Advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma remains associated with a poor prognosis. With first-line (1L) chemotherapy, median overall survival (OS) is approximately 8.8-12.2 months, with many patients unable to receive second- or later-line therapies due to rapid disease progression and declining performance status.^1,2 In this context, optimizing 1L treatment has become increasingly critical, particularly as molecular characterization has enabled more precise, biomarker-driven approaches.^1,2 At the 2026 ASCO Gastrointestinal Cancers Symposium, Dr. Kohei Shitara presented updated efficacy and safety data from the phase 2 ILUSTRO trial, focusing on a triplet regimen combining zolbetuximab, chemotherapy, and PD-1 inhibition in patients with claudin-18.2 (CLDN18.2)-positive advanced GE/GEJ.³ Dr. Daniel Lin from the Thomas Jefferson University Hospital, United States further provided a broader perspective of the evolving role of CLDN18.2 as a clinically actionable biomarker in the frontline setting and highlighted the potential of biomarker-enriched combination strategies.²

Getting 1L therapy right: The role of CLDN18.2 in advanced gastric/GEJ cancer

For patients with advanced G/GEJ cancer, the choice of 1L therapy is critical, as it profoundly impacts subsequent treatment opportunities and overall survival.^1,2 Real‑world evidence and clinical trial data consistently show substantial attrition across treatment lines, with only a minority of patients able to receive second‑ or later‑line therapies.^1,2 This underscores the importance of maximizing therapeutic benefit in the 1L setting.  The 1L treatment landscape of G/GEJ cancer becomes increasingly biomarker‑driven, CLDN18.2 has emerged alongside HER2 and PD‑L1 as an important validated therapeutic target.² CLDN18.2 is a tight junction protein normally confined to the gastric mucosa but aberrantly expressed on the surface of malignant gastric and GEJ tumor cells.^4,5

Evidence supporting CLDN18.2 as a therapeutic biomarker was first demonstrated in the phase 2 FAST study, where patients whose tumors expressed CLDN18.2 in ≥70% of cells with moderate to strong membranous staining by IHC experienced enhanced survival benefit. This cutoff was later standardized to ≥75%  in the phase 3 SPOTLIGHT and GLOW trials and became the definition of claudin 18.2 positivity, with prevalence ranging from 35%-40% in advanced G/GEJ adenocarcinoma.^2,3,6 Phase 3 SPOTLIGHT and GLOW confirmed the clinical benefit of targeting CLDN18.2, showing that adding zolbetuximab to chemotherapy significantly improved outcomes—SPOTLIGHT: progression-free survival (PFS) 10.61 vs. 8.67 months, OS 18.23 vs. 15.54 months; GLOW: PFS 8.21 vs. 6.80 months, OS 14.39 vs. 12.16 months.^7,8

Co-expression of CLDN18.2 and PD-L1 is reported in 26%-79%, depending on assay and scoring thresholds.² However, the optimal first-line strategy for dual-positive patients remains unclear.⁸ Guideline recommendations reflect this uncertainty: National Comprehensive Cancer Network (NCCN) now lists zolbetuximab + fluoropyrimidine/oxaliplatin as a Category 1 preferred 1L option for CLDN18.2-positive, HER2-negative tumors, while European Society for Medical Oncology (ESMO) and Chinese Society of Clinical Oncology (CSCO) recognize CLDN18.2-targeted therapy within biomarker-driven frameworks, but provide no clear guidance for integrating PD-1/PD-L1 inhibitors.^9-11

Zolbetuximab, the first-in-class monoclonal antibody directed targeting CLDN18.2, exerts antitumor activity through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.^2,4-6 Preclinical findings also suggest that CLDN18.2 blockade may modulate the tumor immune microenvironment—enhancing CD8⁺ T‑cell infiltration and improving antitumor activity when combined with PD‑1 inhibition.² These provide a strong rationale for ILUSTRO, the first prospective trial designed to evaluate the combination of zolbetuximab with chemotherapy and PD-1 blockade in 1L dual-positive patients, providing the first clinical insights in this population.³

The ILUSTRO phase 2 trial: Evaluating zolbetuximab triplet therapy in the frontline

The multicohort phase 2 ILUSTRO trial was designed to evaluate zolbetuximab as monotherapy or in combination with chemotherapy and/or PD-1 inhibition in patients with CLDN18.2-positive advanced G/GEJ adenocarcinoma.^3,5 The trial includes several cohorts exploring different treatment strategies, with cohort 4 specifically assessing zolbetuximab in combination with mFOLFOX6 + nivolumab in the 1L setting.^2,3,5 According to Dr. Shitara, this represents the first dataset evaluating a triplet regimen of zolbetuximab, PD-1 inhibition, and chemotherapy specifically in dual-positive patients (CLDN18.2-positive and PD-L1 combined positive score [CPS] ≥1).

Cohort 4 enrolled patients with previously untreated, HER2-negative, locally advanced unresectable or metastatic G/GEJ adenocarcinoma whose tumors demonstrated CLDN18.2 positivity by central immunohistochemistry.^2,3 Other key eligibility criteria also included an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.^2,3 Cohort 4 comprised a safety lead-in phase (cohort 4A) followed by a main efficacy cohort (cohort 4B).^2,3 Cohort 4A evaluated the tolerability of zolbetuximab dosing in combination with nivolumab + mFOLFOX6, while cohort 4B was designed to further assess efficacy and safety, with a planned enrichment of patients with high CLDN18.2 expression (defined as ≥75% of tumor cells with moderate-to-strong membranous staining) (figure 1).³

Encouraging efficacy signals in cohort 4B

Efficacy analyses from cohort 4B focused primarily on progression-free survival (PFS), with additional evaluation of objective response rate (ORR), duration of response, and OS.³ At the time of data cutoff, the median follow-up was 11.5 months (95% CI: 10.9-15.6), with PFS assessed by investigators per RECIST v1.1.³ A total of 12 patients were enrolled in cohort 4A and 71 patients in cohort 4B.³ Across both cohorts (n=77), the median age was 61.0 years (range: 37.0-86.0), 62.3% were male, and 79.1% were of Asian ethnicity.³ Most patients had PD-L1-positive disease (CPS ≥1; 65.3%), and high CLDN18.2 expression (85.5%).³ The majority of tumors were diffuse type (70.7%), followed by intestinal (13.3%), mixed (4.0%), and other subtypes (12.0%).³

In cohort 4B, treatment with zolbetuximab + mFOLFOX6 + nivolumab resulted in a median PFS of 14.8 months (95% CI: 8.3-non estimable [NE]).³ The 6-month and 12-month PFS rates were 72.6% and 59.1%, respectively.³ Stratification by CLDN18.2 expression revealed a more pronounced benefit in patients with high CLDN18.2 expression.³ In this subgroup, median PFS was 18.0 months (95% CI: 11.1-NE), compared with 6.7 months (95% CI: 3.0-NE) in patients with intermediate expression.³ Further biomarker enrichment was observed when PD-L1 status was considered.³ Among patients with high CLDN18.2 expression and a PD-L1 CPS ≥1, median PFS was 23.6 months, compared with 12.1 months in those with PD-L1 CPS <1 (figure 2).³ These findings suggest a gradient of benefit associated with increasing biomarker enrichment, although formal comparisons were not powered in this single-arm phase 2 cohort.^2,3 “The PFS signal appears strongest in patients with both high CLDN18.2 expression and PD-L1 positivity,” Dr. Shitara noted, emphasizing the importance of biomarker context when interpreting these results.

Tumor responses further supported the observed PFS benefit.³ In patients with measurable disease in cohort 4B, ORR was 62.1% (95% CI: 48.4-74.5) overall and 68.1% (95% CI: 52.9-80.9) in the high CLDN18.2 subgroup.³ Waterfall plot analyses demonstrated tumor shrinkage in a substantial proportion of patients, with many achieving at least a partial response (figure 3).³ Duration-of-response analyses indicated that many responses were durable beyond initial assessment, with a median of 19.1 months (95% CI: 10.8-NE), aligning with the favorable PFS outcomes.³ While OS data remained immature at the time of analysis, early trends appeared favorable in patients with high CLDN18.2 expression.³ However, no median OS had yet been reached, and longer follow-up is required before drawing conclusions on the survival benefit.³

Safety, tolerability, and the path forward for zolbetuximab-based combinations

In addition to efficacy, ILUSTRO cohort 4 provided important insights into the safety and tolerability of zolbetuximab triplet therapy in the frontline setting.³ Safety analyses included patients from both cohort 4A and cohort 4B who received zolbetuximab at a dose of 800mg/m² on cycle 1 day 1 followed by 400mg/m² in subsequent cycles, in combination with nivolumab + mFOLFOX6.³ The median duration of treatment was 288.5 days (range: 1-1,271) for zolbetuximab and 226.0 days (range: 1-872) for nivolumab.³ Mean relative dose intensity was high for both agents, at 97.1% for zolbetuximab and 97.0% for nivolumab, reflecting that patients were able to receive nearly all planned doses.³

The overall safety profile of the triplet regimen was manageable, with no unexpected safety signals observed.³ Treatment-emergent adverse events (TEAEs) led to discontinuation of any study drug in 49.4% of patients, while discontinuation of zolbetuximab occurred in 5.2%.³ TEAEs were consistent with the known safety profiles of zolbetuximab or nivolumab + mFOLFOX6.³ Nausea (80.5%) and vomiting (37.7%), common concerns with zolbetuximab, were mostly low grade, with Grade 3 events reported in 0% and 3.9%, respectively.^3,5,12 Other frequently observed TEAEs included decreased appetite (72.7%) and decreased neutrophil count (45.5%).³ “From a tolerability standpoint, the triplet regimen was feasible, with safety findings consistent with prior experience,” Dr. Shitara commented.

Guideline alignment and phase 3 clinical trial pipeline

Taken together, the efficacy and safety findings from ILUSTRO cohort 4B provide a strong rationale for further investigation in a larger, randomized setting.^2,3 These phase 2 data have directly informed the design of the ongoing phase 3 LUCERNA trial (NCT06901531), which is evaluating zolbetuximab in combination with pembrolizumab and chemotherapy as 1L treatment for patients with CLDN18.2-positive, HER2-negative, PD-L1-positive locally advanced unresectable or metastatic G/GEJ adenocarcinoma.^2,3 The LUCERNA study will assess whether the promising signals observed in ILUSTRO translate into meaningful clinical benefit in a larger, globally representative population.^2,3

This biomarker-enriched trial approach reflects the broader shift toward precision medicine in advanced G/GEJ cancers, consistent with current ESMO and NCCN guidance emphasizing comprehensive biomarker profiling to inform treatment selection.^9,10 As Dr. Lin emphasized, this reality underscores the importance of delivering the most effective, biologically informed therapy upfront, when patients are most likely to derive meaningful benefit.² In this context, CLDN18.2 represents a biologically defined and clinically relevant biomarker that may further refine patient selection for targeted and immunotherapy-based combination strategies.^4,9

Conclusion

Emerging data from the phase 2 ILUSTRO trial highlight the potential of zolbetuximab-based triplet therapy as a biomarker-driven first-line strategy for patients with CLDN18.2-positive advanced G/GEJ cancer.³ In cohort 4B, zolbetuximab combined with mFOLFOX6 + nivolumab demonstrated encouraging PFS and response rates, particularly in patients with high CLDN18.2 expression and PD-L1 positivity, while maintaining a manageable safety profile.³ Although these findings remain exploratory, they underscore the importance of precision approaches in the frontline setting, where therapeutic impact may be greatest.^1,2 Ongoing phase 3 evaluation in the LUCERNA trial will be critical to determining the role of zolbetuximab triplet therapy in the evolving treatment paradigm for advanced G/GEJ cancer.^2,3