Gastric cancer, gastroesophageal junction (GEJ) cancer, and esophageal adenocarcinoma (EAC) are among cancers with the highest mortality rate. These tumors are generally diagnosed in the advanced stages, leading to a poor patient prognosis and limited treatment options. The standard of care at this stage is fluoropyrimidine and platinum-based chemotherapy. The availability of immunotherapy, various chemotherapy regimens, and targeted therapies has expanded treatment options, but despite these approaches most patients do not survive beyond 2 years after initiating treatment. Research into new or novel treatment approaches is vital to improve survival in this patient population.
One approach is to target claudins, tight junction molecules in the gastric mucosal cells, that are involved in barrier function, permeability regulation, and the epithelial layer polarity. When the cell polarity becomes disrupted during malignant transformation, epitopes of CLDN18.2 are exposed. Monoclonal antibodies, including zolbetuximab, can then bind to these sites. Through this process, zolbetuximab can mediate the death of tumor cells via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.
The phase 2 FAST study evaluated patient outcomes in adult patients with advanced CLDN18.2-positive gastric/GEJ cancer and EAC with moderate-to-strong CLDN18.2 expression in ≥40% of tumor cells who were treated with zolbetuximab plus epirubicin/oxaliplatin/capecitabine (EOX) versus EOX alone. In arm 1, patients (n = 84) were treated with EOX every 3 weeks. Arm 2 patients (n = 77) received zolbetuximab in an initial loading dose of 800 mg/m2, then 600 mg/m2 plus EOX every 3 weeks. In addition to these 2 treatment arms, a third treatment arm was added after enrollment initiation. This arm included 85 patients who received zolbetuximab 1000 mg/m2 plus EOX every 3 weeks. The study’s primary end point was progression-free survival (PFS) with the secondary study end point being overall survival (OS).
Arm 2 patients demonstrated a significant PFS improvement (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.29-0.67; P <.0005) and OS improvement (HR, 0.55; 95% CI, 0.39-0.77; P <.0005) compared with arm 1 patients. When the patients with moderate-to-strong CLDN18.2 expression in ≥70% tumor cells were evaluated, the PFS improvement was also observed (HR, 0.38; 95% CI, 0.23-0.62; P <.0005). When arm 3 patients were evaluated, there was a significant improvement in PFS (HR, 0.58; 95% CI, 0.39-0.85; P = .0114) compared with arm 1, but this was not found in high CLDN18.2-expressing patients. Adverse events reported in the patients treated with zolbetuximab were primarily grade 1 or 2 anemia, neutropenia, nausea, and vomiting. There were no differences in the report of grade ≥3 adverse events between the study groups.
Zolbetuximab plus EOX conveyed a PFS and OS advantage compared with treatment with EOX alone while demonstrating an acceptable safety profile.
Source
Zahin U, Türeci Ö, Manikhas G, et al. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol. 2021;32:609-619.
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