BACKGROUND: In the phase III SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials, nausea and/or vomiting were the most common adverse events in patients receiving zolbetuximab plus chemotherapy. We further characterize the adverse effects of nausea/vomiting on treatment adherence and efficacy, and evaluate strategies for managing nausea/vomiting through the SPOTLIGHT and GLOW combined analysis. MATERIALS AND METHODS: Ad hoc exploratory analyses included treatment discontinuations, antiemetic use, and progression-free survival (PFS) and overall survival (OS) after censoring patients with inadequate dose exposure (<75% relative exposure intensity) or early discontinuation (within 63 days) of zolbetuximab or placebo initiation. RESULTS: This combined analysis included 1072 patients. Nausea and/or vomiting (nausea/vomiting) were most common on the first zolbetuximab infusion day [nausea: 46.5% (246/529); vomiting: 41.0% (217/529)]; on the second infusion day, nausea dropped to 23.2% (97/418) and vomiting dropped to 24.4% (102/418). Nausea/vomiting continued to decline on subsequent infusion days. More patients on zolbetuximab versus placebo had nausea/vomiting leading to inadequate dose exposure or early discontinuation [9.9% (53/537) versus 0.6% (3/535)]. More white than Asian patients had nausea/vomiting leading to inadequate dose exposure or early discontinuation with zolbetuximab [15.4% (36/234) versus 4.7% (12/254)] and placebo [0.9% (2/224) versus 0.4% (1/255)]. Before censoring, median PFS (mPFS) (hazard ratio) for zolbetuximab versus placebo was 9.2 versus 8.2 months (0.71), and median OS (mOS) was 16.4 versus 13.7 months (0.77). After censoring, mPFS was 10.4 versus 8.2 months (0.65), and mOS was 17.9 versus 13.7 months (0.69). On the first zolbetuximab infusion day, patients without vomiting had higher utilization of three-drug prophylactic regimens than those with vomiting [75.3% (73/97) versus 24.7% (24/97)]. In patients receiving steroids, including as antiemetic prophylaxis, mPFS was 10.5 months with zolbetuximab versus 8.3 months with placebo (0.66), and mOS was 18.4 versus 13.8 months (0.71). CONCLUSION: Optimal antiemetic prophylaxis, with >3 drug classes including steroids, for zolbetuximab-associated nausea/vomiting is important for treatment adherence and maximal clinical benefits.