Background: AXL receptor tyrosine kinase is a novel target expressed on tumour and immune cells. Upregulation of AXL is associated with poor prognosis and resistance to established and emerging cancer therapies. Bemcentinib is a first-in-class, orally bioavailable, selective small molecule AXL kinase inhibitor which is being evaluated across multiple phase II clinical trials in solid tumours and myeloid malignancies both as a monotherapy and in combination with immune-, targeted and chemotherapies. Here we describe predictive and pharmacodynamic biomarkers associated with bemcentinib treatment alone and in combination as well as results of a customised multiplexed immunofluorescent imaging assay. Methods: Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) pre-dose and at C2D1 across six clinical trials including bemcentinib monotherapy as well as combination with pembrolizumab, erlotinib and chemotherapies in NSCLC, TNBC, melanoma and AML/MDS (NCT02488408, NCT03184571, NCT03184558, NCT02872259, NCT02424617, NCT02922777). FFPE tumour samples were analysed using a modified NeoGenomics MultiOmyx Tumor Infiltrating Lymphocyte Panel measuring protein expression of among others AXL, PD-L1 and PD-1. Results: Protein biomarkers predictive of patient benefit following bemcentinib treatment - both alone and in combination with immune-, targeted or chemotherapies -included the bemcentinib target AXL. One cycle of treatment significantly altered plasma AXL protein levels including in patients who benefited from treatment. AXL is expressed in a subset of tumour infiltrating immune cells, primarily macrophages. In addition, AXL and PD-L1 were found to be co-expressed. Conclusions: Predictive biomarker candidates were identified supporting potential companion diagnostics development for bemcentinib treatment. Pharmacodynamic biomarkers indicate that bemcentinib is selective and on target. AXL is expressed on macrophages and is co-expressed with PD-L1.
CITATION STYLE
Holt, B., Micklem, D., Brown, A., Yule, M., & Lorens, J. (2018). Predictive and pharmacodynamic biomarkers associated with phase II, selective and orally bioavailable AXL inhibitor bemcentinib across multiple clinical trials. Annals of Oncology, 29, viii19. https://doi.org/10.1093/annonc/mdy269.061
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