Phase 1 trial of bemcentinib (BGB324), a first-in-class, selective AXL inhibitor, with docetaxel in patients with previously treated advanced non-small cell lung cancer

Objectives: AXL, a transmembrane receptor tyrosine kinase, is highly expressed and associated with poor prog-nosis in non-small cell lung cancer (NSCLC). Bemcentinib (BGB324), a selective orally bioavailable small molecule AXL inhibitor, synergizes with docetaxel in preclinical models. We performed a phase I trial of bem-centinib plus docetaxel in previously treated advanced NSCLC.Materials and Methods: Escalation of two dose levels of bemcentinib (200 mg load x 3 days then 100 mg daily, or 400 mg load x 3 days then 200 mg daily) in combination with docetaxel (60 or 75 mg/m2 every 3 weeks) followed a 3+3 study design. Due to hematologic toxicity, prophylactic G-CSF was added. Bemcentinib mono-therapy was administered for one week prior to docetaxel initiation to assess pharmacodynamic and pharma-cokinetic effects alone and in combination. Plasma protein biomarker levels were measured. Results: 21 patients were enrolled (median age 62 years, 67% male). Median treatment duration was 2.8 months (range 0.7-10.9 months). The main treatment-related adverse events were neutropenia (86%, 76% & GE;G3), diarrhea (57%, 0% & GE;G3), fatigue (57%, 5% & GE;G3), and nausea (52%, 0% & GE;G3). Neutropenic fever occurred in 8 (38%) patients. The maximum tolerated dose was docetaxel 60 mg/m2 with prophylactic G-CSF support plus bemcentinib 400 mg load x 3 days followed by 200 mg daily thereafter. Bemcentinib and docetaxel pharma-cokinetics resembled prior monotherapy data. Among 17 patients evaluable for radiographic response, 6 (35%) patients had partial response and 8 (47%) patients had stable disease as best response. Bemcentinib adminis-tration was associated with modulation of proteins involved in protein kinase B signaling, reactive oxygen species metabolism, and other processes. Conclusion: Bemcentinib plus docetaxel with G-CSF support demonstrates anti-tumor activity in previously treated, advanced NSCLC. The role of AXL inhibition in the treatment of NSCLC remains under investigation.