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Published in: Drugs 1/2016

01-01-2016 | Leading Article

Targeted Therapies for Advanced Oesophagogastric Cancer: Recent Progress and Future Directions

Authors: Kate Young, Ian Chau

Published in: Drugs | Issue 1/2016

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Abstract

The genomic landscape of oesophagogastric (OG) cancer is highly complex. The recent elucidation of some of the pathways involved has suggested a number of novel targets for therapy. This therapy is urgently required as with conventional chemotherapy regimens patients with advanced OG cancer still have a median overall survival of under a year. This review outlines the rationale for the current treatment of OG cancer with chemotherapy and describes both previously conducted and ongoing clinical trials of novel agents in this area. The targets and associated treatments discussed include HER-2, EGFR, VEGF, c-Met, FGFR-2, PI3K, mTOR andIGF-1. To date only two targeted treatments, trastuzumab and ramucirumab, have become part of the treatment paradigm for OG cancer, partly due to difficulties in defining predictive biomarkers in this disease. However, there are a number of promising drugs in the pipeline and this article seeks to describe these and other potential novel approaches including targeting DNA repair deficiencies and the immune system.
Literature
1.
go back to reference Ferlay J, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2014;136:E359–86.PubMedCrossRef Ferlay J, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2014;136:E359–86.PubMedCrossRef
2.
go back to reference Shah MA, Kelsen DP. Gastric cancer: a primer on the epidemiology and biology of the disease and an overview of the medical management of advanced disease. J Natl Compr Canc Netw. 2010;8:437–47.PubMed Shah MA, Kelsen DP. Gastric cancer: a primer on the epidemiology and biology of the disease and an overview of the medical management of advanced disease. J Natl Compr Canc Netw. 2010;8:437–47.PubMed
5.
go back to reference Wagner AD, et al. Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol. 2006;24:2903–9.PubMedCrossRef Wagner AD, et al. Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol. 2006;24:2903–9.PubMedCrossRef
6.
go back to reference Ajani JA, et al. Quality of life with docetaxel plus cisplatin and fluorouracil compared with cisplatin and fluorouracil from a phase III trial for advanced gastric or gastroesophageal adenocarcinoma: the V-325 Study Group. J Clin Oncol. 2007;25:3210–6.PubMedCrossRef Ajani JA, et al. Quality of life with docetaxel plus cisplatin and fluorouracil compared with cisplatin and fluorouracil from a phase III trial for advanced gastric or gastroesophageal adenocarcinoma: the V-325 Study Group. J Clin Oncol. 2007;25:3210–6.PubMedCrossRef
7.
go back to reference Cunningham D, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36–46.PubMedCrossRef Cunningham D, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36–46.PubMedCrossRef
8.
go back to reference Kim HS, et al. Second-line chemotherapy versus supportive cancer treatment in advanced gastric cancer: a meta-analysis. Ann Oncol. 2013;24:2850–4.PubMedCrossRef Kim HS, et al. Second-line chemotherapy versus supportive cancer treatment in advanced gastric cancer: a meta-analysis. Ann Oncol. 2013;24:2850–4.PubMedCrossRef
9.
go back to reference Kang JH, et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012;30:1513–8.PubMedCrossRef Kang JH, et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol. 2012;30:1513–8.PubMedCrossRef
10.
go back to reference Thuss-Patience PC, et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer—a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011;47:2306–14.PubMedCrossRef Thuss-Patience PC, et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer—a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 2011;47:2306–14.PubMedCrossRef
11.
go back to reference Ford HER, et al. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014;15:78–86.PubMedCrossRef Ford HER, et al. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol. 2014;15:78–86.PubMedCrossRef
12.
go back to reference Hironaka S, et al. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 tria. J Clin Oncol. 2013;31:4438–44.PubMedCrossRef Hironaka S, et al. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 tria. J Clin Oncol. 2013;31:4438–44.PubMedCrossRef
13.
go back to reference Wilke H, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15:1224–35.PubMedCrossRef Wilke H, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15:1224–35.PubMedCrossRef
15.
go back to reference Deng N, et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut. 2012;61:673–84.PubMedPubMedCentralCrossRef Deng N, et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut. 2012;61:673–84.PubMedPubMedCentralCrossRef
16.
go back to reference Arteaga C. Targeting HER1/EGFR: a molecular approach to cancer therapy. Semin Oncol. 2003;30:3–14.CrossRef Arteaga C. Targeting HER1/EGFR: a molecular approach to cancer therapy. Semin Oncol. 2003;30:3–14.CrossRef
17.
go back to reference Jørgensen JT, Hersom M. HER2 as a prognostic marker in gastric cancer—a systematic analysis of data from the literature. J Cancer. 2012;3:137–44. doi:10.7150/jca.4090. Jørgensen JT, Hersom M. HER2 as a prognostic marker in gastric cancer—a systematic analysis of data from the literature. J Cancer. 2012;3:137–44. doi:10.​7150/​jca.​4090.
18.
go back to reference Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19:1523–9.PubMedCrossRef Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19:1523–9.PubMedCrossRef
19.
go back to reference Hofmann M, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology. 2008;52:797–805.PubMedCrossRef Hofmann M, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology. 2008;52:797–805.PubMedCrossRef
20.
go back to reference Bang YJ, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–97.PubMedCrossRef Bang YJ, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–97.PubMedCrossRef
21.
go back to reference Rivera F, et al. NeoHx study: perioperative treatment with trastuzumab in combination with capecitabine and oxaliplatin (XELOX-T) in patients with HER2 resectable stomach or esophagogastric junction (EGJ) adenocarcinoma—R0 resection, pCR, and toxicity analysis. 2013 ASCO. J Clin Oncol. 2013;31(suppl abstr 4098). Rivera F, et al. NeoHx study: perioperative treatment with trastuzumab in combination with capecitabine and oxaliplatin (XELOX-T) in patients with HER2 resectable stomach or esophagogastric junction (EGJ) adenocarcinoma—R0 resection, pCR, and toxicity analysis. 2013 ASCO. J Clin Oncol. 2013;31(suppl abstr 4098).
22.
go back to reference Hofheinz R, et al. HER-FLOT: trastuzumab in combination with FLOT as perioperative treatment for patients with HER2-positive locally advanced esophagogastric adenocarcinoma: a phase II trial of the AIO Gastric Cancer Study Group. 2014 ASCO. J Clin Oncol. 2014;32 suppl(abstr 4073). Hofheinz R, et al. HER-FLOT: trastuzumab in combination with FLOT as perioperative treatment for patients with HER2-positive locally advanced esophagogastric adenocarcinoma: a phase II trial of the AIO Gastric Cancer Study Group. 2014 ASCO. J Clin Oncol. 2014;32 suppl(abstr 4073).
23.
go back to reference Kang Y-K, et al. A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer. Br J Cancer. 2014;111:660–6.PubMedPubMedCentralCrossRef Kang Y-K, et al. A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer. Br J Cancer. 2014;111:660–6.PubMedPubMedCentralCrossRef
25.
go back to reference Hecht J, et al. Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma (AC): The TRIO-013/LOGiC Trial. 2013 ASCO Abstracts. J Clin Oncol. 2013;31(suppl; abstr LBA4001). Hecht J, et al. Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma (AC): The TRIO-013/LOGiC Trial. 2013 ASCO Abstracts. J Clin Oncol. 2013;31(suppl; abstr LBA4001).
26.
go back to reference Satoh T, et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN—a randomized, phase III study. J Clin Oncol. 2014;32:2039–49.PubMedCrossRef Satoh T, et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN—a randomized, phase III study. J Clin Oncol. 2014;32:2039–49.PubMedCrossRef
27.
go back to reference Janjigian YY, et al. A phase II study of afatinib in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab-refractory esophagogastric (EG) cancer. 2013 ASCO Abstracts. J Clin Oncol. 2013;31(suppl:Abstract e15017). Janjigian YY, et al. A phase II study of afatinib in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab-refractory esophagogastric (EG) cancer. 2013 ASCO Abstracts. J Clin Oncol. 2013;31(suppl:Abstract e15017).
28.
go back to reference Oh DY, et al. A phase II open-label trial of dacomitinib monotherapy in patients with HER2-positive advanced gastric cancer after failure of at least one prior chemotherapy regimen. 2012 Gastrointestinal Cancers Symposium. J Clin Oncol. 2012;30(suppl 4:Abstract 54). Oh DY, et al. A phase II open-label trial of dacomitinib monotherapy in patients with HER2-positive advanced gastric cancer after failure of at least one prior chemotherapy regimen. 2012 Gastrointestinal Cancers Symposium. J Clin Oncol. 2012;30(suppl 4:Abstract 54).
29.
go back to reference Oda K, Matsuoka Y, Funahashi A, Kitano H. A comprehensive pathway map of epidermal growth factor receptor signaling. Mol. Syst. Biol. 2005;1:2005.0010. Oda K, Matsuoka Y, Funahashi A, Kitano H. A comprehensive pathway map of epidermal growth factor receptor signaling. Mol. Syst. Biol. 2005;1:2005.0010.
30.
go back to reference Begnami MD, et al. Prognostic implications of altered human epidermal growth factor receptors (HERs) in gastric carcinomas: HER2 and HER3 are predictors of poor outcome. J Clin Oncol. 2011;29:3030–6.PubMedCrossRef Begnami MD, et al. Prognostic implications of altered human epidermal growth factor receptors (HERs) in gastric carcinomas: HER2 and HER3 are predictors of poor outcome. J Clin Oncol. 2011;29:3030–6.PubMedCrossRef
31.
go back to reference Kim MA, et al. EGFR in gastric carcinomas: prognostic significance of protein overexpression and high gene copy number. Histopathology. 2008;52:738–46.PubMedCrossRef Kim MA, et al. EGFR in gastric carcinomas: prognostic significance of protein overexpression and high gene copy number. Histopathology. 2008;52:738–46.PubMedCrossRef
32.
go back to reference Lordick F, et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14:490–9.PubMedCrossRef Lordick F, et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14:490–9.PubMedCrossRef
33.
go back to reference Waddell T, et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14:481–9.PubMedPubMedCentralCrossRef Waddell T, et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14:481–9.PubMedPubMedCentralCrossRef
34.
go back to reference Suntharalingham M, et al. The initial report of RTOG 0436: a phase III trial evaluating the addition of cetuximab to paclitaxel, cisplatin, and radiation for patients with esophageal cancer treated without surgery. 2014 Gastrointestinal Cancers Symposium. J Clin Oncol. 2014;(suppl 3, abstr LBA6). Suntharalingham M, et al. The initial report of RTOG 0436: a phase III trial evaluating the addition of cetuximab to paclitaxel, cisplatin, and radiation for patients with esophageal cancer treated without surgery. 2014 Gastrointestinal Cancers Symposium. J Clin Oncol. 2014;(suppl 3, abstr LBA6).
35.
go back to reference Crosby T, et al. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2/3 randomised trial. Lancet Oncol. 2013;14:627–37.PubMedCrossRef Crosby T, et al. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2/3 randomised trial. Lancet Oncol. 2013;14:627–37.PubMedCrossRef
36.
go back to reference Dragovich T, et al. Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J Clin Oncol. 2006;24:4922–7.PubMedCrossRef Dragovich T, et al. Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J Clin Oncol. 2006;24:4922–7.PubMedCrossRef
37.
go back to reference Dutton SJ, et al. Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial. Lancet Oncol. 2014;15:894–904.PubMedCrossRef Dutton SJ, et al. Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial. Lancet Oncol. 2014;15:894–904.PubMedCrossRef
38.
go back to reference Petty R, Dahle-Smith A, M. Z. et al. Epidermal growth factor receptor copy number gain (EGFR CNG) and response to gefitinib in esophageal cancer (EC): results of a biomarker analysis of a phase III trial of gefitinib versus placebo (TRANS-COG). 2014 ASCO Abstracts. J Clin Oncol. 2014(suppl; abstr 4016). Petty R, Dahle-Smith A, M. Z. et al. Epidermal growth factor receptor copy number gain (EGFR CNG) and response to gefitinib in esophageal cancer (EC): results of a biomarker analysis of a phase III trial of gefitinib versus placebo (TRANS-COG). 2014 ASCO Abstracts. J Clin Oncol. 2014(suppl; abstr 4016).
39.
go back to reference Aprile G, et al. Angiogenic inhibitors in gastric cancers and gastroesophageal junction carcinomas: a critical insight. Crit Rev Oncol Hematol. 2015;95:165–78.PubMedCrossRef Aprile G, et al. Angiogenic inhibitors in gastric cancers and gastroesophageal junction carcinomas: a critical insight. Crit Rev Oncol Hematol. 2015;95:165–78.PubMedCrossRef
40.
go back to reference Lieto E, et al. Expression of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) is an independent prognostic indicator of worse outcome in gastric cancer patients. Ann Surg Oncol. 2008;15:69–79.PubMedCrossRef Lieto E, et al. Expression of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) is an independent prognostic indicator of worse outcome in gastric cancer patients. Ann Surg Oncol. 2008;15:69–79.PubMedCrossRef
41.
go back to reference Peng L, et al. Prognostic significance of vascular endothelial growth factor immunohistochemical expression in gastric cancer: a meta-analysis. Mol Biol Rep. 2012;39:9473–84.PubMedCrossRef Peng L, et al. Prognostic significance of vascular endothelial growth factor immunohistochemical expression in gastric cancer: a meta-analysis. Mol Biol Rep. 2012;39:9473–84.PubMedCrossRef
42.
go back to reference Ohtsu A. et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011;29:3968–3976. Ohtsu A. et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011;29:3968–3976.
43.
go back to reference Shen L, et al. Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric Cancer. 2014;18:168–76.PubMedPubMedCentralCrossRef Shen L, et al. Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric Cancer. 2014;18:168–76.PubMedPubMedCentralCrossRef
44.
go back to reference Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol. 2012;30:2119–27.PubMedCrossRef Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol. 2012;30:2119–27.PubMedCrossRef
45.
go back to reference Fuchs CS, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383:31–9.PubMedCrossRef Fuchs CS, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383:31–9.PubMedCrossRef
46.
go back to reference Al-Batran S, et al. RAINBOW: a global, phase III, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel patients with previously treated gastric or gastroesophageal junction (GEJ) adenocarcinoma: Quality-of-life (QoL) results. 2014 AS. J Clin Oncol. 2014; 2:5s(suppl; abstr 4004). Al-Batran S, et al. RAINBOW: a global, phase III, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel patients with previously treated gastric or gastroesophageal junction (GEJ) adenocarcinoma: Quality-of-life (QoL) results. 2014 AS. J Clin Oncol. 2014; 2:5s(suppl; abstr 4004).
47.
go back to reference Yoon H, et al. Ramucirumab (RAM) plus FOLFOX as front-line therapy (Rx) for advanced gastric or esophageal adenocarcinoma (GE-AC): Randomized, double-blind, multicenter phase 2 trial. 2014 ASCO Abstracts. J Clin Oncol. 2014;32:5s(suppl; abstr 4004). Yoon H, et al. Ramucirumab (RAM) plus FOLFOX as front-line therapy (Rx) for advanced gastric or esophageal adenocarcinoma (GE-AC): Randomized, double-blind, multicenter phase 2 trial. 2014 ASCO Abstracts. J Clin Oncol. 2014;32:5s(suppl; abstr 4004).
48.
go back to reference Qin S. Phase III study of apatinib in advanced gastric cancer: a randomized, double-blind, placebo-controlled trial. 2014 ASCO Abstracts. J Clin Oncol. 2014;32:5s(suppl; abstr 4003). Qin S. Phase III study of apatinib in advanced gastric cancer: a randomized, double-blind, placebo-controlled trial. 2014 ASCO Abstracts. J Clin Oncol. 2014;32:5s(suppl; abstr 4003).
49.
go back to reference Nakajima M, et al. The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas. Cancer. 1999;85:1894–902.PubMedCrossRef Nakajima M, et al. The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas. Cancer. 1999;85:1894–902.PubMedCrossRef
50.
go back to reference Jhawer M, et al. Assessment of two dosing schedules of GSK1363089 (GSK089), a dual MET/VEGFR2 inhibitor, in metastatic gastric cancer (GC): Interim results of a multicenter phase II study. 2009 ASCO Abstracts. J Clin Oncol. 2009;27:15s(suppl; abstr 4502). Jhawer M, et al. Assessment of two dosing schedules of GSK1363089 (GSK089), a dual MET/VEGFR2 inhibitor, in metastatic gastric cancer (GC): Interim results of a multicenter phase II study. 2009 ASCO Abstracts. J Clin Oncol. 2009;27:15s(suppl; abstr 4502).
51.
go back to reference Kwak EL, et al. Clinical activity of AMG 337, an oral MET kinase inhibitor, in adult patients (pts) with MET-amplified gastroesophageal junction (GEJ), gastric (G), or esophageal (E) cancer. 2015 Gastrointestinal Cancers Symposium. J Clin Oncol 2015;33(suppl 3; abstr 1). Kwak EL, et al. Clinical activity of AMG 337, an oral MET kinase inhibitor, in adult patients (pts) with MET-amplified gastroesophageal junction (GEJ), gastric (G), or esophageal (E) cancer. 2015 Gastrointestinal Cancers Symposium. J Clin Oncol 2015;33(suppl 3; abstr 1).
52.
go back to reference Cunningham D, et al. Phase III, randomized, double-blind, multicenter, placebo (P)-controlled trial of rilotumumab (R) plus epirubicin, cisplatin and capecitabine (ECX) as first-line therapy in patients (pts) with advanced MET-positive (pos) gastric or gastroesophageal junction (G/GEJ) cancer: RILOMET-1 study. J Clin Oncol 2015;33(suppl; abstr 4000). Cunningham D, et al. Phase III, randomized, double-blind, multicenter, placebo (P)-controlled trial of rilotumumab (R) plus epirubicin, cisplatin and capecitabine (ECX) as first-line therapy in patients (pts) with advanced MET-positive (pos) gastric or gastroesophageal junction (G/GEJ) cancer: RILOMET-1 study. J Clin Oncol 2015;33(suppl; abstr 4000).
53.
go back to reference Cunningham D, et al. MetGastric: a randomized phase III study of onartuzumab (MetMAb) in combination with mFOLFOX6 in patients with metastatic HER2-negative and MET-positive adenocarcinoma of the stomach or gastroesophageal junction. 2013 ASCO Annual Meeting. J Clin Oncol. 2013;31(suppl; abstr TPS4155). Cunningham D, et al. MetGastric: a randomized phase III study of onartuzumab (MetMAb) in combination with mFOLFOX6 in patients with metastatic HER2-negative and MET-positive adenocarcinoma of the stomach or gastroesophageal junction. 2013 ASCO Annual Meeting. J Clin Oncol. 2013;31(suppl; abstr TPS4155).
54.
go back to reference Shah M, et al. Randomized phase II study of FOLFOX ± MET inhibitor, onartuzumab (O), in advanced gastroesophageal adenocarcinoma (GEC). 2015 Gastrointestinal Cancers Symposium. J Clin Oncol. 2015;33(suppl3, abstr2). Shah M, et al. Randomized phase II study of FOLFOX ± MET inhibitor, onartuzumab (O), in advanced gastroesophageal adenocarcinoma (GEC). 2015 Gastrointestinal Cancers Symposium. J Clin Oncol. 2015;33(suppl3, abstr2).
55.
go back to reference Su X, et al. FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study. Br J Cancer. 2014;110:967–75.PubMedPubMedCentralCrossRef Su X, et al. FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study. Br J Cancer. 2014;110:967–75.PubMedPubMedCentralCrossRef
56.
go back to reference Oki E, et al. Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer. Int J Cancer. 2005;117:376–80.PubMedCrossRef Oki E, et al. Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer. Int J Cancer. 2005;117:376–80.PubMedCrossRef
57.
go back to reference Okines AFC, et al. Biomarker analysis in oesophagogastric cancer: results from the REAL3 and TransMAGIC trials. Eur J Cancer. 2013;49:2116–25.PubMedCrossRef Okines AFC, et al. Biomarker analysis in oesophagogastric cancer: results from the REAL3 and TransMAGIC trials. Eur J Cancer. 2013;49:2116–25.PubMedCrossRef
58.
go back to reference Yu G, et al. Overexpression of phosphorylated mammalian target of rapamycin predicts lymph node metastasis and prognosis of chinese patients with gastric cancer. Clin Cancer Res. 2009;15:1821–9.PubMedCrossRef Yu G, et al. Overexpression of phosphorylated mammalian target of rapamycin predicts lymph node metastasis and prognosis of chinese patients with gastric cancer. Clin Cancer Res. 2009;15:1821–9.PubMedCrossRef
59.
go back to reference Ohtsu A, et al. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol. 2013;31:3935–3943. Ohtsu A, et al. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol. 2013;31:3935–3943.
60.
go back to reference Lee SJ, et al. Phase II trial of capecitabine and everolimus (RAD001) combination in refractory gastric cancer patients. Invest New Drugs. 2013;31:1580–6.PubMedCrossRef Lee SJ, et al. Phase II trial of capecitabine and everolimus (RAD001) combination in refractory gastric cancer patients. Invest New Drugs. 2013;31:1580–6.PubMedCrossRef
61.
go back to reference Yoon DH, et al. Phase II study of everolimus with biomarker exploration in patients with advanced gastric cancer refractory to chemotherapy including fluoropyrimidine and platinum. Br J Cancer. 2012;106:1039–44.PubMedPubMedCentralCrossRef Yoon DH, et al. Phase II study of everolimus with biomarker exploration in patients with advanced gastric cancer refractory to chemotherapy including fluoropyrimidine and platinum. Br J Cancer. 2012;106:1039–44.PubMedPubMedCentralCrossRef
62.
go back to reference Zhang C-Η, Awasthi N, Schwarz MA, Schwarz RE. The dual PI3K/mTOR inhibitor NVP-BEZ235 enhances nab-paclitaxel antitumor response in experimental gastric cancer. Int J Oncol. 2013;43:1627–35.PubMedCentral Zhang C-Η, Awasthi N, Schwarz MA, Schwarz RE. The dual PI3K/mTOR inhibitor NVP-BEZ235 enhances nab-paclitaxel antitumor response in experimental gastric cancer. Int J Oncol. 2013;43:1627–35.PubMedCentral
63.
go back to reference Fuereder T, et al. Gastric cancer growth control by BEZ235 in vivo does not correlate with PI3K/mTOR target inhibition but with [18F]FLT uptake. Clin Cancer Res. 2011;17:5322–32.PubMedCrossRef Fuereder T, et al. Gastric cancer growth control by BEZ235 in vivo does not correlate with PI3K/mTOR target inhibition but with [18F]FLT uptake. Clin Cancer Res. 2011;17:5322–32.PubMedCrossRef
64.
go back to reference Baserga R, Peruzzi F, Reiss K. The IGF-1 receptor in cancer biology. Int J Cancer. 2003;107:873–7.PubMedCrossRef Baserga R, Peruzzi F, Reiss K. The IGF-1 receptor in cancer biology. Int J Cancer. 2003;107:873–7.PubMedCrossRef
65.
go back to reference Matsubara J, et al. Clinical significance of insulin-like growth factor type 1 receptor and epidermal growth factor receptor in patients with advanced gastric cancer. Oncology. 2008;74:76–83.PubMedCrossRef Matsubara J, et al. Clinical significance of insulin-like growth factor type 1 receptor and epidermal growth factor receptor in patients with advanced gastric cancer. Oncology. 2008;74:76–83.PubMedCrossRef
66.
go back to reference Molife LR, et al. The insulin-like growth factor-I receptor inhibitor figitumumab (CP-751,871) in combination with docetaxel in patients with advanced solid tumours: results of a phase Ib dose-escalation, open-label study. Br J Cancer. 2010;103:332–9.PubMedPubMedCentralCrossRef Molife LR, et al. The insulin-like growth factor-I receptor inhibitor figitumumab (CP-751,871) in combination with docetaxel in patients with advanced solid tumours: results of a phase Ib dose-escalation, open-label study. Br J Cancer. 2010;103:332–9.PubMedPubMedCentralCrossRef
67.
go back to reference Heitz F, et al. Poly(ADP-ribosyl)ation polymerases: mechanism and new target of anticancer therapy. Expert Rev Anticancer Ther. 2010;10:1125–36.PubMedCrossRef Heitz F, et al. Poly(ADP-ribosyl)ation polymerases: mechanism and new target of anticancer therapy. Expert Rev Anticancer Ther. 2010;10:1125–36.PubMedCrossRef
68.
go back to reference Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol. 2008;26:3785–90.PubMedCrossRef Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol. 2008;26:3785–90.PubMedCrossRef
69.
go back to reference Kubota E, et al. Low ATM protein expression and depletion of p53 correlates with olaparib sensitivity in gastric cancer cell lines. Cell Cycle. 2014;13:2129–37.PubMedPubMedCentralCrossRef Kubota E, et al. Low ATM protein expression and depletion of p53 correlates with olaparib sensitivity in gastric cancer cell lines. Cell Cycle. 2014;13:2129–37.PubMedPubMedCentralCrossRef
70.
go back to reference Bang Y-J, et al. Randomized, double-blind phase II trial with prospective classification by atm protein level to evaluate the efficacy and tolerability of olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer. J Clin Oncol. 2015. doi:10.1200/JCO.2014.60.0320. Bang Y-J, et al. Randomized, double-blind phase II trial with prospective classification by atm protein level to evaluate the efficacy and tolerability of olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer. J Clin Oncol. 2015. doi:10.​1200/​JCO.​2014.​60.​0320.
71.
go back to reference Guo X, et al. Abstract B42: ATM deficiency sensitizes gastric cancer cells to the PARP inhibitior olaparib. Mol Cancer Ther. 2009;8:B42–B42.CrossRef Guo X, et al. Abstract B42: ATM deficiency sensitizes gastric cancer cells to the PARP inhibitior olaparib. Mol Cancer Ther. 2009;8:B42–B42.CrossRef
72.
go back to reference Kang B, et al. Expression status of ataxia-telangiectasia-mutated gene correlated with prognosis in advanced gastric cancer. Mutat Res. 2008;638:17–25.PubMedCrossRef Kang B, et al. Expression status of ataxia-telangiectasia-mutated gene correlated with prognosis in advanced gastric cancer. Mutat Res. 2008;638:17–25.PubMedCrossRef
73.
go back to reference Kim HS, Choi SI, Min HL, Kim MA, Kim WH. Mutation at intronic repeats of the ataxia-telangiectasia mutated (ATM) gene and ATM protein loss in primary gastric cancer with microsatellite instability. PLoS One. 2013;8:e82769.PubMedPubMedCentralCrossRef Kim HS, Choi SI, Min HL, Kim MA, Kim WH. Mutation at intronic repeats of the ataxia-telangiectasia mutated (ATM) gene and ATM protein loss in primary gastric cancer with microsatellite instability. PLoS One. 2013;8:e82769.PubMedPubMedCentralCrossRef
74.
go back to reference Bang YJ, et al. Olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer: a randomized, double-blind phase II study. 2013 ASCO Annual Meeting, Abstracts, Meeting Library. J Clin Oncol. 2013;31(suppl;abstr 4013). Bang YJ, et al. Olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer: a randomized, double-blind phase II study. 2013 ASCO Annual Meeting, Abstracts, Meeting Library. J Clin Oncol. 2013;31(suppl;abstr 4013).
75.
go back to reference Muro K, et al. A phase 1b study of pembrolizumab (Pembro; MK-3475) in patients (PTS) with advanced gastric cancer. Ann Oncol. 2014;25(5):1–41. Muro K, et al. A phase 1b study of pembrolizumab (Pembro; MK-3475) in patients (PTS) with advanced gastric cancer. Ann Oncol. 2014;25(5):1–41.
76.
go back to reference Tirkes T, et al. Response criteria in oncologic imaging: review of traditional and new criteria. Radiographics. 2013;33(5):1323–41. Tirkes T, et al. Response criteria in oncologic imaging: review of traditional and new criteria. Radiographics. 2013;33(5):1323–41.
Metadata
Title
Targeted Therapies for Advanced Oesophagogastric Cancer: Recent Progress and Future Directions
Authors
Kate Young
Ian Chau
Publication date
01-01-2016
Publisher
Springer International Publishing
Published in
Drugs / Issue 1/2016
Print ISSN: 0012-6667
Electronic ISSN: 1179-1950
DOI
https://doi.org/10.1007/s40265-015-0510-y

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