Efficacy and Safety of Bemcentinib in Patients with Myelodysplastic Syndromes or Acute Myeloid Leukemia Failing Hypomethylating Agents
Authors: Kubasch Anne Sophie , Peterlin Pierre , Cluzeau Thomas , Götze Katharina S. , Sockel Katja , Teipel Raphael , Jentzsch Madlen , Kayser Sabine , Attalah Habiba , Chermat Fatiha , Gloaguen Silke , Jersemann Katja , Schipp Dorothea , Giagounidis Aristoteles , McPherson Stuart , Tirado-González Irene , van de Loosdrecht Arjan , Fenaux Pierre , Platzbecker Uwe , Medyouf Hind , Ades Lionel 
Published: November 2020

*AK, PP shared first-, UP, HM, LA shared senior authors
Introduction:
Hypomethylating agents (HMAs) are the standard of care for patients with higher-risk myelodysplastic syndrome (HR-MDS) or acute myeloid leukemia (AML), not eligible for intensive chemotherapy or allogeneic stem cell transplantation. However, the majority of patients do not respond to these agents. Patients failing HMA therapy still have a dismal outcome with very limited treatment options available.
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 MDS and AML.
Methods:
The multicenter phase 2 BERGAMO trial evaluated the safety and efficacy of BEM in patients with HR-MDS or AML, refractory to or relapsing after at least six or four cycles of either azacitidine (AZA) or decitabine (DAC), respectively.
Patients received an initial loading dose of 400mg BEM orally administered on d1-3 of cycle 1 and a maintenance dose of 200mg BEM on d4-28 of cycle 1 as well as on d1-28 in subsequent 28-day cycles.
The primary endpoint was overall response rate (CR, CRi, PR or SD) assessed after 4 treatment cycles. All patients who achieved CR, CRi, PR or SD after 4 cycles of BEM were considered as responders and allowed to continue treatment for a total of up to 9 cycles. Non-responding patients stopped treatment after 4 cycles. Secondary endpoints of the trial included a translational project evaluating the role of biomarkers and response.
Results:
Between 2018 and 2020, 58 patients in 10 European centers were screened (MDS=27/AML=31) with a median age of 78 years (range, 62-86 years). 45 patients (MDS=21, AML=24) received at least one cycle of BEM and were eligible for safety and efficacy analysis after the first 4 months of treatment. Thirty six (80%) out of 45 patients were considered relapsed after a response to HMA, 8 (18%) had primary resistance and 1 patient (2%) had HMA intolerance. The median number of prior AZA or DAC cycles was 13. In addition, 18 patients (40%) (MDS=9/AML=9) were red blood cell transfusion-dependent.
Treatment with BEM was generally well tolerated with only low rates of grade 3-4 hematologic toxicities (n=7). Forty-seven serious adverse events (SAE) occurred in 22 patients (MDS=9/AML=13), mostly due to infectious complications (n=12), hematological toxicity (n=4) or gastrointestinal disturbance (n=6). Until the first 4 months of BEM treatment, the median number of BEM treatment cycles received was 1.5 (range, 0.5-4). During study, 9 patients (20%) died due to infection (MDS=1/AML=3), deterioration of general condition (MDS=1/AML=2) and progressive disease (MDS=0/AML=2). BEM treatment is currently ongoing in four patients (MDS=3/AML=1).
The primary endpoint was met in 9 of 45 patients (20.0%). Within the MDS cohort 33.3% achieved a response (n=7/21; CR=1, CRi= 3, SD=3), while 8.3% of patients (n=2/24) with AML achieved stable disease(SD). The 4 MDS patients achieving CR/CRi had a normal karyotype and a median baseline IPSS-R score of 4 (range 3-5). Among the MDS non-responders 4 patients had a complex karyotype, median IPSS-R score was 5 (range 3-5). Median baseline bone marrow blast count was 15% vs. 13% and median pretreatment hemoglobin-, platelet- and WBC levels were 9.2 g/dl (range 7.9-11.8 g/dl), 51 G/L(range 26-120 G/L) and 1.9x109/l (range 1.18-8.9 x109/l) vs. 9.6 g/dl (range 7.9-11.3 g/dl), 35 G/L (range 0-167 G/L) and 1.45x109/l (range 0.82-6.97 x109/l) comparing MDS responders (CR/CRi) vs MDS non-responders, respectively.
Preliminary data evaluating soluble AXL (sAXL) in blood plasma at baseline showed that 66.6 % (n=2/3) of MDS patients achieving CR/CRi displayed sAXL levels below a defined threshold, while this was only seen in 20% (n=2/10) of MDS non-responders.
Conclusion:
These results of the prospective phase II BERGAMO trial confirm, that single agent BEM is generally safe and well tolerated in this patient population with an unmet medical need. Importantly, BEM showed clinical efficacy in a subgroup of MDS patients. These encouraging clinical results are being further explored by an in depth translational research program aiming to identify additional molecular and biological prognostic factors associated with response.

Disclosures
Kubasch: Celgene: Research Funding; Shire: Research Funding; Novartis: Research Funding. Cluzeau:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Götze:Celgene: Research Funding. Teipel:janssen: Honoraria. Jentzsch:Novartis: Honoraria; JAZZ Pharmaceuticals: Honoraria. Giagounidis:Novartis: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees. McPherson:BerGenBio ASA: Current Employment. van de Loosdrecht:novartis: Honoraria; celgene: Honoraria. Fenaux:Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Platzbecker:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Honoraria, Research Funding. Medyouf:Bergenbio: Consultancy, Research Funding. Ades:Celgene/BMS: Research Funding; novartis: Research Funding; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding.

OffLabel Disclosure:
Bemcentinib is currently undergoing Phase II clinical trials for non-small-cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), acute myeloid leukemia /myelodysplastic syndrome (AML/MDS), melanoma and metastatic pancreatic cancer. In 2019, FDA have granted fast track designation to bemcentinib for the treatment of elderly patients with acute myeloid leukemia (AML) whose disease has relapsed.