摘要：

A novel anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate (ADC) GQ1001 was assessed in patients with previously treated HER2 positive advanced solid tumors in a global multi-center phase Ia dose escalation trial. In this phase Ia trial, a modified 3 + 3 study design was adopted during dose escalation phase. Eligible patients were enrolled, and GQ1001 monotherapy was administered intravenously every 3 weeks. The starting dose was 1.2 mg/kg, followed by 2.4, 3.6, 4.8, 6.0, 7.2 and 8.4 mg/kg. Extra patients were enrolled into 6.0, 7.2, and 8.4 mg/kg cohorts as dose expansion phase. The primary endpoints were safety and to determine the maximum tolerated dose (MTD) based on dose limiting toxicities (DLTs). Pharmacokinetics and anti-tumor efficacy of GQ1001 were assessed. The plasma concentration of free DM1, the payload of GQ1001, was quantitated. A total of 32 patients were enrolled, predominantly in breast (9), gastric or gastro-esophageal junction (9) and salivary gland cancer (4). Median number of prior-line of therapies was 3 (0-11) and 37.5% patients received ≥ 2 lines of anti-HER2 therapies. No DLT was observed during dose escalation. MTD was not reached and dose recommended for dose expansion (DRDE) was determined as 8.4 mg/kg. Grade ≥ 3 treatment-related adverse events rate was 28.1% (9/32) and platelet count decreased (4/32, 12.5%) was the most common one. No drug-related death was observed. Objective response rate and disease control rate of 15 evaluable patients in 7.2 mg/kg and 8.4 mg/kg cohorts were 40.0% (6/15) and 60.0% (9/15). Pharmacokinetics analysis showed low exposure and accumulation of free DM1 in circulation. GQ1001 is well tolerated and shows promising efficacy in previously treated HER2-positive advanced solid tumors. DRDE was determined as 8.4 mg/kg for following trials. Trial registration NCT, NCT04450732, Registered 23 June 2020, https://clinicaltrials.gov/study/NCT04450732.

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