Next Article in Journal
Navigating Neoplasm Risk in Inflammatory Bowel Disease and Primary Sclerosing Cholangitis
Previous Article in Journal
Exploring Experimental Models of Colorectal Cancer: A Critical Appraisal from 2D Cell Systems to Organoids, Humanized Mouse Avatars, Organ-on-Chip, CRISPR Engineering, and AI-Driven Platforms—Challenges and Opportunities for Translational Precision Oncology
Previous Article in Special Issue
Unmet Needs and Their Impact on Quality of Life and Symptoms in Myelodysplastic Neoplasm Patients and Caregivers
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 17
Issue 13
10.3390/cancers17132164
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Treatment and Outcomes in Advanced Gastroesophageal Adenocarcinoma in the Pre-Immunotherapy Era Based on the Spanish AGAMENON-SEOM Registry

by
Paula Jimenez-Fonseca
1,*,
Alberto Carmona-Bayonas
2,
Jaime Álvarez-Cañada
3,
Amy Storfer-Isser
4,
Marta Martin-Richard
5,
Tamara Sauri
6,
Juana María Cano
7,
Elia Martínez Moreno
8,
Pablo Pérez-Wert
9,
Javier López
2,
Francisco Garcia Navalon
10,
Lucía Gómez-González
11,
Maribel Ruiz Martín
12,
Ana Belén Rupérez Blanco
13,
Flora López-López
14,
Emilse Roncancio-Díaz
15,
Belén Corbacho
3,
Marta Mateo
3,
Paloma Anguita-Alonso
3 and
Javier Gallego Plazas
16
1
Medical Oncology Department, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
2
Medical Oncology Department, Hospital Universitario Morales Meseguer, Instituto Murciano de Investigación Biosanitaria (IMIB), University of Murcia, 30008 Murcia, Spain
3
Astellas Pharma Spain, 28046 Madrid, Spain
4
Astellas Pharma, Inc., Northbrook, IL 60062, USA
5
Medical Oncology Department, Catalan Institute of Oncology, 08908 L’Hospitalet, Spain
6
Medical Oncology Department, Hospital Clinic and Translational Genomics and Targeted Therapies in Solid Tumors IDIBAPS, 08036 Barcelona, Spain
7
Medical Oncology Department, Hospital General Universitario de Ciudad Real, 13005 Ciudad Real, Spain
8
Medical Oncology Department, Hospital Universitario de Fuenlabrada, 28942 Madrid, Spain
9
Medical Oncology Department, Hospital Universitario La Paz, 28046 Madrid, Spain
10
Medical Oncology Department, Hospital Universitario Son Llatzer, 07198 Mallorca, Spain
11
Medical Oncology Department, Hospital General Universitario de Alicante, 03010 Alicante, Spain
12
Medical Oncology Department, Hospital Universitario Rio Carrión, 34005 Palencia, Spain
13
Medical Oncology Department, Hospital Universitario de Toledo, 45007 Toledo, Spain
14
Medical Oncology Department, Hospital Universitario del Sureste, Arganda del Rey, 28500 Madrid, Spain
15
Astellas Pharma Europe Ltd., Addlestone KT15 2NX, UK
16
Medical Oncology Department, Hospital General Universitario de Elche, 03203 Alicante, Spain
 
add Show full affiliation list
 
remove Hide full affiliation list
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(13), 2164; https://doi.org/10.3390/cancers17132164
Submission received: 30 April 2025 / Revised: 9 June 2025 / Accepted: 11 June 2025 / Published: 27 June 2025
(This article belongs to the Special Issue Symptom Burden in Cancer: Assessment and Management)
Browse Figures
Versions Notes

Simple Summary

There is an unmet need for targeted therapy for human epidermal growth factor receptor 2–negative (HER2-negative), locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (advanced G/GEJa), which is associated with poor survival outcomes. This study aimed to describe the characteristics, treatment, and survival of HER2-negative and HER2-positive patients with advanced G/GEJa in Spain. Among 1357 patients from the Spanish AGAMENON-SEOM registry who initiated first-line polychemotherapy for advanced G/GEJa between 2015 and 2019 (inclusive), 70.1% had HER2-negative disease. Overall, 56.3% of patients with advanced G/GEJa received only one line of therapy, and most (92.7%) HER2-positive patients received targeted therapy (trastuzumab) as part of first-line treatment. HER2-negative patients had significantly shorter progression-free survival (median of 5.92 months vs. 7.37 months) and overall survival (median of 10.49 months vs. 13.82 months) compared with HER2-positive patients. The survival difference underscores the critical need for targeted first-line therapies for HER2-negative patients.

Abstract

Background/Objectives: Human epidermal growth factor receptor 2–negative (HER2-negative), locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (advanced G/GEJa) is associated with poor survival outcomes, and there is an unmet need for targeted therapy. This study, conducted in the pre-immunotherapy era, aimed to describe the characteristics and management, and compare the survival, of HER2-negative and HER2-positive patients initiating first-line (1L) treatment for advanced G/GEJa in Spain and estimate the number of HER2-negative patients eligible for 1L polychemotherapy. Methods: Patients from the AGAMENON-SEOM registry who initiated 1L polychemotherapy for advanced G/GEJa (2015–2019) in Spain were included. Results: In total, 1357 patients were included (951 [70.1%] HER2-negative; 315 [23.2%] HER2-positive; 91 [6.7%] unknown HER2 status). Most patients (56.3%) received one line of therapy; 27.6% received two lines; and 16.1% received three lines. Among HER2-positive patients, 92.7% received trastuzumab as part of 1L treatment. The use of FOLFOX and CAPOX increased over the study period (2015–2019). HER2-negative patients had significantly shorter progression-free survival (median, 5.92 months [95% CI, 5.59–6.38] vs. 7.37 months [95% CI, 6.55–8.29]; log-rank p < 0.0001) and overall survival (median, 10.49 months [95% CI, 9.74–11.05] vs. 13.82 months [95% CI, 12.30–14.74]; adjusted time ratio, 0.812 [95% CI, 0.722–0.913]; p = 0.0005) than HER2-positive patients. Per probabilistic sensitivity analyses, an estimated 2856 (95% CI, 1619–4134) Spanish patients with HER2-negative advanced G/GEJa were eligible for 1L polychemotherapy in 2024. Conclusions: The survival difference between HER2-positive and HER2-negative patients underscores the critical need for targeted therapies for HER2-negative patients in the 1L setting.

1. Introduction

Gastric cancer is the fifth most common cancer worldwide and a leading cause of cancer-related death, with nearly a million new cases globally and more than 650,000 deaths in 2022 [1]. The worldwide age-standardized 5-year survival rate for stomach cancer was 20–40% in 2000–2014 [2], and patients with locally advanced or metastatic gastroesophageal junction (GEJ) adenocarcinoma have a median survival of 7–11 months [3]. The incidence rate of gastric adenocarcinoma is higher than that of GEJ adenocarcinoma; for example, in an analysis of real-world data from patients with advanced gastric, GEJ, or esophageal adenocarcinoma in the Spanish AGAMENON-SEOM registry, the primary tumor location was the stomach in the majority of patients (78%), compared with the GEJ (13%) or esophagus (9%) [4]. However, data demonstrate a decline in gastric adenocarcinoma and an increase in GEJ adenocarcinoma since the 1970s [1,5,6]. In Spain, gastric cancer was the ninth most common cancer in 2021 and the eighth most common cause of cancer-related death in 2020 [7]. Although mortality rates in Spain are lower than global rates, there are still over 5000 deaths in Spain every year due to gastric cancer [7], and the 5-year net survival rate between 2008 and 2013 was 27.4% among patients with gastric cancer [8]. The burden of gastric and gastroesophageal junction adenocarcinoma (G/GEJa) is high, even compared with other cancers, with increasingly severe symptoms, worsening health-related quality of life, and accelerating healthcare resource utilization and cost as the disease advances [9].
There have been therapeutic advances for patients with human epidermal growth factor receptor 2–overexpressing (HER2-positive) G/GEJa. Notably, trastuzumab is a monoclonal antibody that binds to the extracellular domain of the transmembrane receptor protein HER2, inhibiting proliferation of HER2-expressing tumors and activating antibody-dependent cellular cytotoxicity [10]. Trastuzumab, in combination with chemotherapy, significantly improved overall survival (OS) and progression-free survival (PFS) in patients with HER2-positive, locally advanced unresectable or metastatic G/GEJa (advanced G/GEJa) compared with chemotherapy alone in a clinical study [11] and subsequently became a standard treatment for this disease [12]. Prior to the advent of trastuzumab, patients with HER2-positive G/GEJa had outcomes similar to, or worse than, patients with HER2-negative disease [10,13,14]. However, they now have a survival advantage because of their eligibility for targeted therapy and trastuzumab deruxtecan as second-line (2L) therapy [13,15,16].
Subsequently, therapies targeting programmed death receptor 1 (PD-1), an immune checkpoint protein, became available. Pembrolizumab is a PD-1 inhibitor recently approved, in conjunction with trastuzumab and chemotherapy, for first-line (1L) treatment of patients with HER2-positive G/GEJa expressing programmed death-ligand 1 (PD-L1; combined positive score [CPS] ≥ 1) [17,18,19]. For patients with HER2-negative G/GEJa, pembrolizumab and nivolumab (another PD-1 inhibitor) are approved for 1L treatment of adults with HER2-negative advanced or metastatic G/GEJ or esophageal adenocarcinoma whose tumors express PD-L1 [17,18,20]. When used in combination with chemotherapy in patients with HER2-negative disease, nivolumab and pembrolizumab significantly improved PFS and OS compared with chemotherapy alone [21,22]. Because PD-L1 is not ubiquitously expressed in G/GEJ tumors (~50%) [23,24,25], there remains an unmet need for more effective, targeted treatment for patients with HER2-negative advanced G/GEJa who are not candidates for immunotherapy. Overall, approximately three-quarters of patients with advanced G/GEJa have HER2-negative disease [10,26].
This study was conducted using real-world data from the AGAMENON-SEOM registry to describe the clinical characteristics, treatment patterns, and survival outcomes (PFS and OS) in Spanish patients with advanced G/GEJa. Additionally, this study compared PFS and OS by HER2 status and estimated the number of patients in Spain with HER2-negative advanced G/GEJa who were eligible for 1L polychemotherapy.

2. Methods

2.1. AGAMENON-SEOM Registry

AGAMENON-SEOM is an observational, clinicopathological registry managed by the Spanish Society of Medical Oncology (SEOM). Its purpose is to describe the diagnosis and treatment approaches for G/GEJa in a clinical practice setting according to each participating center’s usual practice [27]. The registry contains data on over 4000 patients from 40 Spanish hospitals, including 2470 patients who received 1L polychemotherapy [4]. Sixteen of the 17 regions in Spain are represented, allowing geographical coverage across the country, with more participating centers located in regions with greater population density.
Eligibility criteria for patients included in this analysis of the AGAMENON-SEOM registry are summarized in Table 1. Briefly, eligible patients are adults (≥18 years) with histologically confirmed advanced gastric, GEJ, or distal esophageal adenocarcinoma who were treated with at least one cycle of 1L polychemotherapy and were followed for at least 3 months (except for patients who died sooner than 3 months after treatment initiation) [28,29,30]. Patients are excluded from the registry if they participated in a clinical trial without standard chemotherapy; received prior systemic therapy for advanced gastric, GEJ, or distal esophageal adenocarcinoma; completed prior neoadjuvant or adjuvant chemotherapy, radiotherapy, or chemoradiotherapy less than 6 months earlier; or were diagnosed with any cancer other than G/GEJa.
The data were gathered using a web-based data collection tool and managed through a website (http://www.agamenonstudy.com/) using filters and a system of queries to guarantee data reliability and control for inconsistent data [31].

2.2. Study Design

This longitudinal cohort study included patients from the AGAMENON-SEOM registry who initiated 1L polychemotherapy for advanced G/GEJa in Spain between 1 January 2015 and 31 December 2019 (Table 1). The study period was between 1 January 2015 and 31 December 2021, allowing at least 2 years of follow-up data for each patient. Patients were excluded from the study if they had distal esophageal cancer (primary site).

2.3. Objectives

Using this cohort of patients who received 1L polychemotherapy for advanced G/GEJa, the objectives of this study were (1) to describe the disease management for all patients and stratified by HER2 status; (2) to describe the sociodemographic and disease characteristics of all patients and stratified by HER2 status; (3) to compare PFS and OS by HER2 status for all 1L regimens, and OS for the subsets of patients who received 1L FOLFOX (folinic acid, fluorouracil, and oxaliplatin) or 1L CAPOX (capecitabine and oxaliplatin); and (4) to estimate the number of patients in Spain with HER2-negative advanced G/GEJa who were eligible for 1L polychemotherapy.

2.4. Statistical Analysis

Descriptive statistics were used to summarize disease management and patient sociodemographic and disease characteristics. PFS was defined as the time from the index date, defined as the initiation date of 1L polychemotherapy for advanced G/GEJa, until the date of progressive disease or date of death by any cause (whichever occurred first). OS was defined as the time from the index date to date of death by any cause. Patients were censored at the date of their last contact or the end of the study (whichever occurred first).
PFS and OS were summarized using Kaplan–Meier estimates. The log-rank test was used to compare PFS and OS for patients with HER2-positive disease and HER2-negative disease. p-values < 0.05 were considered statistically significant. Accelerated failure time (AFT) models with a generalized gamma distribution [32] were used to compare OS for patients with HER2-negative disease and HER2-positive disease, as the proportional hazards assumption was violated for HER2 status. AFT models were fitted without confounders (unadjusted) and with adjustment for confounders that were preselected by study investigators: Lauren histological subtype (intestinal; diffuse; mixed; not available/not classifiable), number of metastatic sites (0–3; ≥4), Eastern Cooperative Oncology Group performance status (ECOG PS: 0; 1; ≥2), presence of bone metastases (yes; no), presence of ascites (yes; no), and neutrophil-to-lymphocyte ratio (NLR) category (<4; 4 to <8; ≥8). The results from the AFT models included the coefficient, standard error, time ratio (TR), 95% confidence interval (CI), and p-value. A TR < 1 indicates that HER2-negative status was associated with shorter survival (accelerated failure) compared with HER2-positive status (the reference category).
Six parameters were required to estimate the number of patients in Spain with HER2-negative advanced G/GEJa who were eligible for 1L polychemotherapy. Since there is no single data source representative of the Spanish population that includes all six parameters, information from the literature and the results of this study were used. The values of each parameter and their data sources were as follows: the number of new cases of G/GEJ cancer in Spain in 2024 (6868 patients; parameter 1 [33]) with advanced disease (84%; parameter 2 [34]) that was adenocarcinoma (90%; parameter 3 [35]) who were eligible for polychemotherapy (78.7%; parameter 4 [30]), were tested for HER2 (93.3%; parameter 5 [results from this study]), and had HER2-negative disease (75.1%; parameter 6 [results from this study]). Probabilistic sensitivity analyses (PSAs) were conducted to account for the plausible variation across parameters 2–6. Each parameter was considered a random variable and was assumed to have a beta distribution. Parameters were simultaneously changed, with values drawn by random sampling from the beta distribution. The PSA was repeated 10,000 times to generate new parameter values, quantify the uncertainty of the parameters, and produce an average estimate and 95% CI.

3. Results

3.1. Disposition

Of 4479 patients with advanced G/GEJa assessed for participation in the AGAMENON-SEOM registry, 3315 patients fulfilled all eligibility criteria and 1164 patients were excluded for the following reasons: 1065 patients did not receive combination chemotherapy using at least two drugs, 50 patients were not followed for at least 3 months, and 49 patients had completed prior neoadjuvant or adjuvant chemotherapy, radiotherapy, or chemoradiotherapy less than 6 months earlier. Of the 3315 patients fulfilling all eligibility criteria for the registry, 1513 patients initiated 1L polychemotherapy for advanced G/GEJa between 1 January 2015 and 31 December 2019. After excluding 156 patients with distal esophageal adenocarcinoma, the final study population included 1357 patients.

3.2. Sociodemographic and Disease Characteristics

Of the 1357 patients with advanced G/GEJa who were included in this study, 951 (70.1%) patients had HER2-negative disease, 315 (23.2%) patients had HER2-positive disease, and 91 (6.7%) patients had unknown HER2 status (Table 2). The median age (range) of all patients at 1L treatment initiation was 64.7 years (19.9–88.5); most patients were male (67.3%), just under half were aged 65 years or older (48.9%), and just over half had a body mass index of 18.5 to <25 kg/m2 (53.9%). Most patients had an ECOG PS of 0–1 (85.5%), a primary tumor site of the stomach (71.6%), and de novo disease (84.5%). The proportions of patients with diffuse (38.5%) and intestinal (37.1%) histologies were similar. Just over half of patients had ≥2 metastatic sites (51.6%), and the most common sites were locoregional lymph nodes (63.3%), peritoneum (48.6%), and non-locoregional lymph nodes (44.2%). Metastatic ascites was reported in 23.6% of patients, and 11.6% of patients had bone metastases. The median (range) NLR was 3.4 (0.3–102.0). Most patients (60.4%) had a low NLR (<4); 27.3% had a moderate NLR (4 to <8); and 10.5% had a high NLR (≥8).
There were some notable differences between patients with HER2-negative disease and patients with HER2-positive disease in terms of sociodemographic and disease characteristics. Compared with patients with HER2-positive disease, patients with HER2-negative disease were slightly younger (median age, 63.8 vs. 65.8 years) and fewer were male (64.7% vs. 75.6%); additionally, their primary tumor site was more likely to be gastric (75.6% vs. 58.1%) and to have diffuse histology (45.4% vs. 18.4%).

3.3. First-Line Treatment

Most patients (56.3%) received only one line of therapy. Between 2015 and 2019, the median (interquartile range) duration of 1L treatment was 4.8 months (2.8–7.2), and patients received a median (interquartile range) of 6 (4–11) chemotherapy cycles during 1L treatment (Table 3). Of the 315 patients with HER2-positive disease, 292 (92.7%) received trastuzumab as part of their 1L treatment regimen. Use of FOLFOX and CAPOX increased during the 2015–2019 period, as these therapies became commonly used 1L regimens for advanced G/GEJa from 2017 onward (Figure 1a). In the overall population and HER2-negative subgroup, the most common 1L chemotherapy regimen in 2019 was FOLFOX (Figure 1a,b); CAPOX was the most common 1L chemotherapy regimen in 2019 for patients with HER2-positive disease (Figure 1c).

3.4. Second- and Third-Line Treatment

As previously noted, a majority of patients (56.3%) received only one line of therapy; 27.6% of patients received two lines of therapy; and 16.1% received three lines of therapy. The most common 2L regimens during the 2015–2019 period were paclitaxel alone and paclitaxel in combination with ramucirumab (Figure 2a). Most patients who received third-line (3L) therapy were treated with monotherapy (Figure 2a). Similar trends for 2L and 3L treatment regimens were observed across HER2-negative and HER2-positive subgroups during the 2015–2019 period (Figure 2b,c).

3.5. PFS

Median PFS for all patients was 6.28 months (95% CI, 5.92–6.64; Figure 3a). Patients with HER2-negative disease had significantly shorter median PFS compared with those who had HER2-positive disease (5.92 months [95% CI, 5.59–6.38] vs. 7.37 months [95% CI, 6.55–8.29]; p < 0.0001; Figure 3b).

3.6. OS

Median OS was 11.05 months for all patients (95% CI, 10.53–11.71; Figure 4a). Patients with HER2-negative disease had a significantly shorter median OS compared with those with HER2-positive disease (10.49 months [95% CI, 9.74–11.05] vs. 13.82 months [95% CI, 12.30–14.74]; p = 0.0004; Figure 4b).
Results from AFT models showed that patients with HER2-negative disease had significantly shorter OS than those with HER2-positive disease (unadjusted TR, 0.790; 95% CI, 0.701–0.890; p = 0.0001 (Table S1); adjusted TR [aTR], 0.812; 95% CI, 0.722–0.913; p = 0.0005 (Table S2)). In the adjusted AFT model, the overall p-value for each confounder was statistically significant. Prognostic factors associated with worse OS included diffuse vs. intestinal histological subtype (aTR, 0.838; 95% CI, 0.742–0.946); ≥4 vs. 0–3 metastatic sites (aTR, 0.749; 95% CI, 0.622–0.900); ECOG PS of 1 vs. 0 (aTR, 0.852; 95% CI, 0.754–0.963) and ECOG PS ≥ 2 vs. 0 (aTR, 0.507; 95% CI, 0.429–0.598); bone metastases (aTR, 0.783; 95% CI, 0.670–0.916); ascites (aTR, 0.744; 95% CI, 0.657–0.841); NLR 4 to <8 vs. <4 (aTR, 0.789; 95% CI, 0.704–0.885) and NLR ≥ 8 vs. <4 (aTR, 0.636; 95% CI, 0.539–0.750; Table S2).

3.7. Comparison of OS by HER2 Status Among Patients Receiving 1L FOLFOX

Median OS was significantly shorter for the 270 patients with HER2-negative disease receiving 1L FOLFOX compared with the 62 patients with HER2-positive disease receiving 1L FOLFOX (10.72 months [95% CI, 9.28–11.55] vs. 16.61 months [95% CI, 11.18–21.09]; p = 0.0009; Figure S1). Patients with HER2-negative disease had significantly shorter OS in the unadjusted AFT model (TR, 0.664; 95% CI, 0.520–0.848; p = 0.0010; Table S3) and after adjusting for confounders (aTR, 0.675; 95% CI, 0.525–0.868; p = 0.0022; Table S4) than patients with HER2-positive disease. In the adjusted AFT model, ECOG PS and NLR were significantly associated with OS. Prognostic factors associated with worse survival included ECOG PS of ≥2 vs. 0 (aTR, 0.619; 95% CI, 0.450–0.852), NLR 4 to < 8 vs. <4 (aTR, 0.731; 95% CI, 0.590–0.905), and NLR ≥8 vs. <4 (aTR, 0.633; 95% CI, 0.477–0.840).

3.8. Comparison of OS by HER2 Status Among Patients Receiving 1L CAPOX

Median OS did not significantly differ between the 228 patients with HER2-negative disease and 98 patients with HER2-positive disease who received 1L CAPOX (11.02 months [95% CI, 8.62–14.44] vs. 13.98 months [95% CI, 11.88–16.09]; p = 0.54; Figure S2). HER2-negative disease was not significantly associated with OS in the unadjusted or adjusted AFT analyses (TR = 0.888; 95% CI, 0.695–1.135; p = 0.34; Tables S5 and S6). In the adjusted AFT model, histological subtype, number of metastatic sites, ECOG PS, and NLR were significantly associated with OS. Prognostic factors associated with shorter OS were diffuse vs. intestinal histological subtype (aTR, 0.631; 95% CI, 0.487–0.817); ≥4 vs. 0–3 metastatic sites (aTR, 0.462; 95% CI, 0.311–0.687); ECOG PS of 1 vs. 0 (aTR, 0.686; 95% CI, 0.523–0.900) and ECOG PS ≥ 2 vs. 0 (aTR, 0.357; 95% CI, 0.238–0.536); NLR 4 to <8 vs. <4 (aTR, 0.609; 95% CI, 0.479–0.773) and NLR ≥ 8 vs. <4 (aTR, 0.642; 95% CI, 0.450–0.915; Table S6).

3.9. Number of Patients with HER2-Negative Disease Eligible for 1L Polychemotherapy

Using PSA, the average estimated number of patients with HER2-negative advanced G/GEJa in Spain who were eligible for 1L polychemotherapy in 2024 was 2856 (95% CI, 1619–4134; Figure S3).

4. Discussion

Advanced G/GEJa is associated with severe symptoms, significant healthcare resource utilization and cost, and poor prognosis, particularly for HER2-negative disease, which lacked targeted therapies before the approval of pembrolizumab and nivolumab for advanced G/GEJa [3,9]. This study aimed to describe the clinical characteristics, treatment patterns, and survival outcomes of patients in Spain with advanced G/GEJa; to compare PFS and OS by HER2 status; and to estimate the number of patients in Spain with HER2-negative advanced G/GEJa who were eligible for 1L polychemotherapy. A majority of patients (56.3%) received only one line of therapy; 27.6% received two lines; and 16.1% received three lines. FOLFOX and CAPOX were the most common 1L regimens from 2017 onward, and paclitaxel alone and paclitaxel in combination with ramucirumab were the most common 2L regimens. Median OS was similar with FOLFOX and CAPOX for patients with HER2-negative G/GEJa (10.72 vs. 11.02, respectively) but was longer with FOLFOX vs. CAPOX for patients with HER2-positive disease (16.61 vs. 13.98, respectively). Median PFS (6.28 months overall) was significantly shorter for patients with HER2-negative vs. HER2-positive disease (5.92 vs. 7.37 months). Median OS (11.05 months overall) was also significantly shorter for patients with HER2-negative vs. HER2-positive disease (10.49 vs. 13.82 months). In adjusted models for all 1L treatment regimens, prognostic factors associated with worse OS included HER2-negative vs. HER2-positive status; diffuse vs. intestinal histological subtype; ≥4 vs. 0–3 metastatic sites; ECOG PS of 1 or ≥2 vs. 0; bone metastases; ascites; NLR 4 to <8 vs. <4; and NLR ≥ 8 vs. <4.
In this cohort of patients, most had de novo disease, a low ECOG PS (0–1), and a low NLR (<4). Over half of patients in this study received only 1L treatment, perhaps reflecting delayed diagnosis and poor prognosis [36,37]. The emergence of FOLFOX and CAPOX as the most common 1L chemotherapy regimens between 2015 and 2019 is consistent with the European Society for Medical Oncology (ESMO) guidelines for gastric cancer, which recommend platinum-fluoropyrimidine doublet chemotherapy for 1L treatment of advanced G/GEJa [36]. Paclitaxel alone and paclitaxel in combination with ramucirumab as the most common 2L treatments also aligns with the most recent ESMO guidelines [36,38].
Consistent with previous estimates that approximately three-quarters of advanced G/GEJa cases are HER2-negative [10,26], 70.1% of patients in this study had HER2-negative disease. Compared with patients with HER2-positive disease, patients with HER2-negative disease were slightly younger and less likely to be male. They were also more likely to have primary gastric (vs. GEJ) tumors with diffuse (vs. intestinal) histology. Male predominance of HER2-positive gastric cancer has been noted previously [39,40,41], as have associations between HER2 overexpression and older age, GEJ primary tumor site, and intestinal histology [10,41,42].
The observed differences in survival between HER2-positive and HER2-negative subgroups (i.e., significantly shorter PFS and OS in patients with HER2-negative disease, and significantly shorter OS after adjusting for confounders in patients with HER2-negative disease, including those receiving 1L FOLFOX) may be mainly attributed to the lack of targeted therapies for patients with HER2-negative disease in the 1L setting during the time period studied (2015–2021). HER2 is a transmembrane receptor tyrosine kinase that is activated by heterodimerization with other members of the human epidermal growth factor receptor family, initiating signal transduction pathways that stimulate proliferation, differentiation, and survival of tumor cells [43]. Targeted therapy for HER2-positive disease, including antibodies that inhibit HER2-mediated signaling by reducing HER2 receptor expression or dimerization (e.g., trastuzumab, which was received by 92.7% of patients with HER2-positive disease as part of their 1L treatment regimen), has contributed to improved survival in that population [13,43]. The differences between HER2-positive and HER2-negative populations may increase further with the advent of trastuzumab deruxtecan [15,16].
In 2021, the immune checkpoint inhibitors nivolumab and pembrolizumab were approved in Europe for 1L treatment of adults with HER2-negative advanced or metastatic gastric, GEJ, or esophageal adenocarcinoma whose tumors express PD-L1 with a CPS ≥ 5 for nivolumab and ≥10 for pembrolizumab [21,22]. The approval for pembrolizumab was updated in 2023 to allow a CPS ≥ 1 [44]; however, in Spain, pembrolizumab financing is restricted to patients whose tumors express PD-L1 with a CPS ≥ 10 [45]. There remains an unmet need for personalized targeted therapy to improve survival outcomes in patients with HER2-negative G/GEJa [36], as not all G/GEJa tumors express PD-L1 [23,24,25] or enough PD-L1 to receive financing (CPS ≥ 5 for nivolumab or CPS ≥ 10 for pembrolizumab in Spain [46]). Furthermore, the estimated 2856 patients with HER2-negative advanced G/GEJa in Spain who were eligible for 1L treatment with polychemotherapy in 2024 represent a substantial proportion of the total number of new cases of G/GEJ cancer in Spain in 2024 (6868 patients), underscoring this unmet need.
This study has several strengths. It is a large-scale, real-world study based on the AGAMENON-SEOM registry database, with broad representation of regions across Spain. The study design allowed for each patient to have at least 2 years of follow-up. The data reflect evolving trends in contemporary disease management over recent years, including shifts in polychemotherapy regimens. Altogether, the study provides detailed, up-to-date information on a large cohort of patients with advanced G/GEJa in Spain.
This study also has limitations. First, the treatment landscape has changed markedly since the introduction of immunotherapies and later treatment lines in HER2-positive disease (trastuzumab deruxtecan). Second, it is retrospective and therefore subject to potential for bias and missing information. Third, it is not a population-based study because the AGAMENON-SEOM registry only includes centers that opt to participate. Access to 2L and 3L treatment may have been limited in some centers. Fourth, there was a minority of patients (6.7%) whose HER2 status was unknown. Fifth, it is not known how many of the patients receiving polychemotherapy would also be suitable for new agents combined with polychemotherapy. When estimating the number of patients with HER2-negative advanced G/GEJa who were eligible for 1L polychemotherapy, there was no single data source representative of patients in Spain with HER2-negative advanced G/GEJa that included all of the required parameters; therefore, multiple sources of data were used for this estimation. To address this limitation, PSA was used to quantify the uncertainty of each parameter and estimate the number of eligible patients.

5. Conclusions

This study is based on a robust analysis of the largest cohort of patients with advanced G/GEJa in Spain, describing clinical characteristics, treatment patterns, and survival outcomes. Comparisons of PFS and OS between patients with HER2-negative and HER2-positive disease provide further evidence that there is a treatment gap for HER2-negative disease, which represents the majority (approximately three-quarters [10,26]) of advanced G/GEJa cases. Irrespective of HER2 status, the aggressiveness of this disease is apparent in the minority of patients who receive subsequent lines of therapy beyond 1L treatment. More effective treatments are critically needed. Findings from this study may help inform new healthcare policies and spur further research toward improving disease management and treatment outcomes.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers17132164/s1, Figure S1: Kaplan–Meier plot of OS by HER2 status among patients receiving 1L FOLFOX; Figure S2: Kaplan–Meier plot of OS by HER2 status among patients receiving 1L CAPOX; Figure S3: PSA to estimate the number of patients with HER2-negative advanced G/GEJa in Spain who were eligible for 1L polychemotherapy in 2024; Table S1: Unadjusted AFT model of OS for patients with HER2-negative and HER2-positive disease: all regimens (n = 1266); Table S2: Adjusted AFT model of OS for patients with HER2-negative and HER2-positive disease: all regimens (n = 1266); Table S3: Unadjusted AFT model of OS for patients with HER2-negative and HER2-positive disease: 1L FOLFOX (n = 332); Table S4: Adjusted AFT model of OS for patients with HER2-negative and HER2-positive disease: 1L FOLFOX (n = 332); Table S5: Unadjusted AFT model of OS for patients with HER2-negative and HER2-positive disease: 1L CAPOX (n = 326); Table S6: Adjusted AFT model of OS for patients with HER2-negative and HER2-positive disease: 1L CAPOX (n = 326).

Author Contributions

Conceptualization, P.J.-F., A.C.-B., J.Á.-C., A.S.-I., E.R.-D., B.C., and J.G.P.; formal analysis, J.Á.-C., A.S.-I., E.R.-D., and B.C.; data curation, P.J.-F., A.C.-B., J.Á.-C., A.S.-I., M.M.-R., T.S., J.M.C., E.M.M., P.P.-W., J.L., F.G.N., L.G.-G., M.R.M., A.B.R.B., F.L.-L., E.R.-D., B.C., M.M., P.A.-A., and J.G.P. All authors have read and agreed to the published version of the manuscript.

Funding

This study was sponsored by Astellas Pharma Europe Ltd.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki. As the AGAMENON-SEOM registry is approved, there is no requirement for additional approval for the AGAPONIS study, which is considered a sub-study. The protocol (ISN/Protocol 8951-MA-3240) was approved on 12 December 2022.

Informed Consent Statement

The study did not involve the collection, use, or transmittal of individually identifiable data; hence, patient informed consent was not required. Living patients enrolled in the AGAMENON-SEOM registry had been informed that their de-identified data would be used for research projects and provided written informed consent at the time of enrollment. Some patients were deceased at the time of inclusion in the AGAMENON-SEOM registry database.

Data Availability Statement

The AGAPONIS study is a collaborative study between Astellas and AGAMENON group, both of which contributed to the creation of the study protocol. The data for this publication are from the AGAMENON registry (https://www.agamenonstudy.com/), which is property of SEOM (Spanish Society of Medical Oncology) exclusively.

Acknowledgments

The authors gratefully acknowledge the investigators of the AGAMENON-SEOM registry and the patients who participated in the study, as well as SEOM and its Outcomes Research and Clinical Practice Evaluation section for promoting this registry. Medical writing/editorial assistance was provided by Stevin Joseph, Pamela Barendt, and Cheryl Casterline (Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, USA) and was funded by Astellas.

Conflicts of Interest

Paula Jimenez-Fonseca: Consultant, advisory, or speaker role: Astellas, AstraZeneca, Bristol–Myers Squibb (BMS), Esteve, Merck Sharp & Dohme (MSD), Novartis, Nutricia, Pfizer, Rovi, Takeda, and Viatris; Research grants: Astellas, AstraZeneca, and BMS. Alberto Carmona-Bayonas: Consultant, advisory, or speaker role: Amgen, Astellas, BMS, and Servier; Research grants: Astellas, AstraZeneca, and BMS. Jaime Álvarez-Cañada: Employee: Astellas. Amy Storfer-Isser: Employee: Astellas. Marta Martin-Richard: Advisory board: Astellas and BMS. Tamara Sauri: Honoraria: BMS, Merck Sharp & Dohme, and BeiGene; Advisory board: BMS; Travel support: BMS. Juana María Cano: Nothing to disclose. Elia Martínez Moreno: Nothing to disclose. Pablo Pérez-Wert: Nothing to disclose. Javier López: Support for attending symposia: Eli Lilly and Daiichi Sankyo. Francisco Garcia Navalon: Nothing to disclose. Lucía Gómez-González: Nothing to disclose. Maribel Ruiz Martín: Nothing to disclose. Ana Belén Rupérez Blanco: Grant for attending meetings. Flora López-López: Educational grants/support: Lilly, MSD, and Roche. Emilse Roncancio-Díaz: Employee: Astellas. Belén Corbacho: Employee: Astellas. Marta Mateo: Employee: Astellas. Paloma Anguita-Alonso: Employee: Astellas. Javier Gallego Plazas: Advisory board: Amgen, Lilly, MSD, and Servier; Research grants: Astellas, AstraZeneca, BMS, Daiichi Sankyo, Lilly, and Servier; Speaker role: Amgen, BMS, Lilly, and Servier; Educational grants: Amgen.

Abbreviations

The following abbreviations are used in this manuscript:
1LFirst-line
2LSecond-line
3LThird-line
AFTAccelerated failure time
aTRAdjusted time ratio
BMIBody mass index
CAPOXCapecitabine and oxaliplatin
CIConfidence interval
CPSCombined positive score
ECOG PSEastern Cooperative Oncology Group performance status
EOXEpirubicin, oxaliplatin, and capecitabine
ESMOEuropean Society for Medical Oncology
FOLFOXFolinic acid, fluorouracil, and oxaliplatin
FPFluorouracil and cisplatin
GEJGastroesophageal junction
G/GEJaGastric/gastroesophageal junction adenocarcinoma
HER2Human epidermal growth factor receptor 2
NLRNeutrophil-to-lymphocyte ratio
OSOverall survival
PCCisplatin and capecitabine
PD-1Programmed death receptor 1
PD-L1Programmed death-ligand 1
PFSProgression-free survival
PSAProbabilistic sensitivity analysis
SEStandard error
SEOMSpanish Society of Medical Oncology
TRTime ratio

References

  1. Bray, F.; Laversanne, M.; Sung, H.; Ferlay, J.; Siegel, R.L.; Soerjomataram, I.; Jemal, A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2024, 74, 229–263. [Google Scholar] [CrossRef]
  2. Allemani, C.; Matsuda, T.; Di Carlo, V.; Harewood, R.; Matz, M.; Niksic, M.; Bonaventure, A.; Valkov, M.; Johnson, C.J.; Esteve, J.; et al. Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): Analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet 2018, 391, 1023–1075. [Google Scholar] [CrossRef] [PubMed]
  3. Gil-Delgado, M.A.; Lucidarme, O.; Bachet, J.B.; Mahi, N.; Khayat, D. Long-term survival in gastroesophageal junction adenocarcinoma: Ramucirumab. Case Rep. Gastroenterol. 2018, 12, 532–539. [Google Scholar] [CrossRef] [PubMed]
  4. Gallego Plazas, J.; Arias-Martinez, A.; Lecumberri, A.; Martinez de Castro, E.; Custodio, A.; Cano, J.M.; Hernandez, R.; Montes, A.F.; Macias, I.; Pieras-Lopez, A.; et al. Sex and gender disparities in patients with advanced gastroesophageal adenocarcinoma: Data from the AGAMENON-SEOM registry. ESMO Open 2022, 7, 100514. [Google Scholar] [CrossRef]
  5. Agarwal, S.; Bell, M.G.; Dhaliwal, L.; Codipilly, D.C.; Dierkhising, R.A.; Lansing, R.; Gibbons, E.E.; Leggett, C.L.; Kisiel, J.B.; Iyer, P.G. Population based time trends in the epidemiology and mortality of gastroesophageal junction and esophageal adenocarcinoma. Dig. Dis. Sci. 2024, 69, 246–253. [Google Scholar] [CrossRef] [PubMed]
  6. Buas, M.F.; Vaughan, T.L. Epidemiology and risk factors for gastroesophageal junction tumors: Understanding the rising incidence of this disease. Semin. Radiat. Oncol. 2013, 23, 3–9. [Google Scholar] [CrossRef]
  7. Spanish Society of Medical Oncology (SEOM). Las Cifras del Cáncer en España [Cancer Figures in Spain] 2021. Available online: https://seom.org/images/Cifras_del_cancer_en_Espnaha_2021.pdf (accessed on 21 April 2025).
  8. Guevara, M.; Molinuevo, A.; Salmeron, D.; Marcos-Gragera, R.; Carulla, M.; Chirlaque, M.D.; Rodriguez Camblor, M.; Aleman, A.; Rojas, D.; Vizcaino Batlles, A.; et al. Cancer survival in adults in Spain: A population-based study of the Spanish network of cancer registries (REDECAN). Cancers 2022, 14, 2441. [Google Scholar] [CrossRef]
  9. Casamayor, M.; Morlock, R.; Maeda, H.; Ajani, J. Targeted literature review of the global burden of gastric cancer. Ecancermedicalscience 2018, 12, 883. [Google Scholar] [CrossRef]
  10. Gravalos, C.; Jimeno, A. HER2 in gastric cancer: A new prognostic factor and a novel therapeutic target. Ann. Oncol. 2008, 19, 1523–1529. [Google Scholar] [CrossRef]
  11. Bang, Y.J.; Van Cutsem, E.; Feyereislova, A.; Chung, H.C.; Shen, L.; Sawaki, A.; Lordick, F.; Ohtsu, A.; Omuro, Y.; Satoh, T.; et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 2010, 376, 687–697. [Google Scholar] [CrossRef]
  12. Okines, A.F.C.; Cunningham, D. Trastuzumab: A novel standard option for patients with HER-2-positive advanced gastric or gastro-oesophageal junction cancer. Therap. Adv. Gastroenterol. 2012, 5, 301–318. [Google Scholar] [CrossRef] [PubMed]
  13. Shitara, K.; Yatabe, Y.; Matsuo, K.; Sugano, M.; Kondo, C.; Takahari, D.; Ura, T.; Tajika, M.; Ito, S.; Muro, K. Prognosis of patients with advanced gastric cancer by HER2 status and trastuzumab treatment. Gastric Cancer 2013, 16, 261–267. [Google Scholar] [CrossRef] [PubMed]
  14. Tanner, M.; Hollmen, M.; Junttila, T.T.; Kapanen, A.I.; Tommola, S.; Soini, Y.; Helin, H.; Salo, J.; Joensuu, H.; Sihvo, E.; et al. Amplification of HER-2 in gastric carcinoma: Association with Topoisomerase IIalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann. Oncol. 2005, 16, 273–278. [Google Scholar] [CrossRef] [PubMed]
  15. Daiichi Sankyo Europe GmbH. Enhertu (Trastuzumab Deruxtecan) [Summary of Product Characteristics]; Daiichi Sankyo Europe GmbH: Munich, Germany, 2025. [Google Scholar]
  16. Daiichi Sankyo, Inc. Enhertu (Fam-Trastuzumab Deruxtecan-Nxki) [Prescribing Information]; Daiichi Sankyo, Inc.: Basking Ridge, NJ, USA, 2025. [Google Scholar]
  17. Merck & Co., Inc. Keytruda (Pembrolizumab) [Prescribing Information]; Merck & Co., Inc.: Rahway, NJ, USA, 2025. [Google Scholar]
  18. Bristol-Myers Squibb Pharma EEIG. Opdivo (Nivolumab) [Summary of Product Characteristics]; Bristol-Myers Squibb Pharma EEIG: Dublin, Ireland, 2025. [Google Scholar]
  19. Janjigian, Y.Y.; Kawazoe, A.; Bai, Y.; Xu, J.; Lonardi, S.; Metges, J.P.; Yanez, P.; Wyrwicz, L.S.; Shen, L.; Ostapenko, Y.; 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, 2197–2208. [Google Scholar] [CrossRef]
  20. Merck Sharp & Dohme, B.V. Keytruda (Pembrolizumab) [Summary of Product Characteristics]; Merck Sharp & Dohme B.V.: Haarlem, The Netherlands, 2025. [Google Scholar]
  21. Bristol Myers Squibb. Bristol Myers Squibb Receives European Commission Approval for Opdivo (Nivolumab) + Chemotherapy for Patients with HER2 Negative, Advanced or Metastatic Gastric, Gastroesophageal Junction or Esophageal Adenocarcinoma [Press Release]. Available online: https://news.bms.com/news/corporate-financial/2021/Bristol-Myers-Squibb-Receives-European-Commission-Approval-for-Opdivo-nivolumab--Chemotherapy-for-Patients-with-HER2-Negative-Advanced-or-Metastatic-Gastric-Gastroesophageal-Junction-or-Esophageal-Adenocarcinoma-/default.aspx (accessed on 21 April 2025).
  22. Merck. European Commission Approves Merck’s KEYTRUDA® (Pembrolizumab) Plus Chemotherapy for Certain Patients with Esophageal Cancer or HER2-Negative Gastroesophageal Junction (GEJ) Adenocarcinoma [Press Release]. Available online: https://www.merck.com/news/european-commission-approves-mercks-keytruda-pembrolizumab-plus-chemotherapy-for-certain-patients-with-esophageal-cancer-or-her2-negative-gastroesophageal-junction-gej-adenocarcinom/ (accessed on 21 April 2025).
  23. Lian, J.; Zhang, G.; Zhang, Y.; Liu, H.; Zhang, J.; Nan, P.; Tian, W. PD-L1 and HER2 expression in gastric adenocarcinoma and their prognostic significance. Dig. Liver Dis. 2022, 54, 1419–1427. [Google Scholar] [CrossRef]
  24. Wainberg, Z.A.; Fuchs, C.S.; Tabernero, J.; Shitara, K.; Muro, K.; Van Cutsem, E.; Bang, Y.J.; Chung, H.C.; Yamaguchi, K.; Varga, E.; et al. Efficacy of pembrolizumab monotherapy for advanced gastric/gastroesophageal junction cancer with programmed death ligand 1 combined positive score ≥10. Clin. Cancer Res. 2021, 27, 1923–1931. [Google Scholar] [CrossRef]
  25. Kulangara, K.; Zhang, N.; Corigliano, E.; Guerrero, L.; Waldroup, S.; Jaiswal, D.; Jansson, M.; Shah, S.; Hanks, D.; Wang, J.; et al. Clinical utility of the combined positive score for programmed death ligand-1 expression and the approval of pembrolizumab for treatment of gastric cancer. Arch. Pathol. Lab. Med. 2019, 143, 330–337. [Google Scholar] [CrossRef]
  26. Xu, Q.; Xu, X.; Tang, H.; Yan, J.; Li, J.; Bao, H.; Wu, X.; Shao, Y.; Luo, C.; Wen, H.; et al. Exploring potential molecular resistance and clonal evolution in advanced HER2-positive gastric cancer under trastuzumab therapy. Oncogenesis 2023, 12, 21. [Google Scholar] [CrossRef]
  27. Perez-Wert, P.; Custodio, A.; Jimenez-Fonseca, P.; Carmona-Bayonas, A.; Lecumberri, A.; Cacho Lavin, D.; Losantos Garcia, I.; Fernandez Montes, A.; Cano, J.M.; Limon, M.L.; et al. Efficacy and safety of chemotherapy in young patients with advanced gastroesophageal adenocarcinoma: Data from the Spanish AGAMENON-SEOM registry. Gastric Cancer 2024, 27, 131–145. [Google Scholar] [CrossRef]
  28. Jimenez-Fonseca, P.; Carmona-Bayonas, A.; Sanchez Lorenzo, M.L.; Plazas, J.G.; Custodio, A.; Hernandez, R.; Garrido, M.; Garcia, T.; Echavarria, I.; Cano, J.M.; et al. Prognostic significance of performing universal HER2 testing in cases of advanced gastric cancer. Gastric Cancer 2017, 20, 465–474. [Google Scholar] [CrossRef]
  29. Alvarez-Mancenido, F.; Jimenez-Fonseca, P.; Carmona-Bayonas, A.; Arrazubi, V.; Hernandez, R.; Cano, J.M.; Custodio, A.; Pericay Pijaume, C.; Aguado, G.; Martinez Lago, N.; et al. Is advanced esophageal adenocarcinoma a distinct entity from intestinal subtype gastric cancer? Data from the AGAMENON-SEOM Registry. Gastric Cancer 2021, 24, 926–936. [Google Scholar] [CrossRef] [PubMed]
  30. Viudez, A.; Carmona-Bayonas, A.; Gallego, J.; Lacalle, A.; Hernandez, R.; Cano, J.M.; Macias, I.; Custodio, A.; Martinez de Castro, E.; Sanchez, A.; et al. Optimal duration of first-line chemotherapy for advanced gastric cancer: Data from the AGAMENON registry. Clin. Transl. Oncol. 2020, 22, 734–750. [Google Scholar] [CrossRef]
  31. Jimenez Fonseca, P.; Carmona-Bayonas, A.; Hernandez, R.; Custodio, A.; Cano, J.M.; Lacalle, A.; Echavarria, I.; Macias, I.; Mangas, M.; Visa, L.; et al. Lauren subtypes of advanced gastric cancer influence survival and response to chemotherapy: Real-world data from the AGAMENON National Cancer Registry. Br. J. Cancer 2017, 117, 775–782. [Google Scholar] [CrossRef]
  32. Cox, C.; Chu, H.; Schneider, M.F.; Munoz, A. Parametric survival analysis and taxonomy of hazard functions for the generalized gamma distribution. Stat. Med. 2007, 26, 4352–4374. [Google Scholar] [CrossRef]
  33. Spanish Society of Medical Oncology (SEOM). Las Cifras del Cáncer en España [Cancer Figures in Spain] 2024. Available online: https://seom.org/images/publicaciones/informes-seom-de-evaluacion-de-farmacos/LAS_CIFRAS_2024.pdf (accessed on 21 April 2025).
  34. Rivera, F.; Vega-Villegas, M.E.; Lopez-Brea, M.F. Chemotherapy of advanced gastric cancer. Cancer Treat. Rev. 2007, 33, 315–324. [Google Scholar] [CrossRef]
  35. Delgado-Guillena, P.; Morales-Alvarado, V.; Ramirez Salazar, C.; Jimeno Ramiro, M.; Llibre Nieto, G.; Galvez-Olortegui, J.; Uchima, H. Frequency and clinical characteristics of early gastric cancer in comparison to advanced gastric cancer in a health area of Spain. Gastroenterol. Hepatol. 2020, 43, 506–514. [Google Scholar] [CrossRef]
  36. Lordick, F.; Carneiro, F.; Cascinu, S.; Fleitas, T.; Haustermans, K.; Piessen, G.; Vogel, A.; Smyth, E.C.; ESMO Guidelines Committee. Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann. Oncol. 2022, 33, 1005–1020. [Google Scholar] [CrossRef] [PubMed]
  37. Kamiya, S.; Rouvelas, I.; Lindblad, M.; Nilsson, M. Current trends in gastric cancer treatment in Europe. J. Cancer Metastasis Treat. 2018, 4, 35. [Google Scholar] [CrossRef]
  38. Obermannová, R.; Alsina, M.; Cervantes, A.; Leong, T.; Lordick, F.; Nilsson, M.; van Grieken, N.C.T.; Vogel, A.; Smyth, E.C.; ESMO Guidelines Committee. Oesophageal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann. Oncol. 2022, 33, 992–1004. [Google Scholar] [CrossRef]
  39. Ceylan, C.; Angin, Y.S.; Baran, N.T.; Kocaaslan, H.; Cengiz, E.; Güngörür, O.; Güzel, M.; Saglam, K.; Aydin, C. Relationship between HER2 and clinicopathological data in gastric adenocarcinomas. J. Surg. Med. 2024, 8, 7–11. [Google Scholar] [CrossRef]
  40. Kunz, P.L.; Mojtahed, A.; Fisher, G.A.; Ford, J.M.; Chang, D.T.; Balise, R.R.; Bangs, C.D.; Cherry, A.M.; Pai, R.K. HER2 expression in gastric and gastroesophageal junction adenocarcinoma in a US population: Clinicopathologic analysis with proposed approach to HER2 assessment. Appl. Immunohistochem. Mol. Morphol. 2012, 20, 13–24. [Google Scholar] [CrossRef] [PubMed]
  41. Lei, Y.; Huang, J.; Zhao, Q.; Jiang, N.; Xu, H.; Wang, Z.; Li, H.; Zhang, S.; Sun, Z. The clinicopathological parameters and prognostic significance of HER2 expression in gastric cancer patients: A meta-analysis of literature. World J. Surg. Oncol. 2017, 15, 68. [Google Scholar] [CrossRef] [PubMed]
  42. Seo, J.Y.; Jin, E.H.; Jo, H.J.; Yoon, H.; Shin, C.M.; Park, Y.S.; Kim, N.; Jung, H.C.; Lee, D.H. Clinicopathologic and molecular features associated with patient age in gastric cancer. World J. Gastroenterol. 2015, 21, 6905–6913. [Google Scholar] [CrossRef] [PubMed]
  43. Ma, C.; Wang, X.; Guo, J.; Yang, B.; Li, Y. Challenges and future of HER2-positive gastric cancer therapy. Front. Oncol. 2023, 13, 1080990. [Google Scholar] [CrossRef]
  44. Merck. European Commission Approves Merck’s KEYTRUDA® (Pembrolizumab) Plus Chemotherapy for New First-Line Indications in Advanced HER2-Negative Gastric or GEJ Adenocarcinoma in Tumors Expressing PD-L1 (CPS ≥1) and Advanced Biliary Tract Cancer [Press Release]. Available online: https://www.merck.com/news/european-commission-approves-mercks-keytruda-pembrolizumab-plus-chemotherapy-for-new-first-line-indications-in-advanced-her2-negative-gastric-or-gej-adenocarcinoma-in-tumors-expressin/ (accessed on 21 April 2025).
  45. Ministerio de Sanidad. BIFIMED: Buscador de la Información Sobre la Situación de Financiación de los Medicamentos—Nomenclátor de ABRIL—2025. Pembrolizumab. Available online: https://www.sanidad.gob.es/profesionales/medicamentos.do?metodo=verDetalle&cn=712570 (accessed on 21 April 2025).
  46. Ministerio de Sanidad. BIFIMED: Buscador de la Información Sobre la Situación de Financiación de los Medicamentos—Nomenclátor de ABRIL—2025. Nivolumab. Available online: https://www.sanidad.gob.es/profesionales/medicamentos.do?metodo=verDetalle&cn=706934 (accessed on 21 April 2025).
Cancers 17 02164 g001aCancers 17 02164 g001b
Figure 1. 1L chemotherapy regimen by year of treatment initiation for (a) all patients, (b) patients with HER2-negative disease, and (c) patients with HER2-positive disease. 1L, first-line; CAPOX, capecitabine and oxaliplatin; EOX, epirubicin, oxaliplatin, and capecitabine; FOLFOX, folinic acid, fluorouracil, and oxaliplatin; FP, fluorouracil and cisplatin; HER2, human epidermal growth factor receptor 2; PC, cisplatin and capecitabine.
Figure 1. 1L chemotherapy regimen by year of treatment initiation for (a) all patients, (b) patients with HER2-negative disease, and (c) patients with HER2-positive disease. 1L, first-line; CAPOX, capecitabine and oxaliplatin; EOX, epirubicin, oxaliplatin, and capecitabine; FOLFOX, folinic acid, fluorouracil, and oxaliplatin; FP, fluorouracil and cisplatin; HER2, human epidermal growth factor receptor 2; PC, cisplatin and capecitabine.
Cancers 17 02164 g001aCancers 17 02164 g001b
Cancers 17 02164 g002aCancers 17 02164 g002b
Figure 2. 1L chemotherapy and 2L/3L treatment regimens for (a) all patients (n = 1357), (b) patients with HER2-negative disease (n = 951), and (c) patients with HER2-positive disease (n = 315). 1L, first-line; 2L, second-line; 3L, third-line; CAPOX, capecitabine and oxaliplatin; EOX, epirubicin, oxaliplatin, and capecitabine; FOLFOX, folinic acid, fluorouracil, and oxaliplatin; FP, fluorouracil and cisplatin; HER2, human epidermal growth factor receptor 2; PC, cisplatin and capecitabine.
Figure 2. 1L chemotherapy and 2L/3L treatment regimens for (a) all patients (n = 1357), (b) patients with HER2-negative disease (n = 951), and (c) patients with HER2-positive disease (n = 315). 1L, first-line; 2L, second-line; 3L, third-line; CAPOX, capecitabine and oxaliplatin; EOX, epirubicin, oxaliplatin, and capecitabine; FOLFOX, folinic acid, fluorouracil, and oxaliplatin; FP, fluorouracil and cisplatin; HER2, human epidermal growth factor receptor 2; PC, cisplatin and capecitabine.
Cancers 17 02164 g002aCancers 17 02164 g002b
Cancers 17 02164 g003
Figure 3. Kaplan–Meier plots of PFS (a) for all patients, all regimens (n = 1357), and (b) by HER2 status, all regimens (n = 1266). CI, confidence interval; HER2, human epidermal growth factor receptor 2; PFS, progression-free survival.
Figure 3. Kaplan–Meier plots of PFS (a) for all patients, all regimens (n = 1357), and (b) by HER2 status, all regimens (n = 1266). CI, confidence interval; HER2, human epidermal growth factor receptor 2; PFS, progression-free survival.
Cancers 17 02164 g003
Cancers 17 02164 g004
Figure 4. Kaplan–Meier plots of OS (a) for all patients, all regimens (n = 1357), and (b) by HER2 status, all regimens (n = 1266). CI, confidence interval; HER2, human epidermal growth factor receptor 2; OS, overall survival.
Figure 4. Kaplan–Meier plots of OS (a) for all patients, all regimens (n = 1357), and (b) by HER2 status, all regimens (n = 1266). CI, confidence interval; HER2, human epidermal growth factor receptor 2; OS, overall survival.
Cancers 17 02164 g004
Table 1. Patient eligibility for the AGAMENON-SEOM registry and this study.
Table 1. Patient eligibility for the AGAMENON-SEOM registry and this study.
Inclusion CriteriaExclusion Criteria
AGAMENON-SEOM registry
•
Histologically confirmed advanced gastric, GEJ, or distal esophageal adenocarcinoma
•
Age ≥ 18 years at diagnosis
•
Received at least 1 cycle of polychemotherapy (combination chemotherapy using 2 or more drugs) as 1L treatment
•
Patients who received 1L treatment within a clinical trial are included, if the treatment received included chemotherapy, regardless of the additional drug
•
Followed for at least 3 months after treatment initiation, except those with an early death during this period
•
Data from regular clinical practice, with at least 3 months of follow-up
•
Provided written informed consent, if alive at time of enrollment
•
Participating in a clinical trial with no standard chemotherapy, regardless of the association of the molecularly targeted therapy
•
Previous systemic therapy for advanced gastric, GEJ, or distal esophageal adenocarcinoma
•
Less than 6 months elapsed from the last recorded date of prior treatment (neoadjuvant or adjuvant chemotherapy, radiotherapy, or chemoradiotherapy)
•
Therapy regimen not coded
•
Epithelial cell carcinoma and squamous cell and esophageal cancers, or any cancer other than G/GEJa
Study
•
Met all inclusion criteria for AGAMENON-SEOM registry
•
Initiated 1L polychemotherapy for advanced G/GEJa during the index period (1 January 2015 to 31 December 2019)
•
Received treatment in Spain
•
Met any exclusion criteria for AGAMENON-SEOM registry
•
Distal esophageal cancer (primary site)
1L, first-line; GEJ, gastroesophageal junction; G/GEJa, gastric/gastroesophageal junction adenocarcinoma.
Table 2. Sociodemographic and disease characteristics.
Table 2. Sociodemographic and disease characteristics.
CharacteristicAll Patients a
(n = 1357)		HER2-Negative
(n = 951)		HER2-Positive
(n = 315)
Age at 1L treatment initiation   
   Median (25th percentile, 75th percentile)64.7 (55.5, 72.0)63.8 (54.6, 71.5)65.8 (56.9, 72.4)
   Minimum–maximum19.9–88.519.8–88.522.9–86.3
Age < 65 years693 (51.1)510 (53.6)144 (45.7)
Male sex913 (67.3)615 (64.7)238 (75.6)
BMI (kg/m2)   
   Underweight: BMI < 18.584 (6.2)65 (6.8)16 (5.1)
   Normal weight: BMI 18.5 to <25731 (53.9)525 (55.2)154 (48.9)
   Overweight: BMI 25 to <30388 (28.6)265 (27.9)101 (32.1)
   Obese: BMI ≥ 30153 (11.3)96 (10.1)44 (14.0)
   Missing1 (0.1)0 (0.0)0 (0.0)
Number of comorbid conditions   
   Median (25th percentile, 75th percentile)0 (0, 1)0 (0, 1)0 (0, 1)
   Minimum–maximum0–60–60–4
   ≥1 comorbid condition610 (45.0)430 (45.2)135 (42.9)
      Chronic cardiopathy160 (11.8)115 (12.1)33 (10.5)
ECOG PS   
   0315 (23.2)225 (23.7)68 (21.6)
   1845 (62.3)590 (62.0)198 (62.9)
   2188 (13.9)131 (13.8)45 (14.3)
   3 or 49 (0.7)5 (0.5)4 (1.3)
Primary tumor site   
   GEJ373 (27.5)225 (23.7)129 (41.0)
   Gastric972 (71.6)719 (75.6)183 (58.1)
   Not available12 (0.9)7 (0.7)3 (1.0)
Tumor stage, locally advanced unresectable, without metastasis93 (6.9)68 (7.2)17 (5.4)
De novo G/GEJa1147 (84.5)777 (81.7)288 (91.4)
Surgery of the primary tumor338 (24.9)272 (28.6)44 (14.0)
Lauren histological type   
   Intestinal504 (37.1)295 (31.0)186 (59.0)
   Diffuse522 (38.5)432 (45.4)58 (18.4)
   Mixed57 (4.2)43 (4.5)10 (3.2)
   Not available/not classifiable274 (20.2)181 (19.0)61 (19.4)
Signet ring cells   
   Not present693 (51.1)442 (46.5)214 (67.9)
   Present, <50%74 (5.5)64 (6.7)9 (2.9)
   Present, ≥50%125 (9.2)107 (11.3)9 (2.9)
   Present, unknown percentage232 (17.1)195 (20.5)21 (6.7)
   Not available233 (17.2)143 (15.0)62 (19.7)
Histological grade   
   Grade 1117 (8.6)62 (6.5)53 (16.8)
   Grade 2326 (24.0)211 (22.2)101 (32.1)
   Grade 3580 (42.7)460 (48.4)87 (27.6)
   Not available334 (24.6)218 (22.9)74 (23.5)
Number of metastatic sites   
   0 or 1657 (48.4)483 (50.8)125 (39.7)
   2409 (30.1)282 (29.7)106 (33.7)
   3176 (13.0)115 (12.1)50 (15.9)
   ≥4115 (8.5)71 (7.5)34 (10.8)
Metastatic site   
   Locoregional lymph nodes859 (63.3)561 (59.0)241 (76.5)
   Peritoneum659 (48.6)505 (53.1)106 (33.7)
   Non-locoregional lymph nodes600 (44.2)406 (42.7)159 (50.5)
   Liver447 (32.9)255 (26.8)165 (52.4)
   Ascites320 (23.6)244 (25.7)47 (14.9)
   Lung180 (13.3)97 (10.2)70 (22.2)
   Bone158 (11.6)114 (12.0)33 (10.5)
   Other168 (12.4)110 (11.6)41 (13.0)
NLR b   
   Median (25th percentile, 75th percentile)3.4 (2.2, 5.1)3.3 (2.2, 4.9)3.6 (2.2, 5.8)
   Minimum–maximum0.3–102.00.3–102.00.8–22.3
NLR category   
   Low: <4819 (60.4)595 (62.6)172 (54.6)
   Moderate: 4 to <8370 (27.3)237 (24.9)102 (32.4)
   High: ≥8142 (10.5)97 (10.2)38 (12.1)
   Not available26 (1.9)22 (2.3)3 (1.0)
Counts and percentages are shown for categorical variables. Median (25th, 75th percentile) and minimum–maximum are shown for noncategorical measures. 1L, first-line; BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group performance status; GEJ, gastroesophageal junction; G/GEJa, gastric/gastroesophageal junction adenocarcinoma; HER2, human epidermal growth factor receptor 2; NLR, neutrophil-to-lymphocyte ratio. a 91 patients had unknown HER2 status. b 26 patients did not have NLR data available (n = 22, patients with HER2-negative disease; n = 3, patients with HER2-positive disease; n = 1, unknown HER2 status).
Table 3. Treatment characteristics.
Table 3. Treatment characteristics.
CharacteristicAll Patients a
(n = 1357)		HER2-Negative
(n = 951)		HER2-Positive
(n = 315)
Year initiated 1L treatment   
   2015335 (24.7)238 (25.0)64 (20.3)
   2016281 (20.7)202 (21.2)58 (18.4)
   2017303 (22.3)219 (23.0)68 (21.6)
   2018249 (18.3)155 (16.3)78 (24.8)
   2019189 (13.9)137 (14.4)47 (14.9)
1L chemotherapy regimen   
   FOLFOX355 (26.2)270 (28.4)62 (19.7)
   CAPOX345 (25.4)228 (24.0)98 (31.1)
   PC154 (11.3)86 (9.0)57 (18.1)
   EOX146 (10.8)131 (13.8)5 (1.6)
   FP107 (7.9)60 (6.3)44 (14.0)
   Other doublet186 (13.7)124 (13.0)46 (14.6)
   Other triplet64 (4.7)52 (5.5)3 (1.0)
1L treatment duration, months b   
   Median (25th percentile, 75th percentile)4.8 (2.8, 7.2)4.6 (2.6, 6.9)5.2 (3.6, 8.5)
   Minimum–maximum0.2–39.70.2–39.70.4–37.9
Number of 1L chemotherapy cycles c   
   Median (25th percentile, 75th percentile)6 (4, 11)6 (4, 11)7 (5, 12)
   Minimum–maximum1–751–601–58
Number of treatment lines   
   1764 (56.3)547 (57.5)162 (51.4)
   2374 (27.6)265 (27.9)90 (28.6)
   3219 (16.1)139 (14.6)63 (20.0)
2L treatment regimen   
   None764 (56.3)547 (57.5)162 (51.4)
   Paclitaxel and ramucirumab202 (14.9)132 (13.9)60 (19.0)
   Paclitaxel165 (12.2)120 (12.6)38 (12.1)
   Ramucirumab6 (0.4)2 (0.2)4 (1.3)
   Other monotherapy110 (8.1)62 (6.5)35 (11.1)
   Doublet90 (6.6)76 (8.0)8 (2.5)
   Immunotherapy8 (0.6)6 (0.6)2 (0.6)
   Other regimen12 (0.9)6 (0.6)6 (1.9)
3L treatment regimen   
   None1138 (83.9)812 (85.4)252 (80.0)
   Monotherapy139 (10.2)94 (9.9)34 (10.8)
   Doublet49 (3.6)30 (3.2)14 (4.4)
   Immunotherapy2 (0.1)1 (0.1)1 (0.3)
   Other regimen29 (2.1)14 (1.5)14 (4.4)
Counts and percentages are shown for categorical variables. Median (25th, 75th percentile) and minimum–maximum are shown for noncategorical measures. 1L, first-line; 2L, second-line; 3L, third-line; CAPOX, capecitabine and oxaliplatin; EOX, epirubicin, oxaliplatin, and capecitabine; FOLFOX, folinic acid, fluorouracil, and oxaliplatin; FP, fluorouracil and cisplatin; HER2, human epidermal growth factor receptor 2; PC, cisplatin and capecitabine. a 91 patients had unknown HER2 status. b For patients receiving polychemotherapy: if the chemotherapy medications had different treatment durations, the longest treatment duration is reported. c For patients receiving polychemotherapy: if the chemotherapy medications had different numbers of cycles, the highest number of cycles is reported.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Jimenez-Fonseca, P.; Carmona-Bayonas, A.; Álvarez-Cañada, J.; Storfer-Isser, A.; Martin-Richard, M.; Sauri, T.; Cano, J.M.; Martínez Moreno, E.; Pérez-Wert, P.; López, J.; et al. Treatment and Outcomes in Advanced Gastroesophageal Adenocarcinoma in the Pre-Immunotherapy Era Based on the Spanish AGAMENON-SEOM Registry. Cancers 2025, 17, 2164. https://doi.org/10.3390/cancers17132164

AMA Style

Jimenez-Fonseca P, Carmona-Bayonas A, Álvarez-Cañada J, Storfer-Isser A, Martin-Richard M, Sauri T, Cano JM, Martínez Moreno E, Pérez-Wert P, López J, et al. Treatment and Outcomes in Advanced Gastroesophageal Adenocarcinoma in the Pre-Immunotherapy Era Based on the Spanish AGAMENON-SEOM Registry. Cancers. 2025; 17(13):2164. https://doi.org/10.3390/cancers17132164

Chicago/Turabian Style

Jimenez-Fonseca, Paula, Alberto Carmona-Bayonas, Jaime Álvarez-Cañada, Amy Storfer-Isser, Marta Martin-Richard, Tamara Sauri, Juana María Cano, Elia Martínez Moreno, Pablo Pérez-Wert, Javier López, and et al. 2025. "Treatment and Outcomes in Advanced Gastroesophageal Adenocarcinoma in the Pre-Immunotherapy Era Based on the Spanish AGAMENON-SEOM Registry" Cancers 17, no. 13: 2164. https://doi.org/10.3390/cancers17132164

APA Style

Jimenez-Fonseca, P., Carmona-Bayonas, A., Álvarez-Cañada, J., Storfer-Isser, A., Martin-Richard, M., Sauri, T., Cano, J. M., Martínez Moreno, E., Pérez-Wert, P., López, J., Garcia Navalon, F., Gómez-González, L., Ruiz Martín, M., Rupérez Blanco, A. B., López-López, F., Roncancio-Díaz, E., Corbacho, B., Mateo, M., Anguita-Alonso, P., & Gallego Plazas, J. (2025). Treatment and Outcomes in Advanced Gastroesophageal Adenocarcinoma in the Pre-Immunotherapy Era Based on the Spanish AGAMENON-SEOM Registry. Cancers, 17(13), 2164. https://doi.org/10.3390/cancers17132164

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Article metric data becomes available approximately 24 hours after publication online.
Back to TopTop