Preliminary Safety and Efficacy of Bgb-11417, a Novel Bcl-2 Inhibitor, in Combination with Azacitidine in Patients with Acute Myeloid Leukemia (AML)

Background/Introduction: The efficacy of Bcl-2 inhibitors for treating AML was recognized by the approval of venetoclax and azacitidine (aza) in patients (pts) with newly diagnosed AML ineligible for intensive chemotherapy. However, survival rates beyond 2 years are low. Compared to venetoclax, BGB-11417 is a much more potent Bcl-2 inhibitor (>10-fold in biochemical assays) with improved selectivity and the potential to achieve deeper target inhibition and responses in the clinical setting. Here, we present updated preliminary results of pts with AML enrolled in BGB-11417-103 (NCT04771130). Methods: BGB-11417-103 is an ongoing dose finding/expansion study evaluating BGB-11417 and aza in pts with AML (treatment-naïve [TN] unfit for intensive chemotherapy or relapsed/refractory [R/R]), myelodysplastic syndrome (MDS), or MDS/myeloproliferative neoplasm. For all indications, pts who received prior aza or Bcl-2 inhibitors were excluded. For pts with AML, the 10-day regimen comprised BGB-11417 at 40 mg (cohort 1), 80 mg (cohort 2), or 160 mg (cohort 3); 160 mg was also used in a 28-day regimen (cohort 4). All dose levels were given in combination with aza (75 mg/m2 x 7 days). In cycle 1, a 4-day ramp-up of BGB-11417 starting at 1/8 target dose was used. Patients with dose-limiting toxicities (DLTs) in cycle 1 were assessed against the number of patients dosed. The safety stopping criteria were based on the number of patients with events where posterior probability of event rate exceeding 0.25 was at least 80%. Responses were determined using 2017 European LeukemiaNet (ELN) criteria with assessment of hematologic improvement. Treatment-emergent adverse events (TEAEs), minimal residual disease (MRD) by flow cytometry, and pharmacokinetics (PK) were also assessed. Results: As of June 1, 2022, 51 pts with AML were treated (16 in cohort 1; 17 in cohort 2; 14 in cohort 3; 4 in cohort 4). Median age was 77 yrs (TN, n=28) and 64 yrs (R/R, n=23) (Table 1). At baseline, 23 pts (45.1%) had adverse-risk cytogenetics, 37 (72.5%) had grade ≥3 neutropenia, and 27 (52.9%) had grade ≥3 thrombocytopenia. At a median follow-up of 2.8 mo (range 0.1-12.3) and median duration of treatment of 1.9 mo (range 0.0-12.3), 2 of 41 evaluable pts experienced DLTs (grade 4 neutropenia and grade 4 thrombocytopenia at 80 mg) (Table 2), which did not meet the safety stopping protocol criteria. Laboratory tumor lysis syndrome (TLS; Howard criteria) was observed in 1 pt (160 mg x 10 days) with a known history of chronic kidney disease; TLS resolved within 4 days. Twenty-one (41%) pts discontinued study drugs: 7 (13.7%) due to AEs, 5 (9.8%) due to disease progression, 4 (7.8%) proceeded to transplant, 3 (5.9%) withdrew consent, 1 (2.0%) per investigator decision, and 1 (2.0%) started new anti-cancer treatment. The most common TEAEs were neutropenia (58.8%), thrombocytopenia (45.1%), anemia (43.1%), febrile neutropenia (33.3%), nausea (39.2%), and constipation (37.3%). Neutropenia was the most common grade ≥3 TEAE observed in 30 (58.8%) pts; most cases did not require dose modification. Grade ≥3 infections occurred in 23 (45.1%) pts, mostly in cycle 1. The general incidence of febrile neutropenia and infections decreased with subsequent cycles. Four (7.8%) pts died due to unrelated TEAEs: bronchopulmonary aspergillosis, pneumonia, pulmonary sepsis, and possible intracranial hemorrhage after a fall. TEAEs leading to dose reduction (5.9%) or dose interruption (11.8%) were infrequent. In TN AML, complete remission (CR)/CR with partial hematologic recovery (CRh) was achieved in 16 (59.3%) and CR in 13 (48.1%) evaluable pts (Table 1). Of the 13 pts in CR, 7 (53.8 %) reached CR by end of cycle 1. In cohort 2 with the longest follow-up, CR was achieved in 8 (72.7%) pts with TN AML. Notably, 7 of these pts are continuing study treatment (median of 5 cycles, range 1-12) without progression. In R/R AML, CR/CRh was seen in 50% of evaluable pts, with a CR rate of 25%. Nine (50.0%; 6 TN, 3 R/R) of 18 evaluable pts with CR/CRh achieved MRD negativity (<0.1% per ELN 2018). In pts with AML treated with 40, 80, and 160 mg, PK increased in a dose-dependent manner at steady state with no drug-drug interaction observed with aza. Conclusion: These results demonstrate that BGB-11417 in combination with aza was effective and generally well tolerated at the 4 dose levels tested in pts with AML, with no dose-dependent toxicities observed. Further evaluation of the 28-day regimen is underway. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal