Clinical implications of zolbetuximab-associated hypoalbuminemia in CLDN18.2-positive gastric or gastroesophageal junction cancer

Background Zolbetuximab enhances outcomes in human epidermal growth factor receptor 2-negative, claudin 18 isoform 2-positive advanced gastric cancer; nevertheless, the clinical implications of zolbetuximab-related hypoalbuminemia are not fully understood. Materials and methods We conducted a single-center retrospective study of 70 patients treated with zolbetuximab plus chemotherapy. We evaluated serial changes in albumin and their clinical implications, including associated on-target toxicities, changes in ascites, and antitumor activity. Results All patients exhibited some level of albumin decrease. The lowest hypoalbuminemia was grades 0-1 in 28 patients (40%), grade 2 in 27 (39%), and grade 3 in 15 (21%). The occurrence of grade ≥2 hypoalbuminemia peaked between cycles 1 and 3 (36%-49%) and then decreased. The median time to grade 3 hypoalbuminemia was 28.0 days, with recovery to grade ≤2 occurring after a median of 16.5 days. Grade 3 hypoalbuminemia correlated with advanced age, poorer performance status, and lower baseline albumin levels; it did not manifest in patients who had previously undergone gastrectomy. It frequently coincided with limb edema (100%), anorexia (93%), endoscopic gastritis (47%), and new or worsening ascites (60%). Most patients who temporarily paused zolbetuximab treatment resumed without recurrent grade 3 hypoalbuminemia. The antitumor activity did not significantly differ in patients with grade 3 events compared with those with grades 0-2 events, with an objective response rate of 71.4% versus 51.7% and a median overall survival of not reached versus 18.0 months (hazard ratio 1.16, P = 0.77). Conclusions Zolbetuximab-associated hypoalbuminemia typically manifests early, is frequently reversible, and is accompanied by transient ascites.