PF259 THE COMBINATION OF BEMCENTINIB, A NOVEL, ORAL, SELECTIVE AXL‐INHIBITOR AND LOW‐DOSE CYTARABINE YIELDS DURABLE RESPONSES IN AML PATIENTS UNFIT FOR INTENSIVE CHEMOTHERAPY
Authors: Loges S. , Heuser M. , Chromik J. , Vigil C.E. , Paschka P. , Re F. , Di Renzo N. , Lemoli R. , Mattei D. , Ben Batalla I. , Hellesøy M. , Micklem D. , Holt R.J. , Schoelermann J. , Lorens K. , Lorens J.B. , Shoaib M. , Aly H. , Brown A. , Fiedler W.M. , Cortes J.E. , Gjertsen B.T. 
Published: June 2019

Background:There is an unmet need in treating AML pts who are unable to tolerate high‐intensity chemo. Treatment of AML pts ≥75 yo is particularly challenging due to co‐morbidities, low treatment tolerance and poor risk disease features in at least half of these pts. Low‐dose cytarabine (LDAC) monotherapy is an approved therapy for elderly pts unfit for intensive chemo and yields 18% CR rate as reported in the MRC AML14 study with median OS of 3–4 months. In order to improve the OS of this challenging pt population, an increase in the CR rate and longer response duration is required. The RTK AXL represents a novel therapeutic target promoting AML cell proliferation and survival by pleiotropic mechanisms and is a negative regulator of anti‐tumor immunity. Bemcentinib is a first‐in‐class, highly selective, oral AXL inhibitor that has previously shown a 43% ORR among 14 r/r AML/hr‐MDS pts with low sAXL, with a favorable safety profile. T‐ and B‐cell receptor diversification as well as clonal stabilization were also reported.Aims:The open label study BGBC003 aimed to establish the RP2D and anti‐leukemic activity of bemcentinib when given as a monotherapy followed by a PhII part designed to explore the safety and efficacy of bemcentinib given in combo with LDAC to patients with newly diagnosed or R/R AML unfit for intensive chemotherapy. Secondary objectives included OS and exploratory biomarker analyses.Methods:The monotherapy dose‐escalation part of the study is complete. During the PhII part, AML pts unfit for intensive therapy received bemcentinib at RP2D (200 mg PO/d) + SOC 10‐day LDAC in 21‐day cycles. At the time of writing, 10 pts were evaluable for response assessment by BM aspirate at C2D1: median age was 76y (range 66–83); 6 patients (60%) had poor cytogenetic risk profile, 1 (10%) and 3 (30%) had favorable or unknown risk, respectively; pts showed a median of 33% myeloblasts at screen (range 3–96%) and 9 of 9 patients (100%) tested for FLT mutations were negative. 6/10 pts (60%) were previously treated including 3 relapsed and 3 refractory. Plasma protein biomarker levels including soluble AXL (sAXL) were measured using the DiscoveryMap v3.3 panel (Myriad RBM) at screen and following treatment.Results:As of March 2019, 4/10 evaluable patients had objective responses (40%, 3 CR/CRi+1 PR), all starting at C2D1. Responses occurred in pts with unfavorable characteristics: 2 previously‐treated including 1 refractory, 3 unfavorable cytogenetics, and 3 >75 yo. CRs were durable at 3.5, 4.9 and 6.9 mos (all ongoing). The pt with PR continues treatment in cycle 2 at time of writing. 2 additional pts (20%, both 76y, 1 relapsed and 1 secondary) showed a durable stable disease at 4.0 and 3.9 mos (1 ongoing). The combo was well tolerated with expected and manageable AEs. Out of all pts dosed with bemcentinib + LDAC, 4 experienced TRAEs (4/13, 31%). The most common TRAEs in this group were anemia (2/13, 15%) and diarrhea (2/13, 15%). 2 pts experienced TRAEs grades 3+ (anemia, thrombocytopenia/PLT count decreased). 2 pts reported febrile neutropenia, none of which were related to the study drug. No tumor lysis syndrome events have been reported.Summary/Conclusion:The potential new non‐intensive combo regimen, bemcentinib + LDAC, induced a response rate of 40% with durable CR/CRis lasting up to 7 mos at time of writing. Responses were seen in elderly AML patients including previously‐treated patients and those with poor‐risk disease, and the combo has the potential to increase the median OS among both relapsed as well as De Novo AML pts not eligible for intensive chemotherapy.