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Evidence to Date on the Therapeutic Potential of Zolbetuximab in Advanced Gastroesophageal Adenocarcinoma.

ABSTRACT: Gastric adenocarcinoma (GAC) continues to be a prevalent worldwide malignancy and a leading cause of cancer death, and it is frequently cited as incurable. Targeted therapy in GAC has lagged behind other solid tumors. The human epidermal growth factor receptor-2 (HER-2) represented the single target in GACs for many years, seen in approximately 20% of patients with advanced GAC. Recent advances in management now include the addition of immunotherapy checkpoint inhibition to select front-line advanced GACs. Unfortunately, outcomes remain poor for most patients. We anticipate finding a key to future discoveries in GACs in next-generation sequencing and more targeted approaches. Claudin 18.2 (CLDN18.2) has emerged as a therapeutic target in GACs. CLDN18.2 is reportedly expressed in 14-87% of GACs, and CLDN18.2 is available for monoclonal antibody (mAb) binding as it is expressed on the outer cell membrane. Here, we review the exploration of CLDN18.2 as a target in GACs via the use of zolbetuximab (IMAB362). Zolbetuximab is now under priority FDA review for GACs, and we eagerly await the review outcome.

SUBMITTER: Rogers JE

PROVIDER: S-EPMC10888045 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Evidence to Date on the Therapeutic Potential of Zolbetuximab in Advanced Gastroesophageal Adenocarcinoma.

Rogers Jane E JE Ajani Jaffer J

Current oncology (Toronto, Ont.) 20240201 2

Gastric adenocarcinoma (GAC) continues to be a prevalent worldwide malignancy and a leading cause of cancer death, and it is frequently cited as incurable. Targeted therapy in GAC has lagged behind other solid tumors. The human epidermal growth factor receptor-2 (HER-2) represented the single target in GACs for many years, seen in approximately 20% of patients with advanced GAC. Recent advances in management now include the addition of immunotherapy checkpoint inhibition to select front-line adv ...[more]

PMID: 38392051

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Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is frequently diagnosed and treated in advanced tumor stages with poor prognosis. More effective screening programs and novel therapeutic means are urgently needed. Recent studies have regarded tight junction protein claudin 18.2 (CLDN18.2) as a candidate target for cancer treatment, and zolbetuximab (formerly known as IMAB362) has been developed against CLDN18.2. However, there are few data reported thus far related to the clinicopathological characteristics of CLDN18.2 expression for PDAC.AimTo investigate the expression of CLDN18.2 in PDAC patients and subsequently propose a new target for the treatment of PDAC.MethodsThe Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Omnibus, and European Genome-phenome Archive databases were first employed to analyze the CLDN18 gene expression in normal pancreatic tissue compared to that in pancreatic cancer tissue. Second, we analyzed the expression of CLDN18.2 in 93 primary PDACs, 86 para-cancer tissues, and 13 normal pancreatic tissues by immunohistochemistry. Immunostained tissues were assessed applying the histoscore. subsequently, they fell into two groups according to the expression state of CLDN18.2. Furthermore, the correlations between CLDN18.2 expression and diverse clinicopathological characteristics, including survival, were investigated.ResultsThe gene expression of CLDN18 was statistically higher (P < 0.01) in pancreatic tumors than in normal tissues. However, there was no significant correlation between CLDN18 expression and survival in pancreatic cancer patients. CLDN18.2 was expressed in 88 (94.6%) of the reported PDACs. Among these tumors, 50 (56.8%) cases showed strong immunostaining. The para-cancer tissues were positive in 81 (94.2%) cases, among which 32 (39.5%) of cases were characterized for strong staining intensities. Normal pancreatic tissue was identified solely via weak immunostaining. Finally, CLDN18.2 expression significantly correlated with lymph node metastasis, distant metastasis, nerve invasion, stage, and survival of PDAC patients, while there was no correlation between CLDN18.2 expression and localization, tumor size, patient age and sex, nor any other clinicopathological characteristic.ConclusionCLDN18.2 expression is frequently increased in PDAC patients. Thus, it may act as a potential therapeutic target for zolbetuximab in PDAC.

Project description:BackgroundPatients with HER2-negative locally advanced or unresectable metastatic gastric cancer and gastroesophageal junction (G/GEJ) adenocarcinoma have limited first-line treatment options and a poor prognosis. The GLOW clinical trial showed that zolbetuximab plus capecitabine plus oxaliplatin (CAPOX) significantly prolonged these patients' overall survival (OS) and progression-free survival (PFS).ObjectivesThis study evaluated the cost-effectiveness of zolbetuximab plus CAPOX as a first-line treatment for HER2-negative locally advanced or unresectable metastatic G/GEJ adenocarcinoma in the United States and China.DesignThe cost-effective analysis.MethodsBased on the GLOW clinical trial data (NCT03653507), we constructed a 10-year Markov model to assess the cost-effectiveness of the zolbetuximab or placebo plus CAPOX treatment regimen. Only direct medical costs were considered. The primary outcomes of the model were quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). One-way and probabilistic sensitivity analyses were employed to assess the robustness of the model.ResultsIn the United States, zolbetuximab plus CAPOX added 0.24 QALYs and resulted in an incremental cost of $196,791.11 compared with placebo plus CAPOX, which had an ICER of $821,515.65 per QALY gained. For China, the zolbetuximab group gained 0.23 QALYs at an incremental cost of $62,822.69, resulting in an ICER of $273,568.01/QALY. One-way sensitivity analysis revealed that the results were most sensitive to the price of zolbetuximab. 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.ConclusionZolbetuximab 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.

Dataset Information

Evidence to Date on the Therapeutic Potential of Zolbetuximab in Advanced Gastroesophageal Adenocarcinoma.

Publications

Evidence to Date on the Therapeutic Potential of Zolbetuximab in Advanced Gastroesophageal Adenocarcinoma.

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