**2.1. Trastuzumab**

HER2 is responsible for GC cell growth when overexpressed [10]. A literature review demonstrates that the mean incidence of HER2-positive gastric cancer is 18%, ranging from 4 to 53% [11], and the most recent research confirmed that the HER2 positivity rate to be 21% among Japanese patients [12]. A systematic analysis demonstrated the potential role for HER2 as a negative prognostic factor [11]; thus, it has become a rational therapeutic target. Trastuzumab, a humanized monoclonal antibody that targets the extracellular domain IV of the HER2, was evaluated by the first landmark randomized controlled trial (RCT) (ToGA trial) [M]. The ToGA trial provided evidence of a significant improvement by the addition of trastuzumab to chemotherapy as compared with chemotherapy alone as a first-line setting. In patients with HER2-positive GC, while trastuzumab could achieve longer mOS, a higher response rate (RR), and a longer median progression free survival (mPFS) (**Table 1**), toxicity did not differ between groups. A post-hoc analysis revealed that the survival differences between groups were more evident in patients with immunohistochemistry (IHC) 2+


advanced state, chemotherapy becomes a mainstay of the treatment [3]. The most frequently used first-line chemotherapy regimens worldwide are platinum derivatives plus fluoropyrimidine doublet or a triplet regimen with the addition of epirubicin or docetaxel. The reality is that chemotherapy has reached a plateau of efficacy for GC with a median overall survival (mOS) of around or less than 12 months [4, 5]. Furthermore, although second-line treatment is recommended for the patients with failure after first-line chemotherapy because it prolongs survival as compared with the best supportive care [6–8], the global standard regimens of

These somewhat painfully slow rates of advances in treatment have been impetus to develop new concepts of strategies. As an example, receptor tyrosine kinases (RTKs) consist of the ligand binding of extracellular domains, a transmembrane domain, and a tyrosine kinase motif, which is involved in a subsequent downstream signal cascade. Since this cascade leads to cell growth, differentiation, adhesion, migration, and apoptosis [9], each step is theoretically a therapeutic target. This review focuses on advances in molecular targeted therapy for

Membrane-bound human epidermal growth factor receptors (HERs) consist of a ligand-binding domain at the extracellular surface, a single transmembrane segment, and a cytoplasmic portion harboring the protein kinase activity. The HER family includes four structurally related members, namely the epidermal growth factor receptor (EGFR, also known as HER1), HER2, HER3, and HER4. Ligand binding to the extracellular domain triggers conformational changes of receptors that form HER-dimerization, and subsequently, activates downstream a signaling cascade and ultimately stimulates tumor cell proliferation. Therefore, HERs are the

HER2 is responsible for GC cell growth when overexpressed [10]. A literature review demonstrates that the mean incidence of HER2-positive gastric cancer is 18%, ranging from 4 to 53% [11], and the most recent research confirmed that the HER2 positivity rate to be 21% among Japanese patients [12]. A systematic analysis demonstrated the potential role for HER2 as a negative prognostic factor [11]; thus, it has become a rational therapeutic target. Trastuzumab, a humanized monoclonal antibody that targets the extracellular domain IV of the HER2, was evaluated by the first landmark randomized controlled trial (RCT) (ToGA trial) [M]. The ToGA trial provided evidence of a significant improvement by the addition of trastuzumab to chemotherapy as compared with chemotherapy alone as a first-line setting. In patients with HER2-positive GC, while trastuzumab could achieve longer mOS, a higher response rate (RR), and a longer median progression free survival (mPFS) (**Table 1**), toxicity did not differ between groups. A post-hoc analysis revealed that the survival differences between groups were more evident in patients with immunohistochemistry (IHC) 2+

second-line chemotherapy have not yet been determined [4].

GC in recent years, as well as problems to be resolved.

most innovative targets for GC treatment.

**2.1. Trastuzumab**

222 Gastric Cancer

**2. Focus on human epidermal growth factor receptors (HERs)**


**Table 1.** Results of phase III or randomized phase II trials of molecular targeting therapy for gastric cancer.

onartuzumab; Ox—oxaliplatin; Pani—panitumumab; Per—pertuzumab; PTX—paclitaxel; Ram—ramucirumab; T—trastuzumab; T-DM1—trastuzumab emtansine.

and fluorescence *in situ* hybridization (FISH) positive tumors or IHC3+ tumors [13]. The ToGA trial also provided evidence of a prolongation of time to the deterioration of healthrelated quality of life [14]. Furthermore, the subgroup analyses of the ToGA trial restricted to Japanese patients [15] and a subsequent similar phase III study recruiting only Chinese patients [16] have confirmed again such promising results, suggesting the efficacy of trastuzumab irrespective of country of origin. The results of the ToGA study have changed the treatment paradigm for GC harboring HER2 overexpression. Subsequently, a HELOISE study has been conducted to investigate the efficacy of different doses of trastuzumab with cisplatin and capecitabine [17], resulting in no differences between 6 and 10 mg of trastuzumab in terms of mOS and mPFS.

However, targeting HER2 raises important issues that must be discussed, namely, heterogeneity and resistance. Heterogeneity should be considered because of a different HER2 positivity rate according to cancer histology, the location of GC, and geographic area, making for various prevalence rates of HER2-positive GC from study to study or from country to country. In the ToGA trial discussed above, the HER2 positivity rate was higher in the intestinal type (31.8%) than in the diffuse type (6.1%), in specimens from the gastroesophageal junction (32.2%) than in those from the stomach (21.4%), and in patients from Asia-Pacific (23.9%) or Europe (23.6%) than in patients from Central/South America (16.1%) [18]. In addition, one-third of IHC3+ patients had <30% of stained cells, suggesting staining variability within the same tumor. Furthermore, variations of scoring criteria between studies may be another explanation for heterogeneity [11]. Since these variations may undoubtedly complicate the interpretation of the results of the clinical trials, there is a need for establishing a unique scoring system specific for GC [19], which could help identify and select HER2-positive patients who benefit from trastuzumab. Another important issue is a trastuzumab resistance, which has begun to arise along with the accumulation of experience of trastuzumab use. Not all HER2-positive patients immediately benefit from trastuzumab, and even those who initially respond to trastuzumab will eventually experience progress, suggesting refractories and resistance. In breast cancer, the majority of those who initially responded to trastuzumab ultimately became resistant during prolonged treatment [20, 21]. In looking at the ToGA trial, mPFS was 6.7 months in the trastuzumab arm or the absolute increase in the RR was only 12%, suggesting that half of the GC patients—even though they were HER2 positive—exhibit acquired resistance within 7 months or do not necessarily respond to trastuzumab.

When considering the onset of nonresponsiveness to trastuzumab, two statuses should be distinguished, namely, resistance and refractoriness. Resistance is a condition of disease progression at first evaluation even under trastuzumab use, whereas refractoriness is a condition of disease progression at second or later evaluations after an initial clinical response [22]. The resistance may be ascribed to intrinsic mechanisms, while refractoriness may be related to acquired properties. The precise mechanisms of these phenomena are unclear; several pathways may be involved, including phosphatidylinositol-3-kinase (PI3K) [23], a mammalian target of rapamycin (mTOR) [23], insulin-like growth factor-1 (IGF-1) [24], and a phosphatase and tensin homolog (PTEN) [25]. This encourages the development of second-generation agents of targeting HER2 to overcome HER2 resistance.

**Reference**

**Publication** 

**Design**

**Phase**

**Experimental arm**

**Agents**

*n*

**Agents**

*n*

**Experimental** 

**Control** 

*p*

**Experimental** 

**Control** 

*p*

**Experimental** 

**Control** 

*p*

**arm**

**arm**

**arm**

**arm**

**arm**

**arm**

**Control arm**

**RR**

**mPFS**

**mOS**

**Study** 

224 Gastric Cancer

**name**

**year**

[65] [66] [67] [73] [87] [88] [92]

2017

1st

III

FOLFOX6,

279

FOLFOX6 283 46

41 RR—response rate; mPFS—median progression free survival; mOS—median overall survival; rII—randomized phase II; NA—not described; NS—not significant; Bev—

bevacizumab; Cape—capecitabine; Cet—cetuximab; Cis—cisplatin; E—epirubicin; EOC—epirubicin, oxaliplatin, capecitabine; Eve—everolimus; F—fluoropyrimidines;

FOLFIRI—leucovorin + 5-fluorouracil + irinotecan; FOLFOX—leucovorin + 5-fluorouracil + oxaliplatin; Iri—irinotecan; L—lapatinib; Nimo—nimotuzumab; Ona—

onartuzumab; Ox—oxaliplatin; Pani—panitumumab; Per—pertuzumab; PTX—paclitaxel; Ram—ramucirumab; T—trastuzumab; T-DM1—trastuzumab emtansine.

Results of phase III or randomized phase II trials of molecular targeting therapy for gastric cancer.

**Table 1.**

NS

6.7

6.8

NS

11

11.3

NS

Ona

Ongoing 1st

III

Cis,

NA

Cis, Cape

NA

ND

ND

ND

ND

ND

ND

ND

ND

ND

RILOMET-2

(NCT021

37343)

Cape,

rilotumumab

2015

1st

III

E, Cis,

304

E, Cis,

305 30

39

0.027

5.7

5.7

0.016

9.6

11.5

0.016

RILOMET-1

(NCT016

97072)

Cape

Cape,

rilotumumab

2016

2nd or

rII

FOLFILI,

45

FOLFILI

45

20

29

ND

3.5

3.3

NS

10.4

8.9

NS

sunitinib

further

2014

3rd

III

Apatinib

176 –

91

2.8

0

NS

2.6

1.8

<0.001 6.5

4.7

0.0149

2014

1st

rII

FOLFOX,

84

FOLFOX

84

45

46

ND

6.4

6.7

ND

11.7

11.5

ND

Ram

Ongoing 1st

III

F, Cis, Ram

NA

F, Cis

NA

ND

ND

ND

ND

ND

ND

ND

ND

ND

RAINFALL

(NCT02

314177)
