Perioperative immunotherapy in gastric cancer in the spotlight

Abstract

Perioperative fluorouracil, leucovorin, oxaliplatin and docetaxel is currently the standard chemotherapy for resectable gastric and gastroesophageal junction adenocarcinomas, based on the results of FLOT4 and ESOPEC trials. This regimen has demonstrated efficacy in tumor downstaging, enhancing the chances of curative resection, and ultimately improving the overall survival. However, despite these advances, the complete response rate in the perioperative setting remains below 10% to 15%, highlighting the need for more effective treatment strategies. Recent studies evaluating immunotherapy, such as the KEYNOTE-585 trial with pembrolizumab and the MATTERHORN trial with durvalumab, have shown promising preliminary results, including improved response rates and event-free survival. Nevertheless, these regimens are not yet considered the standard of care. This article explores the current landscape of perioperative treatments for gastric cancer and discusses future directions in this field.

Key Words: Gastric cancer; Gastroesophageal junction cancer; Perioperative treatment; Neoadjuvant treatment; Chemotherapy; Immunotherapy; Surgery; Gastrectomy

Core Tip: Immunotherapy is reshaping the treatment landscape for resectable gastric and gastroesophageal junction cancers. Despite the established benefit of perioperative leucovorin, oxaliplatin, and docetaxel chemotherapy, complete pathological response rates remain below 15%. Recent phase III trials, including KEYNOTE-585 with pembrolizumab and MATTERHORN with durvalumab, have demonstrated improved pathological responses and event-free survival, particularly in biomarker-enriched subgroups such as microsatellite instability-high or programmed death-ligand 1-positive tumors. This article summarizes the evolving evidence supporting immune checkpoint inhibitors in the perioperative setting and highlights future directions toward biomarker-driven, personalized multimodal therapy for gastric cancer.

INTRODUCTION

Gastric and gastroesophageal junction (G/GEJ) adenocarcinomas are among the most prevalent malignancies worldwide, with a rising incidence over the past three decades, largely attributed to the increasing prevalence of obesity and gastroesophageal reflux disease[1,2]. According to the most recent data from the Global Cancer Observatory, approximately 1.4 million new cases and 1.1 million related deaths have been reported[3]. Despite diagnostic advances, over 60% of patients are still diagnosed at locally advanced stages which compromises the survival rate with surgery alone[4,5]. In this context, multimodal treatment, combining surgery with chemotherapy (CT) or other systemic therapies, has become the standard of care for improving oncologic outcomes[6]. Historically, the addition of perioperative CT to surgical treatment has significantly reduced recurrence and improved overall survival (OS) in G/GEJ adenocarcinomas and, based on landmark clinical trials such as MAGIC and ACCORD, fluoropyrimidine and platinum-based regimens have been incorporated into clinical practice[7,8]. However, a major milestone was reached with the FLOT4 study, which compared the 5-fluorouracil (5-FU), leucovorin, oxaliplatin, and docetaxel (FLOT) regimen to the epirubicin, cisplatin, and fluorouracil (ECF)/epirubicin, cisplatin, capecitabine combinations (ECX), demonstrating superior OS and higher tumor response rates[9]. More recently, the ESOPEC trial confirmed these results, establishing FLOT as the new standard for perioperative treatment[10]. However, despite superior outcomes, the complete pathological response (pCR) with the FLOT regimen is still below 10% to 15%[11]. In addition, a significant proportion of patients are unable to complete the postoperative CT phase owing to treatment-related toxicity, underscoring persistent limitations in achieving both efficacy and tolerability[12]. Given these challenges, immunotherapy has emerged as a novel and encouraging strategy, especially considering the tumor’s molecular heterogeneity and immunosuppressive microenvironment[13]. Notably, a subset of gastric tumors exhibits molecular characteristics associated with immune responsiveness, such as high programmed death-ligand 1 (PD-L1) expression, microsatellite instability(MSI)-high (MSI-H) status, and elevated tumor mutational burden (TMB), providing a strong biological rationale for the use of immune checkpoint inhibitors (ICIs)[14,15]. Initial clinical investigations of ICIs were conducted in the metastatic setting, targeting a patient population with dismal prognoses and limited therapeutic options following progression on standard therapy[16]. Trials such as KEYNOTE-059, ATTRACTION-2, and CheckMate 649 have demonstrated that a proportion of patients can achieve durable responses, particularly in biomarker-enriched subgroups, thus establishing proof-of-concept for immunotherapy efficacy in advanced G/GEJ cancer[17-19]. Building upon these findings, current research is increasingly focused on early settings, where the integration of ICIs aims to potentiate tumor immunogenicity, eradicate micrometastatic disease, and improve surgical outcomes[20,21]. Trials such as KEYNOTE-585, which investigated pembrolizumab, and MATTERHORN, which evaluated durvalumab, have reported encouraging early data suggesting improvements in pCR and event-free survival (EFS), although these approaches have not yet been adopted as the standard of care in clinical practice[22,23]. This article aims to discuss the current landscape of therapies for resectable G/GEJ cancers, with a focus on the evidence supporting the FLOT regimen, its limitations, and emerging perspectives involving immunotherapy and other innovative strategies for the optimal management of these patients.

LITERATURE SEARCH

This narrative review was based on a non-systematic literature search. Relevant studies were identified through manual searches of databases such as PubMed, EMBASE, and Cochrane Library. Keywords used included combinations of terms such as “gastric cancer”, “gastroesophageal junction”, “perioperative chemotherapy”, “immunotherapy”, “immune checkpoint inhibitors”, “neoadjuvant treatment”, and “adjuvant treatment”. The search included publications in English until March 2025. The reference lists of key studies and recent clinical trial data (published and presented at major oncology meetings) were also reviewed to ensure the inclusion of the most up-to-date evidence. Articles were selected based on their relevance to the scope of the review and clinical significance. No formal inclusion or exclusion criteria were applied to the study.

ADJUVANT CHEMOTHERAPY: CURRENT EVIDENCE AND THE ROLE OF THE CLASSIC TRIAL

The role of adjuvant CT for resected G/GEJ adenocarcinomas has been extensively investigated, driven by the understanding that nearly 40% of patients experience disease recurrence within 2 years of curative surgery, significantly compromising OS outcomes[24]. A wide range of chemotherapeutic agents, such as 5-FU, doxorubicin, mitomycin C, epirubicin, and cisplatin, have been tested both as monotherapies and in combination regimens[25,26]. In 2010, a meta-analysis conducted by the Global Advanced/Adjuvant Stomach Tumor Research International Collaboration demonstrated that adjuvant CT significantly improved OS, increasing the 5-year survival rate from 49.6% to 55.3% [hazard ratio (HR) = 0.82, 95% confidence interval (CI): 0.76-0.90, P < 0.001][27].

In 2012, The CLASSIC trial, a pivotal phase III randomized controlled study, redefined adjuvant treatment paradigms in East Asia[28]. This multicenter trial enrolled 1035 patients with advanced gastric adenocarcinoma who underwent R0 resection (complete resection with no tumor within 1 mm) with D2 lymphadenectomy (removal of lymph nodes along the major blood vessels that supply the stomach, including those surrounding the celiac axis and its branches). Patients were randomized to receive adjuvant CT with eight cycles of capecitabine (1000 mg/m² twice daily on days 1-14) plus oxaliplatin (130 mg/m² on day 1) every three weeks [capecitabine, oxaliplatin, docetaxel (CAPOX)] or to undergo observation. A statistically significant improvement in 3-year disease-free survival (DFS) was observed in the CAPOX arm (74% vs 59%, HR = 0.56, 95%CI: 0.44-0.72, P < 0.0001). In 2014, a subsequent long-term analysis confirmed a sustained OS benefit (HR = 0.72, P = 0.0033). Toxicity was manageable but notable, with grade 3-4 adverse events occurring in 56% of patients, including neutropenia, nausea, and peripheral neuropathy[29]. Dose reductions and treatment discontinuations were reported in a significant proportion of patients, underscoring the need for experienced supportive care and individualized dose management in clinical practice. The CLASSIC trial supports that high-quality surgery must be complemented by systemic therapy to address micrometastatic disease. However, its applicability outside East Asia is debated, given the differences in surgical expertise and pathological staging[30]. In clinical practice, CAPOX has been adopted as the standard adjuvant regimen in patients with stage II-III gastric adenocarcinoma after D2 resection (Table 1).

Table 1 Adjuvant therapy: Summary of key randomized trials evaluating adjuvant therapy strategies in gastric and gastroesophageal junction adenocarcinoma.

Trial name	Disease subtype	Strategy	DFS	OS
INT-0116 (SWOG 9008) (2001/2012)	G/GEJ adenocarcinoma	Adjuvant CRT vs observation	10-year median DFS: 27 months (CRT) vs 19 months	10-year median OS: 35 months (CRT) vs 27 months
			HR: 1.51 (1.25-1.83)	HR: 1.32 (1.10-1.60)
			P < 0.001	P = 0.0046
CLASSIC trial (2012/2014)	Gastric adenocarcinoma	Adjuvant CT (CAPOX) vs observation	5-year DFS: 68% (CAPOX) vs 53%	5-year OS: 78% (CAPOX) vs 69%
			HR: 0.58 (0.47-0.72)	HR: 0.66 (0.51-0.85)
			P < 0.0001	P = 0.0015
ARTIST trial (2012/2015)	Mostly gastric adenocarcinoma (few GEJ)	Adjuvant CT vs adjuvant CRT	3-year DFS: 78.2% (CRT) vs 74.2% (CT)	5-year OS: 75% (CRT) vs 73% (CT)
			P = 0.0862
			Subgrup with node metastasis 3-year DFS
			77.5% (CRT) vs 72.3% (CT)
			HR: 0.68 (0.47-0.99)	HR: 1.13 (0.77-1.64)
			P = 0.0471	P = 0.52
ARTIST 2 trial (2021)	Gastric adenocarcinoma only and node positive	Adjuvant	3-year DFS: 64.8% (S-1), 74.3% (SOX), 72.8% (SOXRT)	No OS data so far (secondary endpoint)
		S-1	HR S-1 vs SOX: 0.692, P = 0.042
			HR S-1 vs SOXRT: 0.724, P = 0.074
		SOX vs SOXRT	No difference was found between SOX and SOXRT (HR 0.971, P = 0.879)

DFS: Disease-free survival; OS: Overall survival; G/GEJ: Gastric and gastroesophageal junction; CRT: Chemoradiotherapy; HR: Hazard ratio; CT: Chemotherapy; CAPOX: Capecitabine, oxaliplatin, docetaxel; S-1: Oral 5-fluorouracil; SOX: S-1 and oxaliplatin; SOXRT: S-1 and oxaliplatin plus chemoradiotherapy.

ADJUVANT CHEMORADIOTHERAPY: IMPACT AND LIMITATIONS AFTER CURATIVE D2 RESECTION

Locoregional radiation is supported by evidence showing that most post-surgery recurrences are confined to the upper abdominal region[31]. The Southwest Oncology Group 9008/INT-0116 trial was the first major study to demonstrate OS benefit with adjuvant chemoradiotherapy (CRT) after curative-intent surgery[32]. In this phase III trial, 556 patients with stage IB-IV (M0) G/GEJ adenocarcinoma were randomized to receive either observation or adjuvant therapy consisting of four cycles of bolus 5-FU and leucovorin with concurrent radiotherapy (RT) (total dose of 45 Gy in 25 fractions). At a median follow-up of five years, the CRT arm showed a superior 3-year OS rate (50% vs 41%, P = 0.005) and a prolonged median OS (36 months vs 27 months). The 10-year follow-up confirmed the sustained OS benefit, with an HR of 1.32 (95%CI: 1.10-1.60, P = 0.046)[33]. Despite its practice-changing implications, the INT-0116 trial has been subject to several well-founded criticisms[34]. One of the main concerns was the limited extent of lymphadenectomy: Only 10% of patients underwent D2 dissection, while over half had D0 resection (incomplete lymph node dissection), which is considered suboptimal and likely contributed to the high rate of locoregional recurrence in the control group. Additionally, the RT technique employed was conventional two-dimensional planning, lacking modern conformal approaches, such as intensity-modulated RT, which can reduce toxicity and improve target coverage. The CT regimen, bolus 5-FU and leucovorin, has also been supplanted by more effective and better tolerated fluoropyrimidine-based protocols, including capecitabine or 5-FU. Another limitation of this approach is toxicity. In INT-0116, approximately 33% of patients experienced grade ≥ 3 gastrointestinal toxicity, and hematologic adverse events were frequent. CRT was completed by only 64% of the patients, and three patients died because of toxic effects. This raised concerns regarding protocol adherence and quality of life, particularly in older or frail patients. Nevertheless, in regions where D2 lymphadenectomy is not routinely performed or where surgical quality varies, adjuvant CRT remains a relevant strategy, particularly for patients at a high risk of locoregional failure.

In 2012, the ARTIST trial became the first well-designed and representative phase III study to compare adjuvant CT with adjuvant CRT in patients who had undergone D2 lymphadenectomy[35]. A total of 458 patients were randomized to receive CRT or CT alone. CT consisted of cisplatin combined with either 5-FU or capecitabine. RT was administered with 45 Gy in 25 fractions. This trial demonstrated that adjuvant CRT did not significantly improve OS compared to CT alone. The 3-year DFS rates were 78.2% for the CRT group and 74.2% for the CT group. Five-year OS rates were 75% (CRT) vs 73% (CT), with a HR of 1.13 (95%CI: 0.77-1.64). However, in the subgroup of patients with lymph node-positive disease, CRT was associated with improved 3-year DFS (77.5% vs 72.3%; HR = 0.68, 95%CI: 0.47-0.99), suggesting a potential benefit in this higher-risk population.

Following these results, the ARTIST2 trial, published in 2021, sought to further clarify the role of adjuvant CRT[36]. Unlike the original ARTIST trial, ARTIST2 focused exclusively on patients with node-positive disease. Three adjuvant regimens were compared: S-1 monotherapy (oral 5-FU), S-1 plus oxaliplatin (SOX), and postoperative CRT with S-1 and oxaliplatin (SOXRT). Both SOX and SOXRT demonstrated improved DFS outcomes when compared to S-1 alone. The projected 3-year DFS rates were 64.8% for the S-1 group, 74.3% for those receiving SOX, and 72.8% for the SOXRT arm. However, incorporating RT into the SOX regimen did not lead to a significant decrease in recurrence following D2 gastrectomy (Table 1). These findings suggest that while adjuvant CRT has demonstrated survival benefits in settings with suboptimal surgical treatment, its additional benefit after adequate D2 surgery appears limited[37]. Modern CT regimens alone may achieve comparable outcomes, reserving adjuvant CRT for selected high-risk groups, such as those with extensive nodal involvement, positive margins or incomplete resections[38]. Future strategies should focus on refining patient selection and optimizing multimodal approaches to balance efficacy with treatment-related toxicity, thereby further personalizing adjuvant therapy.

NEOADJUVANT TREATMENT: IMPACT ON SURGICAL AND SURVIVAL OUTCOMES

It is well established that approximately 20% of the patients with G/GEJ adenocarcinomas undergoing primary surgery present with microscopically positive resection margins (R1)[39,40]. This finding prompted a longstanding debate over the role of neoadjuvant CT, and many randomized trials have been conducted[41]. In 2010, the European Organisation for Research and Treatment of Cancer designed a trial to evaluate the efficacy of this strategy[42]. The CT regime consisted of two cycles of cisplatin (50 mg/m²), leucovorin, and 5-FU and was compared with surgery alone. The primary finding of this study was an improvement in R0 resection rates: 81.9% in the neoadjuvant CT group compared to 66.7% in the surgery-only group (P = 0.036). Additionally, lymph node metastases were less frequent in patients who received neoadjuvant CT (61.4% vs 76.5%, P = 0.018). However, after a follow-up of 4.4 years, and due to poor patient accrual, no survival benefit was demonstrated (HR = 0.84, 95%CI: 0.52-1.35, P = 0.466) (Table 2).

Table 2 Neoadjuvant therapy: Overview of pivotal clinical trials investigating neoadjuvant therapy in gastroesophageal cancers.

Trial name	Disease subtype	Strategy	R0 resection rate	OS
EORTC trial (2010)	G/GEJ adenocarcinoma	Neoadjuvant CT vs surgery	81.9% (CT) vs 66.7%; P = 0.036	Median OS not improved
			pCR: 7.1% (CT)	HR OS: 0.84 (0.52-1.35); P = 0.466
CROSS trial (2012)	Mostly distal esophagus (58%)	Neoadjuvant CRT vs surgery	92% (CRT) vs 69%	Median OS: 49.4 months (CRT) vs 24.0 months
	Mostly adenocarcinoma (75%)		pCR: 29% (CRT)	HR OS: 0.657 (0.495-0.871); P = 0.003

R0: Complete resection with no tumor within 1mm; OS: Overall survival; G/GEJ: Gastric and gastroesophageal junction; CRT: Chemoradiotherapy; HR: Hazard ratio; CT: Chemotherapy; pCR: Complete pathological response.

After several studies failed to demonstrate better survival outcomes with neoadjuvant CT, subsequent trials shifted focus toward exploring the potential benefits of neoadjuvant CRT. In 2012, the CROSS study randomized patients with esophageal and GEJ cancer to receive surgery alone or a regimen of weekly carboplatin (area under the curve of 2 mg/mL/minute) and paclitaxel (50 mg/m²) administered over five weeks concurrently with RT (41.4 Gy in 23 fractions), followed by surgical resection[43]. An R0 resection was achieved in 92% of the patients treated with neoadjuvant CRT, in contrast to 69% in the surgery-only arm (P < 0.001). Additionally, pCR was observed in 29% of those receiving CRT. Median OS was 49.4 months with CRT plus surgery vs 24.0 months with surgery alone (HR = 0.657, 95%CI: 0.495-0.871, P = 0.003). The incidence of postoperative complications was comparable between the two treatment groups. The CROSS trial marked a turning point, showing that neoadjuvant CRT not only significantly improved R0 resection and achieved substantial pCR rates but also resulted in a meaningful survival advantage compared to surgery alone, without increasing post-surgical complications.

PERIOPERATIVE STRATEGIES

The treatment landscape of G/GEJ adenocarcinomas began to change in 2006 with the publication of the United Kingdom-based MAGIC trial[7]. This study revealed that administering perioperative CT with ECF led to a significant survival benefit, improving both OS (36.3% vs 23%, HR = 0.75) and PFS (HR = 0.66, 95%CI: 0.53-0.81, P < 0.001) compared to surgery alone (Table 3). These results were reinforced in 2011 by the French FFCD 9703/ACCORD trial, which confirmed the advantage of perioperative CT in patients with resectable G/GEJ junction cancers[8].

Table 3 Perioperative therapy: Landmark studies assessing perioperative therapy in gastric and gastroesophageal junction adenocarcinoma.

Trial name	Disease subtype	Strategy	R0 resection rate	OS
MAGIC (2006)	G/GEJ adenocarcinoma	Perioperative ECF vs surgery	79.3% (ECF) vs 70.3%; P = 0.03	5-year OS: 36.3% (ECF) vs 23%
				HR: 0.75 (0.60-0.93); P = 0.009
FFCD 9703/ACCORD (2011)	G/GEJ adenocarcinoma	Perioperative 5-FU/cisplatin vs sugery	84% (5-FU/cisplatin) vs 74%; P = 0.04	5-year OS: 38% (5-FU/cisplatin) vs 24%
				HR OS: 0.69 (0.5-0.95); P = 0.02
CRITICS (2018)	G/GEJ adenocarcinoma	Perioperative CT vs perioperative CT + postoperative radiotherapy	80% (CT) vs 82% (CT + RDT)	Median OS: 43 months vs 37 months HR 1.01 (0.84-1.22), P = 0.9
FLOT4-AIO (2019)	G/GEJ adenocarcinoma	Perioperative FLOT vs ECF/ECX	85% (FLOT) vs 78% (ECF/ECX); P = 0.0162	Median OS: 50 months vs 35 months
				HR 0.77 (0.63-0.94), P = 0.012
ESOPEC (2024)	GEJ adenocarcinoma	Perioperative FLOT vs preoperative-CRT	94.3% (FLOT) vs 95% (CRT)	3-year OS: 57.4% (FLOT) vs 50.7% (CRT) HR: 0.7 (0.53-0.92), P = 0.01
				5-year OS: 50.6% (FLOT) vs 38.7% (CRT)
			pCR: 16.7% (FLOT) vs 10.1% (CRT)	Median OS: 66 months (FLOT) vs 37 months (CRT)
TOPGEAR	G/GEJ adenocarcinoma	Preoperative CRT + perioperative CT vs perioperative CT	No R0 difference (92%)	Median OS: 46 months (CRT) vs 49 months (CT)
			pCR: 17% (CRT) vs 8% (CT)	HR: 1.05 (0.83-1.31)
RESOLVE (2021)	G/GEJ adenocarcinoma	Perioperative SOX vs	93% (perioperative SOX) vs 88% (adjuvant SOX) vs 87% (adjuvant CAPOX) P = 0.075	No OS data
		Adjuvant SOX vs adjuvant CAPOX	pCR: 19% (perioperative SOX) vs 14% (adjuvant SOX)
RESONANCE (2024)	G/GEJ adenocarcinoma	Perioperative SOX vs adjuvante SOX	94.9% (perioperative SOX) vs 83.7% (adjuvant SOX), P < 0.0001	No OS data
			pCR: 22.3%
AIO/CAO STO 0801 (2018)	GEJ adenocarcinoma	Perioperative ECX ± Pa	No difference in R0 resection rate	No difference in OS: 49% (ECX + Pa) vs 62% (ECX)
			80% (ECX + Pa) vs 82% (ECX)	HR: 1.37 (0.84-2.25), P = 0.2
HERFLOT (2014/2023)	HER2 + G/GEJ adenocarcinoma	Perioperative FLOT ± T	Preliminary data	Preliminary data
			R0 ressection rate: 92.9%	3-year OS: 82.1%
			pCR: 21.4%
PETRARCA (2022)	HER2 + G/GEJ adenocarcinoma	Perioperative FLOT ± T ± Pe	The trial was closed prematurely	The trial was closed prematurely
			R0 ressection rate: 90% (FLOT) vs 93% (FLOT + T + Pe)	Median OS not reached
			pCR: 12% (FLOT) vs 35% (FLOT + T + Pe)	HR: 0.56, P = 0.24

R0: Complete resection with no tumor within 1mm; OS: Overall survival; G/GEJ: Gastric and gastroesophageal junction; ECF: Epirubicin, cisplatin, and fluorouracil; HR: Hazard ratio; CT: Chemotherapy; RT: Radiotherapy; FLOT: Fluorouracil, leucovorin, oxaliplatin, docetaxel; 5-FU: 5-fuorouracil; RDT: Radiotherapy ; ECX: Epirubicin, cisplatin, capecitabine; CRT: Chemoradiotherapy; pCR: Complete pathological response; Pa: Panitumumab; Pe: Pertuzumab; T: Trastuzumab; SOX: S-1 and oxaliplatin; CAPOX: Capecitabine, oxaliplatin, docetaxel.

In 2019, the pivotal FLOT4 trial redefined perioperative standards, showing that a docetaxel-based triplet CT regimen, FLOT, significantly improved OS compared to ECF/ECX (HR = 0.77, 95%CI: 0.63-0.94), with median OS of 50 months vs 35 months[9]. Health economic modeling further supported its adoption: FLOT yielded a favorable cost-effectiveness at conventional willingness-to-pay thresholds[44]. However, despite superior outcomes, pCR rates with the FLOT regimen was still below 10% to 15%. Also, a significant proportion of patients were unable to complete the postoperative CT phase due to treatment-related toxicity[11]. Efforts to enhance perioperative outcomes through the incorporation of RT have consistently failed to demonstrate clinically meaningful benefit[45,46]. Phase III trials such as CRITICS, CRITICS-II, and ESOPEC, more recently, did not show superiority of CRT over CT alone - irrespective of treatment sequence (neoadjuvant or adjuvant) or anatomical site (gastric vs G/GEJ) and current evidence does not support routine inclusion of RT in resectable G/JEG cancer management[10]. TOPGEAR, a phase III trial, compared perioperative CT alone with perioperative CT plus neoadjuvant CRT[47]. Patients received the MAGIC regimen (before 2017) or the FLOT regimen (after 2017) with or without radiation. Although there was higher pCR rate with the trimodality approach (17% vs 8%), at a median follow-up of 67 months, OS and PFS remained statistically comparable.

In East Asia, multiple trials explored alternative perioperative regimens based on S-1, particularly in combination with platinum agents. Notably, the RESOLVE and RESONANCE studies assessed docetaxel-based triplets and demonstrated improvements in PFS and 3-year OS[48,49]. However, these findings were observed in patient populations with distinct molecular and surgical characteristics when compared to Western cohorts. For example, tumors exhibiting Epstein-Barr virus positivity and MSI-H status are more commonly encountered in certain Asian populations, which may influence responsiveness to immunotherapy[50,51]. In contrast, Western patients more frequently present with proximally located tumors and a higher prevalence of obesity-related etiologies[52,53]. These biological and epidemiological differences underscore the limitations of directly extrapolating results between regions and emphasize the importance of region-specific trials that account for variations in surgical techniques, tumor biology, and population genetics. Parallel strategies to enhance systemic control through the addition of targeted to cytotoxic backbones have also been largely negative in phase II/III trials for resectable stage G/GEJ cancers. For instance, the phase III AIO/CAO STO 0801 trial evaluated perioperative ECX with or without panitumumab in GEJ adenocarcinoma and showed no improvement in R0 resection rate (80% vs 82%) or OS 49% vs 62%; HR = 1.37, 95%CI: 0.84-2.25; P = 0.2)[54]. Similarly, in HER2-positive tumors, the HERFLOT study (preliminary data) showed a high R0 resection rate (92.9%) and a 21.4% pCR rate with perioperative FLOT plus trastuzumab, yet definitive survival benefit remains to be established[55]. The PETRARCA phase II trial, which investigated the addition of trastuzumab and pertuzumab to perioperative FLOT, reported improved pCR (35% vs 12%) and R0 resection rates (93% vs 90%), but the study was terminated prematurely and did not demonstrate a statistically significant OS benefit (HR = 0.56; P = 0.24)[56]. To date, no antibody-based therapy has been approved.

PERIOPERATIVE IMMUNOTHERAPY

The success of ICIs in metastatic G/GEJ cancers has spurred investigations into their potential benefits in earlier stages[57]. The rationale for introducing ICIs in this context hinges on their potential to amplify systemic antitumor immunity when administered prior to surgical resection and to facilitate the eradication of micrometastatic disease in the postoperative stage[58]. Encouraging results from early-phase studies supported this hypothesis (Table 4). In GASPAR, a phase II trial of spartalizumab (anti-PD-1) plus FLOT in resectable G/GEJ adenocarcinoma, major pathological response (defined as pCR or < 10% residual tumor) was achieved in 50% of patients[59]. Similarly, the DRAGON study tested camrelizumab combined with rivoceranib and SOX CT, showing a significantly higher pCR rate compared to CT alone (18.3% vs 5.0%, OR = 4.5)[60]. However, enthusiasm was tempered by disappointing results from subsequent phase III trials. The VESTIGE trial, which evaluated adjuvant ipilimumab plus nivolumab following neoadjuvant therapy and surgery, reported inferior median DFS in the immunotherapy arm compared to standard CT (11.4 months vs 20.8 months; HR = 1.55, P = 0.99)[61]. Likewise, the Asian ATTRACTION-5 trial failed to demonstrate a relapse-free survival benefit from the addition of adjuvant nivolumab to CAPOX or S-1 CT (68.4% vs 65.3%, 95%CI: 0.69-1.18, P = 0.44)[62].

Table 4 Perioperative immunotherapy: Emerging data on perioperative immunotherapy in gastric and gastroesophageal junction adenocarcinoma.

Trial name	Disease subtype	Strategy	pCR rate	EFS
GASPAR (2022)	G/GEJ adenocarcinoma	Perioperative FLOT + spartalizumab	Early data: Major response rate of 50%	Not reported yet
DRAGON (2024)	G/GEJ adenocarcinoma	Perioperative SOX ± camrelizumab + rivoceranib	18.3% (SOX + RC) vs 5.0% (SOX)	Not reported yet
			OR: 4.5; P < 0.001
VESTIGE (2020/2025)	G/GEJ adenocarcinoma	Adjuvant Ipi/Nivo vs adjuvant CT after neoadjuvant CT	Not an endpoint	11.4 months (Ipi/Nivo) vs 20.8 months (CT)
				HR: 1.55 (1.07-2.25); P = 0.99
ATTRACTION-5 (2024)	G/GEJ adenocarcinoma	Adjuvant CT (CAPOX or S-1) ± nivolumab	Not an endpoint	3-year RFS: 68.4% (nivolumab) vs 65.3% (CT)
				HR: 0.9 (0.69-1.18); P = 0.44
KEYNOTE-585 (2023)	G/GEJ adenocarcinoma	Perioperative CT (cisplatin-based or FLOT) ± pembrolizumab	12.9% (CT + pembrolizumab) vs 2.0% (CT)	44.4 months (CT + pembrolizumab) vs 25.3 months (CT)
			P < 0.00001	HR: 0.81 (0.67-0.99); P = 0.0198
			For dMMR/MSI: 38.1%	Did not meet the threshold for statistical significance (P = 0.0178)
DANTE (2024)	G/GEJ adenocarcinoma	Perioperative FLOT ± atezolizumab	24% (FLOT + atezolizumab) vs 15% (FLOT); P = 0.032	No data
			For CPS ≥ 10: 33% vs 12%
			For dMMR/MSI: 63% vs 27%
MATTERHORN (2024/2025)	G/GEJ adenocarcinoma	Perioperative FLOT ± durvalumab	19.2% (FLOT + durvalumab) vs 7.2% (FLOT)	2-year EFS: 67.4% vs 58.2% HR: 0.71 (0.58-0.86)
			RR: 2.69, (1.86-3.9), P < 0.00001	The difference between the groups in OS has not reached statistical significance

pCR: Complete pathological response; EFS: Event-free survival; G/GEJ: Gastric and gastroesophageal junction; FLOT: Fluorouracil, leucovorin, oxaliplatin, docetaxel; SOX: S-1 and oxaliplatin; RC: Rivoceranib + camrelizumab; OR: Odds ratio; Ipi/Nivo: Ipilimumab + nivolumab; CT: Chemotherapy; CAPOX: Capecitabine, oxaliplatin, docetaxel; RFS: Relapse-free survival; HR: Hazard ratio; CPS: Combined positive score; dMMR: Deficient mismatch repair; MSI: Microsatellite instability; EFS: Event-free survival; OS: Overall survival.

Adding to this complex landscape, the KEYNOTE-585 trial became the first global phase III study to evaluate perioperative pembrolizumab in combination with CT for locally advanced, resectable G/GEJ adenocarcinoma[22]. Although pembrolizumab significantly increased the pCR rate (12.9% vs 2.0%; P < 0.00001), this did not translate into a statistically significant improvement in EFS (median 44.4 months vs 25.3 months; HR = 0.81; P = 0.0198, above the pre-specified significance threshold) or OS (HR = 0.90; P = 0.174). It is worth noting that this trial was based predominantly on cisplatin-based CT regimens rather than the FLOT protocol, which may have influenced both efficacy outcomes and the generalizability of the results. Meanwhile, the DANTE/IKF-s633 trial demonstrated improved pCR rates with the addition of atezolizumab to perioperative FLOT (24% vs 15%, P = 0.031); however, survival data remain immature, and the trial is still considered exploratory[63]. These mixed results may reflect several underlying factors. First, patient selection might have played a crucial role. The inclusion of a broad population without stratification by PD-L1 expression or other biomarkers may have diluted the potential benefit in immunotherapy-sensitive subgroups[64]. Second, the treatment timing could be critical: While immunotherapy has demonstrated efficacy in metastatic disease, its role in the adjuvant setting - when tumor burden is minimal, and immune activation may be less pronounced - is still under investigation[65]. Lastly, differential responses might also exist between HER2-positive and HER2-negative subgroups, as HER2 expression has been linked to a more immunologically “cold” tumor microenvironment, potentially reducing the effectiveness of immune checkpoint inhibition[66,67]. These findings collectively highlight the importance of better biomarker-driven patient selection and refined trial design. In this evolving context, the MATTERHORN study represents a major turning point in the perioperative treatment landscape, and further contributes to the understanding of perioperative immunotherapy in resectable G/GEJ cancer[23]. This international, randomized, double-blind phase III trial evaluated the addition of durvalumab to perioperative FLOT and demonstrated a significant improvement in EFS (30.4 months vs 17.9 months; HR = 0.68; P = 0.0015). The pCR rate was also significantly higher in the durvalumab arm (18% vs 11%). Updated results presented in 2025 showed a favorable trend in OS (HR of 0.76), although statistical significance has not yet been reached[68]. Subgroup analyses suggested enhanced benefit in patients with PD-L1 combined positive score ≥ 5 and MSI-H tumors. Notably, durvalumab did not impair surgical feasibility or increase severe toxicity. These findings reinforce the therapeutic potential of ICI in the perioperative setting. Longer follow up data is awaited and biomarker-driven strategies, such as stratifying patients based on PD-L1 expression, MSI status, or TMB, are under active investigation to refine treatment approaches.

The evolution of perioperative treatment for G/GEJ adenocarcinomas has been marked by incremental and clinically meaningful advances. Following the paradigm-defining results from the MAGIC and FFCD 9703/ACCORD trials, the FLOT4 trial set a new benchmark by demonstrating superior OS with a docetaxel-based triplet regimen compared to older fluoropyrimidine-platinum combinations[7-9]. These results have been consistently reaffirmed across international cohorts and more recently by the ESOPEC trial, solidifying FLOT as the global standard of care[10]. However, despite these gains, the limitations of cytotoxic CT remain evident. pCR rates with FLOT seldom exceed 15%, and, still, nearly one-third of patients fail to complete postoperative treatment due to toxicity[11]. Moreover, the long-term outcomes remain suboptimal for a significant proportion of patients, particularly those with high-risk molecular or histologic features. Immunotherapy, particularly via immune checkpoint blockade, has emerged as a promising approach to enhance systemic control and capitalize on tumor immunogenicity. Early trials such as KEYNOTE-059, ATTRACTION-2, and CheckMate 649 established proof-of-principle in advanced disease[17-19]. Building on this foundation, multiple ongoing studies have evaluated ICIs in the curative-intent setting. The phase III MATTERHORN and KEYNOTE-585 trials represent important steps toward reshaping the perioperative landscape[22,23]. Both trials demonstrated statistically significant improvements in pCR with durvalumab and pembrolizumab, respectively. While KEYNOTE-585 did not meet the prespecified threshold for EFS significance, the numerical advantage is clinically compelling. Importantly, these trials included biomarker-unselected populations, suggesting potential broader applicability. Nonetheless, OS data remain immature, and the potential for immune-related toxicity, as well as the risk of overtreatment in biomarker-negative patients, warrants caution. Moreover, translational correlative studies are essential to dissect the mechanisms of response and resistance, especially given the molecular heterogeneity of G/GEJ tumors. Looking forward, a precision oncology framework is needed to guide perioperative immunotherapy. Integration of predictive biomarkers - such as PD-L1 combined positive score, MSI status, Epstein-Barr virus status, and TMB - along with emerging tools like circulating tumor DNA and spatial immune profiling, may enable rational patient stratification (Table 5)[50]. Further, combination strategies with anti-angiogenics, targeted agents, or novel immunomodulators need to be further explored in biomarker-enriched populations. In conclusion, perioperative CT with FLOT remains the cornerstone of resectable G/GEJ cancer treatment. Immunotherapy-enhanced regimens offer the next frontier, with promising early efficacy signals and an evolving understanding of tumor-immune dynamics. However, their incorporation into routine clinical practice requires validation through mature survival endpoints, safety data, and cost-effectiveness analysis.

Table 5 Biomarkers relevant to the management of gastric and gastroesophageal junction cancer.

Biomarker	Description	Predictive/clinical implication	Current or potential application
PD-L1 (CPS)	Programmed death-ligand 1 expression in tumor and immune cells (CPS ≥ 1, ≥ 5, ≥ 10)	Higher response rates to ICIs	Used in metastatic setting; under evaluation perioperatively
MSI-H/dMMR	Microsatellite instability-high or mismatch repair deficiency	Strong predictor of response to ICIs; pCR > 50% in some trials	Approved in advanced setting; perioperative trials ongoing
EBV+ tumors	Epstein–Barr virus-associated gastric cancers (about 10% of cases)	Inflammatory microenvironment; often high PD-L1 expression and immune cell infiltration	Investigational use; potential future biomarker
TMB	High number of mutations per megabase of tumor DNA	Associated with increased neoantigen load and ICI responsiveness	Emerging biomarker; no standard use yet
ctDNA	Circulating tumor DNA detectable in plasma	May identify minimal residual disease. Early predictor of recurrence risk	Investigated to guide adjuvant therapy or intensification
Tumor immune microenvironment	Immune infiltrates, T-cell exhaustion markers, inflammatory gene signatures	May stratify tumors as “immune hot” or “cold” and guide combination strategies	Ongoing studies using transcriptomics and spatial profiling
TCGA molecular subtypes	TCGA classification: EBV, MSI, GS, CIN	May correlate with immunogenicity and therapy response; especially relevant for EBV and MSI subtypes	May guide therapy selection in precision oncology approaches
CLDN 18.2	Tight junction protein from the claudin family; detected by IHC	Emerging therapeutic target; clinical trials with zolbetuximab show benefit in CLDN18.2-positive gastric tumors	Approved in metastatic setting in some regions; under investigation in perioperative and earlier-stage disease
FGFR2b	Epithelial isoform of the FGFR2	Associated with poor prognosis and more aggressive tumor phenotype, predicts response to FGFR2b-targeted therapies	FGFR2b has been identified as a therapeutic target in G/GEJ cancers, particularly in subgroups with FGFR2 overexpression or amplification

PD-L1: Programmed death-ligand 1; CPS: Combined positive score; ICI: Immune checkpoint inhibitors; dMMR: Deficient mismatch repair; MSI: Microsatellite instability; MSI-H: Microsatellite instability-high; pCR: Complete pathological response; EBV: Epstein-Barr virus; TMB: Tumor mutational burden; ctDNA: Circulating tumor DNA; TCGA: The cancer genome atlas program; CLDN 18.2: Claudin 18.2; FRFR2b: Epithelial isoform of the fibroblast growth factor receptor; GS: Genomically stable; CIN: Chromosomal instability; IHC: Immunohistochemistry.

Future perspectives

In addition to the aforementioned studies, several phase II and III clinical trials are exploring the integration of immunotherapy and targeted therapy into perioperative and neoadjuvant settings, aiming to improve outcomes beyond standard CT alone. For HER2-positive disease, a Japanese phase II trial evaluated trastuzumab deruxtecan (T-DXd) as a neoadjuvant monotherapy in patients with locally advanced, HER2-positive G/GEJ cancer[69]. Although promising in the metastatic setting, T-DXd in the neoadjuvant context yielded only a modest major pathological response rates of 14.8%, suggesting that single-agent T-DXd may be insufficient in earlier-stage disease. Ongoing trials are now testing T-DXd in combination with other agents such as capecitabine and durvalumab to enhance efficacy[70]. In the biomarker-driven field, SPOTLIGHT, a phase III study, investigated zolbetuximab, an anti-claudin 18.2 (CLDN18.2) monoclonal antibody, in combination with CT for patients with locally advanced or metastatic CLDN18.2-positive G/GEJ cancer[71]. The combination improved PFS and OS, with median OS of 18.2 months vs 15.5 months with CT alone. Though this trial focused on metastatic disease, the results have spurred interest in evaluating zolbetuximab in earlier-stage settings. Another molecular target under investigation in G/GEJ cancers is FGFR2b. Ongoing clinical trials in the advanced disease setting, such as FIGHT and FORTITUDE, are evaluating the role of anti-FGFR2b monoclonal antibodies in patients with FGFR2b overexpression[72,73]. Preliminary results have shown promising efficacy, supporting the potential as a new treatment strategy in this subset of patients. Meanwhile, a phase II trial, the NEONIPIGA, investigated a chemotherapy-free neoadjuvant approach using the combination of nivolumab and ipilimumab in patients with resectable, deficient mismatch repair/MSI-H G/GEJ adenocarcinomas[74]. The rationale was based on the well-established sensitivity of MSI-H tumors to immune checkpoint blockade. Results were highly encouraging, with a pCR rate of 59% and major pathological response in 78% of patients. This study provides compelling evidence that ICIs alone may be a highly effective neoadjuvant strategy in this biomarker-defined subgroup and has influenced ongoing trials evaluating non-surgical or organ-preserving approaches in MSI-H G/GEJ cancer[75-77].

CONCLUSION

Overall, the evolving landscape of G/GEJ cancer treatment reflects a growing emphasis on biomarker-based stratification and multimodality therapy. Immunotherapy and antibody-drug conjugates are being integrated earlier in the treatment course, and the personalization of therapy based on HER2, PD-L1, MSI status, and CLDN18.2 expression is becoming increasingly central to clinical decision-making. While no single strategy has yet replaced perioperative CT as the standard of care, these trials are laying the groundwork for more effective and individualized treatment paradigms.

ACKNOWLEDGEMENTS

The authors would like to acknowledge the support of the Center for Personalized Medicine at Hospital Israelita Albert Einstein and the Department of Surgery at Universidade Federal de São Paulo.