Abstract CT181: A first-in-human (FIH) phase 1 study of SHR-A1921, a TROP-2 targeted antibody-drug conjugate (ADC), in patients with advanced solid tumors

Abstract Background: SHR-A1921 is a novel ADC composed of a humanized anti-trophoblast cell-surface antigen 2 (TROP-2) IgG1 monoclonal antibody attached to a DNA topoisomerase I inhibitor via a tetrapeptide-based cleavable linker. Herein, we present the preliminary clinical results of the FIH study of SHR-A1921. Methods: This is a multi-center, open-label, phase 1 trial (Clinicaltrials.gov, NCT05154604) consisted of dose-escalation, dose-expansion and efficacy-expansion phases. Patients with advanced solid tumors who had failed standard therapy were enrolled. In the dose-escalation phase, SHR-A1921 was planned to be administered from 1.5 mg/kg to 12.0 mg/kg (Q3W, iv) in an i3+3 design, with accelerated titration used for the starting dose; in the dose-expansion phase, additional patients (up to 20-30 per dose level) were enrolled to 2-3 selected tolerable dose levels. The primary objectives were to evaluate the safety and tolerability of SHR-A1921 and to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose. Results: As of Oct 21. 2022, 38 enrolled patients were included for analysis: 18 enrolled during dose-escalation (1.5 mg/kg, n=1; 3.0 mg/kg, n=4; 4.0 mg/kg, n=8; 6.0 mg/kg, n=5) and 20 during dose-expansion (3.0 mg/kg). 71.1% (27/38) were driver gene-negative non-small cell lung cancer (NSCLC) patients who had previously received platinum-based chemotherapy and anti-PD-(L)1 antibody. 4 patients reported dose-limiting toxicities, with all being grade 3 stomatitis (6.0 mg/kg, n=3; 4.0 mg/kg, n=1). The MTD was established as 4.0 mg/kg. Across all dose cohorts, the most common treatment-related adverse events (TRAEs; ≥30%) were nausea (71.1%), stomatitis (65.8%), anemia (42.1%), vomiting, decreased appetite, decreased weight, and rash (36.8% each). Grade ≥3 TRAEs occurred in 12 patients (31.6%); of these, the most common was stomatitis (n=7, 18.4%), and all other events were reported in ≤2 patients. No patients discontinued study treatment due to TRAEs. As of cut-off date, 10 patients (NSCLC, n=5; triple-negative breast cancer, n=2; ampullary cancer, n=2; ovarian cancer, n=1) had partial response: 4 confirmed and 6 requiring further confirmation. The objective response rate was 33.3% (10/30; 95% CI 17.3-52.8) and disease control rate was 80.0% (24/30; 95% CI 61.4-92.3) in evaluable patients. Conclusion: SHR-A1921 showed a manageable safety profile and promising anti-tumor activity in patients with pretreated advanced cancer. The trial is ongoing to assess SHR-A1921 at different dosing frequency and the efficacy in selected cancer types. Citation Format: Jie Wang, Lin Wu, Zhengbo Song, Xingya Li, Caigang Liu, Tianshu Liu, Yiwen Wu, Ze Zhang, Shuni Wang. A first-in-human (FIH) phase 1 study of SHR-A1921, a TROP-2 targeted antibody-drug conjugate (ADC), in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT181.