The novel BTK protein degrader BGB-16673 demonstrated significant antitumor activity with an 84.8% overall response rate in heavily pretreated patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), according to updated results from the phase 1/2 CaDAnCe-101 trial presented at the 2025 European Hematology Association Congress.
The findings represent a potential breakthrough for patients with limited treatment options, as responses were observed regardless of baseline mutations and other high-risk features that typically confer poor prognosis.
Trial Design and Patient Population
The open-label, dose-escalation and expansion study enrolled 66 patients with relapsed/refractory CLL/SLL who had received a median of 4 prior therapies (range, 2-10). The patient population was heavily pretreated, with 93.9% having received a covalent BTK inhibitor, 81.8% a BCL2 inhibitor, and 63.6% having double exposure to both drug classes.
Patients received BGB-16673 orally at doses ranging from 50 mg to 600 mg once daily in 28-day cycles. The median age was 70 years, and the majority (68.2%) were male. Notably, 88.7% of patients had discontinued their prior BTK inhibitor due to disease progression.
The study population included patients with particularly challenging disease characteristics, including Binet stage C disease (46.8%), unmutated IGHV (77.6%), 17p deletion and/or TP53 mutations (65.2%), and complex karyotype (50.0%). BTK mutations were present in 38.1% of patients, while PLCG2 mutations occurred in 15.9%.
Efficacy Results
At a median follow-up of 15.6 months, the overall response rate reached 84.8%, comprising a 4.5% complete response/complete response with incomplete marrow recovery rate, 66.7% partial response rate, and 13.6% partial response with lymphocytosis rate. Additionally, 7.6% of patients achieved stable disease.
The one-year progression-free survival rate was 77.4% (95% CI, 63.1%-86.8%). The median time to first response was 2.8 months (range, 2.0-19.4), with a median time to best response of 3.4 months (range, 2.0-19.4).
Dose-Specific Outcomes
The 200-mg dose level, selected for the trial's expansion phase, showed particularly robust activity with a 93.8% overall response rate in 16 patients. This included a 6.3% complete response/complete response with incomplete marrow recovery rate, 75.0% partial response rate, and 12.5% partial response with lymphocytosis rate. The median duration of exposure at this dose was 16.2 months (range, 2.9-24.6).
Response rates across other dose levels were: 100% at 50 mg (n=1), 81.8% at 100 mg (n=22), 73.3% at 350 mg (n=15), and 91.7% at 500 mg (n=12).
High-Risk Subgroup Analysis
BGB-16673 demonstrated activity across challenging patient subgroups. In patients with double exposure to covalent BTK and BCL2 inhibitors, the overall response rate was 90.5%, while those with triple exposure achieved a 75.0% response rate.
Patients with specific high-risk molecular features also responded well: those with 17p deletion and/or TP53 mutations achieved an 81.4% response rate, complex karyotype patients had a 72.7% response rate, BTK mutation carriers showed a 75.0% response rate, and those with PLCG2 mutations achieved a 90.0% response rate.
Safety Profile
Treatment-emergent adverse events occurred in 95.5% of patients, with 74.2% being treatment-related and 60.8% grade 3 or higher. Treatment-related adverse events of grade 3 or higher occurred in 30.3% of patients. Serious adverse events were reported in 45.5% of patients, with 12.1% being treatment-related.
The most common treatment-emergent adverse events were fatigue (37%), contusion (30%), diarrhea (27%), neutropenia (24% grade ≥3), and anemia (21%). Atrial fibrillation occurred in 2 patients, and 2 patients experienced major hemorrhage events. No cases of pancreatitis were reported.
Nine patients discontinued BGB-16673, with only 2 discontinuations due to treatment-related adverse events. Four patients experienced treatment-emergent adverse events leading to death, but none were related to therapy.
Mechanism of Action
BGB-16673 represents a novel approach to targeting BTK resistance in CLL/SLL. Unlike traditional BTK inhibitors, this oral protein degrader works by tagging BTK for degradation through the cellular proteasome pathway, potentially overcoming resistance mutations that limit the effectiveness of conventional BTK inhibitors.
"Disease progression is common in patients with CLL/SLL who are undergoing treatment with BTK inhibitors, which can be caused by BTK resistance mutations," explained lead study author Lydia Scarfò, MD, from the Università Vita-Salute San Raffaele in Milano, Italy.
Clinical Impact
The treatment also demonstrated rapid improvement in cytopenias among responders, with median platelet counts increasing from 67.0 x 10⁹/L at baseline to 141.0 x 10⁹/L at week 9, neutrophil counts rising from 1.1 x 10⁹/L to 2.1 x 10⁹/L, and hemoglobin levels improving from 99.0 g/L to 108.0 g/L.
"The novel BTK degrader BGB-16673 was safe and well tolerated in this heavily pretreated population of patients with relapsed/refractory CLL and small lymphocytic lymphoma," Scarfò stated. "BGB-16673 shows significant antitumor activity regardless of disease features; patients carrying BTK mutations and those previously exposed to a covalent BTK inhibitor, noncovalent BTK inhibitor, and BCL2 inhibitor responded."
BGB-16673 is currently being evaluated in ongoing phase 2 and 3 trials in patients with relapsed/refractory CLL, representing a potential new treatment option for this challenging patient population.
