Preliminary results from a phase 1/1b first-in-human study of BGB-21447, a next-generation BCL2 inhibitor, in patients with B-cell non-Hodgkin lymphoma

Abstract Introduction: B-cell lymphoma 2 (BCL2)–mediated resistance to the intrinsic apoptosis pathway is a key factor in the pathogenesis and chemoresistance of hematologic malignancies. BGB-21447 is a novel, orally bioavailable BH3 mimetic that was designed to be a highly potent inhibitor of both wild-type and mutant BCL2. BGB-21447-101 (NCT05828589) is a first-in-human phase 1/1b study of BGB-21447 in patients with B-cell malignancies. Presented here are preliminary safety data and antitumor activity in all dose-limiting toxicity (DLT)–evaluable patients with B-cell non-Hodgkin lymphoma (B-NHL) treated with BGB-21447 monotherapy under fasted status in part 1 (dose finding). Methods: BGB-21447-101 is an ongoing, global, open-label, dose-escalation and dose-optimization study to evaluate BGB-21447 in adults with mature B-cell malignancies. Eligible patients have a confirmed diagnosis with a relapsed/refractory B-cell malignancy (ie, diffuse large B-cell lymphoma DLBCL, follicular lymphoma FL, or marginal zone lymphoma MZL), transformed B-NHL, or Richter transformation to DLBCL. Key exclusion criteria include prior malignancy other than the disease under study within 2 years, known central nervous system involvement, autologous stem cell transplant or chimeric antigen receptor T-cell (CAR-T) therapy within 3 months, and prior allogeneic stem cell transplant. In the dose-escalation stage, BGB-21447 is administered orally at planned dose levels ranging from 10 mg to 320 mg using a ramp-up strategy. The primary study objectives are to evaluate the safety/tolerability and determine the recommended phase 2 dose of BGB-21447 monotherapy. Treatment-emergent adverse events (TEAEs) are graded per NCI-CTCAE v5.0. DLTs are assessed from the first dose to day 21 of BGB-21447 treatment at the target dose. Tumor lysis syndrome (TLS) is assessed according to Howard 2011 criteria. Results: As of May 16, 2025, 44 patients with B-NHL had been enrolled in the dose-escalation cohort and received BGB-21447 at target doses ranging from 10 mg to 320 mg. The median age of study patients was 58 years (range, 32-81 years), 56.8% of patients (n=25) were male, 88.6% (n=39) were Asian, and 11.4% were White. Sixteen patients (36.4%) had FL and 12 (27.3%) had DLBCL. Across indications, patients had a median of 3 (range, 0-7) lines of therapy; 63.6% of patients (n=28) had received ≥3 prior lines, 11.4% (n=5) had prior CAR-T therapy, and 4.5% (n=2) had prior bispecific or trispecific antibodies. The median study follow-up was 6.4 months (range, 0.8-22.9 months), and median treatment duration was 2.6 months (range, 0.2-22.5 months). Any-grade TEAEs occurred in 93.2% of patients (n=41; treatment-related, 79.5%) and grade ≥3 TEAEs were seen in 59.1% of patients (n=26; treatment-related, 40.9%). TEAEs occurring in 20% of patients were leukopenia (56.8%; grade ≥3, 20.5%), neutropenia (50.0%; grade ≥3, 27.3%), lymphopenia (36.4%; grade ≥3, 18.2%), anemia (31.8%, grade ≥3, 4.5%), thrombocytopenia (29.5%; grade ≥3, 6.8%), and hypokalemia (22.7%, grade ≥3, 2.3%). During BGB-21447 treatment, 29.5% of patients (n=13) received G-CSF and 9.1% of patients (n=4) received thrombopoietin. Two patients (4.5%) had TEAEs that led to treatment discontinuation. One patient had laboratory TLS that resolved within 3 days with no sequelae; no clinical TLS was observed. In evaluable patients, overall response rates (ORRs) were 38.1% (8/21) in FL/MZL and 33.3% (4/12) in DLBCL, with complete response rates of 14.3% (3/21) in FL/MZL and 16.7% (2/12) for DLBCL. The median time to first response was 2.8 months in FL/MZL and 4.1 months in DLBCL. Marked pharmacodynamic effects were observed following BGB-21447 treatment, as demonstrated by dissociation of the BCL2:BIM complex and decreases in B-cell count in peripheral blood. Conclusions: Initial first-in-human data demonstrate that BGB-21447 is well tolerated in heavily pretreated patients with B-NHL. The safety profile is as expected; as with other BCL2 inhibitors, hematologic toxicities are the most common all-grade and grade ≥3 TEAEs observed. Antitumor activity is encouraging, with ORRs of 38% and 33% observed in patients with FL/MZL and DLBCL, respectively. Enrollment in BGB-21447-101 is ongoing.