Tacabrutideg Is Tolerable and Shows Efficacy Signals Across BTK Inhibitor–Naive CLL and Other B-Cell Malignancies

The BTK degrader tacabrutideg (BGB-16673) was associated with a tolerable safety profile per investigators and showed antitumor activity in BTK inhibitor–naive patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and other B-cell malignancies, according to findings from part 1f of the phase 1 CaDAnCe-101 trial (NCT05006716) presented at the 2026 EHA Congress.¹

A total of 83.3% of patients in the overall population (n = 54) experienced an any-grade treatment-emergent adverse effect (TEAE); TEAEs of grade 3 or higher were seen in 33.3% of patients. The median duration of treatment exposure was 8.1 months (range, 0.4-12.8). The most frequently observed any-grade TEAEs included contusion (bruising; 27.8%), neutropenia/decreased neutrophil count (20.4%), and petechiae (18.5%). The most commonly reported grade 3 or higher TEAE was neutropenia/decreased neutrophil count (14.8%).

Among patients with CLL/SLL (n = 29), the most common grade 3 or higher TEAE was neutropenia/decreased neutrophil count (20.7%). One patient with mantle cell lymphoma (MCL) experienced grade 3 paroxysmal atrial fibrillation, which resolved to sinus rhythm. In the total population, 3 patients had grade 3 infections, and no patients had grade 4 or 5 infections.

Notably, 1 TEAE led to treatment discontinuation due to chronic back pain exacerbation, and 1 other TEAE led to treatment discontinuation and death due to metastatic neoplasm.

“In the first report of BTK [degrader’s] clinical activity in a BTK inhibitor–naive population, [the] novel BTK degrader [tacabrutideg] was well tolerated,” lead study author Irina Mocanu, MD, of The Institute of Oncology at ARENSIA Exploratory Medicine in Chisinau, Moldova, and coauthors wrote in the poster. “BTK inhibitor–naive patients had fewer grade 3 or higher TEAEs compared with heavily pretreated BTK inhibitor–exposed cohorts. No cases of major hemorrhage, opportunistic infections [including invasive fungal infections], or febrile neutropenia occurred.”

What are the relevant design factors of CaDAnCe-101?

Cohort 1f is the monotherapy safety-expansion portion of this open-label trial that enrolled patients with a confirmed diagnosis of CLL/SLL, MCL, marginal zone lymphoma (MZL), Waldenstrom Macroglobulinemia (WM), or Richter transformation. Patients needed to have an ECOG performance status of 0 to 2 (0 to 1 in the European Union), no prior BTK inhibitor exposure, and adequate organ function.

Patients in cohort 1f received oral tacabrutideg at 200 mg once per day.

The primary end points were safety and tolerability, as well as identification of the maximum tolerated dose and recommended dose for expansion. Secondary end points included pharmacokinetics, pharmacodynamics, and preliminary efficacy.

Patients in cohort 1f had a median age of 68 years (range, 42-81). Patients with relapsed/refractory disease (75.9%) had received a median of 2 prior lines of therapy (range, 1-9). Disease subtypes included CLL/SLL (53.7%), MCL (14.8%), MZL (18.5%), WM (9.3%), and Richter transformation (3.7%).

What additional safety findings were seen in cohort 1f of CaDAnCe-101?

Treatment-related TEAEs were reported in 64.8% of patients, and grade 3 or higher treatment-related TEAEs were seen in 24.1% of patients. Serious TEAEs were reported in 11.1% of patients, and the rate of treatment-related serious TEAEs was 3.7%. TEAEs and treatment-related TEAEs, respectively, led to dose interruption (18.5%; 9.3%), treatment discontinuation (3.7%; 0%), and death (1.9%; 0%). No TEAEs led to dose reduction.

What was the efficacy of tacabrutideg in patients with CLL/SLL and other B-cell malignancies?

Due to the small sample sizes in other cohorts, efficacy was only reported in the CLL/SLL cohort. Among efficacy-evaluable patients in this cohort (n = 22), at a median follow-up of 8.2 months (range, 0.4-12.8), the overall response rate (ORR) was 86.4%, including best responses of partial response (PR; 68.2%), PR with lymphocytosis (18.2%), and stable disease (13.6%). Responses were ongoing in all responders as of the data cutoff. The median time to first response was 2.8 months (range, 2.7-5.6), and the median time to best response was 5.5 months (range, 2.7-6.8).

Among evaluable patients with 17p deletions or TP53 mutations (n = 6), 4 responded, and the other 2 remained on treatment with stable disease. All patients with unmutated IGHV (n = 4) responded.

At 6 months, no progression-free survival events were observed. Additionally, all 44 patients with available BTK degradation data in peripheral blood had complete BTK degradation at steady state.

“These encouraging safety and efficacy results could inform future clinical trials,” the authors concluded.

Further reading: OncLive® also covered data with tacabrutideg in a relapsed/refractory CLL/SLL-only cohort of patients from CaDAnCe-101, also presented at EHA 2026.² In this analysis, among 67 evaluable patients, the ORR was 85.1%, the median time to first response at the recommended phase 2 dose (RP2D) was 2.8 months (range, 2.7-8.3), and the median duration of response (DOR) at the RP2D was 20.6 months (range, 0.0-33.1). Across all doses, the median DOR was 20.7 months (range, 0.0-33.1).

References

1. Mocanu I, Frustaci AM, Costa A, et al. Bruton tyrosine kinase (BTK) degrader BGB-16673 in BTK inhibitor–naive patients with CLL/SLL and other B-cell malignancies: results from the phase 1 CADANCE-101 study. Presented at: 2026 EHA Congress; June 11-14, 2026; Stockholm, Sweden. Abstract PS1693.
2. OncLive Staff. Tacabrutideg drives responses in heavily pretreated CLL/SLL. OncLive.com. June 14, 2026. Accessed June 15, 2026. https://www.onclive.com/view/tacabrutideg-drives-responses-in-heavily-pretreated-cll-sll