First-in-human dose escalation and expansion study of SYSA1801, an antibody-drug conjugate targeting claudin 18.2 in patients with resistant/refractory solid tumors.
Authors: Wang Yakun , Gong Jifang , Lin Rongbo , Zhao Shen , Wang Jufeng , Wang Qianli , Zhang Yanqiao , Su Dan , Zhang Jingdong , Dong Qian , Lin Ling , Tian Wen , Chen Ying , Yang Yang , Zhang Xueyuan , Wan Xuechao , Gao Jinfeng , An Na , Jansen Valerie Malyvanh , Shen Lin 
Published: June 2023

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Background: SYSA1801 is a MMAE antibody-drug conjugate (ADC) targeting claudin 18.2 (CLDN18.2), a tight junction protein broadly expressed in gastric, pancreatic, and other solid tumors. CLDN18.2 has a highly selective cell surface expression profile that is limited to normal gastric mucosa, making it a promising ADC therapeutic target. SYSA1801 has shown significant in vitro and in vivo anti-tumor activity in multiple cell lines and patient-derived xenografts expressing CLDN18.2. Methods: This is an open-label, multi-center, phase I study to evaluate the safety, tolerability, pharmacokinetics and efficacy of SYSA1801 in patients (pts) with histologically confirmed resistant/refractory solid tumors that express CLDN18.2 who progressed on or were intolerant to standard treatment, or had no standard treatment. This study consists of two parts; part 1 is a modified 3+3 dose-escalation design with five dose levels of SYSA1801 (0.5, 1, 2, 2.5 and 3 mg/kg) administered intravenously (IV) every 3 weeks (Q3W), followed by dose expansion at effective doses. Part 2 is a cohort expansion at the optimal dose. Here, we present the preliminary results of SYSA1801 for part 1. Results: As of Nov 5, 2022, 33 pts with a median age of 59 yrs (range 22-71) were enrolled to receive up to SYSA1801 3 mg/kg in part 1. 26 pts (78.8%) had gastric cancer (GC) and 7 pts (21.2%) had pancreatic cancer. ECOG PS was 0 in 5 pts (15.2%) and 1 in 28 pts (84.8%). 11 pts (33.3%) had been heavily pretreated (≥3 prior lines). Treatment-related adverse events (TRAEs) of any grade occurred in 25 pts (75.8%), in which 8 (24.2%) were ≥ grade 3. No treatment related death was reported. The most common TRAEs (occurring in >20% of pts) were nausea (42.4%), vomiting (36.4%), dry eye syndrome (21.2%) and anemia (21.2%). Two DLTs (grade-3 nausea and vomiting) occurred at the 3 mg/kg dose. The optimal dose of SYSA1801 is being explored. Of 33 pts enrolled, 21 pts were evaluable for efficacy per RECIST v1.1. Objective response rate (ORR) was 38.1% (95% CI: 18.1-61.6%, 8 PRs) and disease control rate (DCR) was 57.1% (95% CI: 34.0-78.2%, 4 SDs). Among 17 evaluable pts with GC, ORR and DCR were 47.1% (95% CI: 23.0-72.2%, 8 PRs) and 64.7% (95% CI: 38.3-85.8%, 3 SDs). One pt with GC receiving SYSA1801 at 1 mg/kg IV Q3W tolerated treatment for 44 weeks with durable confirmed partial response ongoing at the time of analysis. Another pt with GC who failed previous anti-CLDN18.2 treatment achieved a confirmed PR on SYSA1801 2 mg/kg IV Q3W. Conclusions: SYSA1801 shows promising early signs of efficacy with a well-tolerated safety profile in pts with CLDN18.2-expressing resistant/refractory solid tumors, especially GC. Part 1 of the study is ongoing with part 2 to start when the optimized dose is determined in China; studies outside of Greater China including in the United States are being planned by Elevation Oncology. Clinical trial information: NCT05009966 .