Zanubrutinib Monotherapy Research Articles

Real-world safety profile of zanubrutinib: a disproportionality analysis based on the FAERS database

ObjectiveZanubrutinib is a second-generation Bruton’s tyrosine kinase inhibitor that has been approved for the treatment of several B cell malignancies. The aim of this study was to evaluate adverse events...

CELESTIAL-TNCLL: An ongoing, open-label, multiregional, phase 3 study of sonrotoclax (BGB-11417) + zanubrutinib vs venetoclax + obinutuzumab for treatment-naïve (TN) CLL.

TPS7087 Background: The combination of venetoclax (ven), the first-generation BCL2 inhibitor, and ibrutinib, a BTK inhibitor, has demonstrated efficacy in patients with CLL (Wierda et al. J Clin Oncol. 2021); however, the toxicity profile of this regimen suggests a need for a more tolerable BTK/BCL2 inhibitor combination. Sonrotoclax, a next generation BCL2 inhibitor, is a more selective and more pharmacologically potent inhibitor of BCL2 than venetoclax. In a phase 1 study in patients with TN CLL treated with sonrotoclax + zanubrutinib, efficacy data was promising with ORR and 1-year progression-free survival (PFS) rates of 100% and deep responses based on undetectable measurable residual disease at <10-4 sensitivity (uMRD4). The most common grade ≥3 TEAE was neutropenia, and no tumor lysis syndrome or cardiac toxicity was observed (Tam et al. Blood. 2023). Zanubrutinib, a next-generation BTK inhibitor, significantly improved PFS and had a more tolerable safety profile, including fewer cardiac adverse events vs ibrutinib in a randomized, head-to-head study of patients with CLL/SLL (Brown et al. N Engl J Med. 2023). Presented here is the design of a phase 3 trial aimed at comparing the efficacy of sonrotoclax + zanubrutinib vs ven + obinutuzumab (obi) in patients with TN CLL. Methods: CELESTIAL-TNCLL (BGB-11417-301; NCT06073821) is a randomized, open-label, phase 3 study. Eligible patients must have previously untreated CLL that requires treatment per 2018 iwCLL criteria, measurable disease by CT/MRI, an ECOG performance score of 0-2, and adequate hematologic and organ function. Approximately 640 patients will be randomized 1:1 to receive either 3 cycles of zanubrutinib monotherapy (320 mg total daily dose, orally), followed by zanubrutinib + sonrotoclax for 12 cycles, or standard ven + obi treatment for 12 cycles. Randomization will be stratified by age (<65 vs ≥65 years) and IGHV and del(17p)/ TP53 mutation status. The primary endpoint is PFS as assessed by independent review committee (IRC) according to 2018 iwCLL guidelines with modifications for treatment-related lymphocytosis for patients with CLL (Cheson et al. 2012). Key secondary endpoints include complete response rate (CRR), defined as CR or CR with incomplete hematopoietic recovery, assessed by IRC; rates of uMRD4 in bone marrow and peripheral blood at the first post-treatment follow-up visit based on next-generation sequencing by clonoSEQ; and overall survival. 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. Clinical trial information: NCT06073821 .

Cardiovascular events reported in patients with B-cell malignancies treated with zanubrutinib

AbstractFirst-generation Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has been associated with an increased risk of cardiovascular toxicities. Zanubrutinib is a more selective, next-generation BTK inhibitor. In this analysis, incidence rates of atrial fibrillation, symptomatic (grade ≥2) ventricular arrhythmia, and hypertension were evaluated in a pooled analysis of 10 clinical studies with zanubrutinib monotherapy in patients (N = 1550) with B-cell malignancies and a pooled analysis of head-to-head studies comparing zanubrutinib with ibrutinib (ASPEN cohort 1; ALPINE). Among the 10 studies, most patients (median age, 67 years) were male (66.3%) and had CLL/SLL (60.5%). Overall incidence and exposure-adjusted incidence rates (EAIR) for atrial fibrillation, symptomatic ventricular arrhythmia, and hypertension were lower with zanubrutinib than ibrutinib. Despite a similar prevalence of preexisting cardiovascular events in ASPEN and ALPINE, atrial fibrillation/flutter incidence rates (6.1% vs 15.6%) and EAIR (0.2 vs 0.64 persons per 100 person-months; P < .0001) were lower with zanubrutinib than with ibrutinib. Symptomatic ventricular arrhythmia incidence was low for both zanubrutinib (0.7%) and ibrutinib (1.7%) with numerically lower EAIR (0.02 vs 0.06 persons per 100 person-months, respectively) for zanubrutinib. The hypertension EAIR was lower with zanubrutinib than ibrutinib in ASPEN but similar between treatment arms in ALPINE. The higher hypertension EAIR in ALPINE was inconsistent with other zanubrutinib studies. However, fewer discontinuations (1 vs 14) and deaths (0 vs 6) due to cardiac disorders occurred with zanubrutinib versus ibrutinib in ALPINE. These data support zanubrutinib as a treatment option with improved cardiovascular tolerability compared with ibrutinib for patients with B-cell malignancies in need of BTK inhibitors. These trials were registered at www.ClinicalTrials.gov as # NCT03053440, NCT03336333, NCT03734016, NCT04170283, NCT03206918, NCT03206970, NCT03332173, NCT03846427, NCT02343120, and NCT03189524.

Real-World Outcomes of Zanubrutinib Monotherapy in Chronic Lymphocytic Leukemia: A Multicenter Retrospective Study

Background The second-generation Bruton's Tyrosine Kinase inhibitor (BTKi) zanubrutinib had better BTK specificity and less off-target inhibition than first-generation BTKi ibrutinib. SEQUOIA study demonstrated superior efficacy of frontline zanubrutinib than bendamustine-rituximab combination, and ALPINE study showed improved overall response rate (ORR) and progression free survival (PFS) of zanubrutinib than ibrutinib in relapsed/refractory chronic lymphocytic leukemia (R/R CLL). Meanwhile, adverse event (AE) remained one of the main reasons of zanubrutinib dose reduction and discontinuation. We previously reported the first real-world data of zanubrutinib monotherapy in Chinese CLL patients in our single center, demonstrating zanubrutinib discontinuation significantly deteriorated PFS and overall survival (OS). Herein, we reported the updated results to a multicenter scale, with a special focus on the impact of zanubrutinib dose reduction. Methods From Aug. 2020 to Mar. 2023, CLL pts received zanubrutinib monotherapy for at least 3 months in 7 medical centers in Shanghai were enrolled. Data cut-off time was Jul. 2023. AEs were evaluated and graded according to CTCAE 5.0 and IWCLL criteria. ORR included partial response with lymphocytosis or above. Results In total, 124 pts were enrolled and analyzed. 83 (66.9%) were treatment-naïve (TN) pts and 41 (33.1%) were R/R pts. Zanubrutinib was given 160mg, twice a day. The median age of zanubrutinib initiation was 68 years old (range, 37-87) with a M/F ratio of 2.1:1. Among evaluable pts, 25.0% had TP53 aberration (deletion and/or mutation) and 45.2% had unmutated IGHV. With a median follow-up time of 21.8 months, ORR of the entire cohort, TN and R/R pts were 93.5%, 96.4% and 87.8%, respectively. The estimated PFS and OS rates at 24 months in the entire cohort were 79.6% (95%CI 75.0-84.2%) and 94.2% (95%CI 91.9-96.5%). When stratified by line of therapy, the estimated 24-month PFS rates of TN and R/R pts were 82.7% (95%CI 77.5-87.9%) and 71.8% (95%CI 62.1-81.5%), and 24-month OS rates were 96.1% (95%CI 93.9-98.3%) and 89.1% (95%CI 83.1-95.1%), respectively. Pts with TP53 aberration had a trend of inferior PFS ( P=0.102), and pts received 1 st or 2 nd line zanubrutinib monotherapy had significantly longer PFS compared with 3 rd line or above ( P&amp;lt;0.001) (Fig.1A). No significant impact of gender, age, Binet or Rai stages, 11q deletion or IGHV mutation status on PFS or OS was observed. One hundred and two (82.3%) pts experienced AEs of any grade, and 30 (24.2%) pts experienced AEs of grade 3 or above. The most common grade 3 or above AEs were neutropenia (10.5%) and pneumonia (8.1%). Two pts (1.6%) experienced grade 2 atrial fibrillation. AEs of interest (AEI) are shown in Table 1. Overall, 21 (16.9%) pts had zanubrutinib dose reduction, and the most common reason was AE (61.9%). Zanubrutinib reduction was associated with both inferior PFS (Fig.1B) and OS. Nineteen (15.3%) pts had zanubrutinib discontinuation, and the most common reason was progressive disease (57.9%). Conclusion In our real-world study, the efficacy of zanubrutinib monotherapy in both TN and R/R Chinese CLL pts were slightly inferior to that of clinical trials. Pts receiving ≤ 2 nd line zanubrutinib monotherapy had significantly improved PFS. The toxicity spectrum was similar to data previously reported. Despite an improved safety profile, AE remained the main reason of zanubrutinib dose reduction, and dose reduction significantly associated with shorter PFS and OS. Therefore, better treatment strategies such as combined targeted therapy are required to improve the outcomes of these pts.

A Real-World Study of Zanubrutinib Treatment in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Background: Zanubrutinib, a second-generation non-covalent Bruton's Tyrosine Kinase inhibitor (BTKi), with better BTK specificity, and fewer off-target effects. Zanubrutinib has demonstrated the confirmed effectiveness and safety in clinical trials such as SEQUOIA and ALPINE in chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL), and earlier studies showed its efficacy and safety profile of zanubrutinib monotherapy in the real world. Meanwhile, more valuable insights hope to be gained on zanubrutinib treatment in Chinese CLL/SLL patients (pts) outside of the clinical trial setting. This report provides some outcomes evaluated in a real-world study. Aims: This study further evaluated the effectiveness and safety of zanubrutinib monotherapy/combination treatment in Chinese CLL/SLL pts in a real-world setting. Methods: CLL/SLL pts who received zanubrutinib monotherapy/combination treatment for at least 3 months from Aug. 2017 to Jul. 2023 were enrolled from Jiangsu Province Hospital. The primary outcome was progression free survival (PFS). Baseline characteristics were also collated. Results: 77 pts were analyzed in all. Zanubrutinib was administered orally at 160 mg, twice daily (BID), mono or combined. Among the monotherapy pts, 20 (35.1%) pts were treatment naïve (TN) and 37 (64.9%) pts were refractory/relapsed (R/R). Among the combination treatment pts, 14 (70.0%) pts were TN and 6 (30.0%) pts were R/R. Baseline characteristics were shown in Table 1. The median follow-up time was 31.8 months, and the median PFS was not reached in the entire cohort. The 12-month PFS rate was 95.8% (95%CI 91.3-100.0%) while the 24-month PFS rate was 90.9% (95%CI 84.2-98.2%) (Figure A). After stratified by line of therapy in monotherapy, the estimated 12-month PFS rates of TN and R/R zanubrutinib monotherapy pts were 100.0% (95%CI 100.0-100.0%) and 91.3% (95%CI 82.3-100.0%) (Figure B). The estimated 24-month PFS rates of TN and R/R zanubrutinib monotherapy pts were 93.8% (95%CI 82.6-100.0%) and 84.9% (95%CI 73.5-98.1%). 4 (5.2%) pts interrupted treatment due to AE. 2 pts were TN and 2 pts were R/R. 2 pts received zanubrutinib monotherapy and 2 pts received combination treatment. The AEs included hemoptysis (1, 1.3%), platelet hemoglobin reduction and atrial fibrillation (1, 1.3%), bleeding points in both lower limbs (1, 1.3%), rash and edema (1, 1.3%). All treatment-interrupted pts still received zanubrutinib after interruption by the latest follow-up. 17 (22.1%) pts experienced treatment discontinuation due to progressive disease (PD) or transformation. No pts discontinued zanubrutinib treatment due to AE. PD was the most common reason for treatment discontinuation. 13 (16.9%) pts experienced PD and 4 (5.2%) pts experienced transformations. S ummary/Conclusion: Zanubrutinib shows good efficacy in Chinese CLL/SLL pts in the real-world study. Incidence of AE was low, and no treatment discontinued due to AE, revealing a good safety of zanubrutinib. PD was the main reason for treatment discontinuation. Therefore, the effectiveness and safety of zanubrutinib have been validated in the real world, consistent with clinical trials.

Zanubrutinib and Venetoclax As Initial Therapy for CLL/SLL with Obinutuzumab Triplet Consolidation in Patients with Minimal Residual Disease Positivity (BruVenG)

Background: Bruton's tyrosine kinase inhibitors (BTKi), anti-CD20 antibodies, and B cell lymphoma 2 inhibitors (BCL-2i) are essential therapeutic drug classes in the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Clinical synergy of BTKi and BCL-2i combinations have been observed, which allow for an oral regimen, that can be safely administered in a clinic setting for most patients (Tam et al., 2022; Wierda et al., 2021). Still, it remains uncertain if anti-CD20 antibodies meaningfully add to the effectiveness of oral combination therapy. Recent reports of triplet regimens demonstrate modest improvement in minimal residual disease (MRD) negativity with similar response rates when compared to oral doublets (Davids et al., 2021; Soumerai et al., 2021; Wierda et al., 2021). Additionally, anti-CD20 antibody use causes significant B cell depletion resulting in prolonged immune suppression. Recent reports suggest BTKi use may in fact impair clinical activity of anti-CD20 antibodies, which can be mitigated by using selective BTKi and incorporating anti-CD20 later in the treatment course when lower disease burden is present (Da Roit et al., 2015; Flinsenberg et al., 2020; Pavlasova et al., 2016; Rawstron et al., 2018). Therefore, anti-CD20 therapy may not be required for all patients and could be optimized within a response-adapted strategy. This trial has been developed to assess efficacy and safety of a response adapted consolidative treatment approach utilizing obinutuzumab triplet consolidation in CLL/SLL patients who remain MRD positive after an oral doublet fixed duration treatment with zanubrutinib and venetoclax. This approach looks to maximize MRD negative remissions, spare toxicity by limiting anti-CD20 exposure, and provide a finite therapy. This study will utilize once daily zanubrutinib for which there is limited data in regard to safety and efficacy particularly in combination with venetoclax. Study Design and Endpoints: This is a single center, open label, phase II, investigator initiated clinical trial enrolling 50 subjects evaluating the efficacy and safety of zanubrutinib and venetoclax with obinutuzumab triplet consolidation in subjects who remain MRD positive (BruVenG). Eligible patients must have treatment naïve CLL/SLL and treatment indications per the International Workshop on CLL 2018 guidelines. Subjects with Richter's transformation are excluded. Treatment will consist of lead-in, combination, and consolidation phases. All subjects will be treated with a 3-cycle lead-in of 320mg oral, once daily zanubrutinib monotherapy. Venetoclax will be incorporated at cycle 4, per the standard prescriber insert ramp-up schedule. A final dose of 400mg oral, once daily venetoclax, in combination with 320mg oral, once daily zanubrutinib will be used in all subsequent cycles after ramp-up. At cycle 16, MRD will be assessed in the peripheral blood (PB) and bone marrow (BM) via clonoSEQ (Adaptive Biotechnologies). Subjects who are MRD negative (&amp;lt;1x10 -4 ) in both compartments will stop therapy. Subjects who are MRD positive in PB or BM will continue zanubrutinib and venetoclax for an additional 6 cycles. Obinutuzumab will be added to the oral doublet starting at cycle 17. Standard intravenous obinutuzumab lead-in will occur during cycle 17, followed by standard monthly intravenous dosing of 1000mg through cycle 22. Depending on MRD status, subjects will be treated for 16 or 22 cycles. All subjects who receive consolidation will stop treatment at cycle 23 regardless of end of treatment MRD status. The primary endpoint is cycle 16 PB and BM MRD negativity rates. A co-primary endpoint will be cycle 23 PB and BM MRD negativity rates in subjects who were MRD positive at C16 and who went on to receive at least 1 dose of obinutuzumab. Key secondary endpoints will include cycle 16 overall response rate, 36-month progression free survival, 36-month overall survival, 36-month time to next treatment, 24- and 36-month PB MRD negativity rates, tumor lysis risk reduction rates, and safety. Exploratory endpoints will assess the positive predicative value of the ∆400 biomarker (Soumerai et al., 2021) on MRD negativity at cycle 16. This biomarker will be assessed between cycle 4 and 6. The MRD negative rates at cycle 16 and cycle 23 will be estimated with a 90% confidence interval using the Clopper-Pearson method based on exact binomial distribution.

Genomic Landscape of Ibrutinib- and/or Acalabrutinib-intolerant Patients with B-cell Malignancies Treated with Zanubrutinib in a Phase 2 Study

Introduction:Bruton tyrosine kinase inhibitors (BTKi) have shown remarkable utility in the treatment of B-cell malignancies; yet some patients have experienced toxicities to the BTKis, ibrutinib and acalabrutinib, which lead to dose reduction or treatment discontinuation. Zanubrutinib is a potent and selective next-generation BTKi. BGB-3111-215 (NCT04116437) is an ongoing, phase 2 study of the safety and efficacy of zanubrutinib monotherapy in patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), or marginal zone lymphoma (MZL) who discontinued ibrutinib, acalabrutinib, or acalabrutinib and ibrutinib because of intolerance. Methods:Because the genomic profile of patients with B-cell malignancies who are intolerant to ibrutinib and/or acalabrutinib has not been extensively studied, mutations were assessed using a 106 gene-targeted next-generation sequencing panel (PredicineHEME TM, Predicine) on baseline and disease progression samples. Samples were sequenced to a median depth of &amp;gt;20,000 reads, with a validated sensitivity of 0.25% mutant allele frequency for all genomic regions, and 0.1% for mutational hotspots. Variant allele frequency (VAF) &amp;lt;0.1% for hotspot mutations and &amp;lt;0.25% for non-hotspot mutations were excluded from analysis; germline and CHIP mutations were also excluded from analysis. The association between gene mutations and progression-free survival (PFS, defined as time from the date of first zanubrutinib dose to date of first PD or death) was quantified by the log rank test and the hazard ratio and summarized by the Kaplan-Meier method. Results:As of June 6, 2022, baseline peripheral blood samples were collected from 71 (95.9%) of the 74 patients enrolled in the study. There were 46 patients with CLL, 11 with WM, eight with SLL, three with MCL, and three with MZL. A total of 56 patients were intolerant to ibrutinib only; 15 were intolerant to acalabrutinib or acalabrutinib and ibrutinib. At baseline, high mutation frequencies were observed in TP53, SF3B1, ATM, and NOTCH1 across disease indications ( Figure). The majority of TP53 mutations were missense mutations and located in the DNA binding domain. Nineteen different mutations were identified in ATM and were distributed across the whole gene with a majority clustered in the 3' regions encoding the FAT and PI3 kinase domains. All mutations (n=21) in SF3B1 were missense and 38% (n=8/21) of the mutations occurred at p.K700E/c.A2098G. In NOTCH1, the most common mutation (n=8/14, 57.1%) was a two base pair deletion (c.7541_7542delCT) in the PEST domain of exon 34. In patients with CLL/SLL with TP53, SF3B1, or ATM mutations at baseline, shorter progression-free survival was observed compared to patients without these mutations, suggesting that mutations in DNA damage response and RNA splicing/metabolism pathways are associated with less favorable prognosis. BTK mutations were detected in 4.2% (n=3/71) of baseline samples and in 57.1% (n=4/7) of samples available at disease progression (PD). All BTK mutations were at the C481 BTKi binding site. Two patients with baseline BTK mutations had PD and increased VAF of BTK mutants were detected for both patients at PD. A third patient died due to illness unrelated to treatment. Two patients acquired new BTKC481 mutations at PD. Conclusion: This is the first study to describe the genomic landscape of patients with B-cell malignancies who were intolerant to ibrutinib and/or acalabrutinib. Here we show that the gene mutational profile of these patients at baseline or at/after disease progression is comparable with patients with relapse/refractory disease who tolerate ibrutinib and, consistent with other studies, patients with mutations in TP53, SF3B1 or ATM genes had less favorable prognosis on BTKi. Further, intolerant patients who progressed on zanubrutinib acquired new BTK mutations and/or had an increase in the frequency of BTK mutations. These data contribute to the growing understanding of the mutational profiles of patients with B-cell malignancies, particularly those who were intolerant to BTKi, and further explores the association between mutations and response to subsequent zanubrutinib treatment. This study may provide supporting information to inform treatment guidelines for patients who become intolerant to BTKi.

Combination Treatment with Sonrotoclax (BGB-11417), a Second-Generation BCL2 Inhibitor, and Zanubrutinib, a Bruton Tyrosine Kinase (BTK) Inhibitor, Is Well Tolerated and Achieves Deep Responses in Patients with Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (TN-CLL/SLL): Data from an Ongoing Phase 1/2 Study

Background: The combination of BCL2 and BTK inhibitors has shown synergistic activity. The combination of venetoclax, a BCL2 inhibitor, and ibrutinib, a BTK inhibitor, is an effective treatment for CLL/SLL. Sonrotoclax (BGB-11417) is a BH3 mimetic that binds and inhibits BCL2 with potency &amp;gt;10x that of venetoclax in biochemical assays. Zanubrutinib, a next-generation BTK inhibitor, has shown improved PFS with fewer cardiac adverse events (AEs) vs ibrutinib in a randomized study of patients with CLL/SLL (Brown et al. N Engl J Med. 2023). BGB-11417-101 (NCT04277637) is an ongoing, first-in-human, phase 1/1b dose-escalation/expansion study of patients with various B-cell malignancies. In a preliminary report, sonrotoclax, alone or in combination with zanubrutinib, was well tolerated at all doses tested up to 640 mg. This abstract describes the safety and efficacy data from patients with treatment-naïve (TN) CLL/SLL who received the combination of sonrotoclax and zanubrutinib. Methods:Patients received zanubrutinib (320 mg QD or 160 mg BID) 8-12 weeks before starting sonrotoclax using a ramp-up schedule starting from 1 mg to the intended target dosage of 160 mg or 320 mg QD (doubling weekly [W] or 30% increase every day 5 d/week [D]) to mitigate risk of tumor lysis syndrome (TLS). Patients were treated until progression, unacceptable toxicity, or could elect to stop. TLS was assessed per Howard (2011) criteria; mitigation included mandatory oral hydration and antihyperuricemics. Primary endpoint was safety (reported per CTCAEs v5.0); a secondary endpoint was ORR (per iwCLL 2008 criteria) and minimal residual disease assessed in blood by ERIC flow every 24 weeks (uMRD4; &amp;lt;1 CLL cell per 10,000 leukocytes, or &amp;lt;0.01%) was an exploratory endpoint. Results: As of May 21, 2023, 94 patients with TN-CLL/SLL were enrolled (sonrotoclax 160 mg QD, n=41 [26 W, 15 D] and 320 mg QD, n=53 [25 W, 28 D]); 15 patients were still receiving zanubrutinib monotherapy and 79 started sonrotoclax (160 mg, n=32 [25 W, 7 D] and 320 mg, n=47 [24 W, 23 D]). Median follow-up was 8.5 mo (range: 0.6-18.2) for all patients; 160 mg, 12.1 mo (range: 0.6-18.2); 320 mg, 7.0 mo (range: 1.1-14.6). No deaths have occurred, and all patients remain on study. Treatment-emergent AEs (TEAEs) occurring in ≥20% patients who received sonrotoclax plus zanubrutinib (n=79) are listed in theTable; TEAE frequencies were similar between the two sonrotoclax cohorts. Contusion, neutropenia, and low-grade gastrointestinal toxicity were the most common TEAEs; neutropenia was the most common grade ≥3 TEAE (n=13 [17%]). No cases of clinical or laboratory TLS occurred in either ramp-up schedule; no patient experienced atrial fibrillation. One TEAE (cryptococcal meningitis at 11 weeks treated with azoles) led to treatment discontinuation. Sonrotoclax dose holds occurred in 17 patients (22%) for a median duration of 11 days (range: 3-37) and three patients (4%) had dose reduction. The most common TEAEs resulting in dose holds were COVID-19 (n=9 [11%]) and diarrhea (n=3 [4%]). A total of 56 patients had a response assessment. The ORR was 100% (CR: 160 mg, n=9 [36%]; 320 mg, n=6 [19%]). Across all doses, rate of CR increased with time; overall median time to CR was 10.1 mo (range: 5.4, 17.1). No progression was reported in either cohort (Figure). Week 24 blood uMRD4 rates were 50% (n=12/24) in 160 mg and 65% (n=13/20) in 320 mg patients. Week 48 blood uMRD4 rates were 73% in 160 mg (n=11/15) and 100% (n=1/1) in 320 mg; no patient has lost uMRD4. Conclusion: Sonrotoclax (160 mg and 320 mg) in combination with zanubrutinib was well tolerated in patients with TN CLL/SLL. Only one patient discontinued treatment and three patients had dosage reductions. No TLS was seen with either ramp-up schedule. Acknowledging the short follow up, efficacy is encouraging with 100% ORR in assessed patients and no PFS events. High rates of blood uMRD4 occurred early. Based on these data, a phase 3 study assessing this combination is planned.

330MO Pooled safety analysis of zanubrutinib monotherapy in Asian patients with B cell malignancies

330MO Pooled safety analysis of zanubrutinib monotherapy in Asian patients with B cell malignancies

Evaluation of Bruton tyrosine kinase inhibitors monotherapy and combination therapy in lymphocytic leukemia.

BTKi is an effective treatment in chronic lymphocytic leukemia. However, head-to-head clinical trials between BTKi are rare. To explore evidence-based treatmentdecisions, we conducted this network meta-analysis. We searched in PubMed, Cochrane Library and Embase and selected articles of BTKi treatment in CLL patients, with English restrictions. Objective response rate (ORR), progression-free survival(PFS) and safety were outcomes. Combination therapy and acalabrutinib monotherapy achieved great ORR (greater than 80%). Combination therapy (AO and IR) also performed terrific PFS (> 80%). Compared with ibrutinib monotherapy, zanubrutinib, acalabrutinib and IR showed no significance in overall survival. Diarrhea, hypertension, cardiac events, neutropenia were common adverse events of BTKi therapy. IR had higher incidence of hypertension (0.38, 95% CI 0.28-0.48), and IU was more likely occurred cardiac events. Zanubrutinib monotherapy had lower incidence of total serious adverse reaction (0.42, 95% confidence interval (95% CI): 0.36-0.47),while ibrutinib monotherapy occurred higher adverse reactions of grade ≥ 3 (0.77, 95% CI 0.72-0.82). Although both BTKi monotherapy and combination therapy showed great efficacy, combination therapy did not display priority. Meanwhile, safety of BTKi combination therapy needs to be fully and comprehensively considered.Registration number: CRD42022378732.

The efficacy and safety of Bruton tyrosine kinase inhibitors as monotherapy in the treatment of newly diagnosed patients with Waldenström macroglobulinemia

Objective: To investigate the efficacy and safety of Bruton tyrosine kinase inhibitors (BTKi) ibrutinib or zanubrutinib monotherapy in newly diagnosed patients with Waldenström macroglobulinemia (WM) . Methods: The efficacy and adverse effects of 58 patients with newly diagnosed WM receiving BTKi monotherapy in Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine were analyzed retrospectively from January 2018 to August 2022. Results: The response of 55 patients may be examined. Forty patients received ibrutinib monotherapy for a median of 15 months, with an overall response rate (ORR) of 85%, a main remission rate (MRR) of 70%, and a very good partial remission (VGPR) rate of 10%. Fifteen patients received zanubrutinib monotherapy for a median of 13 months, with an ORR of 93%, an MRR of 73%, and a VGPR rate of 0%. For various reasons, 10 patients were converted from ibrutinib to zanubrutinib. Ibrutinib treatment lasted an average of 7.5 months before conversion. The median duration of zanubrutinib therapy after conversion was 3.5 months. The ORRs before and after conversion were 90% and 100%, MRRs were 80% and 80%, and VGPR rates were 10% and 50%, respectively. After a median of 16 months, the 24-month progression-free survival (PFS) rate of patients who received both BTKi was 86%. PFS did not differ statistically across individuals with low, medium, and high-risk ISS scores (P=0.998). All of the patients survived. The most common side effects of BTKi were neutropenia and thrombocytopenia, which occurred in 12% and 10% of all patients, respectively. Ibrutinib accounts for 5% of atrial fibrillation, and zanubrutinib has a 7% risk of bleeding. Conclusions: In treating WM, ibrutinib or zanubrutinib provides good efficacy and tolerable adverse effects.

Zanubrutinib, Alone and in Combination With Tislelizumab, for the Treatment of Richter Transformation of Chronic Lymphocytic Leukemia.

Zanubrutinib, Alone and in Combination With Tislelizumab, for the Treatment of Richter Transformation of Chronic Lymphocytic Leukemia.

Zanubrutinib Monotherapy for Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Pooled Analysis of Three Studies.

Zanubrutinib is a highly selective irreversible inhibitor of Bruton tyrosine kinase which has shown significant activity in lymphoid malignancies in early phase studies. We report here the long-term follow-up outcomes of zanubrutinib in various lines of therapy in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). This post hoc analysis pooled patients with treatment-naïve (TN) or relapsed/refractory (R/R) CLL/SLL receiving zanubrutinib monotherapy from three phase 1/2 studies (BGB-3111-1002, BGB-3111-AU-003, BGB-3111-205). A total of 211 patients with CLL/SLL (TN 19, R/R 192) were included. After weighting (TN 19, R/R 24), the overall response rate (ORR) was 95.4% and significantly higher in the TN group than in the R/R group (100 vs. 91.0%, p < 0.0001). ORR was also significantly higher in the TN group than in the one prior line of therapy group (100 vs. 98.9%, p < 0.0001). Among those with R/R disease, the ORR was 97.8% in patients with one prior line of therapy (n = 79) and 90.7% in those with > 1 prior lines of therapy (n = 85; p = 0.080). The median follow-up times were 50.1, 35.7, and 45.9months for TN, R/R and all cohorts, respectively. Progression-free survival and overall survival were significantly longer in the TN group and only one prior line of therapy group compared with the > 1 prior lines of therapy group (all p < 0.05) and were similar in the TN group compared with the one prior line therapy group. Efficacy was similar regardless of the presence of genomic aberrations. Most frequent grade ≥ 3 adverse events were infections (41.7%), neutropenia (34.1%), and thrombocytopenia (9.4%). Atrial fibrillation occurred in only 1.9% of patients. With extended follow-up, zanubrutinib yielded long-term benefits and demonstrated a favorable safety profile for patients with TN or RR CLL/SLL. Earlier utilization of zanubrutinib was associated with better outcomes. Clinical Trials.gov identifiers, NCT03189524, NCT02343120 (retrospectively registered), and NCT03206918 (retrospectively registered).

P663: HEALTH-RELATED QUALITY OF LIFE OUTCOMES ASSOCIATED WITH ZANUBRUTINIB VS IBRUTINIB MONOTHERAPY IN PATIENTS WITH RELAPSED/REFRACTORY (RR) CLL/SLL: RESULTS FROM THE RANDOMIZED PHASE 3 ALPINE TRIAL

Background: In the phase 3 ALPINE trial (BGB-3111-305; NCT03734016), efficacy and safety of zanubrutinib, a highly selective, next-generation Bruton tyrosine kinase inhibitor (BTKi), were compared with the first-generation BTKi, ibrutinib, in adult patients with RR chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Aims: This abstract, based on the interim analysis of the ALPINE trial, describes the effects of zanubrutinib monotherapy and ibrutinib monotherapy on the health-related quality of life (HRQoL). Methods: Health-related quality of life was examined by patient-reported outcomes (PROs) measures assessed by EORTC QLQ-C30 and EQ-5D-5L at baseline, Cycle 1, and then every 3rd cycle until end of treatment. Key PRO endpoints included global health status (GHS), physical and role functions, and fatigue, pain, diarrhea, and nausea/vomiting. Descriptive analysis on all the scales was conducted as was a mixed model repeated-measure (MMRM) analysis of the longitudinal QLQ-C30 data. Data presented are from key cycles (7 and 13), corresponding to 6 and 12 months of treatment, respectively. Results: In the intent-to-treat population (N=652; zanubrutinib, n=327; ibrutinib, n=325), adjusted completion rates were high (>85%) in both arms at Cycles 7 and 13. On the QLQ-C30, estimated mean treatment differences and 95% CI in key PRO endpoints demonstrated treatment differences, in favor of zanubrutinib, in GHS, physical functioning, and fatigue in Cycle 7, and diarrhea in Cycle 13 (Table). Mean change from baseline (SD) in EQ-5D-5L VAS showed consistently more improvement with zanubrutinib compared with ibrutinib at both Cycle 7 (8.4 [18.2] vs 4.0 [16.6]) and Cycle 13 (6.8 [18.8] vs 5.2 [17.5]). Image:Summary/Conclusion: In the ALPINE trial, patients with RR CLL/SLL who received zanubrutinib monotherapy reported improvements in key HRQoL endpoints compared with patients who received ibrutinib monotherapy.

Efficacy and Safety of Zanubrutinib in IgA-secerning Lymphoplasmacytic Lymphoma

Non IgM-Lymphoplasmacytic Lymphoma (LPL) is a rare chronic lymph proliferative disorder with worse outcome with respect to classical LPL and Waldenstrom Macroglobulinemia. Therapeutic options are limited and differently from other indolent lymphomas no specific approved therapies are available. Here we present the case of a IgA-secreting LPL previously treated with 6 lines of therapies including immuno-chemotherapy, proteasome inhibitor and radiotherapy. At the last relapse this patient was successfully treated with zanubrutinib monotherapy within the BGB-311-AU-003 trial. Treatment with this BTK inhibitor showed to be well tolerated and led to a rapid and still ongoing response at 4 years follow up.

Zanubrutinib in Combination with Venetoclax for Patients with Treatment-Naïve (TN) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with del(17p): Early Results from Arm D of the SEQUOIA (BGB-3111-304) Trial

Zanubrutinib in Combination with Venetoclax for Patients with Treatment-Naïve (TN) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with del(17p): Early Results from Arm D of the SEQUOIA (BGB-3111-304) Trial

Pooled safety analysis of zanubrutinib monotherapy in patients with B-cell malignancies

AbstractZanubrutinib is a selective Bruton tyrosine kinase (BTK) inhibitor evaluated in multiple B-cell malignancy studies. We constructed a pooled safety analysis to better understand zanubrutinib-associated treatment-emergent adverse events (TEAEs) and identify treatment-limiting toxicities. Data were pooled from 6 studies (N = 779). Assessments included type, incidence, severity, and outcome of TEAEs. Median age was 65 years; 20% were ≥75 years old. Most patients had Waldenström macroglobulinemia (33%), chronic lymphocytic leukemia/small lymphocytic lymphoma (29%), or mantle-cell lymphoma (19%). Median treatment duration was 26 months (range, 0.1-65); 16% of patients were treated for ≥3 years. Common nonhematologic TEAEs were upper respiratory tract infection (URI, 39%), rash (27%), bruising (25%), musculoskeletal pain (24%), diarrhea (23%), cough (21%), pneumonia (21%), urinary tract infection (UTI), and fatigue (15% each). Most common grade ≥3 TEAEs were pneumonia (11%), hypertension (5%), URI, UTI, sepsis, diarrhea, and musculoskeletal pain (2% each). Atrial fibrillation and major hemorrhage occurred in 3% and 4% of patients, respectively. Atrial fibrillation, hypertension, and diarrhea occurred at lower rates than those reported historically for ibrutinib. Grade ≥3 adverse events included neutropenia (23%), thrombocytopenia (8%), and anemia (8%). Serious TEAEs included pneumonia (11%), sepsis (2%), and pyrexia (2%).Treatment discontinuations and dose reductions for adverse events occurred in 10% and 8% of patients, respectively. Thirty-nine patients (4%) had fatal TEAEs, including pneumonia (n = 9), sepsis (n = 4), unspecified cause (n = 4), and multiple organ dysfunction syndrome (n = 5). This analysis demonstrates that zanubrutinib is generally well tolerated with a safety profile consistent with known BTK inhibitor toxicities; these were manageable and mostly reversible.

Zanubrutinib monotherapy for relapsed or refractory non-germinal center diffuse large B-cell lymphoma

AbstractThe non-germinal center B-cell like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL) has poor clinical outcomes. Bruton tyrosine kinase (BTK) inhibitors have established therapeutic activity in B-cell malignancies, with modest activity in DLBCL. Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in patients with relapsed or refractory (R/R) non-GCB DLBCL. The BGB-3111-207 study (NCT03145064) was a multicenter single-arm phase 2 study. Patients received twice-daily oral zanubrutinib, 160 mg, until disease progression or unacceptable toxicity. The primary end point was the overall response rate (ORR). Secondary end points included progression-free survival (PFS) and duration of response (DOR). Overall survival (OS) was an exploratory end point. Forty-one patients were enrolled in China after having progressed or not responded to prior therapy. At data cutoff, 4 patients continued treatment with 37 discontinuations. The median follow-up was 6.8 months, the ORR was 29.3%, and the complete response rate was 17.1%. Median DOR, PFS, and OS were 4.5, 2.8, and 8.4 months, respectively. Adverse events (AEs) leading to treatment discontinuation were reported in 4 patients, and grade ≥ 3 AEs were reported in 48.8% of patients. Major hemorrhage, atrial fibrillation, and/or flutter were not observed. Zanubrutinib demonstrated modest antitumor activity in non-GCB DLBCL, like other BTK inhibitors, as well as a safety profile consistent with previous studies. Through retrospective biomarker testing, potential antitumor activity was observed in patients with both CD79B and MYD88 mutations, who have inferior outcomes to immunochemotherapy. Future studies of zanubrutinib in R/R non-GCB DLBCL will focus on developing mechanism-based treatment combinations and biomarker-driven patient selection.

Zanubrutinib for the treatment of MYD88 wild-type Waldenström macroglobulinemia: a substudy of the phase 3 ASPEN trial

AbstractPatients with Waldenström macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/refractory; 5 treatment-naïve) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.

Earlier Use of Zanubrutinib Monotherapy in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Is Associated with Greater Efficacy: A Pooled Analysis from 3 Studies

Earlier Use of Zanubrutinib Monotherapy in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Is Associated with Greater Efficacy: A Pooled Analysis from 3 Studies