Clin Exp Pharmacol Physiol. 2017;44:613–622. wileyonlinelibrary.com/journal/cep © 2017 John Wiley & Sons Australia, Ltd
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613 DOI: 10.1111/1440-1681.12743R E V I E W A R T I C L E
Gastric cancer management: Kinases as a target therapy
Batoul Farran
1|
Susanne Müller
2|
Raquel C Montenegro
3Abbreviations: AKT, Protein kinase B; ARID1A, AT-rich interactive domain-containing protein 1A; BCR-ABL, Breakpoint cluster region protein- Abelson murine leukemia viral oncogene homolog 1; B-RAF, Proto-oncogene b-RAF; CIK, Cytokine inducer-killer cells; CIN, Chromosomally instable; c-MET, Tyrosine-protein kinase Met/hepatocyte growth factor receptor; CTLA-4, Cytotoxic T-lymphocyte-associated protein 4; Da, Dalton; EBV, Epstein–Barr virus; EGFR, Epidermal growth factor receptor; ERBB2, Er-b b2 receptor tyrosine kinase 2; ERK, Extracellular signal-regulated kinase; FDA, Food and Drug Administration; FGFR, Fibroblast growth factor receptor; FISH, Fluorescence in situ hybridization; FOLFOX, chemotherapy regimen composed of FOL (folinic acid), F (fluorouracil) and OX (oxaliplatin); GC, Gastric cancer; GS, Genomically stable; Her2, Human epidermal growth factor receptor 2; IHC, Immunohistochemistry; JAK, Janus kinase; MAPK, Mitogen-activated protein kinase; MSI, Microsatellite unstable; mTOR, Mechanistic target of rapamycin; OS, Overall survival; PD-L1, Programmed death-ligand 1; PFS, Progression free survival; PI3KCA/B, Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta isoform; PI3K, Phosphatidylinositol-4,5-bisphosphate 3-kinase; PKA, Protein kinase A; PTK, Protein ty-rosine kinase; RTK, Receptor tyty-rosine kinase; SMI, Small-molecule inhibitor; STK, Serine-threonine kinase; TAMs, Tumor-associated macrophages; VEGFR, Vascular endothelial growth factor.
1Department of Structural and Molecular
Biology, University College London, London, UK
2Buchmann Institute for Molecular Life
Sciences, Johann Wolfgang Goethe-University, Frankfurt am Main, DE, Germany
3Drug Research and Development
Center, Federal University of Ceará, Fortaleza, CE, Brazil
Correspondence
Raquel C Montenegro, Drug Research and Development Center, Federal University of Ceará, Fortaleza, CE, Brazil.
Email: rcm.montenegro@gmail.com
Summary
The molecular diagnostics revolution has reshaped the practice of oncology by facili
-tating the identification of genetic, epigenetic and proteomic modifications correlated with cancer, thus delineating ‘oncomaps’ for various cancer types. These advances have enhanced our understanding of gastric cancer, one of the most fatal diseases worldwide, and culminated in the approval of novel molecular therapies such as tras
-tuzumab. Gastric tumours display recurrent aberrations in key kinase oncogenes such as Her2, epidermal growth factor receptor (EGFR), PI3K, mTOR or c- Met, suggesting that these receptors are amenable to inhibition using specific drug agents. In this re
-view, we examine the mutational landscape of gastric cancer, the use of kinase inhibi
-tors as targeted therapies in gastric tumours and the clinical trials underway for novel inhibitors, highlighting successes, failures and future directions.
K E Y W O R D S
gastric cancer, kinases, monoclonal antibodies, precision medicine, small-molecule kinase inhibitors, targeted therapy
1
|
INTRODUCTION
Gastric cancer is a highly fatal malignancy and the third leading cause of death from cancer worldwide. Most of the cases arise in develop -ing countries and exhibit a twofold higher incidence in men than in women. Surgery alone does not usually provide a cure, even for rela -tively early stages of disease. Recurrence rates are unfortunately high and the 5- year survival rate for all stages remains low (25%- 30%).1–3
The past two decades have witnessed the advent of targeted can -cer therapies known as “molecular targeted therapies” or “precision medicine”. The development of targeted therapies requires the iden -tification of candidate targets crucial for cancer growth or survival, as the basis for the design of monoclonal antibodies or small- molecule inhibitors (SMIs) that interfere with the specific target (Figure 1). Examples include trastuzamab for HER- 2- overexpressing breast
cancer and vemurafenib for BRAF- mutant melanoma.4 Genomic test -ing has paved the way for potentially powerful detection tools to uncover new targets.5
2
|
MOLECULAR CLASSIFICATION OF
GASTRIC CANCER
Traditionally, the majority of gastric adenocarcinomas have been clas -sified into two distinct histological subtypes based on Lauren’s clas -sification: intestinal- type and diffuse- type. The intestinal- type is the end- result of an inflammatory process that progresses from chronic gastritis to atrophic gastritis leading to intestinal metaplasia and dysplasia, whereas the diffuse- type is often associated with genetic abnormalities.
Recent molecular profiling studies have permitted the transition from traditional histological classification systems to molecularly based classification schemes. The landmark TCGA study examined 295 gastric cancer tumours using six different molecular analysis platforms encompassing DNA, RNA and protein assays and proposed a novel molecular characterization defined by four genomic subtypes: Epstein– Barr virus (EBV)- positive, microsatellite unstable (MSI), genomically stable (GS) and chromosomal instability (CIN).8 EBV- positive tumours, which represent 9%- 10% of gastric adenocarcinomas, harbour high levels of non- silent PI3KCA mutations (80%), extreme DNA hyper -methylation, mutations in PTEN, SMADA, CDKN2A, ARIDA (55%) and BCOR (23%) and amplification of JAK2, ERBB2, PD- L1 and PD- L, sug -gesting that PI3K, JAK2 and immune checkpoint inhibitors could con -stitute valuable therapeutic options for the treatment of this tumour subtype.8–12
Microsatellite unstable tumours (22%) are prevalent in women and older patients, exhibit elevated levels of microsatellite instability without major chromosomal abnormalities and strongly correlate with MLH1 promoter hypermethylation as well as recurrent mutations in PIK3CA, ERBB3, ERBB2 and epidermal growth factor receptor (EGFR) but lack targetable amplifications.8,9,12,13 GS tumours (20%), associ
-ated with diffuse- type adenocarcinomas, are diagnosed in younger patients and enriched with recurrent CDH1 (37%), RHOA (15%) and inactivating ARID1A mutations. Fusions involving the RHO- family GTPase- activating proteins CLDN18 and ARHGAP26 were also observed and their chimeric products could impact RHOA regulation.
Finally the chromosomal unstable (CIN) subtype accounts for 50% of GC tumours and correlates with extensive aneuploidy, TP53 muta -tions (71%) and RTK- RAS amplification affecting EGFR, ERBB2, ERBB3, VEGFA, FGFR2, Met, NRAS/KRAS, JAK2, CD274, PDCD1LG2 and PIK3CA.8,9,11,12
This in- depth analysis has elucidated the distinct genomic land -scape of each GC molecular subtype, delineating specific mutational axes amenable to targeted molecular inhibition in different patient subsets. These advances have enabled extensive clinical trials inves -tigating potential therapies, leading to the implementation of game- changing therapeutic regimens and ongoing randomized trials of novel targeting compounds.
3
|
KINASES AS TARGETS OF
CANCER THERAPIES
Kinases constitute one of the largest families of proteins encoded by the human genome, with 518 kinase sequences confirmed so far.6,14 Based on their substrate preferences, kinases can be classi
-fied as serine- threonine kinases (STKs), which phosphorylate serine- threonine residues (400 members) or protein tyrosine kinases (PTKs), which phosphorylate tyrosine residues on downstream substrates (90 members).7,15 The elucidation of the first kinase signalling cascade
involving protein kinase A (PKA) in the 1960s marked a milestone in the field,14,16 followed by Varmus and Bishop’s breakthrough dis
-covery that protein kinases can act as oncogenes, which received the 1989 Nobel Prize in Physiology.17
As systematic profiling studies revealed, protein and lipid kinases constitute critical and ubiquitous drivers of neoplastic disease and have generated tremendous research efforts aimed at designing selective inhibitors that antagonize them. The most common exam -ple is the small- molecule inhibitor imatinib, which targets the consti -tutively active mutant kinase BCR- ABL, the hallmark oncogene for Philadelphia chromosome- positive chronic myeloid leukemia (Ph+ CML).7,18 Imatinib obtained FDA approval in 2001 and its success
story established the paradigm for pharmaceutical development in the post- genomic translational era, centred on the identification of an aberrant tumour- specific kinase followed by the design of a specific inhibitor that targets this kinase, compound optimization and clinical testing.7 Various classes of therapeutic drugs exist, including monoclo -nal antibodies and small- molecule kinase inhibitors.
3.1
|
Monoclonal antibodies
Monoclonal antibodies are large water- soluble molecules (typical molecular weight 150,000 Da) that usually target extracellular com -ponents such as ligands and receptors.19 Monoclonal antibodies that
inhibit growth factor receptor pathways encompass Erbitux (cetuxi -mab, Genentech/Roche, San Francisco, CA, USA), which binds to the EGF receptor tyrosine kinase (EGFR),20 thus preventing the interac -tion between EGF/EGFR and blocking the RTK- dependent signal -ling pathway in colorectal cancer.21,22 The humanized monoclonal
F I G U R E 1 Gastric cancer targets. Various small- molecule
antibody Vecitibix (panitumumab, Amgen, Thousand Oaks, CA, USA), can overcome cetuximab- induced resistance.23 The monoclonal anti -bodies Herceptin (trastuzamab, Genentech/Roche), which binds to the extracellular domain of ERBB2/Her2,24,25 and Pertuzamab (Perjeta,
Genentech/Roche), which inhibits the dimerization of Her2, can be used in combination for treating Her2+ breast cancer.26,27 Current
advances include the development of immunotherapeutic vaccines, such as the dHer2 vaccine, which is aimed at inducing comprehensive anti- Her2 immunity28 and is in clinical testing for breast cancer treat -ment. It has reached phase I/II trials and was shown to be safe and well tolerated.29,30
3.2
|
Small- molecule kinase inhibitors
The greatest breakthrough in molecular therapies, however, has stemmed from the development of small- molecule kinase inhibitors, which have markedly improved treatment outcomes for many cancers. SMIs are pharmacologically valuable because they can cross the lipid bilayer cellular membrane to interact with intracellular targets, thus interfering with the intracellular signalling of kinases. Kinase inhibitors can be divided into two classes, irreversible and reversible.14 Unlike monoclonal antibodies, which are very highly specific, SMIs display varying levels of selectivity. Although this type of target promiscuity contrasts with the concept of drug specificity predominant in pharma -ceutical design, the ‘multitargeting’ nature of some kinase inhibitors, such as imatinib or dasatinib, has proved to be their greatest advan -tage, allowing their expansion to the treatment of multiple cancers.7
4
|
ADVANCES IN TARGETED THERAPY
IN GASTRIC CANCER: THE TRASTUZAMAB
STORY
The standard treatment of localized or respectable locally advanced gastric cancer consists in surgical resection and D2 lymphadenectomy in combination with adjuvant therapies.31 Adjuvant treatment options comprise radiochemotherapy, perioperative chemotherapy and adju -vant chemotherapy including fluoropyrimidines, anthracyclines, plati -num agents, taxanes, and irinotecan.13 Combination therapy correlates with higher response rates and confers increased survival advantage compared to single agents. In the United States and Europe, the recommended first- line chemotherapy treatment for gastric adeno -carcinomas is a two- drug platinum- fluoropyrimidine combination of oxaliplatin plus 5- fluorouracil, S1 (in the EU) or capecetabin.12,13,32,33
Despite these various therapeutic options, the median survival rate for gastric cancer patients remains poor (1 year), stressing the need for tailored and genome- guided personalized treatment options with improved efficacy.
The addition of trastuzumab, the first targeted compound approved in GC, for the treatment of Her2- positive patients marked a major turning point in the first- line therapy of GC.12,13 This veritable
success story illustrates how the identification of a kinase biomarker can inform the selection of an effective therapeutic strategy that
targets a detected oncogene in patient populations harbouring this trait. Trastuzumab is a recombinant humanized monoclonal antibody against ERBB2/Her2 and binds to the extracellular domain of Her2, thus suppressing Her2- mediated signalling.34 Trastuzumab for gastric cancer (TOGA) was a phase III randomized controlled trial involving 594 patients with metastatic or locally advanced unrespectable Her2- positive gastric or GEJ adenocarcinoma.35 The patients were assigned
to a chemotherapy regimen composed of capecitabine plus cisplatin or fluorouracil plus cisplatin administered every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. The incorporation of trastuzamab to standard chemotherapy yielded an increased response rate (47% vs 35%), improved progression- free survival (PFS) (6.7 vs 5.5 months) and higher median overall survival (13.8 vs 11.1 months) compared to the chemotherapy alone arm, demonstrating the clinical benefit of trastuzamab addition. In an exploratory study, the clinical benefit of trastuzumab transpired most pronouncedly in the Her2- enriched population displaying IHC3+ and FISH+/IHC2+ tumours as opposed to IHC0 or 1+ cancer. The success of this study was consecrated by the approval of trastuzumab in com -bination with chemotherapy as a standard option for patients with Her2+ GC in 2010.9,34,35
The prospects of targeted therapy as a promising new tool in the therapeutic arsenal of GC were further supported by the approval of ramucirumab by the FDA in 2014 as a second- line treatment alone or in combination with paclitaxel for patients with local relapse or metastatic gastric cancer.36 Ramucirumab is a fully humanized mono -clonal antibody that antagonizes vascular endothelial growth factor (VEGFR)- 2 and inhibits angiogenesis in tumour cells.37 The inclu -sion of ramucirumab was based on the positive results of the phase III REGARD38 and phase III RAINBOW trials,39 which demonstrated improved median PFS and overall survival (OS) benefits.
5
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MOLECULAR TARGETED AGENTS IN GC
CLINICAL TRIAL
5.1
|
Her2 blockade
is currently underway while a phase III trial is evaluating the benefit of administering T- DM1 in association with taxane (clinicaltrials.gov NCT01641939).12
5.2
|
EGFR blockade
Epidermal growth factor receptor is overexpressed in 2.3%- 40% of GCs9 and represents an attractive target for molecular therapy in this
disease. The success of tyrosine kinase inhibitors (TKIs) and anti- EGFR monoclonal antibodies in solid tumours such as colorectal cancer has encouraged studies of their therapeutic potential in GC but results have been mitigated. A phase III EXPAND trial assessing the bene -fit of incorporating the chimeric monoclonal antibody cetuximab to a first- line regimen combining capecitabine and cisplatin in patients with advanced gastroesophageal adenocarcinoma showed negative results.43,44 Unsuccessful outcomes were replicated in the phase III
REAL3 trial exploring the addition of panitumumab to epirubicin, oxaliplatin, and capecitabine,45 as well as in phase II trials of nimotu
-zumab46 and erlotinib.47
5.3
|
VEGFR blockade
Vascular endothelial growth factor is overexpressed in up to 60% of GC and correlates with tumour aggressiveness, recurrence and advanced stage due to increased vascularization and angiogenesis.9,44
While ramucirumab was successfully incorporated into treatment strategies, the anti- VEGFR monoclonal antibody bevacizumab did not achieve the same success. The phase III AVAGAST study comparing bevacizumab addition to chemotherapy alone showed no median OS benefits.48 Interestingly, subgroup analysis revealed regional and eth -nic discrepancies in efficacy outcomes. For instance, while Asian and European patients did not derive any benefits from bevacizumab, its addition increased median OS in pan- American populations, indicating that the inclusion of bevacizumab as part of a combination therapy could improve survival outcomes in certain pre- selected population subsets. Another promising anti- VEGFR agent is the tyrosine kinase inhibitor apatanib, which has emerged as a potential targeted agent following clinical examination.49 A phase III trial of apatanib in Chinese
patients with chemotherapy- refractory advanced or metastatic GC reached its endpoints with prolonged OS and PFS,50 suggesting that
apatanib might provide a third- line option for the treatment of refrac -tory GC,51 although these results remain debated,52 Sunitinib53 and
sorafenib54 are two other TKIs that have been investigated in clinical
trials, yielding mixed results.
5.4
|
Fibroblast growth factor receptor blockade
Fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases that regulate angiogenesis and cell proliferation by activat -ing various downstream signall-ing cascades such as MAPK/ERK and PI3K/AKT/mTOR/p70S6 pathways.55 FGFR amplification is detectedin 3%- 16% of GC patients and constitutes a prognostic factor of poor survival rate.56 Several clinical trials testing the efficacy of FGFR- based
inhibition therapies including AZD4547,57 dovitinib58 and ponatinib59
for the treatment of advanced GC are currently under way. A phase II trial of AZD4547 versus paclitaxel in Asian patients with advanced FGFR2- enriched GC who failed first- line therapy showed no survival improvement.12 An ongoing phase II trial is evaluating the efficacy of dovitinib as a monotherapy for patients with previously treated advanced FGFR2- amplified GC (clinicaltrials.gov NCT01719549).9,12
Another phase I/II trial is testing dovitinib in combination with doc -etaxel as a second- line therapy irrespective of FGFR2 status.9,12
Alternatively, combination therapy using FGFR and/or VEGFR and immune checkpoint inhibitors could constitute a promising strategy for cancer patients.55
5.5
|
PI3K/ATK/mTOR pathway blockade
The PI3K/AKT/mTOR pathway orchestrates the regulation of pivotal cellular functions such as cell growth, proliferation, metabolism and angiogenesis and is one of the most frequently activated pathways in human cancers.60 Based on their structures and substrate prefer -ence, PI3Ks are divided into three different classes (I- III). Three types of PI3K inhibitors have been developed to target this prominent sig -nalling cascade, including pan- class I inhibitors active against p110 isoforms, isoform- specific PI3K inhibitors and dual PI3K/mTOR inhibi -tors, which target both PI3K and mTOR kinases.61 Recent research has shown that PI3KCA, PI3KCB, AKT1 and mTOR are overexpressed in GC cell lines and that the PI3K/AKT/mTOR pathway is activated in up to 60% of GC patients,62 corroborating the therapeutic suscep -tibility of this pathway.10 Consequently, various clinical trials evalu -ating the efficacy of AKT, PI3K and mTOR inhibitors against GC are underway. The AKT inhibitor MK- 2206 was assessed as a second- line therapy for advanced gastric malignancies in a phase II SWOG trial but failed to display sufficient activity.63 In contrast, a phase 1b study of MK- 2206 in association with trastuzamab in patients with advanced Her2- amplified malignancies including GC demonstrated significant clinical activity, warranting further investigation.64 Another AKT inhibitor, AZD5363, is being evaluated in combination with paclitaxel in patients with advanced GC harbouring PI3KCA mutation or ampli -fication (clinicaltrias.gov NCT02451956) or in biomarker negative (PI3KCA/MEK/RAS/TP53/Met) GC patients as a second- line chemo -therapy (clinicaltrials.gov NCT02449655). A phase II trial testing the activity of the AKT inhibitor ipatasertib (GDC- 0068) in combination with modified FOLFOX6 chemotherapy in participants with advanced GC (clinicaltrials.gov NCT01896531) is currently underway.
to an acceptable safety profile in patients with advanced breast and gastric tumours enriched with PI3Kα mutation (clinicaltrials.org NCT01449370).66 The mTOR inhibitor everolimus is an oral formula of a rapamycin analogue and has been investigated in a phase III GRANITE- 1 study, where it was compared to best supportive care in patients with refractory GC who had undergone at least one prior sys -tematic chemotherapeutic trial. Although median PFS was improved, everolimus did not confer a significant OS advantage.67 Despite these negative results, everolimus is currently being investigated in combi -nation with capecitabine and oxaliplatin in a phase I study (clinicaltri -als.gov NCT01049620) and in association with paclitaxel in a phase III trial in a second- line setting (clinicaltrials.gov NCT01248403). Given the disparate results registered by PI3K/AKT/mTOR inhibitors so far, studies evaluating the efficacy of combined RAS/MEK/ERK and PI3K/AKT/mTOR pathways have suggested that dual targeted therapy might be more effective than monotherapy in selected patients.61,68
5.6
|
c- Met blockade
Mesenchymal- epithelial transition (Met) receptor is amplified in 2%- 23% of GC and correlates with poor prognosis.9,12 Advances
in understanding the structure and function of c- Met have permit -ted the development of several inhibitory compounds such as c-Met receptor monoclonal antibodies and small- molecule c- Met kinase inhibitors. Many of these agents are currently undergoing clinical tri -als alone or in combination as potential targeted treatments for GC. The results have been disappointing so far. For instance, two large phase III trials for the c-Met antibody rilotumumab, RILOMET- 1 and RILOMET- 2, were halted in November 2014 due to increased death toxicity.69 Another randomized MetGastric (YO28322) phase III trial
investigating FOLFOX6 in combination with the antibody onartu -zumab was recently terminated due to aggravated death risk.49 SMIs
have also yielded mixed outcomes. The compounds foretinib and tivantinib, for instance, failed to exert antitumour activity in patients with advanced gastric cancer.70,71 The small- molecule kinase inhibi
-tor AMG- 337, which blocks c- Met transduction pathways and pro -vokes cell death in c- Met- enriched tumours, has also been tested. An ongoing phase I first- in- human trial investigating AMG- 337 efficacy in patients with c- Met amplified GC demonstrated sustained antitumour responses (clinicaltrials.gov NCT01253707).69 A phase II study of
AMG- 337 in Met- amplified GC is currently underway (clincaltrials.gov NCT02016534). Additionally, an awaited phase I/II trial will assess the efficacy of AMG- 337 in combination with oxaliplatin, leucoverin cal -cium and fluorouracil for the treatment of patients with advanced GC (clinicaltrials.gov NCT02344810).
6
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IMMUNOTHERAPY
Immunotherapy, which purports to harness the immune system to combat tumours, has emerged as a true paradigm changer in a num -ber of cancers and was designated the 2013 breakthrough of the year by Science.72 Immune- based strategies against cancer are based
on ‘immunization’.73 They act by inducing effective tumour- specific immunity in order to bypass immunological tolerance to the tumour and reinstate anti- tumour immunity.74 The therapeutic potential of immune therapies was kindled by the FDA’s approval of the human -ized antibody pembrolizumab (Keytruda), the first PD- L1 receptor inhibitor that activates a T- cell- mediated immune response against tumour cells of patients with unrespectable or metastatic melanoma, hailed as a “breakthrough therapy”75 in September 2014.76 This mile -stone was reinforced by the accelerated approval of another check -point inhibitor, the monoclonal antibody nivolumab (OPDIVO, Bristol Myers Squibb Co, New York, NY, USA), for the treatment of patients with unresectable or metastatic melanoma following ipilimumab or a B- RAF inhibitor in December 201477 or as a single agent for first- line treatment of patients with B- RAFV600 wild- type melanoma in 2015.78,79
The advent of immunotherapy has ushered in a new wave of pre- clinical and clinical trials aimed at assessing the therapeutic efficacy of immune- modulating therapies in gastric cancer. The gastric tumour microenvironment is enriched with macrophage populations, referred to as tumour- associated macrophages (TAMs) when recruited to the stroma. TAM infiltration results in the immunological inactivation of T cells in gastric carcinomas and constitutes an indicator of poor prognosis.80 Recent studies have indicated that ‘adoptive cell therapy’ using tumour- associated lymphocytes or cytokine inducer- killer cells (CIKs) combined with adjuvant chemotherapy significantly improve PFS and OS rates in gastric cancer patients.74,81 T lymphocytes har
-ness the power of the immune system to combat invading organisms and/or cells and their activity is tightly regulated by checkpoints that preclude the targeting of normal self tissues.82 Tumour cells abrogate T cell function and escape immunity by up- regulating the expression of checkpoint ligands, indicating that the selective targeting of these nat -ural inhibitory mechanisms could reinstate T lymphocyte activity and anti- tumour immunity.83 Two particularly attractive inhibitory receptor targets expressed by T cells are CTLA- 4 and PD- L1, for which antibod -ies have been widely developed and clinically corroborated in various tumour types.82 Interestingly, PD- L1 and PD- L2 expression is poten -tiated in Epstein–Barr virus- positive gastric tumours,8 supporting the potential benefit of implementing immune checkpoint inhibition strat -egies in these GC subtypes.
Recently, a KEYNOTE- 012 trial examined the safety and activity of pembrolizumab as a second- line treatment for patients with PD- L1 positive recurrent or metastatic carcinomas of the stomach or gastro- oesophageal junction.84 The drug induced a sustained anti- tumour response with manageable toxicity profiles in 22% of the tested population. Although the size of the final cohort was small (39 patients) and the EBV status of the patients was not assessed, the preliminary results of this trial indicate that anti- PD- L1 therapies might work in advanced GC and warrant a larger- scale study.85,86
versus paclitaxel in advanced GC patients with tumor progression fol -lowing first- line platinum and fluoropyramidine doublet therapy (clin -icaltrials.gov NCT02370498) to determine whether pembrolizumab activity prolongs PFS and OS or correlates with PD- L1 expression profiles (Table 1). The MK- 3475- 062/KEYNOTE- 062 phase III trial, on the other hand, will compare the clinical performance of pembroli -zumab as a first- line treatment or in combination with cisplatin+5- Fluorouracil versus placebo coupled to dual chemotherapy in patients with advanced gastric cancer (clinicaltrials.gov NCT02494583).
Likewise, the anti- tumour activity of the other FDA- approved anti- PD- L1 agent nivolumab in GC is currently under clinical scru -tiny. The phase I/II CheckMate- 032 study, for instance, is investi -gating the efficacy of nivolumab as a monotherapy or in associa -tion with the CTLA- 4 antibody ipilimumab in solid tumors including advanced or metastatic gastric carcinomas, irrespective of PDL- 1 status (clinicaltrials.gov NCT01928394). Initial results from this trial yielded promising anti- tumour activity and tolerable toxicity profiles in pretreated GC patients.85 In contrast, a phase II trial comparing
the efficacy of ipilimumab versus best supportive care following first- line chemotherapy in patients with unresectable advanced or metastatic GC failed to meet its primary endpoint and was termi -nated post- interim analysis (clinicaltrials.gov NCT01585987).85
Another PD- L1 antibody, avelumab, demonstrated encouraging clinical activity as a first- line maintenance or second- line therapy in patients with advanced GC (clinicaltrials.gov NCT01772004),85
warranting the initiation of two randomized phase III trials assessing avelumab as a third- line treatment (clinicaltrials.gov NCT02625623)
or as maintenance therapy compared to continuation of first- line chemotherapy (clinicaltrials.gov NCT02625610) in subjects with unresectable advanced or metastatic GC. Furthermore, a phase Ib/ II trial investigating the immunogenicity of the anti- PD- L1 antibody MEDI4736 in combination with the anti- CTLA- 4 antibody tremelim -umab and MEDI4736 or tremelim-umab monotherapies is currently underway (clinicaltrials.gov NCT02340975). While these various clinical trials are gauging the feasibility of tailoring novel personal -ized therapies that combine checkpoint inhibitor agents and chemo -therapeutic regimens, another potentially promising strategy resides in the integration of immunotherapeutic drugs with molecularly tar -geted therapies. To determine the clinical efficacy of this approach, two multicentre phase IB/II trials are currently evaluating the anti- tumour activity and toxicity of pembrolizumab in association with the anti- Her2 antibodies trastuzamab (clinicaltrials.gov NCT02901301) and margetuximab (clinicaltrials.gov NCT02689284) in patients with Her2- positive advanced GC. Table 2 summarizes all clinical trials currently investigating immunotherapy alone or in combination with chemotherapy in gastric cancer.
7
|
CONCLUSION
The molecular genotyping revolution has refined our understanding of gastric cancer and heralded the age of genome- guided targeted thera -pies. Kinase receptors are among the most frequently altered onco -genes in GC, rendering them key disease biomarkers and attractive
T A B L E 1 SMI clinical trials in gastric cancer
Target Current status Treatment Treatment benefits
Result P value
Angiogenesis (Multitarget) Phase II 2nd and 3rd line SUNITINIB/FOLFIRI vs Pacebo/ FOLFIRI
PFS months (3.5 vs 3.3)87 Negative P=.66
VEGFR2 Phase III 3rd line or more APATINIB (850 mg/daily vs placebo)
OS months (6.5 vs 4.7) 50 Positive P<.01 VEGFR2 Phase II 3rd line or more APATINIB (850 mg/daily vs
425 mg/BID vs placebo) PFS months (3.67 and 3.20 vs 1.40) 88
Positive
P<.001 and P<.001
Her2 Phase III 2nd line LAPATINIB/PTX vs PTX OS months (11 vs 8.9)41 Negative (Better IH3+)
P=.10
EGFR Phase II Cisplatin/Irinotecan/
GEFITINIB/daily
No benefit so far (clinicaltrials.gov NCT00215995)
Negative
RAF, VEGFR, PDGFR Phase I/II SORAFINIB (400 mg BID) No benefit (clinicaltrials. gov NCT00595985)
Terminated
FGF Phase I/II 2nd line or
more
TKI258 (500 mg p.o. pd) Recruiting (clinicaltrials.
gov NCT01719549) Ongoing
Multikinase inhibitor Phase II FORETINIB (240 mg/daily/5 d/ every 2 wk) or 80 mg/daily
ORR of ≥25%89
(clinicaltrials.gov NCT00725712)
Minimal efficacy
PARP Phase II/III 2nd line OLAPARIB/PTX vs PTX alone
(olaparib 100 mg BID/2xDaily vs PTX 80 mg/m2 i.v. vs
placebo)
PFS months (3.91 vs 3.55) OS months (13.1 vs 8.3)90 (clinicaltrials.gov
NCT01063517)
Ongoing
drug targets. The availability of rapid diagnostic platforms, such as the novel NanoString- based multigene assay which analyzes EGFR, Her2 and MET status in GC patients,91 facilitates the diagnosis and selec
-tion of effective molecular therapies. Despite these advances, the OS rate remains poor, especially since most cases are diagnosed at an advanced stage, which affects patient prognosis. The disparate results of clinical trials investigating kinase inhibitors and/or immunotherapy agents for GC treatment highlight the need for studies in biomarker- enriched populations and novel powerful inhibitors that improve ther -apeutic outcomes in patients.
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T A B L E 2 Immunotherapy drugs clinical trials in Gastric cancer
Target Current Status Treatment Treatment Benefits
Result P value
PD- L1 Phase II Pembrolizumab alone 200 mg i.v. or in
combination with Cisplatin 80 mg/m2
i.v. + 5- Fluoruracil 800 mg/m2
i.v. or Capecitabine 1000 mg/m2 i.v.
Ongoing (clinicaltrials.gov NCT02335411; NCT02494583)
Ongoing
PD- L1 Phase III Pembrolizumab 200 mg i.v. plus Paclitaxel
80 mg/m2 i.v.
Ongoing (clinicaltrials.gov NCT02370498)
Ongoing
PD- L1/CTLA- 4 (IgG1κ) Phase I/II Combination of Nivolumab 3 mg/kg and/
or 1 mg/kg plus Ipilimumab 1 mg/kg and/or Ipilimumab 3 mg/kg and Cobimetinib 60 mg
Recruiting (clinicaltrials.gov NCT01928394)
Ongoing
CTLA- 4 (IgG1κ) Phase II, 1st/2nd line Ipilimumab 10 mg/kg/All Best Supportive
Care (BSC)
OS (12.68 v 12.06) (clinicaltrials.gov NCT01585987)
No statistical analysis provided
PD- L1 Phase III, 3rd line Avelumab 10 mg/kg, Irinotecan 150 mg/
m2, PTX 80 mg/m2 and BSC
Recruiting (clinicaltrials.gov NCT02625623)
Ongoing
PD- L1 Phase III, 1st Line Avelumab 10 mg/kg, Oxaliplatin 85 mg/
m2, 5- Fluorouracil 2600 mg/m2, Leucovorin 200 mg/m2, Capecitabine
1000 mg/m2 and BSC
Recruiting (clinicaltrials.gov NCT02625610)
Ongoing
CTLA- 4/PD- L1 Phase I/II MEDI4736 i.v., Tremelimumab i.v.,
combined or alone
Recruiting (clinicaltrials.gov NCT02340975)
Ongoing
Her2/PD- L1 Phase I/II, 1st Line Pembrolizumab 200 mg i.v., Trastuzumab 6 mg/kg i.v., Capecitabine 1000 mg/m2,
Cisplatin 80 mg/m2
i.v.
Recruiting (clinicaltrials.gov NCT02901301)
Ongoing
Her2/PD- L1 Phase I/II, 1st Line Dose Escalation Margetuximab in combination with Pembrolizumab
Recruiting (clinicaltrials.gov NCT02901301)
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How to cite this article: Farran B, Müller S, Montenegro RC.
