*6.2.3.3. TKIs of VEGF*

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 progression [126].

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

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 early because of low response rates [130].

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

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.

#### *6.2.4. IGF-1 inhibition*

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 requires further studies.

#### *6.2.5. Fibroblast growth factor TKIs*

Fibroblast growth factor (FGF) and its signaling receptors have a major role in cell proliferation, differentiation, and transformation [136].

Although AZD2171 (AZD), a potent oral FGF TKIs, led to tumor inhibition in animal models of gastric cancer, unfortunately, the results of a phase II study [137] showed no statistically significant difference in PFS for FGFR2 amplified gastric cancer patients treated with AZD.

A phase I, first in-human study of JNJ-42756493 (a pan-FGFR TKI) was initiated in advanced solid tumor patients, including gastric cancer, showing that this agent had excellent pharmaceutical properties and safety profile [138].

Ki23057 is an oral TKI broad-range FGF TKI that inhibits the proliferation of gastric scirrhous cancer cells presenting FGFR2 gene amplification. The study of Qiu et al. found that the FGFR2 inhibitor Ki23057 might be therapeutically promising for treating drug-resistant gastric cancer cells, especially when used in combination with other chemotherapeutic drugs. [139].

We expect the results of the ongoing phase I and II clinical trials using TKI such as dovitinib, brivanib, and INCB054828 (FGF inhibitors) in patients with advanced gastric cancer to add new informations regarding the role of FGF inhibitors in this type of tumor [140].
