A global phase 1/2a trial of SHR-A1904, a CLDN18.2-targeting ADC, in advanced solid tumors expressing CLDN18.2.

Abstract

e15018 Background: SHR-A1904, a novel CLDN18.2 targeted ADC, showed promising antitumor activity in pretreated CLDN18.2-positive gastric/gastroesophageal junction cancer (GC/GEJC) in a China-only phase 1 trial (Nat Med. 2025; NCT04877717). Here, we report a 2-part multicenter global study assessing SHR-A1904 in patients (pts) with CLDN18.2-expressing advanced solid tumors (NCT05277168). Methods: During dose escalation (DE), pts with CLDN18.2-expressing (H score ≥1 by central lab IHC) advanced relapsed or refractory (R/R) solid tumors were enrolled to receive SHR-A1904 at 0.6–6.0 mg/kg (Q3W IV) in an i3+3 design. During dose optimization (DO), pts with CLDN18.2-positive (≥50% of cells with 2+ or 3+ staining) advanced R/R GC/GEJC were enrolled to receive SHR-A1904 at 6.0 and 8.0 mg/kg. The primary endpoints were DLT and safety in DE, and efficacy and safety in DO. Exploratory subgroup analyses in Asians vs non-Asians were done at 3.6 mg/kg (the minimal effective dose) or higher. Results: As of Dec 1, 2025, 51 pts were enrolled from Australia, South Korea, the United States, and Moldova, including 41 with GC/GEJC, 9 with pancreatic cancer, and 1 with lung adenocarcinoma. 42 pts received SHR-A1904 at 3.6 mg/kg or higher, 24 of whom were Asian. All pts had prior therapy (≥2 lines, 72.5%). The median follow-up was 6.7 mo (range, 0.2–27.9). During DE, 1 DLT (grade 3 vomiting) occurred at 6.0 mg/kg. Among all pts, TRAEs were reported in 48 (94.1%) pts; the most common were nausea (66.7%), vomiting (52.9%), and fatigue (23.5%). Grade ≥3 TRAEs and serious TRAEs occurred in 21 (41.2%) and 9 (17.6%) pts. No TRAEs led to death. In Asians, TRAEs and Grade ≥3 TRAEs occurred in 22 (91.7%) pts and 11 (45.8%) pts; in non-Asians, TRAEs and Grade ≥3 TRAEs occurred in 17 (94.4%) pts and 9 (50.0%) pts. Overall, ORR, DCR, and CBR (CR + PR + SD ≥24 weeks) were 25.5%, 58.8%, and 33.3%, respectively. The median PFS, OS, and DoR were 2.8 mo (95% CI, 1.7–5.4), 9.8 mo (95% CI, 6.7–15.2), and 5.7 mo (95% CI, 2.8–NR), respectively. Exploratory subgroup analyses by race are shown in Table. After a single dose, C max and AUC of SHR-A1904 increased with the dose except the 4.8 mg/kg group. The mean t 1/2 of SHR-A1904 is around 4.3–7.2 days. Conclusions: SHR-A1904 showed tolerable safety and promising antitumor activity in pretreated CLDN18.2-expressing advanced solid tumors. Furthermore, exploratory subgroup analyses by race support global development of SHR-A1904 in both Asians and non-Asians. Clinical trial information: NCT05277168 . Efficacy summary. Overall (N=51) Asians (N=24) # Non-Asians (N=18) # ORR 25.5 (13; 14.3–39.6) 20.8 (5; 7.1–42.2) 44.4 (8; 21.5–69.2) DCR 58.8 (30; 44.2–72.4) 66.7 (16; 44.7–84.4) 66.7 (12; 41.0–86.7) CBR 33.3 (17; 20.8–47.9) 20.8 (5; 7.1–42.2) 66.7 (12; 41.0–86.7) DoR, mo 5.7 (2.8–NR) 8.5 (2.9–NR) 5.7 (2.8–NR) PFS, mo 2.8 (1.7–5.4) 2.8 (1.5–5.4) 9.7 (1.9–NR) OS, mo 9.8 (6.7–15.2) 9.8 (5.2–NR) 15.2 (9.0–NR) Data are % (n; 95% CI) or median (95% CI). # at 3.6 mg/kg or higher.