TEST:

VENTANA CLDN18 (43-14A) Assay

Characterizing unresectable, metastatic, or recurrent GC with positive CLDN18.2 expression and evaluating intratumoral heterogeneity and prognostic implications of various therapeutics help advance treatment strategies and develop new therapies for patients with GC.

"Roche...announced today that the VENTANA CLDN18 (43-14A) RxDx Assay is the first U.S. Food and Drug Administration (FDA) approved immunohistochemistry (IHC) companion diagnostic for determining CLDN18 protein expression in tumours of patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma. These patients now may be eligible for treatment with Astellas' targeted therapy VYLOY (zolbetuximab)....VYLOY is the first FDA-approved treatment specifically targeting HER2-negative locally advanced unresectable or metastatic gastric or GEJ cancer patients whose tumours are CLDN18.2-positive."

"Roche...announced today that the VENTANA CLDN18 (43-14A) RxDx Assay is the first immunohistochemistry (IHC) companion diagnostic test to receive CE Mark approval for determining CLDN18 protein expression in tumours of patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma. These patients now may be eligible for treatment with Astellas’ targeted therapy VYLOY (zolbetuximab)...The new VENTANA CLDN18 (43-14A) RxDx Assay can help determine CLDN18.2 status and inform clinicians about the likelihood of patients benefiting from CLDN18.2 targeted therapy...The approval of the VENTANA CLDN18 (43-14A) RxDx Assay is based on the results of the SPOTLIGHT and GLOW clinical studies where it was used as the enrollment assay to identify patients whose tumours were CLDN18.2 positive."

This study provides a comprehensive evaluation of CLDN18.2 status and its correlation with the clinicopathologic characteristics of patients with stages II-IV GC in Korea and with crucial biomarkers. It may be valuable for guiding future drug development, expanding treatment options, and ultimately improving patient outcomes in GC.

CLDN18::ARHGAP fusions characterize GECs with distinct clinical and biologic features. Future studies will determine if these cancers can expand the pool of patients considered for CLDN18-targeted therapy.

We demonstrated a concordant analytical performance between the tested CLDN18/CLDN18.2 IHC assays in GC. Their implementation in the clinical setting might help identify patient candidates that could benefit from treatment with CLDN18.2 targeted therapies. Additional research is needed to confirm similar analytical performance between the three IHC assays in other indications.

CLDN18.2-targeted treatment with zolbetuximab in combination with chemotherapy has recently been assessed in two phase III studies of patients with HER2-negative, locally advanced, unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma...It also failed to meet the threshold for accuracy and sensitivity when used on either the Dako or the Leica platforms. These results demonstrate the reliability of IHC testing for CLDN18 expression in gastric tumor samples, when using commercially available platforms with an appropriate methodology and primary antibody selection.

The phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies demonstrated clinically meaningful and statistically significant improvement in progression-free and overall survival with first-line (1L) zolbetuximab (anti-CLDN18.2) + chemotherapy (mFOLFOX6 or CAPOX, respectively) vs placebo + chemotherapy in pts with CLDN18.2+/HER2− disease...Conclusions A high CLDN18.2 prevalence rate (36.4%) was observed in the Asia region which was similar to the global prevalence observed in both the SPOTLIGHT and GLOW phase 3 studies. These data support the relevance of CLDN18.2 as a biomarker in Asian pts with LA unresectable or mG/GEJ adenocarcinoma, for whom zolbetuximab + chemotherapy represents a potential 1L therapy.

Conclusion The VENTANA CLDN18 (43-14A) RxDx Assay met all analytical criteria for performance, demonstrating precision scoring of CLDN18 status in G/GEJ adenocarcinomas. The clinically significant improvements in PFS and OS in CLDN18.2-positive patients, identified by the VENTANA CLDN18 (43-14A) RxDx Assay, support the clinical utility of this assay as a companion diagnostic for reliably identifying patients who may benefit from first-line treatment with the CLDN18.2-targeted therapy zolbetuximab in combination with chemotherapy.

Background Zolbetuximab showed efficacy for gastric cancer with Claudin (CLDN)18.2 expression...Conclusions CLDN18.2 expression was observed in 38% of resected gastric cancer samples, which was consistent with previous reports. CLDN18.2 expression was not related to prognosis and specific relationship was not observed in clinical/molecular characteristics of resected gastric cancer.

The SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) phase 3 studies demonstrated clinically meaningful and statistically significant improvement in PFS and OS with the CLDN18.2-targeted antibody zolbetuximab + chemotherapy (mFOLFOX6 or CAPOX, respectively) vs placebo + chemotherapy as 1L therapy in pts with CLDN18.2+/HER2− disease... Across SPOTLIGHT and GLOW, 3576 pts had valid CLDN18 IHC results; 1399 (39.1%) had CLDN18.2+ tumors. CLDN18.2 prevalence was 43.7% (513/1175) in female pts and 36.9% (886/2401) in male pts. CLDN18.2 prevalence was 44.0% (671/1524) in pts in Europe/Middle East, 37.7% (183/485) in pts in N. America, and 36.5% (479/1314) in pts in Asia Pacific.