European Journal of Cancer (2014) 50, 1247– 1258

Available at www.sciencedirect.com

ScienceDirect journal homepage: www.ejcancer.com

Review

Targeted therapies in gastroesophageal cancer Stefan Kasper a, Martin Schuler a,b,⇑ a b

Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany German Cancer Consortium (DKTK), Heidelberg, Germany

Available online 1 February 2014

KEYWORDS Oesophagus Gastroesophageal Junction

Abstract Gastroesophageal cancers comprising gastric cancer (GC), and cancers of the distal oesophagus and gastroesophageal junction (GEJ) are a global health threat. In Western populations the incidence of GC is declining which has been attributed to effective strategies of eradicating Helicobacter pylori infection. To the contrary, GEJ cancers are on the rise, with obesity and reflux disease being viewed as major risk factors. During the past decade perioperative chemotherapy, pre- or postoperative radio-chemotherapy, and, in Asian populations, adjuvant chemotherapy have been shown to improve the outcome of patients with advanced GC and GEJ cancers suited for surgery. Less progress has been made in the treatment of metastatic disease. The introduction of trastuzumab in combination with platinum/fluoropyrimidine-based chemotherapy for patients with HER2-positive disease has marked a turning point. Recently, several novel agents targeting growth factor receptors, angiogenic pathways, adhesion molecules and mediators of intracellular signal transduction have been clinically explored. Here we summarise the current status and future developments of molecularly targeted therapies in GC and GEJ cancer. Ó 2014 Elsevier Ltd. All rights reserved.

1. Introduction Cancers of the stomach (GC), the gastroesophageal junction (GEJ) and the distal oesophagus are the second ⇑ Corresponding author at: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany. Tel.: +49 201 7232000; fax: +49 201 7235924. E-mail address: [email protected] (M. Schuler).

Abbreviations: ACCORD; Action Clinique COordonne´es en cance´rologie Digestive; AVAGAST; Avastin in Gastric Cancer trial; CLEOPATRA; Clinical Evaluation of Pertuzumab and 0959-8049/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2014.01.009

leading cause of cancer deaths worldwide [24]. Incidence rates and tumour localisation vary considerably between geographical regions thus implying genetic and environmental factors in disease pathophysiology. Adenocarcinomas of the distal stomach are dominant in Eastern Europe, Asia and South America. In contrast, cancers located in the proximal stomach or at the GEJ are more prevalent in Western Europe and North America [36]. This is attributed to the high association of Helicobacter pylori infection and additional nutritional and socioeconomic risk factors with distal GC in less-developed countries [54]. In contrast, risk factors for adenocarcinomas of the GEJ and distal oesoph-

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Trastuzumab; DCR; Disease control rate; ERBB; Erythroblastic Leukemia Viral Oncogene; EXPAND; Erbitux in combination with Xeloda and cisPlatin in AdvaNceD esophagogastric cancer; FAST; First-Line Treatment of Patients with CLDN18.2-Positive adenocarcinomas of the stomach, the esophagus or the gastroesophageal junction; FOLFOX; Folinic acid, Fluorouracil, Oxaliplatin; FOLFIRI; folinic acid, fluorouracil, irinotecan; GRANITE; Gastric Anti-Tumor Trial with Everolimus; HER2; human epidermal growth factor receptor 2; Her-FLOT; herceptin-fluorouracil, leucovorin, oxaliplatin, taxol; JACOB; PERTUZUMAB, TRASTUZUMAB AND CHEMOTHERAPY IN HER2-POSITIVE METASTATIC GASTRIC OR GASTRO-OESOPHAGEAL JUNCTION CANCER; LOGIC; Lapatinib Optimization Study in ErbB2 (HER2) Positive Gastric Cancer; MAGIC; Medical Research Council Adjuvant Gastric Infusional Chemotherapy; MET; Mesenchymal Epithelial Transition Factor; NeoPECX; ECX+ Panitumumab vs. ECX Alone in Locally Advanced Gastric Cancer or Cancer of the Gastroesophageal Junction; RAD-PAC; rad001-paclitaxel; RAINBOW; Paclitaxel With or Without Ramucirumab in Metastatic Gastric Adenocarcinoma; REAL-3; Randomized EOC for Advanced and Locally Advanced Esophagogastric Cancer 3; REGARD; Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma; RILOMET; Rilotumumab with ECX as First-line Therapy in Advanced MET-Positive Gastric or Gastroesophageal Junction Adenocarcinoma; SAKK75/08; Schweizerische Arbeitsgemeinschaft fu¨r Klinische Krebsforschung; SCOPE; Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer; SWOG; Southwest Oncology Group; ToGA; Trastuzumab for Gastric Cancer; TORC; The mammalian Target of Rapamcin complex; TYTAN; http:// www.discoverymedicine.com/category/medical-specialties/ oncology/gynecological-cancer/breast-cancer/tykerb/

agus such as obesity and gastroesophageal reflux disease have become more prevalent in countries adopting a ‘Western’ life style. Accordingly, increased incidence rates have been observed in Western Europe and North Amercia [13]. 2. Current treatment options for localised, locally advanced and metastatic disease Surgical resection and, for very early stage cancers, endoscopic mucosal resection remains the standard of care for localised cancers of the upper gastrointestinal (GI) tract. However, the majority of patients are diagnosed with locally advanced tumours, regional lymph node involvement, or metastatic disease. Based on the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) and Action Clinique COordonne´es en cance´rologie Digestive (ACCORD) trials perioperative chemotherapy has been established as the standard of care for patients with locally advanced GEJ/GC scheduled for surgical resection including extensive (D2) lymphadenectomy in Western Europe [17,92]. Systemic treatments in the perioperative setting

are largely based on platinum and fluoropyrimidine combinations, or in three-drug regimens including taxanes or anthracyclines. Preoperative radio-chemotherapy is another option for patients with advanced adenocarcinomas of the GEJ and the distal oesophagus. In particular, patients achieving a complete pathological response following induction therapy appear to benefit from this approach [83,71]. In contrast, based on the Southwest Oncology Group (SWOG)/Intergroup 0116 trial postoperative radio-chemotherapy has evolved as a standard of care in North American centres. This study mainly enroled patients with less extensive (D0 or D1) lymph node dissection [69]. Adjuvant chemotherapies following gastrectomy and D2 lymph node dissection have improved disease-specific and overall survival in Asian patient populations [63]. The fourth-generation oral fluoropyrimidine S1 combines the 5-fluorouracil prodrug tegafur with two biochemical modulators preventing degradation of 5-fluorouracil and reducing gastrointestinal toxicity. S1 is effective as monotherapy in the adjuvant setting and in combination with platinum agents in advanced cancer stages. It is widely used by Asian oncologists [1,63]. Despite these progresses more than 50% of patients undergoing potentially curative multimodal therapy for locally advanced GEJ/GC ultimately relapse. Palliative chemotherapy prolongs survival and improves cancer-related symptoms in these patients as well as in patients with primary metastatic disease [86]. Adding taxanes to platin- and fluoropyrimidine-based regimens enhances objective remission and disease control rates. However, the median survival time of patients with metastatic disease stagnates approximately at 12 months [17,79,92]. Combination chemotherapy can be more manageable without compromising on efficacy when using oxaliplatin, the oral fluoropyrimidine capecitabine and split-dose regimens instead of cisplatin, 5-fluorouracil and standard scheduling [2,18]. Recent insights into the biology of gastrointestinal cancers have nominated potential targets for novel therapies and biomarkers for stratification of patient populations. Here we review the current status and imminent developments of molecularly targeted therapies in GEJ/GC. 3. Growth factor receptors as therapeutic targets Growth factor receptors are receptor tyrosine kinase proteins located in the plasma membrane. Their physiological function is to transduce signals derived from locally and systemically secreted ligands into the cell to promote proliferation and survival (Fig. 1). Ligand binding induces homo- or heterodimerisation of the receptor molecules, which facilitates autophosphorylation and activation of receptor tyrosine kinase. This leads to the recruitment of adaptor molecules to form signalling complexes at the inner cell membrane.

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Fig. 1. Schematic of a tumour cell with the mechanism of action of targeted therapies. TGF: transforming growth factor, EGF: epithelial growth factor, NK: natural killer cell, ADCC: antibody-dependent cellular cytotoxicity.

Growth factor receptor signalling can be deregulated in cancer by various mechanisms including aberrantly increased receptor expression, autocrine or paracrine ligand secretion and somatic mutations leading to structurally altered receptors with enhanced or constitutive activation. Two pharmacologic strategies have been devised to target growth factor receptors in GI cancers: (i) Monoclonal antibodies (moAbs) binding epitopes of the extracellular domain of growth factor receptors can prevent receptor-ligand interaction, receptor dimerisation and thus activation. In addition, moAbs of specific isotypes may trigger immunological mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), or recruitment of effector cells of the adaptive immune system, which lead to elimination of antibody-marked cells (Fig. 1). Antibodies or recombinant receptor-antibody fusion proteins may also be used to neutralise ligands such as the vascular endothelial growth factor (VEGF), which contribute to tumour progression. (ii) Small molecule compounds have been developed that enter the cell and interfere with the enzymatic function of receptor tyrosine kinases or intracellular signalling molecules to inhibit aberrant signal transduction. Most compounds that have been clinically explored inhibit the kinase activity by competing with adenosine triphosphate (ATP) binding in the catalytic domain of the respective kinase.

4. Targeting receptors of the ERBB family Both strategies have been devised to target receptors of the Erythroblastic Leukemia Viral Oncogene (ERRB) family, including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2)/ERBB2. The EGFR is highly expressed in up to 50% of gastroesophageal adenocarcinomas, which was associated with dismal outcome in patients with metastatic disease. In contrast to EGFR, HER2 is an ‘orphan receptor’ lacking a natural ligand. It unfolds its activity by heterodimerisation with other ERBB family receptors, such as EGFR and HER4. While HER2 overexpression in breast cancer clearly associates with more aggressive tumour biology and disease course [67], its prognostic value in GC is less clear. Highly recurrent somatic mutations leading to structural alterations of the EGFR have not been described in this disease [38,53]. Overexpression of the HER2/ERBB2 receptor is observed in 20–30% of GC, predominantly of the intestinal subtype, and GEJ cancers [35,74]. Due to intratumoural heterogeneity of receptor expression and divergent staining characteristics specific diagnostic skills are demanded from the pathologist to detect HER2-positive GC by immunohistochemistry. Ambiguous cases are thus validated by probing HER2 gene amplification using in situ hybridisation techniques [29].

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Table 1 Anti-epidermal growth factor receptor (EGFR) antibodies. References Indication

Study name

Agents

N

[41]

EXPAND phase III

Capecitabine/ cisplatin ± cetuximab

904 30 versus 29; p = 0.77

REAL-3 phase III

Epirubicine/oxaliplatin/ capecitabine (EOX) versus modified EOX (mEOX) + panitumumab Capecitabine/cisplatin/RT (50 Gy) ± cetuximab

553 46 versus 42; p = 0.42

[85]

[15]

Met gastric cancer (GC) and gastroesophageal junction (GEJ) Met GC and GEJ

Locally advanced AC and SCC oesophagus

SCOPE1 phase II/ III

Overall Progression-free survival response (PFS) [months] rate (ORR) [%]

258 n.a.

Overall survival (OS) [months]

4.4 versus 5.9; hazard ratio (HR) 1.09 [95% confidence interval (CI) 0.92–1.29; p = 0.32] 6.0 versus 7.4; HR 1.22 [95% CI 0.98–1.52; p = 0.068]

15.9 versus 21.6; HR 1.29 [95%CI 0.89–1.85; p = 0.18]

9.4 versus 10.7; HR 1.0 [95% CI 0.87–1.17; p = 0.95] 8.8 versus 11.3; HR1.37 [95% CI 1.07–1.76; p = 0.013] 22.1 versus 25.4; HR 1.53 [95%CI 1.03–2.27; p = 0.035]

AC: adenocarcinoma, EXPAND: Erbitux in combination with Xeloda and cisPlatin in AdvaNceD esophagogastric cancer, m: modified, REAL-3: Randomized EOC for Advanced and Locally Advanced Esophagogastric Cancer 3, RT: radiotherapy, SCC: squamous cell carcinoma, SCOPE1: Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer.

Table 2 Anti-HER2/ERBB2 antibodies. References

Indication

Study name

Agents

N

Overall response rate (ORR) [%]

Progression-free survival (PFS) [months]

Overall survival (OS) [months]

[4]

Met gastric cancer (GC) and gastroesophageal junction (GEJ); Her2/neu positive Met GC and GEJ Her2/neu IHC2+/ FISH+ or IHC3 Met GC and GEJ Her2/neu IHC2+/ FISH+ or IHC3 second-line Asian patients

ToGA phase III

Fluoropyrimidine/ cisplatin ± trastuzumab

594

47 versus 35; p = 0.002

LOGIC phase III

Capecitabine/ oxaliplatin ± lapatinib

545

53 versus 40

TYTAN phase III

Paclitaxel ± lapatinib

261

27 versus 9

6.7 versus 5.5; hazard ratio (HR) 0.71 [95% confidence interval (CI) 0.59–0.85; p = 0.0002] 6.4 versus 5.4; HR 0.86 [95% CI 0.71– 1.04; p = 0.10] 5.4 versus 4.4; HR 0.85; p = 0.2441

13.8 versus 11.1; HR 0.74 [95% CI 0.60–0.91; p = 0.005]; *16.0 versus 11.8; HR 0.65 [95% CI 0.51–0.83; p = 0.036] 12.2 versus 10.5; HR 0.91 [95% CI 0.73–1.12; p = 0.35] 11.0 versus 8.9; HR 0.84; p = 0.2088

[32]

[6]

FISH: fluorescence in situ hybridisation, IHC: immunohistochemistry, LOGIC: Lapatinib Optimization Study in ErbB2 (HER2) Positive Gastric Cancer, ToGA: Trastuzumab for Gastric Cancer, TYTAN: Tykerb with taxol in Asian ErbB2+ gastric cancer. * Explorative subgroup analysis Her2/neu IHC3+ and IHC2+/FISH+.

4.1. Antibodies targeting EGFR Cetuximab (chimeric immunoglobulin G (IgG1)) and panitumumab (human IgG2) were the first anti-EGFR moAbs approved for the treatment of metastatic colorectal cancer based on activity as single agents and in combination with chemotherapy [9,16,21,55,80,81]. It was found that patients with colorectal cancers harbouring somatic mutations of RAS oncogenes do not benefit from anti-EGFR antibody therapy [19,23]. Cetuximab is also approved for the treatment of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), either in combination with radiotherapy in locally advanced disease, or in combination with platinum-based chemotherapy [10,84].

Anti-EGFR moAbs have been extensively studied in patients with metastatic adenocarcinomas of the stomach and GEJ. Several phase I and phase II trials combining moAbs with chemotherapy revealed promising activity and acceptable toxicity profiles [31,36,40,43,44,52,57,58,60,78]. Based on these results two large phase III studies were conducted in patients with advanced GEJ/GC. The Erbitux in combination with Xeloda and cisPlatin in AdvaNceD esophagogastric cancer (EXPAND) trial evaluated the combination of cetuximab with capecitabine and cisplatin [41]. The addition of cetuximab provided no significant benefit in terms of progression-free survival (PFS), overall survival (OS) or overall response rate (ORR, Table 1). Similar results were obtained by the Randomized EOC for

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Advanced and Locally Advanced Esophagogastric Cancer 3 (REAL-3) study, which explored the addition of panitumumab to the EOX (epirubicin, oxaliplatin and capecitabine) chemotherapy regimen [85]. Based on toxicities observed in a prior dose-finding study [52] the chemotherapy doses in the panitumumab arm of REAL-3 had to be modified (mEOX), whereas the control arm received fully dosed chemotherapy. Interestingly, panitumumab combined with mEOX resulted in inferior PFS and OS as compared to EOX (Table 1). Based on these two trials anti-EGFR moAbs in combination with chemotherapy are not recommended for the treatment of patients with metastatic adenocarcinoma of the stomach or GEJ. Defining the role of anti-EGFR moAbs in preoperative radio-chemotherapy or perioperative chemotherapy of patients with locally advanced disease is subject to ongoing trials (NeoPECX ECX+ Panitumumab vs. ECX Alone in Locally Advanced Gastric Cancer or Cancer of the Gastroesophageal Junction, NCT01234324; SAKK75/08 Schweizerische Arbeitsgemeinschaft fu¨r Klinische Krebsforschung, NCT01107639). 4.2. Antibodies targeting HER2 The IgG1 moAbs trastuzumab and pertuzumab prevent heterodimerisation of the HER2/ERBB2 receptor, trigger receptor internalisation and mediate ADCC. Trastuzumab is approved as a single agent and in combination with chemotherapy and antihormonal therapy for the adjuvant and palliative treatment of HER2-positive breast cancer [28,68,70]. Against this background a phase III study, ToGA, was conducted to explore the addition of trastuzumab to cisplatin/fluoropyrimidinebased chemotherapy in the treatment of metastatic HER2-positive GEJ/GC [4]. The addition of trastuzumab significantly increased the ORR and prolonged PFS and OS (Table 2). In an explorative post hoc analysis the subgroup of patients with high (immunohistochemistry (IHC)3+) or intermediate HER2 expression (IHC2+) and gene amplification (fluorescence in situ hybridisation (FISH)+) benefited the most (Table 2). Accordingly, trastuzumab combined with platin/fluoropyrimidine-based chemotherapy has become the standard of care for metastatic, HER2-positive GEJ/GC. The role of trastuzumab in the perioperative therapy of locally advanced HER2-positive GEJ/GC is being explored in trials such as the Her-FLOT herceptin-fluorouracil, leucovorin, oxaliplatin, taxol study (NCT01472029). The moAb pertuzumab was developed to target a different epitope of the HER2/ERBB2 receptor than trastuzumab. Recently, pertuzumab was approved in combination with trastzumab and docetaxel for the first-line treatment of metastatic HER2-positive breast cancer based on the CLEOPATRA Clinical Evaluation of Pertuzumab and Trastuzumab study [7,8]. The ongoing JACOB PERTUZUMAB,

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TRASTUZUMAB AND CHEMOTHERAPY IN HER2-POSITIVE METASTATIC GASTRIC OR GASTRO-OESOPHAGEAL JUNCTION CANCER study (NCT01774786) explores the value of adding pertuzumab to trastuzumab and chemotherapy in metastatic HER2-positive GEJ/GC. 4.3. EGFR and HER2 tyrosine kinase inhibitors The EGFR tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib and the pan-ERBB TKI afatinib are highly effective and have been approved for treatment of patients with metastatic non-small-cell lung cancer (NSCLC) harbouring somatic mutations of the EGFR [46,61,65,93]. Erlotinib and gefinitib were studied in GEJ/GC as monotherapy or in combination with chemotherapy in several smaller phase I and phase II trials [20,24,26,75,77,87]. Some activity in terms of disease control was observed. However, these modest signals failed to trigger further clinical exploration in phase III studies. The dual EGFR/HER2 TKI lapatinib is approved in combination with capecitabine, trastuzumab or antihormonal agents for the treatment of patients with metastatic HER2-positive breast cancer. The LOGIC study investigated the addition of lapatinib to capecitabine and oxaliplatin (CapeOx) in the first-line treatment of patients with HER2-positive GEJ/GC. However, the primary end-point of this trial, prolongation of OS, was not met [33]. Also, the Tykerb with taxol in Asian ErbB2+ gastric cancer (TYTAN) trial exploring the addition of lapatinib to paclitaxel in second-line treatment of Asian patients with HER2-positive GEJ/GC failed to meet its primary end-point [6], Table 2). 5. Targeting MET (hepatocyte growth factor receptor) The Mesenchymal Epithelial Transition Factor (MET) receptor tyrosine kinase is physiologically expressed by stem cells. It is essential for embryonic development and wound healing. Hepatocyte growth factor (HGF), its natural ligand, is mainly secreted by mesenchymal cells. In experimental systems HGF/ MET signals mediate cell migration, invasion and angiogenesis. The former is associated with a particular phenotype termed epithelial-to-mesenchymal transition (EMT). Aberrant MET expression and signalling has been observed in several cancers including papillary renal cell carcinoma, non-small-cell lung cancer, hepatocellular carcinoma and glioblastoma. This can be associated with MET gene amplification [56]. Approximately 10–15% of GC exhibit MET amplification, and high MET protein expression is found in up to 30% of cases. Both have been associated with poor prognosis [3,39,49]. Due to heterogenous staining patterns and a diverging results obtained with different antibodies

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Table 3 mTOR inhibitors. References Indication

Study name

Agents

[21]

Phase II

Everolimus

[51]

Second-line gastric cancer (GC) and gastroesophageal junction (GEJ) Second-line GC and GEJ

N

DCR [%]

53 56

Gastric Anti-Tumor Everolimus ± 650 43.3 Trial with Everolimus BSC (2:1) versus 22.0 (GRANITE-1) phase III

Progression-free survival (PFS) [months]

Overall survival (OS) [months]

2.7

10.1

1.7 versus 1.4; hazard ratio (HR) 5.4 versus 4.3; HR 0.66 [95% confidence interval 0.9 [95% CI 0.75– (CI) 0.56–0.78; p < 0.001] 1.08; p = 0.124]

BSC: best supportive care, GRANITE-1 Gastric Anti-Tumor Trial with Everolimus.

Fig. 2. Schematic of an endothelial cell with the mechanism of action of antiangiogenetic agents. VEGF: vascular endothelial growth factor, PlGF: placental growth factor, VEGFR: vascular endothelial growth factor receptor.

IHC analysis of MET expression requires an intense training of the pathologist, and interlaboratory standardisation and quality control. Restrospective analyes of tumour samples revealed a strong correlation of MET expression intensity with the efficacy of METtargeting antibodies underlining the essential role of accurate testing and pre-defined scoring systems for new stratified trials [12]. Several moAbs and small molecule inhibitors have been developed to target MET in GEJ/GC. Recently, two large randomised phase III studies have been initiated that combine anti-MET moAbs, onartuzumab and rilotumumab, with chemotherapy in treatment of patients with advanced GEJ/GC overexpressing MET. In the MetGastric (NCT01662869) trial 800 patients will be treated with a modified FOLFOX6 Folinic acid, Fluorouracil,

Oxaliplatin protocol with or without onartuzumab. In the RILOMET-1 Rilotumumab with ECX as First-line Therapy in Advanced MET-Positive Gastric or Gastroesophageal Junction Adenocarcinoma study (NCT01697072) 450 patients will receive epirubicin, cisplatin and capecitabine (ECX) with or without rilotumumab. Foretinib, a small molecule MET inhibitor, has shown only moderate single agent activity in pretreated GC patients [66]. Several early clinical trials of additional MET inhibitors either alone or in combination with chemotherapy are ongoing. It remains to be seen whether these agents will enter phase III trials in GEJ/GC. Definition and prospective validation of robust biomarkers indicative of clinical benefit from MET targeting will be critical for the success of antiMET moAbs and MET inhibitors.

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Table 4 Anti-angiogenetic drugs. References

Indication

Study name

Agents

N

ORR [%]

PFS [months]

OS [months]

[50]

Met GC and GEJ

AVAGAST Phase III

Capectiabine/ cisplatin ± bevacizumab

774

46 vs 37.4; p = 0.0315

[43]

2nd line GC and GEJ 2nd line GC and GEJ 2nd line GC and GEJ

Phase II

Sunitinib

51

3.9

6.7 vs 5.3; HR 0.80 [95% CI 0.68–0.93; p = 0.0037] 1.28

12.1 vs 10.1; HR 0.87 [95% CI 0.73–1.03; p = 0.1002]; 5.81

Phase II

Sunitinib

78

2.6

2.3

6.8

Phase II

FOLFIRI ± sorafenib

91

20 vs 29

Advanced GC and GEJ 2nd line GC and GEJ 2nd line GC and GEJ

Phase II

Docetaxel/ cisplatin + sorafenib

44

41

3.6 vs 3.3; HR 1.11; [95% CI 0.70–1.74; p = 0.66] 5.8

10.5 vs 9.0; HR 0.816; [95% CI 0.50–1.34; p = 0.21] 13.6

Phase II

Oxaliplatin + sorafenib

40

2.5

3

6.5

REGARD phase III

BSC ± ramucirumab (2:1)

355

49 vs 23 (DCR)

2nd line GC and GEJ

RAINBOW (Paclitaxel With or Without Ramucirumab in Metastatic Gastric Adenocarcinoma) phase III

Paclitaxel ± ramucirumab

665

28 vs 16; p = 0.0001

2.1 vs 1.3; HR 0.483; [95% CI 0.376–0.620; p < 0.0001] 4.40 vs 2.86; HR 0.635; [95% CI 0.536–0752; p < 0.0001]

5.2 vs 3.8; HR 0.776 [95% CI 0.603–0.998; p = 0.0473] 9.63 vs 7.36; HR 0.807 [95% CI 0.678–0.962; p = 0.0169]

[5]

[45]

[73]

[42]

[27]

[88]

AVAGAST: Avastin in Gastric Cancer Trial, BSC: best supportive care, DCR: disease control rate, FOLFIRI: folinic acid, fluorouracil, irinotecan.

6. Targeting the mammalian target of rapamycin complex The mammalian target of rapamycin (mTOR) is an intracellular serine/threonine kinase that acts in two protein complexes, TORC1 and TORC2 the mammalian target of rapamcin complex. mTOR is centrally involved in multiple pathways regulating cell survival, motility, metabolism and protein synthesis. TORC1 is engaged by the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway, which is frequently deregulated in cancer through aberrant growth factor receptor signalling, loss of the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) tumour suppressor, activating PIK3CA mutations and additional mechanisms. The rapalogue mTOR inhibitors temsirolimus and everolimus have been approved for the treatment of advanced renal cell carcinoma (RCC). Everolimus is also approved for treatment of pancreatic neuroendocrine tumours and hormone receptor-positive metastatic breast cancer in combination with an aromatase inhibitor [7,8,48,90,91]. Based on a phase II study in chemotherapy-pretreated patients with GC, which reported a disease control rate of 56%, Gastric Anti-Tumor Trial with Everolimus (GRANITE-1), a large, placebo-controlled phase III study of everolimus in second/third-line treatment of metastatic GEJ/GC, was conducted [51]. Although median PFS was prolonged and the disease control rate was

increased in the everolimus arm, the primary end-point, prolongation of OS, was not met (Table 3). The ability of everolimus to enhance the activity of second-line treatment with paclitaxel is currently investigated in another phase III trial, rad001-paclitaxel (RAD-PAC) (AIOSTO-0111, NCT01248403). 7. Targeting angiogenesis Aberrant tumour angiogenesis is considered an essential ‘hallmark’ of cancer [32]. During tumour progression an angiogenic switch is postulated to occur in response to hypoxia and nutrient depletion of the tumour. Formation of new blood vessels or sprouting from existing ones is particularly initiated by vascular endothelial growth factor (VEGF), which is secreted by tumour and stromal cells. High VEGF expression in tumour specimens correlated with poor prognosis in GC patients [14]. Two alternative pharmacological strategies have been devised to modulate angiogenic signalling in cancer therapy: (i) Depletion of angiogenic factors by moAbs such as the anti-VEGF antibody bevacizumab, or recombinant receptor-antibody fusion proteins such as aflibercept (Fig. 2). (ii) Targeting angiogenic receptors either with small molecule inhibitors of receptor tyrosine kinases such sunitinib or sorafenib or with moAbs such as the anti-VEGF receptor-2

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(VEGFR2) antibody ramucirumab (Fig. 2). While the role of bevacizumab and antiangiogenic ‘multi-TKI’ in GEJ/GC treatment is not conclusively determined, recent study reports suggest activity of ramucirumab in second-line treatment of metastatic GEJ/GC. 7.1. Anti-VEGF antibody therapy Bevacizumab is a humanised moAb targeting VEGF-A. It has been approved in combination with chemotherapy for the treatment of metastatic colorectal, ovarian and non-small-cell lung cancers, and in combination with interferon-alpha for treatment of metastatic renal cell cancer. It is still approved for combination therapy of metastatic breast cancer in Europe. The large randomised phase III study Avastin in Gastric Cancer Trial (AVAGAST) Avastin in Gastric Cancer Trial evaluated the addition of bevacizumab to palliative chemotherapy with capecitabine and cisplatin in patients with advanced GEJ/GC. Median PFS and ORR were improved in the bevacizumab arm (Table 4), but the primary end-point of the study, prolongation of OS, was not met [50]. Retrospective subgroup analyses suggested that patients with high serum levels of VEGF-A and low levels of neuropilin-1 benefitted the most. Also, a positive effect of bevacizumab was observed in patients treated at United States (US) centres [50,82]. An ongoing randomised phase III trial of the United Kingdom (UK) Medical Research Council in patients with locally advanced GEJ/GC explores the effect of adding bevacizumab to perioperative therapy with epirubicin, capecitabine and cisplatin (NCT00450203). In summary, there are no data to support the use of bevacizumab in palliative treatment of GEJ/GC, whereas its role in perioperative therapy remains to be defined. 7.2. Inhibitors of angiogenic receptor tyrosine kinases The ‘multi-TKI’ sunitinib inhibiting VEGFR1–3, platelet-derived growth factor receptor (PDGFR)-a and -b and additional kinases is approved for the treatment of patients with metastatic renal cell carcinomas (RCCs), gastrointestinal stromal tumours (GISTs) and pancreatic neuroendocrine tumours. Early clinical trials of sunitinib in patients with advanced GEJ/GC progressing after chemotherapy showed very moderate single agent activity [5,43,44]; Table 4). Subsequently, several phase II studies of sunitinib in combination with chemotherapy were conducted in unselected GEJ/GC patient populations. No substantial benefit but increased toxicities were observed [45,46]; Table 4). Sorafenib, another ‘multi-TKI’ inhibiting VEGFR2 and 3, PDGFR-b and other kinases, is approved for the treatment of advanced hepatocellular carcinoma and renal cell cancer. Phase II studies of sorafenib in combination with platin-based chemotherapy in first-

and second-line treatment of advanced GEJ/GC revealed promising results [42,73]; Table 4). Further evaluation in larger trials is required to define a role for sorafenib in GEJ/GC treatment. 7.3. Anti-VEGFR antibody therapy The anti-VEGFR2 moAb ramucirumab showed single agent activity and a favourable toxicity profile in a randomised phase III study (Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD)) conducted in pretreated patients with advanced GEJ/GC. Median PFS and OS with ramucirumab were comparable to results obtained in trials of second-line chemotherapy [27], Table 4). Another randomised phase III study (RAINBOW Paclitaxel with or without Ramucirumab in metastatic gastric adenocarcinoma, NCT01170663) compared the efficacy of paclitaxel in combination with ramucirumab with paclitaxel plus placebo in second-line treatment of GEJ/GC. Recently, primary results demonstrated an improvement of OS for the combination of paclitaxel with ramucirumab of two months (9.63 months versus 7.36 months) [88]. 8. Novel targets An in silico screen for tetraspanin receptors specifically expressed on cancer cells nominated claudin 18.2 as a putative antibody target in GEJ/GC [62]. Claudiximab, a chimeric moAb against claudin 18.2 with optimised ADCC, CDC and direct cytotoxic activities, is in advanced early clinical development in patients with metastatic GEJ/GC. Safety, toxicities and recommended phase II doses of claudiximab were established in monotherapy trials enroling heavily pretreated patients with claudin 18.2-positive adenocarcinoma of the stomach or GEJ, which revealed signals of moderate single agent activity [64]. Currently, a randomised phase II study, First-Line Treatment of Patients with CLDN18.2-Positive adenocarcinomas of the stomach, the esophagus or the gastroesophageal junction (FAST), explores the addition of claudiximab to first-line chemotherapy with EOX in patients with claudin 18.2-positive GEJ/GC (NCT01630083). Recently, the so-called ‘immune checkpoint inhibitors’, antibodies targeting T cell regulatory molecules such as CTLA4, PD-1 or PD-L1, have emerged as potentially effective agents over a wide range of tumour entities [11,30,34,76,89]. The CTLA4 antibody tremelimumab was explored in a phase II trial of second-line treatment in 18 patients with advanced GEJ/GC [59]. The overall response rate of the entire study population was low. However, one patient experienced a durable partial remission. Recently, a phase II trial evaluating the role of the CTLA4 antibody ipilimumab as mainte-

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nance therapy after platinum-based chemotherapy in advanced GEJ/GC was initiated (NCT01585987) [45,46]. PD-L1 expression was detectable in up to 40% of GC/GEJ tumours analysed. In particular, advanced stage tumours stained positively for PD-L1 whereas surrounding normal gastric tissues remained negative [72]. Patients with PD-L1-expressing GEJ/GC appear have inferior overall survival. Hence, targeting the PD-L1, PD-1 interaction seems an attractive strategy in GEJ/ GC. Currently available data from phase I trials with anti-PD-1 and anti-PD-L1 antibodies enroled only very few patients with GEJ/GC [11,30,76]. Accordingly, the potential merit of these antibodies in GEJ/GC treatment is not determined, but they clearly hold promise. 9. Conclusion Multiple clinical trials have been conducted to explore antibodies and small molecule inhibitors targeting ERBB family receptors and angiogenic signalling in the treatment of advanced and metastatic GEJ/GC. So far, trastuzumab has shown convincing clinical activity in patients defined by high intratumoural expression of a biomarker, the antibody target HER2. Recent evidence suggests a role for the anti-VEGFR2 antibody ramucirumab in treatment of patients relapsing after chemotherapy. The identification and validation of novel targets as well as of predictive biomarkers to define patient populations responsive to a specific targeted intervention has been highly successful in treatment of breast cancer or metatastic adenocarcinoma of the lung. It is expected that further insights into GEJ/ GC biology will enable similar progress in this devastating disease.

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Conflict of interest statement None declared. [15]

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Targeted therapies in gastroesophageal cancer.

Gastroesophageal cancers comprising gastric cancer (GC), and cancers of the distal oesophagus and gastroesophageal junction (GEJ) are a global health ...
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