Abstract A008: Intracranial metastases in patients with Claudin 18.2 positive metastatic gastroesophageal cancers

Abstract Background: Claudin 18.2 (CLDN 18.2) - a transmembrane protein integral for tight junction integrity – is overexpressed in a proportion of patients with metastatic gastroesophageal adenocarcinomas (mGEC). Incidence of intracranial metastases (ICM) in mGEC ranges from 0.7-6.6% and is variably associated with several biomarkers. Our clinical observation suggested increased prevalence of ICM in consecutive mGEC patients (pts) screened for clinical trials targeting CLDN 18.2 at our institution, we investigated the association between CLDN 18.2 positivity and ICM. Methods: Consecutive mGEC pts tested for CLDN 18.2 status between October 2021 and August 2023 were analyzed with institutional review board approval. CLDN 18.2 protein expression was quantified immunohistochemically and positive if expression of ≥2+ intensity in ≥75% tumor cells, we also sub-analyzed for any CLDN 18.2 IHC positivity. The primary outcome of time to ICM was analyzed using survival analysis methods. Survival time was calculated as the time from diagnosis to the event. Overall survival (OS) was analyzed via Kaplan-Meier curve of CLDN 18.2 positive and negative pts and compared by log-rank test. Results: Twenty-eight pts were analyzed -median age was 60 years, 24 (86%) were male, 26 (93%) were Caucasian, 2 (7%) were ERBB2 amplified, 5 (18%) were PD-L1 CPS >1, 20 (71%) expressed any amount of CLDN 18.2, and 12 (43%) demonstrated CLDN 18.2 expression of 2+/3+ in >75%. CLDN 18.2 positivity correlated with presence of peritoneal metastases (p= 0.023) but no other sites of metastases. The incidence of ICM in this cohort was 21%. Of the CLDN 18.2 positive patients, one patient each with ICM had genomics positive for APC, BRCA2, GATA4, mutation or amplification, three patients were TP53 mutated, and one was PD-L1 positive. One CLDN18.2 stringently negative but with 20% 3+ IHC positive tumor was ARID1, CDKN2A, MYC, TP53 mutated or amplified and PD-L1 positive, exhibiting brain metastasis one year after diagnosis of metastatic disease. The 5-year cumulative incidence of ICM in pts with CLDN 18.2 positive tumors (any positivity or by our criteria for positivity) was 27% (95% CI [12, 62]) as compared to 12.5% (95% CI [2, 78]) in pts with CLDN 18.2 negative tumors. Increasing CLDN 18.2 expression (continuous) was significantly associated with increased hazard of death (HR 1.91 CI [1.03, 3.54], p=0.04). Conclusions: CLDN 18.2 positivity was associated with peritoneal metastases and worse OS in pts with mGEC. ICM were delayed events, averaging 1-3 yrs after the diagnosis of mGEC in both CLDN 18.2 positive and negative pts. The numerically higher, not significant, cumulative 5-yr incidence of ICM in pts with CLDN 18.2 positive tumors should be interpreted with caution due to the limited sample size. To our knowledge, this is the first report of ICM associated with CLDN 18.2 positivity in pts with mGEC and merits exploration in larger cohorts to ascertain the need for proactive brain imaging in CLDN 18.2 positive mGEC pts. Citation Format: Kavanya Feustel, Lisa Rein, Alexandria Phan, Mandana Kamgar, Razelle Kurzrock, Aniko Szabo, Ben George. Intracranial metastases in patients with Claudin 18.2 positive metastatic gastroesophageal cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A008.