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)

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.

Methodsand 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.