Bruton's Tyrosine Kinase Occupancy Research Articles

Health-Related Quality of Life (HRQoL) in Patients with Relapsed/Refractory Follicular Lymphoma (R/R FL) Treated with Zanubrutinib+ Obinutuzumab Versus Obinutuzumab Monotherapy: The Rosewood Trial

Introduction: Zanubrutinib is a potent and highly selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target effects. In the phase 2 ROSEWOOD study (NCT03332017), zanubrutinib plus obinutuzumab (ZO) demonstrated superior efficacy and a manageable safety profile compared with obinutuzumab monotherapy (O) as treatment for patients with heavily pretreated R/R FL. Here, we report HRQoL outcomes from the ROSEWOOD trial. Methods: Patient-reported outcomes (PROs) were secondary endpoints and assessed using the European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients Questionnaire - C30 (EORTC QLQ-C30) and European Quality of Life 5-Dimensions 5-Levels (EQ-5D-5L). Patients completed questionnaires at baseline (cycle 1 day 1, before the first dose of study drug), then every 12 weeks for 2 years, every 24 weeks for the next 2 years, and then annually until disease progression, death, or withdrawal of consent. Compliance rates were calculated as the number of patients who completed questionnaires vs. the number expected to complete questionnaires at each visit in each arm. PRO endpoints included the EORTC QLQ-C30 global health status (GHS), physical and role function domains, and fatigue, pain, nausea/vomiting, and diarrhea symptom domains, assessed via a mixed model for repeated measures (MMRM) analysis at weeks 12 and 24. Clinically meaningful change was defined as ≥5-point mean difference from baseline (Osoba et al., J Clin Oncol 1998). Descriptive analyses, including change over time, were also performed on QLQ-C30 domains and EQ-5D-5L visual analog scale (VAS) scores. Results: A total of 217 patients were randomized to ZO (n=145) and O (n=72), with similar baseline demographics and disease characteristics between the arms. The median (range) duration of study treatment was 12.2 (0.5-44.1) and 10.6 (0.3-30.3) months, respectively. Compliance rates for PRO assessments in both arms were over 80% at week 12, and 85% at week 24. By week 24, patients in the ZO arm had better overall outcomes in the QLQ-C30 domains of role function, pain, and fatigue than those in the O arm, while patients in both arms experienced improvement in GHS, and physical function and symptoms of nausea/vomiting and diarrhea were maintained ( Table). MMRM analyses revealed clinically meaningful improvement from baseline to week 24 for ZO vs O in change in role function (least squares mean difference [95% CI]: 5.6 [-2.3, 13.5]), pain (-4.9 [-12.6, 2.8] points), and fatigue (-4.7 [-11.6, 2.2]). Based on a descriptive analysis, patients in the ZO arm also experienced greater mean improvement from baseline to week 24 vs the O arm in EQ-5D-5L VAS scores (3.1 vs 2.0). Conclusions: In the ROSEWOOD trial, ZO was associated with improved HRQoL in patients with R/R FL. In particular, patients who received the ZO had larger improvements in fatigue, pain symptoms, and role function, than those who received O monotherapy. These findings suggest that zanubrutinib contributed clinically meaningful benefits to patient HRQoL when added to obinutuzumab.

Zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL): Impact on health‐related quality of life

Introduction: Zanubrutinib (zanu) is a potent and highly selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target effects. In the ALPINE study (NCT03734016), zanu demonstrated superiority to ibrutinib (ibr) in both progression-free survival (PFS) and overall response rate and a more favorable safety profile in R/R CLL/SLL. The purpose of this analysis was to assess health-related quality of life (HRQOL) in patients (pts) treated with zanu and ibr. Results from the data cutoff related to recent PFS analysis (8 Aug 2022) are reported here. Methods: HRQOL was measured by EORTC QLQ-C30 and EQ-5D-5L at baseline, cycle 1, and every 3rd 28-day cycle until end of treatment. Key pt-reported outcome (PRO) endpoints included global health status (GHS), physical and role functions, fatigue, pain, diarrhea, and nausea/vomiting. Descriptive analysis was conducted on all the scales; a mixed-model repeated-measure analysis using key PRO endpoints at the key clinical cycles of cycles 7 (6 months) and 13 (12 months) was performed. Adjusted completion rates were defined as the number of pts who completed the questionnaires at each cycle divided by number still on treatment. Clinically meaningful was defined as a ≥5% mean change difference from baseline. Results: A total of 652 pts were randomized to receive zanu (n = 327) or ibr (n = 325); baseline characteristics were generally similar between arms, although the zanu arm had fewer males versus ibr arm (65.1% vs. 71.4%). At baseline, GHS, functional, and symptom scales scores were similar between arms. Although more ibr-treated pts discontinued treatment due to adverse events versus zanu (22.2% vs. 15.4%), adjusted PRO completion rates were high at cycles 7 and 13 in both the zanu (89.6% and 94.3%) and ibr arm (87.7% and 92.3%), respectively. By cycle 7, GHS scores were improved with zanu versus ibr and by cycle 13, the difference in GHS scores from baseline was no longer significant (Table). Pts in the zanu arm experienced clinically meaningful improvements in physical and role functioning as well as pain and fatigue at cycles 7 and 13, but the difference between arms was not significant. Although pts in the zanu arm reported lower diarrhea scores, the difference between treatments was not significant. Nausea/vomiting scores were maintained in both arms with no measurable difference. VAS scores showed greater improvement from baseline at both cycle 7 (7.92 vs. 3.44) and cycle 13 (7.75 vs. 3.92) of treatment with zanu versus ibr, respectively. Conclusions: In ALPINE, pts with R/R CLL/SLL treated with zanu demonstrated improvement versus ibr in the QLQ-C30 GHS/QoL scale at cycle 7. Other endpoints continued to improve, suggesting treatment with zanu positively affected and improved HRQOL over time. As expected, given the generally good HRQOL at baseline in both arms, the differences between the arms were small and not significant. Encore Abstract - previously submitted to EHA 2023 The research was funded by: BeiGene Keyword: Chronic Lymphocytic Leukemia (CLL) Conflicts of interests pertinent to the abstract. B. Eichhorst Consultant or advisory role: Janssen, AbbVie, Gilead, AstraZeneca, BeiGene, MSD, Lilly Honoraria: Roche, AbbVie, BeiGene, AstraZeneca, MSD Research funding: Janssen, Gilead, Roche, AbbVie, BeiGene, AstraZeneca Educational grants: BeiGene N. Lamanna Consultant or advisory role: Abbvie, AstraZeneca, BeiGene, Eli Lily/Loxo, Genentech, Janssen, Pharmacyclics Research funding: Abbvie, AstraZeneca, BeiGene, Eli Lily/Loxo, Genentech, Octapharma, Oncternal, MingSight, TG Therapeutics S. M. O'Brien Consultant or advisory role: AbbVie, Alexion, Amgen, Aptose Biosciences Inc., Astellas, AstraZeneca, Autolus, BMS, Celgene, DynaMed, Eli Lilly and Company, Gilead, GSK, Janssen Oncology, Johnson and Johnson, Juno Therapeutics, MEI Pharma Inc., Merck, NOVA Research Company, Pfizer, Pharmacyclics, TG Therapeutics, Vaniam Group Inc., Verastem, Vida Ventures Research funding: TG Therapeutics, Pharmacyclics, Pfizer, Nurix Therapeutics, Inc., Mustang, Loxo Oncology Inc., Kite, Gilead, Caribou Biosciences, Inc. BeiGene, Ltd., Alliance, Acerta C. S. Tam Honoraria: BeiGene, AbbVie, Janssen Research funding: Janssen, AbbVie Other remuneration: BeiGene L. Qiu Consultant or advisory role: Janssen, Astra Zeneca, Takeda, Roche, Abbvie, Beigene K. Yang Employment or leadership position: BeiGene Stock ownership: BeiGene Research funding: BeiGene K. Wu Employment or leadership position: BeiGene (Self), Roche/Genentech (Spouse) Stock ownership: BeiGene (Self), Roche/Genentech (Spouse) T. Salmi Employment or leadership position: BeiGene G. Barnes Employment or leadership position: BeiGene Stock ownership: BeiGene J. R. Brown Consultant or advisory role: Abbvie, AstraZeneca, BeiGene, Eli Lily/Loxo, Genentech, Octapharma, Oncternal, MingSight, TG Therapeutics Research funding: BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, SecuraBio, Sun, TG Therapeutics

IMPROVED EFFICACY AND SAFETY OF ZANUBRUTINIB VERSUS IBRUTINIB IN PATIENTS WITH RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA (R/R CLL) IN CHINA: A SUBGROUP OF ALPINE

Introduction: Zanubrutinib is an irreversible, potent, next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target inhibition. In a randomized phase 3 study (ALPINE; NCT03734016), zanubrutinib was compared head to head with ibrutinib as a treatment for R/R CLL (including small lymphocytic lymphoma [SLL]). In the predefined progression-free survival (PFS) final analysis, zanubrutinib demonstrated superior efficacy and a favorable safety profile versus ibrutinib (Brown et al. NEJM 2022). Data from the prespecified subgroup in pts from China are reported here. Methods: Patients (pts) with R/R CLL/SLL who had received ≥1 prior line of therapy and had measurable disease by imaging were randomized (1:1) to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily, until disease progression or unacceptable toxicity. Randomization included stratification by geographical region (China vs. non-China). Data from the subgroup in pts from China were descriptively analyzed. Results: A total of 90 pts in China with R/R CLL/SLL (zanubrutinib, n = 47; ibrutinib, n = 43) were enrolled. Disease characteristics and baseline demographics were balanced between zanubrutinib and ibrutinib (aged ≥65 y [40% vs. 37%]; unmutated IGHV [59.6% vs. 62.8%]; del17p/TP53 mutated [34.0% vs. 32.6%]) with a median age of 60 and 61 y, respectively. Median number of prior therapies was 1. At a median follow-up of 25.3 mo, PFS by independent review committee (IRC) was improved with zanubrutinib versus ibrutinib (hazard ratio [HR]: 0.24; 95% CI 0.09-0.64; nominal 2-sided P = 0.002) with 18-mo landmark PFS rates of 88.9% versus 71.6% for zanubrutinib and ibrutinib, respectively (Figure). Additionally, zanubrutinib was more favorable in high-risk del17p/TP53 mutation (18-mo landmark 80.0% vs. 64.3%; HR: 0.51; 95% CI 0.12-2.13). ORR also favored zanubrutinib over ibrutinib (87.2% vs. 76.7%; 95% CI 0.93-1.38) by IRC. The treatment discontinuation rate was lower with zanubrutinib (14.9%) versus ibrutinib (41.9%) with most due to progressive disease (6.4% vs. 20.9%) and adverse events (AEs; 6.4% vs. 14.0%). Rates of grade ≥3 AEs (64.4% vs. 72.1%) and serious AEs (35.6% vs. 51.2%) were lower with zanubrutinib versus ibrutinib. With zanubrutinib, 4 deaths (8.5%) were reported compared to 8 deaths (18.6%) with ibrutinib (HR: 0.45; 95% CI 0.14–1.50). Keywords: Chronic Lymphocytic Leukemia (CLL), Molecular Targeted Therapies Conflicts of interests pertinent to the abstract L. Fu Employment or leadership position: BeiGene Stock ownership: BeiGene T. Salmi Employment or leadership position: BeiGene Stock ownership: BeiGene K. Wu Employment or leadership position: BeiGene Stock ownership: BeiGene L. Wang Employment or leadership position: BeiGene Stock ownership: BeiGene J. R. Brown Consultant or advisory role AbbVie, Acerta/AstraZeneca, BeiGene, Genentech/Roche, Grifols Worldwide Operations, Hutchmed, iOnctura, Janssen, Kite, Loxo/Lilly, MEI Pharma, Numab Therapeutics, Pfizer, Pharmacyclics Research funding: BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, TG Therapeutics

Efficacy and Safety of Zanubrutinib in Japanese Patients with Mature B-Cell Malignancies

Background/Introduction: Zanubrutinib is a potent, irreversible Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition. Zanubrutinib is approved globally for the treatment of B-cell malignancies in adults. Here, we present the efficacy and safety of zanubrutinib assessed in patients with mature B-cell malignancies enrolled in the ongoing, multicenter, open-label phase 1/2 study in Japan (BGB-3111-111; NCT04172246). Methods: In part 1, safety and tolerability of zanubrutinib were evaluated in 6 enrolled patients with mature B-cell malignancies who received zanubrutinib 160 mg orally twice daily. In part 2, the safety and efficacy of zanubrutinib were evaluated in 47 enrolled patients with relapsed/refractory (RR) mantle cell lymphoma (MCL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and Waldenström macroglobulinemia (WM). Responses were assessed by investigators based on the Lugano Classification for MCL and SLL, 2018 International Workshop on CLL (iwCLL) guidelines with modification for treatment-related lymphocytosis for CLL, and WM response criteria updated at the 6th International Workshop on WM. Results: As of May 10, 2022, 53 patients have been enrolled (12 RR MCL; 17 CLL/SLL; 21 WM; 2 follicular lymphoma; 1 marginal zone lymphoma). Fourteen (26.4%) patients discontinued treatment (9 progressive disease, 2 adverse event [AE], 2 investigator decision, 1 withdrawal by patient). The median age was 71 years (range, 37-84) and 67.9% were men. RR patients (49.1%) received a median of 2 lines of prior therapy (range, 1-8). The median follow-up time was 14.8 months (range, 1.4-27.3). Forty-eight (90.6%) patients experienced ≥1 treatment-emergent adverse event (TEAE). The most common any-grade AEs are summarized in Table 1. Twenty-two (41.5%) patients experienced grade ≥3 AEs; the most common grade ≥3 AEs were neutrophil count decreased (9.4%), platelet count decreased (9.4%), and neutropenia (5.7%). One patient with RR MCL experienced a fatal TEAE of septic shock. Thirty-five (66%) patients had ≥1 TEAE of special interest, including 21 (39.6%) patients with hemorrhage, 17 (32.1%) with infections, and 11 (20.8%) with thrombocytopenia. The most common grade ≥3 TEAEs of special interest were neutropenia (15.1%), infections (11.3%), hemorrhage (9.4%), and thrombocytopenia (9.4%). Investigator-assessed disease responses are reported from part 2. Among patients with MCL, the overall response rate (ORR) was 81.8%. Among patients with CLL/SLL, the ORR (partial response with lymphocytosis or better) was 92.9% in treatment-naïve (TN) patients and 100% in RR patients. The ORR among patients with WM was 92.3%, including 15.4% very good partial response (VGPR) in TN patients, and 100%, including 66.7% VGPR, in RR patients (Table 2). The median duration of overall response has not been reached for any disease cohort. Conclusion: Preliminary data from this phase 1/2 study demonstrate that zanubrutinib can be an efficacious and safe BTK inhibitor for Japanese patients with RR MCL, CLL/SLL, and WM. Safety and efficacy data are comparable with those observed in published data across ethnic groups. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Population pharmacokinetic and pharmacodynamic modeling of evobrutinib in healthy adult participants.

Evobrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has shown therapeutic potential in relapsing multiple sclerosis. This analysis aimed to develop pharmacokinetic (PK) and pharmacodynamic (PD; BTK occupancy [BTKO]) models of evobrutinib and simulate PK and BTKO profiles under alternative dosing regimens. Data were obtained from two phase I evobrutinib studies in healthy adult participants (Japanese and non-Japanese). Overall, 2326 observations were available from 76 participants; n =42 from Study MS200527_0017 Part A received evobrutinib 25, 75, or 200 mg once-daily oral doses for 6 days while fasted; n = 18 from Study MS200527_0019 and n =16 from Study MS200527_0017 Part B received single evobrutinib 75 mg oral doses with food (low-fat meal) and while fasted. Population PK/PD modeling for evobrutinib concentrations and BTKO (fraction unbound) were performed using nonlinear mixed-effects modeling. The effect of once-daily/twice-daily regimens and doses of 10-200 mg on BTKO were simulated. A two-compartment model with sequential zero-first order absorption and first-order elimination adequately described the data. Bioavailability increased by 49% with food compared with when fasted. There was no difference in PK parameters between Japanese and non-Japanese participants. The BTKO profile of evobrutinib was described by the irreversible binding population model. The simulated percentage of participants with minimum BTKO increased in a dose-dependent manner across the BTKO thresholds of interest (70%, 80%, 90%, and 95% occupancy). Evobrutinib doses of 25 mg once-daily, 50 mg twice-daily, or 75 mg twice-daily while fasted are possible choices for further development, assuming BTKO ≥70% at trough is needed to achieve efficacy.

Bioequivalence and Relative Bioavailability Studies to Assess a New Acalabrutinib Formulation That Enables Coadministration With Proton-Pump Inhibitors.

Acalabrutinib is a Bruton tyrosine kinase (BTK) inhibitor approved to treat adults with chronic lymphocytic leukemia, small lymphocytic lymphoma, or previously treated mantle cell lymphoma. As the bioavailability of the acalabrutinib capsule (AC) depends on gastric pH for solubility and is impaired by acid-suppressing therapies, coadministration with proton-pump inhibitors (PPIs) is not recommended. Three studies in healthy subjects (N=30, N=66, N=20) evaluated the pharmacokinetics (PKs), pharmacodynamics (PDs), safety, and tolerability of acalabrutinib maleate tablet (AT) formulated with pH-independent release. Subjects were administered AT or AC (orally, fasted state), AT in a fed state, or AT in the presence of a PPI, and AT or AC via nasogastric (NG) route. Acalabrutinib exposures (geometric mean [% coefficient of variation, CV]) were comparable for AT versus AC (AUCinf 567.8ngh/mL [36.9] vs 572.2ngh/mL [38.2], Cmax 537.2ng/mL [42.6] vs 535.7ng/mL [58.4], respectively); similar results were observed for acalabrutinib's active metabolite (ACP-5862) and for AT-NG versus AC-NG. The geometric mean Cmax for acalabrutinib was lower when AT was administered in the fed versus the fasted state (Cmax 255.6ng/mL [%CV, 46.5] vs 504.9ng/mL [49.9]); AUCs were similar. For AT+PPI, geometric mean Cmax was lower (371.9ng/mL [%CV, 81.4] vs 504.9ng/mL [49.9]) and AUCinf was higher (AUCinf 694.1ngh/mL [39.7] vs 559.5ngh/mL [34.6]) than AT alone. AT and AC were similar in BTK occupancy. Most adverse events were mild with no new safety concerns. Acalabrutinib formulations were comparable and AT could be coadministered with PPIs, food, or via NG tube without affecting the PKs or PDs.

P1160: RESULTS OF A PHASE 2 EXPANDED ACCESS STUDY OF ZANUBRUTINIB IN PATIENTS WITH WALDENSTRÖM MACROGLOBULINEMIA

Background: Bruton tyrosine kinase (BTK) inhibition is an emerging standard of care for Waldenström macroglobulinemia (WM). Zanubrutinib (ZANU; BGB-3111) is a next-generation BTK inhibitor designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. ZANU was recently approved by the United States (US) Food and Drug Administration, Health Canada, and the European Union at a dose of 320 mg once daily (QD) or 160 mg twice daily (BID) for the treatment of adult patients (pts) with WM. BGB-3111-216 (NCT04052854) is a single-arm, expanded access study of ZANU for treatment-naïve (TN) pts who are unsuitable for standard chemoimmunotherapy or pts with relapsed refractory (R/R) WM. Aims: To provide real-world experience with ZANU in pts with WM. Methods: Eligible pts with TN or R/R WM were assigned to receive ZANU at a dose of 320 mg QD or 160 mg BID. The primary endpoint was the number of pts enrolled/treated and the number of enrolling sites. Secondary endpoints of safety and efficacy included treatment emergent adverse events (TEAEs) of special interest, disease response (overall response rate [ORR] and very good partial response or better [VGPR+]), progression-free survival (PFS), and overall survival (OS). Response was evaluated by investigator-assessment according to the 6th International Workshop on WM (Br J Haematol. 2013;160(2):171-6) every 6 months at minimum. The study was closed by the sponsor in July 2021 and active pts were transitioned to commercial ZANU via a patient assistance program. Results: Fifty pts with WM (17 TN; 33 R/R), were enrolled from December 2019 to June 2021 across 10 academic and community medical centers in the US. At study entry, median age was 72 years, 54% had intermediate-risk disease, 40% had high-risk disease, and median number of prior therapies for R/R pts was 2. Median treatment exposure was 9.2 months (range 1.4 to 20.0). Thirty-eight (76%) pts had ≥1 TEAE, and 36 (72%) experienced ≥1 TEAE of special interest (Table). Grade ≥3 TEAEs of special interest included hypertension (8%), infection (8%), atrial fibrillation or flutter (2%), neutropenia (2%), and second primary malignancy (2%). No new safety signals were observed. In the 41 pts with ≥1 response evaluation, 39.0% achieved a best overall response (BOR) of VGPR (16; 95% CI, 24.2-55.5). ORR was 85.4% (35; 95% CI, 70.8-94.4), and major response rate was 73.2% (30; 95% CI, 57.1-85.8). Of the 4 pts who achieved a BOR of progressive disease, 3 had IgM values that met partial response criteria before the first 6 months response assessment. PFS and OS were immature due to short follow-up, and the median was not met. Image:Summary/Conclusion: The results of this real-world expanded access study were consistent with the established ZANU profile in WM and other B-cell malignancies when administered as monotherapy at a daily dose of 320 mg orally (either as 160 mg BID or 320 mg QD) in pts with intermediate or high-risk R/R or TN WM.

[18F]BTK-1: A Novel Positron Emission Tomography Tracer for Imaging Bruton's Tyrosine Kinase.

Bruton's tyrosine kinase (BTK) is a key component of B cell receptor (BCR) signaling, and as such a critical regulator of cell proliferation and survival. Aberrant BCR signaling is important in the pathogenesis of various B cell malignancies and autoimmune disorders. Here, we describe the development of a novel positron emission tomography (PET) tracer for imaging BTK expression and/or occupancy by small molecule therapeutics. Radiochemistry was carried out by reacting the precursor with [18F]fluoride on a GE FX-FN TracerLab synthesis module to produce [18F]BTK-1 with a 6% decay-corrected radiochemical yield, 100 ± 6GBq/µmol molar activity, and a radiochemical purity of 99%. Following intravenous administration of [18F]BTK-1 (3.63 ± 0.59MBq, 0.084 ± 0.05µg), 60-min dynamic images were acquired in two xenograft models: REC-1, an efficacious mantle cell lymphoma model, and U87MG, a non-efficacious glioblastoma model. Subsequent studies included vehicle, pretreatment (10min prior to tracer injection), and displacement (30min post-tracer injection) studies with different reversible BTK inhibitors to examine BTK binding. Human radiation dosimetry was estimated based on PET imaging in healthy rats. Uptake of [18F]BTK-1 was significantly higher in BTK expressing REC-1 tumors than non-BTK expressing U87MG tumors. Administration of BTK inhibitors prior to tracer administration blocked [18F]BTK-1 binding in the REC-1 tumor model consistent with [18F]BTK-1 binding to BTK. The predicted effective dose in humans was 0.0199 ± 0.0007mSv/MBq. [18F]BTK-1 is a promising PET tracer for imaging of BTK, which could provide valuable information for patient selection, drug dose determination, and improving our understanding of BTK biology in humans.

Zanubrutinib for the Treatment of B-cell Malignancies

Selective Bruton's tyrosine kinase (BTK) inhibition is an important therapeutic approach for B-cell malignancies. Ibrutinib, a first-in-class, oral, irreversible BTK inhibitor, has a toxicity profile attributed to off-target inhibition of kinases structurally related to BTK. A highly potent and selective next-generation BTK inhibitor, zanubrutinib, was designed to address intolerance and toxicity concerns associated with ibrutinib. Zanubrutinib provides complete and sustained BTK occupancy in peripheral blood mononuclear cells and lymph nodes, with reduced toxicity compared with ibrutinib. Zanubrutinib received accelerated approval in the USA for patients with previously treated mantle cell lymphoma (2019) and relapsed/refractory (R/R) marginal zone lymphoma (2021) and was approved for Waldenström's macroglobulinaemia (WM) in 2021. Key clinical trials evaluating the efficacy and safety of zanubrutinib include the ASPEN study in patients with WM (ClinicalTrials.gov identifier: NCT03053440), the ALPINE study in patients with R/R chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL; ClinicalTrials.gov identifier: NCT03734016) and the SEQUOIA study in treatment-naïve patients with CLL/SLL with and without del(17p) mutation (ClinicalTrials.gov identifier: NCT03336333). The more selective BTK binding profile, high potency, favourable pharmacokinetic and pharmacodynamic profile, and minimal cardiovascular toxicity of zanubrutinib compared with ibrutinib suggest that zanubrutinib may be an important treatment option when prescribed in accordance with guidelines.

Current approach to Waldenström Macroglobulinemia

Waldenström Macroglobulinemia (WM) is a unique, low grade, IgM lymphoplasmacytic lymphoma with a heterogeneous clinical course. A paucity of high-grade evidence from large phase 3 trials remains a major issue in the field despite a rapidly expanding therapeutic armamentarium against WM. Prior knowledge of the patients’ MYD88L265P and CXCR4 mutation status aids in treatment decision making if Bruton's tyrosine kinase (BTK) inhibitor therapy is being considered. Head-to head comparative data to inform optimal approach are lacking, and a particularly vexing issue for the clinicians is choosing between fixed-duration bendamustine-rituximab (BR) therapy and an indefinite BTK inhibitor-based regimen, given that both approaches are well tolerated and effective, particularly for the patient population harboring MYD88L265P mutation. For the patients with MYD88WT genotype, chemo-immunotherapy such as BR is preferred, although zanubrutinib, a potent second generation BTK inhibitor, with its reduced off target effects and greater BTK occupancy compared to its predecessor, ibrutinib, has also recently shown activity in MYD88WT WM. This review summarizes the current literature pertaining to the diagnosis, prognosis, and the treatment of WM.

Orelabrutinib Monotherapy in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Updated Long Term Results of Phase II Study

IntroductionOrelabrutinib is a novel and highly selective irreversible Bruton tyrosine kinase (BTK) inhibitor approved in China for the treatment of patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We previously reported that orelabrutinib had high bioavailability with ~100% BTK occupancy at 24 hours at 150 mg daily dosing regimen and had demonstrated excellent safety and efficacy profiles in a phase II trial of R/R CLL/SLL. Here we present the long-term result of this study.MethodsThis is an open-label, multicenter, phase II study to evaluate the safety and efficacy following 150 mg oral daily administration of orelabrutinib (NCT03493217). Responses were assessed per 2008 IWCLL criteria with modification for PR with lymphocytosis (PR-L) (Hallek 2008, Cheson 2012) or the Lugano Classification (Cheson 2014) for CLL and SLL, respectively.ResultsA total of 80 patients with R/R CLL/SLL were enrolled. All patients received ≥1 prior treatment with median age of 60.0 years. 70% of patients had Rai stage III-IV disease, 22.5% had del(17p) and/or TP53 mutation, 41.3% had unmutated immunoglobulin heavy chain variable region (IGHV) and 23.8% had del(11q). The median follow-up time was 31. 2 months, with 68.8% remaining on study treatment.The overall response rate (ORR) was 93.8 % (95% CI: 86.01 ~ 97.94%) with 23.8% complete response (CR), 2.5% incomplete marrow recovery (CRi), 56.3% partial response (PR) and 11.3% PR with lymphocytosis (PR-L) by investigators assessed. Median time for achieving first response was 1.84 months. The median duration of response (DOR) and progression-free survival (PFS) were not reached. The estimated 30-month DOR was 70.6%, 30-month PFS was 70.9 % by investigator assessed. The overall response rate was generally consistent across all subgroups analyzed, including those with unfavorable prognostic factors. Comparing to the previous CR/CRi rate of 8.8% reported at median follow up of 14.3 months, the updated CR/CRi rate had achieved 26.3%. Orelabrutinib showed a significant higher CR/CRi rate in R/R CLL/SLL in comparison with other BTK inhibitors at a similar median follow-up period.Extended follow-up demonstrates no emerging safety concerns. Similar to the previous reported safety results (Xu W 2020), most adverse events (AEs) were mild to moderate. The most frequent AEs (>30% of any grade) were neutropenia, thrombocytopenia, upper respiratory tract infection and urine red blood cells positive. No case of atrial fibrillation nor secondary malignancy was reported, no patient experienced ≥3 grade hypertension and only one patient had ≥3 grade diarrhea. Major hemorrhage was reported in 2 patients, one with intracranial hemorrhage (65-year old patient with >10 years hypertension) and the other with vitreous hemorrhage which was assessed as unlikely related to the treatment of orelabrutinib. There were 2 patients (2.5%) and 5 patients (6.3%) reported treatment related AEs leading to treatment discontinuation or dose reduction, respectively.ConclusionsThis updated study result further confirms that orelabrutinib is efficacious in treating R/R CLL patients with significant higher CR rate than other BTK inhibitors, durable response and improved safety profiles. Orelabrutinib provides a favorable therapeutic choice for patients with R/R CLL/SLL and has great potential to be the best candidate for the combination therapy. DisclosuresHu: Astellas Pharma, Inc.: Research Funding. Zhang: Innocare pharma: Current Employment. Zhao: Innocare pharma: Current Employment.

SEQUOIA: Results of a Phase 3 Randomized Study of Zanubrutinib versus Bendamustine + Rituximab (BR) in Patients with Treatment-Naïve (TN) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Background: Zanubrutinib (zanu) is a selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimize off-target effects (Guo, J Med Chem 2019;62:7923-40). In a phase 1/2 study, zanu demonstrated complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes and was associated with durable clinical responses in patients (pts) with CLL/SLL (Tam, Blood 2019;134:851-9). Here, we present interim results for the phase 3 SEQUOIA (BGB-3111-304; NCT03336333) trial, which evaluated the efficacy and safety of zanu vs BR in TN pts with CLL/SLL.Methods: SEQUOIA is an open-label, global phase 3 study that randomized TN pts with CLL/SLL without del(17p) to receive zanu 160 mg twice daily until progressive disease or unacceptable toxicity, or bendamustine 90 mg/m 2 on day 1 and 2 and rituximab 375 mg/m 2 in cycle 1, 500 mg/m 2 in cycles 2-6 for 6 × 28-day cycles. Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Hallek, Blood 2008;111:5446-56) were eligible if they were either ≥65 y or unsuitable for treatment with fludarabine, cyclophosphamide and rituximab. Central verification of del(17p) status by fluorescence in situ hybridization was required. Pts were stratified by age (<65 y vs ≥65 y), Binet Stage (C vs A/B), IGHV mutational status, and geographic region. The primary endpoint was independent review committee (IRC)-assessed progression-free survival (PFS) for zanu vs BR. Secondary endpoints included PFS by investigator assessment (INV), overall response rate (ORR; by IRC and INV), overall survival (OS), and safety. Responses for CLL and SLL were assessed per modified iwCLL criteria (Hallek, Blood 2008;111:5446-56; J Clin Oncol 2012;30:2820-2) and Lugano criteria (Cheson, J Clin Oncol 2014;32:3059-68), respectively. Adverse events (AEs) were recorded until disease progression to support safety evaluation over an equivalent time period.Results: From 31 Oct 2017-22 Jul 2019, 479 pts without del(17p) were randomized to zanu (n=241) and BR (n=238). Treatment groups were well balanced for demographic and disease characteristics (zanu vs BR): median age, 70.0 y vs 70.0 y; unmutated IGHV, 53.4% (125/234) vs 52.4% (121/231); and del(11q), 17.8% vs 19.3%. At median follow-up (26.2 mo), PFS by IRC was significantly prolonged with zanu vs BR (HR 0.42, 95% CI 0.28-0.63, 1-sided and 2-sided P<0.0001; Figure); similar results were observed by INV (HR 0.42, 95% CI 0.27-0.66, 1-sided P<0.0001, 2-sided P=0.0001). Treatment benefit for zanu was observed across subgroups for age, Binet stage, bulky disease, and del(11q) status. Treatment benefit was also observed for pts with unmutated IGHV (HR 0.24, 1-sided and 2-sided P<0.0001), but not for mutated IGHV (HR 0.67, 1-sided P=0.0929). Estimated 24-mo PFS (IRC) for zanu vs BR was 85.5% (95% CI 80.1%- 89.6%) vs 69.5% (95% CI 62.4%-75.5%). ORR by IRC for zanu vs BR was 94.6% (95% CI 91.0%-97.1%) vs 85.3% (95% CI 80.1%-89.5%). Complete response rate was 6.6% with zanu and 15.1% with BR. ORR by INV for zanu vs BR was 97.5% (95% CI 94.7%-99.1%) vs 88.7% (95% CI 83.9%-92.4%) Estimated 24-mo OS for zanu vs BR was 94.3% (95% CI 90.4%-96.7%) and 94.6% (95% CI 90.6%-96.9%).The most common AEs are shown in the Table. AEs of interest occurring during the full reporting period (pooled terms, zanu vs BR) included atrial fibrillation (any grade [gr]: 3.3% vs 2.6%), bleeding (any gr/gr≥3: 45.0%/3.8% vs 11.0%/1.8%), hypertension (any gr: 14.2% vs 10.6%), infection (any gr/gr≥3: 62.1%/16.3% vs 55.9%/18.9%), and neutropenia (any gr/gr≥3: 15.8%/11.7% vs 56.8%/51.1%). Treatment discontinuation due to AEs occurred in 20 pts (8.3%) receiving zanu vs 31 pts (13.7%) receiving BR; 85.5% of pts receiving zanu remain on treatment. AEs leading to death occurred in 11 pts (4.6%) receiving zanu vs 12 pts (5.3%) receiving BR. No sudden deaths were reported.Conclusions: In this global registrational trial, zanu demonstrated statistically significant improvement in PFS compared to BR as assessed by IRC. Superiority was also observed in PFS by INV as well as ORR by both IRC and INV. Zanu was generally well tolerated, with low rates of atrial fibrillation consistent with those observed in the phase 3 ASPEN (Tam, Blood 2020;136:2038-2050) and ALPINE studies (Hillmen, EHA 2021 #LB1900). These data support the potential utility of zanu in the frontline management of pts with TN CLL/SLL. [Display omitted] DisclosuresTam: AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Honoraria; Novartis: Honoraria; Loxo: Consultancy; Roche: Consultancy, Honoraria. Giannopoulos: Polish Myeloma Consortium, Next Generation Hematology Association: Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Honoraria; Pfizer: Honoraria; Teva: Honoraria; TG Therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria, Research Funding; Bei-Gene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi-Genzyme: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Jurczak: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Bayer: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celtrion: Research Funding; Celgene: Research Funding; Debbiopharm: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Šimkovič: Janssen, Gilead, Roche, AstraZeneca, and AbbVie: Other: consultancy fees, advisory board participation fees, travel grants, and honoraria; University Hospital Hradec Kralove: Current Employment; AbbVie: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Merck: Current equity holder in publicly-traded company; Eli Lilly: Current equity holder in publicly-traded company; J&J: Current equity holder in publicly-traded company; Gilead: Other: Travel, Accommodations, Expenses. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Österborg: BeiGene: Research Funding; Gilead: Research Funding. Laurenti: Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Gilead: Honoraria; Roche: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Honoraria. Walker: BeiGene: Consultancy; Acerta: Consultancy. Opat: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Sandoz: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Monash Health: Current Employment. Chan: AbbVie: Membership on an entity's Board of Directors or advisory committees; Eusa: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Travel, Accommodations, Expenses; Celgene: Other: Travel, Accommodations, Expenses; Roche: Speakers Bureau. Ciepluch: Copernicus Wojewodzkie Centrum Onkologii: Current Employment. Greil: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding. Trněný: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; AstraZeneca: Honoraria. Brander: Verastem: Consultancy; ArQule: Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; MEI Pharma: Research Funding; Novartis: Research Funding; LOXO: Research Funding; Ascentage: Research Funding; AstraZeneca: Research Funding; BeiGene: Research Funding; DTRM: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel; NCCN: Other: panel member; ArQule/Merck: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Flinn: Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Verner: Janssen-Cilag Pty Ltd: Research Funding. Brown: Janssen: Consultancy; MEI Pharma: Consultancy; Rigel: Consultancy; Bristol-Myers Squib/Juno/Celegene: Consultancy; Novartis: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; TG Therapeutics: Research Funding; Abbvie: Consultancy; Acerta/Astra-Zeneca: Consultancy; Beigene: Consultancy; Catapult: Consultancy; Loxo/Lilly: Research Funding; Sun: Research Funding; Nextcea: Consultancy; Gilead: Research Funding; SecuraBio: Research Funding; Eli Lilly and Company: Consultancy; Genentech/Roche: Consultancy; Pfizer: Consultancy; Morphosys AG: Consultancy. Kahl: AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy; AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding. Ghia: Sunesis: Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Celgene/Juno/BMS: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; ArQule/MSD: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Tian: BeiGene: Current Employment; AbbVie: Ended employment in the past 24 months. Marimpietri: BeiGene USA: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Paik: BeiGene USA, Inc.: Current Employment, Current equity holder in publicly-traded company. Cohen: BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: Travel, Accommodations, Expenses. Huang: BeiGene: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Robak: Biogen, Abbvie, Octapharma, Janssen: Honoraria, Other: Advisory board; AstraZeneca, Abbvie, Janssen, Octapharma, Gilead,Oncopeptides AB, Pharmacyclics, Pfizer, GlaxoSmithKline, Biogen: Research Funding; Medical University of Lodz: Current Employment. Hillmen: Pharmacyclics: Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; AstraZeneca: Honoraria; SOBI: Honoraria; BeiGene: Honoraria; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. OffLabel Disclosure:Zanubrutinib is an investigational agent and has not been approved for TN CLL/SLL without del(17p) in the US

Semi-Mechanistic PK/PD Modeling and Simulation of Irreversible BTK Inhibition to Support Dose Selection of Tirabrutinib in Subjects with RA.

Tirabrutinib is an irreversible, small‐molecule Bruton’s tyrosine kinase (BTK) inhibitor, which was approved in Japan (VELEXBRU) to treat B‐cell malignancies and is in clinical development for inflammatory diseases. As an application of model‐informed drug development, a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for irreversible BTK inhibition of tirabrutinib was developed to support dose selection in clinical development, based on clinical PK and BTK occupancy data from two phase I studies with a wide range of PK exposures in healthy volunteers and in subjects with rheumatoid arthritis. The developed model adequately described and predicted the PK and PD data. Overall, the model‐based simulation supported a total daily dose of at least 40 mg, either q.d. or b.i.d., with adequate BTK occupancy (> 90%) for further development in inflammatory diseases. Following the PK/PD modeling and simulation, the relationship between model‐predicted BTK occupancy and preliminary clinical efficacy data was also explored and a positive trend was identified between the increasing time above adequate BTK occupancy and better efficacy in treatment for RA by linear regression.

Target modulation and pharmacokinetics/pharmacodynamics translation of the BTK inhibitor poseltinib for model-informed phase II dose selection

The selective Bruton tyrosine kinase (BTK) inhibitor poseltinib has been shown to inhibit the BCR signal transduction pathway and cytokine production in B cells (Park et al.Arthritis Res. Ther.18, 91, https://doi.org/10.1186/s13075-016-0988-z, 2016). This study describes the translation of nonclinical research studies to a phase I clinical trial in healthy volunteers in which pharmacokinetics (PKs) and pharmacodynamics (PDs) were evaluated for dose determination. The BTK protein kinase inhibitory effects of poseltinib in human peripheral blood mononuclear cells (PBMCs) and in rats with collagen-induced arthritis (CIA) were evaluated. High-dimensional phosphorylation analysis was conducted on human immune cells such as B cells, CD8 + memory cells, CD4 + memory cells, NK cells, neutrophils, and monocytes, to map the impact of poseltinib on BTK/PLC and AKT signaling pathways. PK and PD profiles were evaluated in a first-in-human study in healthy donors, and a PK/PD model was established based on BTK occupancy. Poseltinib bound to the BTK protein and modulated BTK phosphorylation in human PBMCs. High-dimensional phosphorylation analysis of 94 nodes showed that poseltinib had the highest impact on anti-IgM + CD40L stimulated B cells, however, lower impacts on anti-CD3/CD-28 stimulated T cells, IL-2 stimulated CD4 + T cells and NK cells, M-CSF stimulated monocytes, or LPS-induced granulocytes. In anti-IgM + CD40L stimulated B cells, poseltinib inhibited the phosphorylation of BTK, AKT, and PLCγ2. Moreover, poseltinib dose dependently improved arthritis disease severity in CIA rat model. In a clinical phase I trial for healthy volunteers, poseltinib exhibited dose-dependent and persistent BTK occupancy in PBMCs of all poseltinib-administrated patients in the study. More than 80% of BTK occupancy at 40 mg dosing was maintained for up to 48 h after the first dose. A first-in-human healthy volunteer study of poseltinib established target engagement with circulating BTK protein. Desirable PK and PD properties were observed, and a modeling approach was used for rational dose selection for subsequent trials. Poseltinib was confirmed as a potential BTK inhibitor for the treatment of autoimmune diseases.Trial registration: This article includes the results of a clinical intervention on human participants [NCT01765478].

A phase 1/2 study of the combination of acalabrutinib and vistusertib in patients with relapsed/refractory B-cell malignancies

In a phase 1b study of acalabrutinib (a covalent Bruton tyrosine kinase (BTK) inhibitor) in combination with vistusertib (a dual mTORC1/2 inhibitor) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), multiple ascending doses of the combination as intermittent or continuous schedules of vistusertib were evaluated. The overall response rate was 12% (3/25). The pharmacodynamic (PD) profile for acalabrutinib showed that BTK occupancy in all patients was >95%. In contrast, PD analysis for vistusertib showed variable inhibition of phosphorylated 4EBP1 (p4EBP1) without modulation of AKT phosphorylation (pAKT). The pharmacokinetic (PK)/PD relationship of vistusertib was direct for TORC1 inhibition (p4EBP1) but did not correlate with TORC2 inhibition (pAKT). Cell-of-origin subtyping or next-generation sequencing did not identify a subset of DLBCL patients with clinical benefit; however, circulating tumor DNA dynamics correlated with radiographic response. These data suggest that vistusertib does not modulate targets sufficiently to add to the clinical activity of acalabrutinib monotherapy. Clinicaltrials.gov identifier: NCT03205046.

Preclinical Mechanisms of Topical PRN473, a Bruton Tyrosine Kinase Inhibitor, in Immune-Mediated Skin Disease Models.

The expression of Bruton tyrosine kinase (BTK) in B cells and innate immune cells provides essential downstream signaling for BCR, Fc receptors, and other innate immune cell pathways. The topical covalent BTK inhibitor PRN473 has shown durable, reversible BTK occupancy with rapid on-rate and slow off-rate binding kinetics and long residence time, resulting in prolonged, localized efficacy with low systemic exposure in vivo. Mechanisms of PRN473 include inhibition of IgE (FcεR)-mediated activation of mast cells and basophils, IgG (FcγR)-mediated activation of monocytes, and neutrophil migration. In vivo, oral PRN473 was efficacious and well tolerated in the treatment of canine pemphigus foliaceus. In this study, we evaluated in vitro selectivity and functionality, in vivo skin Ab inflammatory responses, and systemic pharmacology with topically administered PRN473. Significant dose-dependent inhibition of IgG-mediated passive Arthus reaction in rats was observed with topical PRN473 and was maintained when given 16 h prior to challenge, reinforcing extended activity with once-daily administration. Similarly, topical PRN473 resulted in significant dose-dependent inhibition of the mouse passive cutaneous anaphylaxis IgE-mediated reaction. Multiday treatment with topical PRN473 in rodents resulted in low-to-no systemic accumulation, suggesting that efficacy was mainly due to localized exposure. Reduced skin Ab inflammatory activity was also confirmed with oral PRN473. These preclinical studies provide a strong biologic basis for targeting innate immune cell responses locally in the skin, with rapid onset of action following once-daily topical PRN473 administration and minimal systemic exposure. Dose-dependent inhibition in these preclinical models of immune-mediated skin diseases support future clinical studies.

A Pilot Study of Lower Doses of Ibrutinib in Patients (pts) with Chronic Lymphocytic Leukemia (CLL)

▪Introduction Ibrutinib (IBR) is an oral, small-molecule irreversible inhibitor of Bruton's tyrosine kinase (BTK) approved for treatment-naïve and relapsed/refractory (R/R) pts with CLL at a dose of 420 mg/d. IBR binds covalently to the C481 residue of BTK in a 1:1 stoichiometric ratio. In a phase 1 trial of IBR in pts with R/R B-cell malignancies, no MTD was identified, and ≥95% BTK occupancy was observed at doses ≥2.5 mg/kg/d and correlated with clinical response (Advani, JCO 2013). IBR inhibits a number of other kinases at pharmacologically relevant concentrations (Honigberg, PNAS 2010), which may explain its off-target toxicities, e.g., atrial fibrillation (AF) and bleeding. We previously showed that BTK protein levels in CLL cells from patients on IBR decline over time (Cervantes-Gomez, Leukemia 2016). Therefore, we hypothesized that lower doses of IBR after 1 cycle at 420 mg/d would be sufficient to achieve ≥95% BTK occupancy and inhibit B-cell receptor (BCR) signaling in CLL cells, potentially leading to improved safety and cost savings while maintaining efficacy. Retrospective studies conducted at multiple centers in the US and UK have demonstrated that dose reduction of IBR does not compromise clinical outcomes (Mato, BJH 2017, UK CLL Forum, Haematologica 2016).Methods We designed a pilot study (NCT02801578) in which pts with CLL and ALC ≥20 x 109/L received 420 mg/d, 280 mg/d and 140 mg/d of IBR in 3 consecutive 4-week cycles. Blood was obtained for measurement of IBR levels and various pharmacodynamic (PD) endpoints at 16 timepoints per pt (Figure 1). Response assessment was clinical; bone marrow examinations and imaging were not performed. After completion of the study, pts could continue on IBR (dosed according to their treating physician's discretion) or change therapy as clinically indicated.Results Eleven pts were treated; 1 came off the study after 21 days of IBR (420 mg/d) in C1 and 1 after 21 days of IBR in C1 (420 mg/d) and 5 days of IBR (280 mg/d) in C2 (AAA repair and intolerance to IBR, respectively) and are not evaluable. One pt remains on study. Pharmacokinetic (PK) and PD analyses of blood samples from the other 8 pts have been completed or are ongoing. Baseline pt characteristics and clinical outcomes are summarized in Table 1. Updated results will be presented at the meeting.IBR levels reached an average (avg) of 210 nM on C1D1 at 4h, 240 nM on C2D1, and 63 nM on C3D1 at 4h (n= 8). In all 3 cycles, by 24h after the D1 dose, avg IBR plasma concentrations fell to 25, 22, and 8 nM, respectively. Similarly, avg IBR levels in circulating CLL cells reached 113, 242, and 44 nM in cycles 1-3 on D1 at 4h, respectively (n=5).BTK occupancy was measured by Pharmacyclics using a proprietary high affinity fluorescence probe. In all 8 pts analyzed thus far, an avg ≥98% of target BTK was covalently bound by IBR.BTK phosphorylation at Tyr223 (measured by protein immunoblot analysis) was decreased at all 3 doses, and at 140mg/d of IBR in cycle 3, the levels were 40-50% of control, similar to cycles 1 and 2. Likewise, there was a decline in total BTK levels. PLCgamma2 phosphorylation at Tyr1217 was also reduced over the entire duration of IBR treatment. As reported at the 420mg/d dose, there was a notable increase in pro-apoptotic Bim, while levels of Bcl-2 remained constant. In contrast, there was a decline in Mcl-1 levels. In parallel, there was a decline in S6 (Ser235/236) phosphorylation in CLL cells during therapy. There was also evidence of NF-kappaB pathway modulation, and an increase in IkappaBalpha protein levels, coupled with a decrease in NFAT1 and SHP-1 levels. Further work is ongoing to see if the mRNA levels of the BCR downstream targets are also reduced during therapy with IBR.IBR impairs platelet function. We evaluated platelet functionality using light transmission aggregometry. Data in 2 pts suggest that the lower doses of IBR in cycles 2 and 3 led to reduced inhibition of ristocetin-induced aggregation.Conclusions Taken together, these data suggest that IBR doses as low as 140 mg/d are sufficient to fully occupy BTK and abrogate kinase function. As off-target effects of IBR are not thought to contribute to clinical efficacy in CLL, exploration of lower doses is warranted to reduce the incidence of troublesome side effects such as AF and bleeding, while preserving efficacy. Accordingly, a larger, more definitive trial with clinical endpoints of IBR at a dose of 140 mg/d following 2 cycles at 420 and 280 mg/d is planned. [Display omitted] DisclosuresThompson:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jain:BMS: Research Funding; Abbvie: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Incyte: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Verastem: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wierda:The University of Texas MD Anderson Cancer Center: Employment; Acerta: Research Funding; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Emergent: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Kite: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Genentech/Roche: Consultancy, Honoraria, Research Funding; Karyopharm: Research Funding; Janssen: Research Funding; Juno: Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria.

BGB-3111, a Highly Specific BTK Inhibitor, Is Well Tolerated and Highly Active in Chinese Patients with Relapsed/Refractory B-Cell Malignancies: Initial Report of a Phase 1 Trial in China

Introduction: BGB-3111 is a potent, specific and irreversible inhibitor of Bruton's tyrosine kinase (BTK). In its first-in-human study in Australia, New Zealand, South Korea, US and Europe, it was demonstrated that BGB-3111 can achieve complete, continuous BTK occupancy in peripheral blood mononuclear cells and lymph nodes, associated with durable clinical responses in patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and Waldenström's macroglobulinemia (WM). Here we report the initial findings of a Phase 1 trial of BGB-3111 in Chinese pts with B-cell malignancies.Patients/ Methods: Chinese pts with relapsed/ refractory B-cell malignancies were enrolled to 1 of 2 dose cohorts of BGB-3111 (320 mg PO QD or 160 mg PO BID). Adverse events (AEs) are reported per CTCAE v4.03, responses per standard criteria according to histology (NHL IWG criteria 2014, CLL IWG criteria 2013, WM IWWM criteria 2013), BTK occupancy determined using an irreversible binding assay in PBMCs.Results: As of 8 June 2017, 21 pts have been enrolled. Median number of prior therapies was 3 (range 1-9). 11 pts received 160 mg PO BID and 10 pts received 320 mg PO QD. The median follow-up time is 8.8 months (range 1.7-11.1 months). All pts were included for safety evaluation and efficacy analyses. Complete BTK occupancy at dosing trough in PBMCs was demonstrated at both dose levels. As of the cut-off date, there was no dose limiting toxicity (DLT). The most frequent grade 3 or above AEs (≥ 10%) were neutropenia (28.6%), thrombocytopenia (14%), leukocytosis (14%), and lymphocytosis (14%). 4 SAEs have been reported, including one event each of toxic epidermal necrolysis (G4), febrile neutropenia (G3), neutropenia (G4), and thrombocytopenia (G4). One MZL pt was discontinued due to G4 toxic epidermal necrolysis and two pts (1 CLL and 1 FL) were discontinued due to disease progression after 169 days (CLL) and 92 days (FL) of treatment. One death (one FL pt) was reported after drug discontinuation due to disease progression. There were no major bleeding and atrial fibrillation reported. Response to treatment by histology is summarized in Table 1 and Figure 1. As of the cut-off date, 18/21 pts remain on study treatment.Conclusions: BGB-3111 is well tolerated and highly active in Chinese pts with B-cell malignancies. The BTK inhibition and anti-tumor activity and safety profile of BGB-311 in Chinese patients are similar to those profiles we have seen in the previously reported data for BGB-3111. Several Phase 2 studies in different indications, including CLL/SLL, MCL, WM, and non-GCB DLBCL, have been initiated in China to further evaluate the efficacy and safety of BGB-3111 in Chinese pts. [Display omitted] DisclosuresXue:BeiGene: Employment. Yang:BeiGene: Employment. Zhang:BeiGene: Employment. Wang:BeiGene: Employment. Huang:BeiGene: Employment. Feng:BeiGene: Employment.

Acalabrutinib with Obinutuzumab in Relapsed/Refractory and Treatment-Naive Patients with Chronic Lymphocytic Leukemia: The Phase 1b/2 ACE-CL-003 Study

▪Background : Bruton tyrosine kinase (BTK) inhibitors have greatly improved the survival of patients with chronic lymphocytic leukemia (CLL). Combining BTK inhibitors with engineered CD20 antibodies, such as obinutuzumab, is hypothesized to increase rapidity and depth of response. Acalabrutinib (ACP-196) is a highly selective covalent inhibitor of BTK. The selectivity of acalabrutinib enables twice-daily dosing and potentially enhanced BTK occupancy over 24 hours. This Phase 1b/2 trial evaluated the activity and tolerability of acalabrutinib in combination with obinutuzumab in relapsed/refractory (R/R) and symptomatic, treatment-naive (TN) patients with CLL.Methods: Key eligibility criteria included diagnosis of CLL or small lymphocytic leukemia, measurable nodal disease, Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 and age ≥18 years. Patients were eligible for the R/R cohort if they had ≥1 prior treatment or the TN cohort if previously untreated and ≥65 years of age or <65 years of age and chemoimmunotherapy ineligible. All patients met IWCLL 2008 criteria for treatment. Previous treatment with ibrutinib or another BTK inhibitor was permitted if the patient discontinued for a reason other than on-treatment disease progression. Concomitant use of vitamin K antagonists was excluded. In 28-day cycles, acalabrutinib was administered orally at 100 mg BID or 200 mg QD (n=15, all later switched to 100 mg BID) until progressive disease (PD); obinutuzumab was administered intravenously on days 1 (100 mg), 2 (900 mg), 8 and 15 (1000 mg) of cycle 2 and day 1 (1000 mg) of cycles 3 to 7. The primary endpoints were overall response rate (ORR), defined as partial response + complete response (CR), and safety. Secondary endpoints included duration of response (DOR), time to response (TTR), progression-free survival (PFS) and pharmacodynamics.Results: As of April 28, 2017, 19 TN and 26 R/R patients had been treated. The median age of all patients was 61 years (range, 42 to 76). Baseline characteristics in TN and R/R patients respectively included ECOG PS ≤1 (both 100%), bulky lymph nodes ≥5 cm (53% and 50%), del(17p) (4/18 [22%] and 5/26 [19%]), del11q (5/18 [28%] and 9/26 [35%]) and unmutated IGHV (9/17 [53%] and 17/26 [65%]). Higher median BTK occupancy at trough was observed with 100 mg BID vs 200 mg QD dosing on cycle 1 day 2 (96% vs 87%; p<0.0001) and on cycle 2 day 1 (97% vs 91%; p=0.001). Median follow-up was 17.8 months (range, 1.0 to 23.4) in TN patients and 21.2 months (range, 15.8 to 27.5) in R/R patients. ORR was 95% and 92% in TN and R/R patients, respectively (Table). CR was achieved in 3 (16%) TN patients and 2 (8%) R/R patients. In TN and R/R patients, median TTR was 2.8 months. Time to CR for the 3 TN patients was 5.6, 10.2, and 10.2 months, and for the 2 R/R patients was 10.2 and 15.7 months, respectively. Median DOR was not reached in TN or R/R patients; the 18-month DOR rate was 86% and 94% in TN and R/R patients, respectively. Median PFS (Figure) was not reached in either cohort. Most patients remain on treatment at the time of cut off (89% and 92% of TN and R/R patients, respectively). Study treatment was discontinued in 2/19 TN patients (11%; 1 metastatic squamous cell carcinoma which pre-existed trial therapy, and 1 Richter transformation [RT] at 15.8 months in a patient with del(17p)) and in 2/26 R/R patients (8%; both due to RT at 18.4 and 24.0 months, respectively). In all patients, the most common AEs (≥40%) of any grade were upper respiratory tract infection (69%), diarrhea (65%), nausea (62%), maculopapular rash (58%), increased weight (54%), cough, headache, and infusion-related reaction (50% each), contusion, vomiting, and constipation (42% each). Grade 3/4 AEs (≥5% of all patients) included decreased neutrophil count (24%), decreased platelet count (9%), increased weight and syncope (7% each). There were no cases of major hemorrhage, defined as Grade ≥3, serious AEs and/or any grade or seriousness of central nervous system hemorrhage, or Grade ≥3 contusion or petechiae. One patient (2%) experienced atrial fibrillation (Grade 3) which did not lead to treatment discontinuation.Conclusions: Treatment with acalabrutinib plus obinutuzumab was well-tolerated and yielded high response rates that deepened over time in both R/R and TN patients. Most patients (41/45 [91%]) remain on treatment with a median follow-up of 21 months. [Display omitted] DisclosuresWoyach:Morphosys Inc: Research Funding; Karyopharm Inc: Research Funding; Janssen: Honoraria. Jones:Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Acerta: Honoraria, Research Funding; Genentech: Research Funding; Merck: Research Funding. Covey:Astra-Zeneca: Equity Ownership; Acerta: Employment, Equity Ownership. Hamdy:Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acalabrutinib related patents. Izumi:Acerta Pharma: Employment, Equity Ownership. Patel:Acerta Pharma: Employment. Wang:Acerta Pharma: Employment, Equity Ownership; Astra Zeneca: Equity Ownership. Byrd:Acerta Pharma: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Janssen: Research Funding.

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.