*3.2.2 Cabozantinib*

Cabozantinib is another TKI targeting VEGFR 1–3, MET, RET and AXL [22]. Carbozantinib was approved for thyroid and renal cancer. Phase III study (CELESTIAL) [23] compared the efficacy of carbozantinib as second- and thirdline therapy in advanced HCC patients after failure of a sorafenib compared with placebo. In contrast to regorafenib, this study allowed the inclusion of patients that were intolerant to sorafenib and who had progressive disease on one or two systemic therapies. Carbozantinib led to a significant improvement in overall survival (HR = 0.76, 95% CI = 0.63–0.92, P = 0.0049, 10.2 mons versus 8.0 mons). Other secondary end points such as PFS and ORR were also positive. It is worth noting that 27% of the patients had received 2 previous systemic agents. 30% of populations in this study presented with macrovascular invasion, 78% with extrahepatic spreading and 45% with AFP > 400 ng/dL. Response rate was only 4% with carbozantinib based upon RECIST criteria. The most common adverse effects are HFS, hypertension, increased level of aspartate aminotransferase (AST), fatigue and diarrhea. These adverse effects led to 62% dose reduction and 16% treatment discontinuation.

Carbozantinib can be considered for patients who had progressive disease on one or two systemic therapies with well-preserve liver function and good ECOG PS 0–1.

Because RESORCE and CELESTIAL compared with a placebo arm, it is no data shown that which is superior or inferior in term of efficacy to the other. Biomarkers have not yet been identified. The RESORCE study recently identified a total of five proteins (angiopoietin 1, cystatin B, the latency-associated peptide of TGF-β1, oxidized low-density lipoprotein receptor 1 and C-C motif chemokine ligand 3) that were associated with prolonged survival with regorafenib [24]. In addition, nine plasma miRNAs (MIR30A, MIR122, MIR125B, MIR200A, MIR374B, MIR15B, MIR107, MIR320 and MIR645) were correlated with an improved survival. To what extent these findings will become clinically relevant remains to be seen.

## *3.2.3 Ramucirumab*

Ramucirumab is a human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that inhibits ligand activation of VEGFR2. Phase III study (REACH) [25] conducted for tested efficacy of ramucirumab in term of overall survival in advanced HCC after the failure of sorafenib. The primary end point of the study is OS was not statistically significant, but a meaningful improvement was observed in subgroup patients with baseline AFP > 400 ng/mL. Based on these data, the REACH-2 phase III study [26] analyzed the efficacy of ramucirumab in patients with baseline AFP > 400 ng/mL after failure with sorafenib. Result of this study shown ramucirumab significantly improved overall survival from 7.3 mons to 8.5 mons (HR = 0.71, 95% CI = 0.53–0.95) and median PFS from 1.6 mons to 2.8 mons (HR = 0.45, 95% CI = 0.34–0.60) compared with placebo. Overall response rate was 4.6%. The safety

profile observed in this study was consistent with previously study, only grade III adverse effects occurring were hypertension (12.2%) and hyponatremia (5.6%)

Ramucirumab can be considered for patients in second-line therapy with baseline AFP > 400 ng/mL with well-preserved liver function and good ECOG PS 0–1, thus, the AFP may serve as a marker for the benefit of ramucirumab in the second line setting for advanced hepatocellular carcinoma. Ramucirumab remains the only systemic agent that demonstrated clinical benefit in biomarker selected population in HCC.

#### **3.3 Immunotherapy**

The most promising immunotherapeutic approach has been the use of immune checkpoint inhibitors in vary of cancer type including gastrointestinal malignancies. Immune checkpoint inhibitor can change paradigm of treatment and improve survival and quality of life in many type of cancer. Tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment was demonstrated in hepatocellular carcinoma cell, which shown that HCC is also immunogenic cancer [27]. Some studies have also shown the presence of an immunosuppressive intratumoral milieu driven by constant exposure of the liver to antigens via the portal system and immune dysfunction related to cirrhosis [28]. These results of a phenomenon of immune escape might predict that HCC could be response to immunotherapy and immune checkpoint inhibitor drugs.

#### **3.4 First-line immunotherapy**

Single agent of Immunotherapy has been conducted in two phase III studies as first line therapy. The Checkmate 459 trial, Nivolumab compared to standard of care as sorafenib, failed to meet the primary endpoint as overall survival [29]. Also, with, The KEYNOTE-240 trial of pembrolizumab as second line treatment of advance HCC after failure to sorafenib compared with placebo, failed to meet endpoints of OS and progression free survival [30]. They are not recommended as monotherapy for the treatment of advanced HCC.

To date, new combination immunotherapy with Atezolizumab plus bevacizumab were change paradigm of treatment in advanced HCC. This combination therapy is the first treatment to demonstrate a significant OS benefit compared with sorafenib in Phase III international, open label of patients with locally advanced or metastatic and/or unresectable HCC (IMbrave 150 study) [31]. Patients were allocated randomization with 2:1 ratio to compare efficacy of Atezolizumab plus bevacizumab to sorafenib. The coprimary endpoints were overall survival and progression free survival. The combination therapy demonstrated a significant overall survival benefit (HR = 0.66, 95% CI = 0.52–0.85). The median overall survival was not reached (Not estimate or NE) in the Atezolizumab plus bevacizumab arm, whereas sorafenib arm had median overall survival at 13.2 months. The study reported a significantly PFS of combination therapy compared to sorafenib (6.8 mons vs. 4.3 mons, HR = 0.59, 95% CI = 0.47–0.76, P < 0.0001). The difference in overall response rate was significant (stratified *P* < 0.0001): Atezolizumab plus Bevacizumab arm = 27%, and sorafenib arm = 12%. Complete response was achieved in 18 patients (6%), which is quite promising. The median duration of response of NE and the proportion (80%) of responders with a DOR of >6 months by Atezolizumab plus Bevacizumab arm therapy indicate a considerable durable response to this treatment. Successful benefit both the OS and PFS endpoints at first analysis was surprising and coming to a new era of systemic therapy for HCC as standard of care in first-line therapy due to meet primary endpoint of overall survival benefit.

#### *Systemic Therapy in Hepatocellular Carcinoma DOI: http://dx.doi.org/10.5772/intechopen.100257*

Treatment related adverse effects especially grades III or IV were found more in sorafenib arm (46%) compared to Atezolizumab plus Bevacizumab arm (36%). Immune-related adverse effects were rarely observed in the Atezolizumab plus Bevacizumab arm (expect for infusion reaction in 10.9%, AIHA in 0.3% and adrenal insufficiency in 0.3%). Bleeding events form bevacizumab was minimal occurring at 6.4%. The data suggest that the acceptable safety profile in Atezolizumab plus Bevacizumab.

However, the median progression free survival is only 6.8 months and only 20% of patients do not response to atezolizumab plus bevacizumab, experimental studies need to define options for second-line therapy after progression on immunotherapy. Most of drugs only been tested after sorafenib intolerance or progression and there are currently no phase III study to inform the choice of therapy in this setting. However, a clear rationale for offering a targeted therapy given the existing evidence for efficacy in first- and second-line therapy.

### **3.5 Other combination immunotherapies**

To current knowledge of combination immune checkpoint blockade plus antiangiogenesis translate to new combination therapy that need to find out the clinical benefit. Basic research studies show that lenvatinib and anti-PD-1 antibodies have synergistic effects [32]. Immunotherapy and Molecular targeting agents as combination therapy might have a role in the treatment of HCC in the future. A phase Ib trial of combination use of lenvatinib plus pembrolizumab reported promising results [33]. This combination had a median progression free survival and overall survival of 9.3 months (95% CI: 5.6–9.7) and 22.0 months (95% CI: 20.4–NE), respectively. Overall response rate was higher in 46% (95% CI: 36.0–56.3). A phase III trial (LEAP002) of this combination is currently ongoing. On the other hand, rationale of dual combination immune checkpoint blockade (PD-L1 plus CTLA-4 inhibitor) might have a clinical response too. The results of combination therapy with the durvalumab (PD-L1 antibody) and the tremelimumab (CTLA-4 antibody). The study revealed a median PFS and OS of 2.17 months (95% CI: 1.91–5.42) and 18.73 months (95% CI: 10.78–27.27), respectively. ORR this combination therapy was 24.0% (95% CI, 14.9–35.3). Therefore, this combination therapy is promising, and the phase III HIMALAYA trial of this combination is ongoing too.
