Treatment standards for chronic lymphocytic leukemia (CLL) have been transformed with the advent of effective inhibitors of B-cell receptor signaling such as ibrutinib – a first-in-class inhibitor of BTK. Off-target kinase inhibitions by ibrutinib are thought to contribute to its adverse events. Zanubrutinib is a next-generation BTK inhibitor with minimal off-target effects, sustained BTK occupancy in peripheral blood mononuclear cells and lymph nodes from patients with B-cell malignancies and promising responses in patients with CLL. Described here is a head-to-head Phase III study comparing the efficacy and safety of zanubrutinib with those of ibrutinib in patients with CLL/small lymphocytic lymphoma in the relapsed/refractory setting.

Inhibitors of Bruton's tyrosine kinase (BTK) have established therapeutic activity in patients with Waldenström macroglobulinemia (WM). Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in a phase 1/2 study in patients with WM who were either treatment-naïve (TN) or had relapsed/refractory (R/R) disease. Patients had disease requiring treatment per International Workshop on Waldenström Macroglobulinemia (IWWM) criteria. Treatment was oral zanubrutinib 160 mg twice daily (n=50) or 320 mg once daily (n=23). Efficacy endpoints included overall response rate (ORR) and very good partial response/complete response (VGPR/CR) rates per IWWM-6 criteria (with modification of VGPR definition based on Treon 2015). Between September 2014 and March 2018, 77 patients (24 TN and 53 R/R) began treatment. At a median follow-up of 36.0 months for patients with R/R disease and 23.5 months for TN, 72.7% remained on treatment. Reasons for treatment discontinuation included any adverse events in 13.0% of patients (1 treatment related), disease progression (10.4%), and other (3.9%). The ORR was 95.9%, and the VGPR/CR rate was 45.2%, which increased over time: 20.5% at 6 months, 32.9% at 12 months, and 43.8% at 24 months. Estimated 3-year progression-free survival rate was 80.5%, and overall survival rate was 84.8%. Adverse events of interest included contusion (32.5%, all grade 1), neutropenia (18.2%), major hemorrhage (3.9%), atrial fibrillation/flutter (5.2%), and grade 3 diarrhea (2.6%). Long-term treatment with single-agent zanubrutinib resulted in deep and durable responses in some patients with WM. The safety profile of long-term zanubrutinib therapy in these patients was acceptable.

In this open-label, intra-patient phase I/II trial, bortezomib was replaced with carfilzomib (escalated from 20 to 45 mg/m 2 on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle) for multiple myeloma (MM) patients who progressed while on or within 12 weeks of receiving a bortezomib-containing combination regimen. Study objectives included determination of the maximum tolerated dose (MTD), overall response rate (ORR), clinical benefit rate (CBR), time to progression, time to response, duration of response, progression-free survival and overall survival (OS). Of 38 registered patients, 37 were treated and evaluable for efficacy and safety. Thirty-one carfilzomib-based regimens using 14 different drug combinations were tested. One regimen (carfilzomib (45 mg/m 2 ), ascorbic acid (1000 mg) and cyclophosphamide (2.2 mg/kg)) reached MTD. ORR and CBR were 43.2 and 62.2%, respectively. Median progressionfree survival, time to progression and OS were 8.3, 9.9 and 15.8 months, respectively. Hematologic adverse events (AEs; Xgrade 3) included lymphopenia (35.1%), thrombocytopenia (24.3%), anemia (10.8%) and neutropenia (10.8%). Nonhematologic AEs (Xgrade 3) included fever (5.4%) and hypokalemia (5.4%). These results demonstrate that replacing bortezomib with carfilzomib is safe and can be effective for MM patients failing bortezomib-containing combination regimens. This trial was registered at

Introduction Despite improved response and survival for patients (pts) with follicular lymphoma (FL) receiving rituximab (R) plus chemotherapy, new options are needed. FL is typically characterized by the presence of chromosomal translocation t(14;18), which results in overexpression of the anti-apoptotic protein BCL-2. BCL-2 may also contribute to resistance to chemoimmunotherapy such as bendamustine+R (BR), a regimen commonly used in FL. Venetoclax (VEN), a selective, potent oral BCL-2 inhibitor, is in development for the treatment of B-cell malignancies. Preclinical and early clinical data suggest VEN+R or VEN+BR may improve response over R or chemotherapy alone and is feasible. This open-label study will assess efficacy and toxicity of VEN+R as well as VEN+BR vs BR alone, in pts with relapsed/refractory (R/R) FL (NCT02187861). Methods R/R pts (age ≥18 yrs, confirmed Gr 1-3a FL, ECOG PS 0-2, adequate hematologic function) were assigned (at investigators' discretion) to chemotherapy-free (chemo-free) or randomized to chemotherapy-containing (chemo) arms. Those in the chemo-free Arm (Arm A) received VEN 800mg daily for 1 yr + R (cycles [C] 1, 4, 6, 8, 10 and 12). After a safety run-in (9 pts at 600mg VEN daily + 6 cycles BR), those in the chemo Arm were randomized 1:1 to Arm B (VEN 800mg + 6 cycles BR) or C (BR only). The primary endpoint was complete response (CR) rate by PET-CT. Secondary endpoints include CR rate by CT and overall response rate. Response assessment was per Lugano non-Hodgkin lymphoma assessment (Cheson et al. 2014) 6-8 wks after D1 of C6 (or the cycle non-VEN agents were permanently discontinued: whichever came first). Results One hundred sixty-four pts were enrolled as of May 13, 2016 (Table 1); 53 chemo-free (Arm A) and 111 chemo (9 run-in; 51 Arm B; 51 Arm C). 61% were refractory to prior treatment: 79% Arm A; 56% safety run-in; 43% Arm B; 62% Arm C. One hundred fifty-three of 160 safety evaluable pts (94%) experienced any AE (Table 2). Common AEs (all grades): diarrhea (37%), neutropenia (29%), nausea (25%), fatigue (25%), and IRR (25%). Common AEs for Arm B vs Arm C: nausea (61% vs 38%), neutropenia (51% vs 26%), diarrhea (41% vs 12%), thrombocytopenia (39% vs 20%) and fatigue (37% vs 24%). Neutropenia and thrombocytopenia were the most common Gr 3-4 AEs among all groups. 40 pts had serious AE (SAEs): 14 (27%) Arm A; 4 (44%) run-in; 15 (31%) Arm B; 7 (14%) Arm C. SAEs in >1 pt in any arm: febrile neutropenia (2 run-in; 5 Arm B; 1 Arm C), pneumonia (2 Arm A; 1 Arm B), and LDH increase (2 Arm A). Laboratory tumor lysis syndrome (TLS) events occurred in 2 pts (1 Arm A; 1 Arm B): both manageable and resolved with no clinical complications. Five deaths occurred on study: 3 Arm A (colitis, pulmonary hemorrhage, PD), 1 Arm B (pneumonia), 1 Arm C (PD). Pts with AEs leading to dose interruptions or modification: 28 (54%) Arm A; 7 (78%) run-in; 37 (76%) Arm B; 12 (24%) Arm C. Pts with early drug discontinuations of VEN: 29 (56%) Arm A; 5 (56%) run-in; 11 (22%) Arm B. Early R discontinuations: 28 (54%) Arm A; 3 (33%) run-in; 7 (14%) Arm B; 5 (10%) Arm C. Early B discontinuations: 3 (33%) run-in; 7 (14%) Arm B; 4 (8%) Arm C. Efficacy by PET+CT for safety evaluable patients who reached an assessment event is shown in Table 3. Arm A had 17 (33%) responders with 14% CR. Arm A was predominantly refractory to last treatment (79%): among non-refractory pts (21%), ORR was 64% with 27% CR. There was 68% ORR in Arm B with 50% CR compared with 64% ORR with 41% CR in Arm C. 55 (51%) of chemo pts have yet to reach a response-relevant event. Correlation with expression of BCL-2 family members is pending. Conclusion Early results from the first study evaluating VEN+R and VEN+BR in pts with FL show that daily VEN 800mg has an acceptable benefit/risk ratio. As expected with the known VEN safety profile, both VEN+R and VEN+BR are associated with hematologic and GI toxicity, which appears manageable. Laboratory TLS was rare (<2%) and manageable with no clinical sequelae. Objective response with VEN+R is 33% even in a highly refractory pt population and 64% among non-refractory pts, providing a potential chemotherapy-free option for both groups. While early data shows VEN+BR is associated with more toxicity and some early treatment discontinuations compared with BR alone, data suggest it may be a tradeoff for increased CR and decreased PD. Future data will help determine whether continued VEN treatment beyond initial chemotherapy deepens response. Disclosures Zinzani: Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees. Topp:Amgen: Consultancy, Honoraria, Other: travel, Speakers Bureau; Roche: Honoraria, Other: travel; Pfizer: Consultancy, Other: Travel; Boehringer: Consultancy, Other: Travel, Research Funding; Jazz: Consultancy. Rusconi:Janssen: Consultancy, Other: Congress attendance; Takeda: Consultancy; Teva: Consultancy, Other: Congress attendance. Fleury:Novartis: Consultancy, Speakers Bureau; Lundbeck: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau. Pro:Celegene: Honoraria; Seattle Genetics: Honoraria; Takeda: Honoraria. Hsu:Genetech, Inc.: Employment. Punnoose:Genetech, Inc.: Employment. Hilger:Genetech, Inc.: Employment. Mobasher:Genentech, Inc.: Employment. Hiddermann:Janssen: 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: Research Funding.

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 CLL/SLL. 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 (PK) 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 also be co-administered with strong or moderate CYP3A 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 (pts) with either non-Hodgkin lymphoma, Waldenström macroglobulinemia, or CLL/SLL suggests that zanubrutinib has been generally well tolerated amongst pts 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 in pts with treatment-naïve (TN; n=22) or relapsed/refractory (R/R; n=56) CLL/SLL showed that zanubrutinib was highly active: 96.2% overall response rate (ORR), including 4.5% and 1.8% with complete response in TN and R/R CLL/SLL, respectively (Tam et al. Blood 2019). Study Design and Methods: This ongoing phase 3, randomized, global study (ALPINE; NCT03734016) is designed to compare the efficacy of zanubrutinib to ibrutinib based on ORR in pts with R/R CLL/SLL (Figure). This open-label study randomizes approximately 400 pts 1:1 to each arm, stratified by age (< 65 vs ≥ 65 years), refractory status (yes vs no), geographic region (China vs other), and del(17p)/TP53 mutation status (present vs absent). The study population includes adult pts who have had prior treatment for their CLL/SLL and were either refractory to or relapsed from prior CLL/SLL treatment. Major inclusion criteria include R/R CLL/SLL requiring treatment per International Workshop on CLL (iwCLL) criteria, disease measurable by computed tomography/magnetic resonance imaging, Eastern Cooperative Oncology Group performance status 0-2, and adequate hematologic function. Major exclusion criteria include prior treatment with a BTK inhibitor, current or past history of Richter transformation, clinically significant cardiovascular disease, or history of severe bleeding disorder. Zanubrutinib is dosed at 160 mg twice daily, and ibrutinib is dosed per label at 420 mg daily; treatment in both arms may continue until progression. The primary endpoint is ORR as determined by an independent review committee according to iwCLL guidelines, with modification for treatment-related lymphocytosis for pts with CLL and per 2014 Lugano Classification for pts with SLL. The study is powered to test the non-inferiority, and subsequently the superiority, of the ORR for zanubrutinib vs ibrutinib. Secondary endpoints include progression-free survival, ORR as determined by investigator, safety, duration of response, overall survival, and pt-reported outcomes. Exploratory endpoints include the correlation between clinical outcomes and prognostic and predictive biomarkers. Recruitment began in November 2018 and is ongoing in 14 countries. Disclosures Hillmen: Roche: Research Funding; Gilead: Research Funding; Apellis: Research Funding; Acerta: 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 Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding. Brown:AbbVie: Consultancy; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Juno/Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Sun Pharmaceuticals: Research Funding; Janssen: Honoraria; Teva: Honoraria; Morphosys: Other: Data safety monitoring board; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy. Byrd:Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Ohio State University: Patents & Royalties: OSU-2S. Eichhorst:BeiGene: Research Funding; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lamanna:Celgene: Consultancy; Oncternal: Research Funding; TG Therapeutics: Research Funding; Ming: Research Funding; Infinity/ Verastem: Research Funding. O'Brien:GlaxoSmithKline: Consultancy; Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Regeneron: Research Funding; Eisai: Consultancy; Celgene: Consultancy; Aptose Biosciences, Inc: Consultancy; TG Therapeutics: Consultancy, Research Funding; Amgen: Consultancy; Kite: Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Verastem: Consultancy; Sunesis: Consultancy, Research Funding; Astellas: Consultancy; Vaniam Group LLC: Consultancy. Salmi:BeiGene: Employment. Hilger:BeiGene: Employment, Equity Ownership. Huang:BeiGene: Employment, Equity Ownership. Tam:AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie company: Honoraria; Novartis: Honoraria; BeiGene: Honoraria; Roche: Honoraria. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not yet been approved in the US