The safety, tolerability, and efficacy of BRY812 in patients with advanced solid tumors: Preliminary results from the phase I clinical study.

Abstract

3021 Background: Antibody-conjugated drugs (ADCs) have demonstrated outstanding clinical efficacy in treating a wide range of solid tumors as well as hematological tumors currently. An ongoing multicenter, open-label, phase I clinical study assessed the safety, tolerability and preliminary efficacy of BRY812, the ADC targeting transmembrane protein LIV-1 with MMAE as cytotoxic payload, in advanced solid tumors. Here we report the interim analysis results. Methods: In Phase Ia (dose escalation), the eligible patients with advanced solid tumors were enrolled in each of 7 dose groups (0.25, 0.5, 1.0, 2.0, 2.8, 3.6 and 4.4 mg/kg) for evaluation to determine the MTD of BRY812. An "accelerated titration" method (0.25, 0.5 mg/kg) as well as a modified toxicity probability interval-2 method (subsequent doses) was applied. Subsequently dose expansion was conducted for dose levels of 2.0, 2.8 and 3.6 mg/kg that demonstrated tolerability and relative efficacy. The patients received treatment every 3 weeks until intolerable toxicity or disease progression. The primary endpoint was to evaluate DLT and MTD to determine RP2D, other endpoints included ORR. Results: Overall, as data cut-off date (Dec 13, 2024), 36 patients (including 30 patients with breast cancer) with advanced solid tumors were enrolled, including 20 patients in dose escalation phase and 16 patients in dose expansion respectively. Treatment is still ongoing for 19 patients. No DLT was observed up to 3.6 mg/kg. 4.4 mg/kg was not tolerated due to DLTs (2 of 4 patients experienced DLT events). The most common grade ≥3 TEAE was neutropenia, and grade 4 neutropenia was observed in 3.6 mg/kg (2/12) and 4.4 mg/kg (4/4). 4 patients discontinued treatment due to AE including 2 injury corneal (each of 3.6 & 4.4 mg/kg), 1 peripheral neuropathy (2.8 mg/kg) and 1 hepatic enzyme increase (3.6 mg/kg). Among 34 patients in efficacy analysis, 8 (23.5%) patients and 7 (20.6%) patients had PR and SD, respectively, and 17 (50%) patients had PD, leading to ORR of 23.5% (95% CI: 10.7, 41.1) and DCR of 44.1% (95% CI: 27.2, 62.1). The patients with higher LIV-1 expression showed better efficacy, as among 14 patients with PS2+ enriched, ORR was 43% (6/14 in breast cancer). In addition, ADC and Total antibody clearance were similar. BRY812 showed dose-dependent decrease of clearance in the dose range of 0.25 to 2.0 mg/kg, while approximately linear clearance in the dose range of 2.0 to 4.4 mg/kg, and the half-life were ~7 days. No accumulation was observed after multiple dosing. ADA positive rate was 11.43% (4/35). Conclusions: BRY812 demonstrated favorable safety and tolerability profile, with promising clinical efficacy in patients with advanced solid tumors. Further dose optimization and clinical efficacy will be explored in Phase Ib. Clinical trial information: NCT06038058 .