Zolbetuximab Plus mFOLFOX6 Shows Activity in CLDN18.2+ Gastric/GEJ Cancer

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Frontline treatment with zolbetuximab and chemotherapy has demonstrated efficacy in a phase 2 trial of patients with CLDN18.2-positive, advanced gastric or gastroesophageal junction (GEJ) cancer.

Researchers found that zolbetuximab plus folinic acid, fluorouracil, and oxaliplatin (mFOLFOX6) produced durable responses when used as first-line therapy.

However, zolbetuximab showed no activity when given as monotherapy or in combination with pembrolizumab in the third line or later.

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These results were published in Clinical Cancer Research.

This phase 2 trial (ClinicalTrials.gov Identifier: NCT03505320) included 54 patients with advanced gastric/GEJ cancer. The patients received zolbetuximab as monotherapy in the third line or later (n=30), zolbetuximab plus mFOLFOX6 as first-line treatment (n=21), or zolbetuximab plus pembrolizumab in the third line or later (n=3). High CLDN18.2 expression was present in all but 1 patient, who was in the pembrolizumab cohort.

In patients who received zolbetuximab plus mFOLFOX6, the objective response rate was 71.4%. All 15 responders had a partial response, and the median duration of response was 15.9 months. The disease control rate was 100%.

On the other hand, there were no responses in patients who received zolbetuximab monotherapy or in those who received zolbetuximab plus pembrolizumab.

In patients who received zolbetuximab plus mFOLFOX6, the median progression-free survival (PFS) was 17.8 months. The median PFS was 1.54 months in patients who received zolbetuximab monotherapy and 2.96 months in patients who received zolbetuximab plus pembrolizumab.

At the data cutoff, all patients in the zolbetuximab monotherapy and zolbetuximab-pembrolizumab cohorts had stopped study treatment. The same was true for 95.2% of patients who received zolbetuximab plus mFOLFOX6. The most common reason for discontinuation in all cohorts was progressive disease.

The rate of grade 3 or higher adverse events (AEs) was 95.2% among patients who received mFOLFOX6 plus zolbetuximab, 50% in the zolbetuximab monotherapy arm, and 33.3% in the zolbetuximab-pembrolizumab arm.

Among patients who received zolbetuximab plus mFOLFOX6, the most common grade 3 or higher AEs were decreased neutrophil count (33.3%), neutropenia (28.6%), hypertension (14.3%), and peripheral sensory neuropathy(14.3%).

“Zolbetuximab plus mFOLFOX6 demonstrated promising efficacy in previously untreated patients with CLDN18.2-positive [gastric]/GEJ adenocarcinoma,” the researchers concluded. “These data support the first-line development of zolbetuximab in patients whose tumors are CLDN18.2 positive.”

Earlier this year, researchers reported results from the phase 3 SPOTLIGHT trial, which suggested that adding zolbetuximab to first-line treatment with mFOLFOX6 can improve PFS and overall survival in patients with CLDN18.2-positive, HER2-negative, advanced gastric/GEJ cancer.

The US Food and Drug Administration recently granted priority review to zolbetuximab for this indication.

Disclosures: The phase 2 study was supported Astellas Pharma, Inc. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Klempner SJ, Lee K-W, Shitara K, et al. ILUSTRO: Phase 2 multicohort trial of zolbetuximab in patients with advanced or metastatic Claudin 18.2-positive gastric or gastroesophageal junction adenocarcinoma.Clin Cancer Res. Published online July 25, 2023. doi:10.1158/1078-0432.CCR-23-0204

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