Zolbetuximab, a Claudin 18.2 (CLDN18.2)-targeted IgG1 monoclonal antibody, in combination with frontline chemotherapy, has demonstrated significant improvements in progression-free survival (PFS) and overall survival (OS) for patients with HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN18.2 positive. These findings come from a combined analysis of the phase 3 SPOTLIGHT and GLOW trials, recently published in the New England Journal of Medicine, and supported the FDA approval of zolbetuximab in October 2024.
The pooled analysis included data from 537 patients who received zolbetuximab plus chemotherapy and 535 patients who received placebo plus chemotherapy. The median PFS was 9.2 months (95% CI, 8.4-10.4) in the zolbetuximab arm compared to 8.2 months (95% CI, 7.6-8.4) in the placebo arm (HR, 0.71; 95% CI, 0.61-0.83). The median OS was 16.4 months (95% CI, 15.0-17.9) versus 13.7 months (95% CI, 12.3-15.3), respectively (HR, 0.77; 95% CI, 0.67-0.89).
Expert Commentary
Kohei Shitara, MD, director of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Japan and first author of the pooled analysis, noted, "There were some differences in patient characteristics and country distribution, as well as the chemotherapy backbone, [between SPOTLIGHT and GLOW], so we wanted to perform a pooled analysis. [We observed] a 29% reduction in the risk of progression or death [with zolbetuximab vs placebo]."
Safety Profile
The safety analysis revealed that any-grade treatment-emergent adverse effects (TEAEs) occurred in 99.2% of patients in the zolbetuximab arm (n = 533), with 80.7% experiencing grade 3 or higher severity and 48.0% experiencing serious TEAEs. The most common any-grade TEAEs in the zolbetuximab arm included nausea (76.0%), vomiting (66.8%), and decreased appetite (45.2%). Grade 3 or higher TEAEs included neutropenia (18.2%), decreased neutrophil count (17.8%), and vomiting (14.3%).
Shitara added, "There were no new safety concerns [with zolbetuximab] at this updated follow-up. Gastrointestinal toxicity, such as nausea and vomiting, is more frequently observed with zolbetuximab [compared with] placebo. But, as previously described, these events mostly happen at first infusion and clearly decrease over subsequent cycles."
Trial Details
The GLOW trial was a global, double-blind study that enrolled adult patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. Patients were randomized 1:1 to receive zolbetuximab or placebo plus oral capecitabine and IV oxaliplatin. The primary endpoint was PFS per RECIST 1.1 by independent review committee (IRC).
The SPOTLIGHT trial was a global, placebo-controlled, double-blind trial that enrolled adult patients with CLDN18.2-positive, HER2-negative, treatment-naive locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. Patients were randomized 1:1 to receive zolbetuximab or placebo plus IV folinic acid, fluorouracil, and oxaliplatin. The primary endpoint was PFS per IRC.
Regulatory Status and Future Directions
Zolbetuximab has already been approved in Japan and Europe for the treatment of CLDN18.2-positive gastric cancer. "We are waiting for approval in other regions outside of Japan [and Europe]," Shitara stated. "This is a significant achievement in gastric cancer [because] we have very limited treatment options, but the magnitude of survival benefit was still modest and not enough. We need additional, better treatment [options. Next, we want] to combine [zolbetuximab] with the current available treatments, such as checkpoint inhibitors, and this is supported by clinical and preclinical studies."
