Esophagogastric Junction

BackgroundLimited data exist for global prevalence of claudin 18 isoform 2 (CLDN18.2) positivity and association of CLDN18.2 status with clinical and tumor characteristics in patients with locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. We report prevalence of CLDN18.2 positivity (phase 3; SPOTLIGHT, NCT03504397; GLOW, NCT03653507) and concordance of CLDN18.2 status between a subset of pair-matched tumor samples (phase 2, ILUSTRO, NCT03505320; phase 1, NCT03528629) from clinical studies of zolbetuximab.MethodsTumor samples from patients with LA unresectable or mG/GEJ adenocarcinoma were tested for CLDN18.2 status by immunohistochemistry. Human epidermal growth factor receptor 2 (HER2) expression was tested per central or local assessment.ResultsAcross SPOTLIGHT and GLOW, the prevalence of CLDN18.2 positivity (≥ 75% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining) was 38.4%. Prevalence was similar in gastric versus GEJ adenocarcinoma samples and regardless of collection method (biopsy versus resection) or collection site (primary versus metastatic). CLDN18.2 positivity was most prevalent in patients with diffuse-type tumors. In ILUSTRO and the phase 1 study, concordance of CLDN18.2 positivity was 61.1% between archival (i.e., any time before treatment) and baseline (i.e., ≤ 3 months before first treatment) samples, and concordance of any CLDN18 staining (≥ 1% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining) was 88.9%.ConclusionsCLDN18.2 was a highly prevalent biomarker in patients with HER2-negative, LA unresectable or mG/GEJ adenocarcinoma. CLDN18.2 positivity remained relatively stable over time in many patients. Biomarker testing for CLDN18.2 should be considered in standard clinical practice in these patients.

BackgroundFor patients with esophageal adenocarcinoma or cancer of the gastroesophageal junction, radical esophagectomy with 2-field lymphadenectomy is the cornerstone of the multimodality treatment with curative intent. Both conventional minimally invasive esophagectomy (MIE) and robot assisted minimally invasive esophagectomy (RAMIE) were shown to be superior compared to open transthoracic esophagectomy considering postoperative complications. However, no randomized comparison exists between MIE and RAMIE in the Western World for patients with esophageal adenocarcinoma.MethodsThis is an investigator-initiated and investigator-driven multicenter randomized controlled parallel-group superiority trial. All adult patients (age ≥ 18 and ≤ 90 years) with histologically proven, surgically resectable (cT1-4a, N0-3, M0) esophageal adenocarcinoma of the intrathoracic esophagus or adenocarcinoma of the gastroesophageal junction and with European Clinical Oncology Group performance status 0, 1 or 2 will be assessed for eligibility and included after obtaining informed consent. Patients (n = 218) with resectable esophageal adenocarcinoma of the intrathoracic esophagus or adenocarcinoma of the gastroesophageal junction are randomized to either RAMIE (n = 109) or MIE (n = 109). The primary outcome of this study is the total number of resected abdominal and mediastinal lymph nodes specified per lymph node station.ConclusionThis is the first randomized controlled trial designed to compare RAMIE to MIE as surgical treatment for resectable esophageal adenocarcinoma or adenocarcinoma of the gastroesophageal junction in the Western World. The hypothesis of the proposed study is that RAMIE will result in a higher abdominal and mediastinal lymph node yield specified per station compared to conventional MIE. Short-term results and the primary endpoint (total number of resected abdominal and mediastinal lymph nodes per lymph node station) will be analyzed and published after discharge of the last randomized patient within this trial.Trial registrationClinicalTrials.gov Identifier: NCT04306458 . Registered 13th March 2020, https://clinicaltrials.gov/ct2/show/NCT04306458; Date of first enrolment 18.01.2021; Target sample size 218; Recruitment status: Recruiting; Protocol version 2; Issue date 10.03.2020; Rev. 02.02.2021; Authors ET, PCvdS, PPG.

IntroductionMagnetic sphincter augmentation (MSA) results in less severe side effects compared with Nissen fundoplication, but dysphagia remains the most common side effect reported by patients after MSA. This study aimed to characterize and review the management of postoperative dysphagia and identify the preoperative factors that predict persistent dysphagia after MSA.Material and methodsThis is a retrospective review of prospectively collected data of patients who underwent MSA between 2013 and 2018. Preoperative objective evaluation included upper endoscopy, esophagram, high-resolution impedance manometry (HRIM), and esophageal pH testing. Postoperative persistent dysphagia was defined as a postoperative score of > 3 for the dysphagia-specific item within the GERD-HRQL at a minimum of 3 months following MSA. A timeline of dysphagia and dilation rates was constructed and correlated with the evolution of our patient management practices and modifications in surgical technique.ResultsA total of 380 patients underwent MSA, at a mean (SD) follow up of 11.5 (8.7) months, 59 (15.5%) patients were experiencing persistent dysphagia. Thirty-one percent of patients required at least one dilation for dysphagia or chest pain and the overall response rate to this procedure was 67%, 7 (1.8%) patients required device removal specifically for dysphagia. Independent predictors of persistent dysphagia based on logistic regression model included (1) absence of a large hernia (OR 2.86 (95% CI 1.08-7.57, p = 0.035)); (2) the presence of preoperative dysphagia (OR 2.19 (95% CI 1.05-4.58, p = 0.037)); and (3) having less than 80% peristaltic contractions on HRIM (OR 2.50 (95% CI 1.09-5.73, p = 0.031)). Graded cutoffs of distal contractile integral (DCI), mean wave amplitude, DeMeester score, sex, and body mass index were evaluated within the model and did not predict postoperative dysphagia. Frequent eating after surgery, avoidance of early dilation, and increase in the size of the LINX device selected decreased the need for dilation.ConclusionIn a large cohort of patients who underwent MSA, we report 15.5% rate of persistent postoperative dysphagia. The overall response rate to dilation therapy is 67%, and the efficacy of dilation with each subsequent procedure reduces. Patients with normal hiatal anatomy, significant preoperative dysphagia, and less than 80% peristaltic contractions of the smooth muscle portion of the esophagus should be counseled that they have an increased risk for persistent postoperative dysphagia.

There is an unmet need for effective and safe treatments for patients with metastatic gastric/gastroesophageal junction (mG/GEJ) adenocarcinoma. Targeting claudin 18 isoform 2 (CLDN18.2) and programmed death ligand 1 (PD-L1), represents a promising strategy. Zolbetuximab, a CLDN18.2-targeting antibody, plus chemotherapy improved survival outcomes in patients with CLDN18.2-positive, human epidermal growth factor receptor 2 (HER2)-negative mG/GEJ adenocarcinoma. Cohort 4 of the global, open-label, phase 2 ILUSTRO study examined first-line zolbetuximab plus mFOLFOX6 and nivolumab (a PD-L1 inhibitor). Here we report results from cohorts 4A (safety lead-in phase) and 4B (expansion phase). The primary endpoint of ILUSTRO was specific to cohort 1 and was previously published; the main efficacy endpoint of interest for cohort 4 was progression-free survival (PFS), as assessed by the investigators per Response Evaluation Criteria in Solid Tumors version 1.1. At data cutoff (2 September 2025) for this final analysis, 77 patients were enrolled in 4A + 4B (85.5% with CLDN18.2-high tumors). Cohort 4B median follow-up was 11.5 months, and median PFS (95% confidence interval (CI)) was 14.8 months (8.3-not estimable) overall (n = 71) and 18.0 months (11.1-not estimable) in patients with CLDN18.2-high tumors (n = 59). Objective response rate (measurable disease; 95% CI) was 62.1% (48.4-74.5) in 4B overall (n = 58) and 68.1% (52.9-80.9) in CLDN18.2-high (n = 47). In 4A + 4B, the most common treatment-emergent adverse events were nausea (80.5%) and decreased appetite (72.7%). Efficacy and safety data support randomized evaluation of zolbetuximab plus chemoimmunotherapy in patients with CLDN18.2-positive and PD-L1-positive mG/GEJ adenocarcinoma in the ongoing phase 3 LUCERNA study. ClinicalTrials.gov: NCT03505320 .