700P - First-in-human dose-escalating study of ABSK043, a novel and oral small-molecule inhibitor of PD-L1, in patients with advanced solid tumors

Background

Immunotherapies targeting the PD-1/PD-L1 pathway with therapeutic antibodies have shown remarkable anti-tumor effects. Comparing to antibodies, small molecules render lower immunogenic risk and convenience in administration. ABSK043 is an oral small molecule PD-L1 inhibitor that potently blocks PD-1 and PD-L1 interaction. Here, we report the preliminary results from the first-in-human (FIH) study of ABSK043.

Methods

The FIH study evaluated the safety, tolerability, PK, PD, and preliminary efficacy of ABSK043. Dose escalation adopted the BOIN design, and ABSK043 was given orally QD or BID in patients with advanced solid tumors. PD assessments included PD-L1 inhibition and T-cell function.

Results

As of February 2023, 19 pts were enrolled in 5 doses from 200mg QD to 800mg BID in Australia. No DLT was observed and MTD was not reached. The most common (≥10%) TRAEs were rash (10.5%) and decreased appetite (10.5%). No peripheral neuropathy was reported. A grade 3 treatment-related thyroiditis with hyperthyroidism was reported in one patient (400mg BID) who recovered after steroid therapy. No grade 4 or 5 AEs occurred. Among 7 response evaluable pts in BID dosing, two were genomic instability, one endometrial carcinoma with MSI-H/dMMR (600mg BID) and one breast cancer with Lynch syndrome (400mg BID), both achieved partial response and were IO-naïve. ABSK043 depleted over 90% of surface PD-L1 on ex vivo stimulated whole blood in a dose dependent manner. BID dosing enhanced PD-L1 inhibition. Furthermore, ABSK043 decreased soluble PD-L1 levels in serum. Increases in IL-2 with ex vivo stimulation, CXCL9, and IFN-γ levels were observed post-treatment, indicating the activation of T cells.

Conclusions

ABSK043 was well tolerated up to 800 mg BID with no DLT reported. On-target PD effects were consistent with PD-L1 inhibition and data reported by anti-PD-(L)1 mAbs. Preliminary anti-tumor activity was observed, and further studies are warranted to explore the efficacy in a larger number of patients.

Clinical trial identification

NCT04964375.

Editorial acknowledgement

Legal entity responsible for the study

Abbisko Therapeutics Australia Pty. Ltd.

Funding

Abbisko Therapeutics Australia Pty. Ltd.

Disclosure

M. Hong: Non-Financial Interests, Institutional, Invited Speaker: Novartis. L.L. Meng, B. Shen, H. Li, L. Yao, M. Zhang: Financial Interests, Personal, Full or part-time Employment: Abbisko. All other authors have declared no conflicts of interest.