RARE DISEASE
Adenocarcinoma of the esophagus
Adenocarcinoma of the esophagus
Adenocarcinoma of the esophagus
Synonyms: Esophageal adenocarcinoma
Synonyms: Esophageal adenocarcinoma
Synonyms: Esophageal adenocarcinoma
Drug discovery
48
drugs
With orphan designations
Overview
Adenocarcinoma of the esophagus arises from glandular cells, primarily in the lower esophagus. It is strongly linked to chronic gastroesophageal reflux and Barrett’s metaplasia [1][5][9]. Prognosis remains poor (5-year survival: ~21.6% [14]), with most cases diagnosed at advanced stages due to late symptom onset [3][6][9]. Treatment relies on multimodal approaches, including chemoradiation, surgery, and emerging immunotherapy [1][3][5].
Burden
Accounts for ~1.1% of U.S. cancer cases (22,370 new cases in 2024) but 2.6% of cancer deaths (16,130 estimated deaths) [14]. Over 80% present with regional/distant spread, contributing to high morbidity and healthcare costs [6][10][14]. Global disparities exist, with higher mortality in underserved populations due to delayed diagnosis [2][12].
Therapies
Localized disease: Neoadjuvant chemoradiation (CROSS regimen: carboplatin/paclitaxel + 41.4 Gy radiation) followed by esophagectomy [3][7][11].
Advanced/metastatic disease: Combination chemotherapy (e.g., FLOT), immunotherapy (nivolumab, pembrolizumab), and targeted therapies (trastuzumab for HER2+) [1][7][11].
Palliation: Endoscopic stenting, brachytherapy, or laser therapy for dysphagia [1][5][7].
Categories: rare gastroenterological diseases, rare neoplastic diseases
Research Papers
3,174 drug discovery papers about Adenocarcinoma of the esophagus, with 4 first-in-class and 12 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,174 drug discovery papers about Adenocarcinoma of the esophagus, with 4 first-in-class and 12 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-25 | Pantoprazole as a potential repurposed drug targeting the adenosinergic system in esophageal cancer.
Esophageal cancer remains a major global health burden and is associated with poor prognosis. Adenosine signaling, particularly through CD73 and P1 receptors, contributes to tumor progression and immune modulation. Pantoprazole, a proton pump inhibitor widely used in clinical practice, has recently been suggested as a potential modulator of adenosinergic pathways. This study investigated the ability of pantoprazole to modulate adenosine signaling. In silico docking analyses were performed to assess the binding of pantoprazole to adenosine P1 receptors and CD73, followed by in vitro assays using esophageal adenocarcinoma (OE33) and squamous cell carcinoma (KYSE450) cell lines to evaluate cell growth, adenosinergic signaling, and tumor-related cellular functions following pantoprazole treatment. Docking analyses identified CD73 and P1 receptors, particularly A2A, as favorable molecular targets for pantoprazole. Pantoprazole significantly reduced proliferation and metabolic activity in both cell lines in a concentration-dependent manner, with pronounced inhibition of clonogenic survival in adenocarcinoma cells. Pantoprazole altered P1 receptor expression, particularly A2A, and pharmacological antagonism supported the involvement of these receptors in its antiproliferative effects. Additionally, pantoprazole modulated CD73 expression and reduced cell adhesion and MMP‑2 expression. These findings indicate that pantoprazole exerts antitumor effects by modulating the CD73-adenosine-P1 receptor axis, supporting its potential repurposing as an adjunctive strategy for the treatment of esophageal adenocarcinoma.
2026-09-21 | Targeting Kras signalling in a Trp53/KrasG12D mouse and organoid model inhibits Barrett esophagus to gastroesophageal adenocarcinoma progression
Abstract The lack of experimental systems that faithfully model the genetic and phenotypic progression from Barrett’s esophagus (BE) to gastroesophageal adenocarcinoma (GEAC) has limited mechanistic discovery and preclinical testing. Here, we report a refined L2-IL-1B based mouse model engineered to capture two hallmark alterations of human GEAC: TP53 loss and elevated KRAS signalling driven by wildtype KRAS amplification, which we model in the L2-IL-1B mouse model by using oncogenic Kras G12D activation, since direct modelling of wildtype Kras amplification in vivo remains challenging. This combinatorial genetic approach accelerates malignant transformation and enables controlled, stage-resolved analysis of carcinogenesis at the gastroesophageal junction (GEJ). In parallel, murine Kras G12D driven and human KRAS wildtype amplified organoid systems recapitulate these in vivo phenotypes and provide a platform for functional interrogation of aberrant KRAS signalling, a frequent but understudied driver in GEAC. Using the human derived KRAS wildtype amplified organoids as treatment avatars in addition to the Kras G12D driven mouse model and its corresponding organoids, we demonstrate that KRAS dependent growth is selectively vulnerable to combined SHP2 + MEK1/2 or ERK1/2 inhibition, revealing a therapeutically targetable signalling axis. Together, these integrated in vivo and organoid platforms represent a technical advance for modelling BE progression, dissecting KRAS pathway biology, and evaluating targeted strategies for KRAS amplified GEAC.
2026-08-25 | Executive Summary of the American Radium Society Appropriate Use Criteria for a Multidisciplinary Treatment Approach to the Management of Resectable Esophageal and Gastroesophageal Junction Adenocarcinoma.
In this systematic review and associated guidelines, the American Radium SocietyTM (ARS) thoracic and gastrointestinal oncology expert panels worked together to thoroughly evaluate current literature and provide treatment recommendations for best outcomes for resectable esophagus or gastroesophageal junction adenocarcinoma. To represent a diverse group representing all key specialties, thoracic and gastrointestinal radiation and medical oncologists, gastroenterologists, and thoracic surgeons were included in development of these consensus guidelines. Using the Population, Intervention, Comparator, Outcome, Timing and Study Design framework, the evidence was assessed using Cochrane and PRISMA 2020 methodology. Eligible studies included randomized Phase II and III trials and retrospective subset analyses of randomized controlled trials published between January 1, 2019 and July 7, 2025 in the Ovid Medline database. These references were assessed via ARS Appropriate Use Criteria (AUC) methodology. RAND-UCLA consensus methodology was used to rate the appropriateness of various treatments. For patients with adenocarcinoma of the esophagus or gastroesophageal junction, the standard treatment approach has been trimodality therapy including chemotherapy, radiation, and surgery which is associated with significant long-term toxicity. Recent randomized controlled trials have compared perioperative chemotherapy to trimodality therapy affording the omission of radiotherapy for suitable patients and a resulting reduction in associated treatment-related toxicities. Recommendations for adjuvant and neoadjuvant therapies are provided, including chemotherapy, immunotherapy, targeted therapy and radiation therapy, and active surveillance after chemoradiation is also detailed. The updated 2026 ARS AUC for Operable Esophageal and Gastroesophageal Junction Adenocarcinoma is presented in this manuscript.
2026-08-16 | Transitioning from neoadjuvant chemoradiation to perioperative chemotherapy for esophageal adenocarcinoma: Impact on margins and pathologic outcomes.
Treatment of esophageal adenocarcinoma has historically involved trimodality therapy. Recently, perioperative chemotherapy has become standard of care due to improved survival. We investigated the implications of this change on surgical and pathologic outcomes. This multicenter retrospective analysis included adults who underwent esophagogastrectomy for esophageal/gastroesophageal junction adenocarcinoma between 2023 and 2025. The primary outcome was any positive margin on final pathology. Secondary outcomes included rates of nodal upstage and posttreatment tumor characteristics. Fisher exact and Kruskal-Wallis tests were used for comparisons. In total, 110 patients were included; 22 received perioperative chemotherapy (20.0%), 48 chemoradiation (chemoRT, 43.6%), and 40 induction chemotherapy followed by chemoRT (chemo + chemoRT, 36.3%). On final pathology, 36.4% of patients experienced nodal upstaging in the chemotherapy group (n = 8) relative to 16.7% (n = 8) and 7.5% (n = 3) in the chemoRT and chemo + chemoRT groups (P = .030). Similarly, more patients had tumors exhibiting poor treatment response (tumor regression grade 3) in the chemotherapy group (n = 7, 33.3%) compared with the other 2 groups (n = 2 [4.5%] and n = 4 [10.5%]; P = .007). More patients in the chemotherapy group had any positive final margin (n = 8, 36.4%), as compared with the chemoRT (n = 5, 10.4%) or chemo + chemoRT groups (n = 4, 10.0%; P = .017). Early data suggest greater rates of frozen-to-final esophageal margin discrepancies in the chemotherapy cohort (n = 2 [16.6%] vs n = 1 [2.8%] chemoRT vs n = 2 [6.6%] chemo + chemoRT; P = .232). In this small multi-institutional study, chemotherapy-only preoperative regimens seemed to be associated with increased rates of nodal upstage and margin positivity after esophagectomy relative to radiotherapy-inclusive protocols.
2026-08-12 | Perioperative FLOT chemotherapy for locally advanced esophageal adenocarcinoma: from ESOPEC to daily practice-a retrospective cohort study.
Two neoadjuvant treatment strategies exist for esophageal and gastro-esophageal junction (GEJ) adenocarcinoma: Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) chemoradiotherapy or peri-operative FLOT chemotherapy (5-fluorouracil, leucovorin, oxaliplatin, docetaxel). ESOPEC showed improved overall survival (OS) after FLOT. This study aimed to reassess OS after perioperative FLOT and surgery in real-life. This single center retrospective cohort study included all patients with locally advanced esophageal or GEJ adenocarcinoma (cT1/2N+ or cT3/4N0/+) treated with intended perioperative FLOT and surgery between 2017 and 2023. Primary endpoint was OS. One-hundred forty-four patients were included with mostly high T-stages [cT3 (n=120, 83.3%), cT4 (n=14, 9.7%)] and node-positive tumors [cN1 (n=37, 25.7%), cN2 (n=60, 41.7%), cN3 (n=19, 13.2%)]. Nineteen patients (13.2%) didn't proceed to surgery (PRE), and 19 patients (15.2%) did not receive any postoperative FLOT (PRE-SURG). Finally, 96 (76.8%) started postoperative FLOT (PRE-SURG-POST). Median OS was 53.3 months and after stratification 12.9 months [95% confidence interval (CI): 11.1-14.7] for PRE and 13.0 months (95% CI: 5.6-20.5) for PRE-SURG. Median OS for PRE-SURG-POST was not reached but significantly higher (P<0.001). Median event-free survival (EFS) was 29.6 months for PRE-SURG-POST, compared with 12.4 months (95% CI: 8.8-15.9) for PRE-SURG (P=0.06) and 7.7 months (95% CI: 1.0-14.4) for PRE (P<0.0001). Our results, with predominantly advanced and node positive tumors, corroborate the OS and EFS of perioperative FLOT with surgery observed in the FLOT-4 and ESOPEC-trial. Completion of treatment was associated with improved OS and EFS. This emphasizes the importance of patient selection, high-quality surgery and supportive care to maximize treatment continuation and increasing survival.
oligonucleotides
2025-10-08 | Discovery and Validation of Molecular Biomarkers for Differentiation of Nondysplastic Barrett's Esophagus from High-grade Dysplasia and Esophageal Adenocarcinoma.
Aberrant DNA methylation and copy-number alterations (CNA) drive Barrett's esophagus progression to esophageal adenocarcinoma; however, their combined utility for early detection is unclear. We aimed to identify and validate methylated DNA markers (MDM) and CNAs to distinguish esophageal adenocarcinoma/high-grade dysplasia (HGD) from nondysplastic Barrett's esophagus (NDBE). In this multiphase, multicenter study, we discovered and validated MDMs and quantified CNAs utilizing whole-genome methylation sequencing of esophageal brushings. DNA biomarkers identified from discovery were further validated in independent patients with paired esophageal brushing and swallowed capsule sponge samples. MDMs were filtered against a reduced representation bisulfite sequencing dataset obtained from independent tissue samples to advance only concordant candidates. CNA burden was quantified using ichorCNA-derived aneuploidy scores (AS). Two hundred MDMs discovered in HGD (N = 18) and esophageal adenocarcinoma (N = 18) versus NDBE brushing samples (N = 18) were tested in independent samples (N = 146). A 52-MDM panel achieved a cross-validated AUC of 0.88 [95% confidence interval (CI), 0.82-0.95]; the addition of AS improved discrimination of HGD/esophageal adenocarcinoma from NDBE to 0.91 (95% CI, 0.86-0.97) AUC. At 80% specificity, the combined model detected 93% of esophageal adenocarcinoma and 88% of HGD cases. In paired capsule sponge samples, a 58-MDM panel achieved a cross-validated AUC of 0.77 (95% CI, 0.66-0.88); a combined 58-MDM and AS model achieved AUC 0.80 (95% CI, 0.7-0.9). MDMs and AS discerned HGD/esophageal adenocarcinoma from normal esophagus/NDBE in endoscopic brushing and capsule sponge samples. This approach may improve Barrett's esophagus surveillance. This study demonstrates that combining epigenetic and genomic biomarkers across minimally invasive sampling methods can accurately distinguish HGD/esophageal adenocarcinoma from nondysplastic Barrett's esophagus, offering promising, less invasive strategies to improve BE surveillance and enable endoscopic therapy for esophageal adenocarcinoma prevention and treatment.
2025-09-16 | MicroRNA 196a contributes to the aggressiveness of esophageal adenocarcinoma through the MYC/TERT/NFκB axis.
Barrett's esophagus (BE) is a premalignant lesion that can lead to an invasive esophageal adenocarcinoma (EAC), a type of cancer that usually has a poor outcome. We have previously described a set of four microRNAs (miR-192, 194, 196a and b) that are markers of the disease's progression. To determine whether these miRNAs might also be drivers of invasive EAC development, their overexpression in EAC cells was analyzed. Only the overexpression of miR-196a and miR-196b induced a phenotype switch in non-invasive EAC cells, resembling epithelial-to-mesenchymal transition (EMT). The overexpression of miR-196a promoted EMT and increased cell motility and NFκB signaling. Mechanistically, miR-196a targets the inhibitor of NFκB alpha NFKBIa and also leads to c-MYC protein accumulation by down-regulating VCP expression. This in turn up-regulated TERT expression and reinforced NFκB signaling. NFκB signaling, TERT, and c-MYC inhibition resulted in a reversed-EMT phenotype, with decreased EMT hallmarks and cell motility in miR-196a overexpressing cells. Finally, an immunohistochemical analysis of BE tissue samples showed that c-MYC, TERT, and NFκB signaling increased in BE patients who developed EAC, more so than in patients that did not. The high expression of miR-196a induces aggressive features in non-invasive EAC cells. These effects are dependent on the c-MYC/TERT/NFκB signaling molecular axis. BE patients and non-invasive EAC patients with high miR-196a expression could benefit from therapeutic interventions to prevent EMT or activation of the molecular pathway described in this study.
2025-03-13 | Non-coding RNAs in thoracic disease: Barrett's esophagus and esophageal adenocarcinoma.
Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy with increasing incidence and poor survival rates, primarily due to late-stage diagnosis. This cancer often develops from Barrett's Esophagus (BE), a precancerous condition linked to chronic gastroesophageal reflux disease (GERD). The transition from BE to EAC is a complex multistep process involving numerous genetic, epigenetic, and molecular changes that lead to the malignant transformation of the esophageal epithelium. Despite advancements in understanding the molecular mechanisms underlying EAC, early detection and effective treatment options remain limited, highlighting an urgent need for innovative diagnostic and therapeutic strategies. Recent research has focused on non-coding RNAs (ncRNAs), which play crucial roles in regulating gene expression and cellular processes relevant to cancer progression. Various types of ncRNAs, including microRNAs, long non-coding RNAs, and circular RNAs, have been implicated in the development of BE and EAC by modulating key signaling pathways such as Wnt/β-catenin and NF-κB. Additionally, ncRNAs are stable in biological fluids, presenting opportunities for their use as non-invasive biomarkers for early detection and monitoring of EAC. This review aims to elucidate the involvement of ncRNAs in the progression from BE to EAC, their potential as therapeutic targets, and their emerging roles in intercellular communication. We will also discuss the challenges in translating ncRNA research into clinical applications, emphasizing their promise in revolutionizing early detection and treatment strategies for EAC.
2025-01-14 | Study on the metastatic mechanism of LINC00115 in adenocarcinoma of the Esophagogastric junction.
Adenocarcinoma of the esophagogastric junction (AEG) is a common and deadly cancer, and an in-depth investigation of its molecular mechanisms of metastasis is crucial for discovering new therapeutic targets. This study explores the role of the long non-coding RNA (lncRNA) LINC00115 in AEG metastasis and its underlying mechanisms. Through the analysis of 108 pairs of AEG cancer tissues and matched adjacent tissues, we found a significant upregulation of LINC00115 in AEG tissues, closely associated with TNM staging and lymph node metastasis. Utilizing cell counting kit-8 (CCK-8) assays, colony formation experiments, wound healing assays, flow cytometry for apoptosis and cell cycle analysis, and Transwell assays, we have confirmed that LINC00115 significantly promotes proliferation, migration, and invasion of AEG cells in vitro. Animal experiments further validate the role of LINC00115 in promoting tumor growth and metastasis in vivo. Additionally, our nuclear-cytoplasmic fractionation experiments and RNA fluorescence in situ hybridization (FISH) reveal that LINC00115, along with its interacting protein KH-Type splicing regulatory protein (KHSRP), predominantly localizes to the cell nucleus. By conducting RNA pull-down assays and mass spectrometry (MS) analysis, we have identified a direct interaction between LINC00115 and KHSRP protein and further determined their binding sites through catRAPID and ENCORI databases. This study provides evidence of LINC00115 as a novel biomarker and potential therapeutic target for AEG and offers a fresh perspective on understanding the molecular mechanisms of AEG metastasis.
2024-06-23 | ANPEP/CD13 Expression as a Marker of Lymphovascular Invasion and Survival in Esophageal Adenocarcinoma.
The presence of lymphovascular invasion (LVI) in early esophageal adenocarcinoma (EAC) is associated with more aggressive disease. Molecular markers associated with LVI are still largely unknown. Using a combination of transcriptomic analysis and validation experiments, we sought to describe markers for LVI and survival. We performed NanoString expression profiling using RNA from 60 EAC specimens collected from surgery-only cases between 2000 and 2012. Differentially expressed genes (DEGs) were correlated with pathologic characteristics (T and N status and presence of LVI). Kaplan-Meier and Cox regression analyses were used to correlate gene expression with overall survival. Expression of alanyl aminopeptidase, membrane (ANPEP)/CD13 was validated by immunohistochemistry (IHC) in EAC tissue microarray and in EAC cell lines. We identified >20 up-regulated DEGs in tumor samples containing LVI. Multivariable analysis showed depth of invasion and ANPEP/CD13 expression were independently associated with overall survival, whereas nodal status was not. IHC analysis demonstrated overexpression of the ANPEP/CD13 protein in dysplastic Barrett esophagus and EAC tumors. Kaplan-Meier analysis showed that patients with higher RNA expression and strongly positive ANPEP/CD13 membrane IHC-Histoscore staining have shorter survival (P = .002). Down-regulation of ANPEP/CD13 expression by short hairpin RNA vector reduces colony formation, migration, and invasion of FLO-1 EAC cells. Overexpression of CD13 in SKGT4 EAC cells increases colony formation, motility, and invasion in vitro. Elevated expression of ANPEP/CD13 indicates shorter survival of EAC patients and a more invasive phenotype of cancer cells in vitro. Validation in a larger sample group is required to better understand the clinical significance of ANPEP/CD13 and other candidate genes.
combination
2026-09-23 | Neoadjuvant Chemoradiotherapy Versus Perioperative Chemotherapy ± Immunotherapy in Resectable Esophageal Adenocarcinoma.
We sought to compare pathologic responses, perioperative outcomes, and early survival between induction chemoradiotherapy and perioperative chemotherapy ± immunotherapy in patients with resectable esophageal adenocarcinoma. Using our prospectively maintained institutional database, we retrospectively identified adult patients with resectable, locally advanced esophageal or gastroesophageal junction adenocarcinoma who underwent esophagectomy from January 2013 to October 2024 after induction chemoradiotherapy or perioperative chemotherapy ± immunotherapy. The primary outcome was rate of pathologic complete response. Secondary outcomes included rate of microscopically margin-negative resection, rate of pathologic node-negative status, and perioperative morbidity. Event-free survival and overall survival were estimated using Kaplan-Meier methods and were evaluated using Cox regression. Of 811 patients, 650 (80%) received chemoradiotherapy, and 161 (20%) received chemotherapy ± immunotherapy. Median follow-up was 29.9 months. Chemoradiotherapy was associated with higher rates of pathologic complete response (23% vs. 14%) and pathologic node-negative status (61% vs. 46%; both P<0.001 after adjustment). The rate of microscopically margin-negative resection was 96% in both groups. Two-year event-free survival was higher in the chemotherapy ± immunotherapy group (66% vs. 53%; adjusted hazard ratio, 0.53; P=0.007). Two-year overall survival was not statistically different between groups. On multivariable analysis, perioperative chemotherapy ± immunotherapy and pathologic complete response were independently associated with longer event-free survival. Both induction strategies achieved excellent perioperative outcomes. Despite higher rates of pathologic complete response with chemoradiotherapy, perioperative chemotherapy ± immunotherapy was associated with longer early event-free survival. This association was attenuated in propensity score-matched and 90-day landmark analyses. Longer follow-up is warranted.
2026-01-10 | Phase I-II trial of perioperative chemotherapy plus atezolizumab and tiragolumab in localized esophageal and gastroesophageal junction adenocarcinoma.
418 Background: Management of esophageal and gastroesophageal junction (GEJ) adenocarcinoma focuses on perioperative strategies to increase pathological complete response rates, delay or eliminate metastases, and prolong overall survival. Atezolizumab is a humanized IgG1 monoclonal antibody that blocks PD-L1 from binding its inhibitory receptors, PD-1 and B7-1, thereby boosting tumor-specific T-cell responses and anti-tumor activity. Tiragolumab is a fully human IgG1/κ monoclonal antibody targeting TIGIT, an inhibitory receptor on activated T cells and NK cells that binds CD155. Blocking TIGIT could further enhance T-cell responses. Combining tiragolumab with atezolizumab and chemotherapy may improve outcomes in patients with localized esophageal and GEJ adenocarcinoma. Methods: We conducted a phase I/II study to evaluate the efficacy and safety of combining atezolizumab and tiragolumab with modified FOLFOX (oxaliplatin and 5-fluorouracil) in the perioperative treatment of localized esophageal and GEJ type I or II adenocarcinoma. Eligible patients were treatment naïve with T1N1 or T2-3 (any N) GEJ adeno. Treatment involved FOLFOX on days 1 and 15, followed by atezolizumab (840 mg IV) and tiragolumab (420 mg IV) on the same days of each 28-day cycle, for a total of six doses. Surgery was performed afterward, followed by adjuvant atezolizumab (1200 mg IV) plus tiragolumab (600 mg IV) on day 1 administered every 21 days for sixteen cycles. Results: Twenty-three patients (median age 67) were enrolled (stage IIb: n=6; stage III: n=13; stage IVa: n=4). Twenty patients were evaluated for efficacy. Thus far, 16 patients had undergone surgery. Pathological complete response (pCR, T0N0) has been observed in 18.8% (3/16; 95% CI: 4.1–45.7%), with 1 additional patient showing near-complete response (<1% viable tumor). R0 resection rate was 87.5%. There were no grade 4 treatment-related adverse events, deaths or treatment discontinuations. At a median follow-up of 21.1 months, four patients had died. Estimated 1- and 2-year survival rates were 94.1% and 74.0%, respectively. Conclusions: Results indicate that atezolizumab and tiragolumab in combination with oxaliplatin and 5-fluorouracil has an acceptable safety profile providing high rate of tumor regression. This trial supports further research checkpoint inhibition in patients with localized esophageal and GEJ adenocarcinomas in the perioperative setting. Clinical trial information: NCT03784326 .
2025-06-02 | Synergistic effects of PD-1 antibody and chemotherapy followed by surgery-centric local treatment in patients with limited-metastatic gastric or gastroesophageal adenocarcinoma (ROSETTE trial): an open-label, single-center, randomized phase 2 trial.
Limited metastatic gastric cancer (lmGC) represents an intermediate disease stage, positioned between localized and widely disseminated gastric cancer, and has garnered increasing attention due to its distinct prognostic outcomes. Currently, there is no consensus on the optimal treatment approach for lmGC, raising the question of whether it should align more with the systemic treatment-focused approach used for metastatic gastric cancer or adopt a surgery-centric strategy similar to that used in localized disease. Previous studies have preliminarily explored combining systemic treatment and surgical resection to address both the primary tumor and metastatic lesions. However, these investigations have been constrained by limited evidence and yielded inconclusive findings. ROSETTE trial is an open-label, randomized phase II study designed to investigate treatment strategies for patients with limited metastatic gastric or gastroesophageal adenocarcinoma. Eligible patients, confirmed through comprehensive evaluation including radiography and laparoscopy, are randomized to receive either systemic treatment followed by surgery-centric local treatment, or systemic treatment alone. Systemic treatment combines immunotherapy with chemotherapy, while the surgery-centric local treatment utilizes a surgery-centric, multi-modality approach involving resection of both primary and metastatic tumors where feasible. For unresected or unresectable metastatic lesions, alternative local therapies are provided. The primary endpoint is the 1-year event-free survival (EFS) rate. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), extended EFS, overall survival (OS), pathologic complete response rate (pCR), major pathologic response rate (MPR), and R0 resection rate. The ROSETTE trial aims to evaluate whether systemic treatment followed by surgery-centric local treatment provides a survival advantage over the standard systemic-only approach for patients with limited metastatic gastric cancer. It seeks to build on previous research while addressing limitations such as selection bias inherent to non-randomized designs, patient recruitment challenges, and the complexities of managing surgical complications. By applying the latest evidence and a multi-modality approach, the ROSETTE trial endeavors to offer new insights into optimizing treatment strategies for patient with lmGC. NCT06468280 (Registration date: 05/28/2024).
2025-05-31 | Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III, Randomized LEAP-015 Study.
The phase III randomized open-label LEAP-015 study (ClinicalTrials.gov identifier: NCT04662710) evaluated first-line lenvatinib plus pembrolizumab and chemotherapy versus chemotherapy for advanced metastatic gastroesophageal adenocarcinoma. Eligible participants 18 years and older with untreated human epidermal growth factor receptor 2-negative locally advanced unresectable or metastatic gastroesophageal adenocarcinoma were randomly assigned 1:1 to induction with oral lenvatinib 8 mg once daily plus pembrolizumab 400 mg intravenously once every 6 weeks (×2) and investigators' choice of capecitabine and oxaliplatin once every 3 weeks (×4) or fluorouracil, leucovorin, and oxaliplatin once every 2 weeks (×6) and consolidation with lenvatinib plus pembrolizumab, or chemotherapy. Dual primary end points were progression-free survival (PFS) and overall survival (OS) in participants with PD-L1 combined positive score (CPS) ≥1 and all participants. Secondary end points included objective response rate (ORR) and duration of response. Of 880 participants randomly assigned, 443 received lenvatinib plus pembrolizumab and 437 received chemotherapy. The median follow-ups were 32.2 months (range, 19.0-41.7) in participants with PD-L1 CPS ≥1 and 31.8 months (19.0-41.7) in all participants. At interim analysis, PFS was statistically significant with lenvatinib plus pembrolizumab versus chemotherapy in participants with PD-L1 CPS ≥1 (median, 7.3 v 6.9 months; hazard ratio [HR], 0.75 [95% CI, 0.62 to 0.9]; P = .0012) and all participants (median, 7.2 v 7.0 months; HR, 0.78 [95% CI, 0.66 to 0.92]; P = .0019). The ORR was 59.5% versus 45.4% in participants with PD-L1 CPS ≥1 and 58.0% versus 43.9% in all participants, P < .0001 for both. At final analysis, OS was not statistically significant in participants with PD-L1 CPS ≥1 (median, 12.6 v 12.9 months; HR, 0.84 [95% CI, 0.71 to 1.00]; P = .0244; P value boundary = .0204). Grade ≥3 drug-related adverse event rates were 65% versus 49%. Lenvatinib plus pembrolizumab and chemotherapy versus chemotherapy provided a statistically significant improvement in PFS in advanced unresectable or metastatic gastroesophageal carcinoma at interim analysis although the clinical significance of this difference seems to be limited. No significant improvement occurred in OS in participants with PD-L1 CPS ≥1.
2025-03-14 | PD-1 antibody camrelizumab plus apatinib and SOX as first-line treatment in patients with AFP-producing gastric or gastro-esophageal junction adenocarcinoma (CAP 06): a multi-center, single-arm, phase 2 trial
Alpha-fetoprotein-producing gastric or gastro-esophageal junction (AFP-G/GEJ) cancer, a rare gastric cancer subtype, exhibits increased angiogenesis and more immunosuppression than non-AFP-G/GEJ cancer. The potential benefits of anti-angiogenic agents and immunotherapy for this specific subtype remain unknown. This multi-center, single-arm, phase 2 trial (ClinicalTrials.gov NCT04609176) evaluated the antitumor activity, safety, and biomarkers of camrelizumab plus apatinib and S-1 and oxaliplatin (SOX), followed by maintenance treatment with camrelizumab plus apatinib, as a first-line treatment in patients with AFP-G/GEJ adenocarcinoma. Primary endpoint was the confirmed objective response rate (ORR) per RECIST v1.1 in the full analysis set. Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response, time to response, and safety. Between December 4, 2020, and August 4, 2023, 36 patients were enrolled and treated. The trial met its primary endpoint with a confirmed ORR of 66.7% (95% CI: 49.0-81.4). The DCR was 88.9% (95% CI: 73.9-96.9). With a median follow-up of 11.7 months (range: 3.2-37.9), the median PFS reached 7.8 months (95% CI: 4.9-12.3) and the median OS reached 18.0 months (95% CI: 10.5-NR). No new safety concerns were identified. In exploratory analysis, patients with durable clinical benefit exhibited higher pre-treatment (PD-1+) CD8+ T cell densities and effective scores. First-line treatment with camrelizumab plus apatinib and SOX, followed by maintenance treatment with camrelizumab plus apatinib, is effective and safe in AFP-G/GEJ adenocarcinoma. Further studies are necessary to validate these findings.
antibodies
2026-09-22 | Integrating plasma-derived circulating proteins with multi-omics approaches to identify potential therapeutic targets for esophageal adenocarcinoma.
Background: Esophageal adenocarcinoma (EAC) is a complex disease often preceded by Barrett's esophagus. Objective: This study aimed to identify potential drug targets and support early prevention and treatment. Method: We integrated cis-protein quantitative trait loci (cis-pQTLs) and genome-wide association study (GWAS) data from 35 559 individuals using Mendelian randomization to infer causal relationships, with FDR correction applied. To assess tissue relevance, the source cis-pQTL instruments were examined across three GTEx v8 esophageal tissues, followed by tissue-informed single-variant Wald analyses of CD55 and NDST1. Gene ontology (GO) and KEGG pathway analyses, along with protein-protein interaction (PPI) network analysis, were used to explore biological functions and interactions. Overlapping genes were identified through differential expression analysis using the GEO database. Key feature genes were screened using XGBoost and Lasso regression, and diagnostic performance was evaluated by ROC curve AUC in both training and validation sets. Immune infiltration analysis explored the tumor microenvironment, and molecular docking assessed drug potential. Results: We identified 28 plasma proteins causally linked to EAC. KEGG analysis revealed enrichment in oxidative stress and inflammation-related pathways. Transcriptomic validation confirmed three overlapping genes. CD55 and NDST1 emerged as key markers with strong diagnostic accuracy after Lasso and XGBoost screening. Most significant esophageal SNP-tissue associations were directionally concordant with the corresponding plasma pQTL effects, and the tissue-specific Wald estimates for CD55 and NDST1 were consistent with the primary plasma-based findings. Immune infiltration analysis showed significant changes in immune cell composition in EAC, particularly natural killer cells, plasma cells, and mast cells. Drug prediction and docking supported the druggability of these targets. Conclusion: CD55 and NDST1 are promising therapeutic candidates for EAC. Drugs based on these genetic findings could improve clinical trial success rates and reduce costs.
2026-09-09 | Real-world treatment landscape and clinical outcomes in first-line advanced or metastatic gastroesophageal adenocarcinoma in the United States.
Contemporary real-world evidence in advanced gastric, gastroesophageal junction, or esophageal adenocarcinoma (GC/GEJC/EAC) remains limited. This study evaluated real-world treatment patterns and clinical outcomes in patients with advanced GC/GEJC/EAC treated with first-line therapy in the United States. Treatment patterns were assessed in adults from the Flatiron database with advanced or metastatic HER2-negative GC/GEJC/EAC who initiated first-line treatment between May 1, 2021, and July 31, 2025 (overall cohort). Clinical outcomes were assessed using the Kaplan-Meier method in a subcohort with ≥6 months of follow‑up. Among 2340 eligible patients, the most common first-line regimen was IO+FOLFOX/CAPOX (31.6%). This regimen was used in 47.6% of patients with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 expression. Starting in 2024, zolbetuximab+FOLFOX/CAPOX was administered more frequently in patients with CPS <1 vs ≥1 (6.1% vs 1.9%) and CPS <5 vs ≥5 (4.6% vs 0.8%) expression. In the subcohort (n = 2117), IO+FOLFOX/CAPOX vs FOLFOX/CAPOX was associated with significantly longer median (months; hazard ratio [95% CI]) real-world overall survival (12.3 vs 11.3; 0.81 [0.69-0.94]), time to next treatment or death (8.0 vs 6.1; 0.64 [0.55-0.75]), and time to treatment discontinuation (6.0 vs 3.0; 0.54 [0.47-0.63]). Differences in outcomes were driven by patients with CPS ≥1 expression, with no differences in patients with CPS <1 expression. IO+FOLFOX/CAPOX was the most frequent first-line regimen in advanced or metastatic GC/GEJC/EAC and showed improved real-world outcomes vs FOLFOX/CAPOX. Despite these gains, overall survival remains poor, underscoring unmet needs and the importance of biomarker-informed treatment selection.
2026-08-30 | Ivonescimab in combination with chemotherapy in advanced or metastatic gastric cancer (GC) or esophagogastric junction cancer (EGJC): The UCGI 52 - GRACIE trial.
While the addition of Ivonescimab to chemotherapy has demonstrated promising results in non-small cell lung cancer compared with chemotherapy alone, its efficacy as a first- or second-line treatment in advanced/metastatic gastric cancer remains to be established. GRACIE aims to evaluate the efficacy and safety of Ivonescimab combined with FOLFOX chemotherapy as first-line treatment (Arm-1) or as second-line when combined with paclitaxel or irinotecan or FOLFIRI following progression (Arm-2), in patients with advanced/metastatic gastric cancer and esophageal adenocarcinoma, regardless of actionable targets' presence (PD-L1/HER2/CLDN-18.2). This multicenter, two-arm, non-randomized, open-label exploratory phase II study is recruiting 88 patients, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, over 18 French centers. The primary objective is the Objective Response Rate (ORR) after central review according to RECIST v1.1 in HER2- and CLDN-18.2-negative, treatment-naïve patients (Arm-1) and patients with a single previous line for advanced disease, regardless of biomarkers expression (Arm-2). Secondary objectives are investigator-assessed ORR, Duration-of-Response, Progression-Free Survival, Overall Survival, time to ECOG performance status deterioration, Safety and Quality-of-life. GRACIE will provide crucial information about Ivonescimab plus chemotherapy regimens efficacy either as a first- or second-line treatment in molecularly defined advanced/metastatic gastric and esophageal adenocarcinomas to inform future phase III trials. EU-CTIS: 2025-520694-39-00, ClinicalTRials.gov: NCT06846346.
2026-08-19 | Comprehensive Profiling of Claudin 18.2 Immunohistochemical Expression in 564 Surgically Resected Gastric and Gastroesophageal Junction Adenocarcinomas.
Claudin 18 isoform 2 (CLDN18.2) is a novel therapeutic target for advanced, HER2-negative gastric/gastroesophageal junction (GEJ) adenocarcinoma positive for CLDN18.2 immunohistochemical (IHC) expression, defined as ≥75% tumor cells with moderate-to-strong membranous staining. Clinical studies for emerging CLDN18.2-targeted therapeutics have used less stringent enrollment criteria to test the efficacy of such therapies in patients with moderate-to-low CLDN18.2 IHC expression. Anticipating the advent of such treatments, this study aimed to provide a comprehensive survey of CLDN18.2 expression using a clinical trial-validated CLDN18.2 monoclonal antibody in surgically resected gastric/GEJ adenocarcinomas and characterize CLDN18.2-positive carcinomas using both high- and low-expression thresholds. Crisp membranous CLDN18.2 staining was detected in 59% (335/564) carcinomas, including 57% (164/286) of gastric and 62% (171/278) of GEJ adenocarcinomas. Most gastric (147/164, 90%) and GEJ (166/171, 97%) adenocarcinomas with staining demonstrated moderate or strong staining intensity. Using the high-expression threshold (≥75% tumor cells with moderate-to-strong staining), positive CLDN18.2 expression was observed in 20% (57/286) of gastric and 27% (75/278) of GEJ adenocarcinomas and was associated with Epstein-Barr virus status (P < .001) and stage I gastric adenocarcinomas (P = .02) but stage IV GEJ adenocarcinomas (P = .03). Using a low-expression threshold (≥10% tumor cells with membranous staining), positive CLDN18.2 remained significantly associated with stage I (P = .004) and showed an unadjusted association with improved disease-specific survival in gastric adenocarcinomas (P = .045), which was not retained in multivariable analysis. Whole transcriptomic analysis showed concordance between IHC and CLDN18 messenger RNA expression. Transcriptomic alterations in CLDN18.2 IHC-positive gastric adenocarcinomas included pathways in drug resistance and tumor invasion. In summary, our study presents a detailed characterization of the prevalence and distribution of CLDN18.2 IHC expression patterns. Our results showed that 59% surgically resected gastric/GEJ adenocarcinomas exhibited CLDN18.2 staining. CLDN18.2 IHC positivity defined by both high- and low-expression thresholds may be associated with early-stage gastric adenocarcinoma. These findings expand our recognition of patients who may benefit from CLDN18.2-targeted therapy.
2026-07-23 | Does adding immunotherapy to neoadjuvant chemotherapy increase postoperative morbidity in gastroesophageal junction adenocarcinoma? A propensity score-matched study.
Landmark trials have established the surgical feasibility of neoadjuvant immunotherapy plus chemotherapy (NICT) in gastric and esophageal cancers, yet data specific to the narrow anatomical confines of the gastroesophageal junction (GEJ) remain limited. This study aimed to compare postoperative morbidity between patients receiving NICT and those receiving neoadjuvant chemotherapy (NCT) alone. This single-center, retrospective cohort study included consecutive patients with locally advanced GEJ adenocarcinoma (Siewert II/III) undergoing curative resection after NICT (n=140) or neoadjuvant chemotherapy alone (NCT, n=260). Propensity score matching (1:1) balanced baseline characteristics, including dMMR/MSI-H status and surgical approach, yielding 120 matched pairs. The primary outcome was major complications (Clavien-Dindo ≥III). Secondary outcomes included specific surgical complications, immune-related adverse events (irAEs), and interval to surgery. After matching, NICT was associated with improved major pathological regression (58.3% vs. 45.8%; p=0.028). The primary endpoint was not significantly different between NICT and NCT cohorts (25.8% vs. 22.5%; p=0.538). Critically, no differences were observed in specific technical complications, including anastomotic leak (11.7% vs. 10.0%), conduit failure (3.3% vs. 2.5%), or pulmonary events. irAEs occurred in 13.3% of the NICT cohort without delaying surgical intervention. Multivariable and sensitivity analyses confirmed NICT was not an independent predictor of morbidity. This analysis provides anatomically focused evidence that the addition of immunotherapy to neoadjuvant chemotherapy for GEJ adenocarcinoma is not associated with a statistically significant increase in risk of major postoperative morbidity, anastomotic failure, or operative complexity. While larger randomized trials remain the gold standard, these findings support the extrapolation of established safety data to the technically demanding GEJ location.
other
2026-09-22 | Epigenetic and Transcriptional Dysregulation of Ribosomal Genes in Esophageal Adenocarcinoma: A Multi-omics Mendelian Randomization Study.
The rising incidence and poor prognosis of esophageal adenocarcinoma (EAC) highlight the urgent need to identify novel molecular determinants. Ribosome heterogeneity has emerged as a potential factor in carcinogenesis, yet its causal relevance in EAC remains unclear. We aimed to systematically evaluate the causal effects of ribosome-related genes on EAC risk by integrating multi-omics data. We applied summary-data-based Mendelian randomization (SMR) to analyze 1,329 ribosome-related genes, integrating mQTL, eQTL, pQTL data and a large EAC GWAS. Bayesian colocalization and esophageal tissue transcriptome analyses validated causal signals. We compared mRNA/protein levels of candidate genes in normal HET-1A esophageal cells versus EAC cell lines OE33 and OE19, and validated methylation-gene correlations using the TCGA-ESCA cohort. Crucially, functional assays, including CCK-8, Transwell, colony formation, and apoptosis assays, were performed in OE33 cells following gene overexpression to verify their causal roles. SMR analyses identified EIF2B2 and RPS6KL1 as causal protective genes for EAC; genetically elevated expression of both reduced EAC risk. A regulatory cascade was uncovered, whereby specific CpG methylation repressed gene transcription to alter disease susceptibility. Consistently, EIF2B2 and RPS6KL1 mRNA and protein were markedly lower in OE33/OE19 tumor cells than HET-1A. TCGA data confirmed negative correlation between RPS6KL1 promoter cg19899223 methylation and gene expression (ρ = -0.27, p = 0.00015). Functionally, overexpression of EIF2B2 and RPS6KL1 in OE33 cells significantly suppressed cell viability, invasion, and colony formation, while inducing apoptosis, thereby experimentally validating their tumor-suppressive effects. By integrating multi-omics evidence with functional assays, this study identifies EIF2B2 and RPS6KL1 as causal protective factors in EAC etiology. These findings suggest that maintaining ribosomal homeostasis via these genes acts as a barrier against EAC, highlighting their potential for risk stratification and therapeutic targeting.
2026-07-14 | Causal immune-inflammation mapping of the GERD-Barrett-adenocarcinoma cascade identifies FGF19-HLA-DR⁺ T-cell axis driving esophagogastric junction metaplasia.
Gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), and esophageal adenocarcinoma (EAC) form a recognized pathological continuum, but the causal immune and inflammatory processes driving progression remain incompletely defined. Summary-level genome-wide association study (GWAS) data were analyzed for 91 circulating inflammatory proteins (n = 14,824), 731 immune cell phenotypes (n = 3,757), and three esophageal diseases (GERD, BE, and EAC). Bidirectional and two-step Mendelian randomization (MR) were used to infer causal effects and mediation, with Cochran's Q, MR-Egger, and MR-PRESSO applied to assess heterogeneity and pleiotropy. Causal interaction networks were reconstructed to map immune- and inflammation-dominant regulatory patterns across disease stages, and MR-prioritized signals were experimentally validated in esophagogastric junction (EGJ) organoids and mouse models. MR supported a causal GERD-BE-EAC sequence, with BE mediating 31.95% of the total GERD-to-EAC effect. In total, 139 immune cell traits and 29 inflammatory proteins showed causal links to disease risk. Mediation analyses highlighted M-CSF1 and HLA-DR+CD4 + T cells as central hubs. Guided by the MR-prioritized FGF19-HLA-DR + T-cell axis, experimental studies demonstrated that FGF19 promotes EGJ glandular conversion and increases infiltration of HLA-DR+ CD4+/CD8 + T cells, validated in EGJ organoids and mouse models. This integrated genetic and experimental framework delineates a bidirectional immune-inflammation regulatory network underlying progression from GERD to BE and EAC. FGF19 emerges as a candidate cytokine driving EGJ glandular remodeling through HLA-DR+ CD4+/CD8 + T-cell associated immune activation, providing candidate molecular targets for early prevention and intervention.
2026-05-24 | Autologous T Cell Antigen Coupler Targeting HER2 (TAC01-HER2) in Advanced or Metastatic Solid Tumors.
The T cell antigen coupler (TAC) is a novel genetically engineered receptor that recruits the native T cell receptor upon recognition of an antigen. The downstream activation of TAC T cells has been effective against tumors in preclinical models and safer than chimeric antigen receptor T cells. Human epidermal growth factor receptor 2 (HER2) is a validated biomarker for cancer-targeted therapy, but cell therapy approaches have been met with unmanageable toxicity. We designed a phase 1 clinical trial of TAC01-HER2, an autologous T cell product that targets HER2, in patients with HER2-positive advanced solid tumors. The trial had a dose-escalation phase and a dose-expansion at the recommended phase 2 dose (RP2D). A total of 23 patients with HER2-positive solid tumors were enrolled in this study. The most common treatment-related adverse events were cytokine release syndrome (n=14, 60.9%), anemia (n=5, 21.7%), and increased alanine aminotransferase (n=5, 21.7%). The RP2D was 6-8 × 106 per kg. No treatment-related deaths or adverse events leading to study discontinuation were reported. Two of 9 patients with gastric and gastroesophageal junction (GEJ) cancers had partial responses, and the disease control rate (stable disease or partial response) was 61.1% in the 18 patients with evaluable assessments. The median progression-free survival was 2.6 months (range 0.8-12.4 months), and the overall survival rate at 6 months was 57.9% (95% CI, 36.3%-76.9%). Persistence of TAC T cells in peripheral blood was observed in all patients until at least day 29 after the first infusion. In summary, we demonstrated that treatment with TAC T cells was safe, feasible, and well-tolerated. TAC01-HER2 showed manageable toxicity and early efficacy for patients with HER2-positive gastric, GEJ or esophageal adenocarcinoma who have undergone extensive previous treatments. These results suggest that TAC may offer a promising approach to control T cell activity through cellular therapy.
2026-04-04 | Could venom-derived therapeutics resolve treatment resistance in refractory EAC?
The incidence of esophageal adenocarcinoma is rising in Western countries. Despite advances in chemotherapy and immunotherapy, the prognosis remains poor, with an overall 5-year survival rate below 15%. A major challenge is the cancer's poor and often unpredictable response to current treatments. Animal venoms represent a promising yet underexplored source of therapeutic agents, offering millions of structurally diverse and highly potent bioactive peptides that can modulate a wide array of molecular targets. However, only a small fraction of these peptides has been pharmacologically characterized. This review presents the therapeutic potential of venom-derived peptides in cancer treatment, summarizes the role of ion channels in esophageal adenocarcinoma (EAC), and discusses peptides targeting ion channels that may offer new opportunities for future EAC treatment.
2026-04-03 | Abstract 601: Translational reprogramming disrupts mitosis to drive SMAD4-deficient esophageal adenocarcinoma.
Abstract Esophageal adenocarcinoma (EAC) develops from a precursor lesion named Barrett’s esophagus; a progression that can be mapped by increasing genomic instability. We have previously shown that SMAD4 loss induces tumorigenesis and increased copy number alterations (CNA) in Barrett’s esophagus cells with an existing TP53 mutation. The observed CNA increase was especially pronounced in the resultant SMAD4-deficient tumor cells, suggesting that accumulation of mitotic errors occurs in these cells throughout their oncogenic progression. However, such an effect cannot be explained by our current understanding of canonical SMAD4 signalling. Thus, in this study, we aimed to delineate the role of SMAD4 in maintaining chromosomal stability in EAC. Our multi-omics (RNA-sequencing, proteomics and reverse-phase protein array) approach detected both deregulated translation and mitosis signatures in SMAD4-deficient cells. Using live cell imaging, we demonstrated that TP53-mutant SMAD4-deficient cells exhibit significantly more mitotic errors than TP53-mutant only cells, particularly chromosome segregation defects, which frequently result in chromosomal instability (CIN). Consistent with this, analysis of TCGA data demonstrated that CIN was more prevalent in tumours with both SMAD4 and TP53 mutation than either mutation alone. Further biochemical analyses revealed an increase in cap-dependent translation in these cells, and a decrease in internal ribosome entry site (IRES)-mediated translation. IRES-mediated translation is essential for synthesis of many important mitotic proteins, including a mitosis-specific isoform of a cell cycle kinase. Polysome sequencing showed decreased translation (but not transcription) of this kinase in SMAD4-deficient cells. Ectopic expression of mitosis-specific isoform of this kinase rescued the mitotic errors that arose as a consequence of SMAD4 loss. In sum, we present a model where translational reprogramming disrupts mitosis, inducing CIN and potentially driving EAC tumorigenesis in response to loss of SMAD4. This represents a novel mechanism of tumorigenesis in EAC and a previously unknown role of SMAD4 in maintaining chromosomal integrity. Citation Format: Julia V. Milne, Ka Meng Wu, Sasha Witts, Eric Kusnadi, Kenji Fujihara, Katherine Papastratos, Maree Pechlivanis, Anna Trigos, Metta Jana, Luc Furic, Kaylene Simpson, David Liu, Cuong Duong, Wayne Phillips, Nicholas Clemons. Translational reprogramming disrupts mitosis to drive SMAD4-deficient esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 601.
small molecules
2026-09-25 | Pantoprazole as a potential repurposed drug targeting the adenosinergic system in esophageal cancer.
Esophageal cancer remains a major global health burden and is associated with poor prognosis. Adenosine signaling, particularly through CD73 and P1 receptors, contributes to tumor progression and immune modulation. Pantoprazole, a proton pump inhibitor widely used in clinical practice, has recently been suggested as a potential modulator of adenosinergic pathways. This study investigated the ability of pantoprazole to modulate adenosine signaling. In silico docking analyses were performed to assess the binding of pantoprazole to adenosine P1 receptors and CD73, followed by in vitro assays using esophageal adenocarcinoma (OE33) and squamous cell carcinoma (KYSE450) cell lines to evaluate cell growth, adenosinergic signaling, and tumor-related cellular functions following pantoprazole treatment. Docking analyses identified CD73 and P1 receptors, particularly A2A, as favorable molecular targets for pantoprazole. Pantoprazole significantly reduced proliferation and metabolic activity in both cell lines in a concentration-dependent manner, with pronounced inhibition of clonogenic survival in adenocarcinoma cells. Pantoprazole altered P1 receptor expression, particularly A2A, and pharmacological antagonism supported the involvement of these receptors in its antiproliferative effects. Additionally, pantoprazole modulated CD73 expression and reduced cell adhesion and MMP‑2 expression. These findings indicate that pantoprazole exerts antitumor effects by modulating the CD73-adenosine-P1 receptor axis, supporting its potential repurposing as an adjunctive strategy for the treatment of esophageal adenocarcinoma.
2026-09-21 | Targeting Kras signalling in a Trp53/KrasG12D mouse and organoid model inhibits Barrett esophagus to gastroesophageal adenocarcinoma progression
Abstract The lack of experimental systems that faithfully model the genetic and phenotypic progression from Barrett’s esophagus (BE) to gastroesophageal adenocarcinoma (GEAC) has limited mechanistic discovery and preclinical testing. Here, we report a refined L2-IL-1B based mouse model engineered to capture two hallmark alterations of human GEAC: TP53 loss and elevated KRAS signalling driven by wildtype KRAS amplification, which we model in the L2-IL-1B mouse model by using oncogenic Kras G12D activation, since direct modelling of wildtype Kras amplification in vivo remains challenging. This combinatorial genetic approach accelerates malignant transformation and enables controlled, stage-resolved analysis of carcinogenesis at the gastroesophageal junction (GEJ). In parallel, murine Kras G12D driven and human KRAS wildtype amplified organoid systems recapitulate these in vivo phenotypes and provide a platform for functional interrogation of aberrant KRAS signalling, a frequent but understudied driver in GEAC. Using the human derived KRAS wildtype amplified organoids as treatment avatars in addition to the Kras G12D driven mouse model and its corresponding organoids, we demonstrate that KRAS dependent growth is selectively vulnerable to combined SHP2 + MEK1/2 or ERK1/2 inhibition, revealing a therapeutically targetable signalling axis. Together, these integrated in vivo and organoid platforms represent a technical advance for modelling BE progression, dissecting KRAS pathway biology, and evaluating targeted strategies for KRAS amplified GEAC.
2026-08-25 | Executive Summary of the American Radium Society Appropriate Use Criteria for a Multidisciplinary Treatment Approach to the Management of Resectable Esophageal and Gastroesophageal Junction Adenocarcinoma.
In this systematic review and associated guidelines, the American Radium SocietyTM (ARS) thoracic and gastrointestinal oncology expert panels worked together to thoroughly evaluate current literature and provide treatment recommendations for best outcomes for resectable esophagus or gastroesophageal junction adenocarcinoma. To represent a diverse group representing all key specialties, thoracic and gastrointestinal radiation and medical oncologists, gastroenterologists, and thoracic surgeons were included in development of these consensus guidelines. Using the Population, Intervention, Comparator, Outcome, Timing and Study Design framework, the evidence was assessed using Cochrane and PRISMA 2020 methodology. Eligible studies included randomized Phase II and III trials and retrospective subset analyses of randomized controlled trials published between January 1, 2019 and July 7, 2025 in the Ovid Medline database. These references were assessed via ARS Appropriate Use Criteria (AUC) methodology. RAND-UCLA consensus methodology was used to rate the appropriateness of various treatments. For patients with adenocarcinoma of the esophagus or gastroesophageal junction, the standard treatment approach has been trimodality therapy including chemotherapy, radiation, and surgery which is associated with significant long-term toxicity. Recent randomized controlled trials have compared perioperative chemotherapy to trimodality therapy affording the omission of radiotherapy for suitable patients and a resulting reduction in associated treatment-related toxicities. Recommendations for adjuvant and neoadjuvant therapies are provided, including chemotherapy, immunotherapy, targeted therapy and radiation therapy, and active surveillance after chemoradiation is also detailed. The updated 2026 ARS AUC for Operable Esophageal and Gastroesophageal Junction Adenocarcinoma is presented in this manuscript.
2026-08-16 | Transitioning from neoadjuvant chemoradiation to perioperative chemotherapy for esophageal adenocarcinoma: Impact on margins and pathologic outcomes.
Treatment of esophageal adenocarcinoma has historically involved trimodality therapy. Recently, perioperative chemotherapy has become standard of care due to improved survival. We investigated the implications of this change on surgical and pathologic outcomes. This multicenter retrospective analysis included adults who underwent esophagogastrectomy for esophageal/gastroesophageal junction adenocarcinoma between 2023 and 2025. The primary outcome was any positive margin on final pathology. Secondary outcomes included rates of nodal upstage and posttreatment tumor characteristics. Fisher exact and Kruskal-Wallis tests were used for comparisons. In total, 110 patients were included; 22 received perioperative chemotherapy (20.0%), 48 chemoradiation (chemoRT, 43.6%), and 40 induction chemotherapy followed by chemoRT (chemo + chemoRT, 36.3%). On final pathology, 36.4% of patients experienced nodal upstaging in the chemotherapy group (n = 8) relative to 16.7% (n = 8) and 7.5% (n = 3) in the chemoRT and chemo + chemoRT groups (P = .030). Similarly, more patients had tumors exhibiting poor treatment response (tumor regression grade 3) in the chemotherapy group (n = 7, 33.3%) compared with the other 2 groups (n = 2 [4.5%] and n = 4 [10.5%]; P = .007). More patients in the chemotherapy group had any positive final margin (n = 8, 36.4%), as compared with the chemoRT (n = 5, 10.4%) or chemo + chemoRT groups (n = 4, 10.0%; P = .017). Early data suggest greater rates of frozen-to-final esophageal margin discrepancies in the chemotherapy cohort (n = 2 [16.6%] vs n = 1 [2.8%] chemoRT vs n = 2 [6.6%] chemo + chemoRT; P = .232). In this small multi-institutional study, chemotherapy-only preoperative regimens seemed to be associated with increased rates of nodal upstage and margin positivity after esophagectomy relative to radiotherapy-inclusive protocols.
2026-08-12 | Perioperative FLOT chemotherapy for locally advanced esophageal adenocarcinoma: from ESOPEC to daily practice-a retrospective cohort study.
Two neoadjuvant treatment strategies exist for esophageal and gastro-esophageal junction (GEJ) adenocarcinoma: Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) chemoradiotherapy or peri-operative FLOT chemotherapy (5-fluorouracil, leucovorin, oxaliplatin, docetaxel). ESOPEC showed improved overall survival (OS) after FLOT. This study aimed to reassess OS after perioperative FLOT and surgery in real-life. This single center retrospective cohort study included all patients with locally advanced esophageal or GEJ adenocarcinoma (cT1/2N+ or cT3/4N0/+) treated with intended perioperative FLOT and surgery between 2017 and 2023. Primary endpoint was OS. One-hundred forty-four patients were included with mostly high T-stages [cT3 (n=120, 83.3%), cT4 (n=14, 9.7%)] and node-positive tumors [cN1 (n=37, 25.7%), cN2 (n=60, 41.7%), cN3 (n=19, 13.2%)]. Nineteen patients (13.2%) didn't proceed to surgery (PRE), and 19 patients (15.2%) did not receive any postoperative FLOT (PRE-SURG). Finally, 96 (76.8%) started postoperative FLOT (PRE-SURG-POST). Median OS was 53.3 months and after stratification 12.9 months [95% confidence interval (CI): 11.1-14.7] for PRE and 13.0 months (95% CI: 5.6-20.5) for PRE-SURG. Median OS for PRE-SURG-POST was not reached but significantly higher (P<0.001). Median event-free survival (EFS) was 29.6 months for PRE-SURG-POST, compared with 12.4 months (95% CI: 8.8-15.9) for PRE-SURG (P=0.06) and 7.7 months (95% CI: 1.0-14.4) for PRE (P<0.0001). Our results, with predominantly advanced and node positive tumors, corroborate the OS and EFS of perioperative FLOT with surgery observed in the FLOT-4 and ESOPEC-trial. Completion of treatment was associated with improved OS and EFS. This emphasizes the importance of patient selection, high-quality surgery and supportive care to maximize treatment continuation and increasing survival.
oligonucleotides
2025-10-08 | Discovery and Validation of Molecular Biomarkers for Differentiation of Nondysplastic Barrett's Esophagus from High-grade Dysplasia and Esophageal Adenocarcinoma.
Aberrant DNA methylation and copy-number alterations (CNA) drive Barrett's esophagus progression to esophageal adenocarcinoma; however, their combined utility for early detection is unclear. We aimed to identify and validate methylated DNA markers (MDM) and CNAs to distinguish esophageal adenocarcinoma/high-grade dysplasia (HGD) from nondysplastic Barrett's esophagus (NDBE). In this multiphase, multicenter study, we discovered and validated MDMs and quantified CNAs utilizing whole-genome methylation sequencing of esophageal brushings. DNA biomarkers identified from discovery were further validated in independent patients with paired esophageal brushing and swallowed capsule sponge samples. MDMs were filtered against a reduced representation bisulfite sequencing dataset obtained from independent tissue samples to advance only concordant candidates. CNA burden was quantified using ichorCNA-derived aneuploidy scores (AS). Two hundred MDMs discovered in HGD (N = 18) and esophageal adenocarcinoma (N = 18) versus NDBE brushing samples (N = 18) were tested in independent samples (N = 146). A 52-MDM panel achieved a cross-validated AUC of 0.88 [95% confidence interval (CI), 0.82-0.95]; the addition of AS improved discrimination of HGD/esophageal adenocarcinoma from NDBE to 0.91 (95% CI, 0.86-0.97) AUC. At 80% specificity, the combined model detected 93% of esophageal adenocarcinoma and 88% of HGD cases. In paired capsule sponge samples, a 58-MDM panel achieved a cross-validated AUC of 0.77 (95% CI, 0.66-0.88); a combined 58-MDM and AS model achieved AUC 0.80 (95% CI, 0.7-0.9). MDMs and AS discerned HGD/esophageal adenocarcinoma from normal esophagus/NDBE in endoscopic brushing and capsule sponge samples. This approach may improve Barrett's esophagus surveillance. This study demonstrates that combining epigenetic and genomic biomarkers across minimally invasive sampling methods can accurately distinguish HGD/esophageal adenocarcinoma from nondysplastic Barrett's esophagus, offering promising, less invasive strategies to improve BE surveillance and enable endoscopic therapy for esophageal adenocarcinoma prevention and treatment.
2025-09-16 | MicroRNA 196a contributes to the aggressiveness of esophageal adenocarcinoma through the MYC/TERT/NFκB axis.
Barrett's esophagus (BE) is a premalignant lesion that can lead to an invasive esophageal adenocarcinoma (EAC), a type of cancer that usually has a poor outcome. We have previously described a set of four microRNAs (miR-192, 194, 196a and b) that are markers of the disease's progression. To determine whether these miRNAs might also be drivers of invasive EAC development, their overexpression in EAC cells was analyzed. Only the overexpression of miR-196a and miR-196b induced a phenotype switch in non-invasive EAC cells, resembling epithelial-to-mesenchymal transition (EMT). The overexpression of miR-196a promoted EMT and increased cell motility and NFκB signaling. Mechanistically, miR-196a targets the inhibitor of NFκB alpha NFKBIa and also leads to c-MYC protein accumulation by down-regulating VCP expression. This in turn up-regulated TERT expression and reinforced NFκB signaling. NFκB signaling, TERT, and c-MYC inhibition resulted in a reversed-EMT phenotype, with decreased EMT hallmarks and cell motility in miR-196a overexpressing cells. Finally, an immunohistochemical analysis of BE tissue samples showed that c-MYC, TERT, and NFκB signaling increased in BE patients who developed EAC, more so than in patients that did not. The high expression of miR-196a induces aggressive features in non-invasive EAC cells. These effects are dependent on the c-MYC/TERT/NFκB signaling molecular axis. BE patients and non-invasive EAC patients with high miR-196a expression could benefit from therapeutic interventions to prevent EMT or activation of the molecular pathway described in this study.
2025-03-13 | Non-coding RNAs in thoracic disease: Barrett's esophagus and esophageal adenocarcinoma.
Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy with increasing incidence and poor survival rates, primarily due to late-stage diagnosis. This cancer often develops from Barrett's Esophagus (BE), a precancerous condition linked to chronic gastroesophageal reflux disease (GERD). The transition from BE to EAC is a complex multistep process involving numerous genetic, epigenetic, and molecular changes that lead to the malignant transformation of the esophageal epithelium. Despite advancements in understanding the molecular mechanisms underlying EAC, early detection and effective treatment options remain limited, highlighting an urgent need for innovative diagnostic and therapeutic strategies. Recent research has focused on non-coding RNAs (ncRNAs), which play crucial roles in regulating gene expression and cellular processes relevant to cancer progression. Various types of ncRNAs, including microRNAs, long non-coding RNAs, and circular RNAs, have been implicated in the development of BE and EAC by modulating key signaling pathways such as Wnt/β-catenin and NF-κB. Additionally, ncRNAs are stable in biological fluids, presenting opportunities for their use as non-invasive biomarkers for early detection and monitoring of EAC. This review aims to elucidate the involvement of ncRNAs in the progression from BE to EAC, their potential as therapeutic targets, and their emerging roles in intercellular communication. We will also discuss the challenges in translating ncRNA research into clinical applications, emphasizing their promise in revolutionizing early detection and treatment strategies for EAC.
2025-01-14 | Study on the metastatic mechanism of LINC00115 in adenocarcinoma of the Esophagogastric junction.
Adenocarcinoma of the esophagogastric junction (AEG) is a common and deadly cancer, and an in-depth investigation of its molecular mechanisms of metastasis is crucial for discovering new therapeutic targets. This study explores the role of the long non-coding RNA (lncRNA) LINC00115 in AEG metastasis and its underlying mechanisms. Through the analysis of 108 pairs of AEG cancer tissues and matched adjacent tissues, we found a significant upregulation of LINC00115 in AEG tissues, closely associated with TNM staging and lymph node metastasis. Utilizing cell counting kit-8 (CCK-8) assays, colony formation experiments, wound healing assays, flow cytometry for apoptosis and cell cycle analysis, and Transwell assays, we have confirmed that LINC00115 significantly promotes proliferation, migration, and invasion of AEG cells in vitro. Animal experiments further validate the role of LINC00115 in promoting tumor growth and metastasis in vivo. Additionally, our nuclear-cytoplasmic fractionation experiments and RNA fluorescence in situ hybridization (FISH) reveal that LINC00115, along with its interacting protein KH-Type splicing regulatory protein (KHSRP), predominantly localizes to the cell nucleus. By conducting RNA pull-down assays and mass spectrometry (MS) analysis, we have identified a direct interaction between LINC00115 and KHSRP protein and further determined their binding sites through catRAPID and ENCORI databases. This study provides evidence of LINC00115 as a novel biomarker and potential therapeutic target for AEG and offers a fresh perspective on understanding the molecular mechanisms of AEG metastasis.
2024-06-23 | ANPEP/CD13 Expression as a Marker of Lymphovascular Invasion and Survival in Esophageal Adenocarcinoma.
The presence of lymphovascular invasion (LVI) in early esophageal adenocarcinoma (EAC) is associated with more aggressive disease. Molecular markers associated with LVI are still largely unknown. Using a combination of transcriptomic analysis and validation experiments, we sought to describe markers for LVI and survival. We performed NanoString expression profiling using RNA from 60 EAC specimens collected from surgery-only cases between 2000 and 2012. Differentially expressed genes (DEGs) were correlated with pathologic characteristics (T and N status and presence of LVI). Kaplan-Meier and Cox regression analyses were used to correlate gene expression with overall survival. Expression of alanyl aminopeptidase, membrane (ANPEP)/CD13 was validated by immunohistochemistry (IHC) in EAC tissue microarray and in EAC cell lines. We identified >20 up-regulated DEGs in tumor samples containing LVI. Multivariable analysis showed depth of invasion and ANPEP/CD13 expression were independently associated with overall survival, whereas nodal status was not. IHC analysis demonstrated overexpression of the ANPEP/CD13 protein in dysplastic Barrett esophagus and EAC tumors. Kaplan-Meier analysis showed that patients with higher RNA expression and strongly positive ANPEP/CD13 membrane IHC-Histoscore staining have shorter survival (P = .002). Down-regulation of ANPEP/CD13 expression by short hairpin RNA vector reduces colony formation, migration, and invasion of FLO-1 EAC cells. Overexpression of CD13 in SKGT4 EAC cells increases colony formation, motility, and invasion in vitro. Elevated expression of ANPEP/CD13 indicates shorter survival of EAC patients and a more invasive phenotype of cancer cells in vitro. Validation in a larger sample group is required to better understand the clinical significance of ANPEP/CD13 and other candidate genes.
combination
2026-09-23 | Neoadjuvant Chemoradiotherapy Versus Perioperative Chemotherapy ± Immunotherapy in Resectable Esophageal Adenocarcinoma.
We sought to compare pathologic responses, perioperative outcomes, and early survival between induction chemoradiotherapy and perioperative chemotherapy ± immunotherapy in patients with resectable esophageal adenocarcinoma. Using our prospectively maintained institutional database, we retrospectively identified adult patients with resectable, locally advanced esophageal or gastroesophageal junction adenocarcinoma who underwent esophagectomy from January 2013 to October 2024 after induction chemoradiotherapy or perioperative chemotherapy ± immunotherapy. The primary outcome was rate of pathologic complete response. Secondary outcomes included rate of microscopically margin-negative resection, rate of pathologic node-negative status, and perioperative morbidity. Event-free survival and overall survival were estimated using Kaplan-Meier methods and were evaluated using Cox regression. Of 811 patients, 650 (80%) received chemoradiotherapy, and 161 (20%) received chemotherapy ± immunotherapy. Median follow-up was 29.9 months. Chemoradiotherapy was associated with higher rates of pathologic complete response (23% vs. 14%) and pathologic node-negative status (61% vs. 46%; both P<0.001 after adjustment). The rate of microscopically margin-negative resection was 96% in both groups. Two-year event-free survival was higher in the chemotherapy ± immunotherapy group (66% vs. 53%; adjusted hazard ratio, 0.53; P=0.007). Two-year overall survival was not statistically different between groups. On multivariable analysis, perioperative chemotherapy ± immunotherapy and pathologic complete response were independently associated with longer event-free survival. Both induction strategies achieved excellent perioperative outcomes. Despite higher rates of pathologic complete response with chemoradiotherapy, perioperative chemotherapy ± immunotherapy was associated with longer early event-free survival. This association was attenuated in propensity score-matched and 90-day landmark analyses. Longer follow-up is warranted.
2026-01-10 | Phase I-II trial of perioperative chemotherapy plus atezolizumab and tiragolumab in localized esophageal and gastroesophageal junction adenocarcinoma.
418 Background: Management of esophageal and gastroesophageal junction (GEJ) adenocarcinoma focuses on perioperative strategies to increase pathological complete response rates, delay or eliminate metastases, and prolong overall survival. Atezolizumab is a humanized IgG1 monoclonal antibody that blocks PD-L1 from binding its inhibitory receptors, PD-1 and B7-1, thereby boosting tumor-specific T-cell responses and anti-tumor activity. Tiragolumab is a fully human IgG1/κ monoclonal antibody targeting TIGIT, an inhibitory receptor on activated T cells and NK cells that binds CD155. Blocking TIGIT could further enhance T-cell responses. Combining tiragolumab with atezolizumab and chemotherapy may improve outcomes in patients with localized esophageal and GEJ adenocarcinoma. Methods: We conducted a phase I/II study to evaluate the efficacy and safety of combining atezolizumab and tiragolumab with modified FOLFOX (oxaliplatin and 5-fluorouracil) in the perioperative treatment of localized esophageal and GEJ type I or II adenocarcinoma. Eligible patients were treatment naïve with T1N1 or T2-3 (any N) GEJ adeno. Treatment involved FOLFOX on days 1 and 15, followed by atezolizumab (840 mg IV) and tiragolumab (420 mg IV) on the same days of each 28-day cycle, for a total of six doses. Surgery was performed afterward, followed by adjuvant atezolizumab (1200 mg IV) plus tiragolumab (600 mg IV) on day 1 administered every 21 days for sixteen cycles. Results: Twenty-three patients (median age 67) were enrolled (stage IIb: n=6; stage III: n=13; stage IVa: n=4). Twenty patients were evaluated for efficacy. Thus far, 16 patients had undergone surgery. Pathological complete response (pCR, T0N0) has been observed in 18.8% (3/16; 95% CI: 4.1–45.7%), with 1 additional patient showing near-complete response (<1% viable tumor). R0 resection rate was 87.5%. There were no grade 4 treatment-related adverse events, deaths or treatment discontinuations. At a median follow-up of 21.1 months, four patients had died. Estimated 1- and 2-year survival rates were 94.1% and 74.0%, respectively. Conclusions: Results indicate that atezolizumab and tiragolumab in combination with oxaliplatin and 5-fluorouracil has an acceptable safety profile providing high rate of tumor regression. This trial supports further research checkpoint inhibition in patients with localized esophageal and GEJ adenocarcinomas in the perioperative setting. Clinical trial information: NCT03784326 .
2025-06-02 | Synergistic effects of PD-1 antibody and chemotherapy followed by surgery-centric local treatment in patients with limited-metastatic gastric or gastroesophageal adenocarcinoma (ROSETTE trial): an open-label, single-center, randomized phase 2 trial.
Limited metastatic gastric cancer (lmGC) represents an intermediate disease stage, positioned between localized and widely disseminated gastric cancer, and has garnered increasing attention due to its distinct prognostic outcomes. Currently, there is no consensus on the optimal treatment approach for lmGC, raising the question of whether it should align more with the systemic treatment-focused approach used for metastatic gastric cancer or adopt a surgery-centric strategy similar to that used in localized disease. Previous studies have preliminarily explored combining systemic treatment and surgical resection to address both the primary tumor and metastatic lesions. However, these investigations have been constrained by limited evidence and yielded inconclusive findings. ROSETTE trial is an open-label, randomized phase II study designed to investigate treatment strategies for patients with limited metastatic gastric or gastroesophageal adenocarcinoma. Eligible patients, confirmed through comprehensive evaluation including radiography and laparoscopy, are randomized to receive either systemic treatment followed by surgery-centric local treatment, or systemic treatment alone. Systemic treatment combines immunotherapy with chemotherapy, while the surgery-centric local treatment utilizes a surgery-centric, multi-modality approach involving resection of both primary and metastatic tumors where feasible. For unresected or unresectable metastatic lesions, alternative local therapies are provided. The primary endpoint is the 1-year event-free survival (EFS) rate. Secondary endpoints include objective response rate (ORR), disease control rate (DCR), extended EFS, overall survival (OS), pathologic complete response rate (pCR), major pathologic response rate (MPR), and R0 resection rate. The ROSETTE trial aims to evaluate whether systemic treatment followed by surgery-centric local treatment provides a survival advantage over the standard systemic-only approach for patients with limited metastatic gastric cancer. It seeks to build on previous research while addressing limitations such as selection bias inherent to non-randomized designs, patient recruitment challenges, and the complexities of managing surgical complications. By applying the latest evidence and a multi-modality approach, the ROSETTE trial endeavors to offer new insights into optimizing treatment strategies for patient with lmGC. NCT06468280 (Registration date: 05/28/2024).
2025-05-31 | Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III, Randomized LEAP-015 Study.
The phase III randomized open-label LEAP-015 study (ClinicalTrials.gov identifier: NCT04662710) evaluated first-line lenvatinib plus pembrolizumab and chemotherapy versus chemotherapy for advanced metastatic gastroesophageal adenocarcinoma. Eligible participants 18 years and older with untreated human epidermal growth factor receptor 2-negative locally advanced unresectable or metastatic gastroesophageal adenocarcinoma were randomly assigned 1:1 to induction with oral lenvatinib 8 mg once daily plus pembrolizumab 400 mg intravenously once every 6 weeks (×2) and investigators' choice of capecitabine and oxaliplatin once every 3 weeks (×4) or fluorouracil, leucovorin, and oxaliplatin once every 2 weeks (×6) and consolidation with lenvatinib plus pembrolizumab, or chemotherapy. Dual primary end points were progression-free survival (PFS) and overall survival (OS) in participants with PD-L1 combined positive score (CPS) ≥1 and all participants. Secondary end points included objective response rate (ORR) and duration of response. Of 880 participants randomly assigned, 443 received lenvatinib plus pembrolizumab and 437 received chemotherapy. The median follow-ups were 32.2 months (range, 19.0-41.7) in participants with PD-L1 CPS ≥1 and 31.8 months (19.0-41.7) in all participants. At interim analysis, PFS was statistically significant with lenvatinib plus pembrolizumab versus chemotherapy in participants with PD-L1 CPS ≥1 (median, 7.3 v 6.9 months; hazard ratio [HR], 0.75 [95% CI, 0.62 to 0.9]; P = .0012) and all participants (median, 7.2 v 7.0 months; HR, 0.78 [95% CI, 0.66 to 0.92]; P = .0019). The ORR was 59.5% versus 45.4% in participants with PD-L1 CPS ≥1 and 58.0% versus 43.9% in all participants, P < .0001 for both. At final analysis, OS was not statistically significant in participants with PD-L1 CPS ≥1 (median, 12.6 v 12.9 months; HR, 0.84 [95% CI, 0.71 to 1.00]; P = .0244; P value boundary = .0204). Grade ≥3 drug-related adverse event rates were 65% versus 49%. Lenvatinib plus pembrolizumab and chemotherapy versus chemotherapy provided a statistically significant improvement in PFS in advanced unresectable or metastatic gastroesophageal carcinoma at interim analysis although the clinical significance of this difference seems to be limited. No significant improvement occurred in OS in participants with PD-L1 CPS ≥1.
2025-03-14 | PD-1 antibody camrelizumab plus apatinib and SOX as first-line treatment in patients with AFP-producing gastric or gastro-esophageal junction adenocarcinoma (CAP 06): a multi-center, single-arm, phase 2 trial
Alpha-fetoprotein-producing gastric or gastro-esophageal junction (AFP-G/GEJ) cancer, a rare gastric cancer subtype, exhibits increased angiogenesis and more immunosuppression than non-AFP-G/GEJ cancer. The potential benefits of anti-angiogenic agents and immunotherapy for this specific subtype remain unknown. This multi-center, single-arm, phase 2 trial (ClinicalTrials.gov NCT04609176) evaluated the antitumor activity, safety, and biomarkers of camrelizumab plus apatinib and S-1 and oxaliplatin (SOX), followed by maintenance treatment with camrelizumab plus apatinib, as a first-line treatment in patients with AFP-G/GEJ adenocarcinoma. Primary endpoint was the confirmed objective response rate (ORR) per RECIST v1.1 in the full analysis set. Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response, time to response, and safety. Between December 4, 2020, and August 4, 2023, 36 patients were enrolled and treated. The trial met its primary endpoint with a confirmed ORR of 66.7% (95% CI: 49.0-81.4). The DCR was 88.9% (95% CI: 73.9-96.9). With a median follow-up of 11.7 months (range: 3.2-37.9), the median PFS reached 7.8 months (95% CI: 4.9-12.3) and the median OS reached 18.0 months (95% CI: 10.5-NR). No new safety concerns were identified. In exploratory analysis, patients with durable clinical benefit exhibited higher pre-treatment (PD-1+) CD8+ T cell densities and effective scores. First-line treatment with camrelizumab plus apatinib and SOX, followed by maintenance treatment with camrelizumab plus apatinib, is effective and safe in AFP-G/GEJ adenocarcinoma. Further studies are necessary to validate these findings.
antibodies
2026-09-22 | Integrating plasma-derived circulating proteins with multi-omics approaches to identify potential therapeutic targets for esophageal adenocarcinoma.
Background: Esophageal adenocarcinoma (EAC) is a complex disease often preceded by Barrett's esophagus. Objective: This study aimed to identify potential drug targets and support early prevention and treatment. Method: We integrated cis-protein quantitative trait loci (cis-pQTLs) and genome-wide association study (GWAS) data from 35 559 individuals using Mendelian randomization to infer causal relationships, with FDR correction applied. To assess tissue relevance, the source cis-pQTL instruments were examined across three GTEx v8 esophageal tissues, followed by tissue-informed single-variant Wald analyses of CD55 and NDST1. Gene ontology (GO) and KEGG pathway analyses, along with protein-protein interaction (PPI) network analysis, were used to explore biological functions and interactions. Overlapping genes were identified through differential expression analysis using the GEO database. Key feature genes were screened using XGBoost and Lasso regression, and diagnostic performance was evaluated by ROC curve AUC in both training and validation sets. Immune infiltration analysis explored the tumor microenvironment, and molecular docking assessed drug potential. Results: We identified 28 plasma proteins causally linked to EAC. KEGG analysis revealed enrichment in oxidative stress and inflammation-related pathways. Transcriptomic validation confirmed three overlapping genes. CD55 and NDST1 emerged as key markers with strong diagnostic accuracy after Lasso and XGBoost screening. Most significant esophageal SNP-tissue associations were directionally concordant with the corresponding plasma pQTL effects, and the tissue-specific Wald estimates for CD55 and NDST1 were consistent with the primary plasma-based findings. Immune infiltration analysis showed significant changes in immune cell composition in EAC, particularly natural killer cells, plasma cells, and mast cells. Drug prediction and docking supported the druggability of these targets. Conclusion: CD55 and NDST1 are promising therapeutic candidates for EAC. Drugs based on these genetic findings could improve clinical trial success rates and reduce costs.
2026-09-09 | Real-world treatment landscape and clinical outcomes in first-line advanced or metastatic gastroesophageal adenocarcinoma in the United States.
Contemporary real-world evidence in advanced gastric, gastroesophageal junction, or esophageal adenocarcinoma (GC/GEJC/EAC) remains limited. This study evaluated real-world treatment patterns and clinical outcomes in patients with advanced GC/GEJC/EAC treated with first-line therapy in the United States. Treatment patterns were assessed in adults from the Flatiron database with advanced or metastatic HER2-negative GC/GEJC/EAC who initiated first-line treatment between May 1, 2021, and July 31, 2025 (overall cohort). Clinical outcomes were assessed using the Kaplan-Meier method in a subcohort with ≥6 months of follow‑up. Among 2340 eligible patients, the most common first-line regimen was IO+FOLFOX/CAPOX (31.6%). This regimen was used in 47.6% of patients with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 expression. Starting in 2024, zolbetuximab+FOLFOX/CAPOX was administered more frequently in patients with CPS <1 vs ≥1 (6.1% vs 1.9%) and CPS <5 vs ≥5 (4.6% vs 0.8%) expression. In the subcohort (n = 2117), IO+FOLFOX/CAPOX vs FOLFOX/CAPOX was associated with significantly longer median (months; hazard ratio [95% CI]) real-world overall survival (12.3 vs 11.3; 0.81 [0.69-0.94]), time to next treatment or death (8.0 vs 6.1; 0.64 [0.55-0.75]), and time to treatment discontinuation (6.0 vs 3.0; 0.54 [0.47-0.63]). Differences in outcomes were driven by patients with CPS ≥1 expression, with no differences in patients with CPS <1 expression. IO+FOLFOX/CAPOX was the most frequent first-line regimen in advanced or metastatic GC/GEJC/EAC and showed improved real-world outcomes vs FOLFOX/CAPOX. Despite these gains, overall survival remains poor, underscoring unmet needs and the importance of biomarker-informed treatment selection.
2026-08-30 | Ivonescimab in combination with chemotherapy in advanced or metastatic gastric cancer (GC) or esophagogastric junction cancer (EGJC): The UCGI 52 - GRACIE trial.
While the addition of Ivonescimab to chemotherapy has demonstrated promising results in non-small cell lung cancer compared with chemotherapy alone, its efficacy as a first- or second-line treatment in advanced/metastatic gastric cancer remains to be established. GRACIE aims to evaluate the efficacy and safety of Ivonescimab combined with FOLFOX chemotherapy as first-line treatment (Arm-1) or as second-line when combined with paclitaxel or irinotecan or FOLFIRI following progression (Arm-2), in patients with advanced/metastatic gastric cancer and esophageal adenocarcinoma, regardless of actionable targets' presence (PD-L1/HER2/CLDN-18.2). This multicenter, two-arm, non-randomized, open-label exploratory phase II study is recruiting 88 patients, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, over 18 French centers. The primary objective is the Objective Response Rate (ORR) after central review according to RECIST v1.1 in HER2- and CLDN-18.2-negative, treatment-naïve patients (Arm-1) and patients with a single previous line for advanced disease, regardless of biomarkers expression (Arm-2). Secondary objectives are investigator-assessed ORR, Duration-of-Response, Progression-Free Survival, Overall Survival, time to ECOG performance status deterioration, Safety and Quality-of-life. GRACIE will provide crucial information about Ivonescimab plus chemotherapy regimens efficacy either as a first- or second-line treatment in molecularly defined advanced/metastatic gastric and esophageal adenocarcinomas to inform future phase III trials. EU-CTIS: 2025-520694-39-00, ClinicalTRials.gov: NCT06846346.
2026-08-19 | Comprehensive Profiling of Claudin 18.2 Immunohistochemical Expression in 564 Surgically Resected Gastric and Gastroesophageal Junction Adenocarcinomas.
Claudin 18 isoform 2 (CLDN18.2) is a novel therapeutic target for advanced, HER2-negative gastric/gastroesophageal junction (GEJ) adenocarcinoma positive for CLDN18.2 immunohistochemical (IHC) expression, defined as ≥75% tumor cells with moderate-to-strong membranous staining. Clinical studies for emerging CLDN18.2-targeted therapeutics have used less stringent enrollment criteria to test the efficacy of such therapies in patients with moderate-to-low CLDN18.2 IHC expression. Anticipating the advent of such treatments, this study aimed to provide a comprehensive survey of CLDN18.2 expression using a clinical trial-validated CLDN18.2 monoclonal antibody in surgically resected gastric/GEJ adenocarcinomas and characterize CLDN18.2-positive carcinomas using both high- and low-expression thresholds. Crisp membranous CLDN18.2 staining was detected in 59% (335/564) carcinomas, including 57% (164/286) of gastric and 62% (171/278) of GEJ adenocarcinomas. Most gastric (147/164, 90%) and GEJ (166/171, 97%) adenocarcinomas with staining demonstrated moderate or strong staining intensity. Using the high-expression threshold (≥75% tumor cells with moderate-to-strong staining), positive CLDN18.2 expression was observed in 20% (57/286) of gastric and 27% (75/278) of GEJ adenocarcinomas and was associated with Epstein-Barr virus status (P < .001) and stage I gastric adenocarcinomas (P = .02) but stage IV GEJ adenocarcinomas (P = .03). Using a low-expression threshold (≥10% tumor cells with membranous staining), positive CLDN18.2 remained significantly associated with stage I (P = .004) and showed an unadjusted association with improved disease-specific survival in gastric adenocarcinomas (P = .045), which was not retained in multivariable analysis. Whole transcriptomic analysis showed concordance between IHC and CLDN18 messenger RNA expression. Transcriptomic alterations in CLDN18.2 IHC-positive gastric adenocarcinomas included pathways in drug resistance and tumor invasion. In summary, our study presents a detailed characterization of the prevalence and distribution of CLDN18.2 IHC expression patterns. Our results showed that 59% surgically resected gastric/GEJ adenocarcinomas exhibited CLDN18.2 staining. CLDN18.2 IHC positivity defined by both high- and low-expression thresholds may be associated with early-stage gastric adenocarcinoma. These findings expand our recognition of patients who may benefit from CLDN18.2-targeted therapy.
2026-07-23 | Does adding immunotherapy to neoadjuvant chemotherapy increase postoperative morbidity in gastroesophageal junction adenocarcinoma? A propensity score-matched study.
Landmark trials have established the surgical feasibility of neoadjuvant immunotherapy plus chemotherapy (NICT) in gastric and esophageal cancers, yet data specific to the narrow anatomical confines of the gastroesophageal junction (GEJ) remain limited. This study aimed to compare postoperative morbidity between patients receiving NICT and those receiving neoadjuvant chemotherapy (NCT) alone. This single-center, retrospective cohort study included consecutive patients with locally advanced GEJ adenocarcinoma (Siewert II/III) undergoing curative resection after NICT (n=140) or neoadjuvant chemotherapy alone (NCT, n=260). Propensity score matching (1:1) balanced baseline characteristics, including dMMR/MSI-H status and surgical approach, yielding 120 matched pairs. The primary outcome was major complications (Clavien-Dindo ≥III). Secondary outcomes included specific surgical complications, immune-related adverse events (irAEs), and interval to surgery. After matching, NICT was associated with improved major pathological regression (58.3% vs. 45.8%; p=0.028). The primary endpoint was not significantly different between NICT and NCT cohorts (25.8% vs. 22.5%; p=0.538). Critically, no differences were observed in specific technical complications, including anastomotic leak (11.7% vs. 10.0%), conduit failure (3.3% vs. 2.5%), or pulmonary events. irAEs occurred in 13.3% of the NICT cohort without delaying surgical intervention. Multivariable and sensitivity analyses confirmed NICT was not an independent predictor of morbidity. This analysis provides anatomically focused evidence that the addition of immunotherapy to neoadjuvant chemotherapy for GEJ adenocarcinoma is not associated with a statistically significant increase in risk of major postoperative morbidity, anastomotic failure, or operative complexity. While larger randomized trials remain the gold standard, these findings support the extrapolation of established safety data to the technically demanding GEJ location.
other
2026-09-22 | Epigenetic and Transcriptional Dysregulation of Ribosomal Genes in Esophageal Adenocarcinoma: A Multi-omics Mendelian Randomization Study.
The rising incidence and poor prognosis of esophageal adenocarcinoma (EAC) highlight the urgent need to identify novel molecular determinants. Ribosome heterogeneity has emerged as a potential factor in carcinogenesis, yet its causal relevance in EAC remains unclear. We aimed to systematically evaluate the causal effects of ribosome-related genes on EAC risk by integrating multi-omics data. We applied summary-data-based Mendelian randomization (SMR) to analyze 1,329 ribosome-related genes, integrating mQTL, eQTL, pQTL data and a large EAC GWAS. Bayesian colocalization and esophageal tissue transcriptome analyses validated causal signals. We compared mRNA/protein levels of candidate genes in normal HET-1A esophageal cells versus EAC cell lines OE33 and OE19, and validated methylation-gene correlations using the TCGA-ESCA cohort. Crucially, functional assays, including CCK-8, Transwell, colony formation, and apoptosis assays, were performed in OE33 cells following gene overexpression to verify their causal roles. SMR analyses identified EIF2B2 and RPS6KL1 as causal protective genes for EAC; genetically elevated expression of both reduced EAC risk. A regulatory cascade was uncovered, whereby specific CpG methylation repressed gene transcription to alter disease susceptibility. Consistently, EIF2B2 and RPS6KL1 mRNA and protein were markedly lower in OE33/OE19 tumor cells than HET-1A. TCGA data confirmed negative correlation between RPS6KL1 promoter cg19899223 methylation and gene expression (ρ = -0.27, p = 0.00015). Functionally, overexpression of EIF2B2 and RPS6KL1 in OE33 cells significantly suppressed cell viability, invasion, and colony formation, while inducing apoptosis, thereby experimentally validating their tumor-suppressive effects. By integrating multi-omics evidence with functional assays, this study identifies EIF2B2 and RPS6KL1 as causal protective factors in EAC etiology. These findings suggest that maintaining ribosomal homeostasis via these genes acts as a barrier against EAC, highlighting their potential for risk stratification and therapeutic targeting.
2026-07-14 | Causal immune-inflammation mapping of the GERD-Barrett-adenocarcinoma cascade identifies FGF19-HLA-DR⁺ T-cell axis driving esophagogastric junction metaplasia.
Gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), and esophageal adenocarcinoma (EAC) form a recognized pathological continuum, but the causal immune and inflammatory processes driving progression remain incompletely defined. Summary-level genome-wide association study (GWAS) data were analyzed for 91 circulating inflammatory proteins (n = 14,824), 731 immune cell phenotypes (n = 3,757), and three esophageal diseases (GERD, BE, and EAC). Bidirectional and two-step Mendelian randomization (MR) were used to infer causal effects and mediation, with Cochran's Q, MR-Egger, and MR-PRESSO applied to assess heterogeneity and pleiotropy. Causal interaction networks were reconstructed to map immune- and inflammation-dominant regulatory patterns across disease stages, and MR-prioritized signals were experimentally validated in esophagogastric junction (EGJ) organoids and mouse models. MR supported a causal GERD-BE-EAC sequence, with BE mediating 31.95% of the total GERD-to-EAC effect. In total, 139 immune cell traits and 29 inflammatory proteins showed causal links to disease risk. Mediation analyses highlighted M-CSF1 and HLA-DR+CD4 + T cells as central hubs. Guided by the MR-prioritized FGF19-HLA-DR + T-cell axis, experimental studies demonstrated that FGF19 promotes EGJ glandular conversion and increases infiltration of HLA-DR+ CD4+/CD8 + T cells, validated in EGJ organoids and mouse models. This integrated genetic and experimental framework delineates a bidirectional immune-inflammation regulatory network underlying progression from GERD to BE and EAC. FGF19 emerges as a candidate cytokine driving EGJ glandular remodeling through HLA-DR+ CD4+/CD8 + T-cell associated immune activation, providing candidate molecular targets for early prevention and intervention.
2026-05-24 | Autologous T Cell Antigen Coupler Targeting HER2 (TAC01-HER2) in Advanced or Metastatic Solid Tumors.
The T cell antigen coupler (TAC) is a novel genetically engineered receptor that recruits the native T cell receptor upon recognition of an antigen. The downstream activation of TAC T cells has been effective against tumors in preclinical models and safer than chimeric antigen receptor T cells. Human epidermal growth factor receptor 2 (HER2) is a validated biomarker for cancer-targeted therapy, but cell therapy approaches have been met with unmanageable toxicity. We designed a phase 1 clinical trial of TAC01-HER2, an autologous T cell product that targets HER2, in patients with HER2-positive advanced solid tumors. The trial had a dose-escalation phase and a dose-expansion at the recommended phase 2 dose (RP2D). A total of 23 patients with HER2-positive solid tumors were enrolled in this study. The most common treatment-related adverse events were cytokine release syndrome (n=14, 60.9%), anemia (n=5, 21.7%), and increased alanine aminotransferase (n=5, 21.7%). The RP2D was 6-8 × 106 per kg. No treatment-related deaths or adverse events leading to study discontinuation were reported. Two of 9 patients with gastric and gastroesophageal junction (GEJ) cancers had partial responses, and the disease control rate (stable disease or partial response) was 61.1% in the 18 patients with evaluable assessments. The median progression-free survival was 2.6 months (range 0.8-12.4 months), and the overall survival rate at 6 months was 57.9% (95% CI, 36.3%-76.9%). Persistence of TAC T cells in peripheral blood was observed in all patients until at least day 29 after the first infusion. In summary, we demonstrated that treatment with TAC T cells was safe, feasible, and well-tolerated. TAC01-HER2 showed manageable toxicity and early efficacy for patients with HER2-positive gastric, GEJ or esophageal adenocarcinoma who have undergone extensive previous treatments. These results suggest that TAC may offer a promising approach to control T cell activity through cellular therapy.
2026-04-04 | Could venom-derived therapeutics resolve treatment resistance in refractory EAC?
The incidence of esophageal adenocarcinoma is rising in Western countries. Despite advances in chemotherapy and immunotherapy, the prognosis remains poor, with an overall 5-year survival rate below 15%. A major challenge is the cancer's poor and often unpredictable response to current treatments. Animal venoms represent a promising yet underexplored source of therapeutic agents, offering millions of structurally diverse and highly potent bioactive peptides that can modulate a wide array of molecular targets. However, only a small fraction of these peptides has been pharmacologically characterized. This review presents the therapeutic potential of venom-derived peptides in cancer treatment, summarizes the role of ion channels in esophageal adenocarcinoma (EAC), and discusses peptides targeting ion channels that may offer new opportunities for future EAC treatment.
2026-04-03 | Abstract 601: Translational reprogramming disrupts mitosis to drive SMAD4-deficient esophageal adenocarcinoma.
Abstract Esophageal adenocarcinoma (EAC) develops from a precursor lesion named Barrett’s esophagus; a progression that can be mapped by increasing genomic instability. We have previously shown that SMAD4 loss induces tumorigenesis and increased copy number alterations (CNA) in Barrett’s esophagus cells with an existing TP53 mutation. The observed CNA increase was especially pronounced in the resultant SMAD4-deficient tumor cells, suggesting that accumulation of mitotic errors occurs in these cells throughout their oncogenic progression. However, such an effect cannot be explained by our current understanding of canonical SMAD4 signalling. Thus, in this study, we aimed to delineate the role of SMAD4 in maintaining chromosomal stability in EAC. Our multi-omics (RNA-sequencing, proteomics and reverse-phase protein array) approach detected both deregulated translation and mitosis signatures in SMAD4-deficient cells. Using live cell imaging, we demonstrated that TP53-mutant SMAD4-deficient cells exhibit significantly more mitotic errors than TP53-mutant only cells, particularly chromosome segregation defects, which frequently result in chromosomal instability (CIN). Consistent with this, analysis of TCGA data demonstrated that CIN was more prevalent in tumours with both SMAD4 and TP53 mutation than either mutation alone. Further biochemical analyses revealed an increase in cap-dependent translation in these cells, and a decrease in internal ribosome entry site (IRES)-mediated translation. IRES-mediated translation is essential for synthesis of many important mitotic proteins, including a mitosis-specific isoform of a cell cycle kinase. Polysome sequencing showed decreased translation (but not transcription) of this kinase in SMAD4-deficient cells. Ectopic expression of mitosis-specific isoform of this kinase rescued the mitotic errors that arose as a consequence of SMAD4 loss. In sum, we present a model where translational reprogramming disrupts mitosis, inducing CIN and potentially driving EAC tumorigenesis in response to loss of SMAD4. This represents a novel mechanism of tumorigenesis in EAC and a previously unknown role of SMAD4 in maintaining chromosomal integrity. Citation Format: Julia V. Milne, Ka Meng Wu, Sasha Witts, Eric Kusnadi, Kenji Fujihara, Katherine Papastratos, Maree Pechlivanis, Anna Trigos, Metta Jana, Luc Furic, Kaylene Simpson, David Liu, Cuong Duong, Wayne Phillips, Nicholas Clemons. Translational reprogramming disrupts mitosis to drive SMAD4-deficient esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 601.
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Drug Discovery Landscape
48 orphan drug designations for Adenocarcinoma of the esophagus, including 5 approved therapies.
48 orphan drug designations for Adenocarcinoma of the esophagus, including 5 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
an antibody-drug conjugate composed of a humanized monoclonal antibody PM-012C against fibroblast growth factor receptor 2b (FGFR2b) conjugated to exatecan (topoisomerase I inhibitor) through a cleavable linker Pym-PEG8-Val-Ala-PAB | antibodies | FDA | — | Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd |
envafolimab | antibodies | FDA | 3D Medicines (Sichuan) Co., Ltd | |
7-ethtyl-10-hydroxycamptothecin and irinotecan | small molecules | FDA | — | SN BioScience Inc. |
antibody drug conjugate consisting of PM-012D antibody and linker-payload Pym-PEG8-Val-Ala-PAB-Exd | antibodies | FDA | — | Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd |
antibody-drug conjugate (ADC) consisting of a humanized anti-trophoblast cell surface antigen-2 (TROP2) antibody and a protease-cleavable linker-payload N-PM-0022 (BCN-GGVA-PAB(PEG24)-exatecan) | antibodies | FDA | — | OBI Pharma USA Inc. |
oxazol 2 ylmethyl N [5 [(1R)-1-(6-methoxy-3-pyridyl)ethyl]thiazol-2-yl]carbamate | small molecules | FDA | — | Dewpoint Therapeutics Inc. |
antibody-drug conjugate consisting of an anti-human epidermal growth factor receptor 2 bispecific antibody conjugated to a topoisomerase I inhibitor | antibodies | FDA | Jiangsu Alphamab Biopharmaceuticals Co., Ltd. | |
telisotuzumab adizutecan | antibodies | FDA | AbbVie Inc. | |
nesuparib | small molecules | FDA | Onconic Therapeutics | |
lenvatinib | small molecules | FDA | Eisai Inc. | |
antibody-drug conjugate (ADC) consisting of a humanized anti-trophoblast cell surface antigen-2 (TROP2) antibody (R4702) and a cathepsin B protease-cleavable linker-payload N-PM-0017 (MCCa-PEG24-VA-PAB-exatecan) | antibodies | FDA | — | OBI Pharma USA Inc. |
recombinant humanized IgG1 anti-TROP2 monoclonal antibody conjugated to a topoisomerase I inhibitor | antibodies | FDA | Merck, Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (MSD) | |
Neratinib maleate Tablets | small molecules | FDA | Convalife Pharmaceuticals Co., Ltd. | |
durvalumab [Imfinzi] | antibodies | FDA | Approved | AstraZeneca Pharmaceuticals |
trastuzumab biosimilar conjugated with TLR7/8 via a non-cleavable linker | antibodies | FDA | Bolt Biotherapeutics | |
ex vivo expanded allogeneic cord blood-derived NK cells that have been genetically modified to express a HER2-directed CAR and secrete IL-15 | cell therapies | FDA | Artiva Biotherapeutics, Inc. | |
N-(6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4-(3,3-dimethylpiperazin-1-yl)benzamide hydrochloride | small molecules | FDA | — | 3D Medicines (Beijing) Co., Ltd |
Autologous Claudin18.2-targeted CAR-T cells | cell therapies | FDA | Legend Biotech USA, Inc. | |
Trastuzumab vedotin | antibodies | FDA | Shanghai Miracogen Inc. | |
Docetaxel albumin bound | small molecules | FDA | Conjupro Biotherapeutics, Inc. | |
A CD47-binding, fusion protein containing a high affinity engineered D1 domain of human signal regulatory protein alpha (SIRPalpha) variant 1 (v1) genetically linked to a modified and inactive Fc domain of human IgG | proteins | FDA | ALX Oncology Inc. | |
Humanized, Low-fucose Anti-Claudin 18.2 IgG1 Antibody with Enhanced ADCC | antibodies | FDA | Suzhou Traoscenta Therapeutics Co., Ltd. | |
cinrebafusp | antibodies | FDA | Pieris Pharmaceuticals, Inc. | |
fully human monoclonal IgG1 antibody against the type 2 isoform of human Claudin 18 protein (Claudin 18.2). | antibodies | FDA | Leap Therapeutics, Inc. | |
humanized HER2 targeting monoclonal antibody conjugated to a cytotoxic tubulin inhibitor amberstatin | antibodies | FDA | Ambrx, Inc. | |
Anti-Claudin 18.2 antibody drug conjugate comprised of a Claudin 18.2 targeting monoclonal IgG1 antibody, a linker LND1002, and monomethyl auristatin E | antibodies | FDA | Elevation Oncology, Inc. | |
Humanized Anti-claudin18.2 Autologous Chimeric Antigen Receptor (CAR) T Cells | cell therapies | FDA | CARsgen Therapeutics Corporation | |
half-life extended bispecific T cell engager (BiTE®) antibody construct designed to target both CLDN18.2 and CD3 | antibodies | FDA | Amgen, Inc. | |
humanized IgG4 monoclonal antibody optimized for neutralizing activity against DKK1, a secreted modulator of Wnt signaling | antibodies | FDA | Leap Therapeutics, Inc | |
margetuximab | antibodies | FDA | MacroGenics, Inc. | |
half-life extended bispecific T-cell engager antibody construct targeting MUC17 and CD3 | antibodies | FDA | Amgen Inc. | |
fam-trastuzumab deruxtecan-nxki [Enhertu] | antibodies | FDA | Approved | Daiichi Sankyo, Inc. |
tislelizumab-jsgr [Tevimbra] | antibodies | FDA | Approved | BeOne Medicines USA, Inc. |
crenolanib | small molecules | FDA | AROG Pharmaceuticals, Inc. | |
anti-human epidermal growth factor receptor 2 (HER2) antibody drug conjugate | antibodies | FDA | — | CSPC Dophen Corporation, subsidiary within CSPC Pharmaceutical Group |
humanized immunoglobulin G1 (IgG1) T-cell bispecific (TCB) antibody targeting carcinoembryonic antigen (CEA) | antibodies | FDA | — | Genentech, Inc. |
zanidatamab-hrii [Ziihera] | antibodies | FDA | Approved | Jazz Pharmaceuticals Ireland Limited |
nivolumab [Opdivo] | antibodies | FDA | Approved | Bristol-Myers Squibb Company |
Nivolumab and Ipilimumab | antibodies | FDA | Bristol-Myers Squibb Company | |
bemarituzumab | antibodies | FDA | Amgen Inc. | |
napabucasin | small molecules | FDA | Boston Biomedical, Inc. | |
bispecific antibody (monoclonal antibody) | antibodies | FDA | Elevation Oncology, Inc. | |
bispecific antibody (monoclonal antibody) | antibodies | FDA | Elevation Oncology, Inc. | |
pertuzumab | antibodies | FDA | Genentech, Inc. | |
onartuzumab | antibodies | FDA | Genentech, Inc. | |
lapatinib ditosylate hydrochloride | small molecules | FDA | Novartis Pharmaceuticals Corp. | |
DHA-paclitaxel | small molecules | FDA | — | Luitpold Pharmaceuticals, Inc. |
Tezacitabine | small molecules | FDA | Sanofi-Aventis US, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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