets CTLA-4, a inhibitory T-cell receptor, also showed to be a promising therapeutic strategy in HCC patients who progressed on sorafenib [57].

2.4. Pembrolizumab

The humanized monoclonal antibody pembrolizumab (Keytruda) blocks PD-1 as well. In a non-randomized phase 2 clinical trial, pembrolizumab was effective in patients who were treated previously with sorafenib (KEYNOTE-224) [58]. These results led to testing pembrolizumab compared to placebo in a phase 3 randomized clinical trial. Although median overall survival was longer for the pembrolizumab arm, 13.9 months (95% CI, 11.6 to 16.0 months) and 10.6 months (95% CI, 8.3 to 13.5 months) for placebo, the results were not statistically significant [6].

2.5. Ramucirumab

Regarding antiangiogenic therapies, ramucirumab (Cyramza), a monoclonal antibody against VEGFR2 [59],[60],[61], failed to improve survival in the REACH trial in patients treated previously with sorafenib. However, the reseauthorchers identified AFP serum levels as a prognostic marker showing that patients with high levels of AFP (≥400 ng/mL) benefit from ramucirumab treatment. These observations were validated in REACH-2, a double-blind phase III trial, wherein only patients treated with sorafenib with high AFP levels were included [60]. Ramucirumab improved overall survival (8.5 versus 7.3 months HR 0.710, 95% CI 0.531–0.949; p = 0.0199) and has become the first HCC therapy with biomarker-guided patient selection. Hypertension, liver failure, and hyponatremia were the most common grade 3–4 adverse events.

2.6. Combination Therapies

Regarding ongoing clinical studies, several combinations of treatment regimens are being tested in patients with HCC in both the first line and second line: the RENOBATE study (combination of regorafenib and nivolumab administered as first-line therapy in unresectable HCC), the REGOMUNE trial (avelumab, which targets PD-L1, will be studied together with regorafenib), the GOING trial (second-line treatment with regorafenib, followed by nivolumab treatment in patients who have progressed on sorafenib administration), the ACTION trial (will evaluate the effectivity of cabozantinib in patients who are sorafenib-intolerant or who do not meet the RESORCE criteria), and the COSMIC-312 clinical trial (administration of cabozantinib in combination with the immune checkpoint inhibitor atezolizumab), among some others. So, new therapies are coming and updates on  novel strategies and treatment recommendations [62] will be needed soon.
This entry is adapted from 10.3390/cancers14030621

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