Emerging data from the Phase 1/2 CaDAnCe-101 trial reveals that the Bruton tyrosine kinase (BTK) degrader BGB-16673 demonstrates promising efficacy and a tolerable safety profile in patients with relapsed/refractory (R/R) Waldenström macroglobulinemia (WM) and heavily pretreated R/R chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The findings, presented at the 2024 American Society of Hematology Annual Meeting & Exposition (ASH), highlight the potential of BGB-16673 to overcome BTK inhibitor resistance and provide a new treatment option for these challenging B-cell malignancies.
Efficacy in Waldenström Macroglobulinemia
In the WM cohort, comprising 27 response-evaluable patients, BGB-16673 achieved an objective response rate (ORR) of 81%. The major response rate (partial response [PR] or better) was 74.1%, with a very good PR rate of 25.9%. The median time to first response was one month (0.9-3.7), and responses deepened over time. Notably, responses were observed across various subgroups, including patients receiving the lowest dose (100 mg) and those previously treated with covalent (cBTKi) and noncovalent BTK inhibitors (ncBTKi). Responses were also seen regardless of mutations in BTK, MYD88, CXCR4, and TP53.
Patients enrolled in the WM study had confirmed R/R WM treated with at least two prior therapies, an ECOG performance status of 0 to 2, and adequate organ function. All patients had received an anti-CD20 antibody, and those in the US or EU had also received a cBTKi. The median age of participants was 73 years (range: 56-81), and they had undergone a median of 3 prior therapies. All patients had received prior cBTKis, while 18.5% had received BCL2 inhibitors, and 14.8% had received ncBTKis. Common mutations included MYD88 (92.8%) and CXCR4 (48%).
Safety Profile in Waldenström Macroglobulinemia
Treatment-emergent adverse events (TEAEs) of any grade were reported in 92.6% of patients, with 40.7% experiencing grade 3 or higher TEAEs. The most common TEAE was neutropenia (29.6%; grade 3 or higher, 25.9%). Importantly, no incidents of atrial fibrillation, hypertension, febrile neutropenia, or major hemorrhage occurred. No TEAEs led to treatment discontinuation or dose reduction, and the maximum-tolerated dose (MLD) was not reached. One patient died due to septic shock related to disease progression.
Activity in Relapsed/Refractory CLL/SLL
In the CLL/SLL cohort, BGB-16673 demonstrated an ORR of 77.6% (38 of 49 response-evaluable patients), with a complete response (CR) or CR with incomplete hematologic recovery rate of 4.1%. At the 200 mg dosage, the ORR was 93.8%, including one CR. The median time to first response was 2.8 months (2.6-8.3). Promising activity was also observed in patients with Richter Transformation, with an ORR of 58.3% (7 of 12 evaluable patients), including one CR.
The CLL/SLL study included patients with a median age of 70 years (range: 50-91) who had undergone a median of 4 prior lines of therapy. The majority had received prior cBTKis (93.3%) and BCL2 inhibitors (83.3%). Common mutations included BTK (33.3%) and PLCG2 (14.8%).
Safety in Relapsed/Refractory CLL/SLL
Among 60 safety-evaluable patients with CLL/SLL, 93.3% experienced any TEAE, with 55% experiencing grade 3 or higher TEAEs. There was one dose-limiting toxicity at the 200 mg dose (grade 3 maculopapular rash), which resolved with a dose hold. Seven patients discontinued treatment due to TEAEs, with two related to treatment. Three patients experienced fatal TEAEs, none of which were considered treatment-related. No atrial fibrillation or pancreatitis was reported, but there were two cases of major hemorrhage and one case of febrile neutropenia.
