Upregulation of the receptor tyrosine kinase AXL has been linked with both minor treatment effect of PD-1 blockade and acquired resistance to BRAF inhibitors in melanoma. Bemcentinib is a first-in-class orally bioavailable selective inhibitor of AXL which is currently investigated in several phase II clinical trials. BGBIL006 (NCT02872259) is an open label phase Ib/II trial designed to explore whether combination with bemcentinib improves overall response rates to standard of care therapies in patients (pts) with metastatic melanoma (MM).
Dose escalation of bemcentinib in combination with 150mg twice daily/2mg daily dabrafenib/trametinib (D/T) in newly diagnosed, BRAF+, MM with high tumour load followed a 3 + 3 design (part 1). In part 2, pts were randomised 2:1 to receive D/T or pembro +/- bemcentinib at RP2D, respectively, based on mutation status and tumour load. Pts were allowed to switch D/T with pembrolizumab and vice versa upon progression (part 3). Tumour responses were assessed per investigator using RECIST v1.1. Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) in pts pre-dose and at C2D1.
In part 1, 6 pts were enrolled first line (age 34-71, LDH > 1 x ULN 50%). There was 1 dose limiting toxicity (G3 rash) and an RP2D of bemcentinib in combination with D/T of 200mg daily bemcentinib with full dose D/T was confirmed. As of 2 May 18, a further 17 pts have been enrolled into part 2 of the study and four had progressed to part 3. Grade 3 treatment-related adverse events (AEs) were observed in 7 pts (30%). No G4 AEs or treatment related deaths occurred. Biomarkers candidates predicting treatment benefit were explored. Pre/post treatment changes of soluble proteins will be presented.
Bemcentinib RP2D (200 mg daily) is well tolerated in combination with both D/T and pembro without increased toxicity compared to either therapeutic approach alone. Further investigation of safety and efficacy as well as biomarker candidates is ongoing.
Clinical trial identification
Legal entity responsible for the study
Department for Oncology and Medical Physics, Haukeland University Hospital Bergen.
KLINBFORSK governmental funding.
G. Gausdal: Employee: BerGenBio. B.T. Gjertsen: Stock/ownership: Alden Cancer Therapy II, Kinn Therapeutics AS. J. Lorens: Ownership: BerGenBio ASA. All other authors have declared no conflicts of interest.