Abstract: Introduction: Bruton's tyrosine kinase (BTK) is a downstream intermediary of B cell receptor (BCR) signaling. As revealed by ibrutinib, disruption of BCR signaling results in significant anti-tumor activity in various B cell malignancies. BGB-3111 is a potent, specific and irreversible BTK inhibitor. In biochemical and cellular assays, BGB-3111 was more selective than ibrutinib for BTK vs. EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, BLK and TEC. Activity against these other kinases is implicated in ibrutinib-associated toxicities such as diarrhea, bleeding, and atrial fibrillation. In preclinical animal studies, BGB-3111 demonstrated superior oral bioavailability, achieving higher exposure and more complete target inhibition in the tissues than ibrutinib. We report here the initial results of an ongoing phase 1 trial of BGB-3111 in patients (pts) with advanced B cell malignancies. Patients/Methods: This first-in-human, open label phase 1 study comprised a dose-escalation (DE) component, followed by an ongoing safety, schedule and efficacy expansion component. The results of the planned interim analysis performed at the end of DE are reported here. During DE, pts with relapsed or refractory World Health Organization (WHO) classification defined B-lymphoid malignancies were enrolled to 1 of 5 dose cohorts of BGB-3111 (40, 80, 160, 320mg PO QD; 160mg PO BID) in a modified 3+3 dose escalation design. Adverse events (AEs) were reported per CTCAE v4.03 (patients with baseline cytopenias remained evaluable for neutropenia and thrombocytopenia) and responses per histology-specific standard criteria (NHL IWG criteria 2014; modified CLL IWG criteria 2015; WM IWWM criteria 2013). BGB-3111 pharmacokinetics (PK) was analyzed by dose level, and BTK occupancy determined using an irreversible binding assay in PBMCs. Results: 25 pts were enrolled in DE: 40mg (n=4), 80mg (n=5), 160mg (n=6) and 320mg (n=6) QD, and 160mg BID (n=4). Pts had received a median 2 (range: 1-7) prior therapies, for diagnoses listed in Table 1. As of 30 July 2015, all were evaluable for AE and response. BGB-3111 exposure increased in a dose-proportional manner from 40mg to 320mg daily. The Cmax and AUC0-24h of BGB-3111 at 80mg QD was comparable to that reported for ibrutinib at 560mg QD, and the free drug concentration of BGB-3111 at 40mg QD was comparable for that reported for ibrutinib 560mg QD. Sustained 24 hour BTK occupancy in PBMCs was demonstrated in all pts at 40mg QD (24 hour BTK occupancy 98.6 +/-1.1%), and at all higher dose levels. No dose limiting toxicities (DLT) were encountered, and the maximum tolerated dose (MTD) was not reached. The recommended phase 2 dose (320mg daily) was determined based on the pharmacokinetics, pharmacodynamics, safety and efficacy of BGB-3111. Three pts discontinued BGB-3111 due to disease progression. There were no drug-related SAEs, AEs leading to drug discontinuation, or AE-related deaths. Of 21 ≥grade 3 AEs, 3 were assessed by investigators as potentially drug-related - all were self-limiting neutropenia in CLL pts, two of whom had neutropenia at baseline. No G3/4 bleeding events were recorded. Four pts had a baseline history of atrial fibrillation/flutter (AF); no exacerbation or new event of AF was reported. 16 responses, including 1 complete remission, have been observed. Response by histology is summarized in Table 1 and Figure 1. 22/25 pts remain on study treatment, free of progression, at a median of 204 days (range 138-321). Table. Response by Histology to BGB-3111 Histology n Objective Response (no. in CR) SD Continuing Treatment (as of 30th July 2015) Days on treatment (median; range) CLL 8 6 (0) 2 8 199 (140-252) MCL 6 4 (1) 1 5 227 (165-315) Waldenström's 6 5 (0) 0 5 232 (152-321) DLBCL 2 0 (0) 1 1 159 FL 1 0 (0) 1 1 194 MZL 1 0 (0) 1 1 138 HCL 1 1 (0) 0 1 285 Conclusions: These preliminary Phase 1 results suggest that the selective BTK inhibitor BGB-3111 is safe and highly clinically active. Complete blockade of BTK in PBMC at low doses and excellent tolerability at higher doses raises the possibility that BTK blockade in deep tissue sites will be complete. This question is currently being explored in the expansion phase. Figure 1. Best response in 22 pts evaluated by CT scan (SPD, CLL and NHL) or IgM levels (WM). Not included here are 1 responder with HCL (PR), and 2 pts who progressed before restaging. Figure 1. Best response in 22 pts evaluated by CT scan (SPD, CLL and NHL) or IgM levels (WM). Not included here are 1 responder with HCL (PR), and 2 pts who progressed before restaging. Disclosures Tam: Janssen: Consultancy, Honoraria, Research Funding. Off Label Use: BGB-3111 is not licensed for treatment of B-cell malignancies. Grigg:BMS: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Opat:Janssen Pharmaceuticals: Other: Provision of subsidized medications only. Seymour:Phebra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: 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 support, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hedrick:Beigene: Employment. Yang:Beigene: Employment, Equity Ownership. Wang:Beigene: Employment, Equity Ownership. Luo:Beigene: Employment, Equity Ownership. Xue:Beigene: Employment, Equity Ownership. Roberts:Walter and Eliza Hall Institute of Medical Research: Employment; AbbVie: Research Funding; Servier: Research Funding; Genentech: Research Funding.

Abstract: Introduction : BGB-3111 is a potent, highly specific and irreversible Bruton tyrosine kinase (BTK) inhibitor, with greater selectivity than ibrutinib (IB) for BTK vs. other TEC- and HER-family kinases. We previously reported that BGB-3111 320mg daily (the RP2D, given as a single or split dose) achieved plasma concentrations 6- to10-fold higher than that of IB 560mg QD. Complete BTK occupancy in peripheral blood mononuclear cells (PBMCs) was observed in all pts treated in the dose-escalation (DEsc) component of the Phase 1 trial, and preliminary data suggested that 〉 90% blockade was achievable in lymph nodes (LN). We now report the results of BTK occupancy analyses in LN specimens from a dedicated pharmacodynamics (PD) cohort and update safety and efficacy in patients with CLL/SLL. Aims: (1)To determine BTK occupancy in LN samples from pts receiving either a daily or twice-daily regimen; and (2) to define the safety profile and activity of BGB-3111 in pts with relapsed/refractory (R/R) or previously untreated CLL/SLL. Methods: This Phase 1 trial included a DEsc component in pts with R/R B-cell malignancies, and disease-specific expansion cohorts (ECs), including CLL/SLL, at the RP2D (320mg daily, given either QD or as a split BID dose). Additionally, in a PD cohort, pts with R/R B-cell malignancies were assigned to BGB-3111 160mg BID vs 320mg QD, with paired LN biopsies at baseline and at day 3 (pre-dose), in order to determine BTK occupancy in LN at the time of trough drug exposure. Adverse events (AEs) are reported per CTCAE v4.03, and response according to the 2012 clarification of the International Workshop on CLL criteria (for CLL pts) or the 2014 Lugano Classification (for SLL pts). BTK occupancy was determined by competitive fluorescent probe assay. The data cut-off for this report was 10 June 2016. Results: BTK Occupancy: 30 pts were evaluated for LN BTK occupancy (CLL, n=9; DLBCL, n=3; FL, n=5; MCL, n=6; MZL, n=3; WM, n=4), 23 pts were enrolled in the PD cohort; 7 patients in other ECs (160mg BID) consented to optional paired LN biopsies. BTK occupancy in LN by dose/schedule is shown in Figure 1. Median occupancy was 99.5% (160mg BID, n=18) vs 94.4% (320mg QD, n=12) (p=0.002, Wilcoxon). The proportion of pts with 〉 90% occupancy was 94% (160mg BID) vs 58% (320mg QD) (p=0.027, Fisher exact). Occupancy did not appear to differ amongst histologic subtypes. CLL/SLL Safety and Activity: As of 10 Jun 2016, 45 pts with CLL (n=42) or SLL (n=3) have been enrolled: 8 pts in DEsc (80mg QD [n=1], 160mg QD [n=2] , 160mg BID [n=2], and 320mg QD [n=3] ), and 37 in either the PD cohort or CLL/SLL EC (160mg BID, n=19; 320mg QD, n=18). 29 CLL/SLL pts are included in this analysis; 11 pts were excluded because of short ( 〈 12 weeks) follow-up, and 5 pts accrued at a single study site were excluded because of insufficient study documentation at baseline. Demographic and disease characteristics are shown in Table 1. BGB-3111 was well tolerated with 69% subjects reporting no drug related AE 〉 Gr 1 severity within the first 12 weeks of therapy. The most frequent AEs of any attribution were petechiae/ bruising (38%), upper respiratory tract infection (31%, all Gr 1/2), diarrhea (28%, all Gr 1/2), fatigue (24%, all Gr 1/2), and cough (21%, all Gr 1/2). Three SAEs were assessed as possibly related to BGB-3111 (Gr 2 cardiac failure, Gr 2 pleural effusion and Gr 3 purpura, all n=1). The case of Gr 3 purpura was the only major bleeding event reported. Atrial fibrillation (Gr 2) occurred in one pt. Three pts had temporary dose interruption for AE, and one pt discontinued BGB-3111 for AE. After a median follow-up of 7.5 months (2.9-17.3 months), the response rate is 90% (26/29), with PR in 79% (23/29) and, PR-L in 10% (3/29), SD in 7% (2/29), and non-evaluable response in one pt who discontinued treatment prior to week 12. No instances of disease progression or Richter transformation have occurred. Conclusions: BGB-3111 is well-tolerated and highly active in R/R CLL/SLL. While trough BTK occupancy in lymph nodes was robust with either 320mg QD or 160mg BID dosing, complete and continuous occupancy (median 99.5%) was more frequently achieved with the 160mg PO BID regimen. Late stage clinical trials will determine if the optimized BTK occupancy with this regimen translates into improvements in disease control and reduced drug resistance. Figure. Figure. Disclosures Tam: janssen: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Opat:Roche: Consultancy, Honoraria, Other: Provision of subsidised drugs, Research Funding. Gottlieb:Indee: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees. Simpson:Celgene, Roche, Janssen: Honoraria; Amgen Pharmaceuticals: Research Funding. Anderson:Walter and Eliza Hall Institute of Medical Research: Other: Walter and Eliza Hall Institute of Medical Research receives milestone payments for the development of venetoclax. Kirschbaum:Beigene: Employment. Wang:Beigene: Employment. Xue:Beigene: Employment. Yang:BeiGene: Employment. Hedrick:Beigene: Employment. Seymour:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie 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; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Roberts:Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax; Janssen: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; Servier: Research Funding.

Abstract: Background ENKTL is a subtype of mature T cell and NK cell lymphoma, with a higher incidence in Asia than in Europe and North America. Pts with rr-ENKTL have a poor prognosis after failing an L-asparaginase-based regimen, and lack effective treatment. Epstein-Barr virus (EBV) infection is one of the mechanisms and characteristics of ENKTL, which induces immune tolerance of tumor by upgrading PD-L1 expression in tumor cells. Blocking the PD-1 pathway could, therefore, be an effective treatment for ENKTL. A Phase 2 trial is being conducted to evaluate CS1001, a first full-length, fully human immunoglobulin G4 (IgG4) mAb directed against PD-L1, in pts with rr-ENKTL. Method This is a multicenter, single-arm, Phase 2 clinical trial to evaluate CS1001 monotherapy in rr-ENKTL. Pts aged 18-75 years with rr-ENKTL after failing prior asparaginase-based chemotherapy or chemoradiotherapy were eligible if they had ECOG performance status (PS) ≤ 1, adequate organ function and bone marrow function, and at least one measurable or evaluable lesion. All the pts will receive CS1001 1200 mg intravenously every 3 weeks for up to 2 years, until disease progression, intolerance, etc. The primary endpoint was objective response rate (ORR) assessed by an independent radiological review committee (IRRC) per Lugano 2014 criteria. Key secondary endpoints included ORR by investigators, complete and partial response rate, time to response, duration of response (DoR) and progression-free survival, overall survival and safety. Adverse events (AEs) were summarized according to NCI CTCAE v4.03. Result As of June 17, 2019, 29 pts (male: 16, 55.2%; median age: 44 years, range 30-74) were enrolled. Twenty (20, 69.0%) pts entering the study had an ECOG PS of 1. Twenty-two (22, 75.9%) pts had Stage IV of disease at screening. Eight (8, 27.6%) pts received 2 lines of prior systemic therapy and 6 (20.7%) pts received ≥3 lines of prior systemic therapy. The median duration of follow-up was 5.55 (range, 0.69-12.19) months. Among the 22 efficacy-evaluable pts, the investigator-assessed ORR was 40.9%. A total of 7 (31.8%) pts achieved complete response (CR), and 2 (9.1%) pts had partial response (PR); 1 additional pt achieved PR after pseudo-progression. The DoR ranged from 0.03+ to 8.61+ months; median DoR was not achieved. All CR pts were still in remission. The IRRC assessments were not available at the time of data cut-off. The median duration of treatment was 11.7 (range, 2.9 to 53.0) weeks. Fifteen (15, 51.7%) pts remained on treatment and 14 (48.3%) had discontinued from study treatment (12 due to progressive disease, 2 due to AEs). The majority of pts (25, 86.2%) had treatment-emergent AEs (TEAEs), of whom 21 (72.4%) pts reported treatment-related AEs (TRAEs). The most frequently reported (≥10%) TRAEs were pyrexia (6, 20.7%), blood thyroid stimulating hormone increased (4, 13.8%), white blood cell count decreased (4, 13.8%), and rash (3, 10.3%). Three (3, 10.3%) pts reported Grade (G) ≥3 TRAEs. Two (2) G5 AEs (death and haemophagocytic lymphohistiocytosis) were reported in 2 pts; none was assessed as related to CS1001 by the investigators. Serious AEs were observed in 5 (17.2%) pts, and 1 of them (sinus node dysfunction) was assessed as related to CS1001 by the investigator. Immune-related AEs (irAEs) were reported in 5 pts, including a G3 rash and the remaining irAEs were G1. TEAEs that led to permanent treatment discontinuation occurred in 2 (6.9%) pts, which included haemophagocytic lymphohistiocytosis (G5) and facial nerve disorder (G2). No death or permanent discontinuation due to AEs were assessed as related to the study drug. After data cut-off date, 3 additional pts reached response assessment time point, of which 2 pts achieved CR, resulting in ORR of 44% (11/25) and a CR rate of 36% (9/25). The updated data will be reported at the ASH conference. Conclusion In this study, CS1001 was shown to be active with a high CR rate and durable response, and was generally well-tolerated in pts with rr-ENKTL. The preliminary safety and efficacy profile of CS1001 support further exploration and development of CS1001 in rr-ENKTL pts. Disclosures No relevant conflicts of interest to declare.

Abstract: Introduction: The BTK inhibitor ibrutinib (IB) is highly active in WM, achieving major responses (CR+VGPR+PR) in approximately 70% of pts. However, VGPR is infrequent, with rates ≤15% in reported series (Treon NEJM 2015, Dimopoulos EHA 2016). BGB-3111 is a potent, highly-specific and irreversible BTK inhibitor, with greater selectivity than IB for BTK vs. other TEC- and HER-family kinases, and superior bioavailability. We previously reported that the recommended phase 2 dose of BGB-3111 is 320mg daily (in single or split dose) in pts with advanced B cell malignancies. This achieves plasma levels equivalent to 6-10 fold that of IB, and 〉 90% continuous inhibition of BTK in lymph node biopsies. We specifically investigated the safety and efficacy of BGB-3111 in pts with WM in an expansion cohort of the initial Phase 1 trial. Reported here are updated results of this study, including data from WM specific expansion cohorts. Aims: To define the safety profile, and clinical activity of BGB-3111 in pts with WM. Methods: These results are from a pre-specified a component of a Phase 1 study (Part 1: dose escalation [DEsc] in pts with R/R B cell malignancies, Part 2: disease-specific dose expansion cohorts [EC] at the recommended Phase 2 dose that included patients with relapsed / refractory or previously untreated WM). Adverse events (AEs) were reported per CTCAE v4.03. Responses were determined according to the modified Sixth International Workshop on WM (IWWM) criteria. The data cut-off is 10 June 2016. Results: As of 10 June 2016, 31 pts with WM have been enrolled; 6 pts in DEsc (40mg [n=2], 80mg [n=2] , 160mg QD [n=1], and 320mg QD [n=1] ), and 25 in the WM EC (160mg BID [n=18], 320mg QD [n=7] ). Three pts in DEsc were increased to 160mg QD after analysis of DEsc data, as allowed by protocol. Twenty-four pts are included in this analysis; 5 pts were excluded because of short ( 〈 60 day) follow-up for safety and efficacy, and 2 pts accrued at a single site were excluded because of insufficient documentation at baseline. Patient demographics, disease characteristics, and prior treatment history are summarized in Table 1. BGB-3111 was well tolerated with 71% reporting no drug related AE 〉 Gr 1 severity within the first 12 weeks of therapy. The most frequent AEs ( 〉 20%) of any attribution (all Gr 1/2) were upper respiratory infection (25%), diarrhea (25%), and nausea (21%). There were 2 SAEs assessed as possibly related to BGB-3111 (Gr 2 atrial fibrillation, Gr 3 cryptococcal meningitis); in both cases, BGB-3111 was temporarily held but safely resumed. In total, 2 pts developed AF (one Gr 1, one Gr 2). No serious hemorrhage (≥Gr 3 or CNS hemorrhage of any grade) was reported. After a median follow-up of 7.6 months (2-21 months), the response rate was 92% (22/24). The major response rate was 83% (20/24), with VGPR ( 〉 90% reduction in IgM and reduction in extramedullary disease) in 33% (8/24) and PR (50-90% reduction in IgM and reduction in extramedullary disease) in 50% (12/24) pts. Pts with WM refractory to their last therapy were equally responsive: major response 77% [10/13], VGPR 31% [4/13] , PR 46% [6/13]. Median time to initial response and major response were 29 days and 34 days, respectively. IgM decreased from a median of 29.9g/l at baseline to 3.0g/l; hemoglobin increased from a median of 10.1 g/dl at baseline to 13.5g/l. Two of 3 pts who had a dose increase after reaching a stable IgM plateau had further falls in IgM levels after dose escalation. Kinetics of IgM and hemoglobin response are presented in Figure 1. Lymphadenopathy was present in 8 pts at baseline; serial CT demonstrated reduction or resolution in all 8 pts (27%-100% reduction in SPD). Only one patient discontinued BGB-3111, due to exacerbation of pre-existing bronchiectasis while in VGPR. There have been no cases of disease progression. Analysis of response by genomic characteristics (including MYD88 and CXCR4 mutational status) is ongoing. Conclusions: BGB-3111 is well-tolerated and highly active in WM. The depth and quality of responses, as reflected by the VGPR rate of 33%, warrant a randomized comparison against ibrutinib in pts with WM. Table 1. Table 1. Figure 1. Figure 1. Disclosures Tam: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; janssen: Honoraria, Research Funding. Opat:Roche: Consultancy, Honoraria, Other: Provision of subsidised drugs, Research Funding. Simpson:Amgen Pharmaceuticals: Research Funding; Celgene, Roche, Janssen: Honoraria. Anderson:Walter and Eliza Hall Institute of Medical Research: Other: Walter and Eliza Hall Institute of Medical Research receives milestone payments for the development of venetoclax. Kirschbaum:Beigene: Employment. Wang:Beigene: Employment. Xue:Beigene: Employment. Yang:BeiGene: Employment. Hedrick:Beigene: Employment. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: 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, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Roberts:AbbVie: Research Funding; Servier: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax.