AE Management Is Crucial for Maximizing Zolbetuximab Benefit in Gastric/GEJ Cancer

Treatment with the combination of zolbetuximab (Vyloy) and chemotherapy delivered maximal clinical benefits and was associated with optimal treatment adherence when adverse effects (AEs) were managed effectively among patients with HER2-negative, Claudin 18.2 (CLDN18.2)–positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to findings from exploratory ad hoc analyses from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials.^1,2

The pooled findings were published in ESMO Open, and showed that among 1072 patients, higher median progression-free survival (PFS) and overall survival (OS) estimates were seen with the zolbetuximab-based combinations compared with placebo after the censoring of data from patients who had discontinued treatment early or had inadequate treatment exposure attributed to nausea and/or vomiting. The censored median PFS with zolbetuximab plus chemotherapy was 10.4 months (95% CI, 8.8-12.2) vs 8.2 months (95% CI, 7.7-8.4) with placebo plus chemotherapy (HR, 0.65; 95% CI, 0.56-0.76). ¹ Before censoring, these respective values were 9.2 months (95% CI, 8.4-10.4) vs 8.2 months (95% CI, 7.6-8.4; HR, 0.71; 95% CI, 0.61-0.83).²

The censored median OS with zolbetuximab plus chemotherapy was 17.9 months (95% CI, 16.4-19.5) compared with 13.7 months (95% CI, 12.4-15.3) with placebo (HR, 0.69; 95% CI, 0.60-0.80). ¹ Before censoring, these respective values were 16.4 months (95% CI, 15.0-17.9) vs 13.7 months (95% CI, 12.3-15.3; HR, 0.77; 95% CI, 0.67-0.89). ²

“Nausea and vomiting are important symptoms that can affect patient comfort and treatment continuity for advanced gastric or GEJ cancer, particularly during early cycles when these symptoms are most common,” Sam Klempner, MD, a gastrointestinal medical oncologist at Massachusetts General Hospital in Boston, stated in a news release.¹ “Supportive care measures are therefore an important part of managing patients receiving cancer therapy."

In 2024, the FDA approved first-line zolbetuximab plus fluoropyrimidine- and platinum-containing chemotherapy for the treatment of adult patients with locally advanced unresectable or metastatic, HER2-negative gastric or GEJ adenocarcinoma with CLDN18.2-positive tumors. This regulatory decision was based on findings from both SPOTLIGHT and GLOW.³ SPOTLIGHT evaluated zolbetuximab plus mFOLFOX6 (modified leucovorin, fluorouracil, and oxaliplatin), whereas GLOW examined zolbetuximab in combination with CAPOX (oxaliplatin and capecitabine). Notably, the most common serious AEs across both trials were nausea and vomiting.

“Early cycles are a critical window for supporting patients starting treatment for advanced gastric or GEJ cancer,” Timothy Forrest, RN, BSN, of Massachusetts General Hospital, added in the news release.¹ “Since we know nausea and vomiting are common in this setting, preparing patients, monitoring closely, and using guideline-aligned supportive care can make a meaningful difference to their comfort and ability to continue treatment as planned.”

What additional findings were published in the ad hoc analyses of zolbetuximab use related to AEs in SPOTLIGHT and GLOW?

These analyses aimed to characterize the effects of nausea and vomiting on the efficacy of, and adherence to, the SPOTLIGHT and GLOW regimens, as well as elucidate strategies for the management of these AEs.

Additional data showed that, at day 1 of cycle 1, 75.3% of patients in the zolbetuximab group who received 3-drug antiemetic regimens did not experience vomiting, and 60.8% of these patients did not experience nausea. Furthermore, the rate of patients who did not experience nausea at this time point was 57.9% with the use of steroids 1 vs 49.7% without steroids. The rates of patients who did not experience vomiting with and without steroids at this time point were 63.7% vs 62.6%, respectively.

Among patients who received steroids, including those who received these agents as anti-emetic prophylaxis, the median PFS was 10.5 months (95% CI, 8.9-12.5) with zolbetuximab vs 8.3 months (95% CI, 8.1-9.2) with placebo (HR, 0.66; 95% CI, 0.54-0.81).² The median OS values in these respective populations were 18.4 months (95% CI, 16.4-19.7) vs 13.8 months (95% CI, 12.3-16.0; HR, 0.71; 95% CI, 0.59-0.86).

Nausea and/or vomiting were primarily reported on the first day of zolbetuximab infusion (nausea, 46.5%; vomiting, 41.0%); however, these rates dropped to 23.2% and 24.4%, respectively, on the second infusion day, and declined further at subsequent infusions.

Moreover, the rate of patients who experienced inadequate dose exposure or early treatment discontinuation due to nausea/vomiting was 9.9% in the zolbetuximab group vs 0.6% in the placebo group. Additionally, nausea/vomiting leading to inadequate dose exposure or early treatment discontinuation was more prominent in White vs Asian patients across both the zolbetuximab (White, 15.4%; Asian, 4.7%) and placebo (0.9%; 0.4%) groups.

References

1. Vyloy (zolbetuximab) plus chemotherapy associated with enhanced survival outcomes when common adverse events are effectively managed, according to new ad hoc analyses. News release. Astellas Pharma U.S., Inc. January 8, 2026. Accessed January 9, 2026. https://www.biospace.com/press-releases/vyloy-zolbetuximab-plus-chemotherapy-associated-with-enhanced-survival-outcomes-when-common-adverse-events-are-effectively-managed-according-to-new-ad-hoc-analyses
2. Shitara K, Smyth E, Lordick F, et al. Impact and effective management of nausea/vomiting on patients treated with zolbetuximab + chemotherapy: insights from the phase III SPOTLIGHT and GLOW studies. ESMO Open. Published online January 7, 2026. Accessed January 9, 2026. doi:10.1016/j.esmoop.2025.105931
3. FDA approves zolbetuximab-clzb with chemotherapy for gastric or gastroesophageal junction adenocarcinoma. FDA. October 18, 2024. Accessed January 9, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zolbetuximab-clzb-chemotherapy-gastric-or-gastroesophageal-junction-adenocarcinoma