Combination of bemcentinib (BGB324): A first-in-class selective oral AXL inhibitor, with pembrolizumab in patients with triple negative breast cancer and adenocarcinoma of the lung.

Abstract

TPS43 Background: Activation of the receptor tyrosine kinase AXL has a profound suppressive effect on the innate immune system. AXL is overexpressed on multiple cell types in the tumour immune microenvironment including dendritic cells, NK cells and tumour-associated macrophages. AXL signalling in immune cells supports tumour immune escape by downregulating dendritic cell activity, modulating efferocytosis as well as favouring an immunosuppressive chemokine profile and M-MDSC expansion. AXL is prevalent in tumours resistant to anti-PD-1 therapy (Hugo, 2016). Axl expression in tumour cells confers resistance to effector T cell cytotoxicity. Bemcentinib (BGB324) is a first-in-class, highly selective and orally bioavailable small molecule AXL inhibitor in phase II clinical development. In pre-clinical models of pancreas, breast and lung cancer, inhibition of AXL signalling with bemcentinib reversed multiple tumour immune suppressive mechanisms as evidenced by increased infiltration of cytotoxic T lymphocytes, NK and NKT cells and decreased infiltration of M-MDSCs (Wnuk-Lipinska, 2017). Bemcentinib enhanced the effect of immune checkpoint blockade via PD-1 or CTLA-4 in lung and mammary adenocarcinoma mouse models and achieved sustained tumour immunity. Methods: BGBC007 (NCT03184558) and BGBC008 (NCT03184571) are open-label, phase II studies designed to assess the anti-tumour activity of bemcentinib in combination with pembrolizumab in patients with previously treated TNBC and adenocarcinoma of the lung respectively. All patients will be treated with bemcentinib in combination with pembrolizumab continuously for up to two years. The primary endpoint is objective response rate, secondary endpoints include duration of response, progression free survival according to RECIST 1.1, pharmacokinetics, safety and tolerability. Pretreatment tumour specimens are scheduled to assess AXL expression/signalling and PD-L1 expression; the levels of circulating immune-related cytokines and soluble AXL receptor will also be measured in longitudinal patient plasma samples. Both studies are open to recruitment. Clinical trial information: NCT03184558.

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The State-of-the-Art of Phase II/III Clinical Trials for Targeted Pancreatic Cancer Therapies

“…The AXL receptor tyrosine kinase is overexpressed in approximately 70% of PDAC patients and is associated with metastasis, poor prognosis and chemoresistance [17,18]. By regulating immune cells within the tumour microenvironment, the AXL kinase mediates immune evasion via production of immunosuppressive chemokines [19]. Moreover, AXL expression in tumour cells mediates T cell cytotoxicity resistance, further favouring an immunosuppressive tumour microenvironment.…”

AXL as a Target in Breast Cancer Therapy

“…e median progression-free survival for patients expressing AXL was 5.9 months, compared to 4.0 months for AXL negative patients [100]. Clinical trials for BGB324 in TNBC and other cancers are ongoing [101].…”