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
Mené sur 21 patients atteints d'un cancer du poumon non à petites cellules de stade avancé, cet essai de phase I détermine la dose maximale tolérée et analyse les caractéristiques phamarcocinétiques et pharmacodynamiques du bemcentinib (un inhibiteur sélectif de l'AXL), seul et en combinaison avec le docétaxel
Objectives: AXL, a transmembrane receptor tyrosine kinase, is highly expressed and associated with poor prognosis 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 bemcentinib 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 400mg 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 monotherapy was administered for one week prior to docetaxel initiation to assess pharmacodynamic and pharmacokinetic 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%
≥
G3), diarrhea (57%, 0%
≥
G3), fatigue (57%, 5% vG3), and nausea (52%, 0%
≥
G3). Neutropenic fever occurred in 8 (38%) patients. The maximum tolerated dose was docetaxel 60mg/m2 with prophylactic G-CSF support plus bemcentinib 400 mg load x 3 days followed by 200 mg daily thereafter. Bemcentinib and docetaxel pharmacokinetics 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 administration 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 of anti-tumor activity in previously treated, advanced NSCLC. The role of AXL inhibition in the treatment of NSCLC remains under investigation.
Lung Cancer 2023