Tacabrutideg (BGB-16673), a first-in-class oral BTK degrader, elicited a high overall response rates across dose levels in patients with relapsed/refractory
Across all dose levels (n = 67), the ORR was 85.1%, comprising 2 patients (3.0%) with a complete response (CR) or complete response with incomplete marrow recovery (CRi). At the recommended phase 2 dose (RP2D) of 200 mg (n = 17), the ORR was 94.1%, with 1 patient in CR/CRi (5.9%). Median time to first response at the RP2D was 2.8 months (range, 2.7-8.3), and median duration of response (DOR) was 20.6 months (range, 0.0-33.1); the median DOR across all doses was 20.7 months (range, 0.0-33.1) across all doses.
“There continues to be dramatic development in [the CLL] field,” lead study author Stephan Stilgenbauer, MD, a professor of medicine and the medical director of the Division of CLL, Internal Medicine III at Ulm University, said in an interview with OncLive®. It illustrates the principle that when we target disease biology with novel principles, we can overcome treatment resistance and overcome high-risk disease features, allowing for further progress for our patients."
In August 2024,
CaDAnCe-101 is a phase 1, open-label, dose-escalation and -expansion study evaluating tacabrutideg monotherapy in adult patients with relapsed/refractory B-cell malignancies.
In the CLL/SLL cohorts, patients needed to meet 2018 International Working Group CLL criteria for treatment, and receipt of at least 2 prior therapies were required, including a covalent BTK inhibitor if approved for their disease. Adequate organ function and an ECOG performance status of 0 to 2 (0 to 1 in the European Union) were required.
Tacabrutideg was administered orally once daily in 28-day cycles across dose levels of 50 mg, 100 mg, 200 mg, 350 mg, and 500 mg.
The primary objectives of phase 1 were safety, tolerability, maximum tolerated dose, and determination of the RP2D, established at 200 mg once daily.
The median age among patients with CLL/SLL (n = 67) was 70 years (range, 47-91); 68.7% were male. Among patients with known mutation status, 25 of 66 (37.9%) harbored a BTK mutation at baseline.
In the CLL/SLL cohort, patients had received a median of 4 prior lines of therapy (range, 2-10); 94.0% had received a covalent BTK inhibitor, 82.1% had received a BCL-2 inhibitor, and 37 of 41 evaluable patients (90.2%) were refractory to their last covalent BTK inhibitor and last BCL-2 inhibitor. High-risk disease features were common at baseline; 65.7% harbored 17p deletions and/or TP53 mutations, 76.8% had unmutated IGHV, and 53.5% had complex karyotype with at least 3 chromosomal abnormalities.
Data presented reflected a cutoff of February 25, 2026. Median study follow-up was 25.4 months (range, 0.3-40.1).
Subgroup data showed that among patients refractory to their last covalent BTK inhibitor and last BCL-2 inhibitor (n = 37), the ORR was 83.8%. Among those who had received a prior covalent BTK inhibitor and BCL-2 inhibitor without a noncovalent BTK inhibitor (n=43), the ORR was 93.0%, and the ORR was 75.0% in those who had received all three classes (prior covalent BTK inhibitor, noncovalent BTK inhibitor, and BCL-2 inhibitor; n=12).
Patients with 5 or more prior lines of therapy (n = 29) achieved an ORR of 86.2%. Among those with 17p deletion and/or TP53 mutation (n = 44), the ORR was 79.5%; those with BTK mutations (n = 25) responded at a rate of 76.0%; and those with PLCG2 mutations (n = 10) responded at a rate of 90.0%. Responses were observed across all assessed BTK mutation subtypes, including the common C481S resistance mutation (ORR, 82%; n = 17).
The 24-month progression-free survival (PFS) rate was 53.8% (95% CI, 38.8%-66.6%), with a median PFS of 24.4 months (range, 0-35.9+) across the CLL/SLL cohort.
In a separate BTK inhibitor–naive expansion cohort (part 1f), 54 patients were enrolled across B-cell malignancies, including 29 with CLL/SLL (11 treatment-naive) as of a December 15, 2025, cutoff. Among CLL/SLL patients evaluable for efficacy (n = 22), the ORR was 86.4%, and no PFS events had occurred at 6 months.
Among the 67 patients with CLL/SLL treated at a median duration of exposure of 18.2 months (range, 0.2-36.4), 97.0% experienced at least one treatment-emergent adverse effect (TEAE) of any grade, and 62.7% had a grade 3 or higher TEAEs. Treatment-related grade 3 or higher TEAEs occurred in 34.3% of patients. Twelve patients (17.9%) discontinued treatment due to any TEAE, and 4 (6.0%) discontinued due to a treatment-related TEAE. No treatment-related deaths were reported.
The most common TEAEs of any grade occurring in at least 10% of patients included fatigue, contusion (bruising), diarrhea, neutropenia, anemia, pneumonia, cough, thrombocytopenia, COVID-19, dyspnea, peripheral edema, and pyrexia.
In patients who responded to treatment and had baseline cytopenias, rapid and sustained improvements were observed. Among patients with baseline thrombocytopenia (n = 22), median platelet count increased from 62.5 × 10⁹/L at baseline to 133.5 × 10⁹/L at week 9. Neutrophil counts and hemoglobin levels also improved in parallel with treatment response.
“In early drug development, safety monitoring [for] AEs among patients is of key importance. This was monitored very closely on this trial; not unexpectedly, the majority of patients had AEs, because those patients had heavy prior therapy, had prior infections, and had cytopenias to begin with when they entered the trial,” Stilgenbauer said. “The most common higher-grade AE was neutropenia, which is a laboratory phenomenon that can be managed. The other issue with infections, which is not unexpected because in patients with CLL with the immunodeficiency [and] heavy prior therapy, we frequently see infections as the most common clinically relevant toxicity. Overall...the AE profile that was seen with this drug was deemed favorable, and therefore this drug is now being developed in later phase 2 and 3 trials.”
