The systemic treatment landscape of metastatic esophageal cancer has changed over the past decade. For a long time, platinum-based chemotherapy combinations were the only standard option but now immune checkpoint inhibitors, administered either as monotherapy or in combination with chemotherapy, enable a significantly improved overall survival in selected patients. Prerequisites for appropriate treatment selection are precise histological and molecular classifications of the tumor. In esophageal squamous cell carcinoma, histology and programmed cell death ligand 1 (PD-L1) expression are the principal determinants of first-line treatment. The use of different PD-L1 scoring systems in pivotal clinical trials complicates the application in routine practice. For esophageal adenocarcinoma palliative systemic treatment largely follows contemporary treatment algorithms for metastatic gastric and gastroesophageal junction cancer, incorporating the HER2, Claudin18.2, MSI/MMR and PD-L1 status. This review summarizes the current evidence, focusing on metastatic esophageal squamous cell carcinoma and provides practical recommendations for multidisciplinary patient management.

INTRODUCTION:Despite advances in the multimodal treatment of resectable esophagogastric adenocarcinoma (EGA), relapse rates remain high. No human epidermal growth factor receptor 2 (HER2)-targeted treatment is yet established in the perioperative setting. While trastuzumab deruxtecan (T-DXd) has compelling efficacy and is now a well-established drug in the treatment of advanced HER2-positive EGA, safety and efficacy data from the perioperative setting are still lacking. METHODS:NeoART is a phase Ib/II platform trial evaluating the safety and efficacy of neoadjuvant T-DXd-containing combination regimens for patients with HER2-positive EGA. We report about the safety, feasibility, and preliminary antitumor activity from the safety run-in cohort of the NeoART trial in which patients with locally advanced resectable EGA received three cycles of preoperative T-DXd (5.4 mg/kg, Q3W) combined with 5-fluorouracil (5-FU; 2,600 mg/m2 24 h, Q2W) and folinic acid (FA; 200 mg/m2, Q2W). RESULTS:In the preplanned safety analysis of the first 6 patients recruited to NeoART, no serious adverse events (SAEs) or dose-limiting toxicities (DLTs) were reported during neoadjuvant treatment. Relevant treatment-related adverse events of grades 1-3 were diarrhea, mucositis, and nausea, but none fulfilled the criteria of DLTs. No relevant hematologic toxicity was observed. Five of six patients underwent curative-intent oncologic resection. In one patient, peritoneal carcinomatosis was detected at the time of surgery; therefore, the tumor was not resected. Two patients experienced grade 3 postoperative complications according to Clavien-Dindo classification, including one anastomotic leakage which was classified as an SAE. R0 resection was accomplished in four out of five resected patients. Histopathological complete remission (pCR; ypT0 N0) was observed in two patients. CONCLUSIONS:Neoadjuvant treatment with T-DXd plus 5-FU/FA was found to be well tolerated and showed preliminary signs of activity during the safety run-in period of the NeoART study.

Computed tomography (CT) is a first line imaging tool for staging of esophageal cancer (EC). Previous studies have shown promising results of the prognostic relevance of vessel calcifications quantified by CT, especially coronary and aortic calcifications, in oncological patients. The aim of this study was to analyze the prognostic relevance of aortic calcification assessed in staging CT in patients with EC undergoing curative treatment. All patients with EC treated with neoadjuvant therapy followed by curative resection at the University of Leipzig Medical Center, a tertiary care hospital, were retrospectively evaluated between 2016 and 2023. A total of 89 patients were included in the analysis. Abdominal aorta and iliac artery calcification volume was measured in a semi-automated fashion at baseline before neoadjuvant therapy using staging CT images. The primary endpoint was overall survival and disease-free survival was assessed as a secondary endpoint. For statistical analysis group differences were calculated using the Mann-Whitney-U test. Kaplan-Meier curves and multivariable Cox regression analysis were used to test the effect of aortic calcification volume and clinical variables on mortality. In univariable Cox regression, higher abdominal aortic calcification volume was significantly associated with shorter overall survival (Hazard ratio (HR) 1.259 per 1 cm³, 95

Die systemische Therapie des metastasierten Ösophaguskarzinoms hat sich in den vergangenen Jahren verändert. Während platinbasierte Kombinationschemotherapien lange die einzige Standardoption darstellten, ermöglichen Immuncheckpointinhibitoren heute – als Monotherapie oder in Kombination mit Chemotherapie – bei einem Teil der Patientinnen und Patienten eine signifikante Verlängerung des Gesamtüberlebens. Voraussetzung hierfür ist eine präzise histologische und molekulare Charakterisierung des Tumors. Beim Plattenepithelkarzinom bestimmen v. a. Histologie und PD-L1-Expression die Therapiewahl. Die unterschiedlichen in den Zulassungsstudien verwendeten PD-L1-Scores stellen dabei eine Herausforderung im klinischen Alltag dar. Beim Adenokarzinom orientiert sich die palliative Systemtherapie weitgehend an den aktuellen Therapiekonzepten des metastasierten Magenkarzinoms unter Berücksichtigung von HER2-, Claudin18.2-, MSI- und PD-L1-Status. Der vorliegende Übersichtsartikel fasst die aktuelle Evidenz mit Schwerpunkt auf dem metastasierten Plattenepithelkarzinom zusammen und gibt praktische Empfehlungen für die interdisziplinäre Versorgung.

Objectives Malignant peritoneal mesothelioma (MPM) is a rare disease with unspecific abdominal symptoms which is therefore often diagnosed at an advanced stage. Curative therapy is delivered by radical surgery, whereas palliative therapy consists of systemic chemotherapy. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a laparoscopically applied chemotherapy which was invented to administer high doses of chemotherapy intraperitoneally in palliative cases of peritoneal malignancies. Methods The case of a male patient who received PIPAC treatment as individualized approach for unresectable malignant peritoneal mesothelioma is reported. Results The patient began treatment with PIPAC procedures in 2017 for MPM that was unresectable because of extensive disease on the small bowel and refused systemic chemotherapy as the usual standard of care. We initiated PIPAC with doxorubicin and cisplatin and could reach stable disease within one year of treatment so that the therapy was discontinued for 2.5 years. Due to progressive disease, PIPAC was continued resulting in stable disease for 2 years. In total, the patient received 24 PIPAC procedures with no major surgical or toxic side effects over seven years timespan. Conclusions We report the case of a patient with MPM who could reach long-term survival of seven years due to a total of 24 PIPAC procedures.

Immun- und zielgerichtete Therapien nehmen in der Onkologie einen immer größeren Stellenwert ein, was zu einer deutlichen Verbesserung der Behandlungserfolge geführt hat. Beim Plattenepithelkarzinom des Ösophagus haben sich in diesem Feld bisher v. a. die Immuncheckpointinhibitoren etabliert. In diesem Artikel wird mit Fokus auf das Plattenepithelkarzinom eine Übersicht über die zugelassenen Checkpointinhibitoren, die zulassungsrelevanten Studien und die praktische Handhabung der Substanzgruppe gegeben. Außerdem wird ein Ausblick auf andere histologische Subtypen und experimentelle Targets dargestellt. Für fortgeschrittene bzw. metastasierte Plattenepithelkarzinome sind abhängig vom PD-L1-Status zusätzlich zur Chemotherapie in der ersten Therapielinie die PD-1-Inhibitoren Nivolumab oder Pembrolizumab zugelassen. Außerdem gibt es die Option einer reinen Immuntherapie mit der Kombination aus Nivolumab und Ipilimumab. In der zweiten Therapielinie können Nivolumab oder Tislelizumab eingesetzt werden, wenn zuvor keine Therapie mit Checkpointinhibitoren erfolgt ist. Die Adenokarzinome des Ösophagus werden größtenteils analog zum Adenokarzinom des Magens behandelt.

INTRODUCTION:Body composition including low skeletal muscle mass (LSMM) defined by skeletal muscle index (SMI) and subcutaneous and visceral adipose tissue (SAT and VAT) can be assessed using cross-sectional imaging techniques. Previous studies have shown promising prognostic value for several tumour entities, including esophageal cancer (EC). The aim of this study was to analyse possible associations of body composition parameters in patients with esophageal cancer undergoing curative treatment. METHODS:All patients with EC undergoing curative treatment were retrospectively evaluated between 2016 and 2023. A total of 145 patients (17 female, 11.7 %) with a mean age of 65.9 ± 10.2 years were included in the present analysis. For all patients, staging computed tomography (CT) was used to calculate LSMM, VAT, and SAT. The primary study end point was all-cause overall survival. For statistical analysis group differences were calculated using the Mann-Whitney test. Kaplan-Meier curves and multivariable Cox regression analysis was used to test the effect of body composition parameters on mortality. RESULTS:In total, 51 patients (35.2 %) of the patient cohort died within the observation period. According to the sarcopenia threshold of the SMI, 99 patients (68.2 %) were classified as sarcopenic and according to the VAT threshold, 102 patients (70.3 %) were classified as visceral obese. Sarcopenia and visceral obesity were associated with mortality with a hazard ratio (HR) of 2.05 (95%confidence interval (CI) 1.17, 3.57, p = 0.01) and 2.47 (95%CI 1.39, 4.37, p = 0.002) in univariable analysis, respectively. Only the combination of both, sarcopenic obesity was significantly associated in multivariable analysis (HR 2.47, 95 %CI 1.39; 4.37, p = 0.002) CONCLUSIONS: The combination of CT-defined sarcopenia and visceral obesity showed a strong prognostic relevance in EC undergoing curative resection. The effect of sarcopenia and visceral obesity considered separately was of lesser prognostic significance. CT-defined body composition may help to better stratify patients with EC at risk of worse outcome in clinical practice.

BackgroundTreatment of metastatic and locally advanced unresectable esophagogastric adenocarcinoma (EGA) after first-line therapy has limited efficacy. Sacituzumab govitecan (SG) is an antibody-drug conjugate (ADC) linking a TROP-2-directed antibody to the topoisomerase-I inhibitor SN-38. EGA has a high TROP-2 positivity rate and is sensitive to topoisomerase inhibition. Thus far, limited data on the efficacy and safety of SG in this patient population are available.AimTo evaluate the safety and efficacy of SG in patients with metastatic EGA who progressed under previous treatment. Objective response rate (ORR) is the primary endpoint.Trial designSAGA is a single-arm, non-randomized, open-label multicenter phase Ib/II study. Patients after prior treatment with a fluoropyrimidine-platinum-containing chemotherapy with or without targeted therapy or immunotherapy will be treated with SG intravenously at a dose of 10 mg/kg body weight on days 1 and 8 of a 21-day treatment cycle. After a run-in phase of 20 patients, safety and efficacy will be evaluated and the trial will proceed to a recruitment goal of 56 patients when at least two tumor responses are documented in the run-in phase. A hypothesis of an ORR of 16% is tested against a null hypothesis of an ORR of 5%.Trial identifiersEU CT 2023-505257-40-00, NCT06123468, AIO-STO-0123/ass., IKF-t065

ImportanceAdding immune checkpoint inhibitors to chemotherapy has been associated with improved outcomes in metastatic esophagogastric adenocarcinoma, but treatment combinations and optimal patient selection need to be established.ObjectiveTo investigate the efficacy and tolerability of the programmed cell death ligand 1 (PDL-1) inhibitor avelumab with paclitaxel plus ramucirumab.Design, Setting, and ParticipantsThis multicenter, single-group, phase 2 nonrandomized controlled trial was conducted among patients with second-line metastatic esophagogastric adenocarcinoma. Patients pretreated with platinum plus fluoropyrimidine between April 2019 and November 2020 across 10 German centers (median follow-up, 27.4 months [95% CI 22.0-32.9 months]) were included. Data analysis was performed from January to December 2022.InterventionsPatients received ramucirumab at 8 mg/kg on days 1 and 15, avelumab at 10 mg/kg on days 1 and 15, and paclitaxel at 80 mg/m2 on days 1, 8, and 15 every 4 weeks.Main Outcomes and MeasuresThe prespecified primary end point was overall survival (OS) rate at 6 months, with the experimental therapy considered insufficiently active with an OS rate of 50% or less and a promising candidate with an OS rate of 65% or greater.ResultsOf 60 enrolled patients, 59 patients (median [range] age, 64 [18-81] years; 47 males [70.7%]) were evaluable, including 30 patients with metastatic adenocarcinoma of the stomach and 29 patients with gastroesophageal junction. All patients were pretreated with platinum plus fluoropyrimidine, and 40 patients (67.8%) had received prior taxanes; 24 of 56 evaluable patients (42.9%) had a PDL-1 combined positive score (CPS) of 5 or greater, centrally assessed. The OS rate at 6 months was 71.2% (95% CI, 61.5%-83.7%). The median OS in the intention-to-treat population (59 patients) was 10.6 months (95% CI, 8.4-12.8 months) overall. Among patients assessable by central pathology, median OS was 9.4 months (95% CI, 7.2-11.7 months) in 32 patients with a PDL-1 CPS less than 5 and 14.0 months (95% CI, 6.0-22.1 months) in 24 patients with a PDL-1 CPS of 5 or greater (P = .25). Treatment was generally well tolerated, without unexpected toxicities. Patients with higher vs lower than median T cell repertoire richness showed an increased median OS of 20.4 months (95% CI, 7.7-33.0 months) compared with 8.3 months (95% CI, 3.7-12.9 months; hazard ratio, 0.43; 95% CI, 0.23-0.81; P = .008). Patients with lower vs higher than median cell-free DNA burden had a median OS of 19.2 months (95% CI, 8.9-29.6 months) compared with 7.3 months (95% CI, 3.2-11.4 months; hazard ratio, 0.30; 95% CI, 0.16-0.59; P < .001).Conclusions and relevanceIn this study, the combination of avelumab with paclitaxel plus ramucirumab showed favorable efficacy and tolerability in the second-line treatment for metastatic esophagogastric adenocarcinoma. A PDL-1 CPS score of 5 or greater, cell-free DNA level less than the median, and T cell repertoire richness greater than the median were associated with increased median OS.Trial RegistrationClinicalTrials.gov Identifier: NCT03966118

Importance:Adding immune checkpoint inhibitors to chemotherapy has been associated with improved outcomes in metastatic esophagogastric adenocarcinoma, but treatment combinations and optimal patient selection need to be established. Objective:To investigate the efficacy and tolerability of the programmed cell death ligand 1 (PDL-1) inhibitor avelumab with paclitaxel plus ramucirumab. Design, Setting, and Participants:This multicenter, single-group, phase 2 nonrandomized controlled trial was conducted among patients with second-line metastatic esophagogastric adenocarcinoma. Patients pretreated with platinum plus fluoropyrimidine between April 2019 and November 2020 across 10 German centers (median follow-up, 27.4 months [95% CI 22.0-32.9 months]) were included. Data analysis was performed from January to December 2022. Interventions:Patients received ramucirumab at 8 mg/kg on days 1 and 15, avelumab at 10 mg/kg on days 1 and 15, and paclitaxel at 80 mg/m2 on days 1, 8, and 15 every 4 weeks. Main Outcomes and Measures:The prespecified primary end point was overall survival (OS) rate at 6 months, with the experimental therapy considered insufficiently active with an OS rate of 50% or less and a promising candidate with an OS rate of 65% or greater. Results:Of 60 enrolled patients, 59 patients (median [range] age, 64 [18-81] years; 47 males [70.7%]) were evaluable, including 30 patients with metastatic adenocarcinoma of the stomach and 29 patients with gastroesophageal junction. All patients were pretreated with platinum plus fluoropyrimidine, and 40 patients (67.8%) had received prior taxanes; 24 of 56 evaluable patients (42.9%) had a PDL-1 combined positive score (CPS) of 5 or greater, centrally assessed. The OS rate at 6 months was 71.2% (95% CI, 61.5%-83.7%). The median OS in the intention-to-treat population (59 patients) was 10.6 months (95% CI, 8.4-12.8 months) overall. Among patients assessable by central pathology, median OS was 9.4 months (95% CI, 7.2-11.7 months) in 32 patients with a PDL-1 CPS less than 5 and 14.0 months (95% CI, 6.0-22.1 months) in 24 patients with a PDL-1 CPS of 5 or greater (P = .25). Treatment was generally well tolerated, without unexpected toxicities. Patients with higher vs lower than median T cell repertoire richness showed an increased median OS of 20.4 months (95% CI, 7.7-33.0 months) compared with 8.3 months (95% CI, 3.7-12.9 months; hazard ratio, 0.43; 95% CI, 0.23-0.81; P = .008). Patients with lower vs higher than median cell-free DNA burden had a median OS of 19.2 months (95% CI, 8.9-29.6 months) compared with 7.3 months (95% CI, 3.2-11.4 months; hazard ratio, 0.30; 95% CI, 0.16-0.59; P < .001). Conclusions and relevance:In this study, the combination of avelumab with paclitaxel plus ramucirumab showed favorable efficacy and tolerability in the second-line treatment for metastatic esophagogastric adenocarcinoma. A PDL-1 CPS score of 5 or greater, cell-free DNA level less than the median, and T cell repertoire richness greater than the median were associated with increased median OS. Trial Registration:ClinicalTrials.gov Identifier: NCT03966118.

BACKGROUND:Patients with gastro-oesophageal adenocarcinoma with tumour-positive lymph nodes (ypN+) or positive surgical margins (R1) following neoadjuvant chemotherapy and resection are at high risk of recurrence. Adjuvant nivolumab is effective in oesophageal/oesophagogastric junction cancer and residual pathological disease following chemoradiation and surgery. Immune checkpoint inhibition has shown efficacy in advanced gastro-oesophageal cancer. We hypothesised that nivolumab/ipilimumab would be more effective than adjuvant chemotherapy in high-risk (ypN+ and/or R1) patients with gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and resection. PATIENTS AND METHODS:VESTIGE was an academic international, multicentre, open-label, randomised phase II trial evaluating the efficacy of adjuvant nivolumab/ipilimumab versus chemotherapy in gastro-oesophageal adenocarcinoma at high risk of recurrence. Patients were randomised 1 : 1 to receive standard adjuvant chemotherapy (same regimen as neoadjuvant) or nivolumab 3 mg/kg intravenously (i.v.) every 2 weeks plus ipilimumab 1 mg/kg i.v. every 6 weeks for 1 year. Key inclusion criteria included ypN+ and/or R1 status after neoadjuvant chemotherapy plus surgery. The primary endpoint was disease-free survival in the intent-to-treat population. Secondary endpoints included overall survival, locoregional and distant failure rates, and safety according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. RESULTS:The independent Data Monitoring Committee reviewed data from 189 of the planned 240 patients in June 2022 and recommended stopping recruitment due to futility. At the time of final analysis, median follow-up was 25.3 months for 195 patients (98 nivolumab/ipilimumab and 97 chemotherapy). Median disease-free survival for the nivolumab/ipilimumab group was 11.4 months [95% confidence interval (CI) 8.4-16.8 months] versus 20.8 months (95% CI 15.0-29.9 months) for the chemotherapy group, hazard ratio 1.55 (95% CI 1.07-2.25, one-sided P = 0.99). The 12-month disease-free survival rates were 47.1% and 64.0%, respectively. There were no toxicity concerns or excess early discontinuations. CONCLUSION:Nivolumab/ipilimumab did not improve disease-free survival compared with chemotherapy in patients with ypN+ and/or R1 gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and surgery.

Complete remission of BRAF V600E-driven ACC CUP by BRAF/MEK inhibition underscores importance of precision oncology.

INTRODUCTION:The phase 2 RAMONA study demonstrated that second-line nivolumab ± ipilimumab immunotherapy was feasible and effective in older patients with advanced esophageal squamous cell cancer (ESCC). Here, we presented results from functional status (FS) and quality-of-life (QoL) analyses. MATERIALS AND METHODS:Patients aged ≥65 years with advanced ESCC and disease progression following first-line therapy were enrolled for study treatment with nivolumab ± ipilimumab. Geriatric assessments (GA) consisting of G8 and GoGo/SlowGo evaluation, and quality of life (QoL) assessments with EORTC QLQ-C30 questionnaires were conducted at baseline and during the treatment. A post hoc analysis was performed to compare therapy efficacy, toxicity, and QoL between age groups (≥70 years vs. <70 years) and functionality groups (G8 > 14 vs. ≤14 and GoGo vs. SlowGo). RESULTS:In 66 treated patients with a median age of 70.5 years, older patients had non-inferior overall survival and tumor response compared to younger patients, with no increased treatment-related adverse events. Fitter patients (G8 > 14, GoGo) had a clinically, yet not statistically significant, survival advantage than less fit patients (G8 ≤ 14, SlowGo) patients. Moreover, FS by G8 and GoGo/SlowGo significantly correlated with QoL. Overall, QoL was impaired at baseline but remained stable in all scales over the course of immunotherapy. DISCUSSION:The administration of nivolumab ± ipilimumab second-line immunotherapy in older patients with ESCC did not show age-dependent effects and maintained QoL. GA could identify functional deficits and limitations of QoL and should be implemented in the context of immunotherapy. CLINICALTRIALS:gov: NCT03416244.

Für die Systemtherapie des metastasierten oder irresektablen Magenkarzinoms wurden seit 2021 mehrere Medikamente neu zugelassen. Im vorliegenden Artikel werden die durch die Europäische Arzneimittel-Agentur (EMA) neu zugelassenen Substanzen mit den zulassungsrelevanten Phase-III-Studien vorgestellt. Die Auswahl der Erstlinientherapie hängt von den Biomarkern HER2, PD-L1 und DNA-Mismatch-Reparatur/Mikrosatelliteninstabilität (MSI) ab. Biologisch wirksame Therapeutika werden in der ersten Therapielinie mit einer Chemotherapie, bestehend aus einem Fluoropyrimidin und einem Platinderivat (meist Oxaliplatin), kombiniert. Für die größte Gruppe der HER2-negativen, mikrosatellitenstabilen (MSS-)Tumoren sollten bei positivem PD-L1-Status im Combined Positive Score (CPS) Pembrolizumab (CPS ≥ 1) oder Nivolumab (CPS ≥ 5) in Kombination mit Chemotherapie verordnet werden. Bei HER2-positiven Tumoren, die PD-L1-positiv sind, ist jetzt die Kombination aus Pembrolizumab, Trastuzumab und Chemotherapie zugelassen. MSI-high-Karzinome sollten mit einer Kombination aus Chemotherapie und einem Checkpointinhibitor behandelt werden, auch wenn die Zulassung auf einem positiven PD-L1-Score basiert. In der Zweitlinie ist Trastuzumab-Deruxtecan bei HER2-positiven Tumoren zugelassen. Pembrolizumab-Monotherapie hat eine Zulassung ab der zweiten Linie bei MSI-high-Karzinomen. Voraussetzung ist, dass die Progression nicht unter einer Systemtherapie aufgetreten ist, die bereits einen Checkpointinhibitor enthielt.

Purpose Pazopanib has promising antiangiogenetic activity in solid cancers. The investigator-initiated phase I/II trial evaluated the combination of Topotecan with Pazopanib in platinum-resistant or intermediate-sensitive recurrent ovarian cancer (ROC). Methods Patients (≥ 18 years) with first or second recurrence were enrolled in this multicentre open-label trial. Phase I analysed Topotecan 4 mg/m 2 (day 1, 8, 15, ever 28 days) for six cycles to identify the maximum tolerated dose (MTD) of Pazopanib added in a dose-escalating scheme with 400 mg starting dose. The phase II analysed safety and efficacy aspects. For all patients with clinical remission a maintenance with Pazopanib until progression was allowed. This trial is registered with ClinicalTrials.gov, number NCT 01600573. Results Between June 2012 and February 2017, 11 patients were enrolled in the phase I, and 50 patients in the phase II study. The MTD of Pazopanib was determined by 400 mg/daily. Haematological and liver toxicities determined the dose limiting toxicities (DLT) and the most common grade 3–4 adverse events: leucopenia (25%), neutropenia (22%), thrombocytopenia (19%), accumulation of cholestatic (20%) and hepatocellular damage (15%), which often caused dose modifications, but no new life-threatening events. Overall response was 16% and clinical benefit rate 68%. Median progression-free survival (PFS) was 3.5 months (95% CI 2.0—5.0). Due to early progression only 20% of the patients were able to start with maintenance treatment. Conclusion The combination of pazopanib and weekly topotecan is feasible, resulting in a manageable haematological and liver toxicity, but despite its encouraging response rate, was not associated with a significant survival benefit.

Purpose: Platinum-fluoropyrimidine combinations are standard of care for treatment of metastatic esophagogastric adenocarcinoma. The optimal duration of first-line chemotherapy is unknown, however, and maintenance strategies have not yet been established. Design: MATEO is an international randomized phase II trial exploring efficacy and safety of S-1 maintenance therapy in human epidermal growth factor receptor 2 (HER2)-negative advanced esophagogastric adenocarcinoma. After 3 months of first-line platinum-fluoropyrimidine-based induction therapy, patients without progression were randomized in a 2 : 1 allocation to receive S-1 monotherapy (arm A) or to continue combination chemotherapy (arm B). The primary objective was to show non-inferiority of overall survival in the S-1 maintenance group. Progression-free survival, adverse events, and quality of life were secondary endpoints.Results: From 2014 to 2019, 110 and 55 patients were randomized in arm A and arm B, respectively (recruitment closed prematurely). Median overall survival from randomization was 13.4 months for arm A and 11.4 months for arm B [hazard ratio 0.97 (80% confidence interval 0.76-1.23), P = 0.86]. Median progression-free survival from randomization was 4.3 and 6.1 months for arm A versus arm B, respectively [hazard ratio 1.10 (80% confidence interval 0.86-1.39), P = 0.62]. Patients in arm A had numerically fewer treatment-related adverse events (84.9% versus 93.9%) and significantly less peripheral sensory polyneuropathy & GE;grade 2 (9.4% versus 36.7%).Conclusions: S-1 maintenance following platinum-based induction therapy leads to non-inferior survival outcomes compared with the continuation of platinum-based combination. Toxicity patterns favor a fluoropyrimidine maintenance strategy. These data challenge the continued use of platinum combination chemotherapy after response to 3 months induction therapy in patients with advanced human epidermal growth factor receptor 2-negative esophagogastric adenocarcinoma.