The Combination of AXL Inhibitor Bemcentinib and Low Dose Cytarabine Is Well Tolerated and Efficacious in Elderly Relapsed AML Patients: Update from the Ongoing BGBC003 Phase II Trial (NCT02488408)
Authors: Loges Sonja , Heuser Michael , Chromik Jörg , Vigil Carlos Enrique , Paschka Peter , Re Francesca , Di Renzo Nicola , Lemoli Roberto M. , Mattei Daniele Giovanni , Ben-Batalla Isabel , Hellesoy Monica , Lorens Katherine , Birkett Joseph , McPherson Stuart , Nautiyal Jaya , Micklem David , Gabra Hani , Lorens James B. , Fiedler Walter , Alvarado Yesid , Gjertsen Bjorn T. 
Published: November 2020

Background
Standard low dose cytarabine (LDAC) monotherapy in elderly previously-treated relapsed and primary resistant/refractory (R/R) AML patients unfit for intensive chemotherapy shows limited response (CR rate of up to 17%) and survival benefit (mOS 4-6 mos, Sarkozy, 2013). Hence this vulnerable patient population has significant unmet need for well tolerated and efficacious new treatments. Bemcentinib (BEM) is a selective small molecule inhibitor of AXL, a surface membrane protein kinase receptor mediating resistance to chemotherapeutic agents and decreased antitumor immune response. AXL is overexpressed on leukemic cells, especially in the stem cell compartment, and represents a potential novel target in patients with AML. The ongoing BGBC003 phase II trial includes newly diagnosed (ND), and previously treated R/R AML patients unfit for intensive chemotherapy receiving BEM+LDAC combination treatment. A previously-treated AML patient cohort was selected for expansion, with the objective to explore safety and efficacy and to undertake translational biomarker analysis. Here, we report on preliminary efficacy together with a safety overview for all patients treated with the combination.
Methods and Patient Disposition
AML patients unfit for intensive therapy received BEM at the RP2D (200mg PO/d) + 10-day LDAC in 21-day cycles. Efficacy endpoints included objective response (OR: CR, CRi, PR) and clinical benefit (CB: OR + SD for ≥ 3 treatment cycles). Secondary objectives include overall survival (OS) and exploratory biomarker analyses. The BEM+LDAC cohorts (n=24); with a data cut-off date of 21 July 2020, comprised 7 newly diagnosed and 17 previously-treated (10 relapsed, 7 refractory) AML patients; with a median of 2 prior therapies (ranges: 1-8 relapsed; 1-4 refractory). Median age was 76 years for previously-treated R/R (range 66-81), and 78 for ND patients (range 75-83). Six (35%) R/R and 0% ND pts had a poor cytogenetic risk profile. Median bone marrow (BM) myeloblasts at screening for R/R AML patients was 33.5% (range 3-94%) and 34% (range 3-54) for ND patients. Plasma protein biomarker levels including soluble AXL (sAXL) were measured at screening and following treatment. Single cell RNA sequencing and T-cell repertoire analysis are being conducted to determine the effect of BEM + LDAC on direct tumor-cell killing and antitumor immunity.
Results
At the time of data cut off, previously-treated relapsed patients (n=8) were evaluable for response (as per BM assessment at C2D1; 4/8 (50%) relapsed patients achieved objective response (2 CR, 1 CRi, 1PR) and 6/8 (75%) showed clinical benefit. mDOR was 12.1 wks (range 11.9-16.1 wks, ongoing) with a median time-on-trial of 20.4 wks. Notably responses were reported between wk20 (C5) - wk28 (C7). These later onset responses may reflect the importance of AXL-related immunological mechanisms for relatively chemo-resistant relapsed patients and contribute to a longer time-on-treatment. Three relapsed patients remain on study treatment. In contrast, no refractory patients showed response (0/7) with 2/7 (28%) reporting clinical benefit; median time on trial was 8.6 wks. For evaluable newly-diagnosed patients, response was observed in 3/7 (48%, all CR), and clinical benefit in 5/7 (71%). The mDOR was 69.3 wks (range 62.9-105.1 wks, ongoing) and 2 patients remain on study. Overall, the combination was well tolerated, and in keeping with the known safety profile of LDAC. Treatment related AEs of ≥ Grade 3 observed in ≥ 5% of pts (n=24) across all cohorts were anemia, 4 (16%), thrombocytopenia, 3 (12%), febrile neutropenia 2, (8%) and QTcF prolongation, 1 (4%).
Conclusions
These data show that BEM+LDAC is efficacious and well tolerated in the unfit previously-treated relapsed and newly diagnosed AML populations. No activity was seen in primary resistant/refractory AML patients. An in-depth translational research program aiming to identify predictive molecular and biological factors associated with response in ongoing. Thus, the BEM+LDAC combination warrants further investigation and development in randomized trials with the potential to improve survival outcomes for elderly and unfit AML patients.

Disclosures
Loges: BerGenBio ASA: Research Funding. Heuser:Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Stemline Therapeutics: Consultancy; PriME Oncology: Honoraria; Karyopharm: Research Funding; Amgen: Research Funding; Bayer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BerGenBio ASA: Research Funding; Janssen: Consultancy; Roche: Research Funding; Astellas: Research Funding; Abbvie: Consultancy. Chromik:BerGenBio ASA: Research Funding. Vigil:BerGenBio ASA: Research Funding. Paschka:BerGenBio ASA: Research Funding; Sunesis Pharmaceuticals: Consultancy; AbbVie: Other: Travel, accommodation or expenses, Speakers Bureau; Amgen: Other; Astellas Pharma: Consultancy, Speakers Bureau; Astex Pharmaceuticals: Consultancy; Celgene: Consultancy, Other: Travel, accommodations or expenses; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Otsuka: Consultancy; Janssen Oncology: Other; Agios Pharmaceuticals: Consultancy, Speakers Bureau. Re:BerGenBio ASA: Research Funding. Di Renzo:BerGenBio ASA: Research Funding. Lemoli:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; BerGenBio ASA: Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mattei:BerGenBio ASA: Research Funding. Ben-Batalla:BerGenBio ASA: Research Funding. Hellesoy:BerGenBio ASA: Research Funding. Lorens:BerGenBio ASA: Current Employment. Birkett:BerGenBio ASA: Consultancy. McPherson:BerGenBio ASA: Current Employment. Nautiyal:BerGenBio ASA: Current Employment. Micklem:BerGenBio ASA: Current Employment. Gabra:BerGenBio ASA: Current Employment. Lorens:BerGenBio ASA: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Patents & Royalties. Fiedler:Gilead: Honoraria; Daiichi Sankyo Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support in medical writing; Ariad/Incyte: Membership on an entity's Board of Directors or advisory committees; BerGenBio ASA: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support in medical writing; Celgene: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations, support in medical writing, Research Funding; Servier: Honoraria, Other; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations; BMS: Honoraria. Alvarado:Tolero Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; Jazz Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; BerGenBio ASA: Research Funding; MEI Pharma: Research Funding; Sun Pharma: Research Funding; FibroGen: Research Funding. Gjertsen:Alden Cancer Therapy AS: Current equity holder in private company; Pfizer Inc: Consultancy; BerGenBio AS: Consultancy, Research Funding; Novartis: Consultancy; KinN Therapeutics AS: Current equity holder in private company.