Navigating the clinical challenges of zolbetuximab in patients with claudin positive advanced gastric cancer.

Zolbetuximab, a first-in-class monoclonal antibody targeting Claudin 18.2 (CLDN 18.2), has demonstrated significant survival benefit when combined with chemotherapy in HER2-negative, CLDN 18.2-positive advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma. However, its integration into clinical practice presents two major challenges: the best treatment selection between zolbetuximab or immune checkpoint inhibitor (ICI)-based regimens in patients co-expressing programmed death-ligand 1 (PD-L1), and the management of zolbetuximab-related nausea and vomiting (N/V). We critically reviewed evidence from randomized controlled trials, regulatory approvals, and recent expert consensus on zolbetuximab management. In CLDN 18.2-positive/PD-L1-positive patients, ICIs may offer greater long-term survival benefit especially in case of high PD-L1 CPS, while zolbetuximab may be preferred in patients with negative-to-low CPS or ICIs contraindications. N/V, reported in more than three-quarter of patients, is more frequent and severe during the first infusion, due to zolbetuximab loading dose and faster infusion rate. Proper management includes accurate adherence to high-risk antiemetic protocols (including NK-1/5-HT3 antagonists and corticosteroids) and careful control of infusion rates with a stop and go strategy. In case of CLDN 18.2 and PD-L1 CPS co-positivity, we advocate the use of PD-L1 CPS ≥ 10 as a practical decision-making threshold for favoring ICI-based regimens. However, the treatment selection should be tailored on comorbidities, comprehensive molecular characterization and available subsequent options. To ensure the optimal use of zolbetuximab, special attention is required during the first cycle, due to higher risk of infusion-related N/V. We suggest that the optimization of both prophylactic and on-treatment antiemetic strategies is essential to enhance zolbetuximab adherence and maximize clinical outcomes.