Vyloy (zolbetuximab-clzb)

Zolbetuximab is associated with high rates of nausea and vomiting during the initial infusion, whereas ICIs are associated with risk of later-onset immune-related toxicities that can be fatal in rare cases. In considering the available evidence, our opinion is that zolbetuximab is a reasonable option for initial targeted treatment in HER2-/CLDN18.2-positive advanced G/GEJ when PD-L1 CPS score is <10 based on the reliability of biomarker testing, comparable OS, and avoidance of potentially irreversible ICI-induced immune toxicity.

Clinicians should monitor albumin levels during treatment and consider nutritional support when indicated. These findings provide important insights for optimizing patient management and ensuring safe conversion surgery planning.

Serial PET imaging with 89Zr-labeled zolbetuximab, an anti-CLDN18.2 monoclonal antibody ([89Zr]Zr-DFO-zolbetuximab), and human IgG ([89Zr]Zr-DFO-IgG) as control (5.5-7.4 MBq) was performed 1, 3, and 6 d after injection, followed by ex vivo analysis of biodistribution... CLDN18.2 could serve as a promising biomarker for precise quantitative imaging and effective treatment of GCa and PDAC. This proof-of-concept study encourages the clinical translation of CLDN18.2 as a radiotheranostic in patients with CLDN18.2-expressing tumors.

Treatment was started with zolbetuximab plus 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX), which is typically used for CLDN18.2-positive gastric cancer, resulting in a partial response. This is the first case of zolbetuximab-based therapy applied to adenocarcinoma from a Meckel's diverticulum with a gastric phenotype due to a biomarker profile of gastric cancer. This case highlights the importance of identifying both the biomarker profile and tissue of origin of the tumor.

P1, N=12, Active, not recruiting, Astellas Pharma Global Development, Inc. | Recruiting --> Active, not recruiting

This review examines the mechanisms, safety profiles, and clinical trial outcomes of three targeted agents-bemarituzumab, zolbetuximab, and ramucirumab-which inhibit tumor growth through the FGFR2b, CLDN18.2, and VEGFR2 pathways, respectively. We also compare traditional versus adaptive clinical trial designs, explore emerging challenges such as therapeutic resistance and treatment-related toxicities, and consider implications for personalized medicine. Collectively, these agents represent a paradigm shift from empiric chemotherapy toward biomarker-driven immunotherapy, with the potential to significantly improve survival and quality of life in patients with advanced G/GEJ cancers.

However, GI toxicities are reported from clinical use of both Zolbetuximab and CT041...We also demonstrate and characterize on-target/off-tumor gastric toxicity targeting CLDN18.2 in a preclinical mouse model of CT041-scFv derived CAR T cell therapy. By developing CLDN18.2 fully-human VH-only single domain CARs, we demonstrate that on-target/off-tumor toxicity inversely correlates with affinity of the binder, and that a lower affinity CAR may widen the therapeutic window for CLDN18.2 by decreasing on-target/off-tumor toxicity while preserving efficacy.

For solid cancers, these comprise the antibody-drug-conjugate Mirvetuximab Soravtansine for platinum-resistant ovarian cancer, the monoclonal antibody Zolbetuximab for Claudin-18.2 positive gastric adenocarcinoma and the checkpoint inhibitor Tislelizumab for esophageal squamous cell carcinoma. For the treatment of relapsed or refractory hematologic B cell malignancies, the use of bispecific T cell engaging antibodies like the BCMA-CD3 targeting Teclistamab and CD20-CD3 targeting Glofitamab were approved by the EMA recently.Combinatorial approaches of conventional chemotherapy and checkpoint inhibitors for the treatment of cholangiocarcinoma, urothelial carcinoma and endometrial carcinoma received recent approval.A CD38 antibody-based bridging therapy for the treatment of newly diagnosed multiple myeloma and the Glofitamab-based approach in combination with Gemcitabine and Oxaliplatin for relapsed DLBCL are the latest additions for hematologic malignancies after promising clinical trials.The first T cell products for the treatment of solid cancers using either tumor-infiltrating lymphocytes or TCR-engineered peripheral blood T cells were approved by the FDA in 2024, for the treatment of advanced melanoma (Lifileucel) and synovial sarcoma (Afamitresgene autoleucel). To further expand the success of T cell products to solid tumors, promising preclinical studies suggest solutions to main obstacles, such as modular CAR T cells, targeting of two antigens simultaneously or generation of cytokine-secreting 4th generation CAR T cells.

P2, N=143, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Feb 2027 --> May 2027 | Trial primary completion date: Jan 2026 --> Jul 2026

The diagnostic evaluation of gastric carcinoma should include high-resolution video endoscopy, and its treatment should be stage-adapted and interdisciplinary. Monoclonal antibodies and immune checkpoint inhibitors are increasingly being used for palliative treatment. The new modifications to the clinical practice guideline will promote the use of uniform strategies for perioperative and palliative treatment and supportive measures.

Early-onset transient gastritis frequently occurred following zolbetuximab-containing therapy and was significantly associated with anorexia and hypoalbuminemia. A deeper understanding of gastritis underlying unique GI toxicities may provide insight into effective management.