The global Phase III LUCERNA trial is evaluating zolbetuximab plus pembrolizumab and chemotherapy as first-line treatment for patients with CLDN18.2-positive, HER2-negative, PD-L1-positive advanced gastric and gastroesophageal junction cancer.
Written By: Anshu Gupta, PharmD
Reviewed By: Pharmacally Editorial Team
Patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma whose tumors express both CLDN18.2 and PD-L1 currently have two biomarker-directed first-line treatment options, but no evidence has established the optimal strategy. A newly launched global Phase III study, LUCERNA (NCT06901531), is investigating whether combining the anti-CLDN18.2 monoclonal antibody zolbetuximab with pembrolizumab and platinum-based chemotherapy can improve overall survival compared with pembrolizumab plus chemotherapy alone. The trial is sponsored by Astellas and follows encouraging efficacy observed in the Phase II ILUSTRO study (NCT03505320).
Scientific and Clinical Context
Gastric cancer remains one of the leading causes of cancer-related deaths worldwide, particularly in patients with unresectable or metastatic disease. Although immune checkpoint inhibitors and CLDN18.2-targeted therapy have independently improved outcomes, clinicians lack evidence on whether combining both approaches offers additional benefit.
Zolbetuximab targets claudin 18.2 (CLDN18.2), a tight junction protein highly expressed in many gastric cancers. The antibody kills tumor cells through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Pembrolizumab, an anti-PD-1 antibody, restores T-cell-mediated immune responses. Preclinical models and translational studies suggest these mechanisms may complement each other, potentially enhancing antitumor activity beyond either approach alone.
Phase III LUCERNA Trial Design
LUCERNA is a randomized, double-blind, multicenter Phase III trial enrolling approximately 500 patients with previously untreated, HER2-negative, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma whose tumors are CLDN18.2-positive and PD-L1-positive (combined positive score ≥1). Eligible patients must have an ECOG performance status of 0 or 1.
Participants are randomized 1:1 to receive either:
- Zolbetuximab plus pembrolizumab with CAPOX or mFOLFOX6 chemotherapy, or
- Placebo plus pembrolizumab with the same chemotherapy backbone.
The primary endpoint is overall survival, while key secondary endpoints include progression-free survival and objective response rate. Additional assessments include duration of response, safety, pharmacokinetics, immunogenicity, health-related quality of life, and exploratory biomarker analyses.
The statistical design assumes a median overall survival of 18.6 months in the zolbetuximab arm versus 13 months in the control arm, corresponding to a hazard ratio of 0.70. A total of 253 overall survival events will provide 80% statistical power for the primary analysis. Interim analyses for futility and efficacy are planned before the final analysis.
Evidence Supporting the Combination
The trial builds on results from the Phase II ILUSTRO study, which evaluated zolbetuximab with chemotherapy and checkpoint inhibition in patients with strongly CLDN18.2-positive tumors. That study reported a median progression-free survival of 18.0 months, supporting further evaluation of the triple combination in a larger randomized setting. Previous Phase III studies, including SPOTLIGHT and GLOW, also demonstrated survival benefits when zolbetuximab was added to chemotherapy in CLDN18.2-positive gastric cancer.
Executive Perspective
Investigators note that patients with tumors expressing both CLDN18.2 and PD-L1 are currently eligible for either CLDN18.2-targeted therapy or PD-1 inhibitor-based treatment, but no head-to-head evidence exists to guide treatment selection. LUCERNA addresses this clinical gap by testing whether simultaneous targeting of tumor-specific and immune pathways can further improve survival while maintaining an acceptable safety profile.
Path Forward
Enrollment is ongoing across international study sites, with efficacy and safety monitored by an independent data monitoring committee. If the study meets its primary endpoint, the combination of zolbetuximab, pembrolizumab, and chemotherapy could become a new first-line standard of care for patients with HER2-negative, CLDN18.2-positive, PD-L1-positive advanced gastric and GEJ adenocarcinoma.
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About the Writer
Anshu Gupta (LinkedIn) is a PharmD professional and healthcare writer with interests in clinical research, pharmacovigilance, regulatory affairs, and medical writing. She has presented research at academic conferences and completed certifications in Good Clinical Practice (GCP), ICH-GCP, and drug safety. Passionate about clinical trials and evidence-based medicine, she is committed to translating scientific evidence into accurate, reliable, and accessible healthcare content.