Esophagus

BackgroundImmune checkpoint inhibitors (ICIs) plus fluorouracil-based chemotherapy (Chemo) have been approved as an initial treatment strategy for metastatic or recurrent human epidermal growth factor receptor 2 (HER2)-negative gastric cancer (GC) or gastroesophageal junction cancer (GEJC). However, since programmed cell death protein-1 (PD-1) or its ligand 1 (PD-L1) inhibitors have just recently been investigated for the treatment of unresectable GC/GEJC, there is ongoing debate regarding their safety and effectiveness for prespecified subgroups. The purpose of this research is to establish a foundation toward stratified decision-making by methodically assessing the merits and drawbacks of PD-1/PD-L1 inhibitors combined with chemo in the clinical utilization of advanced HER2-negative GC/GEJC according to certain prominent large-scale randomized controlled trials (RCTs). In addition, we limitedly explored the favorable short-term efficacy of PD-1/CTLA-4 bispecific antibodies for the above-mentioned tumors.MethodsThe researchers retrieved several databases, including PubMed, Embase, Web of Science, ClinicalTrials.gov, and the Cochrane Library, to collect all the relevant literature published since the establishment of the databases until October 30, 2024, and then screened to determine the qualified literature and extracted the relevant information. We only included RCTs for PD-1/PD-L1 inhibitors with or without chemo in advanced GC or GEJC. The primary endpoints were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). A subgroup analysis for the median overall survival (mOS) was conducted for the following variables: microsatellite instability (MSI) status, PD-L1 expression, combined positive scores (CPS), metastasis status, and primary tumor location. When moderate heterogeneity was found, a random-effect model was applied. The outcome indicators were then statistically analyzed, taking advantage of Review Manager 5.4. Hazard ratio (HR) and risk ratio (RR) were selected as the effect values for statistical analysis.ResultsA total of 7 eligible RCTs and 6537 participants were included in this meta-analysis. Combining PD-1/PD-L1 inhibitors with chemo significantly improved patients' OS compared with chemo alone, especially in the tumor cell PD-L1 expression ≥ 1% [HR = 0.62, 95% CI (0.48, 0.81); a p-value = 0.0004], PD-L1 CPS ≥ 10 [HR = 0.66, 95% CI (0.57, 0.77); a p-value ConclusionFor patients with advanced HER2-negative GC/GEJC, PD-1/PD-L1 inhibitors in combination with chemo have almost demonstrated consistent synergistic anti-tumor benefits to survival outcomes when compared to chemo alone. However, the subgroup analysis in this meta-study revealed that neither PD-L1 expression level nor MSI status could fully predict the efficacy of the dual treatment model but faced a higher possibility of serious treatment-related adverse events (sTRAEs), particularly in the synchronous therapy arm. Therefore, urging the need for more investigations into the development of collaborative prognostic forecasting models for achieving precise stratification, established harmonized testing standards and methods for PD-L1 expression and positivity, optimal CPS threshold for benefits, as well as alternative molecular biomarkers for the reason that certain indicators alone may not discriminate responders clearly. Lastly, dual anti-therapy might be a useful tactic for the population with low PD-L1 expression in the future.

BackgroundTemporal and spatial molecular heterogeneity contributes to resistance to targeted and immune therapies in gastric and esophagogastric junction carcinoma (G/EGJ). This study evaluates differences in biomarker expression between primary G/EGJ and paired peritoneal metastases (PM).MethodsWe analyzed 74 cases of primary G/EGJ and paired PM using immunohistochemistry for HER2, PD-L1, Claudin18 (CLDN18), DNA mismatch repair (MMR) proteins, p53, E-cadherin, and in situ hybridization for EBER. Biomarker concordance between primary and metastatic tumors was assessed.ResultsPrimary G/EGJ were predominantly poorly cohesive (45.9%) or mixed-type (37.8%). Regarding predictive biomarkers, low rates of HER2 overexpression (5.4%), MMR deficiency (4.1%), and EBER positivity (1.4%) were observed, while PD-L1 CPS ≥ 1 occurred in 79.7% of cases and CLDN18 positivity was observed in 31.1% of cases. Concordance was perfect for MMR and EBER, while PD-L1 showed the highest discordance (32.4%). HER2 had a low discordance rate (2.7%). CLDN18 exhibited good concordance (86.5%) and showed consistent positivity in PD-L1- and HER2-negative primary tumors (28.6%).ConclusionG/EGJ with PM show distinct molecular features and spatial heterogeneity, with MMR, EBER, and HER2 demonstrating strong concordance, while PD-L1 showed greater variability. As for novel biomarkers, CLDN18.2 shows substantial concordance between primary G/EGJ and PM and could be a promising target in HER2/PD-L1-negative G/EGJ with PM.

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.

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 .