Calquence (acalabrutinib)

P3, N=42, Not yet recruiting, The First Affiliated Hospital of Soochow University

In real-world practice, venetoclax plus obinutuzumab was associated with longer TTNT and improved OS compared to acalabrutinib as first-line therapy in patients with TP53 wild-type CLL.

P2, N=108, Active, not recruiting, AstraZeneca | Trial primary completion date: Jul 2028 --> Oct 2028 | Trial completion date: Jul 2028 --> Oct 2028

In this review, we consider the pharmacologic properties of zanubrutinib that differentiate it from ibrutinib and acalabrutinib, and provide a comprehensive overview of the efficacy and safety data that led to zanubrutinib monotherapy becoming a preferred therapy for a significant subgroup of patients with CLL/SLL. We also highlight trials in CLL/SLL and Richter's transformation with zanubrutinib in targeted therapy combinations that offer the potential for time-limited treatment courses.

To date, neither randomized nor retrospective trials have directly compared these approaches in RR CLL, and only limited data are available comparing venetoclax plus obinutuzumab (VenObi) to BTKi in the first-line setting. We retrospectively analysed 352 patients receiving second-line therapy: 93 VenR and 259 BTKi (ibrutinib: n = 222; acalabrutinib: n = 37)...Treatment discontinuation due to adverse events before month 24 was more frequent with BTKi (22.5% with VenR vs. 34.3% with BTKi), primarily due to infections (10.6% vs. 28.6%) and disease progression (14.3% vs. 22.5%). These preliminary data suggest comparable outcomes and manageable toxicity profiles for both regimens.

P2, N=35, Not yet recruiting, City of Hope Medical Center

Covalent BTKi (cBTKi) such as ibrutinib, acalabrutinib, and zanubrutinib are effective but alterations in the kinase domain at C481 or BTK gatekeeper residue T474 mutations result in development of resistance...We evaluated the efficacy of a new ncBTKi, docirbrutinib (AS-1763), against 14 BTK mutants, including C481S, T474x, and L528x, as well as gatekeeper and kinase domain double mutants, using biochemical assays, cell-line models, and primary CLL lymphocytes. Docirbrutinib potently inhibited BTK autophosphorylation and mutant BTK-driven cell proliferation, with greater effects than ibrutinib and pirtobrutinib against certain mutants. In treatment-naïve and relapsed/refractory CLL samples, docirbrutinib disrupted B-cell receptor signaling and sensitized cells to apoptosis induced by venetoclax and AZD5991. In a dose-escalation trial (NCT05602363), docirbrutinib decreased CCL3/CCL4 biomarkers and inhibited the B-cell receptor pathway signaling in longitudinal samples from patients with relapsed/refractory CLL. These findings establish docirbrutinib as a pan-mutant ncBTKi with potential to improve outcomes for CLL patients, including those with disease resistant to cBTKi and other ncBTKi.

P2, N=4, Active, not recruiting, City of Hope Medical Center | Trial completion date: Feb 2026 --> Feb 2027

P2, N=80, Recruiting, AstraZeneca | Trial completion date: Aug 2027 --> Mar 2029 | Trial primary completion date: Aug 2027 --> Mar 2029

P=N/A, N=45, Completed, iOMEDICO AG | Active, not recruiting --> Completed

P3, N=500, Recruiting, BeOne Medicines | N=186 --> 500

P1/2, N=25, Not yet recruiting, AstraZeneca AB