Next-generation Bruton Tyrosine Kinase Inhibitor Research Articles

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.

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.

Safety and Efficacy Results from the Phase I Study of a Novel Dual Covalent and Non-Covalent Next Generation Inhibitor of Bruton's Tyrosine Kinase LP-168 in Patients with Relapsed/Refractory Mantle Cell Lymphoma

Background: Relapsed/Refractory (R/R) mantle cell Lymphoma (MCL) has poor long-term survival compared with other B-cell malignancies. As a result, there is an urgent need for safe and effective treatments, particularly for patients who have progressed on covalent (c) Bruton tyrosine kinase inhibitors (BTKis) therapy. LP-168 is a highly selective, next-generation BTKi with a unique dual binding mode: covalent binding to wild-type BTK and reversible binding to mutated BTK. Pre-clinical data has demonstrated that LP-168 is highly potent in inhibiting C481 mutated BTK. Here, we report the safety and efficacy of LP-168 monotherapy in the R/R MCL patients as part of an ongoing phase 1 study (NCT04993690) in B-cell malignancies. Methods: This is a Phase 1 first-in-human multicenter open-label study of LP-168 enrolling Chinese patients with B cell Non-Hodgkin Lymphoma (NHL) who have progressed after at least 1 or 2 prior treatments. The study has two parts: Phase 1a: “3+3” dose escalation and Phase 1b: dose expansion in disease-specific cohorts (e.g. R/R MCL, R/R MZL, etc.). Results: Between 10 August 2021 and 31 May 2023, 33 R/R MCL patients who received at least one dose were enrolled and received LP-168 100mg (n=8), 150mg (n=24), and 200mg (n=1) QD, respectively. Baseline characteristics are summarized in Table 1. The median age was 58 (range, 32-79) years old; 27 (81.8%) were male. 15 (45.5%) subjects had intermediate to high risk disease per MCL International Prognostic Index (MIPI). Median lines of prior therapies were 2 (range, 1-11) with 24.2% refractory to the last prior treatment. All patients have received rituximab or a rituximab-containing regimen. 19 (57.6%) subjects have received at least a cBTKi or cBTKi-containing regimen. The most common treatment emergent adverse events (TEAEs) (occurring in ≥20% subjects) were platelet count decreased (30.3%), neutropenia and anemia (27.3% each) and COVID-19 (24.2%), most of which were Grade 1. Grade 3 or more TEAEs were seen in 9 (27.3%) subjects. Serious AE (SAE) (lung infection, oral cavity infection and lymphocytosis, all Grade 3) occurred in 3 (9.1%) subjects. Dose interruptions due to AE occurred in 7 patients (21.2%)，but no AE has led to dose adjustment, drug discontinuation or death. Of 31 efficacy evaluable subjects with median follow up of 5.5 months (range: 2.0-22.5), 24 (77.4%) achieved response including 12 (38.7%) complete metabolic response or complete response (CMR/CR). In addition, 5 (71.4%) out of 7 subjects with blastoid/ pleomorphic variant MCL achieved response (2 CMR/CR, 3 PMR/PR). More importantly, of 17 subjects who had prior cBTKi exposure, 12 (70.6%) responded to LP-168 and 6 (35.3%) achieved CMR. LP-168 also showed efficacy in 2 subjects who have received ≥ 2 cBTKi treatments. Another 2 subjects responded to LP-168 even after disease progression on a cBTKi and a BTK degrader. 5 subjects have achieved progression-free survival (PFS) more than 1 year and are still on treatment (Figure 1). Conclusion: In this Phase 1 trial, the novel BTK inhibitor LP-168 demonstrated a high CR rate and durable response in heavily pre-treated R/R MCL including blastoid/pleomorphic variant with favorable safety. Moreover, LP-168 could effectively overcome the acquired resistance to prior cBTKi. Based on the safety, PK and preliminary efficacy data from the Phase 1 study so far, we have determined the recommended phase 2 dose (RP2D) for MCL as 150 mg QD. A phase 2 trial of LP-168 in R/R MCL is currently ongoing (NCT05716087).

Clinical Outcomes in Patients with Waldenström Macroglobulinemia (WM) Receiving Ibrutinib on the Phase 3 ASPEN Study ≥1 Year After Transitioning to Zanubrutinib

Introduction: Bruton tyrosine kinase inhibitors (BTKi) have become a standard of care in treating patients with WM. Zanubrutinib, a next-generation BTKi, was developed to ensure greater BTK specificity and potency than ibrutinib to avoid toxicities associated with off-target binding and improve efficacy. The ASPEN study (BGB-3111-302; NCT03053440) directly compared outcomes of zanubrutinib and ibrutinib treatment in patients with MYD88-mutated WM. The BGB-3111-LTE1 study (LTE1, NCT04170283) is a long-term extension study to which eligible patients can enroll following participation in parent studies of zanubrutinib for treatment of B-cell malignancies, including patients from comparator treatment arms. Here, we report safety and efficacy outcomes in ibrutinib-tolerant patients from ASPEN at ≥1 yr from initiation of zanubrutinib in the LTE1 study. Methods: All patients (N=47) who enrolled in LTE1 from the ibrutinib arm of ASPEN (Arm B) were included in this ad hoc analysis. Patients began treatment with zanubrutinib at 320 mg total daily dose upon enrollment. Safety and efficacy outcomes were evaluated, including the recurrence of ibrutinib treatment-emergent AEs (TEAEs). Investigators assessed disease response every 6 months, or more frequently as indicated, based on the modified Owen criteria and using parameters at ASPEN study entry (BTKi pretreatment); alternatively, investigators could assess “no evidence of progressive disease” using their clinical judgment. Results: Between June 26, 2020, and June 23, 2022, 47 patients treated with ibrutinib in ASPEN enrolled in LTE1. At ASPEN enrollment, 37 patients (79%) had R/R WM, with a median of 1 prior therapy (range: 1-6). At enrollment to LTE1, the median age was 73 yr (range: 44-89); the median time since ibrutinib treatment initiation was 50.4 months (range: 26-59.3). As of June 23, 2023, 40 patients (85%) remained on study treatment; the median zanubrutinib treatment duration was 15.3 months (range: 5.1-22.1) and the overall median treatment duration with BTKi was 65.5 months (range: 48.1-76.7). The median time from ASPEN study discontinuation to zanubrutinib initiation in LTE1 was 0.07 months (range: 0-4). During LTE1, grade ≥3 and serious TEAEs occurred in 23% and 13% of patients, respectively; infections (6.4%, all COVID-19) were the only grade ≥3 TEAEs occurring in more than 2 patients and no serious TEAEs occurred in more than 2 patients. Worsening of ibrutinib TEAEs of interest for BTKi treatment following the transition to zanubrutinib included infections (n=3), all of which were due to COVID-19 ( Fig 1), anemia (n=1), and neutropenia (n=1). Of the 7 patients who experienced cardiovascular AEs (8 events) in LTE1, all but 1 with grade 2 tachycardia had experienced at least 1 cardiovascular AE during ibrutinib treatment on ASPEN. No new or recurrent episodes of hypertension occurred after patients switched from ibrutinib to zanubrutinib, and no ongoing hypertension worsen. No resolved ibrutinib treatment-emergent atrial fibrillation/flutter recurred; no ongoing atrial fibrillation/flutter worsened following the transition to zanubrutinib. One new case of atrial fibrillation occurred on LTE1 Day 12 in a pt with an extensive cardiovascular history who also experienced grade 2 pericarditis 2 days prior (LTE1 Day 10). No cardiovascular TEAE led to death in LTE1; two deaths occurred both due to COVID-19. Categorical best overall response (BOR) in LTE1 was unchanged from the last response in ASPEN in 34 patients (72%) but improved in 10 patients (21%), including 1 pt in PR and 1 pt in VGPR at the end of ASPEN who had a deepening response to CR. Response worsened from PR to MR in 1 pt, 1 pt had “no evidence of progressive disease,” and 1 pt discontinued before response assessment. Median change in [IgM] from the last response in ASPEN to BOR in LTE1 was -36 mg/dL (-3490, +730); [IgM] was stable or decreased in 29 (73%) of the 40 evaluable patients ( Fig 2). Conclusions: With a median treatment duration of 15 months, worsening of ibrutinib TEAEs of interest for BTKi treatment following transition to zanubrutinib was rare, as was the emergence of new events. Response was maintained or improved in 96% (n=44/46) of efficacy-evaluable patients. While limited by sample size and nonrandomized/ ad hoc analysis, data suggest that patients may transition from ibrutinib to zanubrutinib without compromising safety or efficacy; long-term follow-up is ongoing.

A Novel Dual Covalent and Non-Covalent Next Generation Inhibitor of Bruton's Tyrosine Kinase LP-168 in Patients with Relapsed/Refractory B Cell Non-Hodgkin Lymphoma: Safety and Efficacy Results from a Phase 1 Study

Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKis) have improved clinical outcomes and revolutionized the treatment landscape of several B cell Non-Hodgkin Lymphoma (B-NHL), including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL). However, cBTKi intolerance and resistance remain the main causes of treatment failure. LP-168 is a highly selective, next-generation BTKi with high bioavailability and potency. It can act as a cBTKi which irreversibly inhibits wildtype BTK while can overcome the resistance of cBTKi by non-covalent binding and reversible inhibition of C481 mutated BTK. In this abstract are the results from a Phase 1 trial (NCT04993690) that evaluates the safety and efficacy of LP-168 monotherapy in Chinese patients with relapsed/refractory (R/R) B-NHL. Methods: This multicenter Phase 1 study contains a “3+3” dose escalation part (Phase 1a) followed by a dose expansion part (Phase 1b). Subjects with R/R B-NHL are eligible to receive LP-168 once daily treatment until disease progression or unacceptable toxicity. This study was designed to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of LP-168. The efficacy assessment was based on Lugano 2014, 2018 International Workshop on CLL (iwCLL) and the 6 th International Workshop for WM response criteria. Results: Between 10 August 2021 and 31 May 2023, 68 subjects (33 MCL, 14 diffuse large B cell lymphoma [DLBCL], 15 marginal zone lymphoma [MZL], 3 CLL/SLL, 2 follicular lymphoma [FL] and 1 primary mediastinal large B cell lymphoma [PMBCL]) were enrolled. Cohorts of 100 mg (N=13) 150 mg (N=40) and 200 mg (N=15) taken QD were treated respectively. The median age was 59.2 (range, 32-79) years old; 22 (64.7%) were male. The median number of prior therapies was 2 (range, 1-10) and 25 (36.8%) subjects had received at least a cBTKi-containing regimen. The median follow-up was 4.5 (0.3-21.3) months with 46 subjects remaining on treatment. No dose-limiting toxicities (DLTs) were observed during dose escalation from 100mg QD, 150mg QD to 200mg QD, and the maximum tolerated dose (MTD) was not reached. The most common treatment-emergent adverse events (TEAEs) occurring in ≥20% subjects included neutropenia, platelet count decreased and anemia, most of which were Grade 1 or 2 (as detailed in Table 1). ≥Grade 3 treatment related adverse events (TRAEs, including possibly related, probably related and definitely related) included neutropenia (7.4%), lung infection (2.9%), lymphopenia, leukocytosis, lymphocytosis and oral cavity infection (1.5% each). 9 (13.2%) subjects experienced Serious Adverse Event (SAE). Serious adverse reactions included lung infection, oral cavity infection and lymphocytosis. No major bleeding, hypertension, or atrial fibrillation was observed in this study. Dose reduction occurred in only 1 subject due to AE (immune-mediated pancreatitis, unlikely related). No TEAE led to drug discontinuation. 1 subject experienced Grade 5 lung infection (not related to LP-168). Of 60 efficacy-evaluable subjects, overall response rate (ORR) was 65.0%. In particular, ORR in R/R MCL (N=31) was 77.4% with a CR of 38.7%, non-GCB DLBCL (N=10) had an ORR of 70.0% with a CR of 40.0% and MZL (N=11) had an ORR of 72.7% with a CR of 9.1% (Figure 1). LP-168 steady state plasma exposure increases dose-dependently with limited accumulation at 100 to 200 mg. Plasma concentration peaks at approximately 2 to 3 hours at fasted state, the average terminal half-life was 15.1 hours, supporting once daily dosing. Conclusion: The current results of the Phase 1 study showed that LP-168 was well tolerated at 100-200 mg QD with favorable PK profile and has demonstrated encouraging efficacy in multiple B-cell malignancies, including those who had progressed on prior cBTKi.

A MATCHING‐ADJUSTED INDIRECT COMPARISON OF THE EFFICACY AND SAFETY OF ACALABRUTINIB VERSUS ZANUBRUTINIB IN RELAPSED OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA

Introduction: Next-generation Bruton tyrosine kinase inhibitors (BTKis) acalabrutinib (acala) and zanubrutinib (zanu) were compared with the standard of care BTKi ibrutinib in relapsed/refractory chronic lymphocytic leukemia (RR CLL) in the head-to-head randomized clinical trials (RCTs) ELEVATE-RR and ALPINE, respectively. However, differences in these RCT’s populations prevent comparison of acala and zanu. ASCEND, another RCT assessing acala, had a similar population to ALPINE but a different comparator. Thus, we used unanchored matching-adjusted indirect comparison (MAIC) to compare the efficacy and safety of acala vs zanu using individual patient data (IPD) from ASCEND and published aggregate data from ALPINE. Methods: Acala IPD from ASCEND were weighted to match zanu baseline data from ALPINE. This reduced differences in variables that were prognostic/effect-modifying of progression-free survival (PFS) in an exploratory multivariate cox regression analysis of ASCEND. These included sex, ECOG PS, bulky disease, prior chemoimmunotherapy, del(11q), del(17p), TP53 without del(17p), IGHV status, region, age, prior lines of therapy and Rai stage. An efficacy analysis assessed investigator-assessed PFS (INV PFS) in randomized patients with baseline data (acala, n = 149; zanu, n = 327). Pseudo IPD for INV PFS for zanu were obtained from Kaplan-Meier curves. A safety analysis assessed odds ratios (ORs) of adverse events (AEs) in treated patients with baseline data (acala, n = 148; zanu, n = 324). To compare the incidence of AEs, an artificial data cut-off (Feb 21, 2020) was imposed for acala to match the zanu median treatment exposure (both 28.4 months). Results: After matching, the effective sample size of acala was 99 (66.6%; 65% male; median age 66 years). 12- and 24-month INV PFS are shown in Table 1. The MAIC hazard ratio (HR) for INV PFS is similar for acala vs zanu: HR 0.90, 95% confidence interval (CI) 0.60–1.36. The risk of having grade ≥3 AE (OR 0.66, 95% CI 0.41–1.05), atrial fibrillation (AF; OR 1.32, 95% CI 0.56–3.08), grade ≥3 AF/atrial flutter (OR 0.60, 95% CI 0.12–2.89), grade ≥3 hemorrhage (OR 0.61, 95% CI 0.19–2.03) or an AE leading to discontinuation (OR 1.14, 95% CI 0.61–2.13) was similar with acala vs zanu. The risk of having a serious AE (OR 0.61, 95% CI 0.39–0.97), hypertension (any grade: OR 0.18, 95% CI 0.09–0.37; grade ≥3: OR 0.22, 95% CI 0.09–0.54), any grade hemorrhage (OR 0.54, 95% CI 0.34–0.87) or an AE leading to dose reduction (OR 0.30, 95% CI 0.14–0.67) favored acala vs zanu. Conclusions: Acala and zanu have a similar efficacy in RR CLL, while acala has a lower risk of grade ≥3 hemorrhage, any grade and grade ≥3 hypertension and dose reduction due to AEs vs zanu. Limitations of MAICs mean results should be viewed as hypothesis-generating. Encore Abstract—previously submitted to ASCO 2023, EHA 2023 The research was funded by: AstraZeneca Keyword: Chronic Lymphocytic Leukemia (CLL) Conflicts of interests pertinent to the abstract P. Ghia Consultant or advisory role AbbVie, AstraZeneca, BeiGene, BMS, Janssen, Lilly/Loxo Oncology, MSD, Roche Honoraria: AbbVie, AstraZeneca, BeiGene, BMS, Janssen, Lilly/Loxo Oncology, MSD, Roche Research funding: AbbVie, AstraZeneca, Janssen, Roche A. Skarbnik Consultant or advisory role AstraZeneca, Abbvie, Genentech, Genmab, Novartis, Kite Pharma, Epizyme, Janssen, Morphosys, Pharmacyclcics, SeaGen, TG Therapeutics, Lilly (LOXO) Other remuneration: Speakers' Bureau: AstraZeneca, Abbvie, Beigene, Celgene, Genentech, Janssen, Kite Pharma, Pharmacyclics, SeaGen, TG Therapeutics M. Miranda Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca A. S. Yong Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca J. Roos Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca Other remuneration: Patient/Royalties/Other Intellectual Property: CalciMedica R. Hettle Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca S. Palazuelos-Munoz Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca V. Shetty Employment or leadership position: AstraZeneca Stock ownership: Verona Pharma A. Kittai Consultant or advisory role Abbvie, AstraZeneca, Beigene, BMS, Eli Lilly, Janssen, KITE Research funding: AstraZeneca Other remuneration: Speaker's bureau: Beigene

Safety and efficacy of ABR in pts with TN or R/R MCL: Ph Ib trial.

7546 Background: Acalabrutinib (A) is a next-generation Bruton tyrosine kinase inhibitor approved for relapsed/refractory (R/R) mantle cell lymphoma (MCL). Bendamustine (B) + rituximab (R) is used for treatment-naive (TN) and R/R MCL. We present updated data on safety and efficacy of ABR in patients (pts) with TN or R/R MCL. Methods: Eligible adults received ABR in this phase 1b study (NCT02717624) as follows: ABR for 6 28-d cycles, maintenance A+R for up to 2 y (TN cohort responders), then oral A continuously until progressive disease (PD) or treatment discontinuation due to toxicity (both cohorts). The primary endpoint was safety. Secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR), all per Lugano. Results: Overall, 38 pts were enrolled (TN, n=18; R/R, n=20) with median age 66 y (range, 47–86). Baseline characteristics were (TN and R/R cohorts, respectively): stage IV disease in 88.9% and 95.0%, high-risk simplified MIPI score in 11.1% and 15.0%, bulky disease &gt;5 cm in 16.7% and 30.0% or ≥10 cm in 5.6% and 10.0%, and blastoid morphology in 5.6% and 15.0%; R/R pts had a median of 2 prior lines of therapy. As of the data cutoff date (6/15/22), 6 (33.3%) TN pts and 4 (20.0%) R/R pts were receiving A monotherapy (Table). Most common any-grade AEs were nausea (n=14, 77.8%; TN) and neutropenia (n=11, 55.0%; R/R). Grade 3–4 AEs occurred in 13 (72.2%) TN pts and 17 (85.0%) R/R pts, most commonly neutropenia in both cohorts (n=7, 38.9% [TN]; n=10, 50.0% [R/R]). Serious AEs occurred in 11 (61.1%) TN pts and 13 (65.0%) R/R pts. There were no reports of ventricular tachyarrhythmia. Grade 3 atrial fibrillation occurred in 1 pt outside the safety reporting period and was not related to study treatment. Grade ≥3 major hemorrhage was reported in 2 (11.1%) TN pts and 3 (15.0%) R/R pts. Grade ≥3 hypertension was reported in 3 (16.7%) TN pts and 2 (10.0%) R/R pts. Five TN pts died (AE: pneumonitis, n=1; unknown, n=4) and 6 R/R pts died (AE: COVID and cerebrospinal meningitis, n=2; PD, n=2; unknown, n=2). ORR was 94.4% (n=17) in the TN cohort and 85.0% (n=17) in the R/R cohort, with CR rates of 77.8% (n=14) and 70.0% (n=14), respectively. Median DOR was not estimable (NE) in the TN cohort and 43.5 mo in the R/R cohort. Median PFS and overall survival were NE in the TN cohort (median follow-up 47.6 mo) and 28.6 mo and NE, respectively, in the R/R cohort (median follow-up 20.4 mo). Conclusions: Triple-combination ABR was tolerable and effective in pts with TN or R/R MCL. Clinical trial information: NCT02717624 . [Table: see text]

Long‐term efficacy and safety of zanubrutinib (ZANU) in relapsed/refractory marginal zone lymphoma (R/R MZL): final analysis of the MAGNOLIA (BGB‐3111‐214) trial

Long‐term efficacy and safety of zanubrutinib (ZANU) in relapsed/refractory marginal zone lymphoma (R/R MZL): final analysis of the MAGNOLIA (BGB‐3111‐214) trial

Safety and Efficacy of Acalabrutinib, Bendamustine, and Rituximab in Patients with Treatment‐Naive or Relapsed/Refractory Mantle Cell Lymphoma: Phase Ib Trial

Safety and Efficacy of Acalabrutinib, Bendamustine, and Rituximab in Patients with Treatment‐Naive or Relapsed/Refractory Mantle Cell Lymphoma: Phase Ib Trial

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 in patients with treatment-naïve or relapsed/refractory Waldenström macroglobulinemia: An expanded-access study of 50 patients in the United States.

Zanubrutinib in patients with treatment-naïve or relapsed/refractory Waldenström macroglobulinemia: An expanded-access study of 50 patients in the United States.

Zanubrutinib Demonstrates Superior Progression-Free Survival (PFS) Compared with Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL): Results from Final Analysis of ALPINE Randomized Phase 3 Study

Introduction: CLL/SLL is usually characterized by consecutive relapses and response to therapy ultimately dictates survival. While ibrutinib, a first-generation Bruton tyrosine kinase inhibitor (BTKi), has become standard therapy, it has well-described off-target effects that can limit use. Compared with ibrutinib, zanubrutinib, a next-generation BTKi, provides improved BTK occupancy across disease-relevant tissues with greater kinase selectivity. In a randomized phase 3 study (ALPINE; NCT03734016), zanubrutinib was compared head-to-head with ibrutinib as treatment for R/R CLL/SLL. At predefined response analyses, zanubrutinib demonstrated superior overall response rate (ORR); data from the predefined final PFS analysis are reported here. Methods: Patients (pts) with R/R CLL/SLL who had received ≥1 prior therapy and had measurable disease were randomized 1:1 to receive zanubrutinib or ibrutinib until disease progression or unacceptable toxicity. Stratification was based on age, refractory status, geographical region, and del(17p)/TP53 mutation status. As the primary endpoint of ORR was superior with zanubrutinib, the key secondary efficacy endpoint of PFS was tested for noninferiority under hierarchical testing when 205 PFS events were observed. If PFS noninferiority between zanubrutinib and ibrutinib was demonstrated, superiority of zanubrutinib vs ibrutinib could be tested and claimed if the 2-sided P-value was <.04996. Other endpoints included overall survival (OS), ORR including PR with lymphocytosis (PR-L) or better, and safety parameters including atrial fibrillation/flutter. Results: Pts (N=652) from 15 countries were randomized to receive zanubrutinib (n=327) or ibrutinib (n=325). Demographic and disease characteristics were balanced between zanubrutinib and ibrutinib arms (age ≥65 yrs [61.5 vs 61.5%]; male [65.1 vs 71.4%]; unmutated IGHV [73.1 vs 73.5%]; del(17p) [13.8 vs 15.4%]; TP53 mutated without del(17p) [9.2 vs 7.7%]). Across the study population, median age was 67 and 68 yrs, respectively; in both arms, median prior lines of therapy was 1. With a median follow-up of 29.6 mo (data cutoff, 8 Aug 2022), zanubrutinib PFS, assessed by independent review committee (PFSIRC), was superior to ibrutinib in the ITT population (HR: 0.65 [95% CI, 0.49-0.86]; 2-sided P=.0024 [Fig 1]); identical statistical values were reported when assessed by investigator (INV). Median PFSIRC was 35.0 mo (95% CI, 33.2-44.3) for ibrutinib-treated pts but not reached for zanubrutinib-treated pts. In a predefined subgroup of pts with del(17p)/TP53 mutation, longer PFSIRC was demonstrated with zanubrutinib than ibrutinib (Fig 2). PFS, regardless of IRC or INV assessment, consistently favored zanubrutinib across other major predefined subgroups, including IGHV status. Compared with ibrutinib, zanubrutinib had a higher ORRIRC (86.2 vs 75.7%, nominal 2-sided P=.0007), with a rate of PR-L or better of 91.7% vs 83.1% (nominal 2-sided P=.001). Treatment discontinuation rate was lower with zanubrutinib (26.3%) vs ibrutinib (41.2%) with most due to AEs (16.2 vs 22.8%) or progressive disease (7.3 vs 12.9%); discontinuation rates due to cardiac disorders were 0.3% vs 4.3%. Rates of grade ≥3 AEs (67.3 vs 70.4%), serious AEs (42.0% vs 50.0%), dose interruption (50.0% vs 56.8%), and dose reduction (12.3 vs 17.0%) were also lower with zanubrutinib vs ibrutinib. Rate of atrial fibrillation/flutter was lower with zanubrutinib compared with ibrutinib (5.2% vs 13.3%); rates of other AEs of special interest were similar between treatments. There were no grade 5 AEs due to cardiac disorders with zanubrutinib vs 6 (1.9%) with ibrutinib. Overall, 48 (14.7%) pts treated with zanubrutinib and 60 (18.5%) treated with ibrutinib had died (OS HR: 0.76 [95% CI, 0.51-1.11]). Conclusions: As ALPINE is the first study to demonstrate PFS superiority in a head-to-head comparison of BTK inhibitors, zanubrutinib has now proven superiority to ibrutinib in both ORR and PFS in pts with R/R CLL/SLL. Efficacy benefits with zanubrutinib were observed across all major subgroups, including high-risk pts. Zanubrutinib had a favorable safety profile compared with ibrutinib, with a lower rate of treatment discontinuation and fewer cardiac disorder events, including fewer cardiac events leading to death. These data suggest zanubrutinib is more efficacious and better tolerated than ibrutinib as treatment for R/R CLL/SLL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 1 Study with the Novel B-Cell Lymphoma 2 (Bcl-2) Inhibitor Bgb-11417 As Monotherapy or in Combination with Zanubrutinib (ZANU) in Patients (Pts) with CLL/SLL: Preliminary Data

Background/introduction: The effectiveness of Bcl-2 inhibitors as a treatment for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was established by the approval of venetoclax in pts with CLL/SLL across all lines of therapy. However, the related adverse events (AEs) and emergence of BCL2 mutations, resulting in resistance, can limit the utility of venetoclax. BGB-11417 is a highly selective Bcl-2 inhibitor with potency >10 times that of venetoclax in biochemical assays. BGB-11417 monotherapy is tolerable, with no maximum tolerated dose (MTD) reached after dose escalation through all planned doses to 640 mg once daily (QD) in pts with non-Hodgkin lymphoma (EHA 2022. Abstract P687). The combination of Bcl-2 and Bruton tyrosine kinase (BTK) inhibitors is tolerable with synergistic activity in CLL and mantle cell lymphoma (MCL) (J Clin Oncol 2019;37:2722-9; N Engl J Med 2019;380:2095-103; EHA 2020. Abstract S158; N Engl J Med 2018;378:1211-23). ZANU, a next-generation BTK inhibitor, has shown favorable activity and safety in pts with CLL/SLL (EHA 2021. Abstract LB1900) and Waldenström macroglobulinemia (Blood. 2020;136(18):2038-2050). BGB-11417-101 is an ongoing first-in-human phase 1/1b dose-escalation/expansion study (NCT04277637). Pts with various B-cell malignancies were enrolled; data from CLL/SLL cohorts are presented here. Methods: In separate monotherapy and combination therapy cohorts, pts received escalating doses of BGB-11417 (40, 80, 160, 320, or 640 mg QD) with a ramp-up to the intended target dose to minimize risk of tumor lysis syndrome (TLS). In combination therapy cohorts, pts received ZANU (320 mg QD or 160 mg twice daily) beginning 8-12 weeks before BGB-11417. Dose-limiting toxicity for each cohort was evaluated by a Bayesian logistic regression model during dose ramp-up through day 21 at the intended dose. AEs were reported per Common Terminology Criteria for AEs v5.0. Minimal residual disease (MRD) was assessed by a European Research Initiative on CLL flow cytometry assay. Results: As of May 15 2022, 50 pts with CLL received treatment: 6 monotherapy (all relapsed/refractory [R/R]) and 44 combination (22 R/R; 22 treatment naïve [TN]). The monotherapy CLL cohort received BGB-11417 doses up to 160 mg. Based on emerging safety data from other cohorts, pts in combination cohorts with R/R CLL received BGB-11417 up to 640 mg and pts with TN CLL received up to 320 mg (data include 8 pts in ZANU pretreatment not yet dosed with BGB-11417). MTD has not yet been reached for any CLL cohort, with dose escalation ongoing. Median follow-up was 11.5 mo (range 8.5-18.3) for monotherapy and 5.8 mo (range 0.2-10.5) for combination. Treatment-emergent AEs (TEAEs) across all doses are listed in the Table. With monotherapy, cytopenias were the most common TEAEs (≥50%), with 33% grade ≥3. With combination, contusion, neutropenia, and low-grade gastrointestinal toxicity were the most common TEAEs (≥22.7%); neutropenia was the most common grade ≥3 TEAE (11.4%) with 5 pts. No pts discontinued monotherapy treatment, and 1 pt discontinued combination treatment (disease progression; Richter transformation). Only 1 high-risk pt with CLL on monotherapy had laboratory TLS that resolved with no intervention (overall laboratory TLS ≤2%). No clinical TLS was reported. Diarrhea was mostly grade 1 and grade ≥3 was not seen. Although efficacy data are early, most pts with CLL/SLL had notable reductions in absolute lymphocyte count (ALC) with responses seen at doses as low as 1 mg (Figure), consistent with improved potency of BGB-11417 vs venetoclax. Four responses (66%, partial response [PR] or better) and 32 responses (72.7%, PR with lymphocytosis or better) were observed with mono- and combination therapy, respectively. MRD data are early: among 4 MRD evaluable pts at 160 mg, 3 pts (2 monotherapy; 1 combination) had a peripheral blood CLL count <10-4 at 24 weeks after BGB-11417 initiation. Conclusion: These preliminary data show BGB-11417, alone or in combination with ZANU, was well-tolerated in most patients. Grade ≥3 neutropenia was uncommon and manageable. Efficacy is supported by the rapid reduction in ALC during ramp-up, and early response data are promising. TLS rates are low; the prophylactic measures and ramp-up schedule seem to adequately mitigate TLS across all dose levels tested. Mature MRD data are forthcoming, and venetoclax-treated CLL/SLL cohorts will soon be open for enrollment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase 1 Study with the Novel B-Cell Lymphoma 2 (Bcl-2) Inhibitor Bgb-11417 As Monotherapy or in Combination with Zanubrutinib (ZANU) in Patients (Pts) with Non-Hodgkin Lymphoma (NHL) or Waldenström Macroglobulinemia (WM): Preliminary Data

Background/introduction: The Bcl-2 inhibitor venetoclax has exhibited activity in pts with NHL in monotherapy (Clin Cancer Res 2021;27:4690-5) and in combination regimens (Blood 2019;133;1964-7). BGB-11417 is a highly selective Bcl-2 inhibitor with potency >10 times that of venetoclax in biochemical assays. BGB-11417 has favorable pharmacokinetics and a broad therapeutic index that may result in an improved safety profile. BGB-11417 monotherapy is tolerable, with no maximum tolerated dose (MTD) reached after dose escalation through all planned doses to 640 mg once daily (QD) in pts with NHL (EHA 2022. Abstract P687). The combination of Bcl-2 and Bruton tyrosine kinase (BTK) inhibitors is tolerable with synergistic activity in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL) (J Clin Oncol 2019;37:2722-9; N Engl J Med 2019; 380:2095-103; ASH 2020 Abstract S158; N Engl J Med 2018;378:1211-23). ZANU is a next-generation BTK inhibitor with favorable activity and safety profiles in pts with CLL/SLL (EHA 2021 Abstract LB1900) and WM (Blood. 2020;136(18):2038-2050) with FDA approval for treatment in MCL, marginal zone lymphoma (MZL), and WM. BGB-11417-101 is an ongoing first-in-human phase 1/1b dose-escalation/expansion study (NCT04277637). Data from separate cohorts of MCL, WM and combined NHL (Follicular lymphoma [FL], diffuse large B cell lymphoma [DLBCL], MZL, transformed FL) are presented here. Methods: In the monotherapy cohorts, pts received BGB-11417 (40, 80, 160, 320, or 640 mg QD) with a ramp-up to the intended dose. In combination cohorts, pts received ZANU (320 mg QD or 160 mg twice daily) 8-12 weeks before BGB-11417. Dose-limiting toxicity for each dose cohort was evaluated by a Bayesian logistic regression model during dose ramp-up through day 21 at the intended dose. Responses were assessed per Lugano criteria. Adverse events (AEs) were reported per Common Terminology Criteria for AEs v5.0, and tumor lysis syndrome (TLS) was assessed per Howard (2011) criteria. Results: As of May 15 2022, 45 pts with NHL, WM, or MCL received BGB-11417 (34 monotherapy; 11 combination). Monotherapy pts (n=28 NHL [n=18 DLBCL, n=6 FL, n=4 MZL]; n=6 WM) received BGB-11417 doses ≤640 mg. Combination pts (n=11 MCL) received ZANU, and 9 (82%) had also received BGB-11417 doses ≤160 mg (data include 2 pts who are still in the pretreatment phase with ZANU). Dose escalation to 640 mg was completed for NHL monotherapy; all planned doses were tested, with no MTD reached. Dose escalation is ongoing for monotherapy in WM and combination therapy in MCL cohorts. Median follow-up was 6.5 months (range 0.4-25.3) for monotherapy and 4.8 months (range 0.4-8.9) for combination therapy. Treatment-emergent AEs (TEAEs) across all dose levels are listed in the Table. For monotherapy, the most common TEAEs (≥20%) were nausea (38%), fatigue (24%), constipation, diarrhea and dizziness (21% each); the most common grade ≥3 TEAE was neutropenia (12%). For combination therapy, the most common TEAEs were contusion and neutropenia; grade ≥3 AEs were infrequent. Twenty-five monotherapy pts (22 disease progression [PD]; 1 AE; 2 other reasons) and 2 combination therapy pts (PD) discontinued treatment. No TEAEs leading to death and no TLS were reported to date. Amongst combined NHL cohorts, 23 pts reached the first response assessment time point, but most were treated below the recommended phase 2 dose (RP2D). Of these pts, 3 responded (n=2 DLBCL, n=1 MZL) including 1 complete response (DLBCL), and notable reductions in the sum of the product of perpendicular diameters (SPD) were seen (Figure). In the MCL combination cohort, 6 of 11 (55%) pts responded. In the monotherapy WM cohort, 1 of 4 evaluable pts exhibited minor response at the first dose level tested (80 mg); hemoglobin count increases of more than 20 g/L were seen in 3 of 6 treated pts and all remain on treatment. Conclusion: These initial data show an encouraging safety profile and preliminary evidence of efficacy for BGB-11417 in NHL, MCL, and WM cohorts. No MTD was reached even at the highest dose level of 640 mg QD. All low-grade TEAEs and grade ≥3 neutropenia were manageable. The response data includes NHL patients mostly treated at doses below the RP2D; longer follow-up of BGB-11417 monotherapy and combination therapy at the RP2D is needed. Monotherapy MCL data are forthcoming. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Genomic Characterization of Patients in a Phase 2 Study of Zanubrutinib in BTK Inhibitor-Intolerant Patients with Relapsed/Refractory B-Cell Malignancies

Background/Introduction: Targeting Bruton tyrosine kinase (BTK) to inhibit B-cell receptor signaling is an effective way to treat B-cell malignancies. However, some patients (pts) have experienced toxicities to BTK inhibitors ibrutinib (ibr) and acalabrutinib (acala), which lead to dose reduction or treatment discontinuation. Zanubrutinib (zanu) is a potent and selective next-generation BTK inhibitor (Blood. 2021;138[suppl 1]:1410). BGB-3111-215 (NCT04116437) is an ongoing, phase 2 study of the safety and efficacy of zanu monotherapy in pts with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), or marginal zone lymphoma (MZL) who discontinued ibr, acala, or acala and ibr because of intolerance. Here, we present the gene mutation profile of pts in this study to demonstrate the mutational landscape of pts intolerant to ibr or acala and to explore the association between gene mutations and response to zanu in ibr- and acala- intolerant pts. Methods: Peripheral blood from pts was collected before treatment and at or after the time of disease progression. Genomic DNA was isolated from peripheral blood mononuclear cells or plasma, and the mutational status of targeted genes was assessed using a targeted 106-gene next-generation sequencing (NGS) panel (PredicineHEMETM, Predicine). Samples were sequenced to a median depth of >20,000 reads, with a validated sensitivity of 0.25% mutant allele frequency for all genomic regions. Results: Samples from 63 pts were analyzed, including 63 at baseline and 5 at or after progressive disease (PD). There were 41 pts with CLL, 6 with SLL, 10 with WM, 3 with MCL, and 3 with MZL. The most common mutations at baseline were TP53 (31.7%), SF3B1 (22.2%), ATM (17.5%), NOTCH1 (17.5%), CHEK2 (14.3%), and KRAS (12.7%). Copy number variants were detected, including deletions at ATM locus (9.5%) and RB1 locus (9.5%) and amplifications at CCND2 locus (6.3%). For CLL/SLL, the frequencies of TP53 (27.7%), NOTCH1 (21.3%), SF3B1 (25.5%), ATM (21.3%), and BIRC3 (10.4%) mutations were comparable to those in other studies with high-risk relapsed/refractory CLL pts (Leukemia. 2018;32:3-91; Blood. 2014;123:3247-3254; Leuk Lymphoma. 2018;59[10]:2318-26). For WM, 5 of 10 (50%) samples harbored TP53 mutations, and 4 of 10 samples had MYD88 mutations; all harbored the L265P mutation. Among the 4 pts with MYD88 mutation, CXCR4 gene mutation was detected in 1 case. All 6 pts with MYD88 wild type also had CXCR4 wild type gene, consistent with published data (N Engl J Med. 2015;373:584-6). Baseline mutations were available for the 10 pts with PD, including 8 CLL, 1 SLL, and 1 MCL. Compared to pts without PD, pts with PD had increased frequency of certain mutations: TP53 (60%, P=0.071), ATM (50%, P=0.017), SF3B1 (50%, P=0.035), RB1 (40%, P=0.009), SETD2 (40%, P=0.009), and CDKN2A (30%, P=0.011). This finding suggests that these particular baseline mutations are associated with resistance to zanu. Five pts also had mutations detected at or after PD. Of these, 3 pts had BTK or PLCG2 mutations (submitted). One patient with CLL and without BTK or PLCG2 mutations had ATM and FBXW7 mutations (variant allele frequencies were 86% and 50%, respectively), suggesting DNA damage pathway mutations and NOTCH1 dysregulations may have contributed to disease progression in this patient. Conclusion: Exploratory analysis results confirmed that cell cycle, DNA damage, and NOTCH1 pathway genes were frequently mutated in pts with B-cell malignancies on study BGB-3111-215 (pts intolerant to ibr and/or acala). Pts with mutations associated with poor prognosis at baseline were more likely to develop PD.

Coming of Age for BTK Inhibitor Therapy: A Review of Zanubrutinib in Waldenström Macroglobulinemia.

Waldenström macroglobulinemia (WM) is a rare form of non-Hodgkin B-cell lymphoma with a variable clinical presentation that can impact a patient’s quality of life by causing anemia, peripheral neuropathy, serum hyperviscosity, extramedullary disease, and other symptoms. There are several safe and effective treatment regimens for patients with WM, and the choice of therapy should be made in a personalized fashion considering the patient’s symptoms, comorbidities, and genomic profile. Bruton tyrosine kinase (BTK) inhibitors are a new option to treat patients with WM. Zanubrutinib is a next-generation covalent BTK inhibitor designed to have fewer off-target effects than previous BTK inhibitors. This review summarizes the pharmacokinetic and pharmacodynamic properties of zanubrutinib as well as safety and efficacy findings. Then, it explores the health economic and outcomes research associated with the costs of treating patients with WM and the reasons why zanubrutinib may be a more cost-effective treatment option compared with ibrutinib, a first-generation BTK inhibitor. Future directions for the treatment of WM focus on the use of zanubrutinib in combination therapy. Combinations based on effective ibrutinib or acalabrutinib treatments may be effectively applied with zanubrutinib given the similar mechanism of action for these BTK inhibitors. Combination therapies could also help prevent the development of disease resistance, minimize toxicity, and support treatment regimens of finite duration.

CLL-115 First Interim Analysis of ALPINE Study: Results of a Phase 3 Randomized Study of Zanubrutinib vs Ibrutinib in Patients With Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

CLL/SLL treatment has been transformed with Bruton tyrosine kinase inhibitors (BTKi) such as ibrutinib. Zanubrutinib, a next-generation BTKi, was designed to maximize BTK occupancy and minimize toxicity. ALPINE (NCT03734016) is a global, randomized, phase 3 study of zanubrutinib versus ibrutinib in patients with R/R CLL/SLL; presented here is a pre-planned interim analysis conducted ~12 months after 415 patients enrolled between November 5, 2018, and December 20, 2019. Patients were randomized 1:1 to zanubrutinib (160 mg twice daily) or ibrutinib (420 mg once daily) arms; stratification factors were age (<65 years vs ≥65 years), geographic region, refractory status, and del(17)p/TP53 mutation. Primary endpoint was investigator-assessed overall response rate (ORR) per 2008 IWCLL guidelines or Lugano criteria; the noninferiority of zanubrutinib-to-ibrutinib response ratio was evaluated at the noninferiority margin of 0.8558. If noninferiority was demonstrated, superiority of zanubrutinib versus ibrutinib in ORR was tested. Baseline characteristics (zanubrutinib versus ibrutinib): age ≥65 years: 62.3% versus 61.5%, male sex 68.6% versus 75%; >3 prior therapies: 7.2% versus 10.1%; del(17)p: 11.6% versus 12.5%; TP53 mutation without del(17)p: 8.2% versus 5.8%. With a median follow-up of 15 months, ORR was 78.3% versus 62.5% for zanubrutinib versus ibrutinib, respectively (2-sided P=0.0006, prespecified a=0.0099). ORR was higher for zanubrutinib in patients with del(11)q (83.6% vs 69.1%) and del(17)p (83.3% vs 53.8%); zanubrutinib had higher overall 12-month progression-free survival (PFS; 94.9% vs 84.0%) and overall survival (97.0% vs 92.7%). Significantly fewer patients had atrial fibrillation/flutter (AF) with zanubrutinib versus ibrutinib (2.5% vs 10.1%, 2-sided P=0.0014, prespecified a=0.0099). Zanubrutinib had lower rates of major bleeding (2.9% vs 3.9%), adverse events leading to discontinuation (7.8% vs 13.0%), and death (3.9% vs 5.8%). Zanubrutinib had a higher neutropenia rate (28.4% vs 21.7%) while grade ≥3 infections (12.7% vs 17.9%) were lower. In summary, this interim analysis showed zanubrutinib had a superior ORR, improved PFS, and lower AF rate compared to ibrutinib.

Human T-bet+ B cell development is associated with BTK activity and suppressed by evobrutinib.

Recent clinical trials have shown promising results for the next-generation Bruton’s tyrosine kinase (BTK) inhibitor evobrutinib in the treatment of multiple sclerosis (MS). BTK has a central role in signaling pathways that govern the development of B cells. Whether and how BTK activity shapes B cells as key drivers of MS is currently unclear. Compared with levels of BTK protein, we found higher levels of phospho-BTK in ex vivo blood memory B cells from patients with relapsing-remitting MS and secondary progressive MS compared with controls. In these MS groups, BTK activity was induced to a lesser extent after anti-IgM stimulation. BTK positively correlated with CXCR3 expression, both of which were increased in blood B cells from clinical responders to natalizumab (anti–VLA-4 antibody) treatment. Under in vitro T follicular helper–like conditions, BTK phosphorylation was enhanced by T-bet–inducing stimuli, IFN-γ and CpG-ODN, while the expression of T-bet and T-bet–associated molecules CXCR3, CD21, and CD11c was affected by evobrutinib. Furthermore, evobrutinib interfered with in vitro class switching, as well as memory recall responses, and disturbed CXCL10-mediated migration of CXCR3+ switched B cells through human brain endothelial monolayers. These findings demonstrate a functional link between BTK activity and disease-relevant B cells and offer valuable insights into how next-generation BTK inhibitors could modulate the clinical course of patients with MS.

CO22 Adjusting Survival Data for Treatment Crossover in the ELEVATE-TN Trial By Using a Historical Cohort of Patients Treated with Chemoimmunotherapy in Front-Line Chronic Lymphocytic Leukemia

Acalabrutinib (A) is a next-generation Bruton tyrosine kinase inhibitor (BTKi) approved for chronic lymphocytic leukemia (CLL) treatment. ELEVATE-TN trial interim data (∼47 months median follow-up [FU]) did not show survival benefit for A±obinutuzumab (O) versus chlorambucil+obinutuzumab (C+O) despite significantly superior progression-free survival (PFS). One explanation is C+O-to-A patient crossover (39%), which may have provided added C+O overall survival (OS) benefit. We evaluated OS by adjusting for crossover using a historical C+O cohort.

EE490 The Budget Impact of Zanubrutinib for the Treatment of Waldenstrom's Macroglobulinemia in the United States

Waldenstrom’s macroglobulinemia (WM) is a rare B-cell malignancy of which Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling. Zanubrutinib, a highly selective, next-generation BTK inhibitor was approved for the treatment of adult patients with WM in the United States (US) on August 31, 2021. This study aimed to estimate the budget impact of providing access to zanubrutinib for the treatment of adult patients with WM from the US healthcare payer perspective.