Zanubrutinib (BGB-3111) is an investigational, next-generation irreversible Bruton’s tyrosine kinase (BTK) inhibitor that was shown to be highly potent and selective in nonclinical studies. A global, open-label, multicenter phase 1/2 study was initiated to evaluate zanubrutinib monotherapy in patients with various B-cell malignancies, with indication-specific expansion cohorts. Preliminary results, at a median follow-up of 13.7 months, indicated durable clinical responses with zanubrutinib in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). At the 2019 ASH annual meeting, updated safety and efficacy data (with an additional 12 months of follow-up) were presented in a larger CLL/SLL cohort; these results are summarized here.
Patients received escalating doses of zanubrutinib (from 40 mg once daily); the final recommended phase 2 dose was determined to be 160 mg twice daily or 320 mg once daily until disease progression or unacceptable toxicity. The primary end point was safety/tolerability. Secondary end points included response rate and progression-free survival (PFS).
In this trial (as of May 8, 2019), efficacy and safety analyses were done on 123 patients (CLL, 118; SLL, 5) with CLL/SLL, with no prior BTK therapy. In this cohort, 101 (82%) patients had relapsed/refractory (R/R) CLL/SLL, 22 (18%) patients had received no prior therapy for CLL/SLL, 16 of 99 (16%) patients had del(17p), and 13 of 42 (31%) had p53 mutations.
The most common adverse events (AEs) of any grade occurring in ≥15% were contusion, upper respiratory tract infection, diarrhea, cough, headache, fatigue, urinary tract infection (UTI), back pain, rash, nausea, and neutropenia. Grade ≥3 AEs (≥5%) were neutropenia, pneumonia, and anemia. Serious AEs occurred in 58 (47%) patients; the most common serious AEs were pneumonia and UTI. Treatment discontinuation due to AEs was reported in 5 patients (grade 3 muscle weakness, recurrent squamous-cell carcinoma, grade 3 tachycardia, grade 3 cryptogenic pneumonia, grade 2 pleural effusion). There was 1 death reported (recurrent squamous-cell carcinoma), which was deemed unrelated to the study drug. In terms of AEs of interest, major hemorrhage (2%; hemarthrosis and grade 3 purpura), bleeding (57%; contusion, hematuria, petechia, purpura), neutropenia (19%; decreased neutrophil count, febrile neutropenia), thrombocytopenia (6%), fatigue (20%), headache (23%), atrial fibrillation (3%; 2 grade 3), hypertension (8%), diarrhea (30%; no grade ≥3), secondary malignancies (20%), and arthralgia/myalgia (19%) were reported.
Of the 123 patients evaluable for efficacy, 22 were treatment-naïve (TN) and 101 were R/R. Based on International Workshop on Chronic Lymphocytic Leukemia criteria (2008, with 2012 modification for partial response with lymphocytosis [PR-L]), at a median follow-up of 29.5 months, 118 patients achieved a response (overall response rate [ORR; PR-L or better], 95.9%), including 19 complete responses (CRs; CR or CR with incomplete bone marrow recovery, 15%). In the del(17p) subgroup, the ORR was 94% and CR rate was 6%. The ORR and PFS were comparable in the TN and R/R patient subgroups.
Based on the results, the study investigators concluded that zanubrutinib monotherapy was generally well tolerated and active in the treatment of patients with CLL/SLL, irrespective of del(17p) status.
Cull G, et al. ASH Abstract 500. Session 642.