Zolbetuximab Improves Survival in Gastric Cancer

Results from the phase III SPOTLIGHT trial show that zolbetuximab (IMAB362; Astellas) combined with the modified FOLFOX6 (mFOLFOX6) chemotherapy regimen can improve progression-free survival (PFS) and overall survival (OS) by about 20% for certain patients with claudin 18.2–positive (CLDN18.2⁺), HER2-negative (HER2⁻) gastric or gastroesophageal junction (GEJ) cancers. The findings were presented at the 2023 American Society of Clinical Oncology Gastrointestinal Cancers Symposium in San Francisco, CA, held January 19–21.

“These results support zolbetuximab plus [mFOLFOX6] as a new, potential standard of care for patients with CLDN18.2⁺, HER2⁻ gastric and GEJ adenocarcinoma,” said Kohei Shitara, MD, of the National Cancer Center Hospital East in Chiba, Japan, and lead author of the study.

In normal cells, the CLDN18.2 molecule is restricted to tight junctions of gastric mucosal cells and inaccessible to antibodies. During malignant transformation, CLDN18.2 becomes exposed and vulnerable to zolbetuximab, a chimeric IgG1 mAb directed to it. The earlier phase II FAST study showed that zolbetuximab and the EOX regimen—epirubicin, oxaliplatin, and capecitabine—led to a PFS of 9 months and an OS of 16.5 months in patients with a high expression of CLDN18.2 compared with 5.7 and 8.9 months in those who received EOX alone (Ann Oncol 2021;32:609–19). High CLDN18.2 expression was defined as moderate to strong in at least 70% of tumor cells.

The SPOTLIGHT trial randomly assigned 283 patients with untreated CLDN18.2⁺, HER2⁻ locally advanced inoperable or metastatic gastric cancer to receive an infusion of zolbetuximab and mFOLFOX6 and 282 to receive a placebo and mFOLFOX6. CLDN18.2⁺ was defined as moderate to strong staining on at least 75% of tumor cells. With zolbetuximab/mFOLFOX6, the median PFS was 10.6 months compared with 8.7 months for mFOLFOX6 alone. In addition, the median OS was 18.2 months with zolbetuximab versus 15.5 months in the control arm.

The percentage of patients who experienced grade 3 or lower adverse events (AE) was 86.7% with zolbetuximab and mFOLFOX6 and 77.7% in the mFOLFOX6 cohort, with the most common AEs being nausea, vomiting, and decreased appetite. However, the incidence of serious AEs with zolbetuximab/mFOLFOX6 and mFOLFOX6 alone was 44.8% and 43.5%, respectively. AEs led to five deaths in the zolbetuximab arm and four deaths in the control arm.

“Nausea and vomiting usually occurred at the first or second cycle of zolbetuximab and [were] managed by an infusion adjustment, and the incidence was decreased at subsequent cycles,” said Shitara, adding that this was also the case with chemotherapy alone.

Study discussant David Wang, MD, PhD, of the University of Texas Southwestern Medical Center and VA North Texas Health Care System, both in Dallas, said that zolbetuximab is the first molecularly targeted initial therapy to improve OS in HER2⁻ gastric cancer. He also believes that CLDN18.2 is a predictive marker of response to zolbetuximab for advanced gastric disease.

But “for widespread implementation of this medication, the assay for claudin 18 expression needs to be made more widely available, and there also needs to be standardization for interpretation for positivity,” he said. –Aaron Tallent

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