**5. Conclusions**

The precise mechanisms for this phenomenon are unclear. In addition to the multiple pathways to escape from the VEGF-VEGFR blockade as described earlier, it is possible that tumor hypoxia induced by antiangiogenic therapy triggers another angiogenic switch for cancer cells to survive or forces cancer cells to migrate to their nonhypoxic lesion. At present, there is no clinical evidence that the rebound phenomenon is a result of anti-angiogenic therapy or any adverse effects of the inherent nature of anti-angiogenic therapy. A recent review has proposed putative mechanisms of resistance to antiangiogenic therapy [80], which could uncover evasive or intrinsic changes within the tumor as resistance mechanisms of antiangiogenic therapy. A key molecule involved in another angiogenic switch under conditions of antiangiogenic therapy is the hypoxia inducible factor (HIF) [81]. HIF induces a hepatocyte growth factor (HGF) [82] that subsequently activates a mesenchymal-epidermal transition factor receptor (MET). Activation of this HGF/MET pathway leads to GC cell proliferation, survival, and migration [83]; thus, the HIF and HGF/MET axis is another rational therapeutic target for overcoming the resistance to antiangiogenic therapy. Furthermore, a strategy of HGF/MET inhibition is important because MET solely [84] or its interaction with EGFR [85] or HER3 [86]

A number of inhibitors of the HGF/MET pathway have been developed, including monoclonal antibodies, such as rilotumumab and onartuzumab, or small molecule RTK inhibitor such

Rilotumumab, a humanized monoclonal antibody against HGF, has been investigated by two first-line RCTs. RILOMET-1 is a comparison between rilotumumab plus ECX (epirubicin, cisplatin and capecitabine) and a placebo plus ECX [87], and RILOMET-2 aims to evaluate cisplatin plus capecitabine with or without rilotumumab [88]. A rilotumumab benefit was seen in MET-positive patients [89] or was rilotumumab concentration dependent [90]. A very recent pharmacokinetic study revealed a lack of drug-drug interaction between rilotumumab and ECX [91]; however, the results were negative, thereby recommending the early cessation of the RILOMET-1 study [87]. Onartuzumab is a recombinant, fully humanized, monoclonal anti-MET antibody. A randomized phase II study of FOLFOX with or without onartuzumab failed to gain positive results with regard to mPFS and mOS [92]. Foretinib, an oral small molecule multikinase inhibitor that targets MET and VEGFR-2, has been evaluated by a phase II

GC and breast cancer have similarities with regard to HER2 positivity rate and molecularly targeted agents first used, such as trastuzumab. However, differences are apparent with regard to tumor response to another HER-inhibitor between the two tumors. The evidence obtained by the current clinical trials suggests that GC and breast cancer do not necessarily show the same response to the HER-2 targeted therapies even if both tumors are HER2 positive. Such similarities

may mediate resistance to anti-HER therapy.

study; however, the results are discouraging [93].

**4. Future perspectives**

as foretinib.

230 Gastric Cancer

**3.5. HGF/MET inhibitors—rilotumumab and onartuzumab**

Chemotherapy has reached a plateau of efficacy for GC, with an mOS of around 12 months. Unfortunately, progress in treating this disease with chemotherapy over the last years has lagged behind other malignancies such as breast and colorectal cancer. During this time, molecular targeting therapies for colorectal cancer have evolved and their clinical efficacy has been evaluated by various phase III trials, resulting in the mOS being at least doubled. In GC, the use of molecularly targeted therapies is still in the early stages, but more and more targeted drugs have begun to be developed to target each step of the signaling pathways. Disappointingly, however, both monoclonal antibodies and RTK inhibitors targeting signal transduction pathways failed to meet expectations or their efficacy was modest at best.

Such a painful slow advance is partly ascribed to either the lack of validated biomarkers to predict a therapeutic response or adverse events to molecular targeting therapy or to escape or resistance phenomena. Better therapeutic responses could sometimes be obtained at the expense of adverse events; however, drug-related severe adverse events might depress patient QOL. In addition, the blockade of a single signal transduction axis does not provide long-term efficacy due to escape or resistance phenomena. Research should be continued to bridge these adverse events and efficacy gaps or to circumvent resistance, but we are still far from any major breakthrough. Such a reality is challenging, but thanks to the accumulation of the knowledge of the mechanisms of RTK action and its downstream signal transduction cascade, there are several candidate surrogate biomarkers of response and adverse events, or multiple blockade strategies or kinases are being developed. New predictive biomarkers and the clarification of resistance mechanisms may hopefully lead to the selection of a potentially drug-sensitive cohort, to intensify drug efficacy, and to predict more accurately adverse events, holding promise for more tailored therapies. In this respect, both challenges and progress engender optimism as they unveil biological mechanisms underlying GC, ultimately identifying those patients most likely to benefit.
