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Abstract

The treatment landscape for patients with advanced gastric or gastroesophageal junction adenocarcinoma is evolving, driven by a deeper understanding of molecular profiling and the introduction of novel anticancer drugs. Systemic chemotherapy has improved survival compared to supportive care; however, overall survival worldwide remained limited to approximately 1 year. Recently, the introduction of upfront immune checkpoint inhibitors (ICIs) and/or targeted agents in biomarker-enriched populations has led to clinically meaningful survival improvements. The expansion of treatment options for metastatic disease, combined with the identification of biomarker-selected populations, underscores the importance of tailoring first-line, maintenance, and sequential therapies across multiple lines. In this context, the delivery of an effective first-line treatment is crucial, as less than half of patients retain fitness for additional anti-cancer therapies due to the morbidity associated with disease progression to the initial regimen even within modern clinical trials regardless of the use of targeted therapy or immunotherapy combined with chemotherapy. On the other hand, the expanding therapeutic armamentarium including ICIs, antibody-drug conjugates, and targeted therapies for molecularly selected subgroups, will enable the development of sequential treatment strategies across multiple lines of therapy. This review summarizes the current knowledge about maintenance strategies and subsequent lines of treatment in either biomarker selected and unselected populations.

Keywords

advanced gastroesophageal adenocarcinoma antibody-drug conjugates HER2 inhibitors maintenance therapy second-line therapy

Introduction

Advanced gastric (GC) or gastroesophageal junction (GEJ) cancer represents a hard-to-treat disease, and survival of patients is still poor. The introduction of upfront immune checkpoint inhibitors (ICIs) and claudin 18.2 (CLDN18.2)-targeted treatments widened the first-line therapeutic options in patients with HER2-negative gastroesophageal adenocarcinoma and significantly improved survival in biomarker-enriched subgroups.^1–5 Moreover, the clinical development of several novel drugs including antibody-drug conjugates (ADCs), matched drugs in biomarker-selected populations, or chimeric antigen receptor T cells (CAR-T cells) is widening the therapeutic scenario beyond the first line. In this context, delivery of an effective first-line treatment strategy is crucial, as less than half of patients retain fitness for additional anti-cancer therapies due to the morbidity associated with disease progression to the initial regimen even in more recent trials. Additionally, an effective first-line maintenance strategy may significantly prolong the benefit of an induction treatment, delay performance status deterioration allowing patients to receive sequential treatments.

Methods

We developed a narrative review summarizing the current knowledge about maintenance strategies and subsequent lines of treatment in either biomarker selected and unselected populations. To provide a comprehensive and clinically oriented overview, a literature search on PubMed was performed. Abstract from American Society of Clinical Oncology Annual Meeting, American Association for Cancer Research, and European Society for Medical Oncology Congress was included as well. The narrative review was conducted according to the Scale for the Assessment of Narrative Review Articles.⁶

First-line maintenance strategies

Maintenance therapy is the continuation of treatment following the completion of induction therapy, administered until disease progression or unacceptable toxicity. It typically involves a de-escalation strategy, in which the less toxic agent of a combination regimen is continued to prolong the efficacy of first-line chemotherapy while minimizing cumulative toxicity over time. Switch maintenance strategy involves the use of different agents administered immediately after a pre-specified induction therapy in patients who do not experience disease progression. The rationale behind this strategy is that early administration of a non-cross-resistant regimen may delay progression and ultimately improve survival outcomes. A “stop and go” strategy refers to the administration of a limited chemotherapy course followed by a planned temporary suspension to relieve from toxicity and the reintroduction of the same regimen when disease progression occurs. Agents used in the maintenance regimen should be safe, well-tolerated, cost-effective, and have an easy route of administration. Maintenance regimens have already demonstrated to improve outcomes in some cancer types, including colorectal, lung, and breast cancer, with significant heterogeneity depending on cancer type.^7–10 However, the efficacy of maintenance therapies in advanced GC or GEJ cancers remained unclear until the most recent evidence (Table 1).¹¹

Table 1.

Randomized clinical trials evaluating different maintenance strategies in patients with advanced gastric cancer.

Name	Phase	N (random ratio)	Maintenance strategy	First-line therapy regimen	Maintenance regimen	Primary endpoint	Outcomes	Safety toxicities ⩾ G3−
Li et al.¹²	II	58 (1:1)	De-escalation	5-FU-based ECF/EOF/CAPOX 6 cycles; FOLFOX 12 cycles	Oral UFT vs observation	PFS	PFS (months): 3.2 vs 3.6; p = 0.752 OS (months): 14.2 vs 14.2; p = 0.983	Anemia: 3.4% vs 0% Thrombocytopenia: 3.4% vs 0% Diarrhea: 6.9% vs 0%
Lu et al.¹³	II	60 (1:1)	De-escalation	Paclitaxel + capecitabine ± oxaliplatin, 2–6 cycles	Capecitabine vs observation	PFS^a	PFS (months): 11.0 vs 7.0; p < 0.05 OS (months): 17.0 vs 11.0; p < 0.05	Hematological events: n = 1 vs n = 3 Neuropathy: n = 1 vs n = 0
Lee et al.¹⁴	III	63 (1:1)	De-escalation	CAPOX, 6 cycles	Capecitabine vs observation	PFS	PFS (months): 6.3 vs 4.1; p = 0.01 OS (months): 18.2 vs 16.5; p = 0.624	Thrombocytopenia: 3.1% vs 0% Hand-foot syndrome: 12.5% vs 0%
Park et al.¹⁵	II	121 (1:1)	Stop and go	SOX, 6 cycles	SOX continuation vs SOX stop and go	OS	OS (months): 22.6 vs 22.7 HR = 0.78; 95% CI: 0.50–1.23; p = 0.284 PFS (months): 5.0 vs 2.7; HR = 0.57; 95% CI: 0.38–0.83; p = 0.003	Neutropenia: 35.6% vs 31.1% Fatigue: 28.8% vs 21.0% Neuropathy: 25.4% vs 9.7%
Stocker et al.¹⁶ (MATEO)	II; non-inferiority	165 (2:1)	De-escalation	CDDP/capecitabine, CDDP/5-FU, cisplatin/S-1, FLO/modified FOLFOX-6, EOX/EOF or FLOT, 12 weeks	S1 vs continuation of chemotherapy	OS	OS (months): 13.4 vs 11.4; HR = 0.97; 80% CI: 0.76–1.23; p = 0.86 PFS (months): 4.3 vs 6.2; HR = 1.10; 80% CI: 0.86–1.39; p = 0.62	AEs: 40.6% vs 42.9%; Anemia: 1.9% vs 0% Diarrhea: 3.8% vs 0% Neuropathy: 2.8% vs 6.1%
Bramhall et al.¹⁷	III	123 (1:1)	Switch	5-FU-based	Marimastat vs placebo	OS	OS (days): 253 vs 175; HR = 1.68; 95% CI: 1.16–2.44; p = 0.006	Musculoskeletal symptoms: 12.8% vs 0.6%
Bang et al.¹⁸	II	114 (1:1)	Switch	FOLFOX/CAPOX/ CDDP + 5FU/ CDDP + capecitabine/ CDDP + S1	Ipilimumab vs treatment at the investigator discretion (5FU/capecitabine/no treatment)	irPFS	irPFS (months): 2.92 vs 4.90; HR = 1.44, 80% CI: 1.09–1.91; p = 0.097 OS (months): 12.7 vs 12.1	AEs^b: 22.8% vs 8.9% Diarrhea: 8.8% vs 0% Fatigue: 5.3% vs 0% Erythrodysesthesia: 0% vs 4.4%
Fong et al.¹⁹ (PLATFORM)	II	205 (1:1)	Switch	FOLFOX/CAPOX/ CDDP + capecitabine, 18 weeks	Durvalumab vs observation	PFS	PFS (months): 3.0 vs 3.2; HR = 0.84; 95% CI: 0.62–1.14; p = 0.13 OS (months): 11.3 vs 11.4; HR = 0.98; 95% CI: 0.70–1.36; p = 0.45	AEs: 40.6% vs 25.3% Infection: 5.9% vs 1% Pain: 5 vs 5.1%
Moehler et al.²⁰ (JAVELIN GASTRIC 100)	III	499 (1:1)	Switch	FOLFOX/CAPOX, 12 weeks	Avelumab vs continuation of chemotherapy continuation of chemotherapy	OS	OS (months): 10.4 vs 10.9; HR = 0.91; 95% CI: 0.74–1.11; p = 0.1779	AEs: 54.3% vs 53.8% Neutropenia: <1% vs 8% Neuropathy: 0% vs 3.4
Ciardiello et al.²² (PARALLEL-303)	II	136 (1:1)	Switch	Platinum + fluoropyrimidine, 28 weeks	Pamiparib vs placebo	PFS	PFS (months): 3.7 vs 2.1; HR = 0.8; 95% CI: 0.5–1.2; p = 0.1428 OS (months): 10.2 vs 12.0	AEs: 40.8% vs 30.8%
Gordon et al.²³ (PLATFORM)	II	125 (1:1)	Switch	FOLFOX/CAPOX/ CDDP + capecitabine, 18 weeks	Rucaparib vs observation	PFS	PFS (months): 4.2 vs 2.8; HR = 0.70; 97.5% CI: 0.46–1.08; p = 0.063	AEs^b: 22% Anaemia:5% Fatigue: 3% Neutropenia: 2%
Damato et al.²⁷ (a-MANTRA)	II	64 (1:1)	Switch	Platinum + fluoropyrimidine, 6 months	Regorafenib vs placebo	PFS	PFS (months): 3.91 vs 5.19; HR = 0.736; 80% CI: 0.51–1.04; p = 0.1318 OS (months): 11.25 vs 16.97; HR = 0.596; 80% CI: 0.318–1.103; p = 0.1003	Fatigue: 3.0% vs 6.4% Thrombocytopenia: 3.0% vs 3.2% Hand-foot syndrome: 0% vs 12.9%
Gordon et al.²⁸ (PLATFORM)	II	47 (1:1)	Switch	FOLFOX/CAPOX/ CDDP + capecitabine, 18 weeks	Ramucirumab + capecitabine vs observation	PFS	PSF (months): 5.5 vs 2.5; HR = 0.33; 95% CI: 0.17–0.63; p < 0.001 OS (months): 14.4 vs 7.1; HR = 0.51; 95% CI: 0.36–1.00; p = 0.023	AEs: 57% vs 32% Anemia: 10% vs 0% Fatigue: 10% vs 0% Hypertension: 19% vs 0%
Randon et al.²⁹ (ARMANI)	III	280 (1:1)	Switch	Oxaliplatin-based (CAPOX/FOLFOX), 3 months	Paclitaxel + ramucirumab vs continuation of the same regimen	PFS	PFS (months): 6.6 vs 3.5; HR = 0.61; 95% CI: 0.48–0.79; p = 0.0002 OS (months): 12.6 vs 10.4; HR = 0.75; 95% CI: 0.58–0.96; p = 0.025	AEs^b: 40% vs 21% Neutropenia: 26% vs 10% Neuropathy: 6% vs 7% Hypertension. 6% vs 0%

PFS defined as the interval from the first-line treatment to disease progression or death.

Refers to TRAEs.

5-FU, 5-fluorouracil; AEs, adverse events; CAPOX, capecitabine and oxaliplatin; CDDP, cisplatin; CI, confidence interval; ECF, epirubicin, cisplatin and continuous 5-fluorouracil; EOF, epirubicin, oxaliplatin and continuous 5-fluorouracil; FLO, fluorouracil and oxaliplatin; FLOT, fluorouracil, oxaliplatin and docetaxel; FOLFOX, fluorouracil, folinic acid and oxaliplatin; HR, hazard ratio; irPFS, immune related PFS; OS, overall survival; PFS, progression-free survival; SOX, S-1 and oxaliplatin; TRAEs, treatment related AEs; UFT, uracil and tegafur.

De-escalation maintenance

The first randomized trial to evaluate fluoropyrimidine maintenance in patients with advanced GC who had not progressed after first-line fluoropyrimidine-based chemotherapy (epirubicin, cisplatin and continuous 5-fluorouracil/epirubicin, oxaliplatin and continuous 5-fluorouracil or fluorouracil, folinic acid and oxaliplatin (FOLFOX)/capecitabine and oxaliplatin (CAPOX)) was a phase II randomized study comparing maintenance with oral uracil/tegafur (UFT) to observation. Recruitment was prematurely interrupted due to negative results at the interim analysis: progression-free survival (PFS) was slightly higher in the observation arm (3.2 vs 3.6 months, p = 0.752), while overall survival (OS) was equivalent in both arms (14.2 vs 14.2 months, p = 0.983).¹² The continuation of capecitabine was compared to observation in two different randomized trials. Capecitabine was evaluated as a maintenance versus observation after up to six cycles of paclitaxel and capecitabine. Among the 60 randomized patients, PFS and OS favored the maintenance arm (median PFS: 11.0 vs 7.0 months, p < 0.05; median OS: 17.0 vs 11.0 months, p < 0.05). There were no significant differences in adverse events (AEs) between the two groups.¹³ Capecitabine was compared to observation in 63 patients with partial response or disease stabilization after six cycles of CAPOX. A significant difference in PFS in favor of capecitabine arm (6.3 vs 4.1 months, p = 0.010) was observed. Moreover, median OS was numerically higher in the experimental arm, although the difference was not significant (18.2 vs 16.5 months, p = 0.624).¹⁴

A phase II trial explored the continuation of an intensive first-line regimen versus a “stop-and-go” arm. Here, 121 patients who received 6 cycles of S1 and oxaliplatin (SOX) induction were randomized to the continuation of SOX or a chemotherapy-free interval. PFS was significantly longer in the continuation arm (5.0 vs 2.7 months; hazard ratio (HR) = 0.57; 95% confidence interval (CI): 0.38–0.83; p = 0.003) while OS was similar in the two arms (22.6 vs 22.7 months; HR = 0.78; 95% CI: 0.50–1.23; p = 0.284). Expectedly, a higher incidence of grade 3 or higher AEs was observed in the chemotherapy continuation arm, especially regarding fatigue (28.8% vs 8.1%, p = 0.003) and sensory neuropathy (25.4% vs 9.7%, p = 0.022). Focusing on quality-of-life assessment during the maintenance phase, a significant overall difference was reported favoring the “stop-and-go” arm in terms of health status, physical functioning, role functioning, and fatigue.¹⁵

The phase II German AIO MATEO trial randomized 165 patients with advanced HER2-negative GC without disease progression after a 12-week induction doublet or triplet chemotherapy to demonstrate the non-inferiority for OS of S1 maintenance versus the continuation the same induction chemotherapy. S1 maintenance led to non-inferior outcomes compared to the continuation of platinum-based chemotherapy. Both PFS and OS from randomization did not significantly differ among the two arms (median PFS: 4.3 vs 6.1 months; HR = 1.10; 80% CI: 0.86–1.39; p = 0.62; median OS: 13.4 vs 11.4 months; HR = 0.97; 80% CI: 0.76–1.23; p = 0.86), as well as frequency of grade 3 or higher AEs (40.6% vs 42.9%), while serious AEs were more frequent in chemotherapy continuation arm (14.2% vs 22.4%). Discontinuation of cytotoxic agent was lower in S-1 maintenances arm (10.4% vs 44.9%). Moreover, an improvement in the global health status 9 weeks after randomization was observed in 41.9% of the patients in the maintenance group, compared to the 15.8% in the controls.¹⁶

Switch maintenance strategies

Early clinical trials investigated several non-cross-resistant regimens in the context of switch maintenance strategies. Marimastat, a matrix metalloproteinase inhibitor, was administrated to patients with metastatic GC after 5-FU-based chemotherapy versus placebo. In patients receiving the switch maintenance, a modest significant benefit for marimastat in terms of OS was reported (253 vs 175 days; HR = 1.68; 95% CI: 1.16–2.44; p = 0.006).¹⁷

Several trials also investigated the role of ICIs as a switch maintenance. Ipilimumab was the first ICI investigated in patients with advanced GC as a maintenance treatment after induction chemotherapy with platinum and fluoropyrimidine-based combinations. In a phase II trial, 114 patients were randomized to receive ipilimumab or therapeutic holiday/continuation of chemotherapy as per investigator choice. The rate of progression in the first 6 weeks after randomization was higher in the ipilimumab arm. The primary endpoint was the immune-related PFS, which was lower in ipilimumab group (2.92 vs 4.90 months; HR = 1.44, 80% CI: 1.09–1.91; p = 0.097). Moreover, OS did not differ in the two cohorts.¹⁸

In the PLATFORM phase II trial 205 patients who had disease control after 18 weeks of platinum and fluoropyrimidine-based chemotherapy were randomized to receive switch maintenance with durvalumab or surveillance. PFS was similar between the two groups (3.0 vs 3.2 months; HR = 0.84; 95% CI: 0.62–1.14; one-sided p = 0.13) as well as OS (11.3 vs 11.4 months; HR = 0.98, 95% CI: 0.70–1.36; one-sided p = 0.45).¹⁹

The JAVELIN Gastric 100 was a phase III randomized trial that investigated switch maintenance therapy with avelumab after a 12-week course of FOLFOX/CAPOX versus chemotherapy continuation. Four hundred ninety-nine patients were enrolled in the trial; the primary endpoint of OS was not met (median OS 10.4 vs 10.9 months; HR = 0.91; 95% CI: 0.74–1.11; p = 0.1779) irrespectively of the pre-specified PD-L1 cut off (i.e., ⩾1% by 73-10 assay). In patients with PD-L combined positive score (CPS) ⩾1 median OS was 16.2 months with avelumab and 17.7 months with chemotherapy (HR = 1.13; 95% CI: 0.57–2.23; p = 0.6352). As expected, a consistent benefit from avelumab was described in the Microsatellite Instability (MSI)-High subgroup. Furthermore, no difference in PFS or objective response rate (ORR) was detected between the two groups.²⁰ Consistently, sequential chemotherapy followed by early ICI does not seem to be supported by other trials such as the recently reported MOONLIGHT platform study, which investigated short-course FOLFOX followed by low-dose ipilimumab plus nivolumab compared to FOLFOX until progression.²¹ It should be pointed out that these trials were conducted before the introduction of high PD-L1 expression as a selection biomarker for chemo-ICI upfront combinations.

Two poly ADP ribose polymerase inhibitors (PARPi), pamiparib and rucaparib, were also investigated as maintenance treatment after first-line chemotherapy in patients with molecularly unselected advanced GC. In the PARALLEL-303 phase II trial, 136 patients who received an induction phase with chemotherapy up to 28 weeks were randomized to either pamiparib or placebo. Median PFS was 3.7 months in the experimental arm compared to 2.1 months in control arm (HR = 0.8; 95% CI: 0.5–1.2; p = 0.1428). OS was 10.2 months with pamipanib versus 12.0 months with placebo. A significant increase in toxicity was reported in the experimental arm with an incidence of grade 3 or higher AEs in 26.8% of patients receiving pamiparib compared to 9.2% in controls.²² In the phase II randomized PLATFORM trial, maintenance rucaparib was compared to surveillance after 18 weeks of platinum-based chemotherapy. Among the 125 patients randomized, a numerically higher median PFS was reported with rucaparib (4.2 vs 2.8 months; HR = 0.70; 97.5% CI: 0.46–1.08; p = 0.063), which did not translate into improved OS.²³ The lack of efficacy of PARPi in the maintenance or second-line setting²⁴ may be related to the rapid resistance to platinum agents and lack of selection potentially based on homologous recombination deficiency (HRD). A genomic HRD signature (HRDSig) has been described in approximately 10% of gastric cancers.²⁵ Importantly, HRDSig-positive tumors displayed enhanced sensitivity to PARPi and oxaliplatin even in the context of wild-type genes involved in the homologous recombination pathway such as BRCA, ATM, CDK12, or PALB2.²⁶ Therefore, prospective data are needed to assess the efficacy of PARPi in patients enriched for HR repair-related alterations.

Anti-vascular monoclonal antibodies or tyrosine kinase inhibitors (TKIs) were used within switch maintenance contexts. The phase II a-MANTRA study assessed the efficacy of regorafenib, an oral multi-targeted TKI, as maintenance therapy in patients with advanced GC after a first line of platinum and fluoropyrimidine-based therapy compared to placebo. The study was prematurely closed due to the introduction of immunotherapy in the first-line setting, and the trial did not meet the primary endpoint of PFS (5.19 vs 3.91 months; HR = 0.736; 80% CI: 0.51–1.04; p = 0.1318).²⁷ Ramucirumab plus capecitabine was assessed as a switch maintenance versus observation in patients completing 18-week induction with platinum-based chemotherapy within the PLATFORM trial. Herein, median PFS was increased in the experimental arm (5.5 vs 2.5 months; HR = 0.33; 95% CI: 0.17–0.63; p < 0.001) with a manageable safety profile.²⁸

The ARMANI phase III trial demonstrated the superiority of this non-cross-resistant regimen used in the switch maintenance setting. The trial investigated paclitaxel plus ramucirumab, as a switch maintenance versus continuation of chemotherapy in 280 patients with disease control after an induction phase of 3-month oxaliplatin and fluoropyrimidine in patients with advanced HER2-negative GC. The primary endpoint of PFS was met since median PFS were 6.6 versus 3.5 months in the experimental and control arm, respectively (HR = 0.61; 95% CI: 0.48–0.79; p = 0.0002). The PFS gain translated into improved OS and PFS-2, the latter being defined as the time from random assignment to evidence of tumor progression on the next-line treatment regimen or death, suggesting that the initial benefit of this upfront strategy was retained throughout the subsequent therapeutic lines. Importantly, a similar proportion of patients in the two arms received any additional second-line therapy (58% vs 56%), and only 45% of patients in the control arm were fit enough to receive paclitaxel plus ramucirumab as subsequent regimen. The paclitaxel plus ramucirumab regimen was associated with an increase in grade 3 or higher AEs, mostly neutropenia and ramucirumab-specific toxicities. However, a similar rate of grade 3 or higher peripheral neuropathy was reported.²⁹

Conclusions and future perspectives on maintenance strategies

Overall, these data show that continuation maintenance with fluoropyrimidines is generally not effective because most patients rapidly develop chemotherapy resistance with modest life expectancy (Table 1).

Some of the presented studies reported OS exciding the historical benchmark typically observed in unselected patients with metastatic gastric cancer. This discrepancy can be largely attributed to trial design as many of these studies randomized patients only after achieving disease control following first-line induction chemotherapy and thus intrinsically selecting a population with better prognosis compared to the broader metastatic population. Moreover, most trials were conducted in molecularly unselected cohorts, and biomarker data were either unavailable or inconsistently reported, further complicating comparisons between studies.

The ARMANI trial demonstrated a clear survival benefit of a switch maintenance or early second-line strategy and may represent a therapeutic option in patients with advanced HER2-negative GC who are non-eligible for upfront immunotherapy or ICIs (Figure 1). This benefit may be even higher in those patients with lack of RECIST response to oxaliplatin and fluoropyrimidine doublets, as documented in the trial subgroup analyses conducted in patients with measurable disease.²⁹ Moreover, molecular selection is crucial for switch maintenance with targeted agents or immunotherapy, as inadequate patient selection may account for the failure of many trials.²⁶ Nowadays, a substantial proportion of patients is eligible for chemotherapy in combination with PD-1, CLDN18.2, or FGFR2b inhibitors depending on ongoing study results and regulatory approvals, and the next generation of clinical trials may assess the optimal maintenance strategies in these biomarker-selected subgroups.

Figure 1.

Algorithm of first-line therapy options divided per induction treatment and maintenance treatment. Although chemotherapy de-escalation was not assessed in most of randomized clinical trials, interruption of platinum agent administration can be considered in everyday clinical practice.

Second- and later-line treatments

The morbidity associated with disease progression during first-line chemotherapy significantly impacts the patient’s ability to receive subsequent anticancer therapies. In modern trials, the proportion of patients eligible for second-line therapy is below 50% irrespective of what they received in the first-line setting (Table 2). Longer duration of upfront chemotherapy, no weight loss, younger age, HER2 positivity, and synchronous disease were significantly associated with higher chance of receiving second-line therapy in a large real-world dataset.³⁰ In fact, patients who experience early failure of first-line chemotherapy (i.e., <6 months) have a significantly poorer median OS with second-line therapy compared to those who had a more effective first line treatment (>9 months; 4.0 vs 7.1 months).³¹ Importantly, the survival benefit of second line therapy is supported by several randomized clinical trials with either single agents or combination regimens compared to best supportive care and retrospective datasets.³⁰

Table 2.

Proportion of patients receiving subsequent therapies in modern first-line clinical trials.

Trial	Regimen	Experimental armn (%)	Control armn (%)
^aKEYNOTE-062³⁹	Cisplatin and fluoropyrimidine ± pembrolizumab	118/250 (47%)	132/244 (54%)
^bCheckMate 649¹	Oxaliplatin and fluoropyrimidine ± nivolumab	297/789 (38%)	326/792 (41%)
FIGHT⁵	FOLFOX ± bemarituzumab	33/63 (52%)	34/70 (49%)
SPOTLIGHT³	FOLFOX ± zolbetuximab	135/283 (48%)	148/282 (53%)
GLOW²	CAPOX ± zolbetuximab	118/254 (46%)	140/253 (55%)
KEYNOTE 859⁴	Cisplatin/oxaliplatin and fluoropyrimidine ± pembrolizumab	335/790 (45%)	369/789 (47%)
ORIENT-16¹³³	CAPOX ± sintilimab	109/327 (33%)	150/323 (46%)
RATIONALE-305¹³⁴	Cisplatin and fluoropyrimidine/CAPOX ± tislelizumab	265/501 (53%)	294/496 (59%)
ARMANI²⁹	Paclitaxel + ramucirumab vs FOLFOX/CAPOX	83/144 (58%)	76/136 (56%)
GEMSTONE-303¹³⁵	CAPOX ± sugemalimab	129/241 (54%)	145/238 (61%)
PRODIGE 51-FFCD-GASTFOX¹³⁶	TFOX vs FOLFOX	131/254 (52%)	140/253 (55%)

n defined as number of patients who received subsequent therapies/number of patients enrolled in each arm.

Data for pembrolizumab only arm (n = 254) are not reported.

Data for Nivolumab + ipilimumab arm (n = 409) are not reported.

CAPOX, capecitabine and oxaliplatin; FOLFOX, folinic acid, fluorouracil, and oxaliplatin; TFOX, docetaxel, folinic acid, fluorouracil, and oxaliplatin.

Current guidelines recommend the combination of ramucirumab with or without paclitaxel as second-line therapies irrespective of molecular selection moving from the results of the RAINBOW and REGARD trials.^32–35 The RAMIRIS phase II trial randomized patients to receive second-line FOLFIRI in combination with ramucirumab or paclitaxel plus ramucirumab. The trial failed to meet the primary endpoint of 6-month OS rate for FOLFIRI and ramucirumab. However, this combination is favorably compared to standard paclitaxel plus ramucirumab, and the magnitude of benefit was higher in patients who received docetaxel in the first line or perioperative setting.³⁶ Additional data are reported in Table 3.

Table 3.

Pivotal randomized trials evaluating subsequent lines of therapy.

Trial	Phase	Patients, n (random ratio)	Line	Regimen	Primary endpoint	Outcomes	Safety toxicities ⩾ G3−
TAGS³⁷	III, randomized	507 (2:1)	III+	FTD/TPI vs placebo	OS	OS (months): 5.7 vs 3.6, HR = 0.69, 95% CI 0.56–0.85 p = 0.00029	AEs: 80% vs 58% Neutropenia: 34% vs 19%
Docetaxel or Irinotecan³⁸	III, randomized	195 (2:1)	II/III	Chemotherapy (docetaxel or irinotecan) vs BSC	OS	OS (months): 5.3 vs 3.8, HR = 0.657, 95% CI 0.485–0.891, p = 0.007	Neutropenia: 15% (D) vs 18% (I) vs 2% (BSC)
RAINBOW³⁴	III, randomized	665 (1:1)	II	Paclitaxel ± ramucirumab/placebo	OS	OS (months): 9.6 vs 7.4, HR = 0.807, 95% CI 0.678–0.962, p = 0.017	Neutropenia: 41% vs 19% Febrile neutropenia: 3% vs 2% Hypertension: 14% vs 2%
RINDBeRG⁵⁷	III, randomized	402 (1:1)	III+	Ramucirumab + irinotecan vs irinotecan monotherapy	OS	OS (months): 9.4 vs 8.5, HR = 0.92, 95% CI 0.74–1.13 p = 0.49	Neutropenia: 46.7% vs 30.1% Hypertension: 5.1% vs 0.5%
RADPAC⁴²	III, randomized	300 (1:1)	II+	Paclitaxel ± everolimus/placebo	OS	OS (months): 6.1 vs 5.0, HR = 0.93, 95% CI 0.73–1.18, p = 0.544	AEs: 78.3% vs 69.4% Stomatitis: 13% vs 0.7%; Diarrhea: 7.7% vs 2.1%
GOLD²⁴	III, randomized	525 (1:1)	II	Paclitaxel ± olaparib/placebo	OS	OS (months): 8.8 vs 6.9, HR = 0.79, 95% CI 0.63–1.00, p = 0.026	Neutropenia: 30% vs 23%
ATTRACTION-2⁴⁰	III, randomized	493 (2:1)	III+	Nivolumab vs placebo	OS	OS (months): 5.26 vs 4.14, HR = 0.63, 95% CI 0.51–0.78, p < 0.001	AEs: 10% vs 4% Diarrhea: 1% vs 0%
JAVELIN GASTRIC 300⁴¹	III, randomized	371 (1:1)	III+	Avelumab vs physician’s choice of chemotherapy	OS	OS (months): 4.6 vs 5.0, HR = 1.1, 95% CI 0.9–1.4, p = 0.81	AEs^a: 9.3% vs 31.6% Diarrhea: 0.5% vs 3.4% Neutropenia: 0% vs 4.0%
KEYNOTE-061¹³⁷	III, randomized	395 (1:1)	II	Pembrolizumab vs paclitaxel	OS and PFS (CPS ⩾ 1 population)	OS (months): 9.1 vs 8.3, HR = 0.81, 95% CI 0.66–1.00 PFS (months): 1.5 vs 4.1, HR = 1.25, 95% CI 1.02–1.54	AE^a: 15.0 vs 35.1% Neutrophil count decreased: 0% vs 10.1% Anemia: 2.4% vs 4.7%
REGARD³³	III, randomized	355 (2:1)	II	Ramucirumab vs placebo	OS	OS (months): 5.2 vs 3.8, HR = 0.776, 95% CI 0.603–0.998, p = 0.047	AEs: 57% vs 58% Hypertension: 8% vs 3%
ANGEL⁴³	III, randomized	460 (2:1)	III+	Rivoceranib vs placebo	OS	OS (months): 5.78 vs 5.13 HR = 0.93, 95% CI 0.74–1.15 p = 0.4724	AEs: 76.2% vs 56.3% Hypertension: 17.9% vs 0% Proteinuria: 7.5% vs 0%
INTEGRATE I⁴⁹	II, randomized	152 (2:1)	III+	Regorafenib vs placebo	PFS	PFS (months): vs 0.9, HR = 0.40, 95% CI 0.28–0.59 p < 0.001	AE: 67% vs 52% Hypertension: 10% vs 2% Skin disorders: 6% vs 0%
INTEGRATE IIa⁵⁰	III, randomized	251 (2:1)	III+	Regorafenib vs placebo	OS	OS (months): 4.5 vs 4.0, HR = 0.68, 95% CI 0.52–0.90, p = 0.006	Palmar-plantar erythrodysesthesia: 9% vs 0% Hypertension: 8% vs 0%
COG⁹⁸	III, randomized	459 (1:1)	II	Gefitinib vs placebo	OS	OS (months): 3.73 vs 3.67, HR = 0.90, 95% CI 0.74–1.09, p = 0.293	Diarrhea: 6% vs 1%
CT041-ST-01	II, randomized	156 (2:1)	III+	Claudin-18 isoform 2-specific CAR-T-cell therapy (satri-cel)	PFS	PFS (months): 3.25 vs 1.77, HR = 0.37 95% CI 0.24–0.56, p < 0·0001	AEs: 99% vs 63% Neutrophil count decreased: 66% vs 27% Cytokine release syndrome: 5% vs 0%

Refers to TRAEs.

AE, adverse events; BSC, best supportive care; CI, confidence interval; CPS, combined positive score; FTD, trifluridine; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; TPI, tipiracil; TRAEs, treatment-related AEs.

Importantly, the magnitude of benefit of systemic treatment in patients with heavily pretreated GEJ cancer is quite modest in later lines of therapy. However, even in third or later lines, the advantage of administering single-agent or combination chemotherapy is clear when compared to BSC alone (Table 3). Currently, the standard of care in later line mainly includes single-agent chemotherapy. Trifluridine/tipiracil (FTD/TPI), an oral fluoropyrimidine that combines thymidine-based nucleoside analog combined to a thymidine phosphorylase inhibitor, is administrated from the randomized TAGS trial in patients who had received at least two prior regimens.³⁷ Additional options include irinotecan or docetaxel.³⁸ Before immunotherapy entered the clinical practice as first-line treatment in combination with chemotherapy for PD-L1 positive patients, ICIs were investigated in heavily pretreated patients, demonstrating promising benefit in this population.^39–41 Moreover, several trials tested other compound in advanced lines, including a combination of paclitaxel and everolimus, a kinase inhibitor of the mammalian target of rapamycin serine/threonine kinase signal transduction pathway, or mono-agent rivoceranib, a vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor. However, none of these agents demonstrated an advantage in terms of survival and thus are not considered a standard of care.^42,43

VEGF/VEGFR axis targeting

VEGF plays a pivotal role in the progression of GC by promoting tumor angiogenesis, a process essential for supplying oxygen and nutrients to the rapidly expanding tumor mass. Effective VEGF/VEGFR blockade may represent an option in patients who are non-eligible for specific biomarker-driven treatments. In fact, while the integration of antiangiogenetic drugs ramucirumab and bevacizumab with first-line platinum and fluoropyrimidine chemotherapy did not lead to superior outcomes over chemotherapy in several trials, the use of these agents may be important in the subsequent lines of treatment.^44–48

In second or later treatment lines, different antiangiogenic agents beyond ramucirumab have been evaluated, either as single-agent or in combination with chemotherapy or immune checkpoint inhibition. The INTEGRATE I phase II trial demonstrated a PFS gain with regorafenib compared to placebo (median PFS 2.6 vs 0.9 months; HR = 0.40; 95% CI: 0.28–0.59; p < 0.001).⁴⁹ In a pooled analysis of the phase III randomized INTEGRATE IIa and INTEGRATE regorafenib showed a statistically significant but numerically modest increase in median OS (HR = 0.70; 95% CI: 0.56–0.87; p = 0.001).⁵⁰ The ANGEL phase III trial did not meet its primary endpoint, failing to demonstrate a survival advantage for rivoceranib, a VEGFR-2 inhibitor versus placebo.⁴³

Several trials evaluated potential strategies for implementing the use of antiangiogenic drugs beyond the first line. These studies included early introduction of ramucirumab as switch maintenance as mentioned before in the ARMANI or PLATFORM trials. Additional strategies evaluated the combination of antiangiogenics with ICIs or a sequential VEGF/VEGFR axis blockade approach.

Several trials assessed the combination of antiangiogenic drugs and ICIs since a potential synergy of dual VEGFR and PD-(L)-1 blockade relies on the immunomodulatory effect of VEGF/VEGFR-targeting agents within the tumor microenvironment.⁵¹ Regorafenib was combined with nivolumab in the phase Ib REGONIVO trial. Twenty-five patients with metastatic GC who had previously received at least two lines of therapy were evaluated in the trial. Although the primary endpoint of the study was to determine the maximum tolerated dose of regorafenib when combined to nivolumab, promising results in terms of ORR (44%), PFS (5.6 months), and OS (12.3 months) were reported as well.⁵² Moving from these results the phase III INTEGRATE IIb is ongoing to evaluate the combination compared to investigators’ choice of chemotherapy.⁵³

In the AIO-STO-0218 trial, treatment paclitaxel in combination with ramucirumab and avelumab in the second-line setting after oxaliplatin and fluoropyrimidine therapy resulted in 6-month OS rate of 71.2%.⁵⁴ Similarly, in the phase I/II UMIN-CTR trial with second-line paclitaxel, ramucirumab and nivolumab demonstrated a median OS of 13.1 months.⁵⁵ As expected, in both trials, numerically higher survival was observed in patients with higher PD-L1 expression. Similarly, higher ORR was reported for regorafenib and nivolumab in patients with PD-L1 CPS ⩾1 compared to those with PD-L1-negative tumors (60% vs 25%).

Sequential VEGF/VEGR axis inhibition

Preclinical models and these exploratory analyses support the hypothesis that sequential VEGF/VEGFR inhibition may overcome adaptive resistance mechanisms, such as VEGF-independent angiogenesis and hypoxia-driven pathways. Combining agents with distinct pharmacokinetic profiles or mechanisms of action may sustain anti-angiogenic pressure and improve survival. Despite a promising background, the clinical relevance of this approach has been largely disappointing so far. The phase II RE-ExPEL study evaluated ramucirumab beyond progression in combination with FTD/TPI yielding promising results, with a median OS of 9.07 months.^37,56 However, the large Japanese RINDBeRG trial randomized 402 patients pre-treated with ramucirumab to receive irinotecan with or without ramucirumab. The OS data of this study did not show a survival benefit with the addition of ramucirumab even if a modest increase in PFS was reported.⁵⁷ The results of this trial challenge the use of ramucirumab beyond progression in patients with gastric cancer, at least in the Western population and different antiangiogenic drugs may be used in this context. In fact, the subgroup analyses of ANGEL and INTEGRATE trials showed that the efficacy of treatment with either rivoceranib or regorafenib was retained irrespective of prior ramucirumab.

Biomarkers for VEGF/VEGFR axis blockade

To date, no validated predictive biomarkers of response have been identified. Several studies, conducted in patients receiving second-line treatment with ramucirumab and paclitaxel, have suggested a correlation between high baseline VEGF-A levels and reduced OS. Conversely, elevated VEGFR-2 levels 1 week after treatment initiation were associated with prolonged PFS and OS, positioning VEGFR-2 as a potential predictive biomarker, though unvalidated.^58,59 However, exploratory analyses from the RAINBOW and INTEGRATE trials failed to identify predictive biomarkers for ramucirumab or regorafenib, and thus the identification of predictive biomarkers for antiangiogenic drugs remains elusive.⁵³

In conclusion, a sequential VEGF/VEGFR blockade does not represent a standard strategy in today’s management of advanced GC. However, even after progression on prior anti-angiogenic agents such as ramucirumab, continued inhibition of angiogenic pathways by innovative drugs can still confer a clinically meaningful survival benefit.

Specific strategies in HER2-positive disease

Overexpression of HER2 is observed in 7%–20% gastric cancers worldwide.⁶⁰ The combination of doublet chemotherapy, trastuzumab and pembrolizumab, represents a guideline-recommended option in patients with HER2-positive and PD-L1 CPS ⩾1 based on the results of the KEYNOTE-811 trial.⁶¹

An anti-HER2-based strategy beyond the first line with trastuzumab deruxtecan (T-DXd) is currently recommended.³² In fact, longitudinal HER2 blockade is a relevant strategy for HER2-addicted tumors. However, its clinical application has been challenging since several anti-HER2 agents have failed to show a survival benefit compared to standard second-line treatments after disease progression following first-line trastuzumab therapy. In fact, the use of trastuzumab across different lines of treatment appears to be challenging due to the temporal heterogeneity of HER2 under the therapeutic pressure of anti-HER2 agents. Retrospective data showed that the chance of HER2 down-scoring as acquired resistance driver to trastuzumab (i.e., loss of HER2 amplification or 2/3+ on IHC) occurs in up to 30% of patients and is particularly relevant in initially HER2 2+ tumors.⁶² Similarly, a drop in HER2 somatic copy-number alterations after trastuzumab was detected by circulating tumor DNA (ctDNA) analysis.⁶³ Therefore, HER2 temporal heterogeneity under the therapeutic blockade is likely to impact on the efficacy continuous HER2 blockade. These findings have been recapitulated in several second-line trials with disappointing results. The phase II T-ACT study investigated paclitaxel with or without trastuzumab in 91 trastuzumab-refractory patients. The study found no significant differences in either PFS or OS (median PFS 3.68 vs 3.19 months; HR = 0.91; 80% CI: 0.67–1.22; p = 0.33; median OS 10.2 vs 9.95 months; HR = 1.2; 95% CI: 0.75–2.0; p = 0.20). However, in the small subset of evaluable patients, only 31% retained HER2 positivity (either IHC 3+ or 2+/FISH positive) after progression to first-line trastuzumab and before randomization.⁶⁴ Trastuzumab beyond progression in combination with paclitaxel plus ramucirumab was evaluated in the phase Ib/II Korean HER-RAM trial. ORR was 54% and median PFS 7.1 months.⁶⁵ Here, loss of HER2 expression after first-line trastuzumab was reported in 34.8% of evaluable patients. No significant association between HER2 dynamics and clinical outcomes was observed; however, these data may have been influenced by the limited number of patients and the confounding effect of concurrent paclitaxel plus ramucirumab administration. The ASPEN-06 trial evaluated the combination of paclitaxel, ramucirumab, and trastuzumab beyond progression with or without evorpacept, an anti-CD47 myeloid checkpoint inhibitor in the second or third line of treatment. The combination regimen yielded higher ORR (40.3% vs 26.6%; p = 0.095) and duration of response (15.7 vs 7.6 months). The magnitude of benefit for evorpacept was higher in the subset of patients with HER2 positivity retained after first-line trastuzumab (54.8% vs 23.1%).⁶⁶ Collectively, these data highlight the importance of longitudinal HER2 assessment to guide any sequential HER2 blockade. Moreover, the introduction of novel agents beyond trastuzumab allows an effective HER2 blockade across different treatment lines.

Specifically, ADCs represent a promising strategy in the continuum of care of HER2-positive tumors. Trastuzumab emtansine (T-DM1), trastuzumab conjugated with the microtubule inhibitor emtansine as payload, failed to improve OS and PFS in the GATSBY trial in previously treated HER2-positive advanced GC (median OS 7.9 vs 8.6 months; HR = 1.15; 95% CI: 0.87–1.51; p = 0.86) compared to paclitaxel or docetaxel. In this trial, up to 80% of patients received prior trastuzumab. Even if no clinical subgroup showed an overall treatment benefit with T-DM1, the worst outcomes were observed in patients with initially HER2 2+/ISH positive tumors receiving T-DM1.⁶⁷

T-DXd, an ADC that combines trastuzumab with a novel topoisomerase I inhibitor, overcomes the limitations of T-DM1 due to its pharmacological properties. Specifically, T-DXd has a stable and homogeneous drug-to-antibody ratio, a novel potent payload and by-stander demonstrated effect.⁶⁸ Due to its specific properties, T-DXd may demonstrate activity also in HER2 heterogeneous tumors. Moreover, preclinical data showed that T-DXd may bypass genomic driver of primary resistance to either anti-HER2 monoclonal antibodies and TKIs, such as downstream MAPK alterations (e.g., KRAS amplification).⁶⁹ The clinical development of T-DXd recapitulated these preclinical findings. The results from the DESTINY-Gastric01 trial and DESTINY-Gastric02 led to global approval for T-DXd after failure of prior trastuzumab treatment. In the phase II DESTINY-Gastric01 study, conducted in an Asian population, 187 patients with advanced GC who had been previously treated with at least two lines of therapy including trastuzumab were randomized 2:1 to receive T-DXd or the physician’s choice chemotherapy. The primary endpoint was ORR, while the key secondary endpoint was OS. Notably, the experimental treatment demonstrated a significantly higher ORR compared to chemotherapy (42.9% vs 12.5%, p < 0.01). This benefit was also reflected in median OS (12.5 vs 8.4 months, p = 0.0097). The notable AEs associated with T-DXd included myelosuppression and interstitial lung disease, which were managed through dose reduction or treatment interruption.⁷⁰ Translational analysis of this trial showed that an enrichment of tumor responses was seen in patients with IHC 3+ versus 2+ tumors (58.2% vs 28.6%). Importantly, HER2 status was mostly assessed in trastuzumab-naïve samples and may have changed under the selective pressure of previous HER2 blockade. ctDNA, on the other hand, can provide real-time information on HER2 status. In fact, higher HER2 mRNA gene expression, presence of plasma HER2 amplification, and high plasma HER2 copy number were associated with increased tumor response after T-DXd in this patient population. Tumor responses were observed regardless of the presence of MET or EGFR co-amplification (though to a lesser extent), or RAS co-mutations, which are drivers of primary resistance to trastuzumab.⁷¹ These results were further supported by the single-arm phase II DESTINY-Gastric02 study conducted in a Western population. This study enrolled patients treated with trastuzumab in the first line and assessed for HER2 status after progression. The observed ORR was 33%, with a median OS of 12.1 months. In this trial, ORR was higher in IHC 3+ versus 2+ tumors (47.1% vs 10.0%).⁷² The DESTINY-Gastric04 trial compared T-DXd to standard paclitaxel plus ramucirumab in patients with retained HER2 positivity after progression to a trastuzumab-containing first line regimen. T-DXd significantly improved OS over paclitaxel plus ramucirumab (median OS 14.7 vs 11.4 months; HR = 0.70; 95% CI: 0.55–0.90; p = 0.004). The treatment effect was consistent across all the key clinical and molecular subgroups including patients with HER2 2+/ISH+ tumors.⁷³ These latter patients represented a limited proportion of the trial population.

These data support the use of T-DXd as a preferred second-line regimen in patients with retained HER2 positivity after trastuzumab exposure to allow an effective longitudinal HER2 blockade across treatment lines. Additional trials, such as DESTINY-Gastric03, will properly assess the role of T-DXd in the first line and allow the design of innovative sequencing trials.⁷⁴ In fact, even if T-DXd or novel ADCs represent the individual agent with the higher activity as monotherapy in patients with HER2-positive advanced gastric cancer and may bypass several genomic drivers of resistance to trastuzumab, a lower degree of HER2 expression (e.g., IHC 2+) may impair its activity. Importantly, patients with HER2 2+ have been underrepresented in clinical trials, and more data are required to draw definitive conclusions in this subgroup.

Additional HER2 ADC are under development. There were some promising results with Disitamab vedotin (RC48) in combination with toripalimab, a PD-1 inhibitor in a recent phase I trial. The trial enrolled patients with advanced GC with HER2 IHC ⩾1 or ISH positive. Overall, ORR was 43% with a median PFS of 6.2 months. Activity was observed regardless of HER2 IHC score or prior anti-HER2s.⁷⁵ Additional promising results were observed in the phase I trial of ARX788, anti-HER2 ADC with AS269 as cytotoxic payload, which showed an ORR of 37.9% in patients who received trastuzumab. The confirmed ORR was 41.2% (7/17) in the HER2-positive patients who were centrally confirmed.⁷⁶

Additional data will address optimal sequencing of anti-HER2 monoclonal antibodies versus ADCs and degree of HER2 expression to enrich for activity of selected agents.

Future perspectives

EGFR inhibition

Targeting the EGFR pathway represents a promising strategy in patients with GC e GEJ cancer harboring EGFR amplification. The first trials involving anti-EGFR drugs in a biomarker unselected patient population were mostly disappointing. Several phase II trial evaluated the activity of anti-EGFR-based combinations in patients with metastatic gastroesophageal tumors, including cetuximab, panitumumab, nimotuzumab, erlotinib, gefitinib, matuzumab, and icotinib.^77–94 Moving from this background, randomized phase III studies were conducted in the first-line setting of metastatic disease. The EXPAND trial assessed the efficacy of the addition of cetuximab to first-line chemotherapy,⁹⁵ while the REAL3 trial evaluated the combination of chemotherapy and panitumumab in patients with previously untreated GC/GEJ cancer.⁹⁶ In the EXPAND trial, the median PFS was 4.4 months in patients treated with chemotherapy and cetuximab and 5.6 months in patients treated with chemotherapy (HR = 1.09; 95% CI: 0.92–1.29; p = 0.32), with no apparent benefit from the addition of cetuximab. In the EXPAND trial cohort, the EGFR expression was generally low; however, a survival benefit was shown in patients with high EGFR expression by IHC. In the REAL3 trial, the median OS in patients treated with chemotherapy was 11.3 versus 8.8 months in patients treated with chemotherapy and panitumumab (HR = 1.37; 95% CI: 1.07–1.76; p = 0.013).⁹⁷ The phase III COG trial assessed the efficacy of gefitinib in the second line of treatment of unselected patients with esophageal or GEJ cancers.⁹⁸ The addition of gefitinib demonstrated only a modest benefit in PFS in the trial population, which was mostly restricted to patients with EGFR-amplified tumors (HR for PFS/OS 0.29/0.21).⁹⁹ OS did not differ between the gefitinib and placebo groups, with a median OS of 3.73 and 3.67 months, respectively (HR = 0.90; 95% CI: 0.6–1.18; p = 0.29). Collectively, these trials suggest that EGFR amplification represents the strongest biomarker for EGFR addiction and therapeutic vulnerability to EGFR blockade in advanced GC. In this context, Maron reported on the activity of anti-EGFRs in patients with EGFR amplification. Maron and colleagues identified EGFR amplification in 5% of a selected population of patients with gastroesophageal cancers and treated 7 of them with anti-EGFR-based combinations, either first-line FOLFOX combined with ABT-806 (anti-EGFR monoclonal antibody), second-line FOLFIRI plus cetuximab, or third or later line cetuximab monotherapy.^100,101 In this biomarker-selected population, ORR was 58% with a median PFS of 10 months. As anticipated, primary resistance to anti-EGFRs was related to co-occurrence of several genomic alterations that bypass the therapeutic blockade of EGFR, including co-amplification of KRAS or HER2/MET.¹⁰² In a subsequent study, a cohort of 60 patients with advanced gastroesophageal cancer carrying EGFR amplification was treated with on- or off-protocol EGFR inhibitors, of which 31 (52%) with concurrent chemotherapy. The study showed an ORR of 43% with a median PFS of 4.6 months.¹⁰³ In conclusion, EGFR amplification should be regarded as one of the most promising targets in the context of metastatic gastric cancer. Other than the aforementioned co-amplification of KRAS, HER2/MET, or other oncogenes involved in the EGFR pathway, other plausible resistance mechanisms include the characteristic spatial and temporal EGFR heterogeneous expression. Novel drugs could tackle some of these issues and increase the efficacy of EGFR inhibition in this subset of patients such as amivantamab, a dual targeting bispecific antibody which simultaneously inhibits EGFR and MET, or ADCs which are also active in heterogeneous tumor tissues to their bystander effects. Moreover, a refined definition of predictive biomarkers will be necessary to select the patients, which are more likely to benefit from this strategy.¹⁰⁴

Novel ADCs

The encouraging results of the first trials on ADCs have led to increased efforts by clinical researchers to bring these new drugs into the first and subsequent lines of therapy. Several ADCs are in clinical development in patients with advanced gastric cancer.

Trophoblast surface antigen 2 (TROP-2) is overexpressed in about 66% of gastric cancers.¹⁰⁵ Sacituzumab govitecan is a conjugate of an antibody active against TROP-2 coupled with SN-38, the active metabolite of irinotecan, which is mainly indicated in the second-line treatment of metastatic triple-negative breast cancer. A phase I/II basket clinical trial evaluated sacituzumab govitecan in various epithelial cancers, including esophageal and GC, demonstrating manageable toxicity.¹⁰⁶ Overall, 495 patients were included in the trial, including 19 patients (3.8%) with esophageal cancer and 5 (1%) patients with gastric adenocarcinoma.¹⁰⁷ A recent phase Ib/II trial specifically tailored for patients with advanced gastroesophageal cancer is currently ongoing and will provide new evidence regarding this specific field of treatment.¹⁰⁸ MK-2870 is another TROP-2 ADC linked to a belotecan-derivative topoisomerase 1 inhibitor, which demonstrated durable responses in monotherapy heavily pretreated GC/GEJ cancers in a phase II trial.¹⁰⁹ Among 41 response-evaluable patients treated with MK-2870, the ORR was 22% and Disease Control Rate (DCR) was 80.5% at 9 weeks of follow-up, with a median Duration of Response (DoR) of 7.5 months and a manageable safety profile. A phase III trial is currently comparing MK-2870 versus treatment of physician’s choice after ⩾2 prior lines of systemic therapy.¹¹⁰ Closely recalling the history of T-DXd, the assessment of the degree of TROP-2 expression will be crucial to determining the activity of TROP-2 ADCs.

CLDN18.2 overexpression is observed in up to 25% of patients with gastroesophageal cancers making it an attractive target for both monoclonal antibodies (e.g., zolbetuximab) and ADCs.¹¹¹ The phase I SHR-A1904 trial evaluated DS-9606a, a novel anti-CLDN18.2 ADC linked with a topoisomerase I inhibitor payload, in patients with metastatic solid tumors demonstrating a favorable safety profile, with no dose-limiting toxicity, dose-dependent increase in AEs, or treatment discontinuations. Preliminary analyses confirmed activity in germ-cell tumors and gastric cancer.¹¹² Another phase I/II trial assessed the safety and efficacy of RC118, an anti-CLDN18.2 ADC carrying microtubule-disrupting agent monomethyl auristatin E (MMAE). AEs were observed in all 18 enrolled patients, with 38.9% experiencing grade 3 or higher AEs, mostly nausea, vomiting, and decreased appetite. No treatment-related mortality was reported. Among the 17 patients evaluable for efficacy per RECIST v1.1, the ORR was 47.1% and the DCR was 76.5%. The median PFS was 3.9 months with a median follow-up duration of 4.4 months.¹¹³ The phase I KYM901 trial assessed the activity and safety of CMG901, a different ADC composed by an anti-CLDN18.2 monoclonal antibody linked to MMAE in patients with advanced GC/GEJ cancer and other solid tumors.¹¹⁴ Twenty-seven patients were enrolled in the dose-escalation phase and 107 patients with CLDN18.2 IHC ⩾2+ expression in ⩾5% of tumor cells in the dose-expansion phase. The safety profile was acceptable: G3 or higher AEs were most commonly related to myelosuppression and vomiting. Overall, ORR was 29% which rose slightly to 33% in patients with CLDN18.2 high tumors defined as at least IHC 2+ in at least 20% of tumor cells, which is much lower than the cutoff used for zolbetuximab efficacy. IBI343 is an anti-CLDN18.2 ADC with a payload consisting of the topoisomerase inhibitor exatecan. IBI343 induced tumor responses in patients with CLDN18.2 high tumors (defined by IHC at least 2+ in at least 40% of tumor cells; ORR 37.5%). Higher responses were observed in patients with higher amounts of CLDN18.2.¹¹⁵

These data emphasize the importance of ADCs with the bystander effect, as it is a key determinant of their efficacy. This effect allows for the distribution of antineoplastic activity even in the presence of heterogeneous expression of a given tumor target. Recalling the history of HER2 longitudinal blockade, future trials will evaluate the optimal therapeutic sequencing of monoclonal antibody-based therapies and ADCs in patients with CLDN18.2-positive tumors, while also uncovering the distinct mechanisms of both primary and acquired resistance that may influence sequencing decisions.

HER3 is overexpressed in ~50% of gastric cancers.¹¹⁶ U3-1402 is an anti-HER3 ADC, which already demonstrated promising activity in other types of tumors, and various other ADCs such as AMT-562, MCLA-128, MM-121, CDX/KTN3379, and GSK-2849330 are currently assessing the activity of this novel treatment in gastric and non-gastric cancer.

Mucin1 (MUC1) is overexpressed in several epithelial cells, including the stomach mucosa. Many studies demonstrated significant in vitro activity of anti-MUC1 ADCs against gastric cancer cells. A few in vivo clinical trials assessed the activity and safety of anti-MUC1 ADCs, specifically targeted against the cancer antigen (CanAg) isoform of MUC1.¹¹⁷ A phase II trial enrolled six patients with CanAg-positive gastric or GEJ cancer and treated them with huC242-DM4, an anti-MUC1 ADC, demonstrating a partial response in one patient and drug-related ocular toxicities in three patients, and therefore the program was later discontinued.¹¹⁸

B7-H3 is an emerging biomarker in gastric adenocarcinoma, and its expression is significantly correlated with HER2 over-expression.^119,120 Various trials are currently evaluating anti-B7-H3 ADCs in other settings with promising results, and presumably, in the near future, patients with gastric cancer may also be involved in trials.

Nectin-4 is frequently overexpressed in gastric cancer. Various ongoing trials are assessing the activity and safety of anti-Nectin-4 ADCs in advanced solid tumors.¹²¹ A phase I ongoing study is assessing the safety and activity of ABBV-400, an ADC consisting of the c-Met-targeting telisotuzumab conjugated to a novel topoisomerase I inhibitor payload, in advanced gastric/GEJ cancer that progressed after ⩽2 prior chemotherapy lines. The preliminary efficacy results demonstrated a tolerable safety profile and antitumor activity.¹²²

CAR-T cell therapy

CARs are synthetic receptors specifically engineered to provide T cells the ability to recognize specific target antigens expressed on tumor cells. CAR-T cell therapy is characterized by high on-target specificity and, on the other hand, by significant adverse effects, which often lead to the discontinuation of treatment.^123,124 The use of CAR-T cells still lacks evidence in the setting of solid tumors. To date, only two studies involving CAR-T cell therapy in solid tumors have described a range of activity comparable to that observed in hematologic tumors trials.^125–127 One of these two studies evaluated CLDN18.2-specific CAR-T cells in patients with GC. After the publication of promising results in preclinical studies, CLDN18.2-redirected CAR-T cells were tested in a phase I, single-arm trial by Qi et al.^127,128 in 98 patients with pre-treated advanced CLDN18.2-positive GI cancers, of which 73 (74.5%) with gastric cancer. The final results of the study showed that among 98 patients treated with satricabtagene autoleucel (satri-cel) the ORR was 38.8% and the DCR was 91.8%, with a median PFS and OS of 4.4 and 8.8 months, respectively. Among the 98 patients treated with CLDN18.2-redirected CAR-T cells, 1 had a complete response, specifically in the monotherapy cohort. No dose-limiting toxicities or treatment-related deaths were reported, thus combining an acceptable safety profile with a significant degree of activity. Satri-cel was also tested in the phase Ib ELIMYN18.2 study in heavily pretreated patients with CLDN18.2-positive metastatic GC/GEJ or pancreatic cancer.¹²⁹ Nineteen patients received satri-cel at three dose levels, of which seven with gastric/GEJ cancer. All 19 patients experienced at least 1 AE, while no dose-limiting toxicities occurred, and 17 patients experienced cytokine release syndrome. Among the gastric cancer subgroup, the ORR was 42.9% (3/7), the median DoR was 6.9 months, and the clinical benefit rate was 57.1%. These promising data were supported by a single case of a target lesion complete response among the study population.¹³⁰ Satri-cel was evaluated in a randomized phase II trial in patients with CLDN18.2-positive tumors (defined as ⩾2+ in at least ⩾40% of tumor cells) refractory to at least two treatment lines, compared to investigator’s choice therapy. The study met its primary endpoint of PFS (median PFS 3.2 vs 1.7 months, HR = 0.37, 95% CI: 0.24–0.56, p < 0.0001). ORR was 35% with long-lasting tumor responses highlighting the ability of Satri-cel to unleashing durable antitumor immunity.¹³¹

Other than CLDN18.2, other targets for CAR-T cell therapy in gastric cancer include, and are not limited to, HER2, TROP2, MUC1, CEA, EpCAM, mesothelin, prostate stem cell antigen, NKG2D, folate receptor 1, and ICAM-1, as these antigens have either higher expression or a different structure in gastric cancer cells. Several phase I/II and preclinical trials are currently ongoing and will eventually pave the way for the deepening of the therapeutic arsenal available to oncologists.¹³²

Conclusion

At least three decades of clinical trials demonstrated that the efficacy of first-line regimen is crucial since the chance of receiving later-line therapies is low due to performance status worsening or death after disease progression. Moreover, there is now clear evidence that first-line (switch-) maintenance strategies improve patients’ outcomes. These findings should be considered within the framework of modern disease management, which is increasingly defined by the emergence of multiple therapeutic targets beyond HER2 amplification/overexpression, particularly MMR deficiency, high PD-L1 expression, CLDN18.2 positivity, and FGFR2b overexpression. The upfront use of targeted therapies matched to these biomarkers has led to significant survival benefits for these patients. Therefore, key challenges for innovative clinical trials include determining the optimal therapeutic strategies in the context of overlapping biomarkers and integrating novel treatments—such as ADCs, bispecific antibodies, and CAR-T therapies—to address the spatial and temporal heterogeneity of established biomarkers.

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Silvia Marchesi

Giovanni Randon

References

Janjigian

Shitara

Moehler

, 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(10294): 27–40.

Shah

Shitara

Ajani

, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med 2023; 29(8): 2133–2141.

Shitara

Lordick

Bang

, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet 2023; 401(10389): 1655–1668.

Rha

Yañez

, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2023; 24(11): 1181–1195.

Wainberg

Enzinger

Kang

, et al. Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet Oncol 2022; 23(11): 1430–1440.

Baethge

Goldbeck-Wood

Mertens

SANRA—a scale for the quality assessment of narrative review articles. Res Integr Peer Rev 2019; 4(1): 5.

Sonbol

Mountjoy

Firwana

, et al. The role of maintenance strategies in metastatic colorectal cancer. JAMA Oncol 2020; 6(3): e194489.

Stinchcombe

Socinski

MA.

Maintenance therapy in advanced non-small cell lung cancer: current status and future implications. J Thorac Oncol 2011; 6(1): 174–182.

Rossi

Schinzari

Basso

, et al. Maintenance hormonal and chemotherapy treatment in metastatic breast cancer: a systematic review. Future Oncol 2016; 12(10): 1299–1307.

10.

Morano

Pietrantonio

Anti-epidermal growth factor receptor maintenance therapy in metastatic colorectal cancer—another piece to the puzzle. JAMA Netw Open 2023; 6(9): e2333488.

11.

Roviello

Rodriquenz

Aprile

, et al. Maintenance in gastric cancer: new life for an old issue? Crit Rev Oncol Hematol 2021; 160: 103307.

12.

Zhao

Wang

, et al. Maintenance treatment of Uracil and Tegafur (UFT) in responders following first-line fluorouracil-based chemotherapy in metastatic gastric cancer: a randomized phase II study. Oncotarget 2017; 8(23): 37826–37834.

13.

Bao

L-B

Sun

, et al. Efficacy and safety of capecitabine as maintenance therapy after capecitabine-based combination chemotherapy for patients with advanced esophagogastric junction adenocarcinoma. Eur Rev Med Pharmacol Sci 2015; 19(19): 3605–3612.

14.

Lee

Kim

Cho

, et al. A randomized phase III study of patients with advanced gastric adenocarcinoma without progression after six cycles of XELOX (capecitabine plus oxaliplatin) followed by capecitabine maintenance or clinical observation. J Gastric Cancer 2023; 23(2): 315–327.

15.

Park

Kim

M-J

Nam

B-H

, 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.

16.

Stocker

Lorenzen

Ettrich

, et al. S-1 maintenance therapy in Caucasian patients with metastatic esophagogastric adenocarcinoma—final results of the randomized AIO MATEO phase II trial. ESMO Open 2023; 8(3): 101572.

17.

Bramhall

Hallissey

Whiting

, et al. Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial. Br J Cancer 2002; 86(12): 1864–1870.

18.

Bang

Y-J

Cho

Kim

, 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(19): 5671–5678.

19.

Fong

Patel

Peckitt

, et al. Maintenance durvalumab after first-line chemotherapy in patients with HER2-negative advanced oesophago-gastric adenocarcinoma: results from the randomised PLATFORM study. ESMO Open 2024; 9(7): 103622.

20.

Moehler

Dvorkin

Boku

, 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(9): 966–977.

21.

Lorenzen

Thuss-Patience

Folprecht

, et al. 1203O FOLFOX plus nivolumab and ipilimumab versus FOLFOX induction followed by nivolumab and ipilimumab in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction: results from the randomized phase II Moonlight trial of the AIO. Ann Oncol 2022; 33: S1099.

22.

Ciardiello

Bang

Y-J

Cervantes

, et al. Efficacy and safety of maintenance therapy with pamiparib versus placebo for advanced gastric cancer responding to first-line platinum-based chemotherapy: phase 2 study results. Cancer Med 2023; 12(12): 13145–13154.

23.

Gordon

Fong

CYK

Davidson

, et al. 1515P Maintenance rucaparib after first-line platinum-based chemotherapy in advanced esophagogastric (OG) adenocarcinoma: interim results from the PLATFORM trial. Ann Oncol 2023; 34: S853–S854.

24.

Bang

Y-J

R-H

Chin

, 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(12): 1637–1651.

25.

Alexandrov

Nik-Zainal

Siu

, et al. A mutational signature in gastric cancer suggests therapeutic strategies. Nat Commun 2015; 6(1): 8683.

26.

Petrelli

Rizzolio

Pietrantonio

, et al. BRCA2 Germline mutations identify gastric cancers responsive to PARP inhibitors. Cancer Res 2023; 83(10): 1699–1710.

27.

Damato

Bilancia

Iachetta

, et al. Phase II randomized study of maintenance therapy with regorafenib (REGO) versus placebo after first-line platinum and fluoropyrimidines-based chemotherapy in HER2 negative locally advanced/metastatic gastric (GC) or gastroesophageal junction (GEJ) cancer: results of a-MANTRA study (GOIRC-05-2016). J Clin Oncol 2024; 42(16_suppl): 4056.

28.

Gordon

Cunningham

Rajan

, et al. Maintenance capecitabine plus ramucirumab after first-line chemotherapy in patients with advanced esophagogastric adenocarcinoma: results from the randomized PLATFORM study. JCO Oncol Adv 2025; 2(1): e2400073.

29.

Randon

Lonardi

Fassan

, et al. Ramucirumab plus paclitaxel as switch maintenance versus continuation of first-line oxaliplatin-based chemotherapy in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer (ARMANI): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol 2024; 25(12): 1539–1550.

30.

Barzi

Hess

Zhu

, et al. Real-world outcomes and factors associated with the second-line treatment of patients with gastric, gastroesophageal junction, or esophageal adenocarcinoma. Cancer Control 2019; 26(1): 1073274819847642.

31.

Van Velzen

MJM

Pape

Dijksterhuis

WPM

, et al. The association between effectiveness of first-line treatment and second-line treatment in gastro-oesophageal cancer. Eur J Cancer 2021; 156: 60–69.

32.

Lordick

Carneiro

Cascinu

, et al. Gastric cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol 2022; 33(10): 1005–1020.

33.

Fuchs

Tomasek

Yong

, 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(9911): 31–39.

34.

Wilke

Muro

Van Cutsem

, 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(11): 1224–1235.

35.

Zhang

Pan

, et al. Efficacy and safety of weekly paclitaxel with or without ramucirumab as second-line therapy for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma (RAINBOW-Asia): a randomised, multicentre, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol 2021; 6(12): 1015–1024.

36.

Lorenzen

Thuss-Patience

Pauligk

, 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 German Gastric Cancer Study Group at AIO. Eur J Cancer 2022; 165: 48–57.

37.

Shitara

Doi

Dvorkin

, 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(11): 1437–1448.

38.

Kang

Lee

Lim

, et 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(13): 1513–1518.

39.

Shitara

Van Cutsem

Bang

, et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer. JAMA Oncol 2020; 6(10): 1571.

40.

Kang

Boku

Satoh

, 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(10111): 2461–2471.

41.

Bang

Ruiz

Van Cutsem

, et al. Phase III, randomised trial of avelumab versus physician’s choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol 2018; 29(10): 2052–2060.

42.

Lorenzen

Knorrenschild

Pauligk

, et al. Phase III randomized, double-blind study of paclitaxel with and without everolimus in patients with advanced gastric or esophagogastric junction carcinoma who have progressed after therapy with a fluoropyrimidine/platinum-containing regimen (RADPAC). Int J Cancer 2020; 147(9): 2493–2502.

43.

Kang

Y-K

Ryu

M-H

Di Bartolomeo

, et al. Rivoceranib, a VEGFR-2 inhibitor, monotherapy in previously treated patients with advanced or metastatic gastric or gastroesophageal junction cancer (ANGEL study): an international, randomized, placebo-controlled, phase 3 trial. Gastric Cancer 2024; 27(2): 375–386.

44.

Fuchs

Shitara

Di Bartolomeo

, 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(3): 420–435.

45.

Ohtsu

Shah

Van Cutsem

, 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(30): 3968–3976.

46.

Yoon

Bendell

Braiteh

, et al. Ramucirumab combined with FOLFOX as front-line therapy for advanced esophageal, gastroesophageal junction, or gastric adenocarcinoma: a randomized, double-blind, multicenter phase II trial. Ann Oncol 2016; 27(12): 2196–2203.

47.

Yoshikawa

Muro

Shitara

, et al. Effect of first-line S-1 plus oxaliplatin with or without ramucirumab followed by paclitaxel plus ramucirumab on advanced gastric cancer in East Asia. JAMA Netw Open 2019; 2(8): e198243.

48.

Meulendijks

de Groot

JWB

Los

, et al. Bevacizumab combined with docetaxel, oxaliplatin, and capecitabine, followed by maintenance with capecitabine and bevacizumab, as first-line treatment of patients with advanced HER2-negative gastric cancer: a multicenter phase 2 study. Cancer 2016; 122(9): 1434–1443.

49.

Pavlakis

Sjoquist

Martin

, et al. Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): a multinational placebo-controlled phase II trial. J Clin Oncol 2016; 34(23): 2728–2735.

50.

Pavlakis

Shitara

Sjoquist

, et al. INTEGRATE IIa phase III study: regorafenib for refractory advanced gastric cancer. J Clin Oncol 2025; 43(4): 453–463.

51.

Lee

Yang

Chon

, et al. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp Mol Med 2020; 52(9): 1475–1485.

52.

Fukuoka

Hara

Takahashi

, et al. Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase Ib trial (REGONIVO, EPOC1603). J Clin Oncol 2020; 38(18): 2053–2061.

53.

Lam

Pavlakis

Shitara

, et al. INTEGRATE II: randomised phase III controlled trials of regorafenib containing regimens versus standard of care in refractory Advanced Gastro-Oesophageal Cancer (AGOC): a study by the Australasian Gastro-Intestinal Trials Group (AGITG). BMC Cancer 2023; 23(1): 180.

54.

Thuss-Patience

Högner

Goekkurt

, et al. Ramucirumab, avelumab, and paclitaxel as second-line treatment in esophagogastric adenocarcinoma. JAMA Netw Open 2024; 7(1): e2352830.

55.

Nakajima

Kadowaki

Minashi

, et al. Multicenter phase I/II study of nivolumab combined with paclitaxel plus ramucirumab as second-line treatment in patients with advanced gastric cancer. Clin Cancer Res 2021; 27(4): 1029–1036.

56.

Goetze

Stein

Lorenzen

, et al. Ramucirumab beyond progression plus TAS-102 in patients with advanced or metastatic esophagogastric adenocarcinoma, after treatment failure on a ramucirumab-based therapy. Int J Cancer 2023; 153(10): 1726–1733.

57.

Sakai

Kadowaki

Kawabata

, et al. Randomized phase III trial of ramucirumab beyond progression plus irinotecan in patients with ramucirumab-refractory advanced gastric cancer: RINDBeRG trial. J Clin Oncol 2025; 43(19): 2196–2207.

58.

Fornaro

Musettini

Orlandi

, et al. Early increase of plasma soluble VEGFR-2 is associated with clinical benefit from second-line treatment of paclitaxel and ramucirumab in advanced gastric cancer. Am J Cancer Res 2022; 12(7): 3347–3356.

59.

Spratlin

Cohen

Eadens

, et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol 2010; 28(5): 780–787.

60.

Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014; 513(7517): 202–209.

61.

Janjigian

Kawazoe

Bai

, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet 2023; 402(10418): 2197–2208.

62.

Pietrantonio

Caporale

Morano

, et al. HER2 loss in HER2-positive gastric or gastroesophageal cancer after trastuzumab therapy: implication for further clinical research. Int J Cancer 2016; 139(12): 2859–2864.

63.

Wang

Liu

, et al. Liquid biopsies to track trastuzumab resistance in metastatic HER2-positive gastric cancer. Gut 2019; 68(7): 1152–1161.

64.

Makiyama

Sukawa

Kashiwada

, 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(17): 1919–1927.

65.

Kim

Jung

Kim

, et al. Trastuzumab combined with ramucirumab and paclitaxel in patients with previously treated human epidermal growth factor receptor 2-positive advanced gastric or gastroesophageal junction cancer. J Clin Oncol 2023; 41(27): 4394–4405.

66.

Shitara

Wainberg

Tabernero

, et al. Final analysis of the randomized phase 2 part of the ASPEN-06 study: a phase 2/3 study of evorpacept (ALX148), a CD47 myeloid checkpoint inhibitor, in patients with HER2-overexpressing gastric/gastroesophageal cancer (GC). J Clin Oncol 2025; 43(4_suppl): 332.

67.

Thuss-Patience

Shah

Ohtsu

, 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(5): 640–653.

68.

Ogitani

Aida

Hagihara

, et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin Cancer Res 2016; 22(20): 5097–5108.

69.

Ughetto

Migliore

Pietrantonio

, et al. Personalized therapeutic strategies in HER2-driven gastric cancer. Gastric Cancer 2021; 24(4): 897–912.

70.

Shitara

Bang

Iwasa

, et al. Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial. Nat Med 2024; 30(7): 1933–1942.

71.

Hino

Nishina

Kajiwara

, et al. Association of ERBB2 copy number and gene coalterations with trastuzumab efficacy and resistance in human epidermal growth factor receptor 2-positive esophagogastric and gastric cancer. JCO Precis Oncol 2022; 6: e2200135.

72.

Van Cutsem

di Bartolomeo

Smyth

, et al. Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study. Lancet Oncol 2023; 24(7): 744–756.

73.

Shitara

Van Cutsem

Gümüş

, et al. Trastuzumab deruxtecan or ramucirumab plus paclitaxel in gastric cancer. N Engl J Med 2025; 393(4): 336–348.

74.

Janjigian

Viglianti

Liu

, et al. A phase Ib/II, multicenter, open-label, dose-escalation, and dose-expansion study evaluating trastuzumab deruxtecan (T-DXd, DS-8201) monotherapy and combinations in patients with HER2-overexpressing gastric cancer (DESTINY-Gastric03). J Clin Oncol 2021; 39(3_suppl): TPS261.

75.

Wang

Gong

Wang

, et al. Disitamab vedotin (RC48) plus toripalimab for HER2-expressing advanced gastric or gastroesophageal junction and other solid tumours: a multicentre, open label, dose escalation and expansion phase 1 trial. EClinicalMedicine 2024; 68: 102415.

76.

Zhang

Qiu

Wang

, et al. Phase 1 multicenter, dose-expansion study of ARX788 as monotherapy in HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma. Cell Rep Med 2022; 3(11): 100814.

77.

Moehler

Mueller

Trarbach

, et al. Cetuximab with irinotecan, folinic acid and 5-fluorouracil as first-line treatment in advanced gastroesophageal cancer: a prospective multi-center biomarker-oriented phase II study. Ann Oncol 2011; 22(6): 1358–1366.

78.

Liu

Guo

Zhang

, et al. A multi-center phase II study and biomarker analysis of combined cetuximab and modified FOLFIRI as second-line treatment in patients with metastatic gastric cancer. BMC Cancer 2017; 17(1): 188.

79.

Pinto

Di Fabio

Barone

, et al. Phase II study of cetuximab in combination with cisplatin and docetaxel in patients with untreated advanced gastric or gastro-oesophageal junction adenocarcinoma (DOCETUX study). Br J Cancer 2009; 101(8): 1261–1268.

80.

Lordick

Luber

Lorenzen

, et al. Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Br J Cancer 2010; 102(3): 500–505.

81.

Luber

Deplazes

Keller

, et al. Biomarker analysis of cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric and oesophago-gastric junction cancer: results from a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO). BMC Cancer 2011; 11(1): 509.

82.

Han

, et al. Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer. Br J Cancer 2009; 100(2): 298–304.

83.

Gold

Goldman

Iqbal

, et al. Cetuximab as second-line therapy in patients with metastatic esophageal adenocarcinoma: a phase II Southwest Oncology Group Study (S0415). J Thorac Oncol 2010; 5(9): 1472–1476.

84.

Tebbutt

Price

Ferraro

, et al. Panitumumab added to docetaxel, cisplatin and fluoropyrimidine in oesophagogastric cancer: ATTAX3 phase II trial. Br J Cancer 2016; 114(5): 505–509.

85.

Yoon

Karapetyan

Choudhary

, et al. Phase II study of irinotecan plus panitumumab as second-line therapy for patients with advanced esophageal adenocarcinoma. Oncologist 2018; 23(9): 1004-e102.

86.

Zheng

Shi

, et al. S-1 and cisplatin with or without nimotuzumab for patients with untreated unresectable or metastatic gastric cancer. Medicine 2015; 94(23): e958.

87.

Satoh

Lee

Rha

, 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(4): 824–832.

88.

Moehler

Schad

Maderer

, et al. Lapatinib with ECF/X in the first-line treatment of metastatic gastric cancer according to HER2neu and EGFR status: a randomized placebo-controlled phase II study (EORTC 40071). Cancer Chemother Pharmacol 2018; 82(4): 733–739.

89.

LaBonte

Yang

Zhang

, et al. A phase II biomarker-embedded study of lapatinib plus capecitabine as first-line therapy in patients with advanced or metastatic gastric cancer. Mol Cancer Ther 2016; 15(9): 2251–2258.

90.

Wainberg

Lin

DiCarlo

, et al. Phase II trial of modified FOLFOX6 and erlotinib in patients with metastatic or advanced adenocarcinoma of the oesophagus and gastro-oesophageal junction. Br J Cancer 2011; 105(6): 760–765.

91.

Iyer

Chhatrala

Shefter

, et al. Erlotinib and radiation therapy for elderly patients with esophageal cancer—clinical and correlative results from a prospective multicenter phase 2 trial. Oncology 2013; 85(1): 53–58.

92.

Janmaat

Gallegos-Ruiz

Rodriguez

, et al. Predictive factors for outcome in a phase II study of gefitinib in second-line treatment of advanced esophageal cancer patients. J Clin Oncol 2006; 24(10): 1612–1619.

93.

Rao

Starling

Cunningham

, et al. Matuzumab plus epirubicin, cisplatin and capecitabine (ECX) compared with epirubicin, cisplatin and capecitabine alone as first-line treatment in patients with advanced oesophago-gastric cancer: a randomised, multicentre open-label phase II study. Ann Oncol 2010; 21(11): 2213–2219.

94.

Huang

Fan

, et al. Icotinib in patients with pretreated advanced esophageal squamous cell carcinoma with EGFR overexpression or EGFR gene amplification: a single-arm, multicenter phase 2 study. J Thorac Oncol 2016; 11(6): 910–917.

95.

Lordick

Kang

Chung

, 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(6): 490–499.

96.

Waddell

Chau

Cunningham

, 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(6): 481–489.

97.

Smyth

Vlachogiannis

Hedayat

, et al. EGFR amplification and outcome in a randomised phase III trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastro-oesophageal cancers. Gut 2021; 70(9): 1632–1641.

98.

Dutton

Ferry

Blazeby

, et al. Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial. Lancet Oncol 2014; 15(8): 894–904.

99.

Petty

Dahle-Smith

Stevenson

DAJ

, et al. Gefitinib and EGFR gene copy number aberrations in esophageal cancer. J Clin Oncol 2017; 35(20): 2279–2287.

100.

Maron

Alpert

Kwak

, et al. Targeted therapies for targeted populations: anti-EGFR treatment for EGFR-amplified gastroesophageal adenocarcinoma. Cancer Discov 2018; 8(6): 696–713.

101.

Catenacci

DVT

Lomnicki

Chase

, et al. Personalized ANtibodies for GastroEsophageal Adenocarcinoma (PANGEA): primary efficacy analysis of the phase II platform trial (NCT02213289). J Clin Oncol 2020; 38(4_suppl): 356.

102.

Corso

Pietrantonio

Apicella

, et al. Optimized EGFR blockade strategies in EGFR addicted gastroesophageal adenocarcinomas. Clin Cancer Res 2021; 27(11): 3126–3140.

103.

Maron

Moya

Morano

, et al. Epidermal growth factor receptor inhibition in epidermal growth factor receptor-amplified gastroesophageal cancer: retrospective global experience. J Clin Oncol 2022; 40(22): 2458–2467.

104.

Kotani

Yamaguchi

Kato

, et al. A phase 2, open-label study of amivantamab in patients with previously treated advanced or metastatic gastric or esophageal cancer. J Clin Oncol 2024; 42(3_suppl): 363.

105.

Zhao

Zhu

Zhang

, et al. Trop2 is overexpressed in gastric cancer and predicts poor prognosis. Oncotarget 2016; 7(5): 6136–6145.

106.

Starodub

Ocean

Messersmith

, et al. Therapy of gastrointestinal malignancies with an anti-Trop-2-SN-38 antibody drug conjugate (ADC) (sacituzumab govitecan): phase I/II clinical experience. J Clin Oncol 2015; 33(15_suppl): 3546.

107.

Bardia

Messersmith

Kio

, et al. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial. Ann Oncol 2021; 32(6): 746–756.

108.

Kobitzsch

Stocker

Hacker

, et al. SAGA—a phase Ib/II single-arm, multicenter study of sacituzumab govitecan for patients with metastatic esophagogastric adenocarcinoma. ESMO Gastrointest Oncol 2024; 4: 100051.

109.

Rodon

Wainberg

Zhang

, et al. Abstract CT038: preliminary efficacy and safety results of anti-TROP2 ADC SKB264 (MK-2870) in patients (pts) with previously treated advanced gastric (G) or gastroesophageal junction (GEJ) cancer from a phase 2 study. Cancer Res 2024; 84(7_Suppl): CT038.

110.

Wainberg

Van Cutsem

Shitara

, et al. 1471TiP MK-2870-015: a phase III study of trophoblast antigen 2 (TROP2)-directed antibody-drug conjugate (ADC) sacituzumab tirumotecan (sac-TMT) vs treatment of physician’s choice (TPC) for previously treated metastatic gastroesophageal adenocarcinoma (GEA). Ann Oncol 2024; 35: S909–S910.

111.

Kubota

Kawazoe

Mishima

, et al. Comprehensive clinical and molecular characterization of claudin 18.2 expression in advanced gastric or gastroesophageal junction cancer. ESMO Open 2023; 8(1): 100762.

112.

Ruan

Luo

, et al. 609O CLDN18.2 targeted antibody-drug conjugate (ADC), SHR-A1904, in patients (pts) with gastric/gastroesophageal junction cancer (GC/GEJC): a phase I study. Ann Oncol 2024; 35: S487–S488.

113.

Liu

, et al. 1456P First in human phase I/II trial of claudin 18.2 ADC RC118 in patients with advanced gastric/gastroesophageal junction cancer. Ann Oncol 2024; 35: S903.

114.

Ruan

Liu

Wei

, et al. Claudin 18.2-targeting antibody–drug conjugate CMG901 in patients with advanced gastric or gastro-oesophageal junction cancer (KYM901): a multicentre, open-label, single-arm, phase 1 trial. Lancet Oncol 2025; 26(2): 227–238.

115.

Liu

Zhang

, et al. 396MO Anti-claudin 18.2 (CLDN18.2) antibody-drug conjugate (ADC) IBI343 in patients (pts) with solid tumors and gastric/gastro-esophageal junction adenocarcinoma (G/GEJ AC): a phase I study. Ann Oncol 2024; 35: S160.

116.

Weng

Meng

, et al. AMT-562, a novel HER3-targeting antibody–drug conjugate, demonstrates a potential to broaden therapeutic opportunities for HER3-expressing tumors. Mol Cancer Ther 2023; 22(9): 1013–1027.

117.

Brassard

Hughes

Roskelley

, et al. Antibody-drug conjugates targeting tumor-specific mucin glycoepitopes. Front Biosci (Landmark Ed) 2022; 27(11): 301.

118.

Deslandes

Comparative clinical pharmacokinetics of antibody-drug conjugates in first-in-human phase 1 studies. MAbs 2014; 6(4): 859–870.

119.

Huang

Zhou

Sun

, et al. Evaluation of the role of soluble B7-H3 in association with membrane B7-H3 expression in gastric adenocarcinoma. Cancer Biomark 2022; 33(1): 123–129.

120.

Shao

Zhan

Quan

, et al. Clinical significance of B7-H3 and HER2 co-expression and therapeutic value of combination treatment in gastric cancer. Int Immunopharmacol 2022; 110: 108988.

121.

Bouleftour

Sargos

Magne

Nectin-4: a tumor cell target and status of inhibitor development. Curr Oncol Rep 2023; 25(3): 181–188.

122.

Sharma

Strickler

Sommerhalder

, et al. First-in-human study of ABBV-400, a novel c-Met-targeting antibody-drug conjugate, in advanced solid tumors: results in colorectal cancer. J Clin Oncol 2024; 42(16_suppl): 3515.

123.

Mitra

Barua

Huang

, et al. From bench to bedside: the history and progress of CAR T cell therapy. Front Immunol 2023; 14: 1188049.

124.

Sterner

RM.

CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J 2021; 11(4): 69.

125.

Albelda

SM.

CAR T cell therapy for patients with solid tumours: key lessons to learn and unlearn. Nat Rev Clin Oncol 2024; 21(1): 47–66.

126.

Del Bufalo

De Angelis

Caruana

, et al. GD2-CART01 for relapsed or refractory high-risk neuroblastoma. N Engl J Med 2023; 388(14): 1284–1295.

127.

Liu

Gong

, et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial final results. Nat Med 2024; 30(8): 2224–2234.

128.

Gong

, et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat Med 2022; 28(6): 1189–1198.

129.

Botta

Kelly

Jin

, et al. CLDN18.2 chimeric antigen receptor T cell therapy for patients with advanced gastric and pancreatic adenocarcinoma: results of ELIMYN18.2 phase 1b clinical trial. J Clin Oncol 2024; 42(3_Suppl): 356.

130.

Botta

Chao

, et al. Metastatic gastric cancer target lesion complete response with Claudin18.2-CAR T cells. J Immunother Cancer 2024; 12(2): e007927.

131.

Liu

Peng

, et al. Claudin-18 isoform 2-specific CAR T-cell therapy (satri-cel) versus treatment of physician’s choice for previously treated advanced gastric or gastro-oesophageal junction cancer (CT041-ST-01): a randomised, open-label, phase 2 trial. Lancet 2025; 405(10494): 2049–2060.

132.

Entezam

Sanaei

Mirzaei

, et al. Current progress and challenges of immunotherapy in gastric cancer: a focus on CAR-T cells therapeutic approach. Life Sci 2023; 318: 121459.

133.

Jiang

Pan

, et al. Sintilimab plus chemotherapy for unresectable gastric or gastroesophageal junction cancer. JAMA 2023; 330(21): 2064.

134.

Qiu

Kato

, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial. BMJ 2024; 385: e078876.

135.

Zhang

Wang

, et al. First-line sugemalimab plus chemotherapy for advanced gastric cancer. JAMA 2025; 333(15): 1305.

136.

Zaanan

Bouché

de la Fouchardière

, et al. TFOX versus FOLFOX in first-line treatment of patients with advanced HER2-negative gastric or gastro-oesophageal junction adenocarcinoma (PRODIGE 51-FFCD-GASTFOX): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol 2025; 26(6): 732–744.

137.

Fuchs

Özgüroğlu

Bang

, et al. Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial. Gastric Cancer 2022; 25(1): 197–206.

First-line maintenance strategies and later-line options in patients with advanced gastroesophageal adenocarcinoma

Abstract

Keywords

Introduction

Methods

First-line maintenance strategies

De-escalation maintenance

Switch maintenance strategies

Conclusions and future perspectives on maintenance strategies

Second- and later-line treatments

VEGF/VEGFR axis targeting

Sequential VEGF/VEGR axis inhibition

Biomarkers for VEGF/VEGFR axis blockade

Specific strategies in HER2-positive disease

Future perspectives

EGFR inhibition

Novel ADCs

CAR-T cell therapy

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iDs

References