An unmet need remains for additional treatment options for patients with HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors are both CLDN18.2-positive and PD-L1-positive.
These patients may be eligible for either zolbetuximab plus chemotherapy or an anti-PD-1 antibody plus chemotherapy. However, the absence of direct clinical trial comparisons makes it unclear how these treatment approaches should be prioritized.
The randomized phase 3 LUCERNA trial will evaluate the potential clinical benefit of adding zolbetuximab, an anti-CLDN18.2 antibody, to pembrolizumab and chemotherapy in patients with HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors are both CLDN18.2-positive and PD-L1-positive.
The trial-in-progress article, titled “Zolbetuximab Plus Pembrolizumab and Chemotherapy in CLDN18.2-positive, HER2-negative, PD-L1-positive Gastric or Gastroesophageal Junction Adenocarcinoma: Randomized, Double-blind, Phase III LUCERNA Trial,” appears in the September 2026 issue of ESMO Gastrointestinal Oncology.
Authors: K. Shitara, P. Enzinger, F. Lordick, E. Smyth, S.Y. Rha, E. Van Cutsem, R.-H. Xu, J.H. Strickler, P. Lee, and S.J. Klempner.
Why Combine Zolbetuximab and Pembrolizumab?
Previous phase 3 trials demonstrated progression-free and overall survival benefits when zolbetuximab was added to first-line chemotherapy in patients with HER2-negative, CLDN18.2-positive, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma.
Separately, adding pembrolizumab to first-line chemotherapy improved survival in patients with HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma whose tumors had a PD-L1 combined positive score of at least 1.
Patients whose tumors express both CLDN18.2 and PD-L1 may therefore qualify for either treatment strategy. However, the absence of direct clinical trial comparisons has created uncertainty regarding how these approaches should be prioritized.
The rationale for LUCERNA is based on the potentially complementary immune mechanisms of zolbetuximab and pembrolizumab.
Zolbetuximab is an antibody targeting CLDN18.2. Its antitumor activity involves innate immune mechanisms, including antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Pembrolizumab blocks PD-1 and is intended to enhance adaptive antitumor immune responses mediated by T cells.
Preclinical research in a CLDN18.2-positive mouse model showed greater tumor-growth inhibition with zolbetuximab, chemotherapy, and PD-1 blockade than with any of the evaluated two-treatment combinations.
Tumor samples from patients treated with zolbetuximab alone or with mFOLFOX6 also demonstrated immune remodeling, including increased infiltration by CD8-positive T cells and CD163-positive macrophages.
Clinical support for the combination came from the phase 2 ILUSTRO trial. In patients with HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma with moderate-to-strong CLDN18 staining in at least 75% of tumor cells, zolbetuximab combined with chemotherapy and checkpoint inhibitor therapy produced a median progression-free survival of 18.0 months. The 95% confidence interval ranged from 11.1 months to not estimable.
These findings provided the basis for evaluating the strategy in a randomized phase 3 trial.
Study Design
LUCERNA is a multicenter, randomized, double-blind, placebo-controlled phase 3 trial with a planned enrollment of approximately 500 patients.
Participants will be randomly assigned in a 1:1 ratio to receive:
- Zolbetuximab plus pembrolizumab and chemotherapy
- Placebo plus pembrolizumab and chemotherapy
The chemotherapy backbone will consist of either capecitabine and oxaliplatin, known as CAPOX, or modified folinic acid, fluorouracil, and oxaliplatin, known as mFOLFOX6. The regimen will be selected by the treating investigator.
The zolbetuximab or placebo and pembrolizumab schedules will be aligned with the selected chemotherapy regimen. Pembrolizumab may continue for up to 24 months, while zolbetuximab or placebo will continue until disease progression, toxicity, or another protocol-defined discontinuation criterion is met. Patients may receive up to eight CAPOX treatments, followed by capecitabine at the investigator’s discretion, or up to 12 mFOLFOX6 treatments, followed by folinic acid and fluorouracil.
Because zolbetuximab is considered highly emetogenic, prophylactic antiemetic treatment is recommended, but not required, before each zolbetuximab or placebo administration. Randomization will be stratified by geographic region, categorized as Asia or non-Asia, and PD-L1 expression, categorized as a combined positive score of 1 to less than 10 or at least 10.
The trial is registered on ClinicalTrials.gov as NCT06901531.
Patient Population
Eligible participants must be aged 18 years or older and have histologically confirmed gastric or gastroesophageal junction adenocarcinoma with radiologically confirmed locally advanced unresectable or metastatic disease.
Patients must have an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ function, and tumors meeting all three biomarker requirements:
- HER2-negative
- CLDN18.2-positive
- PD-L1-positive
HER2-negative disease is defined as an immunohistochemistry score of 0 or 1+, or a score of 2+ with negative in situ hybridization testing.
CLDN18.2 positivity is defined as moderate-to-strong membranous CLDN18 staining in at least 75% of tumor cells using the VENTANA CLDN18 43-14A RxDx Assay.
PD-L1 positivity is defined as a combined positive score of at least 1 using the PD-L1 IHC 22C3 pharmDx assay.
Patients with known microsatellite instability-high or mismatch repair-deficient tumors are excluded. Previous treatment with a CLDN18.2-targeted agent is also not permitted.
Patients must generally be untreated for locally advanced unresectable or metastatic disease. However, a maximum of one treatment course of CAPOX or mFOLFOX6, with or without pembrolizumab, is permitted before randomization.
Previous neoadjuvant or adjuvant systemic therapy is allowed when completed at least six months before randomization.
Study Endpoints
The primary endpoint is overall survival, defined as the time from randomization to death from any cause.
The key secondary endpoints are:
- Progression-free survival according to RECIST version 1.1 by investigator assessment
- Objective response rate according to RECIST version 1.1 by investigator assessment
Additional secondary endpoints include duration of response, safety, pharmacokinetics, and immunogenicity.
Exploratory endpoints include health-related quality of life, progression-free survival after subsequent anticancer treatment, and biomarker expression associated with clinical outcomes.
Radiologic evaluations will be performed every nine weeks during the first 54 weeks of treatment and every 12 weeks thereafter until disease progression. Imaging will be evaluated by investigators and will also undergo central review.
The study will also collect blood, serum, and plasma samples for exploratory biomarker analyses. Potential assessments include circulating tumor DNA, cytokines, chemokines, lymphocyte subsets, genetic markers, and activation of antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.
Statistical Design
The endpoints will be tested hierarchically in the following order:
- Overall survival
- Progression-free survival
- Objective response rate
Testing will stop if statistical significance is not established for an earlier endpoint in the hierarchy.
The study aims to enroll approximately 500 patients. A total of 253 overall survival events will provide 80% power to detect a difference between the treatment groups.
The sample-size calculation assumes a median overall survival of 18.6 months with zolbetuximab plus pembrolizumab and chemotherapy and 13.0 months with placebo plus pembrolizumab and chemotherapy, corresponding to a hazard ratio of 0.70.
These values are statistical assumptions used to design the study and should not be interpreted as clinical results.
A futility analysis is planned after 84 overall survival events. An interim efficacy analysis is planned after at least 190 events, with the final overall survival analysis scheduled after at least 253 events if the study continues.
Potential Significance of LUCERNA
LUCERNA is the first trial to evaluate the efficacy and safety of adding zolbetuximab to pembrolizumab and chemotherapy in patients with HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors are CLDN18.2-positive and PD-L1-positive.
The trial will evaluate the potential clinical benefit of adding zolbetuximab to pembrolizumab and chemotherapy as first-line treatment for this patient population. The results of the trial have the potential to support a new standard-of-care option for this patient population.
The study is supported by Astellas Pharma.
The full article is available in ESMO Gastrointestinal Oncology.
Read more about Top 10 Gastroesophageal Cancer Updates – March 2026 on OncoDaily.