Brukinsa (zanubrutinib)

P=N/A, N=37, Active, not recruiting, Zhengzhou University

P3, N=300, Not yet recruiting, BeiGene

P1, N=23, Not yet recruiting, City of Hope Medical Center

P1/2, N=170, Recruiting, BeiGene | Not yet recruiting --> Recruiting

P1, N=20, Not yet recruiting, University of Miami

Adverse events were as expected with zanubrutinib; rate of atrial fibrillation was 7.1%. At a median follow-up of 61.2 months, the results supported the initial SEQUOIA findings and suggested that zanubrutinib was a favorable treatment option for untreated patients with CLL/SLL.

The phase 3 ASPEN study compared the efficacy and safety of zanubrutinib with ibrutinib in patients with WM. While further investigation is required, this analysis supports the potential use and further exploration of Bruton tyrosine kinase inhibitors to treat PN symptoms in patients with WM. ClinicalTrials.gov: NCT03053440.

P2, N=87, Recruiting, BeiGene | Not yet recruiting --> Recruiting

Emerging long-term data from the cBTKi pivotal trials demonstrated that only a minority of pts can remain on Tx long-term (e.g. 42% of pts were still on ibrutinib [Ibr] at 89-months follow-up [FU] in the RESONATE-2 trial, with 24% having discontinued due to an AE; Barr et al...Pts (aged ≥18 years) are eligible to enroll if they have received ≥6 months of a cBTKi (Ibr, acalabrutinib [Acala], or zanubrutinib [Zanu]) for 1L Tx of CLL and are on a stable dose with a partial response (PR) or complete response (CR), per International Workshop on CLL criteria...Approximately 100 pts are planned for enrollment at around 28 sites in the US. The study is actively recruiting.

Introduction : The combination of venetoclax, the first-generation BCL2 inhibitor, and ibrutinib, a BTK inhibitor, has demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL) (Wierda et al. Other secondary endpoints include PFS as assessed by investigator (INV); CRR by INV; rate of uMRD4 based on flow cytometry; overall response rate by IRC and INV; duration of response by IRC and INV; patient-reported outcomes; and safety and tolerability. Recruitment is ongoing at approximately 230 study sites in 20 countries, including 50 sites in the US, 6 in Brazil, and 15 in Canada.

P1/2, N=56, Not yet recruiting, BeiGene

P2, N=144, Not yet recruiting, Ruijin Hospital

P4, N=33, Recruiting, Shanghai Ninth Peopole's Hospital, Shanghai Jiaotong University School of Medicine; Shanghai Ninth Peopole's Hospital, Shanghai Jiaotong University Sc

P2, N=170, Not yet recruiting, Fudan University Shanghai Cancer Center; Fudan University Shanghai Cancer Center

Two pts were switched to zanubrutinib due to PD on U2, both achieved response. AU2 is a highly effective regimen in pts with previously untreated MCL, including those with high-risk genetics (100% CR rate), and achieves a high molecular uMRD rate. Pts who develop progressive disease can be effectively salvaged with subsequent therapies.

Zanubrutinib is a second-generation BTKi with superior PFS and safety compared with ibrutinib (Brown NEJM 2023). Retreatment with zanubrutinib-venetoclax was also well-tolerated and effective. A phase 2 trial of BOVen with ΔMRD400-directed treatment duration is ongoing.

Introduction : Combined treatment with covalent BTK-inhibitor (cBTKi), such as ibrutinib, acalabrutinib, or zanubrutinib with BCL2-inhibitor, venetoclax, +/- CD20 monoclonal antibody obinutuzumab showed high rates of undetectable MRD (U-MRD4, 10-4 sensitivity) remission in patients (pts) with CLL (Jain, NEJM 2019; Munir NEJM 2023; Wierda, JCO 2021; Kater, NEJM Evidence 2022). Adverse event profile was similar to what was noted in previous studies with these agents. Updated data will be presented.

In preclinical studies, lenalidomide has been shown to induce cytotoxicity in ABC DLBCL cells by inhibiting NF-κB signaling and a synergistic effect is seen when B-cell receptor signaling is inhibited by the BTK inhibitor ibrutinib. Similar efficacy was observed across DLBCL subtypes; ORR was numerically higher in the ABC subtype. Further molecular analysis is ongoing.

P2, N=100, Not yet recruiting, VA Office of Research and Development | Trial completion date: Dec 2029 --> Dec 2030 | Trial primary completion date: Jun 2029 --> Jun 2030

P2, N=19, Not yet recruiting, Ruijin Hospital

To compare the safety and efficacy of zanubrutinib plus rituximab and lenalidomide (ZR2) and R-CHOP-like for elderly patients with newly diagnosed DLBCL, we conducted this single-center prospective study. Patients with gastrointestinal DLBCL have to be monitored closely by abdominal enhanced CT every cycle. Overall, ZR2 chemo-free regimen might be more appropriate for elderly DLBCL patients.

P2, N=80, Not yet recruiting, Navy General Hospital, Beijing

P2, N=80, Not yet recruiting, Navy General Hospital, Beijing

P1, N=119, Completed, BeiGene | Phase classification: P1b --> P1

The first-in-class covalent BTK inhibitor, Ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling...To bypass the C481S mutation, non-covalent BTKi, such as Pirtobrutinib, were developed and are active against both wild-type and the C481S mutation...In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTKi and the development of new therapeutic strategies highlight the ongoing advances being made towards the pursuit of a cure for B-cell lymphoid malignancies.

P2, N=106, Recruiting, PETHEMA Foundation | Not yet recruiting --> Recruiting

P2, N=76, Recruiting, Ruijin Hospital | Trial primary completion date: Jun 2024 --> Jun 2025

These data support its use and further evaluation of the BOVen regimen in this high-risk population. NCT03824483.

P4, N=60, Not yet recruiting, AstraZeneca

P2, N=66, Not yet recruiting, Ruijin Hospital

P2, N=42, Recruiting, Sun Yat-sen University

P2, N=42, Active, not recruiting, Sun Yat-sen University | Recruiting --> Active, not recruiting | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2024

P2, N=30, Not yet recruiting, Sun Yat-sen University

P2, N=35, Not yet recruiting, Ruijin Hospital

P2, N=24, Active, not recruiting, Northwestern University | Recruiting --> Active, not recruiting

P2, N=100, Not yet recruiting, The Lymphoma Academic Research Organisation | Trial completion date: Dec 2031 --> Mar 2032 | Initiation date: Sep 2024 --> Dec 2024 | Trial primary completion date: Feb 2028 --> May 2028

P2, N=87, Not yet recruiting, BeiGene

However, bendamustine + rituximab had a more favorable safety profile for grade ⩾3 AEs when compared with ibrutinib (risk ratio 0.62 (95% credible interval 0.40-0.86)), acalabrutinib (0.69 (0.45-0.94)), zanubrutinib (0.64 (0.42-0.91)), and venetoclax + rituximab (0.87 (0.79-0.96)). Our findings showed that venetoclax + rituximab, acalabrutinib, and zanubrutinib have acceptable safety profiles, which indicates that they may be the preferred therapeutic options in the setting of relapsed/refractory CLL. PROSPERO CRD42022304330.

P1/2, N=170, Not yet recruiting, BeiGene

P1/2, N=55, Active, not recruiting, BeiGene | Trial completion date: Sep 2024 --> Jun 2025

P=N/A, N=605, Recruiting, iOMEDICO AG | N=400 --> 605 | Trial completion date: Apr 2027 --> Aug 2028 | Trial primary completion date: Apr 2027 --> Aug 2028

Incidence of atrial fibrillation/flutter was lower with zanubrutinib vs ibrutinib (7.1% vs 17.0%); no cardiac deaths were reported with zanubrutinib vs six cardiac deaths with ibrutinib. This analysis, at 42.5 months median follow-up, demonstrates that zanubrutinib remains more efficacious than ibrutinib with an improved overall safety/tolerability profile.