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Targeted Therapies for Gastric Cancer

Many phase III trials failed to demonstrate a survival benefit from the addition of molecular therapy to conventional chemotherapy for advanced and metastatic gastric cancer, and only three agents were approved by the FDA. Despite recent advances in surgical techniques and in anticancer drugs, and the adoption of perioperative treatments mostly based on conventional chemotherapy, the prognosis of advanced and metastatic gastric cancer remains poor. In the last decade, the addition of molecular therapy did not show any significant survival advantage, and the first reports available documented an increase of the rate of severe adverse effects and related mortality. The survival benefits of molecular therapies available to date for advanced and metastatic gastric cancer are rather unclear, mostly due to inaccurate patient selection, particularly concerning oncogene amplification and copy number.

  • gastric cancer
  • molecular target therapy
  • chemotherapy
  • EGFR inhibitors
  • angiogenesis inhibitors
  • MET inhibitors

1. Introduction

Gastric cancer is one of the most frequent malignancies. It represents the fifth most frequent cancer worldwide (5.6%) and the fourth leading cause of cancer-related death (7.7%) with 768,793 deaths per year in 2020 [1].
Surgical resection with optimal lymphadenectomy is the only curative treatment in cases of AGC [2][3][4][5][6]. In recent decades, several perioperative and postoperative regimens of conventional CT have been investigated, and neoadjuvant treatment has been recommended as mandatory in several national guidelines, but the prognosis of stage III and IV GC remains poor [7][8][9][10]. In 2014, Cancer Genome Atlas Research Network paved the way for a new molecular classification of GC and documented the existence of four subtypes: EBV (9%), MSI (22%), CIN (50%), and GS (20%) [11]. The identification of these subtypes and the related signaling pathways provided a roadmap for GC patient stratification and promising strategies for targeted therapies. Trastuzumab was the first MT approved by the FDA and European Union for AGC; it was subsequently introduced as the standard of care for patients with locally or fAGC displaying HER2 overexpression/amplification [12]. In 2014, the FDA also approved the use of ramucirumab as monotherapy or in combination with paclitaxel for advanced and metastatic GC [13]. To date, only these two MTs (in addition to the antibody–drug conjugate trastuzumab deruxtecan) have been approved, although many other molecular targets have been identified in recent years. Indeed, the majority of phase III trials investigating novel molecular agents failed to demonstrate their efficacy, mostly due to inaccurate patient selection (particularly concerning driver gene amplification and copy number) and the lack of preclinical models supporting proof of concepts followed by structured trials. PDXs are helpful in validating and predicting the response to novel MTs, even though these models are unable to reproduce the same conditions and environmental characteristics of the donor tumor and very rarely allow metastatic dissemination [14]. For this purpose, PDOXs were recently introduced in GC preclinical research to better recapitulate the original cancer background [15].
In 2016, the Cochrane Collaborative Group published a systematic review with the aim of assessing the efficacy and safety of MTs available for the treatment of advanced and metastatic gastric cancer [16]. The authors identified 11 RCTs enrolling a total of 4014 patients with AGC who underwent conventional CT and MT or conventional CT alone. They concluded that the benefit of MTs on survival was unclear and pointed out a significant increase in side effects.

2. Molecular Targets and Target Agents

2.1. Epidermal Growth Factor Receptor

2.1.1. Anti-HER1

Many authors have demonstrated that approximately 30% of GCs show HER1 overexpression [17][18]. Two main monoclonal antibodies (cetuximab and panitumumab) that reduce HER1 activity by binding its extracellular domain have been identified. Moreover, cetuximab can stimulate the activity of the immune system against tumor cells [19]. Unfortunately, the heterogeneity of GC seems to affect the efficacy of cetuximab in most of these patients [20].
Gefitinib and erlotinib, two tyrosine kinase inhibitors, can also inactivate HER1 by binding its intracellular domain and blocking its kinase activity [21]. Unfortunately, phase II trials have shown that these therapies have limited efficacy [22][23]. Recently, Maron et al. and Corso et al. identified a subpopulation of GC patients presenting a high level of EGFR amplification, which is responsive to anti-EGFR drugs [24][25]. They also identified mechanisms of resistance to EGFR-targeted drugs, such as TKR activation, KRAS mutation/amplification, and TSC2 inactivation [25].

2.1.2. Anti HER2

Several authors have shown a direct relationship between HER2 amplification (and the consequent overexpression of its receptor) and many types of tumors [26]. The HER2 gene is a proto-oncogene located on chromosome 17q21. The first drug binding HER2 was trastuzumab. In 2010, the ToGa trial documented the superiority of trastuzumab in combination with conventional chemotherapy compared with chemotherapy alone in terms of OS and DFS for patients with AGC [12]. Nevertheless, only a few patients with GC (less than 20%) gain a real advantage from trastuzumab.
In the past decade, several other anti-HER2 agents have been tested for GC treatment. Lapatinib is a dual kinase inhibitor that acts on EGFR (ErbB1) and HER2 (ErbB2) with the consequent downregulation of HER2 signaling [27].
Pertuzumab is an anti-HER2 monoclonal antibody that prevents heterodimerization between HER2 and other HER family members [28].

2.2. Vascular Endothelial Growth Factor

VEGFs are proteins promoting blood vessel formation. Four types of VEGF (VEGF-A, VEGF-B, VEGF-C, and VEGF-D) have been identified, with three types of corresponding receptors (VEGFR-1, VEGFR-2, and VEGFR-3). Several studies have reported the fundamental role of these signaling proteins in new blood vessel formation and cancer cell proliferation [29]. Furthermore, VEGF expression has been found in approximately 40% of GC [30]. Bevacizumab is an anti-VEGF-A monoclonal antibody that inhibits circulating VEGF-A activity [31]. The efficacy of this monoclonal antibody has been widely documented in several solid tumor treatments [32][33][34] but bevacizumab is still under investigation for its benefit in GC. Some phase II/III trials proved its efficacy in association with conventional chemotherapy in AGC, while others did not report any clear benefits [35][36].

2.3. Mammalian Target of Rapamycin

mTOR is a serine/threonine protein kinase identified in mammalian cells with a leading role in controlling mechanisms of cell growth and proliferation. Human cancers can be characterized by hyperactivity or inactivity of the mTOR pathway, which plays a crucial role in maintaining tumor-modified phenotypes [37].

2.4. Hepatocyte Growth Factor Receptor

HGFR, also known as c-MET, is a proto-oncogenic receptor tyrosine kinase that, after binding to hepatocyte growth factor, induces cell migration and proliferation, promotes mitosis, and inhibits apoptosis. C-MET overexpression and gene amplification are related to a poor prognosis [38][39].
Crizotinib (PF-02341066) is a tyrosine kinase inhibitor of the c-MET receptor and of the TKR anaplastic lymphoma kinase; it has been approved by the FDA for treatment of ALK-positive NSCLC patients.
Another promising agent targeting the HGF-cMET complex is rilotumumab. This human monoclonal antibody impairs the c-MET signaling pathway by binding to and inactivating its ligand HGF [40]. Clinical trials of this drug in GC (including two phase III trials) were halted due to a significant increase in mortality in the experimental arm (rilotumumab in combination with conventional chemotherapy) in one of these trials, but new investigations have begun.
In Figure 1, targeted therapies and oncogenic pathways in gastric cancer are detailed.
Figure 1. Targeted therapy and oncogenic pathways in gastric cancer. Activation of ERK-AMP KINASE: ligand binding to a growth factor receptor activates the small GTP-binding RAS protein, which interacts with RAF protein kinase. RAF phosphorylates and activates MEK (MAP kinase or ERK kinase), which then activates ERK (extracellular signal-regulated kinase) by phosphorylation of tyrosine and threonine residues. Activated ERK translocates into the nucleus where it phosphorylates the Elk-1 transcription. PI3K/AKT/MTOR Pathway: PI3K/AKT/MTOR signaling constitutes an important pathway that consists of two steps: phosphatidylinositol 3-kinase (PI3K) and its downstream molecule serine/threonine protein kinase B (PKB; also known as AKT). The PI3/AKT/mTOR pathway is stimulated by RTK and cytokine receptor activation. Tyrosine residues are then phosphorylated and provide anchor sites for PI3K translocation to the membrane, thus participating in the transduction of various extracellular matrix molecules and cytokines, including mTOR, a serine/threonine protein kinase and a member of the PI3K-associated kinase protein family.

2.5. Preclinical Trials

Preclinical trials have proved to be valuable tools to derive molecular information to better target GC for innovative MTs and stratify patients for clinical trials. The use of organoids, PDXs, and PDOXs in GC research showed interesting patient related tumor characteristics and cancer escape mechanisms. Several authors reported a strong relationship between higher levels of HER2 amplification/copy number and increased benefit of Trastuzumab in AGC [41][42].

3. Molecularly Targeted Therapies for Gastric Cancer

GC is still characterized by a poor prognosis, particularly in cases of metastatic or recurrent disease and in locally advanced stages. The identification and introduction of effective and safe molecular therapies in clinical practice lag behind other malignancies, such as lung and breast cancers.
Unfortunately, findings showed that molecular therapies do not provide a clear survival benefit compared to conventional CT in the case of advanced or metastatic GC.
In 2016, the Cochrane group published the largest systematic review and meta-analysis investigating the survival benefit of MTs for GC patients, with or without conventional treatment. The Cochrane authors identified 11 RCTs (phase II and III studies), and the conclusion was “Adding molecular-targeted treatment to chemotherapy may have a small effect on survival and on stopping further development of the disease, compared with chemotherapy alone, but the evidence is of low quality”.
In the past five years, only eight new phase III RCTs have been conducted.
Most of these studies failed to demonstrate the superiority of MT with or without conventional CT compared with conventional treatment alone or with placebo in terms of survival outcomes. Moreover, two of these eight trials were terminated prematurely. The METGastric Phase III trial was stopped early because of negative results reported in a concomitant Phase II study that concluded: “The addition of onartuzumab to mFOLFOX6 in gastric cancer did not improve efficacy in an unselected population or in a MET immunohistochemistry-positive population” [43][44]. The RILOMET-1 was interrupted prematurely because a safety control committee found more deaths in the experimental arm than in the control arm during a planned interim analysis of safety and survival outcomes [45].
The RCT published by Li was the only positive study; it reported a clear survival benefit in patients with GC treated with apatinib (a VEGFR2 inhibitor) compared with those receiving a placebo in terms of both OS (7.6 vs. 5.0 months, p = 0.0027) and PFS (2.8 vs. 1.9 months, p < 0.001), with an acceptable SAE rate [46]. Accordingly, in 2014, the China Food and Drug Administration approved the use of apatinib as a third-line treatment for metastatic GC.
Despite this positive report, the overall meta-analysis did not show any significant differences in OS and PFS between the experimental (MT) and control arms.
Furthermore, the subgroup analysis according to the type of MT administered (VEGFR or c-MET inhibitors) failed to show a significant prolongation of OS and/or PFS in the experimental arm. Notably, our results may have been unable to identify significant differences between the two arms due to the high heterogeneity found among the included studies. On account of this statistical bias, we conducted two further meta-analyses matching our OS and PFS findings with those reported in the Cochrane review [47][48][49][50][51][52] (Figure 2a,b). Regrettably, these new cumulative analyses maintained high heterogeneity and could not document any survival advantage when MT was added to conventional treatment or administered alone compared to conventional CT or to a placebo.
Figure 2. (a) Forest plot of comparison: molecular-targeted therapy alone/plus chemotherapy versus chemotherapy alone/placebo. Main analyses; outcome: overall survival (data from Cochrane and present review pooled). (b) Forest plot of comparison: molecular-targeted therapy alone/plus chemotherapy versus chemotherapy alone/placebo. Main analyses; outcome: progression free survival (data from Cochrane and present review pooled).
Quality of life was mentioned only in the study by Li et al. [46] and in the RAINFALL study [53] without any significant differences between the two groups.
Finally, the number of serious adverse effects and SAE-related deaths did not increase in the experimental arm. Additionally, the analysis of secondary outcomes confirmed that, to date, the supposed advantage of the administration of MT vs. conventional CT alone is unclear.
In addition, most of the investigated targeted therapies available to date are very expensive; therefore, it is mandatory to evaluate the cost-effectiveness as well. In 2017, Chen et al. [54] evaluated the relationship between the efficacy and the costs of apatinib as a third-line treatment in metastatic GC and concluded that this type of treatment is not cost-effective at all, while another author stated that apatinib is likely to be cost-effective only for patients with solid insurance [55]. Other authors analyzed the cost-effectiveness ratio of ramucirumab + paclitaxel as a second line treatment in AGC as proposed by Wilke et al. [56], concluding that this regimen was cost-ineffective and suggesting that its indirect charges to society be considered [57][58].
Finally, although three MTs have been approved by the FDA (trastuzumab, trastuzumab–deruxtecan, and ramucirumab) and a fourth one by the China Food and Drug Administration (apatinib), most phase III RCTs assessing novel molecular agents failed to demonstrate a survival advantage over conventional treatments. Consistent with the literature, we found four possible reasons for these negative results.
First, only in recent times has GC undergone wide investigational programs from a molecular perspective, which has highlighted the importance of patient selection because of the high number of molecular mutations found in GC [59]. Indeed, several molecular alterations characterizing GC subtypes have been identified and analyzed in the past decade, as in the case of CIN tumors, which manifest the most frequent TKR amplifications, and in the case of 80% of EBV tumors, which display PIK3CA mutations [60].
Second, GC is often characterized by a high grade of heterogeneity, both inside the primary tumor and in distant metastases. Several studies clearly demonstrated the intratumoral heterogeneous pattern of HER2 and c-MET expression [61][62]. Some authors have suggested inactivating alterations to the phylogenetic tree trunk because they promote cancer growth and are present in every tumor cell [63]. Unfortunately, no trunk mutations have been discovered in GC.
Third, several preclinical trials have recently documented a strict relationship between c-MET amplification and copy number and the response grade to anti-MET therapies [64][65] and that c-MET expression alterations are found in only 2% of GCs. However, in clinical trials investigating anti-MET agents, no patient selection was done. This could be one of the reasons for RILOMET-1 and METGastric trial failure.
Finally, many studies have shown different escape mechanisms of cancer cells that could shorten the duration of or even nullify the response to targeted therapies [66][67]. For example, c-MET-addicted GC could overcome c-MET blockade through HER family receptor expression activation. Recently, Apicella et al. showed that combined molecular therapy with anti-MET/EGFR leads to a complete and durable response [64]. For this reason, PDX and PDOX are valuable preclinical tools in validating new targeted therapies tailored to patients’ cancer molecular expression [14][15][68].

4. Conclusions

The results showed that despite their newly documented safety, the molecular therapies available to date for advanced and metastatic gastric cancer do not present clear survival benefits. These unfavorable results are mostly related to inadequate patient selection. Targeted therapies are promising treatments for patients with locally advanced, metastatic, or recurrent gastric cancer as they are for other types of tumors. However, their clinical validation requires accurate patient selection, particularly related to driver oncogene amplification and copy number, and it should take into account preclinical models investigating cancer heterogeneity and escape mechanisms.

This entry is adapted from 10.3390/cancers13164094

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249.
  2. The Italian Gastric Cancer Study Group. Randomized clinical trial comparing survival after D1 or D2 gastrectomy for gastric cancer. Br. J. Surg. 2014, 101, 23–31.
  3. Songun, I.; Putter, H.; Kranenbarg, E.M.-K.; Sasako, M.; van de Velde, C.J. Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol. 2010, 11, 439–449.
  4. Degiuli, M.; Sasako, M.; Ponti, A.; Calvo, F. Survival results of a multicentre phase II study to evaluate D2 gastrectomy for gastric cancer. Br. J. Cancer 2004, 90, 1727–1732.
  5. Hartgrink, H.; Van De Velde, C.; Putter, H.; Bonenkamp, J.; Kranenbarg, E.M.-K.; Songun, V.; Welvaart, K.; Van Krieken, J.; Meijer, S.; Plukker, J.; et al. Extended Lymph Node Dissection for Gastric Cancer: Who May Benefit? Final Results of the Randomized Dutch Gastric Cancer Group Trial. J. Clin. Oncol. 2004, 22, 2069–2077.
  6. Degiuli, M.; Reddavid, R.; Tomatis, M.; Ponti, A.; Morino, M.; Sasako, M.; Rebecchi, F.; Garino, M.; Vigano, L.; Scaglione, D.; et al. D2 dissection improves disease-specific survival in advanced gastric cancer patients: 15-year follow-up results of the Italian Gastric Cancer Study Group D1 versus D2 randomised controlled trial. Eur. J. Cancer 2021, 150, 10–22.
  7. Reddavid, R.; Sofia, S.; Chiaro, P.; Colli, F.; Trapani, R.; Esposito, L.; Solej, M.; Degiuli, M. Neoadjuvant chemotherapy for gastric cancer. Is it a must or a fake? World J. Gastroenterol. 2018, 24, 274–289.
  8. National Comprehensive Cancer Network Gastric Cancer (Version 3.2020). Available online: https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf (accessed on 5 December 2020).
  9. Smyth, E.C.; Verheij, M.; Allum, W.; Cunningham, D.; Cervantes, A.; Arnold, D. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2016, 27, v38–v49.
  10. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2018 (5th edition). Gastric Cancer 2020, 24, 1–21.
  11. Atlass, A.J.; Thorsson, V.; Shmulevich, I.; Reynolds, S.M.; Miller, M.; Bernard, B.; HiNoue, T.; Laird, P.W.; Curtis, C.; Shen, H.; et al. The Cancer Genome Atlas Research Network Comprehensive molecular characterization of gastric adenocarcinoma. Nat. Cell Biol. 2014, 513, 202–209.
  12. Bang, Y.-J.; Van Cutsem, E.; Feyereislova, A.; Chung, H.; Shen, L.; Sawaki, A.; Lordick, F.; Ohtsu, A.; Omuro, Y.; Satoh, T.; 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, 687–697.
  13. Jüttner, S.; Wiβmann, C.; Jöns, T.; Vieth, M.; Hertel, J.; Gretschel, S.; Schlag, P.M.; Kemmner, W.; Höcker, M. Vascular Endothelial Growth Factor-D and Its Receptor VEGFR-3: Two Novel Independent Prognostic Markers in Gastric Adenocarcinoma. J. Clin. Oncol. 2006, 24, 228–240.
  14. Corso, S.; Isella, C.; Bellomo, S.E.; Apicella, M.; Durando, S.; Migliore, C.; Ughetto, S.; D’Errico, L.; Menegon, S.; Rull, D.M.; et al. A Comprehensive PDX Gastric Cancer Collection Captures Cancer Cell–Intrinsic Transcriptional MSI Traits. Cancer Res. 2019, 79, 5884–5896.
  15. Reddavid, R.; Corso, S.; Moya-Rull, D.; Giordano, S.; Degiuli, M. Patient-Derived Orthotopic Xenograft models in gastric cancer: A systematic review. Updates Surg. 2020, 72, 951–966.
  16. Song, H.; Zhu, J.; Lu, D. Molecular-targeted first-line therapy for advanced gastric cancer. Cochrane Database Syst. Rev. 2016, 7, CD011461.
  17. Zhang, Z.; Tang, H.; Lin, J.; Hu, Y.; Luo, G.; Luo, Z.; Cheng, C.; Wang, P. Clinicopathologic and prognostic significance of human epidermal growth factor receptor in patients with gastric cancer: An updated meta-analysis. Oncotarget 2017, 8, 17202–17215.
  18. Navarini, D.; Gurski, R.R.; Madalosso, C.; Aita, L.; Meurer, L.; Fornari, F. Epidermal Growth Factor Receptor Expression in Esophageal Adenocarcinoma: Relationship with Tumor Stage and Survival after Esophagectomy. Gastroenterol. Res. Pract. 2012, 2012, 1–5.
  19. Hara, M.; Nakanishi, H.; Tsujimura, K.; Matsui, M.; Yatabe, Y.; Manabe, T.; Tatematsu, M. Interleukin-2 potentiation of cetuximab antitumor activity for epidermal growth factor receptor-overexpressing gastric cancer xenografts through antibody-dependent cellular cytotoxicity. Cancer Sci. 2008, 99, 1471–1478.
  20. Lordick, F.; Allum, W.; Carneiro, F.; Mitry, E.; Tabernero, J.; Tan, P.; Van Cutsem, E.; van de Velde, C.; Cervantes, A. Unmet needs and challenges in gastric cancer: The way forward. Cancer Treat. Rev. 2014, 40, 692–700.
  21. Rojo, F.; Tabernero, J.; Albanell, J.; Van Cutsem, E.; Ohtsu, A.; Doi, T.; Koizumi, W.; Shirao, K.; Takiuchi, H.; Cajal, S.R.; et al. Pharmacodynamic Studies of Gefitinib in Tumor Biopsy Specimens From Patients With Advanced Gastric Carcinoma. J. Clin. Oncol. 2006, 24, 4309–4316.
  22. Rodriguez, C.P.; Adelstein, D.J.; Rice, T.W.; Rybicki, L.A.; Videtic, G.M.M.; Saxton, J.P.; Murthy, S.C.; Mason, D.P.; Ives, D.I. A Phase II Study of Perioperative Concurrent Chemotherapy, Gefitinib, and Hyperfractionated Radiation Followed by Maintenance Gefitinib in Locoregionally Advanced Esophagus and Gastroesophageal Junction Cancer. J. Thorac. Oncol. 2010, 5, 229–235.
  23. Dragovich, T.; McCoy, S.; Fenoglio-Preiser, C.M.; Wang, J.; Benedetti, J.K.; Baker, A.F.; Hackett, C.B.; Urba, S.G.; Zaner, K.S.; Blanke, C.D.; et al. Phase II Trial of Erlotinib in Gastroesophageal Junction and Gastric Adenocarcinomas: SWOG 0127. J. Clin. Oncol. 2006, 24, 4922–4927.
  24. Maron, S.B.; Alpert, L.; Kwak, H.A.; Lomnicki, S.; Chase, L.; Xu, D.; O’Day, E.; Nagy, R.J.; Lanman, R.B.; Cecchi, F.; et al. Targeted Therapies for Targeted Populations: Anti-EGFR Treatment for EGFR-Amplified Gastroesophageal Adenocarcinoma. Cancer Discov. 2018, 8, 696–713.
  25. Corso, S.; Pietrantonio, F.; Apicella, M.; Migliore, C.; Conticelli, D.; Petrelli, A.; D’Errico, L.; Durando, S.; Moya-Rull, D.; Bellomo, S.E.; et al. Optimized EGFR Blockade Strategies in EGFR Addicted Gastroesophageal Adenocarcinomas. Clin. Cancer Res. 2021, 27, 3126–3140.
  26. Hynes, N.E.; Stern, D.F. The biology of erbB-2/nue/HER-2 and its role in cancer. BBA Rev. Cancer 1994, 1198, 165–184.
  27. Satoh, T.; Xu, R.-H.; Chung, H.; Sun, G.-P.; Doi, T.; Xu, J.-M.; Tsuji, A.; Omuro, Y.; Li, J.; Wang, J.-W.; et al. Lapatinib Plus Paclitaxel Versus Paclitaxel Alone in the Second-Line Treatment ofHER2-Amplified Advanced Gastric Cancer in Asian Populations: TyTAN—A Randomized, Phase III Study. J. Clin. Oncol. 2014, 32, 2039–2049.
  28. Hughes, J.B.; Berger, C.; Rødland, M.S.; Hasmann, M.; Stang, E.; Madshus, I.H. Pertuzumab increases epidermal growth factor receptor down-regulation by counteracting epidermal growth factor receptor-ErbB2 heterodimerization. Mol. Cancer Ther. 2009, 8, 1885–1892.
  29. Jung, Y.; Mansfield, P.; Akagi, M.; Takeda, A.; Liu, W.; Bucana, C.; Hicklin, D.; Ellis, L. Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude mouse model. Eur. J. Cancer 2002, 38, 1133–1140.
  30. Maeda, K.; Chung, Y.-S.; Ogawa, Y.; Kang, S.-M.; Ogawa, M.; Sawada, T.; Sowa, M. Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer 1996, 77, 858–863.
  31. Presta, L.G.; Chen, H.; O’Connor, S.J.; Chisholm, V.; Meng, Y.G.; Krummen, L.; Winkler, M.; Ferrara, N. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997, 57, 4593–4599.
  32. Miller, K.; Wang, M.; Gralow, J.; Dickler, M.; Cobleigh, M.; Perez, E.A.; Shenkier, T.; Cella, D.; Davidson, N.E. Paclitaxel plus Bevacizumab versus Paclitaxel Alone for Metastatic Breast Cancer. N. Engl. J. Med. 2007, 357, 2666–2676.
  33. Hurwitz, H.; Fehrenbacher, L.; Novotny, W.; Cartwright, T.; Hainsworth, J.; Heim, W.; Berlin, J.; Baron, A.; Griffing, S.; Holmgren, E.; et al. Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer. N. Engl. J. Med. 2004, 350, 2335–2342.
  34. Yang, J.C.; Haworth, L.; Sherry, R.M.; Hwu, P.; Schwartzentruber, D.J.; Topalian, S.L.; Steinberg, S.M.; Chen, H.X.; Rosenberg, S.A. A Randomized Trial of Bevacizumab, an Anti–Vascular Endothelial Growth Factor Antibody, for Metastatic Renal Cancer. N. Engl. J. Med. 2003, 349, 427–434.
  35. Ohtsu, A.; Shah, M.A.; Van Cutsem, E.; Rha, S.Y.; Sawaki, A.; Park, S.R.; Lim, H.Y.; Yamada, Y.; Wu, J.; Langer, B.; 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.
  36. Shah, M.A.; Jhawer, M.; Ilson, D.H.; Lefkowitz, R.A.; Robinson, E.; Capanu, M.; Kelsen, D.P. Phase II Study of modified docetaxel, cisplatin, and fluorouracil with bevacizumab in patients with metastatic gastroesophageal adenocarcinoma. J. Clin. Oncol. 2011, 29, 868–874.
  37. Bjornsti, M.-A.; Houghton, P.J. The tor pathway: A target for cancer therapy. Nat. Rev. Cancer 2004, 4, 335–348.
  38. Scagliotti, G.V.; Novello, S.; von Pawel, J. The emerging role of MET/HGF inhibitors in oncology. Cancer Treat. Rev. 2013, 39, 793–801.
  39. Graziano, F.; Galluccio, N.; Lorenzini, P.; Ruzzo, A.; Canestrari, E.; D’Emidio, S.; Catalano, V.; Sisti, V.; Ligorio, C.; Andreoni, F.; et al. Genetic Activation of the MET Pathway and Prognosis of Patients with High-Risk, Radically Resected Gastric Cancer. J. Clin. Oncol. 2011, 29, 4789–4795.
  40. Waddell, T.; Moorcraft, S.Y.; Cunningham, D. Potential role of rilotumumab in the treatment of gastric cancer. Immunotherapy 2014, 6, 1243–1253.
  41. Ughetto, S.; Migliore, C.; Pietrantonio, F.; Apicella, M.; Petrelli, A.; D’Errico, L.; Durando, S.; Moya-Rull, D.; Bellomo, S.E.; Rizzolio, S.; et al. Personalized therapeutic strategies in HER2-driven gastric cancer. Gastric Cancer 2021, 24, 897–912.
  42. Gomez-Martin, C.; Plaza, J.C.; Pazo-Cid, R.A.; Salud, A.; Pons, F.; Fonseca, P.; Leon, A.; Alsina, M.; Visa, L.; Rivera, F.; et al. Level of HER2 Gene Amplification Predicts Response and Overall Survival in HER2-Positive Advanced Gastric Cancer Treated With Trastuzumab. J. Clin. Oncol. 2013, 31, 4445–4452.
  43. Shah, M.A.; Bang, Y.-J.; Lordick, F.; Alsina, M.; Chen, M.; Hack, S.P.; Bruey, J.M.; Smith, D.; McCaffery, I.; Shames, D.S.; et al. Effect of Fluorouracil, Leucovorin, and Oxaliplatin with or Without Onartuzumab in HER2-Negative, MET-Positive Gastroesophageal Adenocarcinoma. JAMA Oncol. 2017, 3, 620–627.
  44. Shah, M.A.; Cho, J.-Y.; Tan, I.B.; Tebbutt, N.C.; Yen, C.-J.; Kang, A.; Shames, D.S.; Bu, L.; Kang, Y.-K. A Randomized Phase II Study of FOLFOX with or Without the MET Inhibitor Onartuzumab in Advanced Adenocarcinoma of the Stomach and Gastroesophageal Junction. Oncologist 2016, 21, 1085–1090.
  45. Catenacci, D.V.T.; Tebbutt, N.C.; Davidenko, I.; Murad, A.M.; Al-Batran, S.-E.; Ilson, D.H.; Tjulandin, S.; Gotovkin, E.; Karaszewska, B.; Bondarenko, I.; et al. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017, 18, 1467–1482.
  46. Li, J.; Qin, S.; Xu, J.; Xiong, J.; Wu, C.; Bai, Y.; Liu, W.; Tong, J.; Liu, Y.; Xu, R.; et al. Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Apatinib in Patients With Chemotherapy-Refractory Advanced or Metastatic Adenocarcinoma of the Stomach or Gastroesophageal Junction. J. Clin. Oncol. 2016, 34, 1448–1454.
  47. Eatock, M.M.; Tebbutt, N.C.; Bampton, C.L.; Strickland, A.H.; Valladares-Ayerbes, M.; Swieboda-Sadlej, A.; Van Cutsem, E.; Nanayakkara, N.; Sun, Y.N.; Zhong, Z.D.; et al. Phase II randomized, double-blind, placebo-controlled study of AMG 386 (trebananib) in combination with cisplatin and capecitabine in patients with metastatic gastro-oesophageal cancer. Ann. Oncol. 2013, 24, 710–718.
  48. Iveson, T.; Donehower, R.C.; Davidenko, I.; Tjulandin, S.; Deptala, A.; Harrison, M.; Nirni, S.; Lakshmaiah, K.; Thomas, A.; Jiang, Y.; et al. Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: An open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study. Lancet Oncol. 2014, 15, 1007–1018.
  49. Koizumi, W.; Yamaguchi, K.; Hosaka, H.; Takinishi, Y.; Nakayama, N.; Hara, T.; Muro, K.; Baba, H.; Sasaki, Y.; Nishina, T.; et al. Randomised phase II study of S-1/cisplatin plus TSU-68 vs S-1/cisplatin in patients with advanced gastric cancer. Br. J. Cancer 2013, 109, 2079–2086.
  50. Rao, S.; Starling, N.; Cunningham, D.; Sumpter, K.; Gilligan, D.; Ruhstaller, T.; Valladares-Ayerbes, M.; Wilke, H.; Archer, C.; Kurek, R.; et al. Matuzumab plus epirubicin, cisplatin and capecitabine (ECX) compared with epirubicin, cisplatin and capecitabine alone as first-line treatment in patients with advanced oesophago-gastric cancer: A randomised, multicentre open-label phase II study. Ann. Oncol. 2010, 21, 2213–2219.
  51. Shen, L.; Li, J.; Xu, J.; Pan, H.; Dai, G.; Qin, S.; Wang, L.; Wang, J.; Yang, Z.; Shu, Y.; 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, 168–176.
  52. Zhang, Z.D.; Kong, Y.; Yang, W.; Zhang, B.; Zhang, Y.L.; Ma, E.M.; Liu, H.X.; Chen, X.B.; Hua, Y.W. Clinical evaluation of cetuximab combined with an S-1 and oxaliplatin regimen for Chinese patients with advanced gastric cancer. World J. Surg. Oncol. 2014, 12, 115.
  53. Fuchs, C.S.; Shitara, K.; Di Bartolomeo, M.; Lonardi, S.; Al-Batran, S.-E.; Van Cutsem, E.; Ilson, D.H.; Alsina, M.; Chau, I.; Lacy, J.; et al. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019, 20, 420–435.
  54. Chen, H.-D.; Zhou, J.; Wen, F.; Zhang, P.-F.; Zhou, K.-X.; Zheng, H.-R.; Yang, Y.; Li, Q. Cost-effectiveness analysis of apatinib treatment for chemotherapy-refractory advanced gastric cancer. J. Cancer Res. Clin. Oncol. 2017, 143, 361–368.
  55. Bai, Y.; Xu, Y.; Wu, B. Cost-effectiveness and budget impact analysis of apatinib for advanced metastatic gastric cancer from the perspective of health insurance system. Gastroenterol. Res. Pract. 2017, 2017.
  56. Wilke, H.; Muro, K.; Van Cutsem, E.; Oh, S.-C.; Bodoky, G.; Shimada, Y.; Hironaka, S.; Sugimoto, N.; Lipatov, O.; Kim, T.-Y.; 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, 1224–1235.
  57. Li, S.; Peng, L.; Tan, C.; Zeng, X.; Wan, X.; Luo, X.; Yi, L.; Li, J. Cost-Effectiveness of ramucirumab plus paclitaxel as a second-line therapy for advanced gastric or gastro-oesophageal cancer in China. PLoS ONE 2020, 15, e0232240.
  58. Saito, S.; Muneoka, Y.; Ishikawa, T.; Akazawa, K. Cost-effectiveness of Paclitaxel + Ramucirumab Combination Therapy for Advanced Gastric Cancer Progressing After First-line Chemotherapy in Japan. Clin. Ther. 2017, 39, 2380–2388.
  59. Apicella, M.; Corso, S.; Giordano, S. Targeted therapies for gastric cancer: Failures and hopes from clinical trials. Oncotarget 2017, 8, 57654–57669.
  60. Liu, X.; Meltzer, S.J. Gastric Cancer in the Era of Precision Medicine. CMGH 2017, 3, 348–358.
  61. Kwak, E.L.; LoRusso, P.; Hamid, O.; Janku, F.; Kittaneh, M.; Catenacci, D.V.T.; Chan, E.; Bekaii-Saab, T.S.; Amore, B.; Hwang, Y.C.; 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. J. Clin. Oncol. 2015, 33, 1.
  62. Asioli, S.; Maletta, F.; Verdun Di Cantogno, L.; Satolli, M.A.; Schena, M.; Pecchioni, C.; Botta, C.; Chiusa, L.; Molinaro, L.; Conti, L.; et al. Approaching heterogeneity of human epidermal growth factor receptor 2 in surgical specimens of gastric cancer. Hum. Pathol. 2012, 43, 2070–2079.
  63. Gerlinger, M.; Rowan, A.J.; Horswell, S.; Larkin, J.; Endesfelder, D.; Gronroos, E.; Martinez, P.; Matthews, N.; Stewart, A.; Tarpey, P.; et al. Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. N. Engl. J. Med. 2012, 366, 883–892.
  64. Apicella, M.; Migliore, C.; Capelôa, T.; Menegon, S.; Cargnelutti, M.; Degiuli, M.; Sapino, A.; Sottile, A.; Sarotto, I.; Casorzo, L.; et al. Dual MET/EGFR therapy leads to complete response and resistance prevention in a MET-amplified gastroesophageal xenopatient cohort. Oncogene 2017, 36, 1200–1210.
  65. Smolen, G.A.; Sordella, R.; Muir, B.; Mohapatra, G.; Barmettler, A.; Archibald, H.; Kim, W.J.; Okimoto, R.A.; Bell, D.W.; Sgroi, D.C.; et al. Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proc. Natl. Acad. Sci. USA 2006, 103, 2316–2321.
  66. Corso, S.; Ghiso, E.; Cepero, V.; Sierra, J.R.; Migliore, C.; Bertotti, A.; Trusolino, L.; Comoglio, P.M.; Giordano, S. Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition. Mol. Cancer 2010, 9, 121.
  67. Corso, S.; Comoglio, P.M.; Giordano, S. Cancer therapy: Can the challenge be MET? Trends Mol. Med. 2005, 11, 284–292.
  68. Hidalgo, M.; Amant, F.; Biankin, A.V.; Budinská, E.; Byrne, A.T.; Caldas, C.; Clarke, R.B.; de Jong, S.; Jonkers, J.; Mælandsmo, G.M.; et al. Patient-derived Xenograft models: An emerging platform for translational cancer research. Cancer Discov. 2014, 4, 998–1013.
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    Giordano, S. Targeted Therapies for Gastric Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/14444 (accessed on 19 May 2022).
    Giordano S. Targeted Therapies for Gastric Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/14444. Accessed May 19, 2022.
    Giordano, Silvia. ''Targeted Therapies for Gastric Cancer,'' Encyclopedia, https://encyclopedia.pub/entry/14444 (accessed May 19, 2022).
    Giordano, S. (2021, September 23). Targeted Therapies for Gastric Cancer. In Encyclopedia. https://encyclopedia.pub/entry/14444
    Giordano, Silvia. ''Targeted Therapies for Gastric Cancer.'' Encyclopedia. Web. 23 September, 2021.
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