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- Copyright © 2019 Giandomenico Roviello et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract
Hindawi Journal of Oncology Volume 2019, Article ID 5692317, 9 pages https://doi.org/10.1155/2019/5692317 Review Article Novel Agents in Heavily Pretreated Metastatic Gastric Cancer: More Shadows Than Lights 1 2 3 Giandomenico Roviello , Alberto D’Angelo, Raheleh Roudi, 4 1 Roberto Petrioli, and Enrico Mini Department of Health Sciences, University of Florence, Viale Pieraccini , Florence, Italy Department of Biology and Biochemistry, University of Bath, Bath BA AY, UK Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran Medical Oncology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy Correspondence should be addressed to Giandomenico Roviello; giandomenicoroviello@hotmail.it Received 25 March 2019; Revised 14 May 2019; Accepted 12 June 2019; Published 4 July 2019 Academic Editor: Pierfrancesco Franco Copyright © 2019 Giandomenico Roviello et al. is Th is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Metastatic gastric cancer is still a disease with a poor prognosis. Recently, dieff rent novel agents (e.g., apatinib, nivolumab, TAS- 102) have demonstrated a survival advantage compared with placebo for patients with heavily pretreated metastatic gastric cancer. Although the possible availability of active agents may be a desirable option in a very poor therapeutic scenario, clinical data from the recent studies with these drugs raise yet controversial issues. eTh purpose of this review is to briefly summarize the results of these novel drugs focusing on the limitations that bring some shadows on their positive therapeutic results. 1. Introduction population and from 2014 is approved in China [5]. In addition, nivolumab, a fully human IgG4 monoclonal anti- Increased survival of metastatic gastric cancer (GC) is still body inhibitor of programmed death-1 (PD-1), also showed an unmet clinical need. Generally, the first line of treatment a survival benefit compared with placebo in patients with is represented by a combination of chemotherapy with plat- advanced gastric cancer refractory to two or more pre- inum and uo fl ropyrimidine with or without a third drug [1]. vious regimens of chemotherapy [6], and more recently, Aeft r progression of disease from rfi st line, taxanes (mainly trifluridine/tipiracil, a novel oral combination cytotoxic drug paclitaxel) and irinotecan have been shown to be effective and also known as TAS-102, has signicfi antly improved overall tolerable [2], while ramucirumab, a human IgG1 monoclonal survival (OS) compared with placebo in heavily pretreated antibody against vascular endothelial growth factor receptor population of patients with advanced gastric cancer [7]. The 2 (VEGFR2), alone or in combination with paclitaxel has purpose of this review is to brieyfl summarize the results of statistically increased survival for GC patients [3, 4]. the studies with these novel drugs focusing on some limits Unfortunately, no clear evidence has been established for that might at least in part reside in their clinical relevance. patients who experience disease progression after a second line of therapy. In particular, no randomised, prospective clinical trial or guideline has supported the use of a specific .. Apatinib. Apatinib is a small-molecule receptor tyrosine drug. Recently, this scenario seems changed as novel agents kinase inhibitor that primarily binds to and inhibits VEGFR2 have been shown to increase survival in third or in a [5]. In addition, this agent inhibits c-Kit and c-SRC tyrosine further line of treatment. Based on the positive results of kinases at higher concentrations [5]. In 2013, Li et al. con- two randomized trials against placebo, apatinib, a small ducted a phase II, randomized, double-blinded, and placebo- selective VEGFR2 tyrosine kinase inhibitor, has been the controlled trial to evaluate the efficacy and safety of daily first to demonstrate a survival advantage in this GC patient apatinib administration as third-line treatment in patients 2 Journal of Oncology aec ff ted by metastatic GC [8]. The study was conducted at They also showed that toxicities were tolerable and clinically 15 hospitals in China with a total of 141 patients enrolled and manageable with elevated aminotransferase (45.2%), hand- randomly assigned to receive placebo (group A, number=48), foot syndrome (40.5%), and secondary hypertension (35.7%) as main adverse events. Up to date, no planned study will apatinib 850 mg once daily (group B, number=47), or apatinib 425 mg twice daily (group C, number=46). Apatinib investigate the role of Apatinib in non-Asian patients and in demonstrated improved OS and progression-free survival third or further line of treatment. (PFS) in heavily pretreated patients with metastatic GC who underwent two or more previous chemotherapy regimens’ .. Nivolumab. Nivolumab is a fully human IgG4 mono- failure. The median OS was significantly higher in patients clonal antibody known as a programmed cell death 1 (PD- treated with apatinib versus those given a placebo with a 1) immune checkpoint inhibitor. PD-1 is a transmembrane median OS of 2.50 months for patients in group A, 4.83 inhibitory immune-receptor, member of the B7-CD28 family, months for patients in group B, and 4.27 months for patients expressed on activated T, B, and natural killer cells [11]. in group C. Also, the PFS was significantly higher in patients Kang et al. assessed the safety and efficacy of nivolumab in administered with apatinib than in placebo with a median 493 patients with advanced gastric or gastroesophageal junc- PFS of 1.40 months for group A, 3.20 months for group B, and tion cancer intolerant of, or refractory to, two or more previ- 3.67 months for group C. As a noteworthy event, 9 patients ous regimens of chemotherapy in the randomised, placebo- (3 treated with apatinib 850mg and 6 treated with apatinib controlled, double-blinded, phase III ATTRACTION-2 [6]. 425mg) had a partial response confirmed on computer The study was performed at 49 hospitals in Taiwan, South tomography scan and 43% of patients given apatinib reached Korea, and Japan and the 493 patients were randomly disease control. assigned at a ratio 2:1 to receive 3mg/kg of nivolumab (n=330) In 2016, Li et al. performed a randomized, double-blind, or placebo (n=163) intravenously every 2 weeks; patients who placebo-controlled phase III trial to evaluate the efficacy had previously been treated with anti-PD-L1 or anti-PD-L2, and safety of apatinib in patients with advanced metastatic anti-PD-1, anti-CD137, or anti-CTLA4 were excluded from gastric cancer or gastroesophageal junction adenocarcinoma, the trial. The primary endpoint of the study was OS. Patients refractory to two or more lines of previous chemotherapy in the nivolumab group had longer survival of 5.26 months regimens [9]. The study was undertaken in 32 centres in compared to the placebo group with 4.14 months. The risk China and involved 267 patients randomly assigned at a of disease progression was lower in nivolumab group (46%) 2:1 ratio to receive apatinib-matching placebo tablets once than the placebo group (60%) and 11.2% of patients in the daily (number=91) or oral apatinib 850 mg in tablet form nivolumab group had an objective response (all confirmed (number=176). This phase III study reported that apatinib, partial responses) in comparison to a 0% in the placebo administered as monotherapy, prolonged OS and PFS: the OS group. In addition, 29.1% of patients in the nivolumab arm was 6.5 months for the apatinib group and 4.7 months for the achieved stable disease compared to the 25.2% of the placebo placebo group; likewise, the PFS improved from 1.8 months arm; thus the percentage of patients with disease control in the placebo group to 2.6 months in the apatinib group. was 40% in the nivolumab group and 25% in the placebo In addition, the objective response rate (ORR) achieved was group. Interestingly, two subgroup analyses indicated that 2.84% with apatinib and 0% with placebo whereas the disease nivolumab improved OS regardless of PD-L1 positivity and control rate (DCR) was critically higher in the apatinib previous ramucirumab treatment. Although symptomatic group (42.05%) compared to the placebo group (8.79%). adverse events were reported equally in both groups and the Unfortunately, no significant differences between the two incidence of serious treatment-related adverse events was low groups with regard to the quality of life have been reported. (mainly pruritus, diarrhoea, rash, and fatigue), a limitation In addition, dose reduction resulting from toxicity was more of this study was the absence of data about the quality common in the apatinib group mainly due to grade 3 to of life. A subsequent analysis from the ATTRACTION-2 4 hand-foot skin reaction (8.5%), proteinuria (2,3%), and showed a similar OS improvement of Nivolumab compared hypertension (4.5%). to placebo in the Japanese subpopulation [12]. In addition, In 2017, Ruan et al. carried out a multicenter, open-label, data from the gastric cohort from the multicenter, phase single-arm phase II study to evaluate the safety and efficacy I/II CheckMate-032 [13] trial demonstrated a clinical activity of apatinib in patients aec ff ted by metastatic GC [10]. They of nivolumab and nivolumab plus ipilimumab in patients enrolled a total of 42 patients from 4 different institutions with chemotherapy-refractory esophagogastric cancer; how- in China with a histologically confirmed metastatic GC ever, phase III studies are awaited to conrfi m these data. diagnosis, with no previous molecular target therapy but a Finally, although several studies are investigating the role of second-line or last chemotherapy regimen failure. All patients nivolumab in GC, no other studies are planned in third or were administered with apatinib 850 mg daily 30 minutes further line of therapy. postprandially on days 1 to 28 of each 4-week cycle. They clearly demonstrated that apatinib is safe and with good efficacy in pretreated metastatic GC patients as the median .. Trifluridine/Tipiracil. TAS-102 is a noveloralcytotoxic PFS and OS reported were 4.0 months (95% CI, 2.8-5.1) chemotherapy consisting of a combination of trifluridine: and 4.5 months (95% CI, 4.0-4.9), respectively. The disease thymidine-based nucleoside analogue and tipiracil: a thymi- control rateand objective responseratewere78.6% and dine phosphorylase inhibitor. For this reason, TAS-102 has a 9.5% aer ft 2 cycles and 57.1% and 19.0% aer ft 4 cycles. unique mechanism of action [14, 15]. Journal of Oncology 3 In 2016, Bando et al. performed a multicenter, phase II, irinotecan in patients with gastrointestinal cancers (including single arm, open-label study to assess the safety, pharmacoki- GC). netic, and efficacy profile of TAS-102 single therapy in patients aec ff ted by advanced GC [6]. Six Japanese institutions and 2. Discussion a total of 29 patients were involved in this clinical trial. All patients were > 19 years old, aeff cted by unresectable The prognosis of metastatic GC is still poor. To date, platinum plus a u fl oropyrimidine is approved as first-line of therapy or recurrent oesophagogastric junction or gastric adenocar- and second-line treatment with ramucirumab and taxane or cinoma with one or two previous chemotherapy regimens irinotecan is widely used in patients who experience disease containing platinum derivatives, irinotecan, taxanes or u fl - progression. The possibility of a third line of therapy is oropyrimidine, and a documented progression of disease; generally considered in patients with good performance sta- theECOG performance status scorewas 0to2organ 2 tus. Single-agent chemotherapy with docetaxel, paclitaxel, or functions reasonable. Patients received a 35 mg/m twice oral irinotecan as well as different combinations was investigated dose (b.i.d.) of TAS-102 per day after meals during a 28-d in small phase II or retrospective studies in this GC patient schedule with treatment on days 1-5 and 8-12. The 35 mg/m population [16–20]; however, no therapy is recommended b.i.d. dose of TAS-102 showed efficacy with no unexpected by internationally recognised treatment guidelines in GC toxicity in advanced GC patients and the primary point–the patients who have failed two previous lines of treatment. disease control rate–has been achieved and exceeded the This scenario could however change as three novel agents primary endpoint target. The investigator determined dis- with a different mechanism of action (apatinib, nivolumab, ease control rate was 65.5% (95% confidence interval, 45.7- and TAS-102) have shown a survival advantage for the rfi st 82.1%) whereas the independent central review’s disease time in recent randomized phase III trials which involved control rate was 51.9%(95%CI, 31.9-71.3%); the median advanced GC patients progressed after at least two previous PFS and OS were, respectively, 2.9 months (95% CI, 1.1- lines of therapy (Tables 1, 2, and 3 [6–8]). In particular, the 5.3 months) and 8.7 months (95% CI, 5,7.14.9 months). TAGS and ATTRACTION-2 trials enrolled about 25% and Neutropenia (69.0%), leucopenia (41.4%), anaemia (20.7%), 40% of patients treated with≥4 previous chemotherapy regi- and anorexia (10.3%) were the main grade III/IV adverse mens which compose a very heavily pretreated population of events reported. patients with metastatic GC [6, 7]. In 2018, Shitara et al. [7] reported the results of a ran- Although the possible availability of active agents may domised, multinational, double-blinded, placebo-controlled, be a positive option in a very poor therapeutic scenario, the and phase III trial to assess the ecffi acy and safety of trifluri- results reported with apatinib, nivolumab, and TAS-102 in the dine/tipiracil at the dose of 35 mg/m twice daily on days 1–5 above studies raise some controversial issues. and days 8–12 every 28 days plus best supportive care as a new First, all the three novel drugs have been tested against option treatment in patients heavily pretreated and affected a placebo. Although this methodological choice of study by metastatic GC. OS was the primary endpoint. The trial was type is theoretically supported by the absence of a specific carried out in 110 academic hospitals of 17 countries, enrolling treatment suggested by guidelines, a very recent phase III trial a total of 507 patients randomly assigned at a 2:1 ratio to the which compared avelumab (a human anti-PD-L1 monoclonal TAS-102 group (number=337) and the placebo group (num- antibody) to the physician’s choice chemotherapy did not ber=170). A survival benetfi was noted with TAS-102: the OS show improvements in OS or PFS in third-line of therapy of was 5.7 months in the TAS-102 group and 3.6 months in GC patients [16]. Similarly, the KEYNOTE-061 trial showed the placebo group; the disease progression at the data cut-off that pembrolizumab (an anti PD-1) did not significantly occurred in 85% of patients in the TAS-102 group and in 92% improve OS compared with paclitaxel as second-line therapy of patients in the placebo group; 14% of patients in the placebo [21]. All these data underline the importance of an active group and 44% of patients in the TAS-102 group achieved an control for the evaluation of novel agents. On the other hand, acceptable disease control. TAS-102 was well-tolerated even other targeted agents (regorafenib and everolimus) tested though a dosage modification due to an any-grade adverse in phase III trials against placebo in the third-line setting event of any cause was reported in 22% of patients in the for this disease did not obtain any survival improvement placebo group and in 58% in the trifluridine/tipiracil group. [22, 23]. A potential limitation of the study was the scheduling of A second limitation of the studies with apatinib, the rfi st tumour assessment performed 8 weeks later after nivolumab, and TAS-102 in third or further line of treatment the randomisation, which might have precluded detection is related to the fact that the absolute survival gain (difference of radiological progression at earlier time points and the between OS of experimental arm with the OS of placebo) absence of data of patients pretreated with ramucirumab. ranges from 1.2 to 2.1 months (Figure 1) and the absolute PFS Finally, quality of life data were investigated but were not gain ranges from 0.16 to 0.8 months only (Figure 2). These reported as they will be in a separate paper. Interestingly, results suggest a limited clinical efficacy in terms of absolute the NCT03686488 study is recruiting patients to evaluate the survival advantages. combination of TAS 102 and ramucirumab in patients with advanced, refractory gastric, or gastroesophageal junction A third limitation of the apatinib and ATTRACTION-2 adenocarcinoma and the phase I/II trial (NCT03368963) will studies is related to the patients enrolled in these trials. The investigate the combination of TAS-102 with nanoliposomal apatinib trial did not perform a double-blind randomization 4 Journal of Oncology Table 1: Characteristics of the analysed trials. Primary Number of Patients Line of Study Phase Years/Range Number of Placebo Arms Experimental arm endpoint Experimental Arm treatment Li et al 2016 III OS/PFS 2011-2012 176 91 III/IV Apatinib ∘∘ TAGS 2018 III OS 2016-2018 337 170 III/IV/V TAS-102 ∘∘∘ ATTRACTION-2 2017 III OS 2014-2016 330 163 III/IV/V Nivolumab PFS: Progression free survival; OS: Overall survival. >III lines: 36% placebo; 34% apatinib ∘∘ >III lines: 62% placebo; 63% TAS-102 ∘∘∘ >III lines: 82% placebo; 80% nivolumab Journal of Oncology 5 Table 2: Data on overall survival, progression-free survival, and tumour response of the included studies. Overall response rate OS (months) PFS (months) Disease control rate (%) (%) Treatment duration of experimental drug Study Exp C Exp C Exp C Exp C (months) arm arm arm arm arm Arm arm Arm Li et al 2016 6.5 4.7 2.6 1.8 1.7∗ 0∗ 31.8∗ 11∗ 2.9 TAGS 2018 5.7 3.6 2 1.8 4 2 44 14 3 ATTRACTION-2 2017 5.3 4.1 1.61 1.4 11 0 40.3 25 1.9 Exp: Experimental; C: control; NA: Not applicable ∗Assessed by independent response evaluation committee 6 Journal of Oncology ff Table 3: Characteristics of patients in the evaluated studies. Primary lesion GEJ Number of > II previous lines of Median age/Male ECOG> 0 Diuse Histology Prior Surgery Peritoneal metastasis Previous Ram. patients junction metastatic sites>2 treatment Study % % % % % % % % % E P EPEPEPE P EPEPEPE P ∘ ∘ Li et al 2016 58/75 58/75 73 83 NR NR 22 23 69 74 21 22 24 27 34 36 NR NR ∘ ∘ TAGS 64/75 63/69 64 60 16 12 29 28 44 44 54 58 26 31 63 62 34 32 ∘ ∘ ∘∘ ∘∘ ATTRACTION-2 62/69 61/73 71 71 NR NR NR NR 60 64 75 73 19 26 79 72 11 13 E: experimental arm; P: placebo arm; NR: Not reported; GEJ: Gastroesophageal; Ram: Ramucirumab Gastrectomy ∘∘ ≥2organs with metastases Journal of Oncology 7 7,00 6,00 5,00 4,00 3,00 2,00 1,00 0,00 months OS Experimental OS placebo DELTA OS Li et al TAGS ATTRACTION-2 Figure 1: Data of median overall survival (OS) of the experimental arm and placebo arm and delta OS dier ff ence between OS of the experimental arm and placebo arm. 3,00 2,50 2,00 1,50 1,00 0,50 0,00 months PFS Experimental PFS placebo DELTA PFS Li et al TAGS ATTRACTION-2 Figure 2: Data of median progression-free survival (PFS) of the experimental arm and placebo arm and delta PFS dier ff ence between PFS of the experimental arm and placebo arm. and enrolled Chinese patients only [8]. The ATTRACTION-2 to be an important endpoint also in gastric cancer patients (nivolumab) trial was conducted in Japan, South Korea, and who have often symptoms related to the extension of disease Taiwan centres and excluded Western patients [6]. The TAGS [24]. While apatinib, nivolumab, and TAS-102 obtained a was the only study that enrolled both Western and Asian statistically significant increased tumour control rate as com- patients [7]. u Th s, differences in the ethnicity of enrolled pared to placebo (Table 2), Li et al. did not show significant patients should be considered in evaluating study results and differences between apatinib or placebo at any time point their transferability to the Caucasian population. about the quality oflifescore [8], theATTRACTION-2 did A fourth limitation of the analysed studies is related to not investigate the effects of nivolumab on the patient quality the poor information of data on quality of life: this outcome of life [6], and quality of life data have not yet been reported is widely incorporated in phase III studies involving patients for the TAGS study [7], although the quality of life is very important in GC [24]. with solid tumours and recently it has been demonstrated 8 Journal of Oncology Figure 3: Pooled analysis according to previous ramucirumab. Finally, another limitation when heavily pretreated in the development and clinical trials of antiangiogenic, patients are investigated raises from the percentage and immunoactivity, and classical cytotoxic cancer therapeutics type of previous lines of treatment. In particular, the should be pursued and specifically addressed to the identi- rate of patients treated with a ramucirumab-based therapy fication of predictive biomarkers to improve the selection of ideal patient candidates in the various settings of the disease. may influence the outcome. Notably, the TAGS and the ATTRACTION-2 study enrolled patients who progressed This approach in the era of precision oncology represents on previous ramucirumab (about 30% in TAGS and 10% in the main route able to obtain more clinical benefits and real ATTRACTION-2). A pooled analysis according to previous breakthrough advancements with all available therapies. ramucirumab revealed that OS was significantly improved with a greater extent in patients not previously treated with Conflicts of Interest ramucirumab (HR=0.66; 95%CI: 0.56-0.78; p<0.00001, I :0% Figure 3) compared with patients treated with ramucirumab The authors declare that they have no conflicts of interest. (HR=0.71; 95%CI: 0.52-0.97; p=0.003; I :0%Figure 3).There- fore, previous ramucirumab-based therapy increases slightly References the risk of death if compared with patients not previously treated with ramucirumab. Apatinib, nivolumab, and TAS- [1] A. D. Wagner, N. L. Syn, M. Moehler et al., “Chemotherapy 102 have been the rfi st anticancer agents to gain a statistically for advanced gastric cancer,” Cochrane Database of Systematic significant advantage in survival in heavily pretreated cohort Reviews, vol. 8, article CD004064, 2017. of patients with metastatic GC within phase III trials. Some [2] M. Salati, K. Di Emidio, V. Tarantino, and S. Cascinu, “Second- concerns have however to be raised on study characteris- line treatments: moving towards an opportunity to improve tics and results such as the absence of an active therapy survival in advanced gastric cancer?” ESMO Open,vol. 2,no. control arm, differences in patient baseline characteristics, 3, article e000206, 2017. limited absolute advantage in survival results, and lack of [3] H. Wilke, K. Muro, E. van Custem et al., “Ramucirumab plus patient quality of life information. These concerns have paclitaxel versus placebo plus paclitaxel in patients with previ- been reflected in the decisions taken by regulatory agencies ously treated advanced gastric or gastro-oesophageal junction worldwide on the approval of these drugs for this indication. adenocarcinoma (RAINBOW): a double-blind, randomised Apatinib has been approved in China only and has obtained phase 3 trial,” e Lancet Oncology, vol. 15, no. 11, pp. 1224–1235, an orphan drug designation in Western countries. Nivolumab 2014. has been approved in Japan [25] but not in Western countries. [4] C.S. Fuchs, J. Tomasek,C.J. Yong etal., “Ramucirumab TAS-102 has been recently approved for this indication in monotherapy for previously treated advanced gastric or gastro- gastric cancer in the USA by FDA, and an application for oesophageal junction adenocarcinoma (REGARD): an inter- the same indication has been filed to the European Medicine national, randomised, multicentre, placebo-controlled, phase 3 trial,” e Lancet,vol.383,no.9911,pp. 31–39,2014. Agency (EMA). As other neoplasms, GC is a heterogeneous disease in [5] G. Roviello,A.Ravelli,A.I. Fiaschi et al.,“Apatinib for the terms of clinical and molecular features, also as a function treatment of gastric cancer,” Expert Review of Gastroenterology of its progression within time. In the near future, eor ff ts &Hepatology, vol.10,no.8,pp.887–892, 2016. Journal of Oncology 9 [6] Y.-K. Kang, N. Boku, T. Satoh et al., “Nivolumab in patients with who failed previous oxaliplatin-based and irinotecan-based advanced gastric or gastro-oesophageal junction cancer refrac- chemotherapies,” Cancer Research and Treatment,vol. 44,no. tory to, or intolerant of, at least two previous chemotherapy 4, pp. 235–241, 2012. regimens (ONO-4538-12,ATTRACTION-2):a randomised, [20] E. J. Kang, S.-A. Im, D.-Y. Oh et al., “Irinotecan combined double-blind, placebo-controlled, phase 3 trial,” e Lancet,vol. with 5-fluorouracil and leucovorin third-line chemotherapy 390, no. 10111, pp. 2461–2471, 2017. after failure of fluoropyrimidine, platinum, and taxane in gastric [7] K. Shitara, T. Doi, M. Dvorkin et al., “Trifluridine/tipiracil cancer: treatment outcomes and a prognostic model to predict versus placebo in patients with heavily pretreated metastatic survival,” Gastric Cancer,vol.16,no.4,pp.581–589, 2013. gastric cancer (TAGS): a randomised, double-blind, placebo- ¨ [21] K. Shitara, M. Ozgur ¨ ogl ˘ u, Y. J. Bang et al., “Pembrolizumab ver- controlled, phase 3 trial,” e Lancet Oncology, vol.19, no.11, sus paclitaxel for previously treated, advanced gastric or gastro- pp.1437–1448,2018. oesophageal junction cancer (KEYNOTE-061): a randomised, [8] J. Li, S. Qin, J. Xu et al., “Apatinib for chemotherapy-refractory open-label, controlled, phase 3 trial,” Lancet,vol. 392, no. 10142, advanced metastatic gastric cancer: results from a randomized, pp. 123–133, 2018. placebo-controlled, parallel-arm, phase II trial,” Journal of [22] N. Pavlakis, K. M. Sjoquist, A. J. Martin et al., “Regorafenib Clinical Oncology,vol.31,no.26, pp. 3219–3225, 2013. for the treatment of advanced gastric cancer (INTEGRATE): [9] J. Li, S. Qin, J. Xu et al., “Randomized, double-blind,pla- a multinational placebo-controlled phase II Trial,” Journal of cebo-controlled phase III trial of apatinib in patients with Clinical Oncology,vol.34,no.23, pp.2728–2735,2016. chemotherapy-refractory advanced or metastatic adenocarci- [23] A. Ohtsu, J. A. Ajani, Y.-X. Bai et al., “Everolimus for previously noma of thestomach or gastroesophageal junction,” Journal of treated advanced gastric cancer: results of the randomized, Clinical Oncology,vol.34,no.13,pp.1448–1454, 2016. double-blind, phase III GRANITE-1 study,” Journal of Clinical [10] H. Ruan,J.Dong, X.Zhou et al.,“Multicenter phase II study Oncology,vol.31,no. 31,pp. 3935–3943,2013. of apatinib treatment for metastatic gastric cancer after failure [24] I. Chau,C. S. Fuchs,A. Ohtsu et al., “Association of quality of second-line chemotherapy,” Oncotarget ,vol. 8,no.61,pp. of life with disease characteristics and treatment outcomes in 104552–104559, 2017. patients with advanced gastric cancer: exploratory analysis of [11] P. Sharma and J. P. Allison, “Immune checkpoint targeting in RAINBOW and REGARD phase III trials,” European Journal of cancer therapy: toward combination strategies with curative Cancer,vol.107,pp.115–123,2019. potential,” Cell, vol.161, no. 2,pp.205–214,2015. [25] K.Kato, T.Satoh, K.Muro et al.,“A subanalysis of Japanese [12] K. Kato,T.Satoh, K. Muro etal.,“A subanalysis of Japanese patients in a randomized, double-blind, placebo-controlled, patients in a randomized, double-blind, placebo-controlled, phase 3 trial of nivolumab for patients with advanced gastric phase 3 trial of nivolumab for patients with advanced gastric or gastro-esophageal junction cancer refractory to, or intolerant or gastro-esophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538- of, at least two previous chemotherapy regimens (ONO-4538- 12, ATTRACTION-2),” Gastric Cancer,2018. 12, ATTRACTION-2),” Gastric Cancer, vol.22,no.2,pp.344– 354, 2019. [13] Y. Y. Janjigian, J. Bendell, E. Calvo et al., “CheckMate-032 study: Efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer,” Journal of Clinical Oncology,vol.36,no.28,pp.2836–2844,2018. [14] N. Tanaka, K. Sakamoto, H. Okabe et al., “Repeated oral dosing of TAS-102 confers high triu fl ridine incorporation into DNA and sustained antitumor activity in mouse models,” Oncology Reports, vol.32, no.6,pp.2319–2326, 2014. [15] M.Fukushima, N.Suzuki,T.Emura et al.,“Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2’-deoxyribonucleosides,” Biochemical Pharmacology,vol.59,no. 10,pp.1227–1236,2000. [16] Y. J. Bang, E. Y. Ruiz, E. Van Cutsem et al., “Phase III, randomised trial of avelumab versus physician’s choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300,” Annals of Oncology, vol.29,no.10,pp. 2052–2060, 2018. [17] R. Shimoyama, H. Yasui, N. Boku et al., “Weekly paclitaxel for heavily treated advanced or recurrent gastric cancer refractory to fluorouracil, irinotecan, and cisplatin,” Gastric Cancer,vol.12, no.4,pp.206–211,2009. [18] T. Kawakami, N. Machida, H. Yasui et al., “Efficacy and safety of irinotecan monotherapy as third-line treatment for advanced gastric cancer,” Cancer Chemotherapy and Pharmacology,vol. 78,no. 4, pp.809–814, 2016. [19] M. J. Lee, I. G. Hwang, J.-S. 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