Claudin 18.2 Positivity Thresholds and Candidate Populations for Targeted Therapy in Pancreatic Ductal Adenocarcinoma: A Real-World Retrospective Cohort.

BACKGROUND/

OBJECTIVES

Claudin 18.2 (CLDN18.2) is expressed in a substantial proportion of pancreatic ductal adenocarcinoma (PDAC) and has emerged as a promising therapeutic target. However, the positivity threshold for enrollment in CLDN18.2-directed trials remains undefined, and ongoing studies use different criteria. We quantified how different CLDN18.2 thresholds influence the size of the candidate population within the same PDAC cohort.

METHODS

In this retrospective single-center study, CLDN18.2 was assessed by immunohistochemistry (43-14A clone, Ventana BenchMark) in 99 PDAC patients (metastatic, n = 71; non-metastatic, n = 28). The candidate population was evaluated at three thresholds: two used in current CLDN18.2 trials (any-intensity [1+/2+/3+] staining in ≥40% and moderate-to-strong [2+/3+] staining in ≥75% of tumor cells) and an exploratory lower bound of any detectable expression (≥5%). Between-threshold reclassification was analyzed as paired data; clinicopathological and survival analyses were exploratory.

RESULTS

The candidate proportion was 40.4% (40/99) at ≥75%, 43.4% (43/99) at ≥40%, and 64.6% (64/99) at ≥5%; among metastatic patients, it was 36.6%, 38.0%, and 59.2%, respectively. Lowering the threshold from ≥75% to ≥40% caused virtually no reclassification (1/71 metastatic, 1.4%; McNemar p = 1.0), whereas lowering it to ≥5% reclassified 16 metastatic patients (22.5%; 95% CI, 14.4-33.5; p < 0.001) as candidates. Among the 64 tumors with detectable expression, median staining was 80% (IQR, 20-90%). Survival analyses were exploratory and underpowered (52 deaths; 80% power for HR ≥ 2.24); no association between CLDN18.2 and overall or progression-free survival was detected at any threshold.

CONCLUSIONS

The stringent thresholds used in current drug development identified nearly identical candidate populations, whereas relaxation to any detectable expression substantially enlarged the pool; CLDN18.2 behaved as a targetable rather than a prognostic biomarker. Our findings highlight the need for a PDAC-specific, response-based CLDN18.2 threshold.