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)
Author:
Loges Sonja12, Heuser Michael3, Chromik Jörg4, Vigil Carlos Enrique5, Paschka Peter6, Re Francesca7, Di Renzo Nicola8, Lemoli Roberto M.9, Mattei Daniele Giovanni10, Ben-Batalla Isabel11, Hellesoy Monica12, Lorens Katherine13, Birkett Joseph13, McPherson Stuart13, Nautiyal Jaya13, Micklem David13, Gabra Hani13, Lorens James B.1314, Fiedler Walter15, Alvarado Yesid16, Gjertsen Bjorn T.17
Affiliation:
1. University Medical Centre Manheim, Manheim, Germany 2. German Cancer Research Centre (DKFZ), Heidelberg, Germany 3. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany 4. University Hospital Frankfurth, Frankfurt, Germany 5. Vanderbilt Ingram Cancer Centre, Nashville, TN 6. University Hospital Ulm, Ulm, Germany 7. University of Parma, Parma, Italy 8. Hematology and SCT Unit, Vito Fazzi Hospital, Lecce, Italy 9. University of Genoa, Genoa, Italy 10. Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy 11. Medical Clinic and Institute of Tumor Biology, Campus Forschung, University Hospital Hamburg-Eppendorf, Hamburg, Germany 12. Haukeland University Hospital, Bergen, Norway 13. BerGenBio ASA, Bergen, Norway 14. Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway 15. University Medical Center, Hamburg-Eppendorf, Hubertus-Wald University Cancer Center, Hamburg, Germany 16. Department of Leukemia, MD Anderson Cancer Center, Houston, TX 17. Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway
Abstract
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.
Publisher
American Society of Hematology
Subject
Cell Biology,Hematology,Immunology,Biochemistry
Cited by
3 articles.
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