Novel BTK Degrader BGB-16673 Demonstrates 85% Response Rate in Heavily Pretreated CLL/SLL Patients
核心洞察
BGB-16673, a novel Bruton tyrosine kinase (搜索) degrader, achieved an 85.3% overall response rate in 68 heavily pretreated patients with relapsed/refractory chronic lymphocytic leukemia (搜索) and small lymphocytic lymphoma (搜索).
The drug showed consistent efficacy regardless of BTK (搜索) mutation status or prior exposure to BTK and BCL-2 (搜索) inhibitors, with particularly strong activity at the 200-mg dose level producing a 94.4% response rate.
Safety profile was manageable with no treatment-related deaths and only 4.4% of patients discontinuing due to treatment-related adverse events after a median follow-up of 19.8 months.
The novel Bruton tyrosine kinase (搜索) (BTK (搜索)) degrader BGB-16673 demonstrated significant antitumor activity with an 85.3% overall response rate in heavily pretreated patients with relapsed or refractory chronic lymphocytic leukemia (搜索) (CLL) and small lymphocytic lymphoma (搜索) (SLL), according to updated results from the phase 1/2 CaDAnCe-101 trial presented at the 67th ASH Annual Meeting.
The study enrolled 68 patients who had received a median of 4 prior lines of therapy, with 94.1% having previously received covalent BTK (搜索) inhibitors and 82.4% having received BCL-2 (搜索) inhibitors. Notably, 89.1% of patients had previously discontinued BTK inhibitor treatment due to disease progression, representing a challenging patient population with limited treatment options.
Robust Efficacy Across Dose Levels
BGB-16673 demonstrated high response rates across all five tested dose levels (50 mg to 600 mg daily). In the overall population, the overall response rate was 85.3%, comprising complete response/complete response with incomplete marrow recovery rates of 2.9%, partial response rates of 72.1%, and partial response with lymphocytosis rates of 10.3%. Stable disease was achieved by 7.4% of patients, while 2.9% experienced disease progression.
The 200-mg dose level showed particularly impressive results, with an overall response rate of 94.4%. This dose level achieved complete response/complete response with incomplete marrow recovery rates of 5.6%, partial response rates of 66.7%, and partial response with lymphocytosis rates of 22.2%. Based on these findings, the 200-mg dose was selected as the recommended dose for expansion in part 2 of the study.
"We also observed sustained disease control, [as evidenced by] an 18-month progression-free survival [PFS] rate of 65.9% with a median follow-up of 19.8 months, and over half of patients remain on treatment [at the time of this analysis]," stated Inhye Ahn, MD, associate director of the CLL Center at Dana-Farber Cancer Institute.
Activity Regardless of High-Risk Features
The drug showed consistent efficacy across various high-risk patient subgroups. In patients who had been double-exposed to both covalent BTK (搜索) and BCL-2 (搜索) inhibitors, the overall response rate was 93.2%, while those with triple exposure to covalent BTK, noncovalent BTK, and BCL-2 inhibitors achieved a 75.0% response rate.
Response rates remained robust across genetic risk factors, with patients harboring del(17p) and/or TP53 mutations achieving an 80.4% response rate, those with complex karyotype achieving 72.7%, patients with BTK (搜索) mutations achieving 76.9%, and those with PLCG2 mutations achieving 90.0%. Patients with six or more prior lines of therapy achieved an 81.3% response rate.
"In an exploratory analysis of genetic subgroups, we also observed comparable PFS rates regardless of baseline BTK (搜索) mutation [status]," Ahn noted during her presentation.
Manageable Safety Profile
At a median follow-up of 19.8 months, BGB-16673 demonstrated a manageable safety profile. While 95.6% of patients experienced treatment-emergent adverse events, 76.5% were treatment-related. Grade 3 or higher adverse events occurred in 61.8% of patients, with 33.8% being treatment-related.
The most common treatment-emergent adverse events were fatigue (36.8%) and contusion (30.9%). Serious treatment-emergent adverse events occurred in 48.5% of patients, with 13.2% being treatment-related. Importantly, no patients experienced treatment-related adverse events leading to death, and only 3 patients (4.4%) discontinued treatment due to treatment-related adverse events.
Seventeen patients (25.0%) experienced grade 3 or higher neutropenia, though 16 patients (23.5%) had grade 2 or higher neutropenia at baseline. Three patients developed atrial fibrillation, but all events were transient and deemed unrelated to treatment. Treatment-related major hemorrhage occurred in 2 patients.
Mechanism and Clinical Impact
BGB-16673 is an oral protein degrader that leverages the cellular proteasome pathway to tag BTK (搜索) for degradation, thereby blocking BTK signaling and leading to tumor regression. This mechanism of action differs from traditional BTK inhibitors and may explain its activity in patients who have developed resistance to conventional BTK inhibitors.
Among responding patients, BGB-16673 was associated with rapid improvements in blood counts, including increases in median platelet counts from 67.5 x 10⁹/L at baseline to 136.0 x 10⁹/L at week 9, neutrophil counts from 1.1 x 10⁹/L to 2.1 x 10⁹/L, and hemoglobin levels from 99.0 g/L to 111.0 g/L.
The median time to first response was 2.8 months in the overall population and 2.9 months in the 200-mg cohort. The median duration of exposure was 13.6 months overall and 14.4 months in the 200-mg cohort.
Future Development
The study enrolled patients with high-risk disease characteristics, including Binet stage C disease in 45.3% of patients, unmutated IGHV in 77.6%, and del(17p) and/or TP53 mutations in 67.6%. BTK (搜索) mutations were present in 39.4% of patients with known mutation status.
"[BGB-16673] is being evaluated in ongoing phase 2 and phase 3 studies in relapsed/refractory CLL, and the current study is also ongoing at over 100 sites across the world," Ahn concluded. The researchers believe these findings support continued development of BGB-16673 in relapsed/refractory B-cell malignancies, particularly CLL/SLL.