Gastroesophageal Junction Adenocarcinoma

Neoadjuvant cadonilimab plus FLOT chemotherapy treatment exhibits promising efficacy with manageable toxicities in locally advanced G/GEJ adenocarcinoma, providing preliminary evidence for further investigation.

Factors for improved PFS include early treatment, lower T stage, fewer metastatic sites, and lower pre-IBIL, post-GLOB, and post-CA125 levels. Nomogram models can help identify patients who may benefit from immunotherapy, providing valuable clinical guidance.

However, the pooled hazard ratio for OS favoured PD-L1 inhibitors (hazard ratios - HR, 0.83, &lsqb;95% CI: 0.78-0.88] and p < 0.00001), while PFS was better after chemotherapy (HR 1.28, &lsqb;95% CI: 1.04-1.58], p = 0.02). Program death ligand-1 inhibitors improve OS, while chemotherapy enhances PFS in advanced G/GEJC, warranting further investigation into the impact of CPS on treatment outcomes.

Zolbetuximab, a monoclonal antibody targeting claudin 18.2, showed a survival benefit in first line metastatic treatment in patients with claudin 18.2 positive gastric and gastro-oesophageal junction adénocarcinoma, in two phase III studies. CAR T-cells specifically targeting this protein have also shown promising efficacy from the second line of treatment. Considering the probable impact of the expression status of claudin 18.2 in future treatment algorithms, this review aims to present the pathophysiology underlying the targeting of claudin 18.2, summarize state of the art results of anti-claudin 18.2 therapies and discuss future challenges for the management of patients with claudin 18.2 positive gastric and gastro-oesophageal junction adenocarcinoma.

Herein, we report extended follow-up data from the INTEGA trial (NCT03409848), which investigated the efficacy of the anti-PD-1 nivolumab, trastuzumab, and FOLFOX chemotherapy (FOLFOX arm) in comparison to a chemotherapy-free regimen involving nivolumab, trastuzumab, and the anti-CTLA-4 ipilimumab (Ipi arm) in the first-line setting for advanced disease...Furthermore, a low NLR characterized patients benefiting from immune- and targeted therapy without the need for additional chemotherapy. This data suggests that patient selection based on inflammatory stress-driven immune changes could help to customize first-line treatment in patients with advanced HER2-positive EGA to potentially improve long-term survival.

P2, N=43, Active, not recruiting, National Cancer Center Hospital East | Recruiting --> Active, not recruiting | Trial primary completion date: Aug 2025 --> Aug 2026

XRCC1 may serve as a key oncogene that elucidates the role of alternative splicing events in the progression of AEG following X-ray treatment.

P2, N=603, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed

P=N/A, N=28, Completed, NovoCure Ltd. | Unknown status --> Completed | Trial completion date: Sep 2021 --> Jun 2024 | Trial primary completion date: Sep 2021 --> Jun 2024

P3, N=183, Completed, Krankenhaus Nordwest | Active, not recruiting --> Completed | Trial completion date: Feb 2026 --> Aug 2024 | Trial primary completion date: Feb 2026 --> Aug 2024

P1/2, N=56, Active, not recruiting, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest | Recruiting --> Active, not recruiting

P=N/A, N=30, Not yet recruiting, Sun Yat-sen University Cancer Center; Sun Yat-sen University Cancer Center

P=N/A, N=90, Not yet recruiting, Department of General Surgery, The First Medical Center, Chinese PLA General Hospital; The First Medical Center, Chinese PLA General Hospital

P=N/A, N=150, Not yet recruiting, Zhejiang Cancer Hospital; Zhejiang Cancer Hospital

P4, N=30, Not yet recruiting, The First Affiliated Hospital of Zhengzhou University; The First Affiliated Hospital of Zhengzhou University

P3, N=435, Not yet recruiting, Fudan University Shanghai Cancer Center; Fudan University Shanghai Cancer Center

P2, N=400, Recruiting, Zhejiang Cancer Hospital; Zhejiang Cancer Hospital

P2, N=30, Not yet recruiting, Renji Hospital affiliated to Shanghai Jiaotong University School of Medicine; Renji Hospital affiliated to Shanghai Jiaotong University School of Medi

P1, N=36, Not yet recruiting, West China Hospital of Sichuan University; West China Hospital of Sichuan University

P2/3, N=654, Recruiting, Sun Yat-sen University Cancer Center; Sun Yat-Sen University Cancer Center | Not yet recruiting --> Recruiting

P2/3, N=429, Recruiting, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest | Trial primary completion date: Sep 2024 --> Dec 2024

P3, N=885, Completed, Jiangsu HengRui Medicine Co., Ltd. | Active, not recruiting --> Completed

P3, N=738, Active, not recruiting, Merck Sharp & Dohme LLC | Trial completion date: Dec 2024 --> Sep 2025

P1/2, N=61, Recruiting, Jeeyun Lee | Not yet recruiting --> Recruiting

In the first-line treatment of HER2-positive advanced gastric cancer, inetetamab and trastuzumab showed comparable efficacy. The inetetamab group showed superior PFS, and both groups had good safety.

P2, N=58, Terminated, Huazhong University of Science and Technology | Trial completion date: Jun 2023 --> Nov 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Mar 2023 --> Nov 2023; slow recruitment forcing early suspension of screening and enrollment

Several factors were associated with prognosis after T-DXd treatment in patients with GC/GEJC. Tumor burden is a potential risk factor for T-DXd-related ILD. Further studies are needed to optimize dosing based on tumor burden and to improve the therapeutic index.

P=N/A, N=110, Recruiting, Imperial College London

P2, N=58, Active, not recruiting, West China Hospital

P3, N=545, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

P3, N=490, Active, not recruiting, Daiichi Sankyo | Recruiting --> Active, not recruiting

P2, N=7, Completed, Imugene Limited | Active, not recruiting --> Completed | Trial completion date: Jul 2026 --> Apr 2024

P1/2, N=36, Completed, Imugene Limited | Active, not recruiting --> Completed | Trial completion date: Aug 2024 --> Mar 2024

The approaches to these targets may act together, in sequence, and even synergistically to improve outcomes. Herein, we review the state of the field, including highlighting ongoing clinical trials and additional emerging agents and approaches.

Multiomics data from The Cancer Genome Atlas linked CCL28 with RUNX3-suppressed diffuse histological subtypes of non-EBV/non-MSI-high GEA. Our data suggest that a high FOXP3+/CD8+ ratio at the invasive margin might indicate tumor immune escape via CCL28, particularly in the RUNX3-methylated diffuse histological subtype.

DKN-01 can be safely combined with frontline fluoropyrimidine/oxaliplatin and tislelizumab and demonstrates encouraging activity independent of PD-L1 expression levels. A randomized phase II trial is ongoing (ClinicalTrials.gov identifier: NCT04363801).

P1/2, N=320, Recruiting, Suzhou Transcenta Therapeutics Co., Ltd. | Trial completion date: Nov 2024 --> May 2025 | Trial primary completion date: Aug 2024 --> Feb 2025

"Roche...announced today that the VENTANA CLDN18 (43-14A) RxDx Assay is the first U.S. Food and Drug Administration (FDA) approved immunohistochemistry (IHC) companion diagnostic for determining CLDN18 protein expression in tumours of patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma. These patients now may be eligible for treatment with Astellas' targeted therapy VYLOY (zolbetuximab)....VYLOY is the first FDA-approved treatment specifically targeting HER2-negative locally advanced unresectable or metastatic gastric or GEJ cancer patients whose tumours are CLDN18.2-positive."

Seventy-four patients (81%) received nivolumab, while the remaining received pembrolizumab. Patients with advanced G/GEJ adenocarcinomas in the real world predominantly received ICIs during later lines of therapy as opposed to first line therapy. Using a CPS cutoff of ≥5 as opposed to CPS <5 predicts for improved survivals in MSS patients and patients receiving low dose ICIs have similar survival outcomes to patients receiving standard dose ICIs within the confines of a heterogenous study cohort.

P2, N=12, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Jan 2027 --> Sep 2024

P=N/A, N=20, Recruiting, M.D. Anderson Cancer Center | Trial completion date: May 2024 --> May 2026 | Trial primary completion date: May 2024 --> May 2026

P1/2, N=150, Active, not recruiting, Suzhou Transcenta Therapeutics Co., Ltd. | Recruiting --> Active, not recruiting | Trial primary completion date: Jun 2024 --> Nov 2024