Contributions
Abstract: EP463
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Clinical
Background
Low-dose cytarabine (LDAC) in elderly relapsed (REL) & refractory (REF) (r/r) AML patients (pts) unfit for intensive therapy shows limited response (CR rate up to 17%) and survival benefit (mOS 4-6mos). This population has significant unmet need for new treatments. Bemcentinib (BEM) is an oral selective small molecule inhibitor of AXL, a RTK mediating poor prognosis, resistance to chemotherapeutics and decreased antitumor immune response. AXL is overexpressed on leukemic cells, especially in the stem cell compartment, and represents an important novel target in pts with AML.
Aims
The ongoing BGBC003 PhII trial cohorts receiving BEM+LDAC (B+L) include newly diagnosed (ND) and r/r AML pts unfit for intensive therapy. Based on observed activity, r/r AML pts were selected in an expansion cohort, to explore safety and efficacy and to undertake translational biomarker analysis. Here, we report on preliminary efficacy in r/r pts, with a safety overview for all pts treated with the combination.
Methods
Pts received BEM at the RP2D (200mg PO/d)+LDAC SoC schedule. Efficacy endpoints included objective response (OR) and clinical benefit (OR+SD [unchanged disease for at least 3 BEM cycles]). Secondary objectives include overall survival (OS) and exploratory biomarker analyses. Single cell RNA sequencing and T-cell repertoire analysis are being conducted to unravel the immunotherapeutic MOA of B+L.
Results
As of 06 Jan 21, the B+L cohorts (n=31) comprised 7 ND and 24 r/r (17 REL, 7 REF) AML pts; here, we focus on r/r pts. Median prior lines of therapy: 1 [1-8] in REL, 3 [1-4] in REF. Median age: 75yrs [66-86] for REL, 75 [71-81] for REF. Adverse cytogenetic risk profile: 5/17 (29%) in REL, 2/7 (29%) in REF. Median bone marrow (BM) myeloblast count at screening: 32% [6-94] for REL, 40% [3-54] for REF.
12 REL pts were evaluable for efficacy (BM assessment at C2D1). 5/12 (42%) achieved remission (4 CR/CRi, 1PR). Notably, first CR/CRi’s were reported between wk13(C5)–wk19(C7). These later onset responses may reflect the importance of AXL-related immunological mechanisms for relatively chemo-resistant relapsed pts and contribute to a longer time-on-treatment (ToT).
An additional 3 had SD; with clinical benefit rate 67%.
Median ToT was 28.0wks for CR/CRi pts. mDOR was 13.1wks [2.1-43.1+] in all responders and 14.0wks [10.0-43.1+] in CR/CRi pts. 7 pts remain on treatment. Survival outcomes continue to mature.
In contrast, no REF pts showed response (0/7), with 2/7 (28%) reporting clinical benefit; median ToT was 8.0wks. No pts remain on treatment.
Previously-reported results of preliminary scRNAseq analysis of these pts indicated differences in the T- and NK cell compartment associated with treatment response, pointing to BEM-mediated immune MOA in context of synergy of B+L. Further analyses of scRNAseq and CITE-seq data are ongoing.
Overall, the safety of B+L (compared with previously published BEM monotherapy) was in keeping with the known safety profile of LDAC. TRAEs of ≥G3 observed in ≥10% of pts were anemia (29% B+L; 0% BEM), platelet count decr. (29% B+L; 0% BEM), thrombocytopenia (19% B+L; 8% BEM), neutrophil count decr. (13% B+L; 0% BEM), white blood cell count decr. (13%B+L; 0% BEM) and ECG QT prolonged (10% B+L; 6% BEM). No G5 TRAEs reported.
Conclusion
These data show that B+L is efficacious and well tolerated in the elderly/unfit REL AML population. An in-depth translational research program aiming to identify predictive molecular and biological factors associated with response is ongoing. B+L should be considered for evaluation in a randomized pivotal trial in this population.
Keyword(s): Cytarabine, Refractory, Relapsed acute myeloid leukemia
Abstract: EP463
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Clinical
Background
Low-dose cytarabine (LDAC) in elderly relapsed (REL) & refractory (REF) (r/r) AML patients (pts) unfit for intensive therapy shows limited response (CR rate up to 17%) and survival benefit (mOS 4-6mos). This population has significant unmet need for new treatments. Bemcentinib (BEM) is an oral selective small molecule inhibitor of AXL, a RTK mediating poor prognosis, resistance to chemotherapeutics and decreased antitumor immune response. AXL is overexpressed on leukemic cells, especially in the stem cell compartment, and represents an important novel target in pts with AML.
Aims
The ongoing BGBC003 PhII trial cohorts receiving BEM+LDAC (B+L) include newly diagnosed (ND) and r/r AML pts unfit for intensive therapy. Based on observed activity, r/r AML pts were selected in an expansion cohort, to explore safety and efficacy and to undertake translational biomarker analysis. Here, we report on preliminary efficacy in r/r pts, with a safety overview for all pts treated with the combination.
Methods
Pts received BEM at the RP2D (200mg PO/d)+LDAC SoC schedule. Efficacy endpoints included objective response (OR) and clinical benefit (OR+SD [unchanged disease for at least 3 BEM cycles]). Secondary objectives include overall survival (OS) and exploratory biomarker analyses. Single cell RNA sequencing and T-cell repertoire analysis are being conducted to unravel the immunotherapeutic MOA of B+L.
Results
As of 06 Jan 21, the B+L cohorts (n=31) comprised 7 ND and 24 r/r (17 REL, 7 REF) AML pts; here, we focus on r/r pts. Median prior lines of therapy: 1 [1-8] in REL, 3 [1-4] in REF. Median age: 75yrs [66-86] for REL, 75 [71-81] for REF. Adverse cytogenetic risk profile: 5/17 (29%) in REL, 2/7 (29%) in REF. Median bone marrow (BM) myeloblast count at screening: 32% [6-94] for REL, 40% [3-54] for REF.
12 REL pts were evaluable for efficacy (BM assessment at C2D1). 5/12 (42%) achieved remission (4 CR/CRi, 1PR). Notably, first CR/CRi’s were reported between wk13(C5)–wk19(C7). These later onset responses may reflect the importance of AXL-related immunological mechanisms for relatively chemo-resistant relapsed pts and contribute to a longer time-on-treatment (ToT).
An additional 3 had SD; with clinical benefit rate 67%.
Median ToT was 28.0wks for CR/CRi pts. mDOR was 13.1wks [2.1-43.1+] in all responders and 14.0wks [10.0-43.1+] in CR/CRi pts. 7 pts remain on treatment. Survival outcomes continue to mature.
In contrast, no REF pts showed response (0/7), with 2/7 (28%) reporting clinical benefit; median ToT was 8.0wks. No pts remain on treatment.
Previously-reported results of preliminary scRNAseq analysis of these pts indicated differences in the T- and NK cell compartment associated with treatment response, pointing to BEM-mediated immune MOA in context of synergy of B+L. Further analyses of scRNAseq and CITE-seq data are ongoing.
Overall, the safety of B+L (compared with previously published BEM monotherapy) was in keeping with the known safety profile of LDAC. TRAEs of ≥G3 observed in ≥10% of pts were anemia (29% B+L; 0% BEM), platelet count decr. (29% B+L; 0% BEM), thrombocytopenia (19% B+L; 8% BEM), neutrophil count decr. (13% B+L; 0% BEM), white blood cell count decr. (13%B+L; 0% BEM) and ECG QT prolonged (10% B+L; 6% BEM). No G5 TRAEs reported.
Conclusion
These data show that B+L is efficacious and well tolerated in the elderly/unfit REL AML population. An in-depth translational research program aiming to identify predictive molecular and biological factors associated with response is ongoing. B+L should be considered for evaluation in a randomized pivotal trial in this population.
Keyword(s): Cytarabine, Refractory, Relapsed acute myeloid leukemia