Targeted therapies in the treatment of gastric cancer

REVIEW ARTICLE

Targeted therapies in the treatment of gastric cancerajco_1407 224..235

Joanne NGEOW, Iain Beehuat TAN and Su Pin CHOODepartment of Medical Oncology, National Cancer Centre, Singapore

Abstract

Gastric cancer (GC) constitutes a major cause of cancer deaths worldwide. Recent improvements in bothsurgical techniques and adjuvant and neoadjuvant radiotherapy and chemotherapy approaches haveincreased the survival of patients with loco-regional disease. However most patients with GC have advanceddisease either at diagnosis or at follow up. Despite recent advances in the treatment of advanced disease,these patients still have poor outcomes. An emerging understanding of the molecular pathways thatcharacterize cell growth, cell cycle, apoptosis, angiogenesis and invasion has provided novel targets in cancertherapy. In this review we describe the current status of targeted therapies in the treatment of GC. Thesetherapeutic strategies include epidermal growth factor receptor inhibitors, antiangiogenic agents, cell cycleinhibitors, apoptosis, promoters and matrix metalloproteinases inhibitors.

Key words: angiogenesis inhibitor, EGFR inhibitor, gastric cancer, targeted therapy.

INTRODUCTION

Gastric cancer (GC) is common, being the secondleading cause of cancer-related deaths worldwide.1

Although the outcome for GC patients remains poor,recent advances in the field of oncology have resulted inthe increased survival of patients with advanced diseaseHowever, most newly diagnosed patients present withregional or distant metastatic disease where the 5-yearoverall survival (OS) is dismal and is generally acceptedas being <10%.2,3 To date, median survival beyond1 year has not yet been achieved in any randomizedstudy with combination chemotherapy4,5 despite anincrease in response rates (RR) in the range of 40–50%with the introduction of more recent regimens includingtaxanes or camptothecin analogues, or both.6–9 In addi-tion, no active second-line therapy has demonstrated adefinitive clinical benefit for patients with advanced GCthat progressed after first-line chemotherapy, whichrenders this clinical setting suitable for new active drugsdevelopment. In 2002 the US National Cancer InstituteProgress Review Group (NCI-PRG) for stomach cancers

recommended defining the biology and molecular fea-tures of the tumor that will help to customize treatmentand predict recurrence or survival for these patients. Inresponse, an increasing number of clinical trials havebeen initiated and completed using targeted therapies.

This article reviews the current status of biotherapy inGC and outlines potential future developments. Somestudies mentioned below include gastroesophageal junc-tion (GEJ) adenocarcinomas, which are largely seen assimilar in biology to gastric adenocarcinomas.

EPIDERMAL GROWTH FACTORRECEPTOR (EGFR) INHIBITORS

Biological agents that target EGFR inhibitors are at theforefront of novel anticancer therapies.10 The EGFR is atyrosine kinase receptor that belongs to the ErbB familyand is abnormally expressed and activated in cancercells in many tumor types. There are several potentialstrategies to target the EGFR, especially monoclonalantibodies (mAb) and the low molecular weight tyrosinekinase inhibitors (TKI), which are the most developedand have reached the clinic. mAb bind to the extracel-lular domain of the receptor and compete with thenatural ligands (tumor growth factor [TGF]-a and EGF)binding to the receptor, thereby blocking activationof the receptor. On the contrary, TKI compete with

Correspondence: Dr Su Pin Choo (MBBS, MRCP)Department of Medical Oncology, National Cancer Centre,Singapore 169610. Email: [email protected]

Accepted for publication 4 February 2011.

Asia–Pacific Journal of Clinical Oncology 2011; 7: 224–235 doi:10.1111/j.1743-7563.2011.01407.x

© 2011 Blackwell Publishing Asia Pty Ltd

adenosine triphosphate (ATP) binding to the tyro-sine kinase portion of the cytoplasmic domain of thereceptor and, thereby, abrogate the receptor’s catalyticactivity.

EGFR have been shown to be heterogeneouslyexpressed in individual gastroesophageal tumors. Of 89gastric adenocarcinomas from Mexican patients exam-ined in one report,11 the staining of neoplastic cells wasweak in 17 (19%, score 1), moderate in 16 (18%, score2) and strong in nine cases (10%, score 3). In an indi-vidual tumor there was heterogeneous EGFR reactivityranging from no reactivity to 3+ reactivity.

MONOCLONAL ANTIBODIESAGAINST EGFR

Cetuximab (Erbitux C225 [Merck, New York]), amonoclonal chimeric immunoglobulin (Ig)G1 antibodydirected against the extracellular domain of EGFR iswell advanced in clinical development12 and has beenapproved for the treatment of advanced colorectal car-cinomas (CRC) refractory to irinotecan-based chemo-therapy in many countries.13–15 Cetuximab has beendemonstrated to enhance the antitumor effect of bothtopotecan and irinotecan in CRC cell lines in vitro andin mouse xenograft models.16,17 This property is of inter-est because irinotecan is one of the most active singleagents in advanced GC.

Cetuximab has been investigated in multiple phase IIstudies in patients with advanced GC alone or in com-bination with various chemotherapy regimens inclu-ding irinotecan, cisplatin or docetaxel, 5-fluorouracil(5-FU), oxaliplatin, folinic acid (FUFOX/FOLFOX) and5-fluorouracil, irinotecan, folinic acid (FOLFIRI). Theresults of some of these trials are summarized in Table 1.

In heavily pretreated patients, single agent cetuximabshowed a low RR of less than 5% but in combinationwith irinotecan, a tumor control rate of over 60% wasachieved.18,19

In an Italian trial, the combination of cetuximabwith irinotecan and 5-FU plus FOLFIRI yielded a 44%overall RR (95% CI: 27.5–60.9%).20 The median timeto progression was 8 months (95% CI: 7–9 months). Inthe trial conducted by the German ArbeitsemeinschaftInternische Onkologie, cetuximab in combination withweekly oxaliplatin, 5-FU and FUFOX also yielded avery promising RR of 65.2% (95% CI: 49.8–78.6%).21

Responses appeared to be independent of the EGFRstatus determined by immunohistochemistry (IHC). Thetime to tumor progression was 7.6 months and OS was9.5 months. These two studies suggest that there may beincreased efficacy when an anti-EGFR antibody is com-bined with chemotherapy. In untreated patients withadvanced GC and cancer of the GEJ the combinationof cetuximab with different chemotherapy achievedRR of between 44 and 69%. Serious cetuximab-relatedadverse events included infusion reactions, skin toxicityand diarrhoea18–25

Cetuximab in combination with cisplatin and capecit-abine (EXPAND Trial) is being investigated in the pal-liative setting in a phase III study.27 Another trial isstudying the combination of cetuximab with irinotecan,5-FU and folinic acid.28

Other anti-EGFR mAb that have a mechanism ofaction similar to cetuximab are also in clinical develop-ment. Panitumumab, a fully human IgG2 monoclonalantibody to the EGFR, an established target in the treat-ment of several solid tumors including colorectal cancer,is being tested in combination with epirubicin, oxalipl-atin and capecitabine in the treatment of advanced GC

Table 1 Summary of selected trials of anti-epidermal growth factor receptor antibodies

Author Agents Disease stageNo of

patientsORR(%)

TTP(months)

OS(months)

Woell et al.18 Cetuximab + oxaliplatin/CPT Metastatic 51 63 6.2 9.5Tebbutt et al.19 Cetuximab + docetaxel Metastatic 38 6 2.1 5.2Pinto et al.20 Cetuximab + FOLFIRI Metastatic (EGFR +ve) 38 44 8 16Lordick et al.21 Cetuximab + FUFOX Metastatic 52 65 7.6 9.5Han et al.22 Cetuximab + FOLFOX Metastatic 40 50 5.5 9.9Pinto et al.23 Cetuximab + Cis/docetaxel Unresectable/metastatic 48 41 NS NSZhang et al.24 Cetuximab + Cis/capecitabine Metastatic 49 48 5.2 NSYeh et al.25 Cetuximab + CI 5-FU/LV/Cis Metastatic 35 69 11.0 14.5Rao et al.26 Matuzumab + ECX Metastatic (phase 1) 21 65 5.2 NS

5-FU, 5-fluorouracil; CI, continuous infusion; Cis, cisplatin; CPT, irinotecan; ECX, epirubicin/cisplatin/capecitabine; FOLFIRI, biweekly bolus5-FU/leucovorin, irinotecan, infusional 5-FU; FOLFOX, biweekly bolus 5-FU/leucovorin, oxaliplatin, infusional 5-FU; FUFOX, weekly oxaliplatin/leucovorin/infusional 5-FU; LV, leucovorin; NS, not stated; ORR, objective response rate; OS, overall survival; TTP, time to progression.

Gastric cancer targeted therapy 225

© 2011 Blackwell Publishing Asia Pty LtdAsia–Pac J Clin Oncol 2011; 7: 224–235

(REAL3 Study) as well as in the perioperative setting.29,30

Initial data from the REAL-3 dose-finding study foundthat panitumumab at 9 mg/kg was well toleratedwhen combined with epirubicin at 50 mg/m2, oxalipl-atin 100 mg/m2 and capecitabine 1000 mg/m2/day.31

The addition of matuzumab to epirubin, cisplatin andxeloda compared with the chemotherapy combinationalone did not increase survival or responses in a ran-domized phase 2 trial.26 Thus, further study with matu-zumab in GC has not been recommended. A phase 2study using nimotuzumab in combination with radia-tion and capecitabine in GC is underway in China.32

ANTI-EGFR TYROSINE KINASEINHIBITORS

A large number of small molecule TKI are directed tothe EGFR family in clinical development. Gefitinib(Iressa, ZD1839, AstraZeneca) has been evaluated inGC in two different studies. In the first study gefitinibwas administered at 250 or 500 mg in Japanese andnon-Japanese patients with advanced GC who hadfailed one or two previous chemotherapy regimens.The safety profile was optimal but clinical activitywas modest, with only one patient achieving a partialresponse (PR) and 12 out of 71 evaluable patientsshowing stabilization of the disease (SD).33 Gefitinibdemonstrated activity against its target, the EGFR; inthese gastric tumors, resulting in a complete and statis-tically significant inhibition of EGFR phosphorylationin tumors. There were hints of biological effects ofEGFR inhibition in some tumors. For example, theproliferation marker Ki67 was significantly inhibited inEGFR-positive tumors treated with gefitinib and thisinhibition in proliferation correlated with a significantreduction in the activation of MAPK.34 All the patientsinvolved in this trial had late stage, metastatic disease,with approximately half of them receiving gefitinib asa third-line therapy. It is possible that the disease wastoo advanced for this biological activity to translateinto a clinical benefit. In another study 27 patients withadvanced esophageal adenocarcinoma were treated withgefitinib 500 mg daily. Almost 70% of the patients hadpreviously received chemotherapy. Overall 37% of the27 patients obtained disease control and treatment waswell tolerated. Interestingly, a gene-profiling analysis inpaired tumor biopsies was done in this study, demon-strating the downregulation of oncogenes associatedwith tumor progression by gefitinib. Ki67 expressionwas decreased in five of seven biopsies.35

Erlotinib (Tarceva OSI-774, Genentech, San Fran-cisco, CA, USA) has also been evaluated in patients withadvanced GC and esophageal adenocarcinomas, withmodest results. In a phase II study performed at theMemorial Sloan Kettering Cancer Center, 22 patientswith either adenocarcinomas or squamous cell carci-noma were treated with erlotinib 150 mg/day. Twopatients achieved PR but both had squamous cell carci-noma histology. Overall, the disease control rate was55%.36 In a second study 70 patients with either GCor gastroesophageal junction adenocarcinoma (GEJC)were treated with erlotinib. No patient in the GC cohort(26 patients) presented an objective response, but fivepatients in the GEJC cohort presented an objectiveresponse (including one complete response [CR]) for anoverall RR of 11%. The median OS was 3–5 monthsand 6–7 months in the GC and GEJC cohorts, res-pectively.37 These preliminary efficacy results with TKI,especially in the GEJC and EC groups, merit furtherclinical evaluation. In addition, there is preclinical evi-dence of a synergistic antitumor effect combining cyto-toxic agents like taxanes, raltitrexed and platinums withgefitinib in several tumor types, including GC.38

Both EGFR MoAb (e.g. cetuxumab) and EGFR TKI(e.g. gefitinib) inhibit the EGFR pathway but havedifferent modes of action at the target level. MoAbare competitive antagonists of EGFR, independent ofreceptor phosphorylation status, while TKI act on thecytosolic ATP binding domain of EGFR by inhibitingEGFR autophosphorylation. Part of the antitumor activ-ity of MoAb can be attributed to antibody-dependentcellular cytotoxicity that can vary between patients withdifferent genotypes for Fc receptors and this can accountfor the variability in MoAb efficacy.39 On the otherhand, pharmacokinetic variability appears to be moremarked with TKI than MoAb due to cytochromep450 polymorphisms and associated treatment on thisenzymatic pathway.40 Furthermore, TKI are adminis-tered orally. This could possibly explain differences inresponse among GC patients, some of whom have hadgastrectomies, to MoAb compared to TKI.

ANTI-HER-2 THERAPY

HER-2 is another member of the EGFR family and isoverexpressed in a proportion of GC. In a recent analy-sis of 1527 gastric tumor samples, 341 (22%) wereHER-2 positive and 1186 HER-2 negative.41 IHC andfluorescence in situ hybridization (FISH) were concor-dant in 87% of samples, with differences largely beingdue to FISH-positive cases that were IHC 0/1+. Her 2

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positivity differed significantly by histological subtype:34% intestinal, 6% in diffuse and 20% in mixed types.HER-2 positivity also varied according to the site of thetumor, with rates of 32% (23/72) in GEJ tumors and18% (149/817) in gastric tumors.42,43 However, a recentstudy combining two independent series, the largest todate (N = 924), demonstrated that HER-2 expression isnot related to GC patient prognosis and suggested thatonly a very small subgroup of intestinal-type GC maypotentially respond to HER-2 -targeting therapy.44 Theauthors also highlight the problem of prominent intra-tumoral heterogeneity of HER-2 expression in GC.For example, HER-2 testing on endoscopic biopsiespretreatment was found to be prone to false negativeresults, in comparison with resected specimens. Morework needs to be done to provide assurance that HER-2status is accurately described in cases of GC.

MONOCLONAL ANTIBODIESAGAINST HER-2

Despite these issues, on 28 January 2010 Europeanauthorities approved trastuzumab (a monoclonal anti-body against HER-2) in combination with chemotherapyfor the first-line treatment of patients with HER-2-positive advanced GC. The license was granted followingthe positive opinion of the Committee for MedicinalProducts for Human Use, and was reviewed throughan accelerated process after promising findings werereported from the international phase III trastuzumabfor gastric cancer (ToGA) study. This study assessed theaddition of trastuzumab to a cisplatin plus fluoropyrimi-dine (FP) chemotherapy doublet for patients with HER-2-positive advanced gastric or GEJ adenocarcinoma andis the first targeted biological therapy to show a survivalbenefit in this difficult-to-treat cancer. The investigatorsreported a clinically and statistically significant benefit interms of RR (47.3 vs 34.5% for cisplatin and FP alone;

P = 0.0017), median PFS (6.7 vs 5.5 months, P = 0.0002)and median OS (13.8 vs 11.1 months, P = 0.0046).45 Apost hoc analysis divided patients into two large sub-groups, with either high (immunohistochemistry 2+ andFISH positive or immunohistochemistry 3+; n = 446) orlow (immunohistochemistry 0 and FISH positive orimmunohistochemistry 1+ and FISH positive; n = 131)levels of HER-2 protein in their tumors. The hazardratio (HR) for patients whose tumors had high HER-2expression was 0·65 (95% CI: 0.51–0.83) and medianOS was 16.0 months (95% CI: 15–19) in those assignedto trastuzumab plus chemotherapy compared with11.8 months (10–13) in those assigned to chemotherapyalone (P = 0.036). Trastuzumab plus FP chemotherapyis now the standard of care for patients with advancedgastric and OGJ cancers which overexpress HER-2.However, determining HER-2 overexpression in GCneeds to be defined better and whether trastuzumab iscost effective in GC is debatable.46

ANTI-HER-2 TYROSINEKINASE INHIBITORS

Lapatinib is an orally active, small molecule dual TKI ofEGFR and HER-2 with known efficacy in trastuzumab-resistant advanced breast cancer. Activity has beenreported in the HER-2-amplified GC cell lines SNU-216and NCI-N87 with unexpected additional activity inselected HER-2-negative and EGFR-negative cell linessuch as SNU-484.47 Additive or synergistic antitumoreffect with 5-FU, cisplatin, oxaliplatin, paclitaxel, irino-tecan48 and trastuzumab49 has been demonstrated in GCcell line studies, providing the rationale for evaluatinglapatinib in combination regimens.

A phase II study of lapatinib monotherapy as a first-line treatment for advanced GC has been presentedalthough not yet published50 (Table 2). In total 47 unse-lected patients with previously untreated advanced GC

Table 2 Summary of trials of anti- HER-2/neu monoclonal antibodies and tyrosine kinase inhibitors


patientsORR(%)

TTP(months)

OS(months)

Bang et al.45 5-FU or capecitabine + Cis vsTrastuzumab + 5-FUor capecitabine + Cis

Metastatic 290 34.5 5.5 mos 11.1 mos

294 47.3 6.7 mos 13.8 mos

Iqbal et al.50 Lapatinib Metastatic 47 7 2 mos 5 mosHecht et al.51 Lapatinib Metastatic (HER-2

amplified)25 0 NS NS

5-FU, 5-fluorouracil; Cis, cisplatin; NS, not stated; ORR, objective response rate; OS, overall survival; TTP, time-to-progression.



were treated with lapatinib 1500 mg daily and the inves-tigators reported evidence of limited single agent activitywith a 12% RR, median time to treatment failure of2 months and OS of just 5 months in the 46 evaluablepatients. A second phase II study of lapatinib mono-therapy in patients with HER-2-positive (measured byIHC or FISH) previously treated adenocarcinoma of theGEJ or the esophagus reported no objective responses.51

A phase II study where lapatinib is given either as a singleagent or combined with capecitabine is recruiting parti-cipants.52 At present lapatinib is being investigated inseveral phase III studies. In the global study (TYTAN),safety data were presented when lapatinib was combinedwith paclitaxel in the second line setting.53 The LoGICtrial in a first-line metastatic setting combining lapatinibwith capecitabine and oxaliplatin is also currently under-way.54 It will be interesting to learn if the phase III trialswill be able to improve on the limited responses seen inthe reported phase II setting.

There are, however, several unanswered issues in rela-tion to HER receptors in GC. First, it is not known whatlevel of HER-2 expression is required to obtain clinicalbenefit. While a relationship appears to exist betweenthe levels of HER-2 expression and a response to tras-tuzumab, no clear association has emerged between thelevels of EGFR and a response to EGFR inhibitors.Second, it remains to be established which patients aremost likely to benefit, and which patients will show thegreatest response to these therapies. There is a clear needto identify predictive markers of response (e.g., gene andproteomic profiles) in order to select patients who aremost likely to benefit from HER-2 inhibitors, and clearlyidentify those patients who will not benefit. Anotherpotential concern that must be addressed if HER-2-positive patients with GC are to continue to benefit fromtrastuzumab treatment is an improved understandingof the development of resistance to these molecularlytargeted therapies. Lessons can be learned from thebreast-cancer setting, where some patients develop resis-tance over time despite an initial response to trastu-zumab. This has led to the dilemma of whether tore-challenge patients with the same drugs, whether toswitch to another drug or whether to try different com-binations of agents. Together, these are active areas ofresearch in breast cancer and will likely become of vitalimportance in gastric-cancer treatments.

ANGIOGENESIS INHIBITORS

One novel approach in the treatment of solid tumorsinvolves therapeutic agents that inhibit the neovascular-

ization process of growing tumors. There is strong evi-dence that links tumor growth and metastasis with theangiogenesis process in most human tumors, includingGC.55 The formation of a vascular network in tumorgrowth involves different complex pathways includingangiogenic factors, membrane receptors and signalingtransduction cascades, leading at the end to new vesselformation.56 The vascular endothelial growth factor(VEGF) is the most potent and specific angiogenic factorand its expression in pathology specimens in patientswith GC has been demonstrated to correlate with recur-rence and prognosis. One recent study suggests that theactivation of the EGFR-pathway contributes to angio-genesis in GC by different mechanisms, including theupregulation of VEGF and neuropilin-1 expression.57

Multiple strategies have been developed to inhibit theVEGF pathway but two different approaches havereached advanced clinical development. The first is thegeneration of a humanized mAb directed to the VEGFitself. Bevacizumab (Avastin, Genentech) is a recombi-nant humanized anti-VEGF mAb that is being clinicallyevaluated in many tumor types. The second strategydirected to the VEGF pathway comprises different smallmolecules TKI that are directed to the receptors of theVEGF, Flt-I and Flt-I/KDR.

Bevacizumab was recently studied in several phaseII trials in gastroesophageal cancer58–62 (Table 3). In astudy in the first-line treatment of advanced disease,bevacizumab combined with cisplatin and irinotecanshowed an impressive RR of 65% with 12.3 monthsmedian OS. Notably, 6% of patients had gastroin-testinal perforations and 25% of patients developedthromboembolism, both known to be adverse effects ofbevacizumab. These toxicities raised concern about thesafety profile of bevacizumab but this was not seen inthe phase II trial combining bevacizumab with doc-etaxel, though it did lead to 10% arterial thromboem-bolic and 15% bleeding complications.59

Apart from questions regarding the toxicity profile,the efficacy of bevacizumab when added to chemo-therapy was disappointing in the only randomized phaseIII study to date. Bevacizumab was combined withcisplatin and capecitabine to give a median OS of12.1 months compared to 10.1 months with chemo-therapy alone in the intent-to-treat population. Whilethe primary end-point was not met (median OS HR0.87; P = 0.1002), there was a significant improvementin PFS and objective RR.63 It remains to be seen ifbevacizumab will play a significant role in the manage-ment of advanced GC. It is being studied in a largerandomized phase III study by the UK Medical Research

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Council in a perioperative setting using bevacizumabwith epirubicin, cisplatin and capecitabine. These twotrials should ultimately clarify the efficacy and also thesafety of bevacizumab in the treatment of stomachcancer.

Another interesting monoclonal antibody targetingthe VEGFR-2, ramucirumab (IMC-1121B) showedactivity in GC in a phase 1 trial and is being investigatedin a phase 3 trial in combination with paclitaxel.65

The anti-angiogenesis effects of VEGFR TKI in GChave been demonstrated in different preclinical models.Sunitinib (Sutent, Pfizer, New York) has been shown tosuppress peritoneal dissemination in an in vivo modelwith mice bearing TMK-I human gastric tumors.66

Results from a phase II study suggest disappointingclinical activity of single agent sunitinib as a second-linetreatment in GC.64 Of 78 patients enrolled, only 2.5%showed a PR, with a further 32% showing SD. VEGF-Trap is a potent antiangiogenic soluble recombinantdecoy protein constructed from VEGF receptor-1 andVEGF receptor-2 binding domains fused to a humanIgG1 constant region peptide.67 Its biological affinity forVEGF is reported to be significantly higher than that ofbevacizumab;68 however there are no preclinical data tosuggest its increased efficacy in GC. VEGF-Trap is cur-rently undergoing several early phase clinical trialswhich include GC. Phase II trials involving VEGF-Traphave focused on other tumor types such as ovariancancer and CRC rather than GC.

Sorafenib is a potent inhibitor of Raf tyrosine kinaseand of several other receptor tyrosine kinases includingVEGFR-2, VEGFR-3 and PDGFR-b. A phase II studyincluding 44 patients with advanced GC or GEJ cancersused the combination of sorafenib with docetaxel andcisplatin. In this trial the objective RR was 38.6%,

including one CR. The median PFS was 5.8 months andOS 14.9 months. The authors are planning to test thiscombination in a phase III study.69

Overall, the role of antiangiogenic drugs for the treat-ment of GC is not yet established. Importantly, safetyconcerns regarding the risk of tumor perforation andthromboembolic events must be studied further. Atpresent, bevacizumab and other anti-VEGF treatmentsare not approved and a careful risk and benefit estima-tion is needed when their use outside of clinical trials isconsidered.

APOPTOSIS PROMOTERS

The transcription factor nuclear factor-kB (NFkB) isimplicated in GC carcinogenesis and survival, and itsinhibition by proteosome inhibition is associated withpreclinical GC antitumor activity.70–72 Activation of theNF-kB signaling pathway can stimulate proliferation orreduce the effectiveness of chemotherapy or radio-therapy.73 Bortezomib (Velcade; PS-341, MillenniumPharmaceuticals, Cambridge, MA, USA) is a small mol-ecule and a potent and selective inhibitor of the protea-some, which has received regulatory approval for thetreatment of refractory myeloma. Bortezomib hasshown antitumor activity in a variety of other tumortypes, including GC. In a phase II study as a single agent,bortezomib 1.3 mg/m2 was administered on days 1, 4, 8,and 11 every 21 days. to 16 patients. No patients dem-onstrated an objective response (95% CI: 0–22%) andone patient achieved SD,74 leading the authors to con-clude that single agent bortezomib is inactive in meta-static gastric adenocarcinoma and should not bepursued.

Table 3 Summary of selected trials of anti-vascular endothelial growth factor monoclonal antibodies and tyrosinase kinaseinhibitors


patientsORR(%) TTP OS

Shah et al.58 Bevacizumab + Cis/CPT Metastatic 47 65 8.3 months 12.3 monthsKelsen et al.59 Bevacizumab + docetaxel/Cis/5-FU Metastatic 44 67 12 months 16.2 monthsEnzinger et al.60 Bevacizumab + docetaxel/Cis/CPT Metastatic 32 63 NS NSEl-Rayes et al.61 Bevacizumab + docetaxel/oxaliplatin Metastatic 23 59 NS NSEnzinger et al.62 Bevacizumab + docetaxel Metastatic (2nd-line) 26 24 NS NSKang et al.63 XP + Bevacizumab Metastatic 387 46 NS 12.1

XP + placebo 387 37 10.1Bang et al.64 Sunitinib Metastatic (2nd-line) 42 5 17.1 weeks 50.7 weeks

5-FU, 5-fluorouracil; Cis, cisplatin; CPT, irinotecan; XP, xeloda (capecitabine) and cisplatin, capecitabine and cisplatin; NS, not stated; ORR,objective response rate; OS, overall survival; TTP, time to progression.



The lack of single agent activity was seen in anotherphase II study in which bortezomib was given alone ina chemotherapy-refractory setting and with irinotecanif the patients were chemo-naive. The cohort ofpatients treated with the combination presented signifi-cant activity with a PR rate of 28% and a median PFSof 3.5 months, whereas in patients treated with bort-ezomib alone the RR was 0% and the median PFS1.4 months.75 The preliminary results from gene profileanalysis of eight paired tumor samples showed that theexpression of 643 genes significantly changed afterbortezomib treatment and 42% of the genes changedby � twofold between pretreatment and on treatment.The pathways that were significantly upregulated anddownregulated were the apoptotic, PI3K and MAPKsignaling pathways.76 We await the full results of thestudy and it would be interesting to see if there aredifferences between patients receiving bortezomib as asingle agent versus bortezomib in combination withchemotherapy. Future studies of proteasome inhibitionin gastric adenocarcinoma should be considered incombination with the targeted inhibition of other non-overlapping oncogenic pathways as a potential rationalapproach.

MATRIX METALLOPROTEINASE(MMP) INHIBITORS

MMP are a family of zinc-dependent proteolyticenzymes that are responsible for the breakdown of con-nective tissue proteins. There is now considerable evi-dence that aberrant MMP expression contributes toinvasive local growth and spread in different tumortypes.77 MMP-2, MMP-7, MMP-9 and MMP-14 areoverexpressed in GC.78–80 Indeed, the expression ofMMP-2 has been shown to be strongly associated withtumor progression and lymph node metastasis in GC.81

Marimastat (BB 2516, TA 2516) is an orally activeMMPI. The data from early clinical trials of marimastatare difficult to interpret as most trials have beenreported in abstract form only or were conducted ascombination phase I/II studies and the results reportedprimarily in terms of activity across all or a selectedrange of doses. A phase III study was conducted inpatients with advanced GC and GEJC comparing mari-mastat versus placebo, with the primary objective beingto demonstrate an advantage in the median OS for thosepatients allocated to receive marimastat.82 A total of 369patients were included in the study who had eitherreceived previous 5-FU-based chemotherapy treatment(123 patients) or were chemo-naive. The analysis of the

population showed a median OS of 5.2 months and4.5 months (HR 1.23, P = 0.07) and a 2-year OS of 9%and 3% (HR 1.27, P = 0.024) in the patients receivingmarimastat and placebo, respectively. However, due toits poor tolerability (musculoskeletal toxicity) this drugwas not further developed in this setting.82 The clinicaldevelopment of another oral MMP inhibitor, prinomas-tat, has also halted due to an unfavourable toxicityprofile.83

MAMMALIAN TARGET OFRAPAMYCIN (mTOR)

The mTOR was discovered about 15 years ago whileinvestigating the mechanism of action of rapamycin.mTOR is found to be a key protein kinase of the phos-phatidylinositol 3-kinase (PI3K)/Akt signaling path-ways. In GC, mTOR expression is commonly observed(60–88%) and has been associated with tumor regres-sion after rapamycin treatment in a variety of in vivosettings.84–86 The main mTOR inhibitors in clinicaldevelopment are rapamycin and its analogues (temsiroli-mus, everolimus, deforolimus). Among these, temsiroli-mus received the approval of the US Food and DrugsAdministration as the first of its class for the treatmentof renal cancer. However, it appears that the response tothese rapamycin analogues is limited even in tumorswith an aberrant activation of mTOR pathways. Thisphenomenon has been attributed to the complexity andcrosstalk of various signaling pathways associated withthe mTOR pathway, leading to resistance to specifictargeting agents. A number of known oncogenic pro-teins affected by mTOR are involved in the progressionof upper gastrointestinal cancers and mTOR inhibitorsmay prove a promising strategy. In a recent studyof everolimus in patients with previously treated GC,the disease control rate was a very respectable 59%,even though the objective RR was 0%.87 Patients withadvanced GC who experienced progression despite priorchemotherapy received everolimus 10 mg orally dailyuntil disease progression or study discontinuation. Theprimary end-point was the disease control rate (DCR),that is, CR, PR or SD. In all 53 patients were assessable(median age, 63 years; 51 and 49% had received oneor two prior chemotherapy regimens, respectively).Although no CR or PR was obtained a decrease intumor size from baseline was observed in 45% ofpatients by central review. The DCR was 56.0% (95%CI: 41.3–70.0%); median PFS was 2.7 months (95%CI: 1.6–3.0 months). These results are certainly en-couraging and warrant the further evaluation of mTOR

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inhibitors in patients with advanced GC. A global phaseIII trial is currently evaluating everolimus comparedto best supportive care in chemotherapy-refractoryadvanced GC (GRANITE-1 trial) and there are anumber of ongoing studies combining everolimus withcytotoxic chemotherapy.

OTHER NOVEL TARGETS

The receptor of the type-I insulin-like growth factor(IGF-IR) is a cell membrane receptor which is activatedby its ligands IGF-1 and IGF-2. IGF-IR has beenidentified as playing a critical role in malignant trans-formation, angiogenesis, metastasis and resistance toapoptosis. Strategies of targeting IGF-IR pathwayinclude the use of neutralizing antibodies and receptortyrosine kinases. A phase I trial combining docetaxeland IGF-IR antibody CP-751 871 showed promise inpatients with advanced gastroesophageal cancers.88

An emerging target is c-MET, which is the receptorfor hepatocyte growth factor. The MET oncogene isamplified in 10–15% of GC89 while c-MET has beenfound to correlate with a poor prognosis in GC.90 Pre-liminary results of foretinib (GSK136089), which actsagainst VEGF-R2 and c-MET has been reported. In all64 patients were enrolled and two doses of the drugwas tested. Although the objective response rate was0%, 21 and 25% of patients in the two cohortsachieved SD.91 Given that only a small number of GChave c-MET amplification, it would be important todetermine if a better objective response rate can beachieved if given to a c-MET amplified group which arecurrently ongoing.

DISCUSSION

Our understanding of tumor biology has greatlyexpanded over the past two decades. Rationallydesigned therapies aimed at specific molecular targetshave shown promising results. While the ToGA studyfindings suggest that HER-2 status should now routinelybe included in the diagnostic work-up of patients withadvanced GC it is important to bear in mind that about80% of patients with GC do not overexpress HER-2(using HER-2 assessment methods developed and vali-dated in breast cancer) and thus there is still a need tocontinue to optimize chemotherapy regimens and testother novel strategies. Although ToGA and a number ofother recent trials offer hope for new treatments, thequestion of what proportion of patients will benefitfrom these costly targeted drugs remains to be deter-

mined, and detailed molecular studies will be needed toguide individualized therapy. Furthermore, it will beinteresting to see whether trastuzumab and other tar-geted agents in this setting are assessed favourably bycost-effectiveness analysis to unlock the true utility oftargeted agents in GC.

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