Final Analysis of the Dose Escalation, Expansion and Biomarker Correlations in the Ph I/II Trial BGBC003 with the Selective Oral AXL Inhibitor Bemcentinib (BGB324) in Relapsed/Refractory AML and MDS

Background AXL has been established as an independent prognostic factor in AML. AXL also represents a novel immune checkpoint because it directly inhibits NK cells and suppresses antigen presentation by antigen-presenting cells. Bemcentinib is a first-in-class, selective, orally bioavailable, AXL kinase inhibitor which is being evaluated as a therapy for solid tumours and myeloid malignancies in multiple phase II clinical trials. Increased levels of the plasma soluble, shed form of the AXL receptor (sAXL) upon bemcentinib exposure have been found across the clinical trial programme. The Phase I/II trial BGBC003 (NCT02488408) evaluates the anti-leukaemic effect of bemcentinib in patients with relapsed / refractory AML and int-2 and high-risk MDS. Methods Part A of the BGBC003 consisted of a dose escalation part per standard 3+3 design, followed by cohort expansion at the recommended phase 2 dose. Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) at pre-dose and after one cycle of treatment. Gene expression analysis was carried out on RNA extracted from BM-MNCs by qPCR using TaqMan. The presence of phosphorylated AXL was measured using Western blotting. The TCRß repertoire was quantified by NGS of DNA isolated from PBMNCs using an Illumina MiSeq sequencer. TCRß genes and the IGH repertoire were analysed with BIOMED2-TCRß-A and -B and BIOMED2-FR1/-FR3 primer pools, respectively. Using genomic DNA as template, the amplicons were tagged with Illumina adapters and indices in two consecutive PCR reactions. Demultiplexing and FastQ formated data output was generated by the MiSeq reporter. Analysis of TCRß and IGH data was performed on a Microsoft Cloud using our in-house analysis pipeline Pippa. Results In total, 36 patients were enrolled in part A of the study: 27 male (75%), median age of 72 years old (51 - 85), 3 patients with MDS (8%), median of 2 lines of prior therapy (0 - 6). A loading dose of 400 mg on days one to three followed by 200 mg daily thereafter has been established as safe and recommended phase 2 dose. In patients who received treatment for at least 21 days (n=28), an ORR (CR/Cri/PR) of 25% (7/28) was observed. Median DoR was 63 days. In the subset of patients with available plasma measurements at screening (n=19), 12 showed low levels of plasma soluble shed AXL and an ORR of 58% (sAXL-low; 7 of 12 patients) was observed. No responses occurred in patients with high levels of sAXL at screening (sAXL-high