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Analytical and Clinical Performance of the VENTANA CLDN18 (43-14A) RxDx Assay in Gastric and Gastroesophageal
Steven P Stratton1, Lizhen Pang1, Judith Pugh1
1Roche Diagnostics Solutions, Tucson, Arizona.
Abstract:
New therapies are needed to treat patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. Zolbetuximab is a monoclonal antibody that targets the tight junction protein claudin 18 isoform 2 (CLDN18.2) in gastric or gastroesophageal junction (G/GEJ) adenocarcinoma cells. We describe the analytical and clinical performance of the VENTANA CLDN18 (43-14A) RxDx Assay (Roche Diagnostics Solutions) as a companion diagnostic immunohistochemistry assay for treatment with zolbetuximab. Analytical performance was assessed in commercially available G/GEJ adenocarcinoma samples. Clinical performance was assessed in the context of 2 phase 3 trials (SPOTLIGHT, NCT03504397; GLOW, NCT03653507) of first-line zolbetuximab plus chemotherapy in patients with HER2-negative, LA unresectable or mG/GEJ adenocarcinoma, whose tumors were CLDN18.2 positive (≥75% of viable tumor cells demonstrating moderate-to-strong membrane CLDN18 staining). Staining acceptability rates were assessed in patients whose tumors were tested for CLDN18.2 status using the VENTANA CLDN18 (43-14A) RxDx Assay and who met enrollment eligibility criteria not related to CLDN18.2 status. Progression-free survival and overall survival were evaluated in the enrolled patients. Analytical performance: positive and negative percent agreement compared with immunohistochemistry reference scoring was 100% for between-antibody, between-detection kit, between-instrument, between-day, and within-run precision studies. Interlaboratory reproducibility exceeded 90% average positive and negative agreement between sites and 94% average positive and negative agreement between readers across 3 sites. Clinical performance: among 3783 patient tumor samples, staining acceptability rates exceeded 94%. Patients identified for eligibility using the VENTANA CLDN18 (43-14A) RxDx Assay demonstrated statistically significant improvement in progression-free survival and overall survival with zolbetuximab plus chemotherapy in both phase 3 trials. The VENTANA CLDN18 (43-14A) RxDx Assay demonstrated robust, reproducible analytical performance and clinical utility as a companion diagnostic for first-line zolbetuximab plus chemotherapy in patients with HER2-negative, LA unresectable or mG/GEJ adenocarcinoma, whose tumors were CLDN18.2 positive.
Insights
A new diagnostic assay accurately identifies claudin 18.2 (CLDN18.2) positive tumors in patients with advanced gastric cancer. This assay supports the use of zolbetuximab plus chemotherapy, improving progression-free and overall survival.
Area of Science:
- Oncology
- Immunohistochemistry
- Molecular Diagnostics
Background:
- Gastric and gastroesophageal junction (G/GEJ) adenocarcinoma, particularly HER2-negative, locally advanced or metastatic types, requires novel therapeutic strategies.
- Zolbetuximab, a monoclonal antibody targeting claudin 18.2 (CLDN18.2), shows promise for these patients.
- A reliable companion diagnostic assay is crucial for identifying patients eligible for zolbetuximab treatment.
Purpose of the Study:
- To evaluate the analytical and clinical performance of the VENTANA CLDN18 (43-14A) RxDx Assay.
- To confirm the assay's utility as a companion diagnostic for zolbetuximab in HER2-negative, advanced G/GEJ adenocarcinoma.
- To assess the impact of CLDN18.2 positivity on treatment outcomes in clinical trials.
Main Methods:
- Analytical validation included precision and reproducibility studies across various conditions.
- Clinical performance was assessed in two Phase 3 trials (SPOTLIGHT and GLOW).
- The VENTANA CLDN18 (43-14A) RxDx Assay was used to identify patients with CLDN18.2-positive tumors (≥75% moderate-to-strong membrane staining).
Main Results:
- The assay demonstrated excellent analytical performance with 100% agreement in precision studies and >90% interlaboratory reproducibility.
- Staining acceptability rates exceeded 94% across 3783 patient tumor samples.
- Patients with CLDN18.2-positive tumors receiving zolbetuximab plus chemotherapy showed statistically significant improvements in progression-free survival and overall survival.
Conclusions:
- The VENTANA CLDN18 (43-14A) RxDx Assay exhibits robust and reproducible analytical performance.
- The assay has demonstrated clinical utility in identifying patients who benefit from first-line zolbetuximab plus chemotherapy.
- This companion diagnostic is essential for the effective use of zolbetuximab in treating HER2-negative, advanced G/GEJ adenocarcinoma.
