Toward a Treatment Sequencing Strategy: A Systematic Review of Treatment Regimens in Advanced Gastric Cancer/Gastroesophageal Junction Adenocarcinoma

Daniel V Catenacci; Joseph Chao; Kei Muro; Salah Eddin Al‐Batran; Samuel J Klempner; Zev A Wainberg; Manish A Shah; Sun Young Rha; Atsushi Ohtsu; Astra M Liepa; Holly Knoderer; Anindya Chatterjee; Eric Van Cutsem

doi:10.1002/onco.13907

. 2021 Sep 3;26(10):e1704–e1729. doi: 10.1002/onco.13907

Toward a Treatment Sequencing Strategy: A Systematic Review of Treatment Regimens in Advanced Gastric Cancer/Gastroesophageal Junction Adenocarcinoma

Daniel V Catenacci ^1,^†,^✉, Joseph Chao ^2,^†, Kei Muro ³, Salah Eddin Al‐Batran ⁴, Samuel J Klempner ⁵, Zev A Wainberg ⁶, Manish A Shah ⁷, Sun Young Rha ⁸, Atsushi Ohtsu ⁹, Astra M Liepa ¹⁰, Holly Knoderer ¹⁰, Anindya Chatterjee ¹⁰, Eric Van Cutsem ¹¹

PMCID: PMC8488781 PMID: 34288262

Abstract

Background

Platinum and fluoropyrimidine combinations typically comprise first‐line (1L) therapy in advanced gastric cancer or gastroesophageal junction adenocarcinoma (G/GEA), although controversy exists regarding the use of 5doublet versus triplet cytotoxic regimens. Historically, second‐line (2L) and third‐line or later (3L+) therapy has been fragmented. Recent trials have increased the need for optimal treatment sequencing in advanced G/GEA.

Materials and Methods

We conducted a systematic search of peer‐reviewed manuscripts of randomized clinical trials examining 1L, 2L, and 3L+ therapy for advanced G/GEA published from 2009 through November 19, 2019. When available, overall survival, progression‐free survival, time to progression, overall response rate, and toxicity were extracted from each and compared descriptively.

Results

In 1L therapy, chemotherapy triplets demonstrated variable efficacy improvements with invariable increased toxicity compared with platinum/fluoropyrimidine doublets. Currently, the only published report of positive outcomes using biologics in 1L describes adding trastuzumab in HER2‐overexpressing advanced G/GEA. In 2L, doublet chemotherapy regimens are not uniformly more efficacious than single‐agent taxanes or irinotecan, and ramucirumab has demonstrated improved outcomes both as monotherapy and in combination.

Conclusion

For advanced G/GEA, review of trial results from 2009–2019 support 1L therapy with platinum and fluoropyrimidine and sequencing with taxanes or irinotecan in combination with biologics as effective 2L options. Escalating to a triplet may add some efficacy at the expense of added toxicity.

Implications for Practice

The rapidly changing treatment landscape for advanced gastric cancer includes increasing options for refractory disease. With multiple first‐line platinum‐based regimens, identification of those with the best benefit‐to‐risk ratio may provide guidance on treatment sequencing strategies. This article presents findings from the published literature of randomized controlled trials that included a first‐line platinum/fluoropyrimidine combination and, for second‐line trials, patients with platinum/fluoropyrimidine‐refractory disease. This guiding summary could be a tool for clinicians to identify the optimal first‐line regimen(s) followed by a strategy for subsequent regimens.

Keywords: Gastroesophageal adenocarcinoma, Systemic therapy, Treatment sequencing, Randomized controlled trials

Short abstract

This review evaluates evidence‐based treatment sequencing strategies for advanced gastric cancer and gastroesophageal junction adenocarcinoma, focusing on randomized controlled trials in which the commonly recommended platinum/fluoropyrimidine‐backbone was used in first‐line treatment and, for second‐line treatment, included a prior platinum and/or fluoropyrimidine.

Introduction

Gastric cancer is the fifth most common cancer and third leading cause of cancer‐related deaths worldwide [1]. Gastric cancer is a histologically and molecularly diverse disease encompassing the stomach and gastroesophageal junction. Adenocarcinoma is the most common histological type, and gastric cancer or gastroesophageal junction adenocarcinoma (G/GEA), with or without esophageal adenocarcinoma, are commonly studied within the same clinical trials [2]. Developments in treatment for locally advanced and unresectable/metastatic G/GEA lag behind other solid malignancies, with a median survival of less than 1 year [3, 4, 5].

Despite multiple options, there is no single standard of care for first‐line (1L), second‐line (2L), or third‐line (3L) and beyond (3L+) treatment of G/GEA [6, 7]. Current guidelines do not address optimizing sequence. The Cochrane reviews by Wagner evaluated the efficacy of chemotherapy versus best supportive care (BSC), combination versus single‐agent chemotherapy, and different chemotherapy combinations [8, 9]. However, the question of treatment sequencing was not addressed.

In the 1L setting, current options include platinum agents, fluoropyrimidines, taxanes, irinotecan, and anthracyclines in doublet or triplet regimens, whereas epirubicin has fallen out of favor [10, 11]. The most commonly used 1L treatment combinations include fluoropyrimidine plus platinum, with or without a third agent [8, 12], although addition of a third cytotoxic agent to established doublet regimens is likely to increase toxicities as reported in 2006 [13]. Unfortunately, the majority of patients who respond to 1L chemotherapy will relapse or experience disease progression [8]. It is unclear if there is a significant benefit with doublet therapies versus monotherapies, intravenous versus oral formulations of fluorouracil (5‐FU), cisplatin versus oxaliplatin, or irinotecan versus docetaxel.

There is disagreement regarding the preferred treatment regimen in the 2L and 3L+ settings. The treatment landscape is fragmented, particularly in the U.S. [14]. Current recommended 2L therapies include the anti–vascular endothelial growth factor receptor‐2 monoclonal antibody, ramucirumab, as monotherapy or combined with paclitaxel, or single chemotherapy agents (irinotecan, docetaxel, or paclitaxel) [12, 15]. The diverse array of regimens is counterproductive to developing clear, standardized, evidence‐based guidelines. Moreover, with the recent publication of several randomized controlled trials (RCTs) investigating novel therapies and chemotherapy combinations, a new evaluation of existing evidence is needed that might better inform physicians and guide treatment recommendations.

We conducted a systematic review from published RCTs to evaluate and synthesize evidence and provide insights into an evidence‐based treatment sequencing strategy for advanced G/GEA. To this end, the review focused on RCTs in which the commonly recommended platinum/fluoropyrimidine‐backbone was used in 1L and, for 2L, RCTs that included a prior platinum and/or fluoropyrimidine. Given the recent changes to the G/GEA landscape, we have discussed top‐line data from seminal trials and approvals in this report.

Materials and Methods

Search Strategy

The systematic literature review (SLR) search, selection, and data extraction were conducted and reported using PRISMA guidelines [16]. The databases MEDLINE, MEDLINE In‐Process, Embase, and the Cochrane Library were searched to identify English‐language publications of RCTs, SLRs, and meta‐analyses since the Cochrane review by Wagner et al. [9]. The search for RCTs was limited to 2009 through November 19, 2019, and the search for SLRs and meta‐analyses was limited to 2015 through November 19, 2019. The review only included RCTs of larger populations: ≥200 and ≥ 40 patients in 1L and 2L or later settings, respectively. Although outside the original SLR parameters, recent phase III RCT data are also discussed in relevant sections.

The RCT search, SLR, and meta‐analyses were structured as follows: study type search terms, disease search terms, treatment search terms, population search terms, and exclusionary search terms. Further details regarding inclusion and exclusion criteria, screening, and study quality assessment methodology from the SLR are available in the supplemental online data.

Synthesis Methods

Overall survival (OS), progression‐free survival (PFS), time to progression (TTP), and overall response rate (ORR) were the primary efficacy endpoints considered. Overviews of adverse events (AEs) were summarized. Included studies were heterogeneous in terms of study design; therefore, results are presented descriptively.

Results

Literature Search Results

The screening process and number of identified articles are detailed in Figure 1. Literature searches identified a total of 920 nonduplicate records, of which 647 and 212 records were excluded during level 1 and 2 screenings, respectively. Seventy publications meeting eligibility criteria were included (Fig. 1). Of these, 27 articles assessed 1L, 34 assessed 2L, and 8 assessed 3L+.

Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) diagram for study inclusion and exclusion. The PRISMA flow chart details the number of articles identified in the literature search and the number of articles included and excluded at each stage. Note that articles from the SLR‐MA search that met the inclusion criteria for reference list review to identify potential primary RCT publications are listed in the PRISMA diagram as excluded at level 2 for reason “other” (as these articles are not primary RCTs).Abbreviations: 2L, second line; 3L, third line; MA, meta‐analysis; RCT, randomized controlled trial; SLR, systematic literature review.

Risk of Bias

The quality of each study was evaluated using the bias assessment tool detailed in supplemental online Table 4.

Description of Included Studies

An overview of the studies is provided in the supplemental online data. Patient demographics and disease characteristics are summarized in Figure 2 and supplemental online Table 1. A summary of treatment interventions for each line of therapy is provided in Figure 3 and supplemental online Table 3.

First‐line, second‐line, and third‐line study overview.Abbreviations: ph1, phase I; ph2, phase II; ph3, phase III.

First‐line, second‐line, and third‐line and beyond interventions. **(A):** First‐line interventions. Targeted therapies include bevacizumab, cetuximab, lapatinib, onartuzumab, panitumumab, rilotumumab, trastuzumab, pertuzumab, and ramucirumab. Chemotherapy includes capecitabine, cisplatin, docetaxel, epirubicin, oxaliplatin, paclitaxel, S‐1, tegafur, 5‐fluorouracil, and leucovorin (folinic acid). Eleven studies compared the efficacy of chemotherapy doublets. **(B):** Second‐line interventions. In the center of the diagram, “12 studies TT vs. CM/PB” include 12 studies with single‐agent (SA) chemotherapy in both arms: six assessing the efficacy of SA versus SA and six assessing SA plus targeted therapy versus control. **(C):** Third‐line interventions. Targeted therapies include avelumab, TAS‐102, nivolumab (ICI), and ipilimumab (ICI). Chemotherapy includes irinotecan and paclitaxel.Abbreviations: ↑, increased/higher dose; BSC, best supportive care; CM, chemotherapy; DB, doublet; ICI, immune checkpoint inhibitor; Pac, paclitaxel; PB, placebo; Pembro, pembrolizumab; TP, triplet; Traz, trastuzumab; TT, targeted therapy; TX, taxane; VP, valproic acid.

Efficacy and Safety of 1L Interventions

First‐line studies varied with respect to trial design and patient populations (supplemental online Table 1). Of 27 RCTs, 22 reported OS and/or PFS data. Fourteen RCTs reported statistically significant findings for OS, 12‐month survival, PFS, TTP, time to treatment failure (TTF), or ORR (Table 1; Table 2; supplemental online Table 2) [17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29]. An overview of AEs is summarized in supplemental online Table 3.

Table 1.

Overview of efficacy results

Trial	Treatment arms	Efficacy variables								Analysis population	Statistical design
Trial	Treatment arms	OS	12‐mo survival	PFS	TTP	TTF	ORR	DOR	DCR	Analysis population	Statistical design
First‐line studies
SOS Ryu 2015 [109]	S‐1 (D1–14) + Cis (D1) vs. S‐1 (D1–21) + Cis (D1 or 8)									ITT (patients who met all eligibility criteria)	A hybrid design was used to test both noninferiority and superiority within the same trial
AVATAR Shen 2015 [110]	PBO + Cap + Cis vs. BEV + Cap + Cis									ITT (all randomized patients)	NR^a
Van Cutsem 2015 [37]	Doc + Ox vs. Doc + Ox + FU/FOL									Full analysis set (all randomized and treated patients analyzed in the arm to which they were randomized); ITT (all randomized patients); per‐protocol (patients who received study treatment and had at least one postbaseline tumor assessment without any major protocol violation)	NR^a
REAL3 Waddell 2013 [18]	Epir + Ox + Cap vs. Epir + Ox + Cap + PAN	^*								ITT (all eligible randomized participants)	NR^a
Wang 2016 [19]	Doc + Cis + FU vs. Cis + FU	^*		^*		^*	^*			ITT	Superiority of Doc + Cis + FU compared with Cis + FU in terms of PFS
JapicCTI‐101021 Yamada 2015 [20]	S‐1 + Ox vs. S‐1 + Cis			^*						Per‐protocol population (noninferiority analysis); ITT for some analyses (all randomized patients excluding patients who took no trial medication)	Noninferiority of S‐1 + Ox compared with S‐1 + Cis in terms of PFS Relative efficacy of S‐1 + Ox and S‐1 + Cis in terms of OS
G‐SOX Bando 2016 [21]	S‐1 + Ox (≥70 yr) vs. S‐1 + Cis (≥70 yr) vs. S‐1 + Ox (<70 yr)					^*				Full analysis set (patients who met the main inclusion criteria and none of the exclusion criteria in the safety analysis set)	Noninferiority of S‐1 + Ox compared with S‐1 + Cis
ToGA Bang 2010 [17]	Tras + Chemo vs. Chemo	^*		^*	^*		^*	^*		All randomized patients (whose tumors overexpressed HER2) who received study medication at least once	NR^a
Curran 2009 [111]	IRI + folinic acid + FU vs. Cis + FU									Full analysis set (treated patients analyzed in the arm to which they were randomized); analyses were also conducted in the per‐protocol population	Noninferiority of FOLFIRI compared with Cis + FU in terms of TTP
Guimbaud 2014 [22]	Epir + Cis + Cap vs. FOLFIRI					^*				ITT	Superiority of FOLFIRI compared with Epir + Cis + Cap in terms of TTF
TRIO‐013/LOGiC Hecht 2016 [23]	LAP + Cap + Ox vs. PBO + Cap + Ox			^*			^*			Primary efficacy population (patients with disease confirmed for HER2 overexpression)	NR^a
Kang 2009 [24]	Cis + Cap vs. Cis + FU	^*		^*			^*			Per‐protocol population^b	Noninferiority of Cis + Cap to Cis + FU in terms of PFS
Kim 2014 [112]	SIM + Cap + Cis vs. PBO + Cap + Cis									ITT (all recruited patients who received any study medication)	NR^a
Li 2015 [113]	S‐1 + Cis vs. FU + Cis									Full population	NR^a
EXPAND Lordick 2013 [114]	CTX + Cap + Cis vs. Cap + Cis									ITT (all patients randomly allocated a study treatment)	NR^a
AVAGAST Ohtsu 2011 [25]	BEV + Cis + Cap/FU vs. PBO + Cis + Cap/FU		^*	^*			^*			ITT (all randomly assigned patients); measurable disease population (response rate only)	NR^a
FLAGS Ajani 2010 [26]	S‐1 + Cis vs. FU + Cis					^*				Full analysis set (patients who received the assigned treatment)	Superiority of S‐1 + Cis compared with FU + Cis in terms of overall survival
DIGEST Ajani 2017 [27]	S‐1 + Cis vs. FU + Cis						^*			ITT (all randomized patients)	NR^a
RILOMET‐1 Catenacci 2017 [28]	Rilotumumab + Epir + Cis + Cap vs. PBO + Epir + Cis + Cap	^*	^*	^*			^*		^*	OS and PFS: ITT (all randomly assigned patients, according to randomly allocated treatment) ORR and DCR: all patients with at least one unidimensional measurable lesion at baseline per RECIST version 1.1	NR^a
Lu 2018 [29]	Pac + Cap vs. Cis + Cap						^*			ITT (all patients who intended to receive treatment)	NR^a
METGastric Shah 2017 [39]	Onartuzumab + mFOLFOX6 vs. PBO + mFOLFOX6									ITT (all randomized patients)	NR^a
Lu 2019 [35]	S‐1 + Doc vs. S‐1 + Cis									Full analysis set was analyzed according to ITT principle Per‐protocol set^c	Noninferiority of S‐1 + Doc compared with S‐1 + Cis in terms of PFS
Shu 2017 [32]	Ox + tegafur vs. Ox + Cis									NR	Noninferiority of Ox + tegafur compared with Ox + S‐1 in terms of PFS and OS (co‐primary endpoints)
HELOISE Shah 2017 [115]	SoC Tras + Cap + Cis vs. higher‐dose Tras + Cap + Cis									Full analysis set (all randomized patients) Per‐protocol set^d	Superiority of higher‐dose Tras compared with SoC Tras in terms of OS
RAINFALL Fuchs 2019 [40]^e	RAM + Cis + Cap/FU vs. PBO + Cis + Cap/FU			^*	^*			^*		PFS was analyzed with data from the first 508 randomized patients^f OS was analyzed in all randomized patients	NR^a
JCOG1013 Yamada 2019 [36]	Doc + Cis/S‐1 vs. Cis/S‐1									ITT (all randomized patients)	Superiority of Doc + Cis and S‐1 compared with Cis and S‐1 in terms of OS
JACOB Tabernero 2018 [38]	Pertuzumab + Tras/Check vs. PBO + Tras/Chemo									ITT (all randomized patients)	NR^a
Second‐line studies
JapicCTI‐090849 Satoh 2015 [62]	Nimotuzumab + IRI vs. IRI									Full analysis set (randomized and received all study medications)	NR^a
TyTAN Satoh 2014 [46]	LAP + Pac vs. Pac						^*			ITT (patients randomized to treatment); mITT (randomized patients confirmed to be FISH positive; HER2:CEP17 ratio ≥ 2)	Superiority of LAP + Pac compared with Pac alone in terms of OS
Sym 2013 [55]	IRI vs. FOLFIRI									ITT (all enrolled patients)	NR^a
JACCRO GC‐05 Tanabe 2015 [56]	S‐1 + IRI vs. IRI									Full analysis set	NR^a
Thuss‐Patience 2011 [47]	IRI + BSC vs. BSC	^*								ITT	NR^a
Yi 2012 [43]	Doc + sunitinib vs. Doc						^*		^*	ITT	NR^a
Study 39 Bang 2015 [48]	Olaparib + Pac vs. PBO + Pac	^*								Overall patient population (enriched for patients with ATM‐low status) and the ATM‐low population	NR^a
COUGAR‐02 Ford 2014 [49]	Doc vs. active symptom control	^*								ITT	NR^a
TCOG GI‐0801/BIRIP Higuchi 2014 [44]	IRI + Cis vs. IRI			^*					^*	Full analysis set	Superiority of IRI + Cis compared with IRI in terms of PFS
REGARD Fuchs 2014 [42]	RAM vs. PBO	^*		^*					^*	ITT (patients randomized to treatment)	NR^a
RAINBOW Wilke 2014 [41]	RAM + Pac vs. PBO + Pac	^*		^*			^*		^*	ITT (patients randomized to treatment)	NR^a
RAINBOW subgroup analysis (East Asia) Muro 2016 [63]	RAM + Pac vs. PBO + Pac			^*			^*		^*	ITT (patients randomized to treatment)	NR^a
RAINBOW subgroup analysis (Japan) Shitara 2016 [64]	RAM + Pac vs. PBO + Pac	^*		^*			^*		^*	ITT (patients randomized to treatment)	NR^a
WJOG 4007 Hironaka 2013 [53]	Pac vs. IRI									Full analysis set (all randomly assigned patients who met the eligibility criteria)	NR^a
Kim 2015 [45]	Doc vs. Doc + Ox			^*					^*	ITT	NR^a
CCOG0701 Nakanishi 2016 [58]	Pac vs. Pac + S‐1									Full analysis set	NR^a
JCOG0407 Nishina 2016 [50]	Best available FU vs. Pac			^*						ITT	NR^a
Roy 2013 [54]	PEP02 vs. IRI vs. Doc									ITT (all recruited subjects who received any study medication); assessable population (patients who had received at least two cycles of treatment and were assessable for response)	NR^a
TRICS Nishikawa 2015 [57]	IRI + Cis vs. IRI									ITT (all randomized patients)	Superiority of IRI + Cis compared with IRI in terms of OS
Bang 2017b [70]^g	Ipilimumab vs. BSC									ITT	NR^a
GOLD Bang 2017a [69]	Olaparib + Pac vs. PBO + Pac									ITT	NR^a
DREAM Kang 2018 [51]	DHP107 (oral Pac) vs. IV Pac									Per‐protocol population (primary endpoint) Full analysis set (secondary endpoints; confirmatory analysis for primary endpoint)	Noninferiority of oral Pac compared with IV Pac in terms of PFS in the per‐protocol population
KEYNOTE‐061 Shitara 2018a [71]^h	Pembrolizumab vs. Pac									ITT	Superiority of pembrolizumab in terms of the primary endpoints (OS and PFS in patients with PD‐L1 CPS ≥1)
GATSBY Thuss‐Patience 2017 [66]	Taxane vs. Tras emtansine									ITT	Superiority of Tras emtansine compared with taxane in terms of OS
SHINE Van Cutsem 2017 [72]	AZD4547 vs. Pac									Full analysis set	NR^a
Lee 2017 [116]	Doc vs. Doc + Cis vs. Doc + S‐1	^*								Modified ITT population, which excluded patients who were deemed ineligible or never started the study treatment from randomization	Superiority of the best treatment in terms of ORR
KCSG ST10‐01 Lee 2019 [117]	Pac vs. IRI									ITT	Noninferiority of IRI vs. Pac in terms of PFS (i.e., median PFS of IRI would be at least longer than 2.65 mo)
ABSOLUTE Shitara 2017 [52]	Nab‐Pac Q3W vs. nab‐Pac QW vs. Pac									Full analysis set (all randomly assigned patients who received at least one dose of the allocated drug and who met the eligibility criteria)	Noninferiority of nab‐Pac vs. Pac in terms of OS
Combined second‐ and third‐line population
Fushida 2016 [60]	Pac vs. Pac + valproic acid									NR (did not include patients that dropped out in the analysis)	NR^a
Kang 2012 [61]	Doc or IRI + BSC vs. BSC	^*								ITT (all randomized patients were included in the analysis)	NR^a
Moehler 2016 [118]	Na‐FOLFIRI + sunitinib vs. Na‐FOLFIRI + placebo									PFS: ITT (set comprising all patients with at least one available postbaseline assessment of the primary analysis variable)	NR^a
GRANITE‐1 Ohtsu 2013 [73]	Everolimus + BSC vs. PBO + BSC			^*						ITT (patients were analyzed per the treatment and stratum to which they were assigned on randomization)	NR^a
INTEGRATE Pavlakis 2016 [74]	Regorafenib + BSC vs. PBO + BSC			^*						Efficacy analysis set (comprised patients deemed eligible on blinded central clinical review)	NR^a
Shitara 2014 [59]	Dose‐escalated Pac vs. Pac			^*					^*	Full analysis set (all eligible patients who received at least one dose of paclitaxel)	Superiority of OS with a one‐sided alpha error of 0.3 and a power of 0.8
Third‐line and beyond studies
Li 2013 [77]	Apatinib 850 mg once daily vs. apatinib 425 mg twice daily vs. PBO	^*		^*					^*	Full analysis set (ITT patients, including those who were randomly assigned to a treatment group but who did not adhere to the full course of treatment)	NR^a
Li 2016 [78]	Apatinib vs. PBO	^*		^*						Full analysis set (consisted of all randomly assigned patients who received at least one dose of study medication)	NR^a
JAVELIN Gastric 300 Bang 2018 [82]	Avelumab + BSC vs. Chemo + BSC									ITT (all randomized patients)	Superiority of avelumab vs. Chemo in terms of OS
ATTRACTION‐2 Kang 2017 [75]	Nivolumab vs. PBO	^*		^*						ITT for survival analyses (all randomized patients) Response evaluable population for tumor response (patients with measurable target lesion)	Superiority of nivolumab compared with placebo
ATTRACTION‐2 subgroup analysis (Japanese patients) Kato 2019 [79]	Nivolumab vs. PBO	^*		^*			^*		^*	ITT for survival analyses (all randomized patients) Response assessment population for response rate (patients with measurable target lesion)	NR^a
ATTRACTION‐2 subgroup analysis (prior Tras use) Satoh 2020 [119]	Nivolumab vs. PBO	^*		^*						ITT (all randomized patients)	NR^a
TAGS Shitara 2018b [76]	Trifluridine/tipiracil + BSC vs. PBO + BSC	^*		^*					^*	ITT for OS and PFS (all randomized patients) ORR and DCR in tumor response assessable population (patients in the ITT population with measurable disease at baseline who underwent at least one tumor assessment while on treatment)	NR^a
CheckMate‐032 Janjigian 2018 [80]	Nivolumab 3 mg/kg vs. nivolumab 1 mg/kg + ipilimumab 3 mg/kg vs. nivolumab 3 mg/kg + ipilimumab 1 mg/kg									Tumor evaluable population	NR^a

Open in a new tab

Shading key: dark green indicates primary endpoint; medium green indicates secondary endpoint; light green indicates additional endpoint (or endpoint not specified).

Statistically significant results were found for this study for this endpoint.

^{^a}

Because the publication did not specifically state whether this was a superiority or a noninferiority study, it can be inferred that it is a superiority study (where a statistically significant p value for the test statistic prompts rejection of the null hypothesis and leads to the conclusion that one treatment is superior to the other).

^{^b}

In Kang et al. (2009) [24], the per‐protocol population was defined as all randomized patients, except those who received <6 weeks of treatment for reasons other than progressive disease or death or < 50% of the anticipated treatment during the first 6 weeks of the trial and those who had major inclusion or exclusion criteria violations or inadequate information regarding tumor burden.

^{^c}

In Lu et al. (2019) [35], the per‐protocol set was defined as all patients who conformed to the test plan with good compliance, took at least one cycle of drugs without taking banned drugs during the study, and completed the case report form without filling in missing data resulting in imputation.

^{^d}

In the HELOISE study [115], OS was assessed as a secondary endpoint in the per‐protocol set, defined as patients with cycle 1 trastuzumab C_trough < 12 μg/mL after the initial loading dose of 8 mg/kg.

^{^e}

In the RAINFALL study [40], investigator‐assessed PFS survival was significantly longer in the ramucirumab group than the placebo group (hazard ratio [HR], 0.753; 95% confidence interval [CI], 0.607–0.935; p = .0106; median PFS 5.7 months [5.5–6.5] versus 5.4 months [4.5–5.7]). A sensitivity analysis based on central independent review of the radiological images did not corroborate the investigator‐assessed difference in PFS (HR, 0.961; 95% CI, 0.768–1.203; p = .74).

^{^f}

In the RAINFALL study [40], enrollment of the first 508 patients, with 346 progression events, was planned to achieve 90% power to detect a difference in investigator‐assessed PFS between the two treatment groups (HR of 0.70, assuming an increase in median PFS from 5.6 months to 8.0 months), with a two‐sided α level of 0.05.

^{^g}

The primary endpoint in the study by Bang et al. (2017b) [70] was immune‐related PFS, per assessment of a blinded independent review committee. Secondary endpoints were PFS by World Health Organization criteria, OS, and immune‐related best overall response rate, and exploratory endpoints included DOR and immune‐related TTP.

^{^h}

The primary endpoints in the KEYNOTE‐061 study (Shitara et al. [2018a] [71]) were OS and PFS in in patients with PD‐L1 CPS of 1 or higher. Secondary endpoints included OS and PFS in the overall population.

Abbreviations: ATM, ataxia telangiectasia mutated; BEV, bevacizumab; BSC, best supportive care; Cap, capecitabine; CEP17, chromosome 17 centromere; Chemo, chemotherapy; Cis, cisplatin; CPS, combined positive score; CTX, cetuximab; D, day; DCR, disease control rate; Doc, docetaxel; DOR, duration of response; Epir, epirubicin; FISH, fluorescence in situ hybridization; FOL, folinic acid; FOLFIRI, irinotecan plus 5‐fluorouracil plus folinic acid (also known as leucovorin); FU, fluorouracil; IRI, irinotecan; ITT, intent‐to‐treat; IV, intravenous; LAP, lapatinib; mFOLFOX6, modified FOLFOX6; mITT, modified intent‐to‐treat; Na‐FOLFIRI, sodium folinate‐FOLFIRI; nab‐Pac, nab‐paclitaxel; NR, not reported; ORR, overall response rate; OS, overall survival; Ox, oxaliplatin; Pac, paclitaxel; PAN, panitumumab; PBO, placebo; PD‐L1, programmed death‐ligand 1; PFS, progression‐free survival; Q3W, once every 3 weeks; QW, once weekly; RAM, ramucirumab; SoC, standard of care; SIM, simvastatin; Tras, trastuzumab; TTF, time to treatment failure; TTP, time to progression.

Table 2.

Overall survival, progression‐free survival, and overall response rate of included first‐, second‐, or third‐line and beyond randomized controlled trials ordered by study publication year

Trial	Treatment	Patients, n	Overall survival^a ^– ^c		Progression‐free survival^a ^– ^c		ORR^a ^– ^c
Trial	Treatment	Patients, n	Median (95% CI), mo	Effect size(95% CI)	Median (95% CI), mo	Effect size (95% CI)	%	Effect size
First‐line studies
Kang 2009 [24]^d ^, ^e	Cis + Cap	139	10.4 (9.1–11.0)	HR, 0.85 (0.65–1.11); p = .005 vs. noninferiority margin of 1.25	5.6 (4.8–6.9)	HR, 0.80 (0.63–1.03); p < .001 vs. noninferiority margin of 1.25
Kang 2009 [24]^d ^, ^e	Cis + FU	137	8.9 (7.3–10.2)		5.0 (3.9–5.7)
FLAGS Ajani 2010 [26]^f ^, ^g	S‐1 + Cis	527	8.6	HR, 0.92 (0.80–1.05); p = .1983	4.8 (4.0–5.5)	HR, 0.99 (0.86–1.14); p = .9158	29.1	p = .40
	FU + Cis	526	7.9		5.5 (4.4–5.8)		31.9
ToGA Bang 2010 [17]^h ^, ⁱ	Tras + Chemo^j	294	13.8	HR, 0.74 (0.60–0.91); p = .0046	6.7	HR, 0.71 (0.59–0.85); p = .0002	47^k	p = .0017
ToGA Bang 2010 [17]^h ^, ⁱ	Chemo	290	11.1		5.5		35^k
AVAGAST Ohtsu 2011 [25]^d ^, ^l	BEV + Cis + Cap/FU^m	252	12.1 (11.1–13.8)	HR, 0.87 (0.73–1.03); p = .1002	6.7 (5.9–7.1)	HR, 0.80 (0.68–0.98); p = .0037
AVAGAST Ohtsu 2011 [25]^d ^, ^l	PBO + Cis + Cap/FU^m	265	10.1 (9.0–11.3)		5.3 (4.4–5.6)
REAL3 Waddell 2013 [18]^d	Epir + Ox + Cap	275	11.3 (9.6–13.0)	HR, 1.37 (1.07–1.76); p = .013	6.0 (5.5–6.5)	HR, 1.22 (0.98–1.52); p = .068	NR	NR
REAL3 Waddell 2013 [18]^d	Epir + Ox + Cap + PAN	278	8.8 (7.7–9.8)		7.4 (6.3–8.5)		NR
EXPAND Lordick 2013 [114]^d ^, ⁿ	CTX + Cap + Cis	455	9.4 (8.3–10.6)	HR, 1.00 (0.87–1.17); p = .95	4.4 (4.2–5.5)	HR, 1.09 (0.92–1.29); p = .32
EXPAND Lordick 2013 [114]^d ^, ⁿ	Cap + Cis	449	10.7 (9.4–11.3)		5.6 (5.1–5.7)
Van Cutsem 2015 [37]ⁱ	Doc + Ox	79	8.97 (7.79–10.87)	NR	4.5 (3.7–5.3)	NR	NR	NR
	Doc + Ox + FU/FOL	89	14.59 (11.70–21.78)		7.7 (7.0–9.4)
	Doc + Ox + Cap	86	11.30 (8.08–14.03)		5.6 (4.3–6.4)		NR
Guimbaud 2014 [22]^d ^, ^o	Epir + Cis + Cap	209	9.49	HR, 1.01 (0.82–1.24); p = .95	5.3	HR, 0.99 (0.81–1.21); p = .96	90.4	NS
Guimbaud 2014 [22]^d ^, ^o	FOLFIRI	207	9.72		5.8		95.7
Kim 2014 [112]^d ^, ^p	SIM + Cap + Cis	120	11.6 (9.2–13.9)	HR, 0.966 (0.722–1.293); p = .818	5.2 (4.3–6.1)	HR, 0.930 (0.684–1.264); p = .664
Kim 2014 [112]^d ^, ^p	PBO + Cap + Cis	124	11.5 (9.9–13.1)		4.6 (3.5–5.7)
SOS Ryu 2015 [109]^h ^, ^q	S‐1 (D1–14) + Cis (D1)	306	14.1 (11.4–15.8)	HR, 0.99 (0.81–1.21); p = .91	5.5 (4.7–6.6)	HR, 0.82 (0.68–0.99); p = .0418	60	p = .065
SOS Ryu 2015 [109]^h ^, ^q	S‐1 (D1–21) + Cis (D1 or 8)	309	13.9 (11.6–15.9)		4.9 (4.2–5.5)		50
AVATAR Shen 2015 [110]^d	PBO + Cap + Cis	102	11.4 (8.6–16.0)	HR, 1.11 (0.79–1.56); p = .56	6.0 (4.9–7.4)	HR, 0.89 (0.66–1.21); p = .47	NR	NR
AVATAR Shen 2015 [110]^d	BEV + Cap + Cis	100	10.5 (8.9–14.1)		6.3 (5.7–7.4)		NR	NR
JapicCTI‐101021 Yamada 2015 [20]^d ^, ^r	S‐1 + Ox	318	14.1 (13.0–15.8)	HR, 0.958 (0.803–1.142) (S‐1 + Ox noninferior to S‐1 + Cis)	5.5 (4.4–5.7)	HR, 1.004 (0.840–1.199); p = .0044 (noninferiority)	55.7	NR
JapicCTI‐101021 Yamada 2015 [20]^d ^, ^r	S‐1 + Cis	324	13.1 (12.1–15.1)		5.4 (4.2–5.7)		52.2
Li 2015 [113]^e	S‐1 + Cis	120	10.0 (8.59–14.52)	p = .82
Li 2015 [113]^e	FU + Cis	116	10.46 (8.92–13.84)
Wang 2016 [19]^d ^, ^s	Doc + Cis + FU	121	10.2 (8.6–11.9)	HR, 0.71 (0.52–0.97); p = .0319	7.2 (5.5–8.8)	HR, 0.58 (0.42–0.80); p = .0008 (log‐rank test)	48.7	p = .0244
Wang 2016 [19]^d ^, ^s	Cis + FU	122	8.5 (7.1–9.5)		4.9 (4.5–6.0)		33.9
G‐SOX Bando 2016 [21]^d	S‐1 + Ox (≥70 yr)	116	17.5	≥70 yr: HR, 0.857 (0.629–1.167); p = .325	5.7	HR, 0.805 (0.588–1.102); p = .174	NR	NR
	S‐1 + Cis (≥70 yr)	104	13.5		5.5		NR
	S‐1 + Ox (<70 yr)	227	13.3	<70 yr: HR, 0.984 (0.800–1.209); p = .877	4.4	HR, 1.019 (0.827–1.256); p = .862	NR
	S‐1 + Cis (<70 yr)	238	13.1		5.3		NR
TRIO‐013/LOGiC Hecht 2016 [23]^d ^, ⁿ	LAP + Cap + Ox	249	12.2	HR, 0.91 (0.73–1.12); p = .3492	6.0	HR, 0.82 (0.68–1.00); p = .0381	NR	NR
TRIO‐013/LOGiC Hecht 2016 [23]^d ^, ⁿ	PBO + Cap + Ox	238	10.5		5.4		NR
DIGEST Ajani 2017 [27]	S‐1 + Cis	239	7.5 (6.7–9.3)	Unstratified: HR, 0.99 (0.76–1.28); p = .9312 Stratified: HR, 0.90 (0.68–1.19); p = .4631	4.4	HR, 0.86 (0.65–1.14); p = .3039	34.7	p = .0122
	FU + Cis	122	6.6 (5.7–8.1)		3.9		19.8
RILOMET‐1 Catenacci 2017 [28]	Rilotumumab + Epir + Cis + Cap	262	8.8 (7.7–10.2)	HR, 1.34 (1.10–1.63); p = .003	5.6 (5.3–5.9)	HR, 1.26 (1.04–1.51); p = .016	29.8	p = .0005
	PBO + Epir + Cis + Cap	267	10.7 (9.6–12.4)		6.0 (5.7–7.2)		44.6
METGastric Shah 2017 [39]	Onartuzumab + mFOLFOX6	217	11.0	HR, 0.82 (0.59–1.15); p = .24	6.7	HR, 0.90 (0.71–1.16); p = .43	46.1	p = .25
	PBO + mFOLFOX6	207	11.3		6.8		40.6
	MET 2+/3+ subgroup: onartuzumab + mFOLFOX6	78	11.0	HR, 0.64 (0.40–1.03); p = .06	6.9	HR, 0.79 (0.54–1.15); p = .22	53.8	p = .23
	MET 2+/3+ subgroup: PBO + mFOLFOX6	92	9.7		5.7		44.6
Shu 2017 [32]	Ox + tegafur	164	13.4 (12.2–15.1)	HR, 0.96 (0.80–1.39)	5.5 (4.6–6.2)	HR, 1.02 (0.82–1.31)	44.5	p = .702
	Ox + Cis	168	14.2 (13.1–16.0)		6.1 (5.6–6.4)		48.8
HELOISE Shah 2017 [115]	SoC Tras + Cap + Cis	124	12.5	HR, 1.24 (0.86–1.78); p = .2401	5.7	HR, 1.04 (0.76–1.40); p = .8222	58.9	p = .76
	Higher‐dose Tras + Cap + Cis	124	10.6		5.6		56.9
Lu 2018 [29]	Pac + Cap	160	12.5 (11.5–14.5)	HR, 0.878 (0.685–1.125); p = .30	4.994 (4.304–6.275)	HR, 0.906 (0.706–1.164); p = .44	43.1	p = .01
	Cis + Cap	160	11.8 (10.0–13.7)		5.257 (4.665–5.815)		28.8
Lu 2019 [35]	S‐1 + Doc	150	405 days	p = .5127	180 days	p > .05	NR	NR
	S‐1 + Cis	150	378 days		171 days		NR
RAINFALL Fuchs 2019 [40]^t ^, ^u	RAM + Cis + Cap/FU^v	326	11.2 (9.9–11.9)	HR, 0.962 (0.801–1.156); p = .68	Investigator‐assessed: 5.7 (5.5–6.5) Independent review: 5.5 (4.2–5.8)	Investigator‐assessed: HR, 0.753 (0.607–0.935); p = .011 Independent review: HR, 0.961 (0.78–1.203); p = .74	41.1	p = .17
	PBO + Cis + Cap/FU^o	319	10.7 (9.5–11.9)		Investigator‐assessed: 5.4 (4.5–5.7) Independent review: 5.4 (4.4–5.7)		36.4
JACOB Tabernero 2018 [38]	Pertuzumab + Tras/Chemo	388	17.5 (16.2–19.3)	HR,0.84 (0.71–1.00); p = .057	8.5 (8.2–9.7)	HR, 0.73 (0.62–0.86); p = .0001	56.7	p = .026
	PBO + Tras/Chemo	392	14.2 (12.9–15.5)		7.0 (6.4–8.2)		48.3
JCOG1013 Yamada 2019 [36]	Doc + Cis/S‐1	370	14.2 (12.9–15.9)	HR, 0.99 (0.85–1.16); p = .47	7.4 (6.7–7.8)	HR, 0.99 (0.86–1.15); p = .92	59	p = .50
	Cis/S‐1	371	15.3 (14.2–16.2)		6.5 (5.9–7.4)		56
Second‐line studies
Thuss‐Patience 2011 [47]^w ^– ^y ^, ^as	IRI + BSC	21	4.0 (3.6–7.5)	All patients died: HR, 0.48 (0.25–0.92); p = .012	ITT population: 2.5 (1.6–3.9) Per‐protocol population: 2.6 (1.7–4.3)	NR (results provided for IRI arm only)	0^z	NR
	BSC	19	2.4 (1.7–4.9)		NR (results provided for IRI arm only)		NR
Yi 2012 [43]^x ^, ^as	Doc + sunitinib	56	8.0 (5.4–10.6)	HR, 0.94 (0.60–1.49); p = .802	NR	NR	41.1	p = .002
	Doc	49	6.6 (3.6–9.7)		NR		14.3
Sym 2013 [55]^x ^, ^aa ^, ^as	IRI	29	5.8 (3.0–8.7)	HR, 1.21 (0.69–2.11); p = .514	2.2 (0.2–4.3)	HR, 1.20 (0.72–2.02); p = .481	17.2	p = .525
	FOLFIRI	30	6.7 (5.3–8.2)		3.0 (2.0–3.7)		20.0
WJOG 4007 Hironaka 2013 [53]^aa ^, ^ab ^, ^as	Pac	108	9.5 (8.4–10.7)	HR, 1.13 (0.86–1.49); p = .38	3.6 (3.3–3.8)	HR, 1.14 (0.88–1.49); p = .33	20.9	p = .24
	IRI	111	8.4 (7.6–9.8)		2.3 (2.2–3.1)		13.6
Roy 2013 [54]^x ^, ^aa ^, ^as	PEP02^ac	44	7.3 (3.84–9.17)	NR	2.7 (1.54–3.65)	NR	13.6	NR
	IRI	44	7.8 (4.90–9.20)		2.6 (1.48–4.34)		6.8
	Doc	44	7.7 (5.32–12.32)		2.7 (1.41–5.45)		15.9
TyTAN Satoh 2014 [46]^x ^, ^aa ^, ^as	LAP + Pac	132	11.0^ad	HR, 0.84 (0.64–1.11); p = .1044	5.5^ad	HR, 0.85 (0.63–1.13); p = .2441^ad	27^ad	Estimated OR, 3.85 (1.80–8.87); p < .001
	Pac	129	8.9^ad		4.4^ad		9^ad
COUGAR‐02 Ford 2014 [49]^at	Doc	84	5.2 (4.1–5.9)	HR, 0.67 (0.49–0.92); p = .01	NR	NR	NR	NR
	Active symptom control	84	3.6 (3.3–4.4)		NR		NR
TCOG GI‐0801/BIRIP Higuchi 2014 [44]^x ^, ^aa ^, ^as	IRI + Cis	64	10.7	HR, 1.00 (0.69–1.44); p = .9823	3.8	HR, 0.68 (0.47–0.98); p = .0398	22	p = .4975
	IRI	63	10.1		2.8		16
REGARD Fuchs 2014 [42]^x ^, ^aa ^, ^av	RAM	238	5.2 (IQR, 2.3–9.9)	HR, 0.776 (0.603–0.998); p = .047	2.1 (IQR, 1.3–4.2)	HR, 0.483 (0.376–0.620); p < .0001	3	p = .76
	PBO	117	3.8 (IQR, 1.7–7.1)		1.3 (IQR, 1.1–2.1)		3
RAINBOW Wilke 2014 [41]^ae ^, ^af ^, ^av	RAM + Pac	330	9.6 (8.5–10.8)	HR, 0.807 (0.678–0.962); p = .017	4.4 (4.2–5.3)	HR, 0.635 (0.536–0.752); p < .0001	28	p = .0001
	PBO + Pac	335	7.4 (6.3–8.4)		2.9 (2.8–3.0)		16
JACCRO GC‐05 Tanabe 2015 [56]^aa ^, ^ag ^, ^as	S‐1 + IRI	145	8.8 (IQR, 5.6–15.7)	p = .92 HR for death, 0.99 (0.78–1.25)	3.8 (IQR, 1.9–6.6)	HR for disease progression or death, 0.85 (0.67–1.07); p = .16	7.6	NS
	IRI	148	9.5 (IQR, 5.6–14.1)		3.4 (IQR, 1.6–5.3)		7.4
JapicCTI‐090849 Satoh 2015 [62]^as	Nimotuzumab + IRI	40	250.5 days^ah (171.0–306.0)	HR, 0.994 (0.618–1.599)^ah; p = .9778	73.0 days (55.0–112.0)	HR, 0.860 (0.516–1.435); p = .5668	18.4	p = .3060
	IRI	42	232.0 days^ah (148.0–319.0)		85.0 days (37.0–93.0)		10.3
Study 39 Bang 2015 [48]^ae ^, ^ah ^, ^au ^, ^ax	Olaparib + Pac	62	13.1	HR, 0.56 (0.35–0.87); p = .010	3.9	HR, 0.80 (80% CI, 0.62–1.03); p = .131	26.4	NS
	PBO + Pac	62	8.3		3.6		19.1
TRICS Nishikawa 2015 [57]^ai ^, ^as	IRI + Cis	84	13.9 (10.8–17.6)	HR, 0.834 (0.596–1.167); p = .288	4.6 (3.4–5.9)	HR, 0.860 (0.610–1.203); p = .376	NR	NR
	IRI	84	12.7 (10.3–17.2)		4.1 (3.3–4.9)		NR
Kim 2015 [45]^x ^, ^ae	Doc	27	7.2 (6.0–8.4)	p = .353	2.0 (1.2–2.9)	p = .002	14.8	p = .40
	Doc + Ox	25	8.1 (7.6–8.6)		4.9 (3.6–6.6)		24.0
RAINBOW subgroup analysis (East Asia) Muro 2016 [63]^ae ^, ^aj ^, ^as	RAM + Pac	109	12.1	HR, 0.986 (0.727–1.337); p = .929	5.5	HR, 0.628 (0.473–0.834)	34	OR, 2.24 (1.18–4.24); p = .0134
	PBO + Pac	114	10.5		2.8		20
RAINBOW subgroup analysis (Japan) Shitara 2016 [64]^ae ^, ^ak ^, ^aw	Japanese: RAM + Pac	68	11.4	HR, 0.880 (0.603–1.284); p = .5113	5.6	HR, 0.503 (0.348–0.728); p = .0002	41.2	p = .0035
	Japanese: PBO + Pac	72	11.5		2.8		19.4
	Western: RAM + Pac	198	8.6	HR, 0.7326 (0.580–0.909); p = .005	4.2	HR, 0.631 (0.506–0.786); p < .0001	26.8	p = .0004
	Western: PBO + Pac	200	5.9		2.8		13.0
CCOG0701 Nakanishi 2016 [58]^aa ^, ^al ^, ^as	Pac	40	10.0 (0.4–74.1)	HR, 0.834 (0.511–1.359)	4.6 (0.4–74.1)	HR, 0.862 (0.543–1.367); difference NS^b	27	p = .767
	Pac + S‐1	49	10.0 (1.3–72.0)		4.6 (0.4–59.6)		22
JCOG0407 Nishina 2016 [50]^w ^, ^as	Best available FU	49	7.7 (6.7–9.0)	HR, 0.89 (0.57–1.38); p = .298	2.4 (1.7–3.6)	HR, 0.58 (0.38–0.88); p = .005	NR	NR
	Pac	51	7.7 (6.0–9.7)		3.7 (2.6–3.7)		NR
Bang 2017b [70]^w ^, ^ae	Ipilimumab	57	12.7 (10.5–18.9)	NR	irPFS: 2.92 (1.61–5.16) PFS (mWHO criteria): 2.73 (1.45–2.96)	irPFS: HR, 1.44 80% CI, 1.09–1.91); p = .097 mWHO criteria: HR, 1.59 (80% CI, 1.20–2.10); p = .034 (“consistent with irPFS” [improvement was not observed])	1.8	NR
	BSC	57	12.1 (9.3–NE)		irPFS: 4.90 (3.45–6.54) PFS (mWHO criteria): 4.90 (3.45–6.08)		7.0	NR

GOLD Bang 2017a [69]^x	Olaparib + Pac	263	8.8 (7.4–9.6)	HR, 0.79 (97.5% CI, 0.63–1.00); p = .026 (NS)^an	3.7 (3.7–4.2)	HR, 0.84 (97.5% CI, 0.67–1.04); p = .065	17 (adjusted, 24)^ae	OR, 1.69 (97.5% CI, 0.92–3.17); p = .055
	PBO + Pac	262	6.9 (6.3–7.9)		3.2 (2.2–3.5)		11 (adjusted, 16)^ae
	ATM‐negative tumors subgroup: Olaparib + Pac	48	12.0 (7.8–18.1)	HR, 0.73 (97.5% CI, 0.40–1.34); p = .25	5.3 (3.5–9.0)	HR, 0.74 (97.5% CI, 0.42–1.29); p = .22	25 (adjusted, 38)^ae	OR, 4.24 (0.95–23.23); p = .031
	ATM‐negative tumors subgroup: PBO + Pac	46	10.0 (6.4–13.3)		3.7 (1.9–5.3)		11 (adjusted, 16)^ae
GATSBY Thuss‐Patience 2017 [66]^x ^, ^ae	Taxane	117	8.6 (7.1–11.2)	HR, 1.15 (0.87–1.51); p = .86	2.9 mo (2.8–4.0)	HR, 1.13 (0.89–1.43); p = .31	19.6	p = .8406
	Tras emtansine	228	7.9 (6.7–9.5)		2.7 (1.6–2.7)		20.6
SHINE Van Cutsem 2017 [72]^x ^, ^ae	AZD4547	41	5.5 (95% CI, NR)	HR, 1.31 (80% CI, 0.89–1.95); p = .8156	1.8	HR, 1.57 (80% CI, 1.12–2.21); p = .9581	2.6	OR, 0.09 (80% CI, 0.02–0.35); p = .9970
	Pac	30	6.6 (95% CI, NR)		3.5		23.3
Lee 2017 [116]^aa	Doc	23	10.0 (7.8–12.2)	All vs. Doc + S‐1: p = .023 Doc + S‐1 vs. Doc: p = .421 Doc + Cis vs. Doc: p = .035	1.3 (1.0–1.5)	All vs. Doc + S‐1: p = .072 Doc + Cis vs. Doc: p = .804 Doc + S‐1 vs. Doc: p = .072	4.3	p > .990 vs. Doc
	Doc + Cis	23	5.6 (4.4–6.7)		1.8 (0.8–2.9)		4.3
	Doc + S‐1	23	6.9 (2.1–11.7)		2.7 (1.0–4.4)		8.7
ABSOLUTE Shitara 2017 [52]	Nab‐Pac Q3W	243	10.3 (8.7–11.4)	Nab‐Pac Q3W vs. Pac: HR, 1.06 (0.87–1.31); p = .062	3.8 (3.5–4.4)	Nab‐Pac Q3W vs. Pac: HR, 1.03 (0.85–1.24); p = .778	25	(18.6–33.1); p = .897 vs. Pac
	Nab‐Pac QW	240	11.1 (9.9–13.0)	Nab‐Pac QW vs. Pac: HR, 0.97 (97.5% CI, 0.76–1.23); p = .0085	5.3 (4.0–5.6)	Nab‐Pac Q3W vs. Pac: HR, 0.88 (0.73–1.06); p = .176	33	(25.2–40.8); p = .106 vs. Pac
	Pac	243	10.9 (9.4–11.8)		3.8 (3.7–3.9)		24	(18.0–31.4)
DREAM Kang 2018 [51]^x ^, ^ae ^, ^ai	DHP107 (oral Pac)	118	9.7 (7.1–11.5)	HR, 1.04 (0.76–1.41); p = .824	3.0 (1.7–4.0)	HR, 0.85 (0.64–1.13)	NR	NR
	IV Pac	118	8.9 (7.1–12.2)		2.6 (1.8–2.8)		NR
KEYNOTE‐061 Shitara 2018a [71]^ae ^, ^ay	Pembrolizumab	296	NR	NR	NR	NR	12.2	NR
	Pac	296	NR	NR	NR	NR	15.2	NR
	PD‐L1 CPS ≥1 subgroup: Pembrolizumab	196	9.1 (6.2–10.7)	HR, 0.82 (0.66–1.03); p = .0421 (NS)^ao	1.5 (1.4–2.0)	HR, 1.27 (1.03–1.57)	16	NR
	PD‐L1 CPS ≥1 subgroup: Pac	199	8.3 (7.6–9.0)		4.1 (3.1–4.2)		14	NR
KCSG ST10‐01 Lee 2019 [117]^x ^, ^ae ^, ^am	Pac	54	8.57 (7.1–10.0)	HR, 1.39 (0.91–2.11); p = .126	3.47 (2.2–4.7)	HR, 1.27 (0.86–1.88); p = .234	15.8	p = .355
	IRI	58	7.03 (5.6–8.4)		2.10 (1.4–2.8)		13.6
Combined second‐ and third‐line populations
Kang 2012 [61]^as	Doc or IRI + BSC	133	5.3 (4.1–6.5)	HR, 0.657 (0.485–0.891); p = .007	NR	NR	NR	NR
	BSC	69	3.8 (3.1–4.5)		NR		NR
GRANITE‐1 Ohtsu 2013 [73]^aa ^, ^ap ^, ^as	Everolimus + BSC	439	5.4 (4.8–6.0)	HR, 0.90 (0.75–1.08); p = .124	1.7 (1.5–1.9)	HR, 0.66 (0.56–0.78); p < .001	4.5	(95% CI for the rate, 2.6–7.1)
	PBO + BSC	217	4.3 (3.8–5.5)		1.4 (1.4–1.5)		2.1	(95% CI for the rate, 0.6–5.3)
Shitara 2014 [59]^ae ^, ^aq ^, ^as	Dose‐escalated Pac	44	11.8 (7.6–16.3)	HR, 0.75 (0.45–1.22); p = .12	4.3 (3.0–5.7)	HR, 0.55 (0.34–0.90); p = .017	30.3	(95% CI for the rate, 15.6–48.7)
	Pac	45	9.6 (7.4–11.7)		2.5 (1.8–3.7)		17.1	(95% CI for the rate, 6.6–33.7)
Fushida 2016 [60]^ae ^, ^as	Pac	33	9.8	HR, 1.19 (0.702–2.026); p = .51	4.5	HR, 1.29 (0.753–2.211); p = .35	NR	NR
	Pac + valproic acid	31	8.7		3.0		NR
Moehler 2016 [118]^x ^, ^as	Na‐FOLFIRI + sunitinib	45	10.4 (4.5–10.9)	HR, 0.82 (0.50–1.34); p = .42	3.5 (1.4–5.6)	HR, 1.11 (0.70–1.74); p = .66	20	NR
	Na‐FOLFIRI + placebo	45	8.9 (5.9–11.8)		3.3 (1.5–5.2)		29	NR
INTEGRATE Pavlakis 2016 [74]^ae ^, ^ar ^, ^as	Regorafenib + BSC	97	5.8 (4.4–6.8)	HR, 0.74 (0.51–1.08); p = .147	2.6 (1.8–3.1)	HR, 0.40 (0.28–0.59); p < .001	3.0	(95% CI for the rate, 1–9)
	Placebo + BSC	50	4.5 (3.4–5.2)		0.9 (0.9–0.9)		2	(95% CI for the rate, 0–11)
Third‐line and beyond studies
Li 2013 [77]	Apatinib 850 mg once daily	47	4.83 (4.03–5.97)	HR, 0.37 (0.22–0.62); p < .001	3.67 (2.17–6.80)	HR, 0.18 (0.10–0.34); p < .001)	0	(95% CI for the rate, 1.3–17.5)
	Apatinib 425 mg twice daily	46	4.27 (3.83–4.77)	HR, 0.41 (0.24–0.72); p = .0017	3.20 (2.37–4.53)	HR, 0.21 (0.11–0.38); p < .001	6.38	(95% CI for the rate, 4.9–26.3)
	PBO	48	2.5 (1.87–3.70)		1.40 (1.20–1.83)		13.04	(95% CI for the rate, 0.0–7.4)
Li 2016 [78]	Apatinib	146	6.5 (4.8–7.6)	HR, 0.709 (0.537–0.937); p = .0149	2.6 (2.0–2.9)	HR, 0.444 (0.331–0.595); p < .001	2.84 (1.70)	p = .1695 (p = .5532)
	PBO	78	4.7 (3.6–5.4)		1.8 (1.4–1.9)		0
ATTRACTION‐2 Kang 2017 [75]^ay	Nivolumab	330	5.26 (4.60–6.37)	HR, 0.63 (0.51–0.78); p < .0001	1.61 (1.54–2.30)	HR, 0.60 (0.49–0.75); p < .0001	11.2	NR
	PBO	163	4.14 (3.42–4.86)		1.45 (1.45–1.54)		0
JAVELIN Gastric 300 Bang 2018 [82]^ay	Avelumab + BSC	185	4.6 (3.6–5.7)	HR, 1.1 (0.9–1.4); p = .81	1.4 (1.4–1.5)	HR, 1.73 (1.4–2.2); p > .99	2.2	NR
	Chemo + BSC	185	5.0 (4.5–6.3)		2.7 (1.8–2.8)		4.3
TAGS Shitara 2018b [76]	Trifluridine/tipiracil + BSC	337	5.7 (4.8–6.2)	HR, 0.69 (0.56–0.85); p = .00029	2.0 (1.9–2.3)	HR, 0.57 (0.47–0.70); p < .0001	4	p = .28
	PBO + BSC	170	3.6 (3.1–4.1)		1.8 (1.7–1.9)		2
CheckMate‐032 Janjigian 2018 [80]^ay	Nivolumab 3 mg/kg	59	6.2 (3.4–12.4)	NR	1.4 (1.2–1.5)	NR	7	NR
	Nivolumab 1 mg/kg + ipilimumab 3 mg/kg	49	6.9 (3.7–11.5)		1.4 (1.2–3.8)		20	NR
	Nivolumab 3 mg/kg + ipilimumab 1 mg/kg	52	4.8 (3.0–8.4)		1.6 (1.4–2.6)		4	NR
ATTRACTION‐2 subgroup analysis (Japanese patients) Kato 2019 [79]^ay	Nivolumab	152	5.4 (4.6–7.4)	HR, 0.58 (0.42–0.78); p = .0002	1.7 (1.6–2.8)	HR, 0.53 (0.39–0.72); p < .0001	14.0	p = .0023
	Placebo	74	3.6 (2.8–5.0)		1.5 (1.5–1.6)		0
ATTRACTION‐2 subgroup analysis (prior Tras use) Satoh 2020 [119]^ay	History of Tras: nivolumab	59	8.3 (5.3–12.9)	HR, 0.38 (0.22–0.66); p = .0006	1.6 (1.5–4.0)	HR, 0.49 (0.29–0.85); p = .0111	16.9	NR
	History of Tras: PBO	22	3.1 (1.9–5.3)		1.5 (1.3–2.9)		0
	No history of Tras: nivolumab	271	4.8 (4.1–6.0)	HR, 0.71 (0.57–0.88); p = .0022	1.6 (1.5–2.4)	HR, 0.64 (0.51–0.80);p = .0001	7.7	NR
	No history of Tras: PBO	141	4.2 (3.6–4.9)		1.5 (1.5–1.5)		0

Open in a new tab

^{^a}

In Ajani et al. (2010) [26], Ryu et al. (2015) [109], Waddell et al. (2013) [18], Wang et al. (2016) [19], Bando et al. (2016) [21], Bang et al. (2010) [17], Guimbaud et al. (2014) [22], Hecht et al. (2016) [23], Li et al. (2015) [113], and Lordick et al. (2013) [114], data were not reported as being either adjusted or unadjusted.

^{^b}

In Shen et al. (2015) [110], Van Cutsem et al. (2015) [37], Yamada et al. (2015) [20], and Kang et al. (2009) [24], unadjusted data are presented for OS and PFS; for other endpoints, data were not reported as being either adjusted or unadjusted.

^{^c}

In Kim et al. (2014) [112] and Ohtsu et al. (2011) [25], unadjusted data are presented for OS, PFS, and response; for other endpoints, data were not reported as being either adjusted or unadjusted.

^{^d}

In Shen et al. (2015) [110], Waddell et al. (2013) [18], Wang et al. (2016) [19], Yamada et al. (2015) [20], Bando et al. (2016) [21], Guimbaud et al. (2014) [22], Hecht et al. (2016) [23], Kang et al. (2009) [24], Kim et al. (2014) [112], Lordick et al. (2013) [114], and Ohtsu et al. (2011) [25], RECIST version 1.0 criteria were used.

^{^e}

In Kang et al. (2009) [24] and Li et al. (2015) [113], only patients with measurable disease were included.

^{^f}

In Ajani et al. (2010) [26], RECIST criteria were used, but no version number was provided.

^{^g}

In Ajani et al. (2010) [26], patients were stratified based on whether disease was measurable (95.6% of patients had measurable disease).

^{^h}

In Bang et al. (2010) [17] and Van Cutsem et al. (2015) [37], there was no indication that RECIST criteria were used.

^ⁱ

In Bang et al. (2010) [17], patients were stratified based on whether disease was measurable (~90% of patients had measurable disease).

^{^j}

Cap plus Cis or FU plus Cis, chosen at the investigator's discretion.

^{^k}

“Overall tumor response rate” (complete response plus partial response).

^{^l}

In Ohtsu et al. (2011) [25], the measurable disease population was used to evaluate response rate (~79% of patients had measurable disease).

^{^m}

Patients unable to take oral medications received FU. Switching from Cap to FU during the study was not permitted.

^ⁿ

In Hecht et al. (2016) [23] and Lordick et al. (2013) [114], no information was provided regarding the handling of data from patients with measurable versus nonmeasurable disease.

^{^o}

In Guimbaud et al. (2014) [22], patients were stratified based on whether disease was measurable (the proportion of patients with measurable disease was not provided).

^{^p}

In Kim et al. (2014) [112], patients were stratified based on whether disease was measurable (~64% of patients had measurable disease).

^{^q}

In Ryu et al. (2015) [109], response rate was calculated only for patients with measurable disease (~61% of patients).

^{^r}

In Yamada et al. (2015) [20], those with no measurable disease were excluded from the per‐protocol population (~2.5% of patients).

^{^s}

In Wang et al. (2016) [19], those with no measurable disease were excluded from the efficacy population (~1.3% of patients).

^{^t}

In Ryu et al. (2015) [109] and Fuchs et al. (2019) [40], RECIST version 1.1 criteria were used.

^{^u}

In Fuchs et al. (2019) [40], adjusted data were presented for PFS; for other endpoints, data were not reported as being either adjusted or unadjusted.

^{^v}

FU IV infusion was permitted in patients unable to take oral capecitabine.

^{^w}

In Thuss‐Patience et al. (2011) [47], Nishina et al. (2016) [50], and Bang et al. (2017b) [70], there was no indication that RECIST criteria were used.

^{^x}

In Satoh et al. (2015) [62], Satoh et al. (2014) [46], Sym et al. (2013) [55], Thuss‐Patience et al. (2011) [47], Yi et al. (2012) [43], Higuchi et al. (2014) [44], Fuchs et al. (2014) [42], Kim et al. (2015) [45], Roy et al. (2013) [54], Bang et al. (2017a) [69], Kang et al. (2018) [51], Thuss‐Patience et al. (2017) [66], Van Cutsem et al. (2017) [72], Lee et al. (2019) [117], and Moehler et al. (2016) [118], no information was provided regarding the handling of data from patients with measurable versus nonmeasurable disease.

^{^y}

In Thuss‐Patience et al. (2011) [47], there was no indication that RECIST criteria were used.

^{^z}

No objective remission according to World Health Organization criteria.

^{^aa}

In Satoh et al. (2015) [62], Satoh et al. (2014) [46], Sym et al. (2013) [55], Tanabe et al. (2015) [56], Higuchi et al. (2014) [44], Fuchs et al. (2014) [42], Hironaka et al. (2013) [53], Nakanishi et al. (2016) [58], Roy et al. (2013) [54], Lee et al. (2017) [116], and Ohtsu et al. (2013) [73], RECIST version 1.0 criteria were used.

^{^ab}

In Hironaka et al. (2013) [53], response rate was assessed in patients with measurable disease at baseline (~80% of patients).

^{^ac}

PEP02 is a highly stable liposomal nanocarrier formulation of irinotecan.

^{^ad}

ITT population. Similar results were obtained for the modified ITT population (i.e., randomly assigned patients confirmed FISH positive by central laboratory).

^{^ae}

In Bang et al. (2015) [48], Wilke et al. (2014) [41], Muro et al. (2016) [63], Shitara et al. (2016) [64], Bang et al. (2017a) [69], Kang et al. (2018) [51], Kim et al. (2015) [45], Shitara et al. (2018b) [76], Thuss‐Patience et al. (2017) [66], Van Cutsem et al. (2017) [72], Lee et al. (2019) [117], Fushida et al. (2016) [60], Pavlakis et al. (2016) [74], and Shitara et al. (2014) [59], RECIST version 1.1 criteria were used.

^{^af}

In Wilke et al. (2014) [41], patients were stratified based on whether disease was measurable (~81% of patients had measurable disease).

^{^ag}

In Tanabe et al. (2015) [56], response rate was calculated only for patients with measurable disease (~82% of patients had measurable disease).

^{^ah}

Eighteen‐month OS.

^{^ai}

In Nishikawa et al. (2015) [57] and Kang et al. (2012) [61], RECIST criteria were used, but no version number was provided.

^{^aj}

In Muro et al. (2016) [63], patients were stratified based on whether disease was measurable (~72% of East Asian patients and ~ 81% of non–East Asian patients had measurable disease).

^{^ak}

In Shitara et al. (2016) [64], patients were stratified based on whether disease was measurable (72.1% of Japanese patients and 83.4% of Western patients had measurable disease).

^{^al}

In Nakanishi et al. (2016) [58], measurable disease was an adjustment factor during randomization (~42% of patients had measurable disease).

^{^am}

In Lee et al. (2019) [117], response evaluation was conducted on patients with at least one measurable lesion (38/54 in the paclitaxel group and 44/58 in the irinotecan group).

^{^an}

In the GOLD study (Bang et al. [2017a] [69]), statistical significance was set at p < .025.

^{^ao}

In the KEYNOTE‐061 study (Shitara et al. [2018a] [71]), statistical significance was set at p < .0215.

^{^ap}

In Ohtsu et al. (2013) [73], objective response of complete response or partial response, only assessed in the patients with measurable disease at baseline (approximately 86% in the everolimus plus BSC group and 88% in the placebo plus BSC group).

^{^aq}

In Shitara et al. (2014) [59], objective response of complete response or partial response, only assessed in the patients with measurable disease at baseline (78% in the weekly paclitaxel group and 75% in the dose‐escalated weekly paclitaxel group).

^{^ar}

In Pavlakis et al. (2016) [74], only patients with measurable disease were included in the study.

^{^as}

In Satoh et al. (2015) [62], Satoh et al. (2014) [46], Sym et al. (2013) [55], Tanabe et al. (2015) [56], Thuss‐Patience et al. (2011) [47], Yi et al. (2012) [43], Higuchi et al. (2014) [44], Muro et al. (2016) [63], Hironaka et al. (2013) [53], Kim et al. (2015) [45], Nakanishi et al. (2016) [58], Nishina et al. (2016) [50], Roy et al. (2013) [54], Nishikawa et al. (2015) [50], Fushida et al. (2016) [60], Kang et al. (2012) [61], Moehler et al. (2016) [28], Ohtsu et al. (2013) [73], Pavlakis et al. (2016) [74], and Shitara et al. (2014) [59], data were not reported as being either adjusted or unadjusted.

^{^at}

In Ford et al. (2014) [49], adjusted data are presented for OS; for other endpoints, data were not reported as being either adjusted or unadjusted.

^{^au}

In Bang et al. (2015) [48], adjusted data are presented for OS and PFS; for other endpoints, data were not reported as being either adjusted or unadjusted.

^{^av}

In Fuchs et al. (2014) [42] and Wilke et al. (2014) [41], unadjusted data are presented for OS and PFS; for other endpoints, data were not reported as being either adjusted or unadjusted.

^{^aw}

In Shitara et al. (2016) [64], adjusted data are presented for ORR and disease control rate; for other endpoints, data were not reported as being either adjusted or unadjusted.

^{^ax}

In Bang et al. (2015) [48], response rate was calculated only for patients with measurable disease (~81% of patients).

^{^ay}

In Bang et al. (2018) [82], Kang et al. (2017) [75], Kato et al. (2019) [79], Shitara et al. (2018a) [71], and Janjigian et al. (2018) [80], data were not reported as being either adjusted or unadjusted. In Satoh et al. (2020) [119], adjusted data are presented for ORR and disease control rate; for other endpoints, data were not reported as being either adjusted or unadjusted.

Abbreviations: ATM, ataxia telangiectasia mutated; BEV, bevacizumab; BSC, best supportive care; Cap, capecitabine; Chemo, chemotherapy; CI, confidence interval; Cis, cisplatin; CPS, combined positive score; CTX, cetuximab; D, day; Doc, docetaxel; Epir, epirubicin; FOL, folinic acid FOLFIRI, irinotecan plus 5‐fluorouracil plus folinic acid (also known as leucovorin); FU, fluorouracil; HR, hazard ratio; IQR, interquartile range; IRI, irinotecan; irPFS, immune‐related progression‐free survival; ITT, intent‐to‐treat; IV, intravenous; LAP, lapatinib; MET, mesenchymal‐epithelial transition; mWHO, modified World Health Organization; nab‐Pac, nab‐paclitaxel; NR, not reported; NS, not significant; OR, odds ratio; ORR, overall response rate; Ox, oxaliplatin; Pac, paclitaxel; PAN, panitumumab; PBO, placebo; PD‐L1, programmed death‐ligand 1; PFS, progression‐free survival; QW, once weekly; Q3W, once every 3 weeks; RAM, ramucirumab; SIM, simvastatin; SoC, standard of care; Tras, trastuzumab.

Chemotherapeutic Agents

The majority of studies assessed combination chemotherapy in both arms. Only one study included a monotherapy arm.

In this SLR, studies that excluded patients with HER2‐overexpressing (HER2+) tumors generally evaluated regimens without biomarker targets, focusing on new combinations to optimize the benefit‐to‐risk ratio. Eleven RCTs compared the efficacy and/or safety of different doublet regimens. Cisplatin plus capecitabine versus cisplatin plus 5‐FU showed noninferior OS and PFS and higher ORR while not significantly affecting toxicity [24].

Two studies compared the effect of S‐1 plus cisplatin versus 5‐FU plus cisplatin [26, 27]. The FLAGS study found that median TTF was longer and the AE profile was more favorable with S‐1 plus cisplatin than with 5‐FU plus cisplatin [26]. The DIGEST study found no significant difference in OS between S‐1 plus cisplatin and 5‐FU plus cisplatin [27]. Although outside the inclusion parameters used in this review, the SC‐101 and START studies established the benefits of frontline S‐1–based combination therapies in Asian populations [30, 31]. SC‐101 demonstrated superior benefits for S‐1 plus cisplatin compared with S‐1 monotherapy or 5‐FU plus cisplatin in Chinese patients, and the START study demonstrated significant clinical benefits (OS, 12.5 vs. 10.8 months; p = .032; PFS, 5.3 vs. 4.2 months; p = .001) in Korean and Japanese patients treated with docetaxel plus S‐1 compared with S‐1 monotherapy.

Shu et al. found that oxaliplatin plus S‐1 was noninferior to oxaliplatin plus tegafur in terms of PFS and OS [32]. The G‐SOX study evaluated S‐1 plus oxaliplatin or S‐1 plus cisplatin and showed noninferiority that was statistically significant [21]. These results may have been mediated by the observed better tolerability with oxaliplatin versus cisplatin in the elderly. In G‐SOX, discontinuation rates due to AEs and serious AEs were higher in the S‐1 plus cisplatin group than in the S‐1 plus oxaliplatin group. Although outside the inclusion parameters of this review, Al‐Batran et al. compared fluorouracil, leucovorin, and oxaliplatin (FLO) with fluorouracil, leucovorin, and cisplatin (FLP) in patients with advanced gastric cancer [33]. No significant OS or PFS benefits were observed between FLO and FLP arms, although in older adults FLO was associated with increased efficacy. Importantly, FLO was associated with significantly lower frequency of AEs (e.g., any grade vomiting 31% [FLO] vs. 52% [FLP]) and treatment‐related serious AEs (9% [FLO] vs. 19% [FLP]). Along these lines, although the randomized phase II CALGB 80403 study of cetuximab with one of three chemotherapy regimens (epirubicin, cisplatin, and continuous‐infusion fluorouracil; irinotecan plus cisplatin; or folinic acid plus 5‐FU plus oxaliplatin [FOLFOX]) did not meet the inclusion criteria of 200 or more patients in 1L, its results indicated that FOLFOX was better tolerated and was the recommended backbone for 1L [34]. The FOLFOX arm reported fewer treatment modifications and discontinuations due to treatment‐related AEs or deaths [34]. These data suggest better tolerability for oxaliplatin‐based regimens versus cisplatin, with comparable efficacy.

One study compared the effect of cisplatin and docetaxel when paired with S‐1 [35]. OS was numerically longer with S‐1 plus docetaxel than with S‐1 plus cisplatin (405 days vs. 378 days; p = .5127), although the difference was not significant. One study compared the effect of paclitaxel plus capecitabine with cisplatin plus capecitabine [29]. Lu et al. found no significant difference in OS between the two regimens [29]. These data suggest that a taxane‐based doublet may be a suitable alternative to a platinum‐based doublet.

Despite statistically significant longer OS (10.2 vs. 8.5 months; hazard ratio [HR], 0.71; p = .0319) and PFS (7.2 vs. 4.9 months; HR, 0.58; p = .0008) and improved ORR in patients treated with a modified combination of docetaxel plus cisplatin/5‐FU (mDCF) relative to cisplatin/5‐FU, toxicity was greater [19]. Incidence of grade 3/4 AEs (e.g., neutropenia) was higher in the mDCF arm [19]. A Japanese study showed no OS benefit (14.2 vs. 15.3 months; HR, 0.99) but higher grade 3 or worse AEs (neutropenia, leukopenia, and anorexia) when docetaxel was added to cisplatin plus S‐1 [36].

A single three‐arm RCT compared doublet with two triplet chemotherapy regimens: docetaxel plus oxaliplatin versus this doublet combined with 5‐FU (TEF) or capecitabine [37]. With better safety, median PFS (mPFS) of 7.7 months, median OS of 14.6 months, and ORR of 46.6% in TEF‐treated patients, TEF was deemed to have a significantly better therapeutic index. These studies demonstrate that although efficacy is better with triplet regimens, toxicities are increased compared with doublets.

Guimbaud et al. were the first to prospectively address therapy sequencing (1L and 2L) ECX (epirubicin, cisplatin, and capecitabine) followed by FOLFIRI (folinic acid plus 5‐FU plus irinotecan) versus FOLFIRI followed by ECX [22]. Although PFS, OS, and ORR were similar, FOLFIRI administered prior to ECX as 2L led to a statistically significant increase in the primary endpoint of TTF relative to ECX given first (median 5.1 vs. 4.2 months, respectively). First‐line FOLFIRI was also better tolerated with lower rates of grade 3/4 toxicities and hematologic AEs but similar rates of nonhematologic AEs [22].

Targeted Therapies

Findings from the current SLR in patients with HER2+ tumors support those of a previous Cochrane review (2010), which recommended trastuzumab plus cisplatin plus 5‐FU or capecitabine [9]. In ToGA, addition of trastuzumab to chemotherapy improved OS (13.8 vs. 11.1 months), PFS (6.7 vs. 5.5 months), ORR (47% vs. 35%), TTP, and duration of response [17]. Similarly, in the TRIO‐013/LOGiC study, mPFS was longer and ORR was higher with the addition of lapatinib to a combination of capecitabine plus oxaliplatin; however, lapatinib increased toxicity and OS was not significantly improved [23]. In the JACOB trial, addition of pertuzumab to trastuzumab plus chemotherapy did not significantly improve OS [38].

Two studies (RILOMET‐1 and METGastric) assessed the impact of adding targeted therapy (rilotumumab or onartuzumab) to chemotherapy in patients with advanced mesenchymal‐epithelial transition (MET)–positive G/GEA, a population with a poor prognosis [28, 39]. However, neither improved clinical outcomes when combined with chemotherapy.

RAINFALL assessed the impact of adding ramucirumab to chemotherapy (cisplatin plus capecitabine or 5‐FU) in patients with HER2‐negative tumors. Investigator‐assessed PFS was significantly longer for ramucirumab plus chemotherapy versus placebo plus chemotherapy; however, the benefit was not confirmed by an independent, central review, and there was no difference in OS between groups [40]. In the AVAGAST study, the addition of bevacizumab to chemotherapy did not improve OS [25].

The remaining 1L targeted therapy studies included in this review reported either no significant differences in PFS or OS or worsened clinical efficacy in the investigational versus comparator arm [18]. Despite several attempts, targeted therapies in 1L have not yielded significant benefits except for patients with HER2+ tumors.

Efficacy and Safety of 2L Interventions

Of the included studies, singlets and doublets with or without a targeted agent were the most commonly assessed interventions. Fifteen of the 34 included RCTs reported statistically significant findings for OS, PFS, TTF, ORR, and/or disease control rate (DCR) [26, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50].

Chemotherapeutic Agents

Consistent with prior reviews [8, 9], single‐agent chemotherapy prolonged OS when compared with BSC or active symptom control measures in the post‐1L setting [47, 49]. RCTs that compared monotherapies included the JCOG0407 trial, where paclitaxel improved mPFS by 1.3 months compared with 5‐FU [50]. This PFS benefit appeared to outweigh the toxicity profile. The DREAM study assessed the efficacy of DHP107, an oral paclitaxel, in patients with advanced gastric cancer after failure of first‐line therapy [51]. DREAM demonstrated PFS noninferiority and a similar safety profile for DHP107. The ABSOLUTE study showed noninferior OS with weekly nab‐paclitaxel compared with standard paclitaxel [52].

WJOG 4007 evaluated paclitaxel versus irinotecan and found similar OS and manageable toxicities for both [53]. Roy et al. showed the ORR of irinotecan was lower than that of either docetaxel or PEP02, a liposomal irinotecan (6.8% vs. 15.9% vs. 13.6%, respectively), although mPFS was similar [54].

Additional RCTs suggested that irinotecan combination regimens (e.g., FOLFIRI or irinotecan plus cisplatin) may be suitable post‐1L chemotherapy. Sym et al. indicated the addition of 5‐FU/leucovorin is as effective and tolerable as irinotecan monotherapy [55]. Thuss‐Patience et al. found that OS (4.0 vs. 2.4 months, respectively) was longer when irinotecan was added to BSC [47]. In the TCOG GI‐0801 study, irinotecan plus cisplatin improved PFS and DCR, but not OS or ORR, when compared with cisplatin alone [44]. JACCRO GC‐05 [56] and TRICS [57] concluded that the addition of a second cytotoxic agent did not improve irinotecan efficacy. Taken together, these studies suggest the benefit‐to‐risk ratio for paclitaxel and irinotecan monotherapies in 2L is equivalent, whereas combination irinotecan‐based chemotherapy, namely, modified FOLFIRI or irinotecan plus cisplatin, may be suitable although clinical benefit is debatable.

Taxane‐containing doublets (docetaxel plus oxaliplatin) compared with taxane monotherapy (docetaxel) improved mPFS from 2 to 4.9 months in docetaxel alone, although OS and ORR were not different [45]. In contrast, the doublet of paclitaxel plus S‐1 did not improve efficacy over paclitaxel alone [58]. Moreover, there were nearly twice as many discontinuations due to AEs in the combination, although grade 3/4 AE rates were similar between treatment arms. Lee et al. reported the addition of S‐1, but not cisplatin, to docetaxel resulted in better PFS compared with docetaxel alone. These data indicate that careful consideration of efficacy and toxicities is necessary, especially of AEs observed in 1L, when planning taxane/platinum‐based doublet therapies in 2L.

Several studies included in the SLR combined 2L and 3L. Shitara et al. reported that dose‐escalated paclitaxel resulted in longer PFS compared with standard‐dose paclitaxel [59]. Frequency of all grades of neutropenia was significantly higher with dose‐escalated paclitaxel; however, no significant difference was observed in the proportion of patients experiencing grade 3 or higher AEs. Fushida et al. reported that the addition of paclitaxel to valproic acid did not significantly improve OS or PFS [60]. Kang et al. observed longer OS (5.3 vs. 3.8 months) and similar tolerability when docetaxel or irinotecan were added to BSC [61].

Targeted and Immunotherapies

Targeted therapies, either alone or in combination, were investigated in 13 2L studies [41, 42, 43, 46, 48, 62, 63, 64]. Two trials examined ramucirumab as monotherapy (vs. BSC in REGARD) or combined with paclitaxel (RAINBOW) [41, 42]. OS and PFS were significantly improved in the ramucirumab‐containing arms in both studies. In REGARD, OS was 5.2 versus 3.8 months and PFS was 2.1 versus 1.3 months, respectively. In RAINBOW, OS was 9.6 versus 7.4 months and PFS was 4.4 versus 2.9 months, respectively. Although not powered to show significance, post hoc analyses supported clinical benefits for ramucirumab plus paclitaxel efficacy in both East Asian and non–East Asian patients [63, 64]. Unlike PFS, significant OS benefits were not noted in either of these two subgroup analyses in Asian populations, and the authors suggested that post‐discontinuation therapy may play a role in the observed modest OS differences [63, 64]. Recently, the phase III RAINBOW‐Asia study demonstrated significant PFS benefit for ramucirumab combined with paclitaxel compared with paclitaxel alone; however, no OS benefits were observed [65]. Taken together, these studies indicate that in Asian populations the OS benefit from a ramucirumab plus paclitaxel regimen may be limited. The pan‐tyrosine kinase inhibitor, sunitinib, combined with docetaxel was compared with docetaxel alone for the primary endpoint of TTP in a phase II trial. Although TTP was not statistically different, higher ORR was observed and safety was reduced in the doublet combination arm [43].

In TyTAN, addition of lapatinib to paclitaxel failed to demonstrate significant survival benefits (PFS, OS) versus paclitaxel alone in patients with HER2+ tumors [46]. Of note, when compared with similar subgroups of patients treated with paclitaxel, patients treated with the doublet combination who had higher HER2 expression or who were mainland Chinese patients had improved OS (11.0 vs. 8.9) and PFS (5.5 vs. 4.4) [46]. Safety was not affected by the addition of lapatinib to paclitaxel. In the GATSBY study, trastuzumab emtansine was not superior to a taxane in improving OS in patients with HER2+ tumors [66]. The COG phase III study analyzed gefitinib (epidermal growth factor receptor [EGFR] inhibitor) versus placebo in esophageal cancer demonstrating no statistical OS or PFS benefit, although palliative benefits in subgroups were observed [67, 68]. More recently, the JAPICTI RCT compared irinotecan alone with adding irinotecan to nimotuzumab, an anti‐EGFR targeting antibody [62]. The primary endpoint, PFS, was similar between treatment arms, although patients with high EGFR levels by immunohistochemistry had improved OS, PFS, and ORR without adversely affecting safety [62]. Despite these results, the phase III study of nimotuzumab with irinotecan was terminated (NCT01813253).

Other studies of targeted 2L therapies included olaparib, ipilimumab, pembrolizumab, and trastuzumab emtansine. Bang et al. (Study 39, 2015) showed that the addition of PARP inhibitor olaparib to paclitaxel improved OS in patients with low ataxia telangiectasia mutated levels in the intent‐to‐treat population, although these results are discordant with the GOLD trial in which OS benefit was not observed [48, 69]. Bang et al. (2017b) reported that ipilimumab monotherapy did not improve PFS or OS compared with BSC [70]. In KEYNOTE‐061, pembrolizumab did not significantly improve OS compared with paclitaxel in patients with programmed death‐ligand 1 (PD‐L1) combined positive score (CPS) of 1 or higher [71]. In the study by Van Cutsem et al., AZD4547 (a selective fibroblast growth factor receptor [FGFR] 1–3 tyrosine kinase inhibitor) did not significantly improve PFS compared with paclitaxel in patients with FGFR2 polysomy or gene amplification [72]. These negative results indicate that further studies are necessary to support the possibility for improving outcomes in biomarker enriched subgroups.

The GRANITE study failed to show statistically significant benefit for OS (primary), unlike for PFS, comparing everolimus plus BSC with placebo plus BSC [73]. The phase II INTEGRATE study, evaluating both 2L and 3L therapy, found that addition of regorafenib to BSC significantly improved PFS; the phase III study is ongoing [74].

Overall, these studies indicate that, in a 2L setting, single‐agent chemotherapy (or combination with targeted therapy) is more efficacious than BSC, highlighting the need for careful consideration of control arms in future study designs.

Efficacy and Safety of 3L+ Interventions

Eight articles were identified that assessed 3L+ treatments: six primary RCTs and two secondary reports. Four of the six RCTs reported significant findings for OS, PFS, DCR, and/or TTP [75, 76, 77, 78]. One secondary study reported significant findings for ORR [79].

ATTRACTION‐2 showed statistically significantly longer OS (5.3 vs. 4.1 months) and PFS (1.61 vs. 1.45 months) and higher DCR with nivolumab (anti–PD‐1 monoclonal antibody) than placebo in Asian patients with disease progression after at least two prior chemotherapies [75]. The safety profile was manageable, and survival benefit with nivolumab was sustained beyond 1 year, independent of PD‐L1 expression (although this was evaluated with tumor positivity score (TPS), not combined positivity score (CPS)). Subgroup analyses of Japanese patients and patients with prior trastuzumab use from the ATTRACTION‐2 study also demonstrated similar clinical and safety results.

Similarly, the phase I/II CheckMate‐032 study demonstrated that nivolumab as monotherapy and combined with ipilimumab (dual PD‐1/cytotoxic T‐lymphocyte–associated antigen 4 blockade) produced some durable responses, long‐term OS, and a manageable safety profile in Western patients who experienced disease progression following at least one prior chemotherapy regimen [80]. Nivolumab was approved for 3L treatment of metastatic gastric cancer in Japan, Taiwan, and Korea, supported by results from the ATTRACTION‐2 study [80, 81].

The JAVELIN Gastric 300 study found that avelumab did not statistically significantly improve OS, PFS, or ORR compared with chemotherapy, with a trend to worse OS [82]. The studies conducted in China by Li et al. found that apatinib significantly improved OS (6.5 vs. 4.7 months) and PFS (2.6 vs. 1.8 months) compared with placebo with an acceptable safety profile [77, 78]; however, the global phase III ANGEL study, which included patients from Europe and North America in addition to Asia, failed to show significant OS benefit in the overall population (3L+) [83].

The TAGS study reported statistically significantly longer OS (5.7 vs. 3.6 months), PFS (2.0 vs. 1.8 months), and DFS with trifluridine/tipiracil (TAS‐102) compared with placebo [76].

Discussion

Unlike previous SLRs, this SLR aimed to inform optimal treatment sequencing in advanced metastatic G/GEA. This study parallels earlier work by Wagner et al. that identified study types, disease, treatment, and population [9]. All 1L RCTs in the current study had a fluoropyrimidine/platinum combination in at least one treatment arm, and 1L, 2L, and 3L+ treatments were considered separately to address the treatment sequencing question. In previous reports, HER2 status was not considered, and comparisons of singlet or doublet regimens versus supportive care, and doublets compared with monotherapy, were a primary focus [9]. Despite our focus on larger RCTs in this population with advanced G/GEA, descriptive cross‐trial comparisons that cannot account for confounding variables between differing study populations are limitations of this assessment. Treatment decisions are heavily reliant on clinician discernment of available evidence, and this report attempts to highlight important differences in the studies included within.

Despite considerable improvements in therapeutic options, the treatment of advanced G/GEA remains heterogeneous [3].

For those likely to tolerate chemotherapy, doublet regimens (i.e., platinum/fluoropyrimidine) are preferable over triplet chemotherapy. Doublets often exhibited lower toxicity rates, which may outweigh any incremental clinical benefits seen with triplet therapy. For example, the toxicity observed with addition of a third chemotherapy (docetaxel or epirubicin) to a platinum/fluoropyrimidine appears to outweigh a survival benefit, as was observed in the V325 study [13]. However, an mDCF regimen shows promise of extending survival with acceptable toxicity in two trials [19, 84]. Controversy remains with taxane triplets. The phase III JCOG1013 trial (n = 741) was recently published comparing cisplatin plus S‐1 (CS) versus CS plus docetaxel (DCS) in an exclusively Japanese patient population [36]; no significant difference was seen in OS between CS and DCS (median 15.3 vs. 14.2 months). In line with other trials examining taxane triplets, higher grade 3/4 neutropenia was seen with DCS (58.5%) versus CS (32.1%). Another emerging regimen is FOLFIRINOX (irinotecan plus platinum plus fluoropyrimidine), while not a randomized study, demonstrated similar clinical outcomes to platinum/fluropyrimidine/taxane but with better tolerabilty due to non‐overlapping toxicity [85]. For 1L treatment of HER2+ advanced G/GEA, trastuzumab should be added to platinum/fluoropyrimidine, although recently, oxaliplatin‐based regimens (capecitabine plus oxaliplatin [XELOX] or FOLFOX) have also been widely adopted instead of cisplatin/fluoropyrimidine for HER2+ tumors [86, 87].

For patients with advanced HER2‐negative G/GEA and a good performance status but who are not amenable to surgical resection, 1L recommended treatment options include FOLFOX or a combination of capecitabine plus oxaliplatin. The 2L RAINBOW study did not enroll patients with a prior docetaxel containing triplet therapy, and an exploratory analysis indicated increased toxicities with prior triplet compared with doublet therapies [88]. Given the improvements in OS in patients with favorable performance status using various 2L regimens, sequentially navigating patients to active 2L therapy as opposed to upfront triplets containing taxanes may provide survival benefits with less toxicity. Triplet 1L chemotherapy, however, may be a consideration for patients with heavy disease burden severe cancer‐related symptoms at diagnosis but with minimal comorbidities.

With a greater emphasis of biologic, targeted agents in 1L trials, the lower toxicity of doublet versus triplet chemotherapy favors a backbone regimen such as FOLFOX. Indeed, the majority of recently published 1L clinical trial data with other targeted agents with or without a chemotherapy backbone has reported negative results. Theoretically, with taxane use increasing in 2L therapy, restricting taxanes in 1L could prevent drug resistance.

For G/GEA that progressed on a fluoropyrimidine/platinum 1L therapy (plus trastuzumab for HER2+ tumors), taxane‐based therapy, or consideration of ramucirumab monotherapy if the patient is not a good candidate for cytotoxic chemotherapy, is indicated. Efficacy, safety, and treatment compliance are high‐priority considerations when choosing a 2L therapy. Data also support use of irinotecan, either as monotherapy or in FOLFIRI. The addition of ramucirumab to an irinotecan backbone is a possibility, particularly in patients with neuropathy including oxaliplatin‐induced neuropathy from 1L therapy. Evidence supports ramucirumab plus FOLFIRI or ramucirumab plus irinotecan as an alternative in 2L patients ineligible for ramucirumab/paclitaxel [89, 90, 91]. In a retrospective analysis by Klempner et al., patients receiving ramucirumab plus FOLFIRI (after 1L platinum plus fluoropyrimidine) had ORR of 23%, DCR of 79%, mPFS of 6.0, and median OS (mOS) of 13.4 months [89]. Lorenzen et al. reported that patients with prior taxane use receiving ramucirumab plus FOLFIRI had ORR of 24%, DCR of 67%, mPFS of 4.3, and mOS of 7.5 months [90], whereas Park et al. reported ORR of 25% for patients who advanced on 1L and were then treated with ramucirumab plus irinotecan [91]. The authors posit that a shorter time to initiation of 2L treatment following disease progression or development of unacceptable toxicity, but before patients experience performance status decline, is a key consideration. This in turn will benefit patients who are eligible to further receive 3L treatment options like TAS‐102 that demonstrated statistically significant survival benefits (OS, PFS, DCR) in the TAGS study [76].

The Argument for Limiting Time on 1L/Maintenance 1L Therapy in Advanced G/GEA

Based on the success of maintenance therapy in colorectal cancer (OPTIMOX1 [92] and CAIRO3 [93]), many oncologists have adapted this approach to advanced G/GEA. Following a predetermined length of 1L therapy (typically 4–6 months), maintenance therapy may provide similar (or better) efficacy with less toxicity (particularly cumulative oxaliplatin‐related neuropathy) compared with continuing 1L therapy until disease progression. Maintenance options include switch therapy or low‐dose continuation of a 1L agent (i.e., 5‐FU or capecitabine). In support of maintenance therapy, the 1L trial, ToGA, stopped chemotherapy after six cycles but continued trastuzumab [17]; AVAGAST and RAINFALL stopped cisplatin after six cycles but continued bevacizumab/placebo or ramucirumab/placebo with fluoropyrimidine, respectively [25, 40]. OS rates were similar to other phase III studies without a maintenance approach, indicating that not all agents in 1L need to be continued indefinitely. The mPFS across major 1L trials ranged from 4.4 to 8.5 months. Park et al. compared continuous versus stop‐and‐go chemotherapy after disease stabilization with 1L induction chemotherapy [94]. After receiving six cycles of S‐1 plus oxaliplatin (SOX), patients were randomized to receive continuous SOX until progression (continuous arm) or to have a chemotherapy‐free interval followed by SOX reintroduction at progression (stop‐and‐go arm). Continued chemotherapy improved PFS but not duration of disease control or OS, had a negative impact on quality of life, and increased frequencies of adverse events, suggesting that the stop‐and‐go strategy may be an appropriate option compared with continuous 1L therapy. Indeed, for the use of oxaliplatin in 1L treatment regimens, the International Duration Evaluation of Adjuvant Therapy in therapy for colorectal cancer demonstrated more than doubling of grade 2 or higher neurotoxicity rates, 16.6% versus 47.7%, with 3 versus 6 months of FOLFOX exposure, respectively [95].

Potential for Integrating Immunotherapeutics

Beyond this review, we include a discussion of immunotherapeutics in the context of treatment sequencing in metastatic G/GEA. Immunotherapy has received significant attention in recent years, advancing therapy options in many tumor types. Recent large, phase III, randomized studies in the 2L and 3L settings of G/GEA compared monotherapy immune checkpoint inhibitors (ICIs) targeting the PD‐1/PD‐L1 signaling axis with standard monotherapy cytotoxic therapy (paclitaxel or irinotecan); however, reported results failed to meet primary endpoints for KEYNOTE‐061 and JAVELIN Gastric 300, even for PD‐L1–positive patients [71, 82]. Pembrolizumab in the 3L setting was considered an option based on results from a single‐arm phase II study (KEYNOTE‐059) of PD‐L1–positive patients, the incidence of which is ~50%–60% of G/GEA when using a CPS cutoff of ≥1 (CPS of both PD‐L1–expressing tumor and immune cells) [96], however the conditional approval has since been withdrawn. Nivolumab is also a 3L+ option in Asian patients based on improved OS versus placebo in the phase III ATTRACTION‐2 study [75]. In the 2L setting or later, pembrolizumab was shown to be efficacious in tumors with high microsatellite instability (MSI) or mismatch repair deficiency, the incidence of which is ~3% in metastatic G/GEA [97], as did a combined analysis of KEYNOTE‐059, KEYNOTE‐061, and KEYNOTE‐062 [105]. Recently, pembrolizumab received tumor‐agnostic U.S. Food and Drug Administration (FDA) approval for high tumor mutational burden (TMB) (≥10 mutations per megabase) based on the KEYNOTE‐158 study [98]. It is important to note that KEYNOTE‐158 did not include patients with G/GEA, although an exploratory analysis from the 2L KEYNOTE‐061 study reported positive association with clinical outcomes in patients with TMB‐high gastric cancer treated with pembrolizumab [99].

A Korean phase II trial of pembrolizumab also identified Epstein‐Barr virus–positive tumors as a small molecular subset exhibiting a high proportion of durable responses [100]. Key 1L studies with ICIs have also been reported [101, 102, 103, 104]. JAVELIN Gastric 100 failed to demonstrate avelumab switch maintenance therapy as superior to continuation of 1L FOLFOX/CAPOX (capecitabine plus oxaliplatin) chemotherapy [101]. A post hoc analysis using the CPS assay, as opposed to the trial's predefined analysis of tumor cell enumeration only (TPS), to determine PD‐L1 expression demonstrated OS benefit of avelumab therapy, highlighting challenges to assay heterogeneity. KEYNOTE‐062 failed to demonstrate significant benefit of 1L pembrolizumab monotherapy to chemotherapy, in patients preselected for PD‐L1 CPS ≥1 [102]. ATTRACTION‐4 analyzed the benefit of 1L nivolumab plus chemotherapy versus chemotherapy (SOX/CAPOX) in a non–PD‐L1 selected Asian population; statistical PFS benefit was observed for ICI plus chemotherapy, whereas OS failed to demonstrate such benefits [103]; PD‐L1 data were not reported to date to determine differential benefit in outcome as would be expected based on all studies to date. Meanwhile CheckMate‐649, investigating 1L nivolumab plus FOLFOX/XELOX against FOLFOX/XELOX, demonstrated significant benefits for all endpoints of ICI plus chemotherapy in a global population with the analysis restricted to patients with PD‐L1 CPS ≥5 [104] and recently received FDA approval in all comers as a 1L regimen while NCCN guidelines have provided a tiered recommendation based on PD‐L1 score with category 1 for CPS ≥5, category 2B for CPS 1‐4, and no recommendation for CPS 0. Overall, these recent studies demonstrate a combination regimen (ICI plus chemotherapy) to be efficacious compared with ICI monotherapy in 1L, particularly at higher PD‐L1 cutoffs. Irrespective, the ICI plus chemotherapy regimen from CheckMate‐649 is expected to become 1L therapy of choice for PD‐L1 CPS ≥5, whereas 2L options are expected to remain unchanged. It is also important to highlight the role of significant benefits seen in patients with MSI‐high tumors treated with ICIs, including within CheckMate‐649 where overall survival was most pronounced in this group, with the median overall survival of 8.8 months versus not reached in the 1L chemotherapy versus 1L chemotherapy plus nivolumab arms, respectively (HR 0.33, 95% C.I. 0.12‐0.87). Pembrolizumab is FDA approved for patients with MSI‐high or mismatch repair–deficient tumors in 2L and beyond, and data from recent trials continue to demonstrate benefit in this patient subgroup [105]. Although outside the parameters of this review, it is important to note additional recent FDA approvals. KEYNOTE‐590 analyzed pembrolizumab in combination with cisplatinum and fluoropyrimidine‐based chemotherapy in 1L and demonstrated a statistically significant improvement in OS and PFS for patients receiving ICI plus chemotherapy irrespective of PD‐L1 status, but again with improvements notably in tumors with PD‐L1 CPS ≥10. This FDA approval provides another ICI regimen for patients with esophageal and gastroesophageal junction Siewert type I carcinoma, and similar to the tiered recommendation of the NCCN guidlines for nivolumab, a tiered recommendation for pembrolizumab includes category 1 for CPS ≥10, category 2B for CPS 1‐9, and no recommendation for CPS 0. More recently, based on the KEYNOTE‐811 study, the FDA granted accelerated approval for 1L pembrolizumab plus trastuzumab in combination with fluoropyrimidine‐ and platinum‐containing chemotherapy for patients with locally advanced unresectable/metastatic HER2+ gastric or gastroesophageal adenocarcinoma based on interim analysis response rates. Coming shortly after the CheckMate‐649 and KEYNOTE‐590 approvals, the KEYNOTE‐811 approval expands the frontline ICI availability to HER2+ patients, and the outcomes of the phase 3 study are awaited, as are the assessments to determine whether or not their is differential benefit by PD‐L1 status in HER2+ tumors as their has repeatedly been shown in HER2‐ patients.

Overview of Studies Published After the Review Inclusion Period and Trials in Progress

Several large RCTs were either presented in abstract form or published in peer‐reviewed journals after this literature search was performed or did not meet the inclusion criteria. Some are currently considered by oncologists when selecting regimens. For example, in the U.S., there is notable off‐label use of trastuzumab continuation into 2L, despite the phase II randomized T‐ACT trial (WJOG7112G) demonstrating that trastuzumab continued, with or without paclitaxel, does not provide additional benefit for patients with HER2+ advanced G/GEA refractory to 1L trastuzumab plus platinum/fluoropyrimidine [106]. However, the notion of loss of HER2 amplification in resistant disease in a large proportion of patients in that and other studies leads to the possibility of continued anti‐HER2 therapy in those patients not having this conversion take place [108]. Recently, the DESTINY‐Gastric01 study reported significant benefit of trastuzumab deruxtecan (T‐DXd) versus paclitaxel or irinotecan in 3L and was approved in Japan and by the FDA. Importantly, patients had received a 1L trastuzumab‐containing regimen, thereby making T‐DXd a novel option for HER2+, trastuzumab‐resistant, G/GEA tumors. Significant benefits favoring T‐DXd were observed (mOS, 12.5 vs. 8.4 months; HR, 0.59; p = .01; ORR, 51.3% vs. 14.3%; p < .0001) with interstitial lung disease being a notable AE from T‐DXd. [107]. Additional studies with T‐DXd in 2L (NCT04014075, NCT04704934) and 1L (NCT03329690) are ongoing.

With similar conclusions to those of this report, the PANGEA phase 2 study highlights the importance of optimally sequenced therapies and endorses a combined personalized treatment strategy, starting from diagnosis and across all treatment lines, to enhance benefits compared with standard treatment approaches [108].

Considering all the evidence discussed in this SLR, we propose a treatment sequencing algorithm (Fig. 4). The regimen chosen at each line of therapy should balance the patient's performance status and comorbidities with the potential for serious AEs. It is important to consider that the proposed sequence or algorithm was not tested in clinical trial settings but was based on discussions of trial evidence in this review. In 1L, considering a doublet is recommended based on manageable toxicities compared with triplets; in addition, the recent approvals of CheckMate‐649, KEYNOTE‐590, and KEYNOTE‐811 should be considered as 1L ICI plus chemotherapy options. In 2L (and 3L), T‐DXd should be considered for HER2+ patients, although challenges to rebiopsy exist, and hence liquid biopsy to determine HER2 status should be considered where feasible. Beside a FOLFIRI/irinotecan‐based regimen, combinations with biologics like ramucirumab plus taxane/irinotecan options should be considered for eligible patients, especially in patients who are ineligible to receive a taxane due to neuropathies in 1L. Furthermore, patients with MSI‐high and TMB‐high status should be considered for ICI‐based treatment (pembrolizumab). In 3L, TAS‐102 is a chemotherapy option along with chemotherapy‐free options with the ICIs pembrolizumab (CPS >1) and nivolumab, which should be considered. Overall, screening patients for signs of progression across all lines of therapy is recommended so that eligible patients can be administered subsequent treatment options in a timely manner.

Potential treatment sequencing algorithm. The proposed sequential algorithm is based on the current analysis of randomized controlled trials as described in this systematic literature review. Recent approvals and key trial readouts are highlighted under “Key Considerations” and discussed in this article (see Discussion section). Checkmate‐649, KEYNOTE‐590, and KEYNOTE‐811 are noted under 1L options that should be considered in treatment planning; HER2‐ tumors will be assessed and dichotimzed into PD‐L1 CPS ≥5 or ≥10 and eligible for anti‐PD1 therapy, or HER2‐/PD‐L1‐ and receive chemotherapy alone. These sequences were not tested in a clinical trial setting. 3L options also include irinotecan or taxane, whichever not yet used previously. Pembrolizumab in 3L had its approval recently voluntarily withdrawn; nivolumab approved for 3L only in Asia.Abbreviations: 1L, first line; 2L, second line; CAPOX, capecitabine plus oxaliplatin; CPS, combined positive score; DCF, docetaxel plus cisplatin/5‐fluorouracil; FOLFOX, folinic acid plus 5‐FU plus oxaliplatin; FOLFIRI, folinic acid plus 5‐fluorouracil plus irinotecan; HER2+, HER2 overexpressing; HER2−, HER2 negative; ICI, immune checkpoint inhibitor; MSI‐h, high microsatellite instability; SOX, S‐1 plus oxaliplatin; TAS‐102, trifluridine/tipiracil; T‐DXd, trastuzumab deruxtecan; TMB, tumor mutational burden.

Conclusion

To our knowledge, this is the first systematic review that begins to address treatment sequencing in unresectable, advanced G/GEA, including recent evidence from larger RCTs. It builds upon currently available guidelines and provides a framework for planning effective disease management, with the potential for further improvement in outcomes for patients and select patient subgroups.

Author Contributions

Conception/design: Daniel V. Catenacci, Joseph Chao, Astra M. Liepa, Holly Knoderer, Anindya Chatterjee, Eric Van Cutsem

Collection and/or assembly of data: Kei Muro, Salah Eddin Al‐Batran, Zev A. Wainberg

Data analysis and interpretation: Daniel V. Catenacci, Joseph Chao, Salah Eddin Al‐Batran, Samuel J. Klempner, Zev A. Wainberg, Manish A. Shah, Sun Young Rha, Atsushi Ohtsu, Astra M. Liepa, Holly Knoderer, Anindya Chatterjee, Eric Van Cutsem

Manuscript writing: Daniel V. Catenacci, Joseph Chao, Kei Muro, Salah Eddin Al‐Batran, Samuel J. Klempner, Zev A. Wainberg, Manish A. Shah, Sun Young Rha, Atsushi Ohtsu, Astra M. Liepa, Holly Knoderer, Anindya Chatterjee, Eric Van Cutsem

Final approval of manuscript: Daniel V. Catenacci, Joseph Chao, Kei Muro, Salah Eddin Al‐Batran, Samuel J. Klempner, Zev A. Wainberg, Manish A. Shah, Sun Young Rha, Atsushi Ohtsu, Astra M. Liepa, Holly Knoderer, Anindya Chatterjee, Eric Van Cutsem

Disclosures

Daniel V. Catenacci: Amgen, Astellas Pharma, Bristol‐Myers Squibb, Five Prime Therapeutics, Foundation Medicine, Genentech/Roche, Gritstone Oncology, Guardant Health, Eli Lilly & Co., Merck, Seattle Genetics, Taiho Pharmaceutical, Tempus (H); Joseph Chao: Eli Lilly & Co., Merck, Amgen, Macrogenics, Ono Pharmaceuticals, Daiichi‐Sankyo, Foundation Medicine, Bristol‐Myers Squibb, AstraZeneca, Astellas (C/A), Merck (RF, H); Samuel J. Klempner: Eli Lilly & Co., Bristol‐Myers Squibb, Merck, Astellas, Daiichi‐Sankyo, Pieris, Natera Inc. (C/A), Turning Point Therapeutics (OI); Zev A. Wainberg: Amgen, AstraZeneca, Bayer, Bristol‐Myers Squibb, Merck, Five Prime, Eli Lilly & Co., Macrogenics, Gilead, Seagen, Novartis, Array (C/A), Novartis, Plexxikon (RF); Astra M. Liepa: Eli Lilly & Co. (E, OI); Anindya Chatterjee: Eli Lilly & Co. (E, OI); Eric Van Cutsem: Array, Astellas, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol‐Myers Squibb, Celgene, Daiichi, Halozyme, GlaxoSmithKline, Incyte, Ipsen, Eli Lilly & Co., Merck Sharp & Dohme, Merck KGaA, Novartis, Pierre Fabre, Roche, Servier, Sirtex, Taiho (C/A), Amgen, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Celgene, Ipsen, Eli Lilly & Co., Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier (RF—institution). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board

Supporting information

See http://www.TheOncologist.com for supplemental material available online.

Appendix S1: Supplemental Methods

Click here for additional data file.^{(169.9KB, pdf)}

Supplemental Tables

Click here for additional data file.^{(537.7KB, pdf)}

Acknowledgments

Eli Lilly & Co. provided funding to RTI Health Solutions for the SLR and also provided medical writing and editing support, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). Hannah M. Messersmith of Eli Lilly & Co. provided writing support for this manuscript. Eli Lilly & Co. contracted with Syneos Health for editorial support provided by Antonia Baldo.

Disclosures of potential conflicts of interest may be found at the end of this article.

References

1.Bray F, Ferlay J, Soerjomataram I et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394–424. [DOI] [PubMed] [Google Scholar]
2.Pellino A, Riello E, Nappo F et al. Targeted therapies in metastatic gastric cancer: Current knowledge and future perspectives. World J Gastroenterol 2019;25:5773–5788. [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Gambardella V, Fleitas T, Tarazona N et al. Precision medicine to treat advanced gastroesophageal adenocarcinoma: A work in progress. J Clin Med 2020;9:3049. [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Sastre J, Garcia‐Saenz JA, Diaz‐Rubio E. Chemotherapy for gastric cancer. World J Gastroenterol 2006;12:204–213. [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Power DG, Kelsen DP, Shah MA. Advanced gastric cancer–slow but steady progress. Cancer Treat Rev 2010;36:384–392. [DOI] [PubMed] [Google Scholar]
6.Abrams T, Hess LM, Zhu YE et al. Predictors of heterogeneity in the first‐line treatment of patients with advanced/metastatic gastric cancer in the U.S. Gastric Cancer 2018;21:738–744. [DOI] [PubMed] [Google Scholar]
7.Barzi A, Thara E. Angiogenesis in esophageal and gastric cancer: A paradigm shift in treatment. Expert Opin Biol Ther 2014;14:1319–1332. [DOI] [PubMed] [Google Scholar]
8.Wagner AD, Syn NL, Moehler M et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2017;(8):CD004064. [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Wagner AD, Unverzagt S, Grothe W et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2010;(3):CD004064. [DOI] [PubMed] [Google Scholar]
10.Elimova E, Janjigian YY, Mulcahy M et al. It is time to stop using epirubicin to treat any patient with gastroesophageal adenocarcinoma. J Clin Oncol 2017;35:475–477. [DOI] [PubMed] [Google Scholar]
11.Van Cutsem E, Sagaert X, Topal B et al. Gastric cancer. Lancet 2016;388:2654–2664. [DOI] [PubMed] [Google Scholar]
12.Smyth EC, Verheij M, Allum W et al. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow‐up. Ann Oncol 2016;27(suppl 5):v38–v49. [DOI] [PubMed] [Google Scholar]
13.Van Cutsem E, Moiseyenko VM, Tjulandin S et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first‐line therapy for advanced gastric cancer: A report of the V325 Study Group. J Clin Oncol 2006;24:4991–4997. [DOI] [PubMed] [Google Scholar]
14.Harada K, Lopez A, Shanbhag N et al. Recent advances in the management of gastric adenocarcinoma patients. F1000Res 2018;7:F1000 Faculty Rev‐1365. [Google Scholar]
15.Ajani JA, D'Amico TA, Almhanna K et al. Gastric cancer, version 3.2016, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2016;14:1286–1312. [DOI] [PubMed] [Google Scholar]
16.Moher D, Liberati A, Tetzlaff J et al. Preferred reporting items for systematic reviews and meta‐analyses: The PRISMA statement. PLoS Med 2009;6:e1000097. [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Bang YJ, Van Cutsem E, Feyereislova A et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2‐positive advanced gastric or gastro‐oesophageal junction cancer (ToGA): A phase 3, open‐label, randomised controlled trial. Lancet 2010;376:687–697. [DOI] [PubMed] [Google Scholar]
18.Waddell T, Chau I, Cunningham D et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): A randomised, open‐label phase 3 trial. Lancet Oncol 2013;14:481–489. [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Wang J, Xu R, Li J et al. Randomized multicenter phase III study of a modified docetaxel and cisplatin plus fluorouracil regimen compared with cisplatin and fluorouracil as first‐line therapy for advanced or locally recurrent gastric cancer. Gastric Cancer 2016;19:234–244. [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Yamada Y, Higuchi K, Nishikawa K et al. Phase III study comparing oxaliplatin plus S‐1 with cisplatin plus S‐1 in chemotherapy‐naive patients with advanced gastric cancer. Ann Oncol 2015;26:141–148. [DOI] [PubMed] [Google Scholar]
21.Bando H, Yamada Y, Tanabe S et al. Efficacy and safety of S‐1 and oxaliplatin combination therapy in elderly patients with advanced gastric cancer. Gastric Cancer 2016;19:919–926. [DOI] [PubMed] [Google Scholar]
22.Guimbaud R, Louvet C, Ries P et al. Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: A French intergroup (Fédération Francophone de Cancérologie Digestive, Fédération Nationale des Centres de Lutte Contre le Cancer, and Groupe Coopérateur Multidisciplinaire en Oncologie) study. J Clin Oncol 2014;32:3520–3526. [DOI] [PubMed] [Google Scholar]
23.Hecht JR, Bang YJ, Qin SK et al. Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2‐positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO‐013/LOGiC–a randomized phase III trial. J Clin Oncol 2016;34:443–451. [DOI] [PubMed] [Google Scholar]
24.Kang YK, Kang WK, Shin DB et al. Capecitabine/cisplatin versus 5‐fluorouracil/cisplatin as first‐line therapy in patients with advanced gastric cancer: A randomised phase III noninferiority trial. Ann Oncol 2009;20:666–673. [DOI] [PubMed] [Google Scholar]
25.Ohtsu A, Shah MA, Van Cutsem E et al. Bevacizumab in combination with chemotherapy as first‐line therapy in advanced gastric cancer: A randomized, double‐blind, placebo‐controlled phase III study. J Clin Oncol 2011;29:3968–3976. [DOI] [PubMed] [Google Scholar]
26.Ajani JA, Rodriguez W, Bodoky G et al. Multicenter phase III comparison of cisplatin/S‐1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: The FLAGS trial. J Oncol 2010;28:1547–1553. [DOI] [PubMed] [Google Scholar]
27.Ajani JA, Abramov M, Bondarenko I et al. A phase III trial comparing oral S‐1/cisplatin and intravenous 5‐fluorouracil/cisplatin in patients with untreated diffuse gastric cancer. Ann Oncol 2017;28:2142–2148. [DOI] [PubMed] [Google Scholar]
28.Catenacci DVT, Tebbutt NC, Davidenko I et al. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first‐line therapy in advanced MET‐positive gastric or gastro‐oesophageal junction cancer (RILOMET‐1): A randomised, double‐blind, placebo‐controlled, phase 3 trial. Lancet Oncol 2017;18:1467–1482. [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Lu Z, Zhang X, Liu W et al. A multicenter, randomized trial comparing efficacy and safety of paclitaxel/capecitabine and cisplatin/capecitabine in advanced gastric cancer. Gastric Cancer 2018;21:782–791. [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Jin M, Lu H, Li J et al. Randomized 3‐armed phase III study of S‐1 monotherapy versus S‐1/CDDP (SP) versus 5‐FU/CDDP (FP) in patients (pts) with advanced gastric cancer (AGC): SC‐101 study. J J Clin Oncol. 2008;26(suppl 15):4533a. [Google Scholar]
31.Koizumi W, Kim YH, Fujii M et al. Addition of docetaxel to S‐1 without platinum prolongs survival of patients with advanced gastric cancer: A randomized study (START). J Cancer Res Clin Oncol 2014;140:319–328. [DOI] [PMC free article] [PubMed] [Google Scholar]
32.Shu Z, Ding D, Li Y. Adjuvant chemotherapy for chemotherapy‐naive advanced gastric cancer patients with oxaliplatin plus tegafur versus oxaliplatin plus S‐1. Int J Clin Exp Med 2017;10:9322–9329. [Google Scholar]
33.Al‐Batran SE, Hartmann JT, Probst S et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: A study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol 2008;26:1435–1442. [DOI] [PubMed] [Google Scholar]
34.Enzinger PC, Burtness BA, Niedzwiecki D et al. CALGB 80403 (Alliance)/E1206: A randomized phase II study of three chemotherapy regimens plus cetuximab in metastatic esophageal and gastroesophageal junction cancers. J Clin Oncol 2016;34:2736–2742. [DOI] [PMC free article] [PubMed] [Google Scholar]
35.Lu J, Zhou Z, Wu C et al. S‐1 combined with docetaxel (SD) versus S‐1 combined with cisplatin (SP) in the treatment of advanced gastric cancer: Randomized, controlled, multicenter and clinical study. Int J Clin Exp Med 2019;12:9359–9365. [Google Scholar]
36.Yamada Y, Boku N, Mizusawa J et al. Docetaxel plus cisplatin and S‐1 versus cisplatin and S‐1 in patients with advanced gastric cancer (JCOG1013): An open‐label, phase 3, randomised controlled trial. Lancet Gastroenterol Hepatol 2019;4:501–510. [DOI] [PubMed] [Google Scholar]
37.Van Cutsem E, Boni C, Tabernero J et al. Docetaxel plus oxaliplatin with or without fluorouracil or capecitabine in metastatic or locally recurrent gastric cancer: A randomized phase II study. Ann Oncol 2015;26:149–156. [DOI] [PubMed] [Google Scholar]
38.Tabernero J, Hoff PM, Shen L et al. Pertuzumab plus trastuzumab and chemotherapy for HER2‐positive metastatic gastric or gastro‐oesophageal junction cancer (JACOB): Final analysis of a double‐blind, randomised, placebo‐controlled phase 3 study. Lancet Oncol 2018;19:1372–1384. [DOI] [PubMed] [Google Scholar]
39.Shah MA, Bang YJ, Lordick F et al. Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2‐negative, MET‐positive gastroesophageal adenocarcinoma: The METGastric randomized clinical trial. JAMA Oncol 2017;3:620–627. [DOI] [PMC free article] [PubMed] [Google Scholar]
40.Fuchs CS, Shitara K, Di Bartolomeo M et al. Ramucirumab with cisplatin and fluoropyrimidine as first‐line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): A double‐blind, randomised, placebo‐controlled, phase 3 trial. Lancet Oncol 2019;20:420–435. [DOI] [PubMed] [Google Scholar]
41.Wilke H, Muro K, Van Cutsem E et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro‐oesophageal junction adenocarcinoma (RAINBOW): A double‐blind, randomised phase 3 trial. Lancet Oncol 2014;15:1224–1235. [DOI] [PubMed] [Google Scholar]
42.Fuchs CS, Tomasek J, Yong CJ et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro‐oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo‐controlled, phase 3 trial. Lancet 2014;383:31–39. [DOI] [PubMed] [Google Scholar]
43.Yi JH, Lee J, Lee J et al. Randomised phase II trial of docetaxel and sunitinib in patients with metastatic gastric cancer who were previously treated with fluoropyrimidine and platinum. Br J Cancer 2012;106:1469–1474. [DOI] [PMC free article] [PubMed] [Google Scholar]
44.Higuchi K, Tanabe S, Shimada K et al. Biweekly irinotecan plus cisplatin versus irinotecan alone as second‐line treatment for advanced gastric cancer: A randomised phase III trial (TCOG GI‐0801/BIRIP trial). Eur J Cancer 2014;50:1437–1445. [DOI] [PubMed] [Google Scholar]
45.Kim JY, Ryoo HM, Bae SH et al. Multi‐center randomized phase II study of weekly docetaxel versus weekly docetaxel‐plus‐oxaliplatin as a second‐line chemotherapy for patients with advanced gastric cancer. Anticancer Res 2015;35:3531–3536. [PubMed] [Google Scholar]
46.Satoh T, Xu RH, Chung HC et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second‐line treatment of HER2‐amplified advanced gastric cancer in Asian populations: TyTAN–a randomized, phase III study. J Clin Oncol 2014;32:2039–2049. [DOI] [PubMed] [Google Scholar]
47.Thuss‐Patience PC, Kretzschmar A, Bichev D et al. Survival advantage for irinotecan versus best supportive care as second‐line chemotherapy in gastric cancer–a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer 2011;47:2306–2314. [DOI] [PubMed] [Google Scholar]
48.Bang YJ, Im SA, Lee KW et al. Randomized, double‐blind phase II trial with prospective classification by ATM protein level to evaluate the efficacy and tolerability of olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer. J Clin Oncol 2015;33:3858–3865. [DOI] [PubMed] [Google Scholar]
49.Ford HE, Marshall A, Bridgewater JA et al. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR‐02): An open‐label, phase 3 randomised controlled trial. Lancet Oncol 2014;15:78–86. [DOI] [PubMed] [Google Scholar]
50.Nishina T, Boku N, Gotoh M et al. Randomized phase II study of second‐line chemotherapy with the best available 5‐fluorouracil regimen versus weekly administration of paclitaxel in far advanced gastric cancer with severe peritoneal metastases refractory to 5‐fluorouracil‐containing regimens (JCOG0407). Gastric Cancer 2016;19:902–910. [DOI] [PubMed] [Google Scholar]
51.Kang YK, Ryu MH, Park SH et al. Efficacy and safety findings from DREAM: A phase III study of DHP107 (oral paclitaxel) versus i.v. paclitaxel in patients with advanced gastric cancer after failure of first‐line chemotherapy. Ann Oncol 2018;29:1220–1226. [DOI] [PubMed] [Google Scholar]
52.Shitara K, Takashima A, Fujitani K et al. Nab‐paclitaxel versus solvent‐based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): An open‐label, randomised, non‐inferiority, phase 3 trial. Lancet Gastroenterol Hepatol 2017;2:277–287. [DOI] [PubMed] [Google Scholar]
53.Hironaka S, Ueda S, Yasui H et al. Randomized, open‐label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol 2013;31:4438–4444. [DOI] [PubMed] [Google Scholar]
54.Roy AC, Park SR, Cunningham D et al. A randomized phase II study of PEP02 (MM‐398), irinotecan or docetaxel as a second‐line therapy in patients with locally advanced or metastatic gastric or gastro‐oesophageal junction adenocarcinoma. Ann Oncol 2013;24:1567–1573. [DOI] [PubMed] [Google Scholar]
55.Sym SJ, Hong J, Park J et al. A randomized phase II study of biweekly irinotecan monotherapy or a combination of irinotecan plus 5‐fluorouracil/leucovorin (mFOLFIRI) in patients with metastatic gastric adenocarcinoma refractory to or progressive after first‐line chemotherapy. Cancer Chemother Pharmacol 2013;71:481–488. [DOI] [PubMed] [Google Scholar]
56.Tanabe K, Fujii M, Nishikawa K et al. Phase II/III study of second‐line chemotherapy comparing irinotecan‐alone with S‐1 plus irinotecan in advanced gastric cancer refractory to first‐line treatment with S‐1 (JACCRO GC‐05). Ann Oncol 2015;26:1916–1922. [DOI] [PubMed] [Google Scholar]
57.Nishikawa K, Fujitani K, Inagaki H et al. Randomised phase III trial of second‐line irinotecan plus cisplatin versus irinotecan alone in patients with advanced gastric cancer refractory to S‐1 monotherapy: TRICS trial. Eur J Cancer 2015;51:808–816. [DOI] [PubMed] [Google Scholar]
58.Nakanishi K, Kobayashi D, Mochizuki Y et al. Phase II multi‐institutional prospective randomized trial comparing S‐1 plus paclitaxel with paclitaxel alone as second‐line chemotherapy in S‐1 pretreated gastric cancer (CCOG0701). Int J Clin Oncol 2016;21:557–565. [DOI] [PubMed] [Google Scholar]
59.Shitara K, Yuki S, Tahahari D et al. Randomised phase II study comparing dose‐escalated weekly paclitaxel vs standard‐dose weekly paclitaxel for patients with previously treated advanced gastric cancer. Br J Cancer 2014;110:271–277. [DOI] [PMC free article] [PubMed] [Google Scholar]
60.Fushida S, Kinoshita J, Kaji M et al. Paclitaxel plus valproic acid versus paclitaxel alone as second‐or third‐line therapy for advanced gastric cancer: A randomized phase II trial. Drug Des Devel Ther 2016;10:2353–2358. [DOI] [PMC free article] [PubMed] [Google Scholar]
61.Kang JH, Lee SI, Lim Det al. Salvage chemotherapy for pretreated gastric cancer: A randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol 2012;30:1513–1518. [DOI] [PubMed] [Google Scholar]
62.Satoh T, Lee KH, Rha SY et al. Randomized phase II trial of nimotuzumab plus irinotecan versus irinotecan alone as second‐line therapy for patients with advanced gastric cancer. Gastric Cancer 2015;18:824–832. [DOI] [PMC free article] [PubMed] [Google Scholar]
63.Muro K, Oh SC, Shimada Y et al. Subgroup analysis of East Asians in RAINBOW: A phase 3 trial of ramucirumab plus paclitaxel for advanced gastric cancer. J Gastroenterol Hepatol 2016;31:581–589. [DOI] [PubMed] [Google Scholar]
64.Shitara K, Muro K, Shimada Y et al. Subgroup analyses of the safety and efficacy of ramucirumab in Japanese and Western patients in RAINBOW: A randomized clinical trial in second‐line treatment of gastric cancer. Gastric Cancer 2016;19:927–938. [DOI] [PubMed] [Google Scholar]
65.Xu RH, Zhang YQ, Pan H et al. RAINBOW‐Asia: A randomized, multicenter, double‐blind, phase III study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first‐line chemotherapy with platinum and fluoropyrimidine. J Clin Oncol 2021;39(suppl 3):199a. [Google Scholar]
66.Thuss‐Patience PC, Shah MA, Ohtsu A et al. Trastuzumab emtansine versus taxane use for previously treated HER2‐positive locally advanced or metastatic gastric or gastro‐oesophageal junction adenocarcinoma (GATSBY): An international randomised, open‐label, adaptive, phase 2/3 study. Lancet Oncol 2017;18:640–653. [DOI] [PubMed] [Google Scholar]
67.Ferry DR, Dutton SJ, Mansoor W et al. Phase III multi‐centre, randomised, double‐blind, placebo‐controlled trial of gefitinib versus placebo in esophageal cancer progressing after chemotherapy, COG (cancer oesophagus gefitinib). Ann Oncol 2012;23(suppl 9):IXE12. [DOI] [PubMed] [Google Scholar]
68.Dutton SJ, Ferry DR, Blazeby JM et al. Gefitinib for oesophageal cancer progressing after chemotherapy (COG): A phase 3, multicentre, double‐blind, placebo‐controlled randomised trial. Lancet Oncol 2014;15:894–904. [DOI] [PubMed] [Google Scholar]
69.Bang YJ, Xu RH, Chin K et al. Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first‐line therapy (GOLD): A double‐blind, randomised, placebo‐controlled, phase 3 trial. Lancet Oncol 2017;18:1637–1651. [DOI] [PubMed] [Google Scholar]
70.Bang YJ, Cho JY, Kim YH et al. Efficacy of sequential ipilimumab monotherapy versus best supportive care for unresectable locally advanced/metastatic gastric or gastroesophageal junction cancer. Clin Cancer Res 2017;23:5671–5678. [DOI] [PubMed] [Google Scholar]
71.Shitara K, Ozguroglu M, Bang YJ et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro‐oesophageal junction cancer (KEYNOTE‐061): A randomised, open‐label, controlled, phase 3 trial. Lancet 2018;392:123–133. [DOI] [PubMed] [Google Scholar]
72.Van Cutsem E, Bang YJ, Mansoor W et al. A randomized, open‐label study of the efficacy and safety of AZD4547 monotherapy versus paclitaxel for the treatment of advanced gastric adenocarcinoma with FGFR2 polysomy or gene amplification. Ann Oncol 2017;28:1316–1324. [DOI] [PubMed] [Google Scholar]
73.Ohtsu A, Ajani JA, Bai YX et al. Everolimus for previously treated advanced gastric cancer: Results of the randomized, double‐blind, phase III GRANITE‐1 study. J Clin Oncol 2013;31:3935. [DOI] [PMC free article] [PubMed] [Google Scholar]
74.Pavlakis N, Sjoquist KM, Martin AJ et al. Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): A multinational placebo‐controlled phase II trial. J Clin Oncol 2016;34:2728–2735. [DOI] [PMC free article] [PubMed] [Google Scholar]
75.Kang YK, Boku N, Satoh T et al. Nivolumab in patients with advanced gastric or gastro‐oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO‐4538‐12, ATTRACTION‐2): A randomised, double‐blind, placebo‐controlled, phase 3 trial. Lancet 2017;390:2461–2471. [DOI] [PubMed] [Google Scholar]
76.Shitara K, Doi T, Dvorkin M et al. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): A randomised, double‐blind, placebo‐controlled, phase 3 trial. Lancet Oncol 2018;19:1437–1448. [DOI] [PubMed] [Google Scholar]
77.Li J, Qin S, Xu J et al. Apatinib for chemotherapy‐refractory advanced metastatic gastric cancer: Results from a randomized, placebo‐controlled, parallel‐arm, phase II trial. J Clin Oncol 2013;31:3219–3225. [DOI] [PubMed] [Google Scholar]
78.Li J, Qin S, Xu J et al. Randomized, double‐blind, placebo‐controlled phase III trial of apatinib in patients with chemotherapy‐refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol 2016;34:1448–1454. [DOI] [PubMed] [Google Scholar]
79.Kato K, Satoh T, Muro K et al. A subanalysis of Japanese patients in a randomized, double‐blind, placebo‐controlled, phase 3 trial of nivolumab for patients with advanced gastric or gastro‐esophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO‐4538‐12, ATTRACTION‐2). Gastric Cancer 2019;22:344–354. [DOI] [PMC free article] [PubMed] [Google Scholar]
80.Janjigian YY, Bendell J, Calvo E et al. CheckMate‐032 study: Efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer. J Clin Oncol 2018;36:2836–2844. [DOI] [PMC free article] [PubMed] [Google Scholar]
81.Smyth EC, Moehler M. Late‐line treatment in metastatic gastric cancer: Today and tomorrow. Ther Adv Med Oncol 2019;11:1758835919867522. [DOI] [PMC free article] [PubMed] [Google Scholar]
82.Bang YJ, Ruiz EY, Van Cutsem E 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. Ann Oncol 2018;29:2052–2060. [DOI] [PMC free article] [PubMed] [Google Scholar]
83.Kang YK, Kang WK, Di Bartolomeo M et al. Randomized phase III ANGEL study of rivoceranib (apatinib) 1 best supportive care (BSC) vs placebo 1 BSC in patients with advanced/metastatic gastric cancer who failed 2 prior chemotherapy regimens. Ann Oncol 2019;30(suppl 5):V877–V878. [Google Scholar]
84.Shah MA, Janjigian YY, Stoller R et al. Randomized multicenter phase II study of modified docetaxel, fisplatin, and fluorouracil (DCF) versus DCF plus growth factor support in patients with metastatic gastric adenocarcinoma: A study of the US Gastric Cancer Consortium. J Clin Oncol 2015;33:3874–3879. [DOI] [PubMed] [Google Scholar]
85.Park H, Jin RU, Wang‐Gillam A et al. Folfirinox for the treatment of advanced gastroesophageal cancers. JAMA Oncol 2020;6:1231. [DOI] [PMC free article] [PubMed] [Google Scholar]
86.Soularue E, Cohen R, Tournigand C et al. Efficacy and safety of trastuzumab in combination with oxaliplatin and fluorouracil‐based chemotherapy for patients with HER2‐positive metastatic gastric and gastro‐oesophageal junction adenocarcinoma patients: A retrospective study. Bull Cancer 2015;102:324–331. [DOI] [PubMed] [Google Scholar]
87.Ryu MH, Yoo C, Kim JG et al. Multicenter phase II study of trastuzumab in combination with capecitabine and oxaliplatin for advanced gastric cancer. Eur J Cancer 2015;51:482–488. [DOI] [PubMed] [Google Scholar]
88.Klempner SJ, Wainberg ZA, Muro K et al. Impact of frontline doublet versus triplet therapy on clinical outcomes: Exploratory analysis from the RAINBOW study. J Clin Oncol. 2020;38(suppl 15):4543a. [Google Scholar]
89.Klempner SJ, Maron SB, Chase L et al. Initial report of second‐line FOLFIRI in combination with ramucirumab in advanced gastroesophageal adenocarcinomas: A multi‐institutional retrospective analysis. The Oncologist 2019;24:475–482. [DOI] [PMC free article] [PubMed] [Google Scholar]
90.Lorenzen S, Thuss‐Patience PC, Pauligk C et al. FOLFIRI plus ramucirumab versus paclitaxel plus ramucirumab as second‐line therapy for patients with advanced or metastatic gastroesophageal adenocarcinoma with or without prior docetaxel: Results from the phase II RAMIRIS study of the AIO. J Clin Oncol 2020;38(suppl 15):4514a. [DOI] [PubMed] [Google Scholar]
91.Park H, Sanjeevaiah A, Suresh R et al. Ramucirumab and irinotecan in patients with previously treated gastroesophageal adenocarcinoma: Interim analysis of a phase II trial. Ann Oncol 2020;31(suppl 3):S132. [Google Scholar]
92.Tournigand C, Cervantes A, Figer A et al. OPTIMOX1: A randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop‐and‐go fashion in advanced colorectal cancer–a GERCOR study. J Clin Oncol 2006;24:394–400. [DOI] [PubMed] [Google Scholar]
93.Simkens LH, van Tinteren H, May A et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): A phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet 2015;385:1843–1852. [DOI] [PubMed] [Google Scholar]
94.Park SR, Kim MJ, Nam BH et al. A randomised phase II study of continuous versus stop‐and‐go S‐1 plus oxaliplatin following disease stabilisation in first‐line chemotherapy in patients with metastatic gastric cancer. Eur J Cancer 2017;83:32–42. [DOI] [PubMed] [Google Scholar]
95.Shi Q, Paul J, Grothey A. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med 2018;379:396–397. [DOI] [PubMed] [Google Scholar]
96.Fuchs CS, Doi T, Jang RW et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: Phase 2 clinical KEYNOTE‐059 trial. JAMA Oncol 2018;4:e180013. [DOI] [PMC free article] [PubMed] [Google Scholar]
97.Marabelle A, Le DT, Ascierto PA et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair–deficient cancer: Results from the phase II KEYNOTE‐158 study. J Clin Oncol 2020;38:1–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
98.Marabelle A, Fakih M, Lopez J et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: Prospective biomarker analysis of the multicohort, open‐label, phase 2 KEYNOTE‐158 study. Lancet Oncol 2020;21:1353–1365. [DOI] [PubMed] [Google Scholar]
99.Fuchs CS, Özgüroğlu M, Bang YJ et al. The association of molecular biomarkers with efficacy of pembrolizumab versus paclitaxel in patients with gastric cancer (GC) from KEYNOTE‐061. J Clin Oncol 2020;38(suppl 15):4512a. [Google Scholar]
100.Kim ST, Cristescu R, Bass AJ et al. Comprehensive molecular characterization of clinical responses to PD‐1 inhibition in metastatic gastric cancer. Nat Med 2018;24:1449–1458. [DOI] [PubMed] [Google Scholar]
101.Moehler M, Dvorkin M, Boku N et al. Phase III trial of avelumab maintenance after first‐line induction chemotherapy versus continuation of chemotherapy in patients with gastric cancers: Results from JAVELIN Gastric 100. J Clin Oncol 2021;39:966–977. [DOI] [PMC free article] [PubMed] [Google Scholar]
102.Shitara K, Van Cutsem E, Bang YJ et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first‐line, advanced gastric cancer: The KEYNOTE‐062 phase 3 randomized clinical trial. JAMA Oncol 2020;6:1571–1580. [DOI] [PMC free article] [PubMed] [Google Scholar]
103.Boku N, Ryu MH, Oh DY et al. LBA7_PR Nivolumab plus chemotherapy versus chemotherapy alone in patients with previously untreated advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer: ATTRACTION‐4 (ONO‐4538‐37) study. Ann Oncol 2020;31(suppl 4):S1192a. [Google Scholar]
104.Janjigian YY, Shitara K, Moehler M et al. First‐line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro‐oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open‐label, phase 3 trial. Lancet 2021;398:27–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
105.Chao J, Fuchs CS, Shitara K et al. Assessment of pembrolizumab therapy for the treatment of microsatellite instability‐high gastric or gastroesophageal junction cancer among patients in the KEYNOTE‐059, KEYNOTE‐061, and KEYNOTE‐062 clinical trials. JAMA Oncol 2021;7:895–902. [DOI] [PMC free article] [PubMed] [Google Scholar]
106.Makiyama A, Sukawa Y, Kashiwada T et al. Randomized, phase II study of trastuzumab beyond progression in patients with HER2‐positive advanced gastric or gastroesophageal junction cancer: WJOG7112G (T‐ACT Study). J Clin Oncol 2020;38:1919–1927. [DOI] [PubMed] [Google Scholar]
107.Shitara K, Bang YJ, Iwasa S et al. Trastuzumab deruxtecan in previously treated HER2‐positive gastric cancer. N Engl J Med 2020;382:2419–2430. [DOI] [PubMed] [Google Scholar]
108.Catenacci DVT, Moya S, Lomnicki S et al. Personalized antibodies for gastroesophageal adenocarcinoma (PANGEA): A phase 2 study evaluating an individualized treatment strategy for metastatic disease. Cancer Discov 2021;11:308–325. [DOI] [PMC free article] [PubMed] [Google Scholar]
109.Ryu MH, Baba E, Lee KH et al. Comparison of two different S‐1 plus cisplatin dosing schedules as first‐line chemotherapy for metastatic and/or recurrent gastric cancer: A multicenter, randomized phase III trial (SOS). Ann Oncol 2015;26:2097–2101. [DOI] [PubMed] [Google Scholar]
110.Shen L, Li J, Xu J et al. Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: Randomized, double‐blind, phase III study (AVATAR study). Gastric Cancer 2015;18:168–176. [DOI] [PMC free article] [PubMed] [Google Scholar]
111.Curran D, Pozzo C, Zaluski J et al. Quality of life of palliative chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction treated with irinotecan combined with 5‐fluorouracil and folinic acid: Results of a randomised phase III trial. Qual Life Res 2009;18:853–861. [DOI] [PMC free article] [PubMed] [Google Scholar]
112.Kim ST, Kang JH, Lee J et al. Simvastatin plus capecitabine‐cisplatin versus placebo plus capecitabine‐cisplatin in patients with previously untreated advanced gastric cancer: A double‐blind randomised phase 3 study. Eur J Cancer 2014;50:2822–2830. [DOI] [PubMed] [Google Scholar]
113.Li YH, Qiu MZ, Xu JM et al. S‐1 plus cisplatin versus fluorouracil plus cisplatin in advanced gastric or gastro‐esophageal junction adenocarcinoma patients: A pilot study. Oncotarget 2015;6:35107–35115. [DOI] [PMC free article] [PubMed] [Google Scholar]
114.Lordick F, Kang YK, Chung HC et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): A randomised, open‐label phase 3 trial. Lancet Oncol 2013;14:490–499. [DOI] [PubMed] [Google Scholar]
115.Shah MA, Xu RH, Bang YJ et al. HELOISE: Phase IIIb randomized multicenter study comparing standard‐of‐care and higher‐dose trastuzumab regimens combined with chemotherapy as first‐line therapy in patients with human epidermal growth factor receptor 2‐positive metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol 2017;35:2558–2567. [DOI] [PubMed] [Google Scholar]
116.Lee KW, Kim BJ, Kim MJ et al. A multicenter randomized phase II study of docetaxel vs. docetaxel plus cisplatin vs. docetaxel plus S‐1 as second‐line chemotherapy in metastatic gastric cancer patients who had progressed after cisplatin plus either S‐1 or capecitabine. Cancer Res Treat 2017;49:706–716. [DOI] [PMC free article] [PubMed] [Google Scholar]
117.Lee KW, Maeng CH, Kim TY et al. A phase III study to compare the efficacy and safety of paclitaxel versus irinotecan in patients with metastatic or recurrent gastric cancer who failed in first‐line therapy (KCSG ST10‐01). The Oncologist 2019;24:18–e24. [DOI] [PMC free article] [PubMed] [Google Scholar]
118.Moehler M, Gepfner‐Tuma I, Maderer A et al. Sunitinib added to FOLFIRI versus FOLFIRI in patients with chemorefractory advanced adenocarcinoma of the stomach or lower esophagus: A randomized, placebo‐controlled phase II AIO trial with serum biomarker program. BMC Cancer 2016;16:699. [DOI] [PMC free article] [PubMed] [Google Scholar]
119.Satoh T, Kang YK, Chao Y et al. Exploratory subgroup analysis of patients with prior trastuzumab use in the ATTRACTION‐2 trial: A randomized phase III clinical trial investigating the efficacy and safety of nivolumab in patients with advanced gastric/gastroesophageal junction cancer. Gastric Cancer 2020;23:143–153. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

See http://www.TheOncologist.com for supplemental material available online.

Appendix S1: Supplemental Methods

Click here for additional data file.^{(169.9KB, pdf)}

Supplemental Tables

Click here for additional data file.^{(537.7KB, pdf)}

[onco13907-bib-0001] 1.Bray F, Ferlay J, Soerjomataram I et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394–424. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0002] 2.Pellino A, Riello E, Nappo F et al. Targeted therapies in metastatic gastric cancer: Current knowledge and future perspectives. World J Gastroenterol 2019;25:5773–5788. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0003] 3.Gambardella V, Fleitas T, Tarazona N et al. Precision medicine to treat advanced gastroesophageal adenocarcinoma: A work in progress. J Clin Med 2020;9:3049. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0004] 4.Sastre J, Garcia‐Saenz JA, Diaz‐Rubio E. Chemotherapy for gastric cancer. World J Gastroenterol 2006;12:204–213. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0005] 5.Power DG, Kelsen DP, Shah MA. Advanced gastric cancer–slow but steady progress. Cancer Treat Rev 2010;36:384–392. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0006] 6.Abrams T, Hess LM, Zhu YE et al. Predictors of heterogeneity in the first‐line treatment of patients with advanced/metastatic gastric cancer in the U.S. Gastric Cancer 2018;21:738–744. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0007] 7.Barzi A, Thara E. Angiogenesis in esophageal and gastric cancer: A paradigm shift in treatment. Expert Opin Biol Ther 2014;14:1319–1332. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0008] 8.Wagner AD, Syn NL, Moehler M et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2017;(8):CD004064. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0009] 9.Wagner AD, Unverzagt S, Grothe W et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2010;(3):CD004064. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0010] 10.Elimova E, Janjigian YY, Mulcahy M et al. It is time to stop using epirubicin to treat any patient with gastroesophageal adenocarcinoma. J Clin Oncol 2017;35:475–477. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0011] 11.Van Cutsem E, Sagaert X, Topal B et al. Gastric cancer. Lancet 2016;388:2654–2664. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0012] 12.Smyth EC, Verheij M, Allum W et al. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow‐up. Ann Oncol 2016;27(suppl 5):v38–v49. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0013] 13.Van Cutsem E, Moiseyenko VM, Tjulandin S et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first‐line therapy for advanced gastric cancer: A report of the V325 Study Group. J Clin Oncol 2006;24:4991–4997. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0014] 14.Harada K, Lopez A, Shanbhag N et al. Recent advances in the management of gastric adenocarcinoma patients. F1000Res 2018;7:F1000 Faculty Rev‐1365. [Google Scholar]

[onco13907-bib-0015] 15.Ajani JA, D'Amico TA, Almhanna K et al. Gastric cancer, version 3.2016, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2016;14:1286–1312. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0016] 16.Moher D, Liberati A, Tetzlaff J et al. Preferred reporting items for systematic reviews and meta‐analyses: The PRISMA statement. PLoS Med 2009;6:e1000097. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0017] 17.Bang YJ, Van Cutsem E, Feyereislova A et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2‐positive advanced gastric or gastro‐oesophageal junction cancer (ToGA): A phase 3, open‐label, randomised controlled trial. Lancet 2010;376:687–697. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0018] 18.Waddell T, Chau I, Cunningham D et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): A randomised, open‐label phase 3 trial. Lancet Oncol 2013;14:481–489. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0019] 19.Wang J, Xu R, Li J et al. Randomized multicenter phase III study of a modified docetaxel and cisplatin plus fluorouracil regimen compared with cisplatin and fluorouracil as first‐line therapy for advanced or locally recurrent gastric cancer. Gastric Cancer 2016;19:234–244. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0020] 20.Yamada Y, Higuchi K, Nishikawa K et al. Phase III study comparing oxaliplatin plus S‐1 with cisplatin plus S‐1 in chemotherapy‐naive patients with advanced gastric cancer. Ann Oncol 2015;26:141–148. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0021] 21.Bando H, Yamada Y, Tanabe S et al. Efficacy and safety of S‐1 and oxaliplatin combination therapy in elderly patients with advanced gastric cancer. Gastric Cancer 2016;19:919–926. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0022] 22.Guimbaud R, Louvet C, Ries P et al. Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: A French intergroup (Fédération Francophone de Cancérologie Digestive, Fédération Nationale des Centres de Lutte Contre le Cancer, and Groupe Coopérateur Multidisciplinaire en Oncologie) study. J Clin Oncol 2014;32:3520–3526. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0023] 23.Hecht JR, Bang YJ, Qin SK et al. Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2‐positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO‐013/LOGiC–a randomized phase III trial. J Clin Oncol 2016;34:443–451. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0024] 24.Kang YK, Kang WK, Shin DB et al. Capecitabine/cisplatin versus 5‐fluorouracil/cisplatin as first‐line therapy in patients with advanced gastric cancer: A randomised phase III noninferiority trial. Ann Oncol 2009;20:666–673. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0025] 25.Ohtsu A, Shah MA, Van Cutsem E et al. Bevacizumab in combination with chemotherapy as first‐line therapy in advanced gastric cancer: A randomized, double‐blind, placebo‐controlled phase III study. J Clin Oncol 2011;29:3968–3976. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0026] 26.Ajani JA, Rodriguez W, Bodoky G et al. Multicenter phase III comparison of cisplatin/S‐1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: The FLAGS trial. J Oncol 2010;28:1547–1553. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0027] 27.Ajani JA, Abramov M, Bondarenko I et al. A phase III trial comparing oral S‐1/cisplatin and intravenous 5‐fluorouracil/cisplatin in patients with untreated diffuse gastric cancer. Ann Oncol 2017;28:2142–2148. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0028] 28.Catenacci DVT, Tebbutt NC, Davidenko I et al. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first‐line therapy in advanced MET‐positive gastric or gastro‐oesophageal junction cancer (RILOMET‐1): A randomised, double‐blind, placebo‐controlled, phase 3 trial. Lancet Oncol 2017;18:1467–1482. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0029] 29.Lu Z, Zhang X, Liu W et al. A multicenter, randomized trial comparing efficacy and safety of paclitaxel/capecitabine and cisplatin/capecitabine in advanced gastric cancer. Gastric Cancer 2018;21:782–791. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0030] 30.Jin M, Lu H, Li J et al. Randomized 3‐armed phase III study of S‐1 monotherapy versus S‐1/CDDP (SP) versus 5‐FU/CDDP (FP) in patients (pts) with advanced gastric cancer (AGC): SC‐101 study. J J Clin Oncol. 2008;26(suppl 15):4533a. [Google Scholar]

[onco13907-bib-0031] 31.Koizumi W, Kim YH, Fujii M et al. Addition of docetaxel to S‐1 without platinum prolongs survival of patients with advanced gastric cancer: A randomized study (START). J Cancer Res Clin Oncol 2014;140:319–328. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0032] 32.Shu Z, Ding D, Li Y. Adjuvant chemotherapy for chemotherapy‐naive advanced gastric cancer patients with oxaliplatin plus tegafur versus oxaliplatin plus S‐1. Int J Clin Exp Med 2017;10:9322–9329. [Google Scholar]

[onco13907-bib-0033] 33.Al‐Batran SE, Hartmann JT, Probst S et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: A study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol 2008;26:1435–1442. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0034] 34.Enzinger PC, Burtness BA, Niedzwiecki D et al. CALGB 80403 (Alliance)/E1206: A randomized phase II study of three chemotherapy regimens plus cetuximab in metastatic esophageal and gastroesophageal junction cancers. J Clin Oncol 2016;34:2736–2742. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0035] 35.Lu J, Zhou Z, Wu C et al. S‐1 combined with docetaxel (SD) versus S‐1 combined with cisplatin (SP) in the treatment of advanced gastric cancer: Randomized, controlled, multicenter and clinical study. Int J Clin Exp Med 2019;12:9359–9365. [Google Scholar]

[onco13907-bib-0036] 36.Yamada Y, Boku N, Mizusawa J et al. Docetaxel plus cisplatin and S‐1 versus cisplatin and S‐1 in patients with advanced gastric cancer (JCOG1013): An open‐label, phase 3, randomised controlled trial. Lancet Gastroenterol Hepatol 2019;4:501–510. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0037] 37.Van Cutsem E, Boni C, Tabernero J et al. Docetaxel plus oxaliplatin with or without fluorouracil or capecitabine in metastatic or locally recurrent gastric cancer: A randomized phase II study. Ann Oncol 2015;26:149–156. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0038] 38.Tabernero J, Hoff PM, Shen L et al. Pertuzumab plus trastuzumab and chemotherapy for HER2‐positive metastatic gastric or gastro‐oesophageal junction cancer (JACOB): Final analysis of a double‐blind, randomised, placebo‐controlled phase 3 study. Lancet Oncol 2018;19:1372–1384. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0039] 39.Shah MA, Bang YJ, Lordick F et al. Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2‐negative, MET‐positive gastroesophageal adenocarcinoma: The METGastric randomized clinical trial. JAMA Oncol 2017;3:620–627. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0040] 40.Fuchs CS, Shitara K, Di Bartolomeo M et al. Ramucirumab with cisplatin and fluoropyrimidine as first‐line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): A double‐blind, randomised, placebo‐controlled, phase 3 trial. Lancet Oncol 2019;20:420–435. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0041] 41.Wilke H, Muro K, Van Cutsem E et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro‐oesophageal junction adenocarcinoma (RAINBOW): A double‐blind, randomised phase 3 trial. Lancet Oncol 2014;15:1224–1235. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0042] 42.Fuchs CS, Tomasek J, Yong CJ et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro‐oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo‐controlled, phase 3 trial. Lancet 2014;383:31–39. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0043] 43.Yi JH, Lee J, Lee J et al. Randomised phase II trial of docetaxel and sunitinib in patients with metastatic gastric cancer who were previously treated with fluoropyrimidine and platinum. Br J Cancer 2012;106:1469–1474. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0044] 44.Higuchi K, Tanabe S, Shimada K et al. Biweekly irinotecan plus cisplatin versus irinotecan alone as second‐line treatment for advanced gastric cancer: A randomised phase III trial (TCOG GI‐0801/BIRIP trial). Eur J Cancer 2014;50:1437–1445. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0045] 45.Kim JY, Ryoo HM, Bae SH et al. Multi‐center randomized phase II study of weekly docetaxel versus weekly docetaxel‐plus‐oxaliplatin as a second‐line chemotherapy for patients with advanced gastric cancer. Anticancer Res 2015;35:3531–3536. [PubMed] [Google Scholar]

[onco13907-bib-0046] 46.Satoh T, Xu RH, Chung HC et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second‐line treatment of HER2‐amplified advanced gastric cancer in Asian populations: TyTAN–a randomized, phase III study. J Clin Oncol 2014;32:2039–2049. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0047] 47.Thuss‐Patience PC, Kretzschmar A, Bichev D et al. Survival advantage for irinotecan versus best supportive care as second‐line chemotherapy in gastric cancer–a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer 2011;47:2306–2314. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0048] 48.Bang YJ, Im SA, Lee KW et al. Randomized, double‐blind phase II trial with prospective classification by ATM protein level to evaluate the efficacy and tolerability of olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer. J Clin Oncol 2015;33:3858–3865. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0049] 49.Ford HE, Marshall A, Bridgewater JA et al. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR‐02): An open‐label, phase 3 randomised controlled trial. Lancet Oncol 2014;15:78–86. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0050] 50.Nishina T, Boku N, Gotoh M et al. Randomized phase II study of second‐line chemotherapy with the best available 5‐fluorouracil regimen versus weekly administration of paclitaxel in far advanced gastric cancer with severe peritoneal metastases refractory to 5‐fluorouracil‐containing regimens (JCOG0407). Gastric Cancer 2016;19:902–910. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0051] 51.Kang YK, Ryu MH, Park SH et al. Efficacy and safety findings from DREAM: A phase III study of DHP107 (oral paclitaxel) versus i.v. paclitaxel in patients with advanced gastric cancer after failure of first‐line chemotherapy. Ann Oncol 2018;29:1220–1226. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0052] 52.Shitara K, Takashima A, Fujitani K et al. Nab‐paclitaxel versus solvent‐based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): An open‐label, randomised, non‐inferiority, phase 3 trial. Lancet Gastroenterol Hepatol 2017;2:277–287. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0053] 53.Hironaka S, Ueda S, Yasui H et al. Randomized, open‐label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol 2013;31:4438–4444. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0054] 54.Roy AC, Park SR, Cunningham D et al. A randomized phase II study of PEP02 (MM‐398), irinotecan or docetaxel as a second‐line therapy in patients with locally advanced or metastatic gastric or gastro‐oesophageal junction adenocarcinoma. Ann Oncol 2013;24:1567–1573. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0055] 55.Sym SJ, Hong J, Park J et al. A randomized phase II study of biweekly irinotecan monotherapy or a combination of irinotecan plus 5‐fluorouracil/leucovorin (mFOLFIRI) in patients with metastatic gastric adenocarcinoma refractory to or progressive after first‐line chemotherapy. Cancer Chemother Pharmacol 2013;71:481–488. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0056] 56.Tanabe K, Fujii M, Nishikawa K et al. Phase II/III study of second‐line chemotherapy comparing irinotecan‐alone with S‐1 plus irinotecan in advanced gastric cancer refractory to first‐line treatment with S‐1 (JACCRO GC‐05). Ann Oncol 2015;26:1916–1922. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0057] 57.Nishikawa K, Fujitani K, Inagaki H et al. Randomised phase III trial of second‐line irinotecan plus cisplatin versus irinotecan alone in patients with advanced gastric cancer refractory to S‐1 monotherapy: TRICS trial. Eur J Cancer 2015;51:808–816. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0058] 58.Nakanishi K, Kobayashi D, Mochizuki Y et al. Phase II multi‐institutional prospective randomized trial comparing S‐1 plus paclitaxel with paclitaxel alone as second‐line chemotherapy in S‐1 pretreated gastric cancer (CCOG0701). Int J Clin Oncol 2016;21:557–565. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0059] 59.Shitara K, Yuki S, Tahahari D et al. Randomised phase II study comparing dose‐escalated weekly paclitaxel vs standard‐dose weekly paclitaxel for patients with previously treated advanced gastric cancer. Br J Cancer 2014;110:271–277. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0060] 60.Fushida S, Kinoshita J, Kaji M et al. Paclitaxel plus valproic acid versus paclitaxel alone as second‐or third‐line therapy for advanced gastric cancer: A randomized phase II trial. Drug Des Devel Ther 2016;10:2353–2358. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0061] 61.Kang JH, Lee SI, Lim Det al. Salvage chemotherapy for pretreated gastric cancer: A randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol 2012;30:1513–1518. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0062] 62.Satoh T, Lee KH, Rha SY et al. Randomized phase II trial of nimotuzumab plus irinotecan versus irinotecan alone as second‐line therapy for patients with advanced gastric cancer. Gastric Cancer 2015;18:824–832. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0063] 63.Muro K, Oh SC, Shimada Y et al. Subgroup analysis of East Asians in RAINBOW: A phase 3 trial of ramucirumab plus paclitaxel for advanced gastric cancer. J Gastroenterol Hepatol 2016;31:581–589. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0064] 64.Shitara K, Muro K, Shimada Y et al. Subgroup analyses of the safety and efficacy of ramucirumab in Japanese and Western patients in RAINBOW: A randomized clinical trial in second‐line treatment of gastric cancer. Gastric Cancer 2016;19:927–938. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0065] 65.Xu RH, Zhang YQ, Pan H et al. RAINBOW‐Asia: A randomized, multicenter, double‐blind, phase III study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first‐line chemotherapy with platinum and fluoropyrimidine. J Clin Oncol 2021;39(suppl 3):199a. [Google Scholar]

[onco13907-bib-0066] 66.Thuss‐Patience PC, Shah MA, Ohtsu A et al. Trastuzumab emtansine versus taxane use for previously treated HER2‐positive locally advanced or metastatic gastric or gastro‐oesophageal junction adenocarcinoma (GATSBY): An international randomised, open‐label, adaptive, phase 2/3 study. Lancet Oncol 2017;18:640–653. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0067] 67.Ferry DR, Dutton SJ, Mansoor W et al. Phase III multi‐centre, randomised, double‐blind, placebo‐controlled trial of gefitinib versus placebo in esophageal cancer progressing after chemotherapy, COG (cancer oesophagus gefitinib). Ann Oncol 2012;23(suppl 9):IXE12. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0068] 68.Dutton SJ, Ferry DR, Blazeby JM et al. Gefitinib for oesophageal cancer progressing after chemotherapy (COG): A phase 3, multicentre, double‐blind, placebo‐controlled randomised trial. Lancet Oncol 2014;15:894–904. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0069] 69.Bang YJ, Xu RH, Chin K et al. Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first‐line therapy (GOLD): A double‐blind, randomised, placebo‐controlled, phase 3 trial. Lancet Oncol 2017;18:1637–1651. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0070] 70.Bang YJ, Cho JY, Kim YH et al. Efficacy of sequential ipilimumab monotherapy versus best supportive care for unresectable locally advanced/metastatic gastric or gastroesophageal junction cancer. Clin Cancer Res 2017;23:5671–5678. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0071] 71.Shitara K, Ozguroglu M, Bang YJ et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro‐oesophageal junction cancer (KEYNOTE‐061): A randomised, open‐label, controlled, phase 3 trial. Lancet 2018;392:123–133. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0072] 72.Van Cutsem E, Bang YJ, Mansoor W et al. A randomized, open‐label study of the efficacy and safety of AZD4547 monotherapy versus paclitaxel for the treatment of advanced gastric adenocarcinoma with FGFR2 polysomy or gene amplification. Ann Oncol 2017;28:1316–1324. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0073] 73.Ohtsu A, Ajani JA, Bai YX et al. Everolimus for previously treated advanced gastric cancer: Results of the randomized, double‐blind, phase III GRANITE‐1 study. J Clin Oncol 2013;31:3935. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0074] 74.Pavlakis N, Sjoquist KM, Martin AJ et al. Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): A multinational placebo‐controlled phase II trial. J Clin Oncol 2016;34:2728–2735. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0075] 75.Kang YK, Boku N, Satoh T et al. Nivolumab in patients with advanced gastric or gastro‐oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO‐4538‐12, ATTRACTION‐2): A randomised, double‐blind, placebo‐controlled, phase 3 trial. Lancet 2017;390:2461–2471. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0076] 76.Shitara K, Doi T, Dvorkin M et al. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): A randomised, double‐blind, placebo‐controlled, phase 3 trial. Lancet Oncol 2018;19:1437–1448. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0077] 77.Li J, Qin S, Xu J et al. Apatinib for chemotherapy‐refractory advanced metastatic gastric cancer: Results from a randomized, placebo‐controlled, parallel‐arm, phase II trial. J Clin Oncol 2013;31:3219–3225. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0078] 78.Li J, Qin S, Xu J et al. Randomized, double‐blind, placebo‐controlled phase III trial of apatinib in patients with chemotherapy‐refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol 2016;34:1448–1454. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0079] 79.Kato K, Satoh T, Muro K et al. A subanalysis of Japanese patients in a randomized, double‐blind, placebo‐controlled, phase 3 trial of nivolumab for patients with advanced gastric or gastro‐esophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO‐4538‐12, ATTRACTION‐2). Gastric Cancer 2019;22:344–354. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0080] 80.Janjigian YY, Bendell J, Calvo E et al. CheckMate‐032 study: Efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer. J Clin Oncol 2018;36:2836–2844. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0081] 81.Smyth EC, Moehler M. Late‐line treatment in metastatic gastric cancer: Today and tomorrow. Ther Adv Med Oncol 2019;11:1758835919867522. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0082] 82.Bang YJ, Ruiz EY, Van Cutsem E 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. Ann Oncol 2018;29:2052–2060. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0083] 83.Kang YK, Kang WK, Di Bartolomeo M et al. Randomized phase III ANGEL study of rivoceranib (apatinib) 1 best supportive care (BSC) vs placebo 1 BSC in patients with advanced/metastatic gastric cancer who failed 2 prior chemotherapy regimens. Ann Oncol 2019;30(suppl 5):V877–V878. [Google Scholar]

[onco13907-bib-0084] 84.Shah MA, Janjigian YY, Stoller R et al. Randomized multicenter phase II study of modified docetaxel, fisplatin, and fluorouracil (DCF) versus DCF plus growth factor support in patients with metastatic gastric adenocarcinoma: A study of the US Gastric Cancer Consortium. J Clin Oncol 2015;33:3874–3879. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0085] 85.Park H, Jin RU, Wang‐Gillam A et al. Folfirinox for the treatment of advanced gastroesophageal cancers. JAMA Oncol 2020;6:1231. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0086] 86.Soularue E, Cohen R, Tournigand C et al. Efficacy and safety of trastuzumab in combination with oxaliplatin and fluorouracil‐based chemotherapy for patients with HER2‐positive metastatic gastric and gastro‐oesophageal junction adenocarcinoma patients: A retrospective study. Bull Cancer 2015;102:324–331. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0087] 87.Ryu MH, Yoo C, Kim JG et al. Multicenter phase II study of trastuzumab in combination with capecitabine and oxaliplatin for advanced gastric cancer. Eur J Cancer 2015;51:482–488. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0088] 88.Klempner SJ, Wainberg ZA, Muro K et al. Impact of frontline doublet versus triplet therapy on clinical outcomes: Exploratory analysis from the RAINBOW study. J Clin Oncol. 2020;38(suppl 15):4543a. [Google Scholar]

[onco13907-bib-0089] 89.Klempner SJ, Maron SB, Chase L et al. Initial report of second‐line FOLFIRI in combination with ramucirumab in advanced gastroesophageal adenocarcinomas: A multi‐institutional retrospective analysis. The Oncologist 2019;24:475–482. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0090] 90.Lorenzen S, Thuss‐Patience PC, Pauligk C et al. FOLFIRI plus ramucirumab versus paclitaxel plus ramucirumab as second‐line therapy for patients with advanced or metastatic gastroesophageal adenocarcinoma with or without prior docetaxel: Results from the phase II RAMIRIS study of the AIO. J Clin Oncol 2020;38(suppl 15):4514a. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0091] 91.Park H, Sanjeevaiah A, Suresh R et al. Ramucirumab and irinotecan in patients with previously treated gastroesophageal adenocarcinoma: Interim analysis of a phase II trial. Ann Oncol 2020;31(suppl 3):S132. [Google Scholar]

[onco13907-bib-0092] 92.Tournigand C, Cervantes A, Figer A et al. OPTIMOX1: A randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop‐and‐go fashion in advanced colorectal cancer–a GERCOR study. J Clin Oncol 2006;24:394–400. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0093] 93.Simkens LH, van Tinteren H, May A et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): A phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet 2015;385:1843–1852. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0094] 94.Park SR, Kim MJ, Nam BH et al. A randomised phase II study of continuous versus stop‐and‐go S‐1 plus oxaliplatin following disease stabilisation in first‐line chemotherapy in patients with metastatic gastric cancer. Eur J Cancer 2017;83:32–42. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0095] 95.Shi Q, Paul J, Grothey A. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med 2018;379:396–397. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0096] 96.Fuchs CS, Doi T, Jang RW et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: Phase 2 clinical KEYNOTE‐059 trial. JAMA Oncol 2018;4:e180013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0097] 97.Marabelle A, Le DT, Ascierto PA et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair–deficient cancer: Results from the phase II KEYNOTE‐158 study. J Clin Oncol 2020;38:1–10. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0098] 98.Marabelle A, Fakih M, Lopez J et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: Prospective biomarker analysis of the multicohort, open‐label, phase 2 KEYNOTE‐158 study. Lancet Oncol 2020;21:1353–1365. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0099] 99.Fuchs CS, Özgüroğlu M, Bang YJ et al. The association of molecular biomarkers with efficacy of pembrolizumab versus paclitaxel in patients with gastric cancer (GC) from KEYNOTE‐061. J Clin Oncol 2020;38(suppl 15):4512a. [Google Scholar]

[onco13907-bib-0100] 100.Kim ST, Cristescu R, Bass AJ et al. Comprehensive molecular characterization of clinical responses to PD‐1 inhibition in metastatic gastric cancer. Nat Med 2018;24:1449–1458. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0101] 101.Moehler M, Dvorkin M, Boku N et al. Phase III trial of avelumab maintenance after first‐line induction chemotherapy versus continuation of chemotherapy in patients with gastric cancers: Results from JAVELIN Gastric 100. J Clin Oncol 2021;39:966–977. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0102] 102.Shitara K, Van Cutsem E, Bang YJ et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first‐line, advanced gastric cancer: The KEYNOTE‐062 phase 3 randomized clinical trial. JAMA Oncol 2020;6:1571–1580. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0103] 103.Boku N, Ryu MH, Oh DY et al. LBA7_PR Nivolumab plus chemotherapy versus chemotherapy alone in patients with previously untreated advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer: ATTRACTION‐4 (ONO‐4538‐37) study. Ann Oncol 2020;31(suppl 4):S1192a. [Google Scholar]

[onco13907-bib-0104] 104.Janjigian YY, Shitara K, Moehler M et al. First‐line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro‐oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open‐label, phase 3 trial. Lancet 2021;398:27–40. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0105] 105.Chao J, Fuchs CS, Shitara K et al. Assessment of pembrolizumab therapy for the treatment of microsatellite instability‐high gastric or gastroesophageal junction cancer among patients in the KEYNOTE‐059, KEYNOTE‐061, and KEYNOTE‐062 clinical trials. JAMA Oncol 2021;7:895–902. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0106] 106.Makiyama A, Sukawa Y, Kashiwada T et al. Randomized, phase II study of trastuzumab beyond progression in patients with HER2‐positive advanced gastric or gastroesophageal junction cancer: WJOG7112G (T‐ACT Study). J Clin Oncol 2020;38:1919–1927. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0107] 107.Shitara K, Bang YJ, Iwasa S et al. Trastuzumab deruxtecan in previously treated HER2‐positive gastric cancer. N Engl J Med 2020;382:2419–2430. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0108] 108.Catenacci DVT, Moya S, Lomnicki S et al. Personalized antibodies for gastroesophageal adenocarcinoma (PANGEA): A phase 2 study evaluating an individualized treatment strategy for metastatic disease. Cancer Discov 2021;11:308–325. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0109] 109.Ryu MH, Baba E, Lee KH et al. Comparison of two different S‐1 plus cisplatin dosing schedules as first‐line chemotherapy for metastatic and/or recurrent gastric cancer: A multicenter, randomized phase III trial (SOS). Ann Oncol 2015;26:2097–2101. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0110] 110.Shen L, Li J, Xu J et al. Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: Randomized, double‐blind, phase III study (AVATAR study). Gastric Cancer 2015;18:168–176. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0111] 111.Curran D, Pozzo C, Zaluski J et al. Quality of life of palliative chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction treated with irinotecan combined with 5‐fluorouracil and folinic acid: Results of a randomised phase III trial. Qual Life Res 2009;18:853–861. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0112] 112.Kim ST, Kang JH, Lee J et al. Simvastatin plus capecitabine‐cisplatin versus placebo plus capecitabine‐cisplatin in patients with previously untreated advanced gastric cancer: A double‐blind randomised phase 3 study. Eur J Cancer 2014;50:2822–2830. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0113] 113.Li YH, Qiu MZ, Xu JM et al. S‐1 plus cisplatin versus fluorouracil plus cisplatin in advanced gastric or gastro‐esophageal junction adenocarcinoma patients: A pilot study. Oncotarget 2015;6:35107–35115. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0114] 114.Lordick F, Kang YK, Chung HC et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): A randomised, open‐label phase 3 trial. Lancet Oncol 2013;14:490–499. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0115] 115.Shah MA, Xu RH, Bang YJ et al. HELOISE: Phase IIIb randomized multicenter study comparing standard‐of‐care and higher‐dose trastuzumab regimens combined with chemotherapy as first‐line therapy in patients with human epidermal growth factor receptor 2‐positive metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol 2017;35:2558–2567. [DOI] [PubMed] [Google Scholar]

[onco13907-bib-0116] 116.Lee KW, Kim BJ, Kim MJ et al. A multicenter randomized phase II study of docetaxel vs. docetaxel plus cisplatin vs. docetaxel plus S‐1 as second‐line chemotherapy in metastatic gastric cancer patients who had progressed after cisplatin plus either S‐1 or capecitabine. Cancer Res Treat 2017;49:706–716. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0117] 117.Lee KW, Maeng CH, Kim TY et al. A phase III study to compare the efficacy and safety of paclitaxel versus irinotecan in patients with metastatic or recurrent gastric cancer who failed in first‐line therapy (KCSG ST10‐01). The Oncologist 2019;24:18–e24. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0118] 118.Moehler M, Gepfner‐Tuma I, Maderer A et al. Sunitinib added to FOLFIRI versus FOLFIRI in patients with chemorefractory advanced adenocarcinoma of the stomach or lower esophagus: A randomized, placebo‐controlled phase II AIO trial with serum biomarker program. BMC Cancer 2016;16:699. [DOI] [PMC free article] [PubMed] [Google Scholar]

[onco13907-bib-0119] 119.Satoh T, Kang YK, Chao Y et al. Exploratory subgroup analysis of patients with prior trastuzumab use in the ATTRACTION‐2 trial: A randomized phase III clinical trial investigating the efficacy and safety of nivolumab in patients with advanced gastric/gastroesophageal junction cancer. Gastric Cancer 2020;23:143–153. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Toward a Treatment Sequencing Strategy: A Systematic Review of Treatment Regimens in Advanced Gastric Cancer/Gastroesophageal Junction Adenocarcinoma

Daniel V Catenacci

Joseph Chao

Kei Muro

Salah Eddin Al‐Batran

Samuel J Klempner

Zev A Wainberg

Manish A Shah

Sun Young Rha

Atsushi Ohtsu

Astra M Liepa

Holly Knoderer

Anindya Chatterjee

Eric Van Cutsem

Abstract

Background

Materials and Methods

Results

Conclusion

Implications for Practice

Short abstract

Introduction

Materials and Methods

Search Strategy

Synthesis Methods

Results

Literature Search Results

Figure 1.

Risk of Bias

Description of Included Studies

Figure 2.

Figure 3.

Efficacy and Safety of 1L Interventions

Table 1.

Table 2.

Chemotherapeutic Agents

Targeted Therapies

Efficacy and Safety of 2L Interventions

Chemotherapeutic Agents

Targeted and Immunotherapies

Efficacy and Safety of 3L+ Interventions

Discussion

The Argument for Limiting Time on 1L/Maintenance 1L Therapy in Advanced G/GEA

Potential for Integrating Immunotherapeutics

Overview of Studies Published After the Review Inclusion Period and Trials in Progress

Figure 4.

Conclusion

Author Contributions

Disclosures

Supporting information

Acknowledgments

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases