Abstract
9081 Background: AXL, a transmembrane receptor tyrosine kinase, is overexpressed and associated with poor prognosis and treatment resistance in non-small cell lung cancer (NSCLC). Bemcentinib (BGB324) is a selective orally bioavailable small molecule inhibitor of AXL, currently in phase 2 clinical development, that has demonstrated synergistic activity with docetaxel in in vivo models of NSCLC. This phase I dose escalation and expansion trial assessed the safety, tolerability, and preliminary efficacy of bemcentinib in combination with docetaxel in previously treated advanced NSCLC. Methods: Dose escalation of daily bemcentinib in combination with docetaxel (60 or 75 mg/m2 every 3 weeks) followed a standard 3+3 design. Bemcentinib monotherapy was administered for one week prior to docetaxel initiation to assess pharmacodynamic effects alone and in combination. Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) pre-dose (C1D-7), C1D1, and C2D1. Results: A total of 21 patients (pts) were enrolled with median age 62 (range 39-84) and 67% male. A median of 3 (range 1-13) cycles of therapy were administered. Principal treatment-related adverse events were neutropenia (86%, 76% ≥G3), diarrhea (57%, 0% ≥G3), fatigue (52%, 5% ≥G3), and nausea (52%, 0% ≥G3). Neutropenic fever ≥G3 occurred in 7 (33%) pts. The maximum tolerated dose was 60 mg/m2 docetaxel plus 200 mg bemcentinib daily with prophylactic G-CSF support. Pharmacokinetics of bemcentinib alone and in combination with docetaxel were highly similar. Among 15 evaluable pts, 4 (27%) pts had partial response and 9 (60%) pts had stable disease as the best radiographic response. Bemcentinib treatment resulted in changes in plasma levels of proteins associated with regulation of sterol synthesis and AKT signaling. Conclusions: Bemcentinib in combination with docetaxel and prophylactic G-CSF support has a manageable safety profile, leads to decreases in systemic factors associated with tumor growth and metastasis, and demonstrates evidence of anti-tumor activity in previously treated, advanced NSCLC. Further studies to identify the patient population most likely to benefit from this regimen are warranted. Clinical trial information: NCT02922777.
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