Claudin18.2 (CLDN18.2) expression and efficacy in pancreatic ductal adenocarcinoma (PDAC): Results from a phase I dose expansion cohort evaluating IBI343.

4017 Background: CLDN18.2 is highly expressed in nearly 60% of PDAC cases. Yet to date, there are no approved targeted therapies and prognoses for these patients (pts) remain poor. IBI343, consisting of an anti-CLDN18.2 Fc silenced monoclonal antibody and the topoisomerase I inhibitor, exatecan, is the first CLDN18.2 antibody-drug conjugate to have shown encouraging efficacy in PDAC. Here, we report results from a phase 1 study (NCT05458219) in pts with PDAC treated with IBI343 by CLDN18.2 expression status (≥60% vs < 60%). Methods: Eligible pts with advanced PDAC and moderate to high expression of CLDN18.2 (defined as immunohistochemistry [IHC] membrane staining intensity ≥2 in ≥40% of tumor cells by IHC VENTANA CLDN18 [43-14A] Assay) who failed or were intolerant to standard treatment were enrolled. IBI343 was administered every 3 weeks at multiple dose levels (1, 3, 4.5, 6, 8, and 10 mg/kg). Endpoints included safety, objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) per RECIST v1.1, and overall survival (OS). Results: As of December 27, 2024, 83 pts from China and Australia were enrolled. 44 and 12 pts with CLDN18.2 expression ≥1 in ≥60% (+) and < 60% (-) of tumor cells, respectively, received IBI343 at 6mg/kg in the dose expansion phase (median age, 60 and 64 years; male, 54.5% and 66.7%; received prior treatments ≥2L, 61.4% and 83.3%). Among all treated pts (n = 83), treatment-emergent adverse events (TEAEs) occurred in 82 (98.8%) pts and ≥Grade 3 (G3) TEAEs in 42 (50.6%) pts. TEAEs led to treatment discontinuation in 6 (7.2%) pts. No TEAE led to death. Most common TEAEs were anemia (66.3%, 15.7% ≥G3), neutrophil count decreased (48.2%, 9.6% ≥G3), and WBC count decreased (47.0%, 9.6% ≥G3). The safety profile of IBI343 in PDAC was comparable to previous reports. Among CLDN18.2+ pts (n = 44), confirmed ORR was 22.7% (95% CI, 11.5–37.8); DCR was 81.8% (95% CI: 67.3–91.8), median PFS was 5.4 (95% CI, 4.1–7.4) months (mos), median OS was 8.5 (95% CI, 6.6–12.1) mos, and in 10 pts with confirmed partial response median DOR was 6.7 (95% CI, 3.2–7.7) mos. Among CLDN18.2+ pts who received 1 and 2 lines of prior treatment, median OS was 12.1 (95% CI, 6.6–not calculable [NC]) mos and 9.1 (95% CI, 5.1–NC) mos, respectively. Among CLDN18.2- pts (n = 12), no pt had an objective response, DCR was 41.7% (95% CI: 15.2–72.3), median PFS was 1.4 (1.3–3.2) mos, which was shorter than what was seen in CLDN18.2+ pts (Ad hoc analysis: nominal P < .0001; HR = 0.198 [95% CI: 0.089-0.439]) and median OS was 6.2 (95% CI,1.4–9.0) mos. Conclusions: IBI343 was well tolerated and continues to show encouraging efficacy in pts with PDAC. Efficacy benefit was most pronounced in those with CLDN18.2 expression ≥60%, suggesting that CLDN18.2 can be a predictive biomarker for response to IBI343 in PDAC. The trial is enrolling in Australia, China, and US. Clinical trial information: NCT05458219 .