Selective Bruton's Tyrosine Kinase Research Articles

Acalabrutinib in Chinese patients with relapsed/refractory chronic lymphocytic leukemia: Primary analysis from an open-label, multicenter phase 1/2 trial.

Acalabrutinib is a highly selective Bruton tyrosine kinase inhibitor approved in the United States and Europe for chronic lymphocytic leukemia (CLL) based on phase 3 trials with limited representation of Asian populations. This phase 1/2 trial evaluates acalabrutinib in Chinese adults with relapsed/refractory (R/R) CLL receiving acalabrutinib 100mg twice daily in 28-day cycles until disease progression or treatment discontinuation due to adverse events (AEs) presenting substantial clinical risk. The primary endpoint was blinded independent central review (BICR)-assessed overall response rate (ORR). A total of 60 patients from 20 sites in China received acalabrutinib (median age 62years; median 1 prior therapy line; 21.7% with del(17p) and/or TP53 mutation; 51.7% with unmutated IGHV). Median total treatment duration was 19.4months (range 0.6-28.2) with 53 patients (88.3%) receiving acalabrutinib at data cutoff; median study follow-up was 20.2months. BICR-assessed ORR was 85.0% (95% CI, 73.4-92.9). Median duration of response, progression-free survival (PFS), and overall survival (OS) were not reached. Estimated 12-month and 18-month PFS rates were 91.5% (95% CI, 80.9-96.4) and 78.8% (95% CI, 60.9-89.2); OS rates were both 96.7% (95% CI, 87.3-99.2). AEs of grade ≥ 3 occurred in 25 patients (41.7%), most commonly decreased neutrophil count (13.3%, n = 8), pneumonia (6.7%, n = 4), and upper respiratory tract infection (6.7%, n = 4). AEs led to treatment discontinuation in 2 patients (paraneoplastic pemphigus; rectal neoplasm). This study demonstrated high ORR in acalabrutinib-treated Chinese patients with R/R CLL with no unexpected safety concerns. This trial is registered on ClinicalTrials.gov (NCT03932331).

Latest Results From an Ongoing First-in-Human Phase 1a/B Study of NX-5948, a Selective Bruton's Tyrosine Kinase (BTK) Degrader, in Patients With Relapsed/Refractory CLL and Other B-Cell Malignancies

Latest Results From an Ongoing First-in-Human Phase 1a/B Study of NX-5948, a Selective Bruton's Tyrosine Kinase (BTK) Degrader, in Patients With Relapsed/Refractory CLL and Other B-Cell Malignancies

CLL-638 Latest Results From an Ongoing Firstin-Human Phase 1a/B Study of NX-5948, a Selective Bruton's Tyrosine Kinase (BTK) Degrader, in Patients With Relapsed/Refractory CLL and Other B-Cell Malignancies

CLL-638 Latest Results From an Ongoing Firstin-Human Phase 1a/B Study of NX-5948, a Selective Bruton's Tyrosine Kinase (BTK) Degrader, in Patients With Relapsed/Refractory CLL and Other B-Cell Malignancies

Bruton's tyrosine kinase inhibition limits endotoxic shock by suppressing IL-6 production by marginal zone B cells in mice.

Sepsis is a systemic inflammatory response to a severe, life-threatening infection with organ dysfunction. Although there is no effective treatment for this fatal illness, a deeper understanding of the pathophysiological basis of sepsis and its underlying mechanisms could lead to the development of new treatment approaches. Here, we demonstrate that the selective Bruton's tyrosine kinase (Btk) inhibitor acalabrutinib augments survival rates in a lipopolysaccharide (LPS)-induced septic model. Our in vitro and in vivo findings both indicate that acalabrutinib reduces IL-6 production specifically in marginal zone B (MZ B) cells rather than in macrophages. Furthermore, Btk-deficient MZ B cells exhibited suppressed LPS-induced IL-6 production in vitro. Nuclear factor-kappa B (NF-κB) signaling, which is the downstream signaling cascade of Toll-like receptor 4 (TLR4), was also severely attenuated in Btk-deficient MZ B cells. These findings suggest that Btk blockade may prevent sepsis by inhibiting IL-6 production in MZ B cells. In addition, although Btk inhibition may adversely affect B cell maturation and humoral immunity, antibody responses were not impaired when acalabrutinib was administered for a short period after immunization with T-cell-independent (TI) and T-cell-dependent (TD) antigens. In contrast, long-term administration of acalabrutinib slightly impaired humoral immunity. Therefore, these findings suggest that Btk inhibitors may be a potential option for alleviating endotoxic shock without compromising humoral immunity and emphasize the importance of maintaining a delicate balance between immunomodulation and inflammation suppression.

Zanubrutinib Combined Regimen As Bridging Treatment on Promising Clinical Outcome of CD19 Chimeric Antigen Receptor T-Cell Therapies in Relapsed or Refractory Large B-Cell Lymphoma

Background Relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) shows poor clinical outcomes. Anti-CD19 chimeric antigen receptor-T cells (CAR-T) therapy is emerging as the second-line therapy of choice, but in real-world studies its efficacy and long term follow is not promising. Effective bridging therapy can reduce tumor burden and improve CAR-T efficacy. Zanubrutinib, a selective Bruton tyrosine kinase (BTK) inhibitors, combined regimens have established therapeutic activity by targeting B-cell receptor signaling and have individually shown efficacy in patients with R/R DLBCL. Thus, the present study evaluated the efficacy and safety of zanubrutinib-combined regimen as bridging treatment in CD19 CAR-T therapy. Methods This retrospective study includes all patients participant in the clinical trail (NCT 02537977) between January 2020 and December 2022. All 21 heavily treated patients with r/r DLBCL who received zanubrutinib-combined regimens as bridging therapy are included. Patient clinical characteristics were collected upon patient enrollment. Efficacy outcomes included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), whereas safety outcomes included incidence of adverse events. The zanubrutinib combined regimens are zanubrutinib with IMIDs, chemotherapy and/or rituximab. Results: Of the 21 evaluable patients, median age of patients is 57 year old and median treatment line is 3. 19 patients (90%) are non-GCB subtype and 18 patients(86%) are IPI score >3. 14 patients(67%) are double expression and 7 patients (33%) have TP53 mutation. Objective response rate(ORR) is 81%; of whom, 10 patients(48%) got complete remission(CR) and 7 patients(33%) got partial remission(PR). With a median follow-up of 25 months, the median PFS was 12.8 months and median OS was not yet reached. 8 CR patients and 3 PR patients maintain long-term remission and are still under followup. 18 patients (86%) has grade 1-2 cytokines release syndrome(CRS) and 3 patients(14%) has grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS). No severe CRS and >1 grade ICANS were observed. The most common hematologic toxicities included grade ≥3 neutropenia (90%) and grade 3/4 thrombocytopenia (71%). No patients had grade ≥3 non hematologic toxicities. Conclusion: Zanubrutinib-combined regimens are effective and safe as bridging therapy in CD19 CAR-T therapy. More prospective studies are further command.

Zanubrutinib Plus Salvage Chemotherapy in Refractory/Relapsed Diffuse Large B-Cell Lymphoma Patients Non-Candidate for Autologous Stem Cell Transplantation: A Retrospective Study

Introduction ：Salvage chemotherapy followed by autologous stem cell transplantation (auto-SCT) is effective for relapsed or refractory DLBCL (R/R DLBCL). However, many patients are unable to undergo auto-SCT due to age, comorbidities, tolerance, economy and other factors. R/R DLBCL has poor clinical outcomes when treated with conventional salvage chemotherapy. Zanubrutinib, a selective Bruton's tyrosine kinase (BTK) inhibitor, has been shown to have modest antitumor activity in R/R DLBCL. Here we aimed to evaluate the efficacy and safety of Zanubrutinib plus salvage chemotherapy in autologous stem cell transplantation-ineligible R/R DLBCL patients. Methods: We retrospectively reviewed R/R DLBCL patients who were administered with Zanubrutinib 160mg*bid plus BR （Bendamustine 90mg/㎡*d1-2+Rituximab 375mg/㎡*d0）or R2 （Lenalidomide 25mg* d1-21 +Rituximab 375mg/㎡*d0）in our center between January, 2019 and July, 2023. Results: 49 R/R DLBCL patients were enrolled,including 30 patients in the Zanubrutinib plus BR group(ZBR)and19 patients in the Zanubrutinib plus R2 group(ZR2). Median age at this study was 60 years (range, 33-80). The best overall response rate (ORR) was 57.1% and complete remission rate was 12.2%. The ORR of ZBR group and ZR2 group were 63.2% and 53.3%, respectively. The response rate was lower in elderly, patients with ≥4 line treatment, refractory patients, patients with TP53 mutations, or without MYD88 and CD79A/B mutations. TThere was a positive correlation between the number of treatment cycles and ORR. With a median follow-up of 22 months (range, 6-43), the median progression-free survival (PFS) was 6.0 months, and the overall survival (OS) was 21.0 months. For OS, univariate analysis suggested that the number of treatment cycles was an independent favorable prognostic factor for OS. In multivariate analysis, , relapsed patients had better OS compared with refractory patients, and response after treatment was an independent favorable factor for OS. The most common grade-3/4 adverse events were neutropenia (55.0%), thrombocytopenia (44.9%), and pneumonia (30.1%). Conclusion: Zanubrutinib combined with BR or R2 showed promising efficacy and acceptable safety in R/R DLBCL patients, which may be a potential treatment option for autologous stem cell transplantation-ineligible R/R DLBCL patients.

Initial Findings from a First-in-Human Phase 1a/b Trial of NX-5948, a Selective Bruton's Tyrosine Kinase (BTK) Degrader, in Patients with Relapsed/Refractory B Cell Malignancies

Introduction: Although BTK inhibitors (BTKi) are effective therapeutics in the treatment of B cell malignancies, emerging BTK resistance mutations in chronic lymphocytic leukemia (CLL), as well as potential growth-promoting kinase-independent scaffolding function of BTK, present a need for improved or new approaches. NX-5948 is a novel, orally administered small molecule that induces specific BTK protein degradation by the cereblon E3 ligase complex without degradation of other cereblon neo-substrates. Importantly, NX-5948 induces degradation of wild-type and mutant forms of BTK in B-cells [Noviski et al. 2023] at sub-nanomolar potencies and exhibits potent tumor growth inhibition in TMD8 xenograft models that contain either wild-type BTK or BTKi-resistant mutations [Robbins 2021]. Here we provide the first disclosure of preliminary safety and efficacy findings from a Phase 1a trial of NX-5948 in patients with relapsed/refractory B cell malignancies. Methods: NX-5948-301 is a Phase 1, first-in-human, dose-escalation and cohort-expansion trial evaluating the safety, tolerability, and clinical activity of NX-5948 in relapsed/refractory CLL and various subtypes of non-Hodgkin's lymphoma (NHL). Key eligibility criteria: ≥2 prior lines of therapy; measurable or other evaluable disease per indication-specific response criteria; Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1. Phase 1a (dose escalation) evaluates safety and tolerability of NX-5948 via a standard 3+3 dose escalation in patients with relapsed/refractory B cell malignancies. Approximately 110 patients (30 in Phase 1a, 80 in Phase 1b) may be enrolled and treated until confirmed disease progression or unacceptable toxicity. Endpoints include dose-limiting toxicities (DLTs); treatment-emergent adverse events (TEAEs); deaths; changes in safety parameters; objective response rate per disease-specific response criteria. Phase 1b (dose expansion) will include up to four expansion cohorts. Results: As of June 9, 2023, 14 patients were enrolled in Phase 1a and received NX-5948 at 50 mg (n=7), 100 mg (n=4), or 200 mg (n=3) orally once daily. Median age was 65 (range 46-79) years; female/male ratio 28.6%/71.4%; white 92.9%; ECOG PS 0/1 21.4%/78.6%; primary diagnoses were CLL (n=4), diffuse large B cell lymphoma (DLBCL, n=4), mantle cell lymphoma (MCL, n=3), marginal zone lymphoma (MZL, n=2), and follicular lymphoma (FL, n=1). Median number of prior therapies was 4.5 (range 2-10), which included: for CLL - BTKi (n=4/4) and BCL2 inhibitor (n=3/4); for NHL - BTKi (n=5/10), bispecific antibody (n=3/10), and CAR-T (n=2/10). NX-5948 was well tolerated with no DLTs and no TEAEs resulting in drug discontinuation or dose reduction. In addition, there were no NX-5948-related grade ≥3 TEAEs or related serious adverse events. The most common TEAEs were purpura/contusion (57.1%, all below grade 3), nausea (35.7%), and thrombocytopenia (35.7%). No atrial fibrillation/flutter or hypertension was reported. Median duration of treatment was 2.8 (range 0.5-9.6) months with 9/14 patients remaining on treatment. Current data indicate that NX-5948 exhibits dose-dependent pharmacokinetics (PK) and a half-life of ~24 hours, supporting once daily dosing (Figure a). Rapid, robust and sustained BTK degradation was observed in all patients, regardless of absolute BTK starting level, tumor type, or NX-5948 dose (Figure b). Of three evaluable patients with CLL receiving the lowest dose of 50 mg, early signs of clinical activity were observed including one confirmed partial response (PR; at 8 and 16 weeks) and 2 patients with stable disease (SD; at 8 weeks). Further treatment responses will be reported at the time of presentation. Summary/conclusion: Current findings in this heavily pre-treated population of patients with CLL and NHL are encouraging and indicate that NX-5948 is safe and well tolerated and has clinical activity, supporting continuation of its development in CLL and NHL. NX-5948 also exhibits dose-proportional PK, resulting in rapid, robust and sustained BTK degradation. Additional data with higher dose levels and longer treatment duration will be presented at the meeting.

Acalabrutinib in Chinese Patients (Pts) with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL): 12-Month Efficacy and Safety Results from an Open-Label, Multicenter Phase 1/2 Trial

Background: CLL is a rare, incurable, relapsing disease occurring in approximately 0.3/100,000 individuals in China. Acalabrutinib (acala) is a highly selective Bruton tyrosine kinase inhibitor with minimal off-target activity approved in the US and Europe for treatment of CLL. Pivotal studies supporting acala's approval had limited inclusion of Asian populations. In the first phase 1/2 trial (NCT03932331) in Chinese pts with R/R CLL, acala demonstrated high response rates and acceptable tolerability at the 6-mo follow-up (Yang S et al. HemaSphere, 2023;7(S3):3716). We present 12-mo results from this trial. Methods: Adults with active CLL, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and who received ≥1 prior systemic therapies for CLL were enrolled to receive acala 100 mg twice daily in 28-day cycles until disease progression or treatment discontinuation due to adverse events (AEs) presenting substantial clinical risk. The primary endpoint was overall response rate (ORR) per 2018 International Workshop on Chronic Lymphocytic Leukemia criteria as assessed by blinded independent central review (BICR). Secondary endpoints included duration of response (DOR) and progression-free survival (PFS) as assessed by BICR; ORR, DOR, and PFS as assessed by investigators (INV); overall survival (OS); and AEs. Results: Sixty pts from 20 sites in China received acala (median age 62 y; 31.7% female; 21.7% with del(17p) and/or TP53 mutation; 51.7% with unmutated IGHV; median 1 prior line of therapy). At the updated data cutoff of December 22, 2022, 53 pts (88.3%) were receiving acala; reasons for acala discontinuation were progressive disease (5.0%; n=3), AEs (3.3%; n=2), pt decision (1.7%; n=1), and other (1.7%; n=1). Median duration of treatment was 19.4 mo (range 0.6-28.2). BICR-assessed ORR was 85.0% (95% CI 73.4, 92.9); no pt had complete response (CR). Median DOR by BICR was not reached (NR). At a median follow-up of 20.2 mo, median PFS by BICR was NR; the estimated 12-mo and 18-mo PFS rates were 91.5% (95% CI 80.9, 96.4) and 78.8% (95% CI 60.9, 89.2), respectively ( Figure). When assessed by INV, ORR was 85.0% (95% CI 73.4, 92.9) with 1 pt having CR, median DOR was NR, and median PFS was NR; estimated 12-mo and 18-mo PFS rates were 95.0% (95% CI 85.2, 98.3) and 87.2% (95% CI 69.1, 95.0), respectively. Median OS was also NR; the estimated 12-mo and 18-mo OS rates were both 96.7% (95% CI 87.3, 99.2). AEs of any grade were reported in 58 pts (96.7%); 25 pts (41.7%) had grade ≥3 AEs, most commonly decreased neutrophil count (13.3%, n=8), pneumonia, and upper respiratory tract infection (each 6.7%, n=4) ( Table). AEs leading to treatment discontinuation included paraneoplastic pemphigus (n=1) and rectal neoplasm (n=1). AEs leading to dose interruption were reported in 13 pts (21.7%), most commonly COVID-19 (5.0%), neutrophil count decreased (3.3%), and platelet count decreased (3.3%). Nine pts (15.0%) had serious AEs (SAEs); only 1 SAE occurred in >1 pt (pneumonia, n=2). Fatal AEs (occurring ≤30 d after last dose) were reported in 1 pt (cardiac arrest in a 73-y-old pt with multiple cardiorespiratory comorbidities on study day 34). Among events of clinical interest, neutropenia was reported in 24 pts (40.0%) and hypertension was reported in 3 pts (5.0%). There were no cases of atrial fibrillation/flutter, major hemorrhage, interstitial lung disease/pneumonitis, second primary malignancies, or tumor lysis syndrome. Conclusions: Twelve-mo data in Chinese pts with R/R CLL treated with acala demonstrated a high ORR, with responses that were durable and clinically meaningful. Continuous treatment with acala was well tolerated with manageable toxicities; no unexpected safety observations were observed in Chinese pts with R/R CLL.

Remibrutinib demonstrates favorable safety profile and sustained efficacy in chronic spontaneous urticaria over 52 weeks

Remibrutinib (LOU064), an oral, highly selective Bruton tyrosine kinase inhibitor, offers fast disease control in patients with chronic spontaneous urticaria (CSU) who remain symptomatic despite treatment with second-generation H1 antihistamines. It is currently in phase 3 development for CSU. We sought to evaluate long-term safety and efficacy of remibrutinib in patients with CSU inadequately controlled with H1 antihistamines. In this phase 2b extension study, patients who completed the core study and had a weekly Urticaria Activity Score (UAS7) ≥16 at the beginning of the extension study received remibrutinib 100 mg twice daily for 52 weeks. The primary objective was to assess long-term safety and tolerability. Key efficacy end points included change from baseline in UAS7 and proportion of patients with complete response to treatment (UAS7= 0) and well-controlled disease (UAS7 ≤6) at week 4 and over 52 weeks. Overall, 84.3% (194/230) of patients entered the treatment period and received ≥1 doses of remibrutinib. The overall safety profile of remibrutinib was comparable between the extension and core studies. Most treatment-emergent adverse events were mild to moderate and considered unrelated to remibrutinib by investigators. The 3 most common treatment-emergent adverse events by system organ class were infections (30.9%), skin and subcutaneous tissue (26.8%), and gastrointestinal disorders (16.5%). At week 4 and 52, mean± SD change from baseline in UAS7 was -17.6± 13.40 and -21.8± 10.70; UAS7= 0 (as observed) was achieved in 28.2% and 55.8% and UAS7 ≤6 (as observed) was achieved in 52.7% and 68.0% of patients, respectively. Remibrutinib demonstrated a consistent favorablesafety profile with fast and sustained efficacy for up to 52 weeks in patients with CSU.

Phase 1 Study of Acalabrutinib Plus Danvatirsen (AZD9150) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Including Circulating Tumor DNA Biomarker Assessment.

Novel targeted and immunotherapies have improved outcomes in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but toxicities limit widespread use. The selective Bruton tyrosine kinase (BTK) inhibitor acalabrutinib has activity in patients with R/R DLBCL, but durable responses are uncommon. STAT3 inhibition has demonstrated clinical activity in DLBCL. Final results of the Phase 1 study of acalabrutinib plus STAT3 inhibitor (danvatirsen; AZD9150) in patients with R/R DLBCL are reported. Danvatirsen 200 mg intravenous infusion (Days 1, 3, 5 [Cycle 1]; weekly infusions starting Day 8, Cycle 1) was administered in combination with oral acalabrutinib 100 mg twice daily until progressive disease (PD) or unacceptable toxicity. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics, and immunogenicity. Seventeen patients received combination treatment. One dose-limiting toxicity (Grade 3 liver transaminase) occurred in one patient. The most common reason for treatment discontinuation was PD (65%). In evaluable patients (n=17), objective response rate was 24%; median duration of response was 1.9 months. All responders with available DLBCL cell-of-origin data were either activated B-cell or nongerminal center B-cell like subtype. Genetic subtype did not correlate with response. Baseline and longitudinal plasma cell-free DNA (cfDNA) concentrations were mostly higher in nonresponding patients. cfDNA changes were generally concordant with imaging. Pretreatment circulating B-cell levels were higher in responders versus nonresponders. Targeting both STAT3 and BTK in combination is safe and tolerable but efficacy is limited in R/R DLBCL. Results support evaluation of circulating tumor DNA as a biomarker for clinical response.

First interim analysis of a phase 1 study of zanubrutinib (zanu) plus lenalidomide (len) in patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL).

7557 Background: Effective therapies for R/R DLBCL are limited in China, especially for pts ineligible for high-dose therapy/stem cell transplantation (HDT/SCT). Preclinical data suggest synergy of len with zanu, a potent and selective Bruton tyrosine kinase inhibitor approved for various B-cell malignancies. Here, we present interim analysis results of an ongoing phase 1, open-label, dose-escalation/expansion study of zanu + len in R/R DLBCL (NCT04436107). Methods: Pts with R/R DLBCL ineligible for HDT/SCT with ≥1 prior line of adequate systemic therapy were enrolled. Dose escalation (part 1): Len 15 mg, 20 mg, or 25 mg orally once daily on days 1-21 of each 28-day cycle. Dose expansion (part 2): Len 25 mg. Zanu 160 mg was given orally twice daily continuously in parts 1 and 2. Primary endpoints were safety and recommended phase 2 dose (RP2D) of len (part 1) and overall response rate (ORR) by investigator based on Lugano classification (part 2). Interim analysis was performed when the 19th pt in part 2 completed first tumor assessment. Pts who received len 25 mg (RP2D) in parts 1 and 2 were analyzed separately. Results: As of November 8, 2022, 46 pts were treated and included in interim analysis (27 in part 1; 19 in part 2; 30 at RP2D). Median age was 60 years (range, 29–82), 83% had stage III–IV disease, 37% had refractory disease, 70% had non-germinal center B-cell (non-GCB) like disease; median number of prior systemic therapies was 1 (range, 1–5). Median exposure to zanu and len was 3.9 months (mo) (range 0.4–24.9), median follow-up was 6.6 mo (range 0.5–25.5). ORR was 46% overall (95% CI: 30.9–61.0; complete response [CR]: 24%) and 57% at RP2D (95% CI: 37.4–74.5; CR: 30%). At RP2D, ORR was 61% (95% CI: 38.5–80.3; CR: 35%) for pts with non-GCB disease and 50.0% (95% CI: 11.8–88.2; CR: 17%) for GCB. At RP2D, median duration of response was not reached and 6-mo event-free rate was 59% (95% CI: 23.8–82.8). Median progression-free survival was 5.5 mo (95% CI: 2.8-not estimable) with a 9-mo event-free rate of 37% (95% CI: 17.6–57.4). Overall, 46 (100%) pts experienced ≥1 treatment-emergent adverse event (TEAE). At RP2D, grade ≥3 TEAEs occurred in 60% of pts, most commonly neutrophil count decreased (43%), white blood cell count decreased (23%), and pneumonia (13%). One pt (2%) had febrile neutropenia (grade 3) but recovered within 2 days. TEAEs led to discontinuation of both len and zanu in 2 pts (cardiopulmonary failure unrelated to treatment [part 1, len 20 mg], pulmonary embolism [part 1, len 25 mg]) and discontinuation of len in 2 pts (platelet count decreased [part 1, len 20 mg], rash [part 2]). Two TEAEs leading to death were reported, unrelated to treatment. Conclusions: Zanu 160 mg plus len 25 mg combination showed an acceptable safety profile with promising efficacy. Further evaluation of the combination in a larger sample size is planned in future analysis. Clinical trial information: NCT04436107 .

Experience of using acalabrutinib therapy in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma

Introduction. Thanks to scientific advances and discoveries in the study of tumor cell biology, new effective drugs for the treatment of chronic lymphocytic leukemia/ small lymphocytic lymphoma have emerged. Currently, there are drugs with different application points at the molecular level. One such drug is acalabrutinib, which is a selective second-generation inhibitors of Bruton tyrosine kinase and has a more favorable toxicity profile.Objective. To evaluate the efficacy of acalabrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.Materials and methods. Since February 2020 acalabrutinib (100 mg 2 p/day orally) has been administered to 7 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (mean age 64 years) at the Hematology Research Center. Six patients received acalabrutinib in 1st-line therapy and one patient received acalabrutinib in 2nd-line therapy. The mean comorbidity index (CIRS) of the patients was 10 points (range, 8 to 14). Most patients had at least one of the adverse prognostic factors - IGHV nonmutated gene status, TP53 gene aberration (del17p13 and/or TP53 gene mutation), complex karyotype disorders.Results. All patients achieved partial remission of the disease (overall response 100% in the form of regression of B-symptoms, lymphocytic leukocytosis, splenomegaly) at the control period of treatment with acalabrutinib +12 months. The most frequent adverse events when taking acalabrutinib were the occurrence of headache in the first month of taking the drug, spontaneous subcutaneous hematomas. No hematologic toxicity, infectious complications, or cardiac complications were noted. At a median follow-up of 34 months, no patient showed disease progression.Conclusions. The selective Bruton tyrosine kinase inhibitor acalabrutinib has demonstrated high efficacy in patients with adverse risk factors, good tolerability and minimal toxicity, including in comorbid patients.

CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression Free Survival on BTK Inhibitor Therapy

Background: Acalabrutinib, a highly selective Bruton tyrosine kinase inhibitor (BTKi), is effective and well tolerated for patients with chronic lymphocytic leukemia (CLL). During treatment with BTKis, transient lymphocytosis is observed due to the efflux of CLL cells from lymphoid organs. CD49d, the alpha chain of the CD49d/CD29 integrin very late antigen-4 (VLA-4), is a key mediator in CLL microenvironmental interactions. High CD49d expression has been associated with inferior response to ibrutinib (Tissino, 2018). Here, we investigated the role of CD49d in response to acalabrutinib in 48 patients with CLL enrolled in a single-center, phase 2 study (NCT02337829). Methods: Patients were divided into CD49d positive (CD49d+, n = 27, 56%) and CD49d negative (CD49dneg, n = 21, 44%) groups based on the established 30% cutoff, as assessed by flow cytometry. CD49d activation was measured as VLA-4 receptor occupancy (RO), as described (Tissino, 2018). Time to progression was estimated using the Kaplan-Meier method. RNA sequencing (RNA-seq) of CD19+ selected CLL cells from CD49d+ (n = 10) and CD49dneg (n = 10) subsets was performed at baseline and 6 months on acalabrutinib. Results: After the first month on acalabrutinib, the median increase in absolute lymphocyte count (ALC) for CD49d+ CLL was 6.4% vs. 50.4% for CD49dneg (P = .02). However, the increase in ALC on day 3 of 42% and 48%, respectively, was comparable (P = .8). A subset of patients showed bimodal CD49d (bimCD49d) expression, with concomitant presence of CD49d positive and negative subpopulations. In these cases, the fraction of CD49d+ CLL cells increased significantly on day 3 (P = .002), but decreased at 6 months (P = .004), suggesting that CD49d+ cells may be better able to remain tissue bound on chronic therapy or reenter lymphoid tissues at higher rates than CD49dneg cells. While constitutive VLA-4 activation was reduced in patients on acalabrutinib, BCR and CXCR4 stimulation still increased VLA-4 RO on CLL cells even after 6 months of treatment. PI3K, in addition to BTK signaling, is implicated in inside-out activation of VLA-4. In vitro, addition of the PI3K inhibitor duvelisib to acalabrutinib-treated CLL cells completely blocked BCR- but not CXCR4- induced VLA-4 activation. The overall response rate of the study was 95.8% (Sun, 2020). Sixteen patients progressed at a median of 42.5 months, 3 with transformation. Time to progression for patients with CD49d+ and CD49dneg CLL (applying 30% cutoff) did not differ (P = .4). However, at 72 months 50% of the combined CD49d+ and bimCD49d patients (n = 37) were estimated progression-free vs 90% of patients with a homogeneous CD49dneg CLL population (n = 11, P = .02). Of 13 patients progressing with CLL, 12 (92%) were CD49d+ or bimodal CD49d and 11 (85%) had BTK and/or PLCG2 mutations. To dissect the impact of CD49d expression on CLL pathobiology and the response to acalabrutinib, we compared transcriptomes of CD49d+ and CD49dneg subsets by RNA-seq. A distinct gene expression profile separated the groups by principal component analysis. Using gene set enrichment analysis, CD49d+ CLL showed constitutively more immunoreceptor, NF-kappa B, and cytokine/JAK-STAT signaling, as well as enhanced cell survival, adhesion and migration capacity compared to CD49dneg CLL (FDR <.25). After 6 months on acalabrutinib, all 20 patients achieved a clinical response and all samples showed downregulation of B-cell receptor and NF-kappa B target genes, as expected for BTKi therapy. Interestingly, on acalabrutinib, CD49d+ samples not only maintained a higher level of activation compared to CD49dneg CLL, but differences in the degree of cytokine (IL-6, IL-10) and STAT3 signaling became more prominent. Conclusion. CD49d+ and CD49dneg CLL cells are rapidly mobilized out of lymph nodes at the start of acalabrutinib therapy, but CD49d+ cells appear able to reenter or persist in lymphoid tissues better than CD49dneg cells. Bimodal CD49dneg and CD49d+ cases share an increased risk of disease progression, with most patients having detectable BTK or PLCG2 mutations at the time of progression. The transcriptional program of CD49d+ CLL reflects upregulation of survival and activation pathways that may increase tolerance to BTKi therapy and set the stage for clonal evolution. Thus, CD49d/VLA-4 emerges as a microenvironmental factor that contributes to BTKi resistance and a possible therapeutic target to improve on BTKi therapy.

Acalabrutinib Plus Venetoclax and Rituximab in Patients with Treatment-Naïve (TN) Mantle Cell Lymphoma (MCL): 2-Year Safety and Efficacy Analysis

Background: Acalabrutinib is a highly selective Bruton tyrosine kinase inhibitor approved for relapsed/refractory mantle cell lymphoma (MCL). We investigated safety and efficacy of chemotherapy-free induction with combination acalabrutinib, venetoclax, and rituximab (AVR) in treatment-naive patients (pts) with MCL to eliminate intensive chemoimmunotherapy exposure and reduce associated toxicity and complications. We previously reported 90% complete response (CR) and 75% molecular response rates at 20.5 mo median follow-up (ASH 2021). We present updated safety and efficacy results at 2 y median follow-up. Methods: Adults with treatment-naive MCL received AVR in this open-label, single-arm, multicenter phase 1b study (NCT02717624). Pts received A+R for six 28-d cycles with maintenance R for up to 2 y for responders and oral A continuously until progressive disease (PD) or undue toxicity. V was started at cycle 2 with standard 5-wk ramp-up to 400 mg/d and continued for 2 y. Primary endpoint was safety. Secondary endpoints were overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Treatment response was assessed by clinical examination, computed tomography (CT), and positron emission tomography (PET) by Lugano criteria, with minimal residual disease (MRD) assessment by clonoSEQ assay in peripheral blood (at partial response [PR], CR, and PD). Bone marrow (BM) was assessed at screening and CR. Results: Twenty-one pts were enrolled (median age 66 y [51-85]; Ann Arbor stage IV disease, 90.5% [n=19]; initial BM involvement, 71.4% [n=15]; high-risk simplified MIPI score, 19% [n=4]; blastoid histology, 4.8% [n=1]; pleomorphic variant, 0%; bulky disease >5 cm or >10 cm, 33.3% [n=7] and 4.8% [n=1]; Ki-67 proliferation index ≥30%, 47.6% [n=10]). At data cutoff (March 29, 2022), 15 (71.4%) pts remained on study; 6 (28.6%) had discontinued study, due to death (5 [23.8%]) or start of new therapy (1 [4.8%]). Eleven (52.4%) pts remained on at least 1 study drug and 7 pts (33.3%) discontinued all 3 drugs: 2 due to PD and 5 due to COVID-19 death. Ten pts (47.6%) discontinued A (adverse event [AE]=5, investigator's decision [ID]=3, PD=2); 17 discontinued V (completed regimen=9, PD=2, AE=4, ID=1, other=1); and 17 discontinued R (completed regimen=10, PD=2, AE=4, ID=1) All 21 pts (100%) completed the 6 initial cycles of treatment (induction) per protocol. Most common any-grade AEs in ≥20% of pts were diarrhea (15 [71.4%]), headache (11 [52.4%]), fatigue (10 [47.6%]), and neutropenia (8 [38.1%]). Grade 3/4 AEs were reported in 12 (57.1%) pts, most commonly (>1 pt) neutropenia (7 [33.3%]) and pneumonia (3 [14.3%]). Serious AEs (SAEs) occurred in 12 (57.1%) pts. SAEs in ≥2 pts were COVID-19 (5 [23.8%]), pneumonia (3 [14.3%]), and pyrexia (2 [9.5%]). Overall, 7 pts had COVID-19; 6 (28.6%) cases were treatment-emergent (up to 30 days after last dose) and 4 (19.0%) pts died. The seventh pt with COVID-19 died outside the treatment-emergent period. Table 1 shows events of clinical interest. At data cutoff, ORR was 100% (n=21), CR rate was 90% (n=19), and PR rate was 10% (n=2) by PET/CT. By Lugano, CR rate was 71% (n=15) since 4 pts were missing BM biopsy to confirm CR. Median (range) time to initial response and best response were 2.8 (0.7-5.6) and 3.0 (0.7-18.3) mo, respectively. Median DOR was not reached even after censoring COVID-19 deaths. With a median follow-up of 25.8 (8-38.5) mo, the median PFS and OS were not reached. PFS rates at 1 y and 2 y were 90% (95% CI 65.6-97.4) and 54.4% (21.6-78.5), respectively (both were 94.7% [68.1-99.2] after censoring COVID-19 deaths) (Figure 1). OS rates at 1 y and 2 y were 95.2% (95% CI 70.7-99.3) and 74.1% (48.4-88.3), respectively (both were 100% after censoring). In total, 5 pts died, all from COVID-19. MRD data were available for 12 pts (57.1%) at cycle 6 (all MRD negative at 10-6) and 14 pts (66.7%) at cycle 12 (12 negative at 10-6; 14 negative at 10-4). Fourteen of 16 (87.5%) evaluable pts had MRD negativity (10-6) at least once during treatment. Among the 15 pts who achieved CR by PET/CT, 13 (86.7%) were MRD negative at 10-6 and 1 pt was MRD negative at 10-5 at least once during treatment; 1 pt had no follow-up MRD assessments. Conclusions: AVR combination is well tolerated and induces durable and deep clinical and molecular responses in treatment-naive MCL pts. This study strongly supports further clinical investigation of AVR for treatment-naive MCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

IBCL-117 ASPEN: Long-Term Follow-Up Results of a Phase 3 Randomized Trial of Zanubrutinib vs Ibrutinib in Patients With Waldenström Macroglobulinemia

ASPEN is a randomized, open-label, phase 3 study comparing zanubrutinib, a potent and selective Bruton tyrosine kinase inhibitor (BTKi), with the first-generation BTKi, ibrutinib, in Waldenström macroglobulinemia (WM). Data with a median follow-up of 43 months are presented. In cohort 1, patients with MYD88 mutations were randomized 1:1 to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily; stratifications were CXCR4 mutations and prior lines of therapy. In cohort 2, patients without MYD88 mutations received zanubrutinib 160 mg twice daily. The primary endpoint was the proportion of patients with complete response/very good partial response (CR+VGPR). In cohorts 1 and 2, 201 (zanubrutinib=102; ibrutinib=99) and 28 patients were enrolled, respectively. More cohort 1 patients in the zanubrutinib versus ibrutinib arm had CXCR4 mutations (32% [33/98] vs 20% [20/92] with next-generation sequencing data) and were aged >75 years (33% vs 22%). With median treatment durations of 42 (zanubrutinib) and 41 (ibrutinib) months, 67% and 58% remain on treatment, respectively. Investigator-assessed CR+VGPR rate was 36% versus 22% (zanubrutinib vs ibrutinib; P=0.02) and 31% in cohort 2 (1 CR). CR+VGPR rates for wild-type CXCR4 were 45% versus 28% (zanubrutinib vs ibrutinib; P=0.04) and were 21% versus 5% (P=0.15) for mutated CXCR4. Median progression-free survival and overall survival were not yet reached. Rates of atrial fibrillation, diarrhea, hypertension, localized infection, hemorrhage, muscle spasms, pneumonia, grade ≥3 infection, and adverse events leading to discontinuation/death were lower for zanubrutinib versus ibrutinib, as were exposure-adjusted incidence rates of atrial fibrillation/flutter and hypertension (0.2 vs 0.8 and 0.5 vs 1.0 persons/100 person-months; P<0.05); neutropenia rate was higher. Zanubrutinib safety outcomes were similar between cohorts. ASPEN is the largest phase 3 WM trial with head-to-head BTKi comparison. At a median follow-up of 43 months, zanubrutinib had higher CR+VGPR rates and clinically meaningful advantages in long-term safety/tolerability versus ibrutinib.

Abstract 3330: GB5121 is a novel highly potent and selective CNS-penetrant BTK inhibitor for CNS malignancies

Abstract Inhibitors of Bruton’s tyrosine kinase (BTK) are approved treatments for several B cell lymphomas. However, they are characterized by modest selectivity and/or limited central nervous system (CNS) penetrance in instances of CNS disease. GB5121 is an orally available, selective, irreversible small molecule BTK inhibitor. GB5121 was selected based on its potency, specificity, and high brain penetrance in preclinical models. We evaluated its pharmacodynamic properties using both cell-free enzymatic and cell-based functional assays, showing covalent BTK inactivation with a potency in the nM range. GB5121 furthermore demonstrated rapid BTK inactivation kinetics (Kinact/Ki) in both peripheral and CNS tissue, a critical parameter for covalent irreversible inhibitors. In a kinome scan, GB5121 exhibited high kinase selectivity against 349 kinases with only TEC/TXK demonstrating &amp;gt;50% inhibition at 1 µM; GB5121 did not inhibit phosphorylation of EGFR in a cell-based assay. When compared with other BTK inhibitors, GB5121 showed superior CNS target occupancy using a probe-based ELISA measuring free BTK in the brain of mice receiving 3 daily oral doses of 10 mg/kg. GB5121 also demonstrated significantly higher brain to plasma ratio in mice with an intact blood brain barrier. Specifically, GB5121 showed ~2-fold higher brain concentrations with lower plasma levels than ibrutinib. In non-human primates, a 1:1 brain to plasma concentration ratio was demonstrated for GB5121 for up to 8 hours with both oral (30 mg/kg) and IV (2 mg/kg) doses. Together, these features differentiate GB5121 from both FDA-approved BTK inhibitors as well as those currently under clinical investigation. Our data supports the use of GB5121 in clinical trials where BTK is a known driver of malignancies, including in CNS lymphoma. Citation Format: Isharat Yusuf, Sunil Sahdeo, Taylor Ismaili, Zachary Naiman, David Guimond, Theodore Schiff, Bryan Clemons, Krystal Herman, Bryanna Paulson, Kay Hou, Kristen Taylor Meadows, Michael Kennedy, Mark Rose, Laura Carter. GB5121 is a novel highly potent and selective CNS-penetrant BTK inhibitor for CNS malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3330.

Abstract 1400: AS-1763: a highly potent, noncovalent and next generation BTK inhibitor for the treatment of patients with B-cell malignancies having C481S mutation in BTK

Abstract Introduction: Bruton's tyrosine kinase (BTK) has been recently recognized as a validated drug target for the treatment of B-cell malignances. The emergence of clinical resistance to the first-generation covalent BTK inhibitors is, however, becoming a serious concern. Patients are reported to develop resistance during the treatment due to substitution of cysteine residue at position 481 with serine (C481S mutation) in BTK, which prevents the covalent binding of the first-generation irreversible BTK inhibitors, resulting in the loss of inhibitory activities. Therefore, there is a high unmet medical need for new therapeutic approaches to overcome the BTK C481S-mediated resistance. Material and methods: Compounds were tested in biochemical assays using recombinant human wildtype (WT) and C481S mutant BTKs. Cellular activity of AS-1763 was evaluated in human diffuse large B cell lymphoma (DLBCL) cell lines, OCI-Ly10 and its BTK[C481S] knock-in cells. The in vivo antitumor activity of AS-1763 was assessed in two tumor xenograft mouse models bearing WT or BTK [C481S] knock-in OCI-Ly10 cells. Results: We have discovered AS-1763 as an orally available, highly potent, selective and reversible BTK inhibitor. AS-1763 showed potent inhibitory activities for WT BTK (an activated form, BTK[A]) and the C481S mutant with sub-nanomolar IC50s (IC50 = 0.85 and 0.99 nM for BTK[A] and BTK[C481S], respectively). In cellular assays, AS-1763 exhibited strong antiproliferative activities for WT and BTK [C481S] knock-in OCI-Ly10 cells. AS-1763 demonstrated significant tumor growth inhibition and tumor regression in WT as well as BTK[C481S] knock-in OCI-Ly10 xenograft model. Conclusions: The preclinical data support the clinical development of AS-1763 in patients with B-cell malignancies both having WT and C481S mutation in BTK. The first-in-human Phase 1 clinical trial of AS-1763 in healthy volunteers (EudraCT 2020-005599-37) is currently ongoing, and the Phase 1b study in patients is expected to begin in 2022. Citation Format: Wataru Kawahata, Tokiko Asami, Takao Kiyoi, Takayuki Irie, Shigeki Kashimoto, Hatsuo Furuichi, Masaaki Sawa. AS-1763: a highly potent, noncovalent and next generation BTK inhibitor for the treatment of patients with B-cell malignancies having C481S mutation in BTK [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1400.

ASPEN: Long-term follow-up results of a phase 3 randomized trial of zanubrutinib (ZANU) versus ibrutinib (IBR) in patients with Waldenström macroglobulinemia (WM).

7521 Background: ASPEN is a randomized, open-label, phase 3 study comparing ZANU, a potent and selective Bruton tyrosine kinase inhibitor (BTKi), with the first-generation BTKi IBR in patients with WM. We present data with a median follow-up of 43 months. Methods: Patients with MYD88 mutations were assigned to cohort 1 and randomized 1:1 to receive ZANU 160 mg twice daily or IBR 420 mg once daily. Randomization was stratified by CXCR4 mutational status and lines of prior therapy (0 vs 1-3 vs &gt; 3). Patients without MYD88 mutations were assigned to cohort 2 and received ZANU 160 mg twice daily. The primary endpoint was proportion of patients achieving complete response or very good partial response (CR+VGPR). Results: A total of 201 patients (ZANU arm, n = 102; IBR arm, n = 99) were enrolled in cohort 1 and 28 patients were enrolled in cohort 2. A larger proportion of patients in the ZANU arm of cohort 1 vs IBR had CXCR4 mutations by next-generation sequencing (32% vs 20%, or 33 of 98 vs 20 of 92 with data available) and were aged &gt; 75 years (33% vs 22%). Median duration of treatment was 42 months (ZANU) and 41 months (IBR), with 67% and 58% remaining on treatment, respectively. The CR+VGPR rate by investigator was 36% with ZANU vs 22% with IBR ( p= 0.02) in cohort 1, and 31% in cohort 2. One patient achieved CR (cohort 2). In patients with wild type or mutant CXCR4 from cohort 1, CR+VGPR rates with ZANU vs IBR were 45% vs 28% ( p= 0.04) and 21% vs 5% ( p= 0.15) , respectively. Median progression-free survival and overall survival were not yet reached. Rates of atrial fibrillation, diarrhea, hypertension, localized infection, hemorrhage, muscle spasms, pneumonia, and adverse events leading to discontinuation or death were lower with ZANU vs IBR (Table). Exposure-adjusted incidence rates of atrial fibrillation/flutter and hypertension were lower with ZANU vs IBR (0.2 vs 0.8 and 0.5 vs 1.0 persons per 100 person-months, respectively; p&lt; 0.05). Rate of neutropenia was higher and rate of grade ≥3 infection was lower with ZANU vs IBR. Safety outcomes of ZANU were similar between cohorts 1 and 2. Conclusions: ASPEN is the largest phase 3 trial with head-to-head BTKi comparison in WM. At a median follow-up of 43 months, ZANU was associated with higher CR+VGPR rate and demonstrated clinically meaningful advantages in long-term safety and tolerability vs IBR. Clinical trial information: NCT03053440. [Table: see text]

Physiologically Based Absorption Modelling to Explore the Formulation and Gastric pH Changes on the Pharmacokinetics of Acalabrutinib.

Acalabrutinib, a selective Bruton's tyrosine kinase inhibitor, is a biopharmaceutics classification system class II drug. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to mechanistically describe absorption of immediate release capsule formulation of acalabrutinib in humans. Integration of in vitro biorelevant measurements, dissolution studies and in silico modelling provided clinically relevant inputs for the mechanistic absorption PBPK model. The batch specific dissolution data were integrated in two ways, by fitting a diffusion layer model scalar to the drug product dissolution with integration of drug substance laser diffraction particle size data, or by fitting a product particle size distribution to the dissolution data. The latter method proved more robust and biopredictive. In both cases, the drug surface solubility was well predicted by the Simcyp simulator. The model using the product particle size distribution (P-PSD) for each clinical batch adequately captured the PK profiles of acalabrutinib and its active metabolite. Average fold errors were 0.89 for both Cmax and AUC, suggesting good agreement between predicted and observed PK values. The model also accurately predicted pH-dependent drug-drug interactions between omeprazole and acalabrutinib, which was similar across all clinical formulations. The model predicted acalabrutinib geometric mean AUC ratios (with omeprazole vs acalabrutinib alone) were 0.51 and 0.68 for 2 batches of formulations, which are close to observed values of 0.43 and 0.51~0.63, respectively. The mechanistic absorption PBPK model could be potentially used for future applications such as optimizing formulations or predicting the PK for different batches of the drug product.

Zanubrutinib monotherapy in relapsed/refractory indolent non-Hodgkin lymphoma

AbstractOutcomes for marginal zone lymphoma (MZL) and follicular lymphoma (FL) remain suboptimal, owing to the limited number of approved agents and the incurable nature of the diseases. BGB-3111-AU-003 was a phase 1/2, open-label, multicenter, single-agent study of the selective Bruton's tyrosine kinase inhibitor zanubrutinib in 385 patients with B-cell malignancies. Here, we present safety and efficacy outcomes for the 53 enrolled patients with relapsed/refractory MZL (n = 20) and relapsed/refractory FL (n = 33), all of whom were enrolled during the part 2 dose expansion, and therefore received zanubrutinib at the recommended phase 2 dose. Treatment with zanubrutinib was generally well tolerated, with most adverse events being ≤ grade 2. Atrial fibrillation/flutter was not reported. Two patients required dose reduction, and 4 patients discontinued treatment because of adverse events. Response was assessed by an independent review committee for MZL and the investigators for FL, per Lugano 2014 classification for non-Hodgkin lymphoma. In patients with MZL, the overall response rate (ORR) was 80%, and the complete response (CR) rate was 20%. With median follow-up of 33.8 months, median progression-free survival (PFS) was not reached. In patients with FL, the ORR was 36.4%, and the CR rate was 18.2%. After a median follow-up of 33.9 months, median PFS was 10.4 months. In conclusion, the results of this study suggest a favorable benefit–risk profile and support zanubrutinib as a potentially meaningful addition to available therapies for patients with relapsed/refractory MZL and FL. This trial was registered at www.clinicaltrials.gov as #NCT02343120.