**3.5 Pembrolizumab**

Pembrolizumab is another monoclonal antibody directed against PD-1 that has been used as therapy for patients with advanced HCC [44]. The KEYNOTE trials were conducted to evaluate the efficacy of pembrolizumab and were expanded to compare the use of pembrolizumab following disease progression while on sorafenib to best supportive care. Despite pembrolizumab reducing the risk of death by 22%, there was no significant difference in OS between the two groups [44, 45]. Continued research is ongoing regarding the use of this anti-PD-1 agent for advanced HCC treatment.

#### **3.6 Ramucirumab**

Ramucirumab is a monoclonal antibody directed against vascular endothelial growth factor receptor 2 (VEGFR-2) that is approved for advanced HCC therapy in patients with alpha-fetoprotein (AFP) levels ≥400 ng/mL. Ramucirumab was initially compared versus placebo in a double-blind, multicenter, randomized control phase III trial known as REACH-1; unfortunately, there was no statistically significant difference in OS for those given ramucirumab or placebo in those who had failed first line sorafenib therapy [46]. Following subgroup analysis of the REACH-1 trial, the REACH-2 trial showed that ramucirumab had a statistically significant survival benefit compared to placebo in patients with AFP ≥400 ng/mL [47, 48]. The side-effect profile of ramucirumab is mild, with only reported increased frequency of hypertension and proteinuria, making it a second-line therapy for advanced HCC by the ASCO for patients with AFP ≥400 ng/mL [18, 46, 47]. Given its specific target population, ramucirumab is not routinely used in HCC patients with AFP <400 ng/mL.

#### **3.7 Ipilimumab**

Ipilimumab is a monoclonal antibody that targets cytotoxic T-lymphocyteassociated protein 4 (CTLA-4) to downregulate immune function. The Checkmate 040 trial assessed the use of ipilimumab alongside nivolumab for advanced HCC patients and demonstrated combination therapy to have an object response rate twice as high as nivolumab monotherapy (31% vs. 14%) This combination therapy was also well tolerated with an acceptable side effect profile when compared to similar systemic therapy [49, 50].

The Checkmate 040 trial was expanded to investigate triple combination therapy consisting of nivolumab, ipilimumab, and cabozantinib altogether [51]. When compared to the combination of just nivolumab and ipilimumab, those on triple therapy had a longer period of progression-free survival (6.8 months vs. 5.5 months). Treatment related adverse events were higher in those taking triple therapy with a discontinuation rate of 20% in the triple therapy group and 3% in the double therapy group [51].

#### **4. Locoregional therapy**

Therapies in the form of embolization fall under the category of locoregional therapy and are typically contraindicated in patients with advanced HCC with underlying vascular invasion, extrahepatic spread, or poor performance status. However, some patients with advanced HCC classified as BCLC stage C have benefited from locoregional therapies [52].

#### **4.1 TACE**

Advanced HCC patients with tumor invasion off a branch of the portal vein or limited extrahepatic disease involvement have been trialed with TACE therapy [53]. TACE consists of injecting an emulsified chemotherapeutic agent into the hepatic artery flowing towards the underlying tumor, followed by embolization of the vessel to contain the drug and localize cell death within the malignancy [52, 53]. TACE has historically been more successful in localized disease without extrahepatic or diffuse vascular involvement and serves as the first-line treatment for intermediate (BCLC stage B) HCC. Consensus regarding the overall clinical utility of TACE

*Treatment of Advanced Hepatocellular Carcinoma DOI: http://dx.doi.org/10.5772/intechopen.99837*

in advanced HCC when compared to systemic therapy remains under discussion [54]. Certain studies have shown TACE to be clinically safe and feasible in select advanced HCC patients with good collateral blood flow, and a meta-analysis reported TACE to be associated with higher treatment responses in advanced HCC when compared to other more conservative treatment approaches [54]. However, a retrospective analysis by Pinter and colleagues demonstrated no significant difference in OS between patients treated with TACE versus sorafenib, with Child-Pugh class predicting OS in these patients [55]. Meanwhile, Choi et al., reported through retrospective analysis that TACE in addition to sorafenib is associated with significantly increased time to progression when compared to sorafenib therapy alone, though no difference was seen with regard to OS [56]. Other retrospective studies including the TACTICS trial also found that combining TACE with sorafenib in advanced HCC improved progression-free survival when compared to sorafenib therapy alone [57–61].

#### **4.2 Y-90 trans-arterial radio-embolization**

Y-90 trans-arterial radio-embolization (TARE) is a therapy modality by which the isotope yttrium90 is delivered in in small vector beads to malignancy areas through branches of the hepatic artery [62]. TARE has been applied to treatment of advanced HCC in tumors that invade discrete segmental areas of the liver. Additionally, TARE has been shown to decrease overall portal vein tumor thrombus load [62]. Recent data indicates that when comparing the efficacy of TARE vs. sorafenib in advanced HCC patients, those who underwent TARE had a significantly higher tumor response rate, though there was no significant difference in OS [63]. Studies have also been conducted on combining TARE with systemic therapy in advanced HCC. No clear benefit was seen when combining TARE with sorafenib [64]; however, there have been case reports or series of positive outcomes in combining TARE with different systemic modalities [65, 66].

Most recently, a multicenter, single-arm, retrospective study conducted at three separate medical centers called the LEGACY study assessed the clinical efficacy of TARE therapy in unrespectable HCC [67]. Chemoembolization served as a primary treatment for 72.2% of the cohort with advanced disease. The three-year OS rate for the entire cohort was 86.6% with 62.2% of patients experiencing a duration of response of greater than six months [67]. This study led to the FDA approval of TheraSphere Y-90 Glass Microsphere for treatment of advanced HCC [68].

Garin et al. conducted research on the dosimetry of TARE therapy through a randomized, multicenter, open-label phase II trial known as DOSISPHERE-01 [69]. Patients received either a standard dose of Y-90 to the perfused lobe or a personalized dose of Y-90 targeted to the index lesion. Results showed that personalized dosimetry significantly improved response rates when compared to standard dosimetry in cases of locally advanced HCC (71% vs. 35%, p < 0.01) [69].

#### **4.3 Hepatic artery infusion chemotherapy**

Hepatic artery infusion chemotherapy (HAIC) has been used in the treatment of advanced HCC to directly delivery high concentrations of chemotherapeutic agents [70]. Studies on advanced HCC lesions that were unresectable, refractory to TACE, or associated with portal vein thrombus (PVT) have demonstrated positive responses to HAIC within patient cohorts. Groups in Korea and Japan have implemented HAIC with agents including cisplatin, 5-fluororuacil (5-FU), and pegylated interferon α-2b [70]. A randomized trial comparing interferon therapy coupled with 5-FU HAIC to sole interferon therapy in advanced HCC patients

showed a significantly higher response rate (45.6% vs. 24.6%, p < 0.05) and longer median progression free survival (6.5 months vs. 3.3 months, p=0.0048) in the patients who received HAIC [71]. In their study comparing HAIC and sorafenib in advanced HCC patients, Song and colleagues reported that the median overall survival was significantly longer in the patients who received HAIC (OS: 7.1 months vs. 5.5 months, p < 0.05) [72].

## **5. Surgery**

As medical and surgical expertise continue to improve, surgery is no longer contraindicated in some advanced HCC patients [73]. Surgical resection of advanced HCC, either in the form of hepatectomy or en-bloc resection, has been revisited as a potentially efficacious way of increasing OS. Data has shown that the overall median survival time in advanced HCC patients with PVT who undergo surgical resection to be between 8 and 22 months, with OS between 21.7% to 69.6% at one year [74]. Given the high incidence of post-operative recurrence, multi-disciplinary approach to surgical planning on a case-by-case basis is needed [74, 75]. Liang and colleagues performed a meta-analysis and found that patients who underwent surgical resection of advanced HCC with PVT had longer OS than those who were treated with TACE therapy [76].

The combination of systemic therapy with surgical resection has also been applied to advanced HCC patients. Takeyama et al. studied the use of sorafenib as a potential neo-adjuvant therapy prior to surgical resection. Patients who underwent surgical resection following treatment with sorafenib had a significantly increased three-year survival than patients who underwent therapy with sorafenib alone [77]. Incorporating surgical resection with other treatment modalities including TACE and radiofrequency ablation have also promoted positive prognostic outcomes in select patients [74, 75]. Overall, the indication for surgical therapy in advanced HCC patients with or without PVT requires a multi-disciplinary approach and may entail utilizing systemic or locoregional therapy during treatment planning.

### **6. Future directions**

Several systemic agents have been trialed for treatment of advanced HCC over the past decade. As newer agents are approved for use in advanced HCC, combined treatment options remain intriguing topics for investigation. Gosain et al. have hypothesized that sorafenib and pembrolizumab may have synergistic effects and are currently conducting a trial to evaluate the efficacy of these drugs when used in combination [78]. Given the favorable response rates of nivolumab that were seen in the Checkmate 040 trial, Welling et al. are conducting a phase II, randomized control of nivolumab combined with HuMax-IL8 and cabiralizumab (an anti-CSF1R antibody) in advanced HCC patients. HuMax-IL8 (now known as BMS-986253) is a novel, fully human monoclonal antibody that inhibits interleukin-8 (IL-8) [79]. Combining locoregional with systemic therapy is also under investigation [80]. Among multiple studies being conducted, the EMERALD-1 trial is a randomized, double-blind, placebo-controlled phase III study assessing anti-PD-1 agent durvalumab alongside TACE therapy with or without bevacizumab [81].

Alternative molecular targets are also being evaluated. El-Khouiery et al. are currently working on an advanced HCC phase I trial of humanized agonist IgG2 monoclonal antibodies to a specific tumor necrosis factor receptor known as OX40. Underlying safety and pharmacodynamic dose-dependent response are now being

#### *Treatment of Advanced Hepatocellular Carcinoma DOI: http://dx.doi.org/10.5772/intechopen.99837*

investigated [82]. Another phase I trial currently underway involves a small activating RNA (saRNA) known as MTL-CEBPA that targets transcription factor C/EBP-α, which is involved in hepatic homeostasis and cell-cycle control. The preliminary results showed that it is relatively safety and can have potential synergistic efficacy with tyrosine kinase inhibitors in HCC [83]. Like new combinations of locoregional-systemic combinations and new uses of systemic agents, novel moleculartargeting agents offer hope for improved outcomes in advanced HCC.
