Key Clinical Takeaways: 

• Design/Population: ILUSTRO cohort 4 is a phase 2 study evaluating first-line zolbetuximab plus mFOLFOX6 and nivolumab in patients with HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma with CLDN18.2 expression in at least 50% of tumor cells. Prior systemic therapy for advanced disease was not allowed.
• Key Outcomes: The triplet regimen achieved median PFS exceeding 12 months in the overall population and up to 18 months among patients with high CLDN18.2 expression, with ORRs exceeding 60%. Activity appeared numerically greater in tumors with high CLDN18.2 expression
• Clinical Relevance: These findings support CLDN18.2 as a clinically meaningful biomarker and suggest that zolbetuximab combined with chemotherapy and immunotherapy may represent an effective first-line strategy in this molecularly defined population. Ongoing phase 3 evaluation will further clarify its role in clinical practice.

According to results from cohort 4 of the phase 2 ILUSTRO trial, zolbetuximab plus mFOLFOX6 and nivolumab demonstrated clinical promise among patients with HER2-negative locally advanced unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma with high CLDN18.2 expression. 

These findings were presented by Kohei Shitara, MD, National Cancer Center Hospital East, Kashiwa, Japan, at the 2026 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in San Francisco, California.

In this study, researchers enrolled 77 patients with moderate to strong CLDN18.2 expression in at least 50% of tumor cells. Patients received a loading dose of 800 mg/m² of zolbetuximab 240 mg of nivolumab and mFOLFOX6 on cycle 1 day 1, as established in cohort 4A, followed by 400 mg/m² of zolbetuximab plus 240 mg of nivolumab and mFOLFOX6 every 2 weeks in 42-day cycles. Prior anti-cancer therapy for advanced disease was not permitted. Primary end points included progression-free survival (PFS) and overall response rate (ORR), with safety as a key secondary end point.

At analysis, 28.6% of patients remained on zolbetuximab treatment. Median PFS was 12.9 months in the overall population and 14.8 months in patients with high CLDN18.2 expression (n = 65). In cohort 4B, median PFS was 14.8 months in the overall population and 18 months in patients with high CLDN18.2 expression (n = 59). In the overall population, the ORR was 62.9% in patients with measurable disease and 68.6% in those with high CLDN18.2 expression. In cohort 4B, the ORR was 62.1% in  patients with measurable disease and 68.1% in those with high CLDN18.2 expression. 

Treatment-related adverse events occurred in 98.7% of patients, and serious treatment-related adverse events occurred in 23.4%. The most common adverse events included nausea (80.5%), decreased appetite (72.7%), peripheral sensory neuropathy (45.5%), and decreased neutrophil count (45.5%). Treatment-related adverse events led to zolbetuximab discontinuation in 4 patients.

“Zolbetuximab [plus] mFOLFOX6 and nivolumab showed promising activity…particularly in those with high CLDN18.2 expression,” concluded Dr Shitara et al. “The ongoing phase 3 LUCERNA trial is assessing [first-line] zolbetuximab [plus] pembrolizumab and chemotherapy in patients with [HER2-negative locally advanced unresectable or metastatic] G/GEJ adenocarcinoma with CLDN18.2[-positive] and PD-L1[-positive] tumors.”

Source: 

Shitara K, Shoji H, Fazio N, et al. Phase 2 ILUSTRO trial of 1L zolbetuximab plus mFOLFOX6 and nivolumab in patients with CLDN18.2+ locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma.Presented at ASCO Gastrointestinal Cancers Symposium. January 8 - 12, 2026; San Francisco, California. LBA284