Zolbetuximab plus chemotherapy prolongs survival in CLDN18.2+/HER2- gastric/GEJ adenocarcinoma

Improving outcomes for patients diagnosed with HER2-negative advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma remains an unmet clinical need. The results of GLOW and SPOTLIGHT, recently presented at ASCO GI 2023, showed that zolbetuximab plus chemotherapy prolongs survival in these patients. Based on these findings, zolbetuximab plus chemotherapy has the potential to become a new standard of care for patients with CLDN18.2+/HER2- locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma.

Currently, there is an unmet need for innovative targeted therapies to improve outcomes for patients diagnosed with HER2-negative locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma.^1,2 One potential therapeutic target for these patients is Claudin 18.2 (CLDN18.2), a protein expressed in normal gastric mucosa cells and retained in most G/GEJ adenocarcinomas.³ In the FAST study, zolbetuximab, a first-in-class monoclonal antibody targeting CLDN18.2, prolonged survival of patients with LA unresectable or mG/GEJ adenocarcinoma when combined with chemotherapy.² At ASCO GI 2023, the results of two phase 3 trials evaluating the efficacy and safety of zolbetuximab in this setting were presented. The GLOW and SPOTLIGHT studies analysed zolbetuximab combined with capecitabine and oxaliplatin (CAPOX) (GLOW study) or with folinic acid (5-FU) and oxaliplatin (mFOLFOX6) (SPOTLIGHT study) as first-line treatment for patients with CLDN18.2+/ HER2-, LA unresectable or mG/GEJ adenocarcinoma.^1-3

Study findings

The phase 3 GLOW and SPOTLIGHT trials included 507 and 565 patients with CLDN18.2+ /HER2- LA unresectable or mG/GEJ adenocarcinoma, respectively. Patients were randomly assigned 1:1 to receive zolbetuximab or placebo, both in combination with CAPOX (GLOW study) or mFOLFOX6 (SPOTLIGHT study). The primary endpoint was, for both studies, progression-free survival (PFS), while overall survival (OS) was a key secondary endpoint.^1-3

In the GLOW study, PFS was significantly prolonged with zolbetuximab + CAPOX compared to placebo + CAPOX (8.21 vs. 6.80; HR: 0.687; p=0.0007). This PFS benefit translated into an improved OS with zolbetuximab + CAPOX (14.39 vs. 12.16 months, HR 0.771; p=0.0118). Comparable results were observed in the SPOTLIGHT study, where PFS was significantly improved with zolbetuximab + mFOLFOX6 compared to placebo + mFOLFOX6 (10.61 vs. 8.67 months, HR: 0.751, p=0.0066). OS was also significantly improved with zolbetuximab + mFOLFOX6 (median 18.23 vs. 15.54 months, HR: 0.750; p=0.0053).^1-3

Based on the findings of GLOW and SPOTLIGHT trials, zolbetuximab in combination with chemotherapy has demonstrated the potential to serve as an innovative therapeutic option and a possible new standard of care for patients diagnosed with CLDN18.2+/HER2- LA unresectable or mG/GEJ adenocarcinoma.^1-3

References

1. Xu R-H, Shitara K, Ajani JA, et al. Zolbetuximab + CAPOX in 1L claudin-18.2+ (CLDN18.2+)/HER2− locally advanced (LA) or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Primary phase 3 results from GLOW. Presented at ASCO GI; Abstract 405736.
2. Shitara K, Lordick F, Bang Y-J, et al. Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) withclaudin-18.2+ (CLDN18.2+) / HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Primary results from phase 3 SPOTLIGHT study. Presented at ASCO GI 2023; Abstract LBA292.
3. Zolbetuximab Plus CAPOX Improves Survival in Certain Gastric Cancers. Press release, 21st March 2023.