Preliminary efficacy and safety of the Bruton tyrosine kinase degrader BGB-16673 in patients with relapsed/refractory Richter transformation: Results from the ongoing phase 1 CaDAnCe-101 study

Abstract Introduction There is no standard of care treatment for Richter transformation (RT) of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) to diffuse large B-cell lymphoma (DLBCL). Existing therapies, including chemoimmunotherapy (CIT) and Bruton tyrosine kinase (BTK) inhibitors ± checkpoint inhibitors, may induce responses, but they are not durable and patient outcomes are poor. BGB-16673 is an orally available protein degrader that blocks BTK signaling by tagging BTK for degradation through the cell's proteasome pathway, leading to tumor regression. CaDAnCe-101 (BGB-16673-101; NCT05006716) is an ongoing open-label, phase 1/2 study evaluating BGB-16673 monotherapy in patients with B-cell malignancies. Here, preliminary safety and efficacy results of BGB-16673 are presented in patients with relapsed/refractory (R/R) RT who were treated in the phase 1 portion of the study. Methods Eligible patients must have confirmed R/R RT treated with ≥1 prior RT-directed therapy, an ECOG performance status of 0-2 (0-1 in the EU), and adequate organ function; patients with progressive CLL/SLL who had a prior history of RT were included in the RT cohort. In the US, EU, and Australia, patients must have previously received a covalent BTK inhibitor. BGB-16673 was dosed once daily (QD) orally in 28-day cycles (6 planned dose levels: 50-600 mg QD). The primary phase 1 objectives were to assess safety and tolerability per NCI-CTCAE v5.0 and to establish the maximum tolerated dose and recommended dose for expansion. A secondary objective was to assess the overall response rate (ORR) per 2014 Lugano criteria, with the first assessment occurring after 12 weeks of treatment. Results As of May 23, 2025, 24 patients with RT were enrolled and treated in 1 of 4 BGB-16673 dose cohorts (100 mg, n=5; 200 mg, n=7; 350 mg, n=10; 500 mg, n=2). Median age in all patients was 67 years (range, 47-83 years). The median number of prior therapies for either CLL/SLL or RT was 3 (range, 1-11), of which a median of 2 (range, 1-11) were given for RT. Prior therapies included covalent BTK inhibitors (n=20 [83.3%]), BCL2 inhibitors (n=13 [54.2%]), noncovalent BTK inhibitors (n=4 [16.7%]), allogeneic or autologous stem cell transplant (SCT; n=2 [8.3%] each), and chimeric antigen receptor-T cell therapy (n=1 [4.2%]). All patients received CIT for RT prior to study enrollment (23/24 received anthracycline-based CIT). Overall, 19.0% of patients (4/21) had BTK mutations prior to BGB-16673 treatment. At baseline, 83.3% (20/24) of patients had TP53 mutation, 90.9% (10/11) had unmutated IGHV, and 23.8% (5/21) had PLCG2 mutation. Median follow-up was 5.2 months (range, 0.6-17.8 months). In total, 91.7% of patients had any-grade treatment-emergent adverse events (TEAEs) and 66.7% had grade ≥3 TEAEs. Any-grade TEAEs that occurred in ≥15% of patients were neutropenia/neutrophil count decreased (37.5%), nausea (20.8%), diarrhea (16.7%), peripheral edema (16.7%), and pneumonia (16.7%). Grade ≥3 TEAEs that occurred in ≥10% of patients were neutropenia/neutrophil count decreased (33.3%), anemia (12.5%), and pneumonia (12.5%). No cases of atrial fibrillation or febrile neutropenia occurred. Major hemorrhage occurred in 4.2% of patients (n=1; grade 2 subdural hematoma). TEAEs led to dose reductions in 2 patients (8.3%) and to death in 1 patient (4.2%; pyrexia in the context of progressive disease, not deemed to be treatment related). In 21 response-evaluable patients (3 patients with ongoing treatment had not reached the first response assessment by the data cutoff), the ORR was 52.4% (n=11), including a complete response rate of 9.5% (n=2). One patient with an ongoing response discontinued treatment to undergo allogeneic SCT. Responses were seen in 55.6% of patients (10/18) previously treated with a covalent BTK inhibitor, in patients with (4/4 [100%]) and without (7/17 [41.2%]) known BTK mutations, with TP53 mutations (9/18 [50.0%]), and with PLCG2 mutations (2/5 [40.0%]). Median time to first response was 2.8 months (range, 2.6-4.6 months). Among the 11 patients who attained a response, 5 maintained a response for ≥6 months; of the remaining patients, 3 were censored and 3 experienced events prior to 6 months. Conclusions Data from this ongoing study demonstrate that the BTK degrader BGB-16673 has a tolerable safety profile and a promising ORR of 52.4%, with evidence of responses lasting >6 months in heavily pretreated patients with R/R RT.

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