Treatment options in patients with metastatic gastric cancer: Current status and future perspectives

Abstract

Despite advances in the treatment of gastric cancer, it remains the world’s second highest cause of cancer death. As gastric cancer is often diagnosed at an advanced stage, systemic chemotherapy is the mainstay of treatment for these patients. However, no standard palliative chemotherapy regimen has been accepted for patients with metastatic gastric cancer. Palliative chemotherapy including fluoropyrimidine, platin compounds, docetaxel and epirubicin prolongs survival, and improves a high quality of life to a greater extent than best supportive care. The number of clinical investigations associated with targeted agents has recently increased. Agents targeting the epidermal growth factor receptor 1 and human epidermal growth factor receptor 2 (HER2) have been widely tested. Trastuzumab was the first target drug developed, and pivotal phase III trials showed improved survival when trastuzumab was integrated into cisplatin/fluoropyrimidine-based chemotherapy in patients with metastatic gastric cancer. Trastuzumab in combination with chemotherapy was thus approved to be a new standard of care for patients with HER2-positive advanced esophagogastric adenocarcinoma. Thus, the evaluation of HER2 status in all patients with metastatic gastroesophageal adenocarcinoma should be considered. Other agents targeting vascular endothelial growth factor, mammalian target of rapamycin, and other biological pathways have also been investigated in clinical trials, but showed little impact on the survival of patients. In this review, systemic chemotherapy and targeted therapies for metastatic gastric cancer in the first- and second-line setting are summarized in the light of recent advances.

Core tip: Although palliative chemotherapy have been demonstrated to improve survival and quality of life, the prognosis of patients with metastatic gastric cancer remains poor and responses to first-line chemotherapy are partial and heterogeneous. In order to improve the results of currently available treatments, remarkable advancements in new targeted agents have recently been obtained. The addition of trastuzumab to cisplatin/fluoropyrimidine-based chemotherapy significantly improved survival in patients with human epidermal growth factor receptor 2-positive metastatic gastric cancer, which is now the new standard of care. Our manuscript will elucidate current systemic chemotherapy and promising targeted therapies for metastatic gastric cancer in the first- and second-line setting in the light of recent advances.

INTRODUCTION

Gastric cancer is the second most common cause of cancer death worldwide. Although the overall incidence and mortality of this disease have dramatically declined over the last few decades, it remains a major health problem[1,2]. Radical gastrectomy is the only curative treatment of gastric cancer, but recurrences are common, being detected in approximately 60% of patients[3]. In addition, gastric cancer is often diagnosed at an advanced stage, other than in Japan and Korea, where screening is widely performed. For these patients, systemic chemotherapy is the mainstay of treatment[4,5]. Although recent phase III studies showed some benefit from chemotherapy regimens including docetaxel, capecitabine, irinotecan, cisplatin and oxaliplatin[5], there is no internationally accepted standard of care.

Treatment responses and prognosis are highly variable even within the same stage. Therefore, a thorough understanding of cancer biology is essential for better management of gastric cancer in the future. To date, molecular targets such as epidermal growth factor (EGFR) receptor, vascular endothelial growth factor (VEGF) receptor and human epidermal growth factor receptor 2 (HER2) have been tested by clinical trials in metastatic gastric cancer[6,7]. A recent phase III trial proved the benefit of trastuzumab (anti-HER2 antibody) in combination with chemotherapy in advanced HER2-positive gastric cancer or esophagogastric junction[8]. Despite these marked advances, the prognosis of patients with advanced gastric cancer remains poor. Therefore, new therapeutic molecular targets are required to improve the survival of patients[7].

In this article, we review the currently available treatments in light of the most recent publications and guidelines, along with promising therapeutic options that are still under development for patients with advanced gastric cancer.

CURRENT TREATMENT OPTIONS FOR ADVANCED GASTRIC CANCER

First-line chemotherapy

Palliative chemotherapy versus best supportive care (BSC) for patients with metastatic gastric cancer has been evaluated in several clinical trials, which showed that palliative chemotherapy improved overall survival (OS) for several mo longer on average than supportive care[9-12]. A meta-analysis performed by Wagner et al[12] demonstrated an overall HR of 0.39 (95%CI: 0.28-0.52) for OS in favor of chemotherapy compared with BSC, which translates to a benefit in weighted mean average survival of about 6 mo. Moreover, chemotherapy also provided relief of symptoms, and improved and prolonged a high quality of life more than BSC[9].

In the last 20 years, multiple randomized trials testing different combination regimens in patients with metastatic gastric cancer have indicated that there is no international consensus regarding the best management approach[13-16], and meta-analysis of these studies[12] has demonstrated that combination chemotherapy is superior to monotherapy, with a HR of 0.83 for OS (95%CI: 0.74-0.93) in favor of combination chemotherapy.

In the early 1980s, the FAM chemotherapy regimen (fluorouracil, doxorubicin mitomycin) was accepted as the gold standard regimen for patients with metastatic gastric cancer[17]. Subsequently, in a study carried out by Webb et al[18], 274 patients with metastatic esophagogastric cancer were randomly assigned to receive either epirubicin, cisplatin and fluorouracil (ECF) or fluorouracil, doxorubicin, and methotrexate (FAMTX). The patients treated with ECF had a significantly longer median OS (8.9 mo vs 5.7 mo, P = 0.0009) than the FAMTX group. Multiple randomized studies have compared various fluorouracil-based regimens and of all the combination regimens, ECF has been considered to be the reference standard regimen in the United States and Europe based on OS and quality of life benefits[19].

The REAL-2 trial reported that oxaliplatin and capecitabine were found to be noninferior to cisplatin and fluorouracil, with manageable toxicity profiles[20]. This trial compared capecitabine with fluorouracil and oxaliplatin with cisplatin in 1002 patients with advanced esophageal, gastroesophageal junction, or gastric cancer. In a two-by-two design, patients with histologically confirmed advanced esophagogastric cancer were randomized to receive one of four epirubicin-based regimens [ECF, epirubicin, oxaliplatin and fluorouracil (EOF), epirubicin, cisplatin and capecitabine (ECX) and epirubicin, oxaliplatin and capecitabine (EOX)]. The median OS times in the ECF, EOF, ECX and EOX groups were 9.9, 9.3, 9.9 and 11.2 mo, respectively. For the capecitabine-fluorouracil and oxaliplatin-cisplatin comparisons, the results indicated a noninferior median OS in patients treated with capecitabine rather than 5-FU (HR_death: 0.86; 95%CI: 0.82-0.99) and in patients treated with oxaliplatin in place of cisplatin (HR_death: 0.92; 95%CI: 0.80-1.10)[20]. Since REAL-2, oxaliplatin and capecitabine have often been substituted for cisplatin and 5-FU within the ECF regimen in many cancer centers.

Another phase III randomized noninferiority trial, ML17032, performed by Kang et al[21], compared the combination capecitabine and cisplatin (XP) with the combination of fluorouracil and cisplatin (FP) in patients with previously untreated advanced gastric cancer in the first-line setting. Both overall response rates (ORR) and median OS times were superior for patients treated with the XP regimen (ORR; 41% vs 29% and OS; 10.5 mo vs 9.3 mo, respectively), although the median progression-free survival (PFS) time was found to be similar for both regimens (5.6 mo for XP and 5.0 mo for FP). The authors concluded that capecitabine is as effective as fluorouracil in the treatment of patients with advanced esophagogastric cancer. Thereafter, a meta-analysis of the REAL-2 and ML17032 trials demonstrated that OS was superior in the 654 patients who received capecitabine-based regimens compared with the 664 patients treated with fluorouracil-based combinations, but there was no significant difference with respect to PFS between treatment groups[22].

An incremental improvement in OS was also suggested in the V325 trial[23]. This randomized multinational phase III trial evaluated the combination of docetaxel, cisplatin and fluorouracil (DCF) in patients with untreated advanced gastric cancer. Four hundred and forty-five patients were randomized to receive either DCF every 3 wk or cisplatin and fluorouracil (CF). Time-to-progression (TTP) for patients who received DCF was significantly longer than that of patients treated with CF (5.6 mo vs 3.7 mo; HR = 1.47; 95%CI: 1.19-1.82; P < 0.001; risk reduction 32%). Moreover, the median OS time was significantly worse for patients who received DCF compared with patients who received CF (9.2 mo vs 8.6 mo; HR = 1.29; 95%CI: 1.0-1.6; P = 0.02; risk reduction 23%)[23]. High toxicity rates were reported in this trial, especially involving febrile neutropenia, which was more common in patients who received DCF (29% vs 12%); the death rate in the study was 10.4% for patients who received the DCF regimen and 9.4% for patients treated with the CF arm.

As the DCF regimen resulted in high toxicity profiles, several clinical trials have tested modifications of the DCF regimen with the aim of reducing toxicity and improving tolerability[24-26]. The recent GATE phase II study carried out by Van Cutsem et al[27] showed that the combination of docetaxel, oxaliplatin and fluorouracil (DOF) had a better RR, TTP and median OS time (47%, 7.7 and 15 mo, respectively) compared with the combination docetaxel and oxaliplatin (23%, 4.5 and 9 mo, respectively) and docetaxel, oxaliplatin and capecitabine (26%, 5.6 and 11 mo, respectively) in patients with previously untreated advanced gastric cancer. Furthermore, the DOF regimen produced a better safety profile compared to other regimens.

Al-Batran et al[28], in their phase III trial, reported that median PFS showed a tendency to be better in patients who received a combination of fluorouracil, leucovorin and oxaliplatin (FLO) than that of patients who received a combination of fluorouracil, leucovorin and cisplatin (FLP) (5.8 mo vs 3.9 mo, P = 0.077). On the other hand, the median OS time did not differ significantly (10.7 mo vs 8.8 mo, P > 0.05) between the two groups. Thereafter, the authors performed a post hoc subgroup analysis in patients older than 65 years, and the FLO regimen produced a significantly superior RR (41.3% vs 16.7%), median PFS (6.0 mo vs 3.1 mo, P = 0.029) and time-to-treatment failure (5.4 mo vs 2.4 mo, P < 0.001), and an improved median OS (13.9 mo vs 7.2 mo, P = 0.08) compared with the FLP regimen. In addition, there was significantly less toxicity with FLO in this trial.

The comparison of irinotecan-containing versus non-irinotecan-containing regimens (mainly fluorouracil-cisplatin) showed a nonstatistically significant trend toward better survival with irinotecan (HR for death: 0.86, 95%CI: 0.73-1.02) in the previous meta-analysis[5]. Furthermore, irinotecan-based regimens have also been tested comprehensively and found to be active in single arm and randomized clinical trials[29-34]. In a phase III randomized trial performed by Dank et al[32], irinotecan in combination with fluorouracil and folinic acid (IF) was compared with the combination of cisplatin and infusional fluorouracil (CF) in patients with advanced adenocarcinoma of esophagogastric cancer. The results of this trial showed that the IF regimen resulted in improved TTP, but not OS, compared with CF. However, IF was better with respect to toxic deaths, discontinuation for toxicity, severe neutropenia, thrombocytopenia and stomatitis. The authors concluded that IF may provide an acceptable, platinum-free front-line treatment alternative for metastatic gastric cancer. Another phase II trial revealed that the combination of capecitabine and irinotecan had a similar ORR (37.7% vs 42%, respectively) and median PFS (4.2 mo vs 4.8 mo, respectively), but a trend towards better median OS (10.2 mo vs 7.9 mo, respectively) than the capecitabine-cisplatin regimen[34].

S-1 is an oral fluoropyrimidine that includes three different agents: tegafur, gimeracil (5-chloro-2,4 dihydropyridine) and oteracil (potassium oxonate). This novel oral agent has shown promising results in patients with advanced gastric cancer, but the majority of data supporting the use of S-1 for advanced gastric cancer are from studies including Asian patients[5,35]. The randomized phase III SPIRITS trial in 298 patients with advanced gastric cancer showed that both the median PFS (6.0 mo vs 4.0 mo) and median OS (13 mo vs 11 mo, P = 0.04) for patients who received combined S1 plus cisplatin were significantly better than those of patients who received S-1 alone in an Asian population. On the other hand, the grade 3 and 4 toxicity rates were significantly higher[36].

Tegafur is metabolized differently in Western and Asian populations, and as a result, the maximally tolerated dose also differs. Therefore, Western experience with combined S-1 plus cisplatin for advanced gastric cancer is limited, but also promising[37,38]. In their phase III FLAGS trial including 1053 patients with advanced esophagogastric adenocarcinoma, Ajani et al[39] randomized patients to cisplatin plus either 5-FU or S-1. They showed that the median OS was not significantly inferior with S-1/cisplatin compared to the CF regimen (8.6 mo vs 7.9 mo). In addition, S-1/cisplatin was associated with a more favorable side effect profile and fewer treatment-related deaths[39]. It is thought that the lower cisplatin dose intensity in the S-1/cisplatin arm (75 mg/m² vs 100 mg/m²) may have contributed to the survival and toxicity results. Despite the results of the FLAGS trial, future studies are needed to confirm the activity of S-1 in Western populations. Recently, updated results of the phase III START trial presented at the 2012 ESMO meeting showed that among the 635 patients with metastatic gastric cancer analysed, the median OS time was 12.48 mo when S-1 was combined with docetaxel compared to 10.78 mo in patients who received S-1 alone. Neutropenia was the most frequent adverse event in the docetaxel/S-1 arm, with one death occurring from grade 4 thrombocytopenia[40]. Selected phase III clinical trials of current chemotherapy regimens for patients with advanced gastric cancer in the first-line setting are summarized in Table 1.

Table 1.

Selected phase III clinical trials of current chemotherapy regimens for patients with advanced gastric cancer in the first-line setting

Ref.	Regimen	No. of patients	Response rate	Median PFS/TTP and OS (mo)
Van Cutsem et al[23]	DCF vs CF	445	37% vs 25%	TTP, 5.6 vs 3.7; OS, 9.2 vs 8.6
Cunningham et al[20]	EOF vs EOX vs ECX vs ECF	1002	42.4% vs 47.9% vs 46.4% vs 40.7%	PFS, 6.5 vs 7.0 vs 6.7 vs 6.2;OS, 9.3 vs 11.2 vs 9.9 vs 9.9
Kang et al[21]	CX vs CF	316	41% vs 29%	PFS, 5.6 vs 5.0; OS, 10.5 vs 9.3
Al-Batran et al[24]	FLC vs FLO	220	34.8% vs 24.5%	PFS, 5.8 vs 3.9; OS, 10.7 vs 8.8
Dank et al[32]	IF vs CF	333	31.8% vs 25.8%	TTP, 5.0 vs 4.2; OS, 9.0 vs 8.7
Koizumi et al[36]	CS vs S	305	54% vs 31%	PFS, 6.0 vs 4.0; OS, 13 vs 11
Ajani et al[39]	CS vs CF	1053	29.1% vs 31.9%	PFS, 4.8 vs 5.5; OS, 8.6 vs 7.9
Yoshida et al[40]	DS vs S	635	38.8% vs 26.8%	PFS, 5.29 vs 4.17; OS, 12.48 vs 10.78

DCF: Docetaxel, cisplatin and fluorouracil; CF: Cisplatin and fluorouracil; EOF: Epirubicin, oxaliplatin and fluorouracil; EOX: Epirubicin, oxaliplatin and capecitabine; ECX: Epirubicin, cisplatin and capecitabine; ECF: Epirubicin, cisplatin and fluorouracil; CX: Cisplatin and capecitabine; FLO: Fluorouracil, leucovorin and oxaliplatin; FLC: Fluorouracil, leucovorin and cisplatin; IF: Irinotecan and cisplatin; CS: Cisplatin and S-1; S: S-1; DS: Docetaxel and S-1; PFS: Progression-free survival; OS: Overall survival; TTP: Time-to progression.

Targeted therapy

Anti-HER2 agents: EGFR overexpression has been found in different cancer types including gastric cancer and is believed to be associated with tumor invasion, high grade histology, and poor prognosis[41]. The EGFR family comprises four members, of which epidermal growth factor receptor 1 (EGFR1) and HER2 (EGFR-II) have been comprehensively investigated as targets for drugs in patients with metastatic gastric cancer. HER2 amplification and HER2 overexpression increase from 12% to 27% and 9% to 23%, respectively, in esophagogastric cancer, a similar percentage to that seen in breast cancer[42-46]. HER2 positivity is reported to be more frequent in patients with intestinal histology (34%) than in those with diffuse-type histology (6%), as well as in gastroesophageal junction (32%) compared to gastric cancer (18%)[46].

The trastuzumab for gastric cancer (ToGA) trial, a pivotal randomized, prospective, multicenter, phase III clinical trial, evaluated the efficacy of anti-HER2 trastuzumab in combination with chemotherapy in patients with HER-2-positive advanced, mostly metastatic, gastric cancer[8]. After screening 3807 patients, 584 eligible HER2-positive patients according to immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), were randomized to trastuzumab plus chemotherapy (fluorouracil or capecitabine and cisplatin) or chemotherapy alone. The study treatment was administered every 3 wk for six cycles, and trastuzumab was continued every 3 wk until disease progression, unacceptable toxicity, or withdrawal of consent. Crossover to trastuzumab at disease progression was not permitted. The ORR was significantly higher in the trastuzumab-containing arm (47% vs 35%). At a median follow-up of 17.1 to 18.6 mo, the median OS was significantly longer in the trastuzumab-containing arm (13.8 mo vs 11.1 mo, HR = 0.74, 95%CI: 0.60-0.91, P = 0.0046). There was no significant difference in rates of any adverse event, and cardiotoxicity was equally rare in both arms (an asymptomatic decrease in the left ventricular ejection fraction, 5% vs 1%). Grade 3 to 4 heart failure was reported in one and two patients, respectively. In subgroup analysis, trastuzumab was most effective in prolonging survival in the subgroup of patients with IHC 3+ tumors (HR = 0.66, 95%CI: 0.50-0.87), less effective in patients with IHC 2+ tumors (HR = 0.78, 95%CI: 0.55-1.10), and ineffective in those with HER2 gene-amplified, but non protein-expressing (IHC 0 or 1+) tumors[8]. In the light of these findings, trastuzumab in combination with chemotherapy was approved to be a new standard of care for patients with HER2-positive advanced esophagogastric adenocarcinoma. Therefore, all patients with metastatic gastroesophageal adenocarcinoma should be evaluated in terms of HER2 status.

Lapatinib, an orally active tyrosine kinase inhibitor, has double targeted inhibition of both EGFR1 and HER2. The results of the randomized, phase III TyTAN trial were presented at the 2013 ASCO Gastrointestinal Cancer Symposium[47]. The addition of lapatinib produced no significant benefit with respect to PFS (5.4 mo vs 4.4 mo) or OS (11.0 mo vs 8.9 mo) in the intent to treat population of advanced gastric cancer. On the other hand, there was significant benefit in both PFS (5.6 mo vs 4.2 mo) and OS (14.0 mo vs 7.6 mo) for patients with IHC 3+. The preliminary results of the TRIO-013/LOGiC trial were presented at the 2013 ASCO annual meeting[48]. In 545 patients with advanced gastroesophageal cancer, the benefit derived from the addition of lapatinib to chemotherapy was tested in first-line treatment. The combination of lapatinib and capecitabine/oxaliplatin did not significantly improve the median OS (12.2 mo vs 10.5 mo, HR = 0.91, 95%CI: 0.73-1.12) compared with chemotherapy alone. No correlation between intensity of staining for HER2 by IHC and outcomes was found. However, in subgroup analysis, Asian patients (median OS, 16.5 mo vs 10.9 mo, HR 0.68) and those under age 60 (median OS, 12.9 mo vs 9 mo, HR 0.69) seemed to benefit from lapatinib. The addition of lapatinib was associated with increased toxicity.

Anti-EGFR1 agents: EGFR is a transmembrane tyrosine kinase receptor involved in the proliferation and survival of cancer cells. EGFR overexpression is associated with advanced stages and poor prognosis in gastric cancer patients[49], and EGFR expression has been reported in 60% of gastric cancer patients[50,51]. Anti-EGFR monoclonal antibodies bind to the extracellular domain of EGFR in its inactive state; they compete for receptor binding by occluding the ligand-binding region, and thereby block ligand-induced EGFR tyrosine kinase activation. Cetuximab is a chimeric monoclonal antibody targeting EGFR and it’s inhibition prevents tumor cell growth, angiogenesis, invasion, and metastasis, and induces apoptosis. The efficacy of this anti-EGFR monoclonal antibody in combination with chemotherapy has been reported in several phase II clinical trials[52-54]. On the other hand, the benefit derived from the addition of cetuximab to chemotherapy could not be confirmed in a phase III trial comparing chemotherapy alone in the first-line setting. In a recent phase III (EXPAND) trial, 904 patients with advanced gastroesophageal adenocarcinoma were randomized to capecitabine and cisplatin with or without cetuximab[55]. The median PFS for patients who received the cetuximab-chemotherapy regimen was 4.4 mo compared with 5.6 mo for patients treated with chemotherapy alone (HR = 1.09, 95%CI: 0.92-1.29, P = 0.32). Moreover, the cetuximab arm resulted in more grade 3-4 adverse events (88% vs 77%). Similar results were reported in another phase III trial of panitumumab. The REAL3 trial evaluated the benefit of the addition of panitumumab to chemotherapy in 553 patients with previously untreated advanced unselected esophagogastric cancer[56]. Patients were randomly allocated (1:1) to receive up to eight 21-day cycles of EOX or modified EOX (with a reduction in oxaliplatin to 100 mg/m² and capecitabine to 1000 mg/m² per day) plus panitumumab. The authors indicated that the addition of panitumumab was associated with a similar response rate but a significantly worse OS (median 8.8 mo vs 11.3 mo). In the light of these results, the addition of an anti-EGFR antibody to chemotherapy cannot be considered a standard approach for patients with advanced esophagogastric adenocarcinoma.

Small molecule tyrosine kinase inhibitors (TKI) have also been tested for advanced esophagogastric cancer in phase II trials. The activity of erlotinib was suggested in patients with unresectable or metastatic adenocarcinoma originating in the EGJ or stomach in first-line treatment in the SWOG trial[57]. Six of the 70 patients obtained an ORR (9%, one complete), all of whom had EGJ tumors. The predictive significance of EGFR expression with respect to clinical outcome was not shown.

Anti-VEGF/VEGFR agents: VEGF is overexpressed by up to 60% and its overexpression correlates with an advanced stage, higher risk of recurrence and tumor aggressiveness and is an indicator for poor prognosis[58-60]. Anti-VEGF agents have recently been developed and comprise monoclonal antibodies and TKIs.

Bevacizumab is a humanized monoclonal antibody against VEGF, which is an endothelial cell-specific mitogen and the most potent driver of angiogenesis in tumorigenesis as it increases microvascular permeability. The inhibition of VEGF-A prevents pathological angiogenesis by inhibiting its interaction with VEGFR-2. This inhibition by bevacizumab has had a positive impact on patient outcomes in several malignancies including colorectal, lung, and renal cell carcinoma, as well as recurrent glioblastoma[50]. Several phase II trials produced promising results when using bevacizumab in combination with different chemotherapeutic agents in treatment-naive patients with locally advanced or metastatic gastric cancer[61-63].

The recently published AVAGAST, phase III trial evaluated the benefit of bevasizumab in combination with cisplatin and capecitabine as a first-line therapy in 774 patients with advanced gastric carcinoma[64]. Patients received capecitabine and cisplatin (XP) in combination with either bevacizumab or a placebo. AVAGAST did not reach its primary endpoint with no significant difference in OS (12.1 mo in bevacizumab-arm vs 10.1 mo in placebo-chemotherapy arm; HR = 0.87, P = 0.1002); however, both PFS (6.7 mo vs 5.3 mo, HR = 0.80, P = 0.0037) and ORR (46.0% vs 37.4%, P = 0.0315) improved significantly in the bevacizumab arm. In an unplanned subgroup analysis, OS for the pan-American subgroup was 6.8 mo for placebo vs 11.5 mo for bevacizumab (HR = 0.63). For European and Asian-Pacific subgroups, the OS was 8.6 vs 11.1 mo (HR = 0.85), and 12.1 mo vs 13.9 mo (HR = 0.97), respectively, with all results favoring bevacizumab. It was not clear whether the discrepancy came from genetic differences in ethnicity or from differences in treatment patterns, but Asian patients had fewer EGJ primaries, a lower frequency of liver metastases, and received second-line chemotherapy more often than did pan-American patients. Similar negative results for the addition of bevacizumab to XP in Asian patients with advanced gastric cancer were also presented at the 2012 ASCO Gastrointestinal Cancers Symposium in a preliminary report of the AVATAR study[65].

Ramucirumab (IMC-1121B) is a fully humanized monoclonal antibody aganist VEGFR-2[66]. Several phase II and phase III trials are currently underway or planned including ramucirumab plus chemotherapy vs chemotherapy plus placebo or best supportive care in both the first- and second-line setting (NCT00917384, NCT01170663, NCT01246960).

Apatinib is a TKI agent targeting VEGFR-2 (VEGFR), and its anti-angiogenesis effect has been demonstrated in preclinical tests. A recently published phase II trial tested apatinib in patients with chemotherapy-refractory advanced metastatic gastric cancer. The median OS times were 2.50, 4.83 and 4.27 mo, in the placebo, apatinib 850 mg, once and apatinib 450 mg, twice daily arms respectively, and the median PFS times were 1.40, 3.67, and 3.20 mo respectively. The differences between the apatinib and placebo groups were statistically significant for both PFS (P < 0.001) and OS (P < 0.001 and 0.0017)[67]. Toxicities were tolerable or manageable. A phase III trial evaluating apatinib vs placebo for patients with advanced gastric cancer in the third-line setting is ongoing (NCT01512745).

Sunitinib and sorafenib are multi-target TKIs that also inhibit the VEGF receptor, as well as other TKs. Early reported phase II trials have indicated mixed results. In a phase II trial of sunitinib monotherapy for second-line treatment of metastatic gastric cancer, a partial response was obtained in only two of 78 patients, while another 25 showed a best response of stable disease ≥ 6 wk. Median PFS and OS were 2.3 and 6.8 mo, respectively[68]. Another open-label randomized phase II trial for the second-line treatment of 107 patients with unresectable or metastatic gastric cancer evaluated the combination of sunitinib plus docetaxel vs docetaxel monotherapy[69]. Although the sunitinib arm was associated with a significantly higher ORR, there was no significant difference in either TTP or OS. The combination of sorafenib plus docetaxel and cisplatin was tested in a phase II trial in the first-line setting for patients with locally advanced or metastatic esophagogastric adenocarcinoma[70]. This trial demonstrated that the ORR was 41% and the median OS was 13.6 mo; the major grade 3 or 4 toxicity was neutropenia. However, these results will need to be further evaluated in a randomized trial in comparison with historical data on docetaxel plus cisplatin alone. There are a number of studies of locally advanced or metastatic gastroesophageal adenocarcinoma patients currently underway or planned for sunitinib and sorafenib combined with capecitabine-cisplatin or oxaliplatin-capecitabine, S-1-cisplatin, the FOLFIRI regimen, and new agents (NCT00555620, NCT00524186, NCT01020630). Table 2 shows selected phase III clinical trials of targeted therapies in patients with advanced gastric cancer.

Table 2.

Phase-III trials regarding targeted therapies in advanced gastric cancer

Ref.	Study/setting	Treatment	No. of patients	Response rate	Median PFS/TTP and OS (mo)
Anti-HER2 agents
Bang et al[8]	ToGA/first-line	Trastuzumab + CX/CF vs CX/CF	584	47% vs 35%	PFS, 6.7 vs 5.5; OS, 13.8 vs 11.1
Bang et al[47]	TyTAN/second-line	Lapatinib + P vs P	430	NA	PFS, 5.4 vs 4.4; OS, 11.0 vs 8.9
Hecht et al[48]	TRIO-013/LOGiC/first-line	Lapatinib + CAPOX vs CAPOX	545	53% vs 40%	PFS, 6.0 vs 5.4; OS, 12.2 vs 10.5
Anti EGFR1 agents
Lordick et al[55]	EXPAND/first-line	Cetuximab + CX vs CX	904	29% vs 30%	PFS, 4.4 vs 5.6; OS, 9.4 vs 10.7
Waddell et al[56]	REAL-3/first-line	Panitumumab + mEOX vs EOX	553	42% vs 46%	PFS, 6.0 vs 7.4; OS, 8.8 vs 11.3
Anti-VEGF agents
Ohtsu et al[64]	AVAGAST/first-line	Bevacizumab + CX vs placebo + CX	774	46% vs 37.4%	PFS, 6.7 vs 5.3; OS, 12.1 vs 10.1
mTOR inhibitors
Ohtsu et al[76]	GRANITE-1/first-line	Everolimus + BSC vs placebo + BSC	656	4.5% vs 2.1%	PFS, 1.7 vs 1.4; OS, 5.4 vs 4.3

HER2: Human epidermal growth factor receptor 2; EGFR1: Epidermal growth factor receptor 1; VEGF: Vascular endothelial growth factor; mTOR: Mammalian target of rapamycin; CX: Cisplatin and capecitabine; CF: Cisplatin and fluorouracil; P: Paclitaxel; CAPOX: Capecitabine and oxaliplatin; EOX: Epirubicin, oxaliplatin and capecitabine; mEOX: Modified EOX; BSC: Best supportive care; PFS: Progression-free survival; TTP: Time-to progression; OS: Overall survival; NA: Not applicable.

Other targeted agents: Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that integrates multiple signals from growth factors and hormones and plays a central role in the control of cell survival, hyperplasia, apoptosis, and other important physiological functions critical to tumorigenesis and cancer development, and is thus a potential target of anti-cancer therapy[71]. The first mTOR targeting agent was everolimus, an oral mTOR serine/threonine kinase inhibitor approved for the treatment of renal cell carcinoma, breast cancer, and progressive neuroendocrine tumors of pancreatic origin[72-74]. A phase II study performed by Doi et al[75], in 53 patients with previously treated metastatic gastric cancer, reported that the median PFS and OS times were 2.7 and 10.1 mo, respectively, with good tolerability. A subsequent phase III GRANITE-1 trial evaluated everolimus or BSC plus placebo in 656 previously treated advanced gastric cancer patients and the results of this trial showed insignificant benefit for the median OS (5.39 mo) in the everolimus arm when compared to the placebo arm (4.3 mo, P = 0.1244). On the other hand, promising results regarding PFS with everolimus treatment were reported in this study. The median PFS time was 1.68 mo in patients who received everolimus compared with patients treated with placebo (1.41 mo, HR = 0.68, P < 0.0001)[76]. There are currently several ongoing phase II and III studies in metastatic gastroesophageal adenocarcinoma patients comparing everolimus combined with paclitaxel, 5-FU, cisplatin, leucovorin and capecitabine (NCT01248403, NCT00632268, NCT01099527).

c-MET (mesenchymal-epithelial transition factor) is an oncogene encoding membrane TK receptor, and binding of hepatocyte growth factor (HGF), its ligand, to the receptor TK MET is implicated in the malignant process of multiple cancers, making disruption of this interaction a promising therapeutic strategy. MET expression or amplification has been found to be associated with poor prognosis in gastric cancer[77,78]. Onartuzumab is a humanized, monovalent (one-armed) monoclonal antibody against the MET receptor and blocks HGF binding to MET. The efficacy and safety of onartuzumab in combination with mFOLFOX6 in patients with metastatic HER2-negative gastroesophageal adenocarcinoma is currently being evaluated in phase II and III trials (NCT01590719, NCT01662869). Rilotumumab is another human monoclonal antibody (IgG2) against HGF that blocks binding of HGF to its receptor MET, inhibiting HGF/MET-driven activities in cells. A phase II, double-blind, randomized study evaluated the efficacy and safety of rilotumumab with ECX regimen in patients with previously untreated metastatic gastroesophageal adenocarcinoma. The primary results of this study showed that the primary endpoint of PFS showed a tendency for a better outcome with rilotumumab plus ECX. The addition of rilotumumab to chemotherapy improved the median PFS from 4.2 to 5.6 mo (HR = 0.64). The secondary endpoint of OS also trended in favor of rilotumumab, with an improved median OS from 8.9 to 11.1 mo (HR = 0.73). The most common adverse events seen in the rilotumumab plus ECX arms were peripheral edema, neutropenia, anemia, thrombocytopenia and deep vein thrombosis. An exploratory analysis according to the MET protein expression level was presented at the 2012 ASCO annual meeting[79]. The addition of rilotumumab to ECX chemotherapy in patients with gastric tumors with high MET expression improved the median OS from 5.7 to 11.1 mo (HR = 0.29, P = 0.012). Conversely, in patients with gastric tumors with low MET expression, the addition of rilotumumab to chemotherapy was associated with a trend towards unfavorable OS (HR = 1.84). These results have led to a phase III study to confirm the efficacy of rilotumumab in advanced esophagogastric cancer with high MET expression. This study is currently ongoing (RILOMET-1 trial, NCT01697072).

According to pre-clinical studies, histone deacetylase inhibitors (HDAC) have been found to be potential therapeutic targets in gastric cancer[80]. Vorinostat is a novel targeted agent that prevents tumor cell proliferation, survival and angiogenesis through histone deacetylase inhibition. Phase I/II studies comparing the effect of vorinostat with that of standard chemotherapy regimens in patients with advanced gastric cancer are underway (NCT01045538 and NCT00537121).

Second-line chemotherapy

Despite the improvement in survival of patients with metastatic gastric cancer, most patients develop progression of disease after first-line chemotherapy. Some patients with gastric cancer after failure of the first-line regimen are treated with second-line chemotherapy, but there was no standard second-line option until the positive results of recent phase III trials[81]. In a Korean trial 202 patients with advanced gastric cancer who had received one or two prior chemotherapy regimens involving both a fluoropyrimidine and a platinum agent, and with a performance status (PS) of 0 or 1, were randomly assigned to either salvage chemotherapy (docetaxel 60 mg/m² every 3 wk or irinotecan 150 mg/m² every 2 wk) or best supportive care in a 2:1 fashion[82]. The authors showed that second-line chemotherapy was associated with a significant improvement in median OS (5.3 mo) versus BSC (3.8 mo) (HR = 0.657, P = 0.007), and patients were also significantly more likely to receive further salvage chemotherapy. There was no difference in median OS between docetaxel and irinotecan (5.2 mo vs 6.5 mo, P = 0.116).

In a smaller randomized, AIO trial carried out by Thuss-Patience et al[83], 40 patients with tumor progression after first-line chemotherapy and a PS of 0-2 were randomized to BSC or single-agent irinotecan. The median OS was significantly longer for patients treated with irinotecan chemotherapy than that of patients who received BSC (4 mo vs 2.4 mo, HR = 0.48, P = 0.012).

Similarly, the phase III COUGAR-02 trial showed a modest survival benefit for single-agent docetaxel (75 mg/m² every 3 wk) in 168 patients who progressed within 6 mo of a platinum/fluoropyrimidine chemotherapy regimen. A preliminary report of this trial was presented at the 2013 ASCO annual meeting and the addition of docetaxel to BSC was associated with few ORR (7%), stable disease in 46% and a modest but statistically significant prolongation of median OS (5.2 mo vs 3.6 mo)[84]. A high rate of grade 4 toxicity was noted in the docetaxel arm, but symptom scores for pain were significantly better.

A meta-analysis of these trials was recently published[81]. The authors indicated that a significant reduction in the risk of death (HR = 0.64, P < 0.0001) was found with second-line chemotherapy. In addition, subgroup analysis showed a significant reduction in the risk of death with both irinotecan (HR = 0.55, P = 0.0004) and docetaxel (HR = 0.71, P = 0.004). In conclusion, the authors reported evidence to support the efficacy of second-line chemotherapy in the treatment of metastatic gastric cancer. In the light of these findings, although not all patients may be eligible for second-line therapy, it should be considered an option in appropriate patients.

A results of randomized, phase III, TCOG GI-0801 trial was presented at the 2013 ASCO Gastrointestinal Cancers Symposium and median PFS for irinotecan plus cisplatin (4.17 mo) was significantly better than irinotecan alone (3.03 mo; P = 0.0324) in patients with previously treated with S-1-based chemotherapy for advanced gastric cancer[85]. No significant differences were detected in the TTF and RR (TTF, 3.4 mo vs 2.9 mo; RR; 21.9% vs 16.4% with irinotecan plus cisplatin and irinotecan alone, respectively). OS was immature. Related adverse events were comparable with irinotecan plus cisplatin and irinotecan. The authors concluded that irinotecan in combination with cisplatin has promising efficacy for the second-line chemotherapy compared with single agent irinotecan for metastatic gastric cancer. Recent phase III clinical trials of second-line chemotherapy regimens for patients with advanced gastric cancer after failure of the first-line regimen are described in Table 3.

Table 3.

Second-line chemotherapy trials in patients with advanced gastric cancer

Ref.	Regimen	No. of patients	Response rate	Median PFS/TTP and OS (mo)
Kang et al[82]	Docetaxel or irinotecan + BSC vs BSC	202	-	TTP, NA; OS, 5.3 vs 3.8
Thuss-Patience et al[83]	Irinotecan vs BSC	40	44% vs 5%	PFS, 2.6 vs NA; OS, 4.0 vs 2.4
Ford et al[84]	Docetaxel + BSC vs BSC	168	7% vs NA	PFS, 5.6 vs 5.0; OS, 5.2 vs 3.6
Shimada et al[85]	Irinotecan + cisplatin vs irinotecan	130	21.9% vs 16.4%	PFS, 4.17 vs 3.03; OS, NA

BSC: Best supportive care; NA: Not applicable; PFS: Progression-free survival; OS: Overall survival; TTP: Time-to progression.

CONCLUSION

Recent trials of multiple agent chemotherapy regimens have demonstrated positive results in terms of improved survival; however, the prognosis of patients with metastatic gastric cancer remains poor and responses to first-line chemotherapy are modest and heterogeneous. Therefore, in patients with refractory gastric cancer, although not all patients may be eligible, second-line chemotherapy should be considered an option in appropriate patients in the light of recent phase III trials and meta-analyses. In order to improve the results of currently available treatments, clinical investigations of targeted agents have recently been conducted. Agents targeting EGFR1 and HER2 have been widely tested. The addition of trastuzumab to cisplatin/fluoropyrimidine-based chemotherapy significantly improved survival in patients with HER2-positive metastatic gastric cancer, which is now the new standard of care by recent ToGA trial. However, this benefit is limited to only approximately 20% of patients with metastatic gastric cancer. Therefore, there remains a critical need for both the development of more effective agents. Other clinical trials of agents targeting VEGF, mTOR, and other biological pathways, have shown marginally positive results. However, future studies are needed to confirm the benefit of adding these targeted agents to chemotherapy and for the detection of novel, molecular, predictive factors and therapeutic targets in order to identify better and optimal treatment modalities for metastatic gastric cancer.