Durable Responses Observed in Elderly AML Patients Unfit for Intensive Chemotherapy with First-in Class Selective AXL Inhibitor Bemcentinib (BGB324) in Combination with LDAC: Phase II Open-Label Study
Authors: Loges Sonja , Heuser Michael , Chromik Jörg , Vigil Carlos Enrique , Paschka Peter , Re Francesca , Di Renzo Nicola , Lemoli Roberto Massimo , Mattei Daniele Giovanni , Ben Batalla Isabel , Hellesoy Monica , Micklem David , Holt Robert J. , Lorens James B. , Shoaib Muhammad , Aly Hassan , Hanekom Wouter , Fiedler Walter , Cortes Jorge E. , Gjertsen Bjorn T. 
Published: November 2019

Background
There is an unmet need in treating patients (pts) with AML who are unfit for intense chemotherapy due to advanced age and/or presence of co-morbidities. This population often has poor risk disease features. Low-dose cytarabine (LDAC) monotherapy is a SOC therapy for elderly, unfit pts. The CR rate with LDAC is 18% as reported in the MRC AML14 study, with a median OS of approximately 4-5 months (Burnett et al, 2007). To improve the OS of this challenging patient population, an increase in the CR rate and longer response duration is essential.
The receptor tyrosine kinase AXL represents a novel therapeutic target promoting AML cell proliferation and survival and is a negative regulator of anti-tumor immunity.
Bemcentinib is a first-in-class, highly selective, potent, oral AXL kinase inhibitor with a favorable safety profile. We have previously reported bemcentinib monotherapy anti-leukemic activity in r/r AML and MDS pts. Bemcentinib treatment was also reported to induce T- and B-cell receptor diversification as well as clonal stabilization have also been reported.
We report on cohort B2 of an open-label Phase II study (BGBC003), designed to explore the safety and efficacy of bemcentinib given in combinations with LDAC to pts with AML unfit for intensive chemotherapy. Secondary objectives are OS and exploratory biomarker analyses.
Methods
In Part B2, AML pts unfit for intensive chemotherapy received bemcentinib at the RP2D (200mg PO/d) + SOC LDAC SQ for 10 days in 21-day cycles (dosing according to standard practice). Primary endpoints include identifying safety and tolerability of combination, and secondary endpoints include OR, RFS and OS. Plasma protein biomarker levels including soluble AXL (sAXL) were measured using the DiscoveryMap v3.3 panel (Myriad RBM) at baseline and following treatment.
Results
A total of 16 pts were enrolled. Median age was 76 years (range 66-83). Of the 13 pts with available cytogenetic results, 5 pts (38%) had a poor risk cytogenetic profile, 7 (54%) were intermediate, 1 (8%) favorable. Bone marrow results showed a median of 35% myeloblasts at screen (range 3-96%).
As of July 2019, 15 pts were evaluable for response by BM aspirate on or after C2D1. Six of the evaluable pts had objective responses (ORR 40%, 4 CR/CRis + 2 PRs). Five of the responses (4 CR/CRi + 1 PR) were durable, ranging from 3.4 to 11.7 mos, all still ongoing. All 5 pts with durable responses were >75 years old (range: 76-83). Survival of these 5 pts ranged from 8.8-12.4 months at cut-off, with no relapse or significant events yet reported. Of these 5 pts, 1 had relapsed disease, 3 had secondary AML, and 2 had unfavorable cytogenetics.
Additionally, 3 pts (aged 71-78 years old) had durable stable disease lasting approximately 4 mos, with 1 remaining on study. Of the 3 pts, 1 had newly-diagnosed and 2 refractory AML, and at least 1 had secondary AML.
The RFS and OS data is not yet mature and will be reported at a later stage.
The combination was generally well tolerated with expected and manageable AE profile, with pts continuing the combination up to >19 cycles at cut-off. All pts experienced at least one AE regardless of relation to study treatment, the most common being diarrhea (7/16, 44%) and anaemia (6/16, 38%). The most common treatment-related AEs (TRAEs) were diarrhea (4/16, 25%), electrocardiogram QTc prolongation (3/16, 19%) and decreased platelet count (3/16, 19%). Of these TRAEs, 1 drug interruption and 1 withdrawal were reported; none of these events were reported as SAEs. SAEs occurring in >1 patient were febrile neutropenia (4/16, 25%; 1 related to study drug), and pyrexia (2/16, 12.5%; not related to study drug). These SAEs are typically observed in AML.
Conclusions
The combination of bemcentinib + LDAC induced a response rate of 40% in pts with newly-diagnosed and relapsed AML. CRs were durable, lasting more than 11 mos in some pts. Durable responses were seen in elderly AML pts including those with adverse disease features. AEs reported were as expected in this population. The DOR of the combination has the potential to improve the OS in this population. Further biomarker exploration will be reported at the conference.
Encouraging results in this elderly pt population will lead to further clinical development with this treatment combination.

Disclosures
Loges: BerGenBio ASA: Honoraria, Other: Advisory Board, Travel Support, Research Funding. Heuser:Synimmune: Research Funding; Bayer Pharma AG, Berlin: Research Funding. Paschka:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Takeda: Other: Travel expenses; Agios: Membership on an entity's Board of Directors or advisory committees; BMS: Other: Travel expenses, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesis: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Travel expenses; Otsuka: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Amgen: Other: Travel expenses; Abbvie: Other: Travel expenses. Micklem:BerGenBio ASA: Employment, Equity Ownership. Holt:BerGenBio ASA: Employment. Lorens:BerGenBio ASA: Employment, Equity Ownership. Shoaib:BerGenBio ASA: Consultancy. Aly:BerGenBio ASA: Consultancy. Hanekom:BerGenBio ASA: Consultancy. Fiedler:Amgen, Pfizer, Novartis, Jazz Pharmaceuticals, Ariad/Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen, Pfizer, Abbvie: Other: Support in medical writing; Amgen, Jazz Pharmaceuticals, Daiichi Sanchyo Oncology, Servier: Other: Support for meeting attendance; Amgen: Research Funding. Cortes:Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy; Immunogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding. Gjertsen:Research Council of Norway: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ACTII AS: Equity Ownership; Seattle Genetics: Consultancy; BerGenBio AS: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Helse Vest Health Trust: Research Funding; ERA PerMed: Research Funding; Haukeland University Hospital / University of Bergen: Employment; KinN Therapeutics AS: Equity Ownership; EU Horizon 2020: Research Funding; Daiichi Sankyo: Consultancy; BerGenBio: Consultancy; The Norwegian Cancer Society: Research Funding.