Vyloy (zolbetuximab-clzb)

A regimen of capecitabine, oxaliplatin, and zolbetuximab was chosen as the primary chemotherapy regimen. Endoscopic and pathological improvements of the gastritis were confirmed three months after the discontinuation of zolbetuximab. This report describes the first case of prolonged severe gastrointestinal symptoms with severe gastritis caused by zolbetuximab, as demonstrated by endoscopic and histopathological evidence.

P=N/A, N=377, Not yet recruiting, Astellas Pharma Korea, Inc.

P3, N=500, Not yet recruiting, Astellas Pharma Global Development, Inc.

Recently, zolbetuximab, an anti-claudin 18.2 monoclonal antibody, was the first of these agents to get FDA approval. Here, we review zolbetuximab's place in therapy along with other agents being explored.

Human epidermal growth factor receptor 2 (HER2) was the first molecular biomarker to be used in gastric cancer with trastuzumab being the first approved targeted therapy for HER2-positive gastric cancer. Programmed death-ligand 1 positivity and microsatellite instability can guide the use of immunotherapies, such as pembrolizumab and nivolumab. More recently, zolbetuximab has been approved for patients with claudin 18.2-positive diseases in some countries. More targeted therapies, including savolitinib for MET-positive patients, are currently under clinical investigation...Novel testing and analysis techniques, such as artificial intelligence-assisted image analysis and multiplex immunohistochemistry, and emerging therapeutic strategies, including combination therapies that integrate immune checkpoint inhibitors with targeted therapies, offer potential solutions to some of these challenges. This article reviews recent progress in gastric cancer testing, outlines current challenges, and explores future directions for biomarker testing and targeted therapy for gastric cancer.

CLDN18-positive cases demonstrated significantly improved survival at the cohort's median overall survival (23 months, p < 0.05), suggesting that claudin expression could serve as a both a diagnostic and prognostic marker. Our findings indicate that 32.5 % of PDAC tumors in this cohort are positive for CLDN18, suggesting that a significant proportion of patients with PDAC could benefit from zolbetuximab and other CLDN18.2 targeted immunotherapies if pancreatic cancer therapeutic trials prove successful.

Although CLDN18.2 expression in PM mirrored that in primary lesions, the levels were generally reduced. When zolbetuximab is used for GC patients with peritoneal involvement, it is preferable to assess the expression of CLDN18.2 in the disseminated lesions.

P2, N=140, Not yet recruiting, China Medical University, China

In vitro, 4A7 demonstrated significantly enhanced binding activity, as well as robust antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), outperforming IMAB362, a clinical investigational antibody...4A7 shows great promise as a next-generation therapeutic for Claudin18.2-positive cancers, offering improved efficacy and reduced immunogenicity. This study not only highlights 4A7's potential to address unmet clinical needs but also provides a foundation for future innovations in monoclonal antibody-based cancer therapy.

Examining how to improve upon outcomes will be of benefit. Additionally, there are GAC subsets who may also have benefit from zolbetuximab but need more close examination such as those with moderate CLDN18.2 expressed tumors, low CLDN18.2 expressed tumors, and CLD18-ARHGAP fusion patients.

Outpatient zolbetuximab administration proved safe and feasible in a community setting when implemented with appropriate protocols and support systems. This implementation model could serve as a template for delivering complex cancer therapies in resource-limited settings.

Other biomarkers with targeted therapies are being studied including fibroblast growth factor receptor, trophoblast cell surface antigen-2, and epidermal growth factor receptor. Additionally, epidemiological distinctions are starting to drive therapy such as in EBV in GAC.

The high expression of Claudin 18.2 in neoplastic tissue and absence in normal cells suggested that this protein had an attractive role in PDA as both a diagnostic and a prognostic-therapeutic marker. High expression of Claudin 18.2 in neoplastic tissue was associated with more favorable prognostic parameters and the high percentage of positive samples obtained suggests that Zolbetuximab may be suitable for a large number of patients.

In conclusion, CLDN18.2-positive colorectal adenocarcinomas are frequently MMR deficient, BRAF V600E mutated, and demonstrate distinct histologic features. Future studies addressing the efficacy of zolbetuximab therapy in this subset of colorectal cancers are needed.

P=N/A, N=80, Recruiting, Yonsei University

From an oncological perspective, however, immunohistochemical analysis of claudin 18.2 protein expression has become increasingly clinically relevant nowadays since the impressive therapeutic benefits of the claudin 18.2 antibody zolbetuximab have been widely recognized. Systematic studies evaluating its expression, including in vulvar cancer, are needed to understand whether such treatment strategies may eventually benefit patients with vulvar neoplasia.

The GLOW trial also confirmed efficacy, with median OS improving from 12.16 months to 14.39 months (HR, 0.771; P  = .0118). Zolbetuximab's targeted action, combined with manageable adverse effects, positions it as a promising therapy for advanced gastric cancer.

P1/2, N=57, Not yet recruiting, Asan Medical Center

Trastuzumab with chemotherapy is the standard regimen for HER2-positive GC/GEJC. While, for HER2-negative cases, chemotherapy with or without immune checkpoint inhibitors (ICIs)such as nivolumab or pembrolizumab are regarded as the standard therapy...We will highlight the previous clinical trials of zolbetuximab and provide future perspective of CLDN18.2 targeted therapy. In addition, we will introduce the ongoing development of various CLDN18.2 targeting therapies such as newer monoclonal antibodies, antibody-drug conjugates(ADCs), chimeric antigen receptor T-cell(CAR- T)therapy, and bispecific antibodies.

Therapies like monoclonal antibodies (e.g., zolbetuximab), bispecific antibodies, and antibody-drug conjugates have shown significant potential in improving clinical outcomes...However, challenges such as patient selection, resistance mechanisms, and toxicity management remain critical. This review highlights the therapeutic landscape, clinical advancements, and future directions of targeting Claudin 18.2 in gastric and pancreatic cancer treatment.

The GLOW clinical trial showed that zolbetuximab plus capecitabine plus oxaliplatin (CAPOX) significantly prolonged these patients' overall survival (OS) and progression-free survival (PFS). Zolbetuximab plus CAPOX had 0% cost-effectiveness at the willingness-to-pay thresholds of $150,000/QALY in the United States and $38,188/QALY in China. Zolbetuximab plus CAPOX may be a cost-effective option for patients with locally advanced, unresectable, or metastatic G/GEJ adenocarcinoma when the price of zolbetuximab reduced by 83.37% ($367.7/100 mg) in the United States and 82.25% ($110.8/100 mg) in China.

P2, N=143, Active, not recruiting, Astellas Pharma Global Development, Inc. | Recruiting --> Active, not recruiting

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.

In PD-L1low HER-2 negative GEAC, the benefit of first-line ICI is modest, yet significant. Further translational work is warranted to better select patients who could benefit from immunotherapy in this setting. Meanwhile, alternative therapeutic options such as zolbetuximab in Claudin18.2-positive disease must be taken into account.

"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."

"Roche...announced today that the VENTANA CLDN18 (43-14A) RxDx Assay is the first immunohistochemistry (IHC) companion diagnostic test to receive CE Mark approval 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)...The new VENTANA CLDN18 (43-14A) RxDx Assay can help determine CLDN18.2 status and inform clinicians about the likelihood of patients benefiting from CLDN18.2 targeted therapy...The approval of the VENTANA CLDN18 (43-14A) RxDx Assay is based on the results of the SPOTLIGHT and GLOW clinical studies where it was used as the enrollment assay to identify patients whose tumours were CLDN18.2 positive."

A significant portion of surgically resected PCC specimens showed CLDN18.2 positivity. Additionally, since the expression level of CLDN18.2 gradually decreases with increased paraffin block storage time, reflex testing can be considered at the time of the cancer diagnosis.

FDA approval of zolbetuximab's, an anti-CLDN18.2monoclonal antibody, is expected soon. Additionally, bemarituzumab, ananti-FGFR2b monoclonal antibody, has shown improvements in combination withchemotherapy in those with HER2 negative GAC with FGFR2 overexpression...Lastly, TROP-2 has emergedas an exciting solid tumor target and study is expected in GAC. All three ofthese therapeutic targets have seen an abundance of drug development in recentyears, and we anticipate newer targeted agents driving therapeutic decisions inGAC in the coming years.

The effect of antiemetics (dexamethasone, ondansetron, fosaprepitant, and olanzapine) on emesis induced by zolbetuximab was investigated. Fosaprepitant showed suppressive effects on emesis, and use of dexamethasone or concomitant use of fosaprepitant with other antiemetics tended to alleviate gastric tissue damage. The onset of emesis in humans receiving zolbetuximab may be associated with damage in the gastric mucosa, and antiemetics may mitigate gastrointestinal adverse events.

The human/humanized anti‑CLDN18.2 mAb osemitamab, and ADCs AZD0901, IBI343 and LM‑302, with single‑agent ORRs of 28‑60%, have been tested in phase III clinical trials. In addition, bsAbs, CAR T cells and their derivatives targeting CLDN4, 6 or 18.2 are in phase I and/or II clinical trials. AZD0901, IBI343, zolbetuximab and the anti‑CLDN1 mAb ALE.C04 have been granted fast track designation or priority review designation by the US Food and Drug Administration.

P2, N=393, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Apr 2025 --> Aug 2026 | Trial primary completion date: Sep 2024 --> Aug 2026

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

At the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, the final results of the phase 3 SPOTLIGHT trial were presented, demonstrating a significant survival benefit from the addition of the CLDN18.2-specific antibody zolbetuximab to chemotherapy in the first-line treatment of advanced gastroesophageal adenocarcinomas with ≥ 75% CLDN18.2 expression...In addition, several early-phase trials presented at ASCO 2024 investigate other CLDN18.2-targeting approaches in CLDN18.2-positive refractory advanced solid tumors, including the CLDN18.2-targeting antibody-drug conjugates LM-302 and IBI343, the bispecific anti-CLDN18.2/CD3 antibody IBI38, and the chimeric antigen receptor T cell therapy satricabtagene autoleucel. These novel approaches could potentially expand the benefit of CLDN18.2-targeting therapies to a broader range of tumor types and to tumors expressing lower levels of CLDN18.2.

In CD-associated small bowel adenocarcinomas, Cadherin 17 expression was frequently retained and Claudin 18 was frequently co-expressed. Claudin 18 had a positive correlation with the expression of gastric mucins. These results suggest that CD-associated small bowel adenocarcinomas may be candidates for Cadherin 17- and Claudin 18-targeted immunotherapies.

Currently, both pembrolizumab and nivolumab have been approved for the first-line treatment of tumors with positive PD-L1 expression...The antibody-drug conjugate trastuzumab-deruxtecan is a promising second-line treatment option for HER2-positive tumors after treatment failure with trastuzumab.In addition, the bispecific antibody zanidatamab shows promising results in first-line treatment. New targeted therapies against CLDN18.2 and FGFR2b are showing promising results. The anti-claudin 18.2 (CLDN18.2) antibody zolbetuximab leads to improved survival compared to chemotherapy alone in patients with CLDN18.2 positive disease in first-line therapy, with approval expected in 2024.

Patients in SPOTLIGHT and GLOW maintained measured HRQoL relative to baseline when treated with first-line zolbetuximab added to chemotherapy. Zolbetuximab plus chemotherapy improved PFS and OS without negatively affecting HRQoL in key PRO domains compared with placebo plus chemotherapy.

Several pre-analytical and analytical variables may interfere with adequate CLDN18.2 staining interpretation, thus this article provides practical guidance on CLDN18.2 testing and scoring in gastric/gastroesophageal junction adenocarcinomas in order to identify patients who may respond to targeted therapy with monoclonal antibodies directed against CLDN18.2. Based on available data, moderate to strong (2+/3+) membrane staining in ≥75% of adenocarcinoma cells is the proposed cut-off for clinical use of the monoclonal antibody anti-CLDN18.2 (zolbetuximab).

Importantly, both CLDN18.2 expression and the number of tumor-infiltrating NK cells were significantly higher in EBV-associated GC compared to other molecular subtypes. Our findings support the effectiveness of zolbetuximab in CLDN18.2-positive GC, and offer a novel insight into the treatment of this cancer type, highlighting its potential effectiveness for CLDN18.2-positive/EBV-associated GC.

Zolbetuximab is also undergoing regulatory review for HER2-, CLDN18.2+ advanced gastric or GEJ adenocarcinoma in the USA, the EU, China, Australia and several other countries. This article summarizes the milestones in the development of zolbetuximab leading to this first approval for the treatment of patients with CLDN18.2+ gastrointestinal malignancies.

CLDN18.2 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.

Due to the excellent targeting ability of zolbetuximab for CLDN18.2, &lsqb;125I]I-zolbetuximab exhibits strong specific binding and retention with cells and tumors highly expressing CLDN18.2. However, the balance between mAb's longer cycle time in vivo and targeting binding and retention ability should be intensively considered for using this kind of radiopharmaceutical in the diagnosis and treatment of CLDN18.2-positive gastric cancer.

Further studies are needed to determine its role within current gastric cancer treatment sequencing, including HER2-targeted therapies and immunotherapies. Management strategies will also be needed to better mitigate zolbetuximab-related treatment side effects, including gastrointestinal (GI) toxicities.