A phase 1 trial of claudin 18.2-specific antibody-drug conjugate CMG901 in patients with advanced gastric/gastroesophageal junction cancer.

434420 Background: Claudin 18.2 (CLDN18.2) is a promising therapeutic target for advanced gastric/gastroesophageal junction (G/GEJ) cancer. CMG901, a potential first-in-class CLDN18.2-targeted antibody-drug conjugate carrying monomethyl auristatin E (MMAE), has demonstrated potent anti-tumor activity in preclinical studies. Methods: This phase 1 trial included a dose-escalation phase (part A; 0.3-3.4 mg/kg) and a dose-expansion phase (part B; 2.2, 2.6, and 3.0 mg/kg) to evaluate safety, tolerability, and anti-tumor activity of CMG901 in patients (pts) with advanced G/GEJ cancer and other solid tumors. CLDN18.2 expression was not required for study entry in part A, but CLDN18.2 expression of ≥2+ membrane staining intensity in ≥5% tumor cells was required for G/GEJ cancer in part B. CMG901 was administrated intravenously every 3 weeks until disease progression or unacceptable toxicity. Primary endpoints were safety/tolerability and maximum tolerated dose (MTD) for part A, and objective response rate (ORR, per RECIST v1.1) and recommended phase 2 dose in part B. Here we present the G/GEJ cancer data from this ongoing trial. Results: MTD was not reached during dose escalation. As of July 24, 2023, 113 G/GEJ cancer pts received CMG901 at doses of 2.2-3.0 mg/kg (6 pts from part A and 107 pts from part B). The median prior lines of systemic therapy were 2 (range 1-6). Most common TEAEs were anaemia (62.8%), vomiting (57.5%), and hypoalbuminaemia (57.5%). Neutrophil count decreased (18.6%) and anaemia (13.3%) were the most frequent grade ≥3 TEAEs. Of 89 evaluable (≥1 post-treatment scan) CLDN18.2-positive pts, confirmed ORR was 32.6% (Table). For all 93 CLDN18.2-positive pts, the median progression-free survival was 4.76 months (95%CI 3.35-6.14) after a median follow-up of 5.98 months. The median overall survival (OS) was not reached, with an OS rate of 56.4% at 9 months. Conclusions: CMG901 demonstrated promising clinical efficacy in CLDN18.2-positive G/GEJ cancer pts, with a manageable safety profile. These results support further evaluation of CMG901 in CLDN18.2-positive G/GEJ cancer. Clinical trial information: NCT04805307 .[Table: see text]