Bruton's Tyrosine Kinase Occupancy Research Articles

An Open-Label, Single-Arm, Multicenter Study of Ibrutinib in Japanese Patients With Steroid-dependent/Refractory Chronic Graft-Versus-Host Disease

Chronic graft-versus-host disease (cGVHD) is a serious complication after allogeneic stem cell transplantation. There are no well-established treatment options for cGVHD after primary steroid-based treatment. Ibrutinib showed clinical benefit with an acceptable safety profile in steroid-dependent/refractory cGVHD patients in a Phase 1b/2 study (PCYC-1129-CA, NCT02195869), with which it was approved in the United States for adult cGVHD patients after failure of ≥1 systemic treatments. This open-label, single-arm, multicenter study was conducted to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of ibrutinib in Japanese patients ≥12 years of age with steroid-dependent/refractory cGVHD (NCT03474679). Patients were assessed on the basis of the National Institutes of Health (NIH) Consensus Development Project Criteria for Clinical Trials in cGVHD (2014). All patients received ibrutinib at a dose of 420 mg orally once daily, with a dose reduction to 280 mg/d on the concomitant use of voriconazole. Nineteen patients, including 1 adolescent, were enrolled and treated with ibrutinib in the study. At the time of clinical data cutoff (when the last patient completed the efficacy assessment at week 37), 10 of 19 patients (52.6%) remained on treatment whereas 9 of 19 patients (47.4%) had discontinued ibrutinib. The median duration of ibrutinib treatment was 9.63 (range 0.6 to 16.7+) months. The best overall response rate was 73.7%, and the rate of sustained response for ≥20 weeks was 71.4% for the responders (52.6% of all patients). Responses were seen across all the involved organs for cGVHD. Median daily corticosteroid dose requirement decreased by 0.06 mg/kg/d from baseline to week 36, whereas an improvement in the Lee cGVHD Symptom Scale score was observed in 42.1% of patients. The most common treatment-emergent adverse events (TEAEs) were pneumonia and stomatitis (36.8% each), upper respiratory tract infection (31.6%), cellulitis and platelet count decreased (26.3% each), and nausea (21.1%). Furthermore, 11 of 19 patients (57.9%) were reported with ≥1 treatment-emergent serious adverse events; the most common being pneumonia (26.3%) and cellulitis (15.8%). In total, 4 of 19 patients (21.1%) died during the study, of which 3 of 19 patients (15.8%) had TEAEs leading to death whereas 1 patient died of peritonitis, which occurred >30 days after the last dose of ibrutinib. Treatment-emergent adverse events leading to ibrutinib discontinuation were reported in 3 of 19 patients (15.8%). Ibrutinib was rapidly absorbed with a median time to reach maximum plasma concentration (tmax) of ~4.0 hours. Steady-state exposures were ~3.0- and ~1.4-fold higher for the patients receiving fluconazole (n = 8) and voriconazole (n = 4) with ibrutinib, respectively, as compared with patients not receiving CYP3A inhibitors (n = 7). Mean Bruton's tyrosine kinase occupancy was 88.1% at 4 hours after dose on day 1, and occupancy levels were maintained throughout the assessment period, regardless of the ibrutinib daily dose. Ibrutinib showed a clinically meaningful response and an acceptable safety profile in Japanese patients with steroid-dependent/refractory cGVHD; the safety profile was consistent with the known safety profile of ibrutinib in adults and with that seen in cGVHD patients receiving concomitant steroid treatment. Overall, the results were generally consistent with findings observed in the PCYC-1129-CA study.

Concentration of evobrutinib, a BTK inhibitor, in cerebrospinal fluid during treatment of patients with relapsing multiple sclerosis in a phase 2 study

Background Evobrutinib, a highly selective Bruton's tyrosine kinase (BTK) inhibitor, demonstrated a low annualized relapse rate (75mg twice-daily: 0.11, 95%CI 0.04–0.25) in a phase 2 randomized controlled trial in patients with relapsing multiple sclerosis (RMS; NCT02975349). This was maintained in an open-label extension (OLE) through 108 weeks (0.12, 95%CI 0.06–0.22; 75mg once-daily for ∼48 weeks, then 75mg twice-daily). Evobrutinib concentrations in the brain achieved high BTK occupancy in an experimental autoimmune encephalomyelitis model. We investigated evobrutinib distribution into cerebrospinal fluid (CSF) in patients with RMS. Methods Plasma and CSF samples were collected 2–3 hours post-dose from phase 2 OLE patients (75mg twice-daily for >1 year, including ≥6 days uninterrupted dosing before sampling) and evobrutinib concentrations measured. Plasma protein binding was measured ex vivo in sub-study participant samples to determine free plasma evobrutinib concentrations. Results Nine patients from one center were enrolled: 89% female, median age 50.5 years and median disease duration 6.9 years (at phase 2 study baseline); all had stable RMS. In plasma, mean total evobrutinib concentration (95%CI) was 115.0 (71.8–184.3) ng/mL and free evobrutinib concentration was 5.5 ng/mL. Evobrutinib was quantifiable in the CSF of all patients; the geometric mean concentration in CSF was 3.21 (2.27–4.55) ng/mL; 58% of the free plasma concentration. Conclusion Evobrutinib administered at an efficacious, steady-state dose was detected in the CSF of patients with RMS at concentrations consistent with free plasma concentrations. Therefore, evobrutinib may inhibit BTK-expressing cells, including B cells and microglia, in the central nervous system.

Discovery of a Potent and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase with Oral Anti-Inflammatory Activity.

Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase that plays a critical role in the activation of B cells, macrophages, and osteoclasts. Given the key role of these cell types in the pathology of autoimmune disorders, BTK inhibitors have the potential to improve treatment outcomes in multiple diseases. Herein, we report the discovery and characterization of a novel potent and selective covalent 4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide BTK inhibitor chemotype. Compound 27 irreversibly inhibits BTK by targeting a noncatalytic cysteine residue (Cys481) for covalent bond formation. Compound 27 is characterized by selectivity for BTK, potent in vivo BTK occupancy that is sustained after it is cleared from systemic circulation, and dose-dependent efficacy at reducing joint inflammation in a rat collagen-induced arthritis model.

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.

Long-Term Safety and Efficacy of Orelabrutinib Monotherapy in Chinese Patients with Relapsed or Refractory Mantle Cell Lymphoma: A Multicenter, Open-Label, Phase II Study

Background: In spite of years of effort, Mantle Cell Lymphoma (MCL) remains a clinical challenge. The clinical significance of Bruton's Tyrosine Kinase (BTK) inhibitor has been validated with the approvals by FDA for the treatment of multiple subtypes of NHL including refractory and relapse (r/r) MCL. However, some serious adverse events (AEs) due to poor target selectivity (inhibition of EGFR, TEC, BMX and others), such as diarrhea, sever bleeding and atrial fibrillation, remain as challenges in clinic. Orelabrutinib is a novel, potent irreversible BTK inhibitor with high selectivity for BTK. Results of early clinical study showed that it has excellent safety/tolerability profiles and favorable pharmacokinetic/pharmacodynamic properties. Sustained ~100% BTK occupancy at 24 hours was achieved with once daily dosing regimen of 50 mg and above. In this presentation, we will report an updated analysis of orelabrutinib in Chinese patients with r/r MCL with minimum of 12 cycles of treatment. Aims: To evaluate the sustained efficacy and long-term safety of orelabrutinib in Chinese patients with r/r MCL. Methods: This is an open-label, multicenter, two stages, phase II study. The primary endpoint was objective response rate (ORR) assessed per Lugano criteria (2014). Safety and other efficacy (DOR, PFS, OS) evaluations were chosen as secondary endpoints. Results: A Total 106 patients, were enrolled in this study with median follow up time of 15.0 months. 79.2% of the patients were male and median age of 62.0 years old. Most patients were at advanced stage (73.6% were at stage IV and 20.8% were at stage III). According to per protocol analysis, 87 (87.9%) patients achieved ORR and 93.9% patients achieved disease control. The median duration of response (DOR) was not reached, the DOR rate at 12 months was 73.7%, as expected the median PFS and OS were not reached, the PFS and OS rates at 12-month were 70.8% and 88.7% respectively. Comparing to the results of previous analysis, the CR rate, by conventional CT method, increased to 27.4% and it was expected a higher rate of in depth response may occur with prolonged treatment. Further analysis showed orelabrutinib was efficacious in all subgroups (age, gender, status, stage, prior therapy, etc.). Orelabrutinib demonstrated excellent safety profile in r/r MCL patients. The frequently reported treatment related adverse events (TRAE) were primarily hematological toxicities including thrombocytopenia, neutropenia, leukopenia, and hypertension. The frequently reported grade 3 or higher AEs of any cause was thrombocytopenia . No treatment related ≥grade 3 GI and cardio toxicity, nor severe bleeding, were observed. Of the 106 patients, 32 experienced serious AEs; and 17 of them, mainly hematological toxicities and / or infections were treatment-related. Comparing to the safety data of median follow up of 10.5 months, there was only a mild increase of adverse events rate after extended treatments; the safety profiles were essentially the same. These results suggested that safety events primarily occurred during early treatment and it appeared less eventful with orelabrutinib continue treatment. Conclusion: Orelabrutinib showed continuous efficacious in treating patients with r/r MCL. In addition, orelabrutinib is safe and well tolerated with no treatment related grade 3 or higher diarrhea, atrial fibrillation/flutter or severe bleeding in this study. Results of prolong treatment expected to produce a higher rate of in depth response without altering its safety profiles support orelabrutinib being a better selection for BTKi therapy. The improved safety as a resulting of high target selectivity, and the convenience of daily dosing regimen provides orelabrutinib as preferred therapeutic choice for B cell malignancy. Disclosures Zhang: Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Xu:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment.

Efficacy and Safety of Zanubrutinib in Patients with Relapsed/Refractory Marginal Zone Lymphoma: Initial Results of the MAGNOLIA (BGB-3111-214) Trial

Efficacy and Safety of Zanubrutinib in Patients with Relapsed/Refractory Marginal Zone Lymphoma: Initial Results of the MAGNOLIA (BGB-3111-214) Trial

Safety and Efficacy of the Bruton Tyrosine Kinase Inhibitor Zanubrutinib (BGB-3111) in Patients with WaldenstrC6m Macroglobulinemia from a Phase 2 Trial

Safety and Efficacy of the Bruton Tyrosine Kinase Inhibitor Zanubrutinib (BGB-3111) in Patients with WaldenstrC6m Macroglobulinemia from a Phase 2 Trial

Phase 2 Study of Zanubrutinib in Patients with Relapsed/Refractory B-Cell Malignancies Intolerant to Ibrutinib/Acalabrutinib

Phase 2 Study of Zanubrutinib in Patients with Relapsed/Refractory B-Cell Malignancies Intolerant to Ibrutinib/Acalabrutinib

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

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

Clinical and biological implications of target occupancy in CLL treated with the BTK inhibitor acalabrutinib

AbstractInhibition of the B-cell receptor pathway, and specifically of Bruton tyrosine kinase (BTK), is a leading therapeutic strategy in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Target occupancy is a measure of covalent binding to BTK and has been applied as a pharmacodynamic parameter in clinical studies of BTK inhibitors. However, the kinetics of de novo BTK synthesis, which determines occupancy, and the relationship between occupancy, pathway inhibition and clinical outcomes remain undefined. This randomized phase 2 study investigated the safety, efficacy, and pharmacodynamics of a selective BTK inhibitor acalabrutinib at 100 mg twice daily (BID) or 200 mg once daily (QD) in 48 patients with relapsed/refractory or high-risk treatment-naïve CLL. Acalabrutinib was well tolerated and yielded an overall response rate (ORR) of partial response or better of 95.8% (95% confidence interval [CI], 78.9-99.9) and an estimated progression-free survival (PFS) rate at 24 months of 91.5% (95% CI, 70.0-97.8) with BID dosing and an ORR of 79.2% (95% CI, 57.9-92.9) and an estimated PFS rate at 24 months of 87.2% (95% CI, 57.2-96.7) with QD dosing. BTK resynthesis was faster in patients with CLL than in healthy volunteers. BID dosing maintained higher BTK occupancy and achieved more potent pathway inhibition compared with QD dosing. Small increments in occupancy attained by BID dosing relative to QD dosing compounded over time to augment downstream biological effects. The impact of BTK occupancy on long-term clinical outcomes remains to be determined. This trial was registered at www.clinicaltrials.gov as #NCT02337829.

Trial in progress: A phase III, randomized, open-label study comparing zanubrutinib plus rituximab versus bendamustine plus rituximab in patients with previously untreated mantle cell lymphoma (MCL).

TPS8071 Background: Bruton tyrosine kinase (BTK) mediates B-cell proliferation, migration, and adhesion. BTK inhibition has emerged as a strategy for targeting B-cell malignancies, including MCL. Zanubrutinib is a next-generation BTK inhibitor that was designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases, with favorable pharmacokinetic and pharmacodynamic properties. Zanubrutinib monotherapy has been evaluated in 118 patients (pts) with relapsed/refractory MCL in 2 single-arm studies: BGB-3111-206 [NCT03206970] and BGB-3111-AU-003 [NCT02343120]. The overall response rate (ORR) by independent review committee (IRC) in both trials was 84% with median durations of response of 19.5 and 18.5 months, respectively. First-line treatment for MCL has failed to cure most pts, particularly elderly or transplant-ineligible groups, and chemotherapy-based approaches result in cumulative, long-term risks. The study described herein is designed to evaluate the safety and efficacy of zanubrutinib plus rituximab versus bendamustine plus rituximab in elderly pts and pts with comorbidities with previously untreated MCL who are ineligible for stem cell transplant. Methods: This ongoing phase 3, open-label study will enroll ≈500 pts to be randomized 1:1, stratified by MCL International Prognostic Index score (low vs intermediate/high), age ( < 70 vs ≥70 years), and geographic region (North America/Europe vs Asia-Pacific). In arm A, pts will receive up to six 28-day cycles of oral zanubrutinib 160 mg twice daily in combination with intravenous (IV) rituximab 375 mg/m2 on day 1 of each cycle. After 6 cycles, zanubrutinib will continue as a monotherapy until progressive disease, unacceptable toxicity, or withdrawal of consent. In arm B, pts will receive up to six 28-day cycles of IV bendamustine 90 mg/m2 on days 1 and 2 of each cycle and rituximab 375 mg/m2 on day 1 of each cycle, followed by observation. Eligible pts must have histologically confirmed MCL and be aged ≥70 years, or 65-69 years with defined comorbidities. Disease response will be assessed per the 2014 Lugano Classification for non-Hodgkin lymphoma. The primary endpoint is progression-free survival (PFS) determined by IRC. Key secondary end points include PFS by investigator assessment, ORR, time to and duration of response, overall survival, and safety. Recruitment is ongoing. Clinical trial information: NCT04002297 .

Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results

AbstractTherapeutic targeting of Bruton tyrosine kinase (BTK) has dramatically improved survival outcomes for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Acalabrutinib is an oral, highly selective BTK inhibitor that allows for twice-daily dosing due to its selectivity. In this phase 1b/2 study, 134 patients with relapsed/refractory CLL or SLL (median age, 66 years [range, 42-85 years]; median prior therapies, 2 [range, 1-13]) received acalabrutinib 100 mg twice daily for a median of 41 months (range, 0.2-58 months). Median trough BTK occupancy at steady state was 97%. Most adverse events (AEs) were mild or moderate, and were most commonly diarrhea (52%) and headache (51%). Grade ≥3 AEs (occurring in ≥5% of patients) were neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%), and diarrhea (5%). Atrial fibrillation and major bleeding AEs (all grades) occurred in 7% and 5% of patients, respectively. Most patients (56%) remain on treatment; the primary reasons for discontinuation were progressive disease (21%) and AEs (11%). The overall response rate, including partial response with lymphocytosis, with acalabrutinib was 94%; responses were similar regardless of genomic features (presence of del(11)(q22.3), del(17)(p13.1), complex karyotype, or immunoglobulin variable region heavy chain mutation status). Median duration of response and progression-free survival (PFS) have not been reached; the estimated 45-month PFS was 62% (95% confidence interval, 51% to 71%). BTK mutation was detected in 6 of 9 patients (67%) at relapse. This updated and expanded study confirms the efficacy, durability of response, and long-term safety of acalabrutinib, justifying its further investigation in previously untreated and treated patients with CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02029443.

Activity of ibrutinib plus R-CHOP in diffuse large B-cell lymphoma: Response, pharmacodynamic, and biomarker analyses of a phase Ib study

IntroductionThis unplanned post-hoc analysis was based on data from the phase Ib DBL1002 study (NCT01569750) and evaluated the association between molecular biomarkers and clinical response to combined treatment with ibrutinib plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in diffuse large B-cell lymphoma (DLBCL) subtypes. MethodsDLBCL subtyping was conducted using immunohistochemistry. Next-generation sequencing using immunoglobulin H primers assessed minimal residual disease (MRD). A quantitative assay evaluated Bruton's tyrosine kinase (BTK) occupancy by ibrutinib in peripheral blood mononuclear cells. Targeted DNA sequencing examined genetic variants by DLBCL subtype. Secreted protein expression was evaluated with a SomaLogic analyte panel. ResultsAmong 21 patients with DLBCL (median age 53.5 years), 17 achieved a complete response (CR) and 4 a partial response (PR). Of the 11 subtyped patients, 9 had a CR (5/7 germinal center B-cell–like [GCB] and 4/4 non-GCB) and 2 had a PR (both GCB). Nine of 12 patients tested for MRD achieved early (cycle 2 day 1) MRD negativity; most had a CR. There was near-complete BTK occupancy at 4 h postdose. Mutation analysis (n = 19) revealed variants including CREBBP, KMT2D, LRP1B, BCL2, and TNFRSF14; only 1 CD79B and TP53 each; no CARD11 or MYD88. ConclusionsIn this study, first-line ibrutinib plus R-CHOP benefited patients with DLBCL, with good overall response rate and early MRD negativity. With a caveat of small sample size, our results showed that a favorable genetic profile and younger patient age may be important to beneficial clinical outcome with ibrutinib plus R-CHOP in DLBCL.

A Quantitative Systems Pharmacology (QSP) Model to Predict Receptor Occupancy of Bruton's Tyrosine Kinase (BTK) Inhibitors in Peripheral Blood Mononuclear Cells, Bone Marrow and Lymph Nodes of Patients with B-Cell Malignancies

Background: Bruton tyrosine kinase (BTK) is a key component of the B-cell receptor signaling pathway. The BTK inhibitors ibrutinib and acalabrutinib have been approved for the treatment of various B-cell malignancies. Zanubrutinib is a potent and highly specific next-generation BTK inhibitor currently in Phase 3 clinical testing. Achieving complete and sustained target engagement with respect to BTK receptor occupancy is thought to be an important factor for attaining deeper and durable clinical responses with the BTK inhibitors. Testing for BTK occupancy in peripheral blood mononuclear cells (PBMC) can be assessed in clinical studies. However, it is difficult to sample deep target tissues such as bone marrow (BM) and lymph nodes (LN) in patients to assess receptor occupancy. The objectives of this work were (1) to develop a QSP model to describe and predict the BTK receptor occupancy in PBMC, BM and LN after dosing with these BTK inhibitors in patients with B-cell malignancies, (2) to understand the impact of different dosing regimens (once daily (QD) v/s twice daily (BID)) on BTK receptor occupancy. Methods: A mathematical model was developed that describes: (1) pharmacokinetics (PK) of BTK inhibitors; (2) intracellular concentration of BTK inhibitors in PBMC, BM and LN; (3) binding of BTK inhibitors with BTK including competition with ATP and (4) BTK degradation/turnover rate. This QSP model includes ibrutinib with its metabolite PCI-45227, acalabrutinib with its metabolite ACP-5862, and zanubrutinib. Previously developed minimal Physiologically-based Pharmacokinetic (PBPK) models were used to reproduce PK of BTK inhibitors. Intracellular concentrations of BTK inhibitors were described in the model in accordance with PBPK equations for small molecules (Rodgers and Rowland. J Pharm Sci. 2006) and on the basis of their physico-chemical properties. Parameters and interindividual variability in parameter values were taken from previously developed models and estimated using experimental data. Sensitivity analyses using key model parameters such as BTK degradation/turnover rate were performed. The model was validated using available in vitro and clinical data on BTK occupancy. Results: The QSP model accurately described the observed clinical data on PK of BTK inhibitors during treatment with different doses and regimens of ibrutinib, acalabrutinib and zanubrutinib. There was good agreement between model prediction and observed BTK occupancy in PBMC and LN (Figure 1 and Figure 2). Zanubrutinib (160 mg BID) was predicted to result in higher median BTK occupancy with less variability in both PBMC and LN than ibrutinib (420 mg QD, 560 mg QD) and acalabrutinib (100 mg BID). In the absence of clinical BTK occupancy data in BM, the model predicted that steady-state trough BTK occupancy in BM were also predicted to be higher after zanubrutinib 160 mg BID administration, than those after ibrutinib 560 mg or 420 mg QD administration, and after acalabrutinib 100 mg BID administration. These differences are attributed to the PK properties (higher AUC and fraction unbound in plasma), binding properties to BTK (Kd, inactivation rate constant), and higher lipophilicity for zanubrutinib. The model predicted that 160 mg BID of zanubrutinib resulted in higher median trough BTK occupancy than 320 mg QD with less variability which is consistent with the observed clinical data (Figure 3). Conclusions: A QSP model was successfully developed and validated, which predicted higher median BTK occupancy with less variability for zanubrutinib in PBMC, BM and LN than ibrutinib and acalabrutinib. A BID dosing regimen produces higher BTK occupancy than a QD regimen over the dosing interval. Ongoing clinical trials with 160 mg BID zanubrutinib will help to determine if improved BTK occupancy in these peripheral and deep target tissues translate into improvements in clinical outcomes. Disclosures Sahasranaman: BeiGene: Employment, Equity Ownership. Demin:BeiGene USA, Inc.: Consultancy; InSysBio LLC: Employment. Shchelokov:InSysBio LLC: Employment; BeiGene USA, Inc.: Consultancy. Musatova:BeiGene USA, Inc.: Consultancy; InSysBio LLC: Employment. Budha:BeiGene Ltd.: Employment, Equity Ownership. Ou:BeiGene: Employment.

Efficacy and Safety of Zanubrutinib in Patients with Treatment-Naive Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with Del(17p): Initial Results from Arm C of the Sequoia (BGB-3111-304) Trial

Efficacy and Safety of Zanubrutinib in Patients with Treatment-Naive Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with Del(17p): Initial Results from Arm C of the Sequoia (BGB-3111-304) Trial

Phase 2 Study of Zanubrutinib (BGB-3111) in Patients with Relapsed/Refractory Marginal Zone Lymphoma

Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, which mediates B-cell proliferation, migration, and adhesion. Inhibition of BTK has emerged as a strategy for targeting B-cell malignancies including marginal zone lymphoma (MZL). Zanubrutinib (BGB-3111) is an investigational, next-generation BTK inhibitor that was designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. Increased specificity may minimize toxicities reported with ibrutinib potentially due to off-target inhibition such as diarrhea, thrombocytopenia, bleeding, atrial fibrillation, rash, and fatigue (Coutre et al. Blood Advances 2019). In non-clinical studies, zanubrutinib has been shown to be highly potent, selective, bioavailable, and irreversible, with potentially advantageous pharmacokinetic and pharmacodynamic properties. Complete and sustained BTK occupancy has been observed with zanubrutinib treatment in both peripheral blood mononuclear cells and in lymph nodes (Tam et al. Blood 2019). Based on drug-drug interaction studies and population PK analyses (internal data), zanubrutinib may be co-administered with strong or moderate CYP3A4 inhibitors at a reduced dose, proton pump inhibitors, vitamin K antagonists, as well as direct oral anticoagulants. Zanubrutinib does not prolong the QT interval. Pooled clinical data from 6 zanubrutinib monotherapy trials including 682 patients with either non-Hodgkin lymphoma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia suggests that zanubrutinib has been generally well tolerated amongst patients with B-cell malignancies (Tam et al. EHA 2019). This data further showed that some toxicities often associated with BTK inhibitors were infrequent with zanubrutinib, including 1.9% atrial fibrillation/flutter (0.6% grade ≥3), 2.5% major hemorrhage (2.1% grade ≥3), 10.9% fatigue (0.7% grade ≥3), 18.0% rash (0.1% grade ≥3), 18.3% thrombocytopenia (6.6% grade ≥3), and 19.4% diarrhea (0.9% grade ≥3). Early clinical data from a phase 1 study demonstrated responses in 7 of 9 patients with relapsed/refractory (R/R) MZL treated with zanubrutinib (Tam et al. ASH 2017); the remaining 2 patients had stable disease indicating an encouraging rate of overall disease control. Study Design and Methods: This ongoing global phase 2, single-arm, open-label study (MAGNOLIA; NCT03846427) is examining zanubrutinib monotherapy in patients with R/R MZL who have received 1 or more prior lines of systemic therapy (Figure). Eligible patients must have histologically confirmed diagnosis of MZL including splenic, nodal, and extranodal subtypes, have received prior anti-CD20 antibody therapy, and have measurable disease. Patients must have documented clinical need for therapy as well as adequate marrow and organ function. Patients are treated with oral zanubrutinib at 160 mg twice daily until progressive disease, unacceptable toxicity, or withdrawal of consent. The primary efficacy endpoint is ORR according to the Lugano Classification (Cheson et al. J Clin Oncol. 2014) measured by computed tomography and bone marrow assessment data as determined by an independent review committee (IRC). A 2-sided Clopper-Pearson 95% CI for ORR will be calculated. Key secondary endpoints include ORR by investigator assessment, time to and duration of response, time to treatment discontinuation, progression-free survival (all determined by IRC and investigator assessments), overall survival, safety, and patient-reported outcomes. All patients are tested for the MYD88 mutation at study entry. Recruitment is ongoing. Disclosures Opat: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Epizyme: Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Novartis: Consultancy. Marcus:Gilead: Consultancy; Roche: Other: Travel, Accommodations, Expenses, Speakers Bureau; Takeda: Other: Travel, Accommodations, Expenses; Roche-Genentech: Honoraria. Portell:Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; Acerta/AstraZeneca: Research Funding; Kite: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Bayer: Consultancy; Amgen: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Research Funding; Pharmacyclics: Consultancy. Reed:BeiGene: Employment, Equity Ownership, Other: Travel, Accommodations, Expenses. Tankersley:BeiGene: Employment, Equity Ownership. Huang:BeiGene: Employment, Equity Ownership. Trotman:Pharmacyclics: Research Funding; Roche: Research Funding; BeiGene: Research Funding; Janssen: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not yet been approved in the US

Treatment with the Bruton Tyrosine Kinase Inhibitor Zanubrutinib (BGB-3111) Demonstrates High Overall Response Rate and Durable Responses in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Updated Results from a Phase 1/2 Trial

Treatment with the Bruton Tyrosine Kinase Inhibitor Zanubrutinib (BGB-3111) Demonstrates High Overall Response Rate and Durable Responses in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Updated Results from a Phase 1/2 Trial

Alpine: Phase 3 Trial of Zanubrutinib (BGB-3111) Vs Ibrutinib in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Alpine: Phase 3 Trial of Zanubrutinib (BGB-3111) Vs Ibrutinib in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Randomized Phase 2 Zanubrutinib (BGB-3111) + Obinutuzumab Vs Obinutuzumab Monotherapy in Patients with Relapsed/Refractory Follicular Lymphoma (R/R FL)

Randomized Phase 2 Zanubrutinib (BGB-3111) + Obinutuzumab Vs Obinutuzumab Monotherapy in Patients with Relapsed/Refractory Follicular Lymphoma (R/R FL)

An Update on Safety and Preliminary Efficacy of Highly Specific Bruton Tyrosine Kinase (BTK) Inhibitor Zanubrutinib in Combination with PD-1 Inhibitor Tislelizumab in Patients with Previously Treated B-Cell Lymphoid Malignancies

An Update on Safety and Preliminary Efficacy of Highly Specific Bruton Tyrosine Kinase (BTK) Inhibitor Zanubrutinib in Combination with PD-1 Inhibitor Tislelizumab in Patients with Previously Treated B-Cell Lymphoid Malignancies