*6.2.6.1. Anti-HGF/c-MET monoclonal antibodies*

*6.2.3.3. TKIs of VEGF*

120 Gastric Cancer

gression [126].

*6.2.4. IGF-1 inhibition*

requires further studies.

*6.2.5. Fibroblast growth factor TKIs*

differentiation, and transformation [136].

Apatinib is an anti-VEGF-2 small molecule TKI evaluated in China [124]. Phase II and III studies have shown that apatinib was the first discovered anti-VEGF-2 molecule TKI with benefits for Asian patients with advanced gastric cancer [125], representing a significant progress for third-line treatment, although it prolonged OS by less than 2 months. Further studies are needed to assess the efficacy and safety of this agent in Caucasians. Based on these positive results, apatinib was approved by the Chinese Food and Drug Administration (CFDA) for metastatic adenocarcinoma of the stomach after second-line chemotherapy pro-

Sunitinib represents an oral multitargeted TKI of VEGFR, PDGFR, c-KIT (stem cell factor receptor), rearranged during transfection, and FMS-like tyrosine kinase-3 receptor; when administrated in a phase III trial as second-line monotherapy in patients with advanced gastric cancer, it showed a median OS of 6.8 months [127]. The efficacy of sunitinib in advanced

Sorafenib (Nexavar) is a multitargeted TKI. A phase II study using sorafenib combined with docetaxel and cisplatin as a second-line treatment for gastric cancer patients obtained very long median PFS and median OS [129], although other clinical trials have been terminated

Pazopanib is an oral agent that inhibits angiogenesis through multiple pathways (VEGFR, PDGFR, and c-KIT), which is currently under investigation in two phase II trials in patients with advanced gastric tumors: the PaFLO trial (FLO ± pazopanib as first-line treatment) [131]

Regorafenib is an oral multikinase; a phase II trial investigating the efficacy of regorafenib in the treatment of refractory advanced esophagogastric cancer demonstrated a significantly longer median PFS (11 wk versus 3.9 wk) and OS (25 wk versus 19.4 wk) for the regorafenib group versus the placebo group [133] but with serious drug-related toxicity. The role of regorafenib in advanced gastric cancer will be better assessed by the ongoing phase I and II trials.

IGF-1 receptor (IGF-1R) is a transmembrane tyrosine kinase receptor promoting tumor angiogenesis, growth, and metastasis in several cancers, including gastroesophageal tumors [134]. Figitumumab is a humanized IgG2 monoclonal antibody against IGF-1R. Some phase I clinical trials have assessed the overall safety and pharmacokinetic profile of figitumumab administrated in patients with advanced solid tumors [135]. Its role in gastric cancer treatment

Fibroblast growth factor (FGF) and its signaling receptors have a major role in cell proliferation,

and another trial associating pazopanib with capecitabine and oxaliplatin [132].

gastric cancer was also confirmed by other studies [128].

early because of low response rates [130].

Rilotumumab is a human monoclonal antibody directed against HGF, demonstrated to show efficacy in locally advanced/metastatic gastric cancer patients with MET overexpression by immunohistochemistry (phase II study). Unfortunately, due to the increased toxicity of the agent and treatment-related deaths in the RILOMET-1 trial, all of the clinical trials investigating the role of rilotumumab in gastric tumors, including the phase III RILOMET-1 (with ECX) and RILOMET-2 (with cisplatin and capecitabine) studies, were interrupted.

Onartuzumab is a humanized antibody directed against MET that is also being investigated in a first-line, phase III trial in MET-positive, HER2-negative gastroesophageal patients in combination with mFOLFOX6. The results of this study revealed unfortunately that this treatment could not prolong OS [142].
