Abstract: Background: The Bruton tyrosine kinase (BTK) inhibitor zanubrutinib has demonstrated greater selectivity for BTK versus other TEC- and EGFRfamily kinases in biochemical assays, and favorable pharmacokinetic/pharmacodynamic properties in preclinical studies. In a phase 1 clinical trial, zanubrutinib showed complete and sustained 24-hour BTK occupancy in both peripheral blood mononuclear cells and lymph node biopsies from patients treated with 160 mg twice daily (Tam et al. Blood 2016;128:642). Zanubrutinib was also associated with high and durable responses in patients with WaldenstrC6m macroglobulinemia (WM) (Tam, ASCO 2020, abstract 8007; Dimopoulos, EHA 2019, abstract PF487; Trotman, EHA 2019, abstract PF481). Here we present initial safety and efficacy data from a phase 2 trial of zanubrutinib in patients with relapsed or refractory (R/R) WM. Methods: BGB-3111-210 (ClinicalTrials.gov: NCT03332173) is a pivotal, single-arm, open-label, multicenter, phase 2 study conducted in China. Patients with R/R WM aged b %18 years and with b %1 prior line of standard chemotherapy-containing regimen (with completion of b %2 continuous treatment cycles) receive zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. The primary objective is to evaluate the efficacy of zanubrutinib as measured by major response rate (MRR), defined as the proportion of patients achieving complete response (CR), very good partial response (VGPR), or partial response (PR), as assessed by an independent review committee (IRC) according to an adaptation of the 6th International Workshop on WM response criteria. Secondary endpoints include progression-free survival (PFS), overall response rate (ORR), duration of major response, and safety. The safety analysis set includes all patients who received b %1 dose of zanubrutinib. All efficacy endpoints are analyzed in patients with pathologically confirmed WM and with baseline immunoglobulin M (or M-protein) b %5 g/L. Adverse event (AE) severity is graded according to NCI CTCAE v4.03. Results: As of August 31, 2019, a total of 44 patients with R/R WM were enrolled and treated, with a median follow-up of 18.58 months. Baseline characteristics are summarized in Table 1. For the 43 patients evaluable for efficacy (1 patient was excluded from the efficacy analysis due to baseline immunoglobulin M & lt;5g/L), MRR per IRC was 69.8% (n=30, Table 1), with b % VGPR achieved in 32.6% of patients (n=14). As of data cutoff date, median PFS and median duration of major response were not reached. The most frequently reported (b %20%) treatment-emergent AEs (TEAEs) included neutrophil count decreased (56.8%), platelet count decreased (29.5%), white blood cell count decreased and upper respiratory tract infection (27.3% each), diarrhea (25.0%), weight increased and arthralgia (20.5% each). Grade 3 or higher AEs reported in b %5% of patients included neutrophil count decreased (31.8%), platelet count decreased (20.5%), lung infection (13.6%), white blood cell count decreased (11.4%), pneumonia (9.1%), anemia and upper respiratory tract infection (6.8% each). Most bleeding events were grade 1 or 2 originating in skin or mucous membranes. Major hemorrhage (serious or grade b %3 bleeding, or central nervous system bleeding of any grade) was reported in 2 patients (4.5%). No cases of atrial fibrillation/flutter or tumor lysis syndrome were reported. Two patients died within 30 days of last study treatment: one due to acute hepatitis B and multiple organ dysfunction syndrome, both of which were related to study drug per investigator's judgment, the other due to unknown reason, which was unlikely to be related to study drug as assessed by the investigator. TEAEs leading to discontinuation of zanubrutinib (n=1 each) included lung infection, laryngeal cancer, WM (investigator reported WM as AE due to unexpected rapid progression and suspected it to be a transformation), intracranial mass, acute hepatitis B (grade 5), and multiple organ dysfunction syndrome (grade 5). Conclusions: Zanubrutinib was shown to be highly active in patients with R/R WM, as demonstrated by a high MRR, b %VGPR rate. Zanubrutinib was generally well tolerated, consistent with previous reports of zanubrutinib treatment in patients with various B-cell malignancies. Disclosures Zhou: Henan Cancer Hospital: Current Employment. Guo:BeiGene Co., Ltd.: Current Employment, Current equity holder in private company. Du:BeiGene Co., Ltd.: Current Employment, Current equity holder in private company. Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Novotny:BeiGene USA, Inc.: Current Employment, Current equity holder in private company. Zhong:BeiGene Co., Ltd.: Current Employment, Current equity holder in private company. OffLabel Disclosure: Zanubrutinib is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that is being evaluated as a monotherapy and in combination with other therapies to treat various B-cell malignancies. Zanubrutinib is approved in the United States to treat adult patients with MCL who have received at least one prior therapy and in China for the treatment of MCL in adult patients who have received at least one prior therapy and CLL or SLL in adult patients who have received at least one prior therapy. Zanubrutinib is not approved for use outside of the United States and China.

Abstract: 7574 Background: For Follicular lymphoma (FL) patients (pts) of 3 rd or higher line, treatment options are limited. Parsaclisib is a potent, highly-selective, next-generation PI3Kδ inhibitor. Initial safety and efficacy data were previously presented (Zhong Zheng et al. ASH 2021; NCT04298879). Here, we report safety, efficacy and survival data of the multicenter, open-label phase 2 study of parsaclisib in 3 rd or higher line FL pts in China. Methods: Key eligibility included, age ≥ 18 years, histologically confirmed FL grade 1, 2, or 3a, ≥ 2 prior systemic therapies, ECOG PS ≤ 2, and ineligible for hematopoietic stem cell transplantation (HSCT). Pts received parsaclisib 20 mg once daily (QD) for 8 weeks followed by 2.5 mg QD, till disease progression (PD), unacceptable toxicity, death or withdrawn consent. Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required. Primary endpoint was objective response rate (ORR) evaluated by an Independent Review Committee (IRC) according to Lugano 2014 criteria, secondary endpoints included: duration of response (DOR), PFS, OS, and safety and tolerability. Results: As of the data cutoff date (Dec 12, 2021), 61 pts (median age: 50yr; male [n = 35, 57.4%] ) were enrolled. Forty-eight pts remained on treatment and 13 pts had discontinued study treatment mainly due to PD (n = 11). With a median follow-up time 9.5 months (range 6.0-19.7months), the median duration of treatment was 251.0 days (range: 23.0-589.0 days). All 61 pts were evaluable for response, the ORR and complete response rate (CRR) were 86.9% (n = 53, 95% CI: 75.8-94.2%) and 31.1% (n = 19, 95% CI: 19.9-43.3%), respectively. The median time to response (TTR) was 8.0 weeks (95% CI: 7.9-8.0%), and the median DOR was not reached (95% CI: 9.2 months-NC), and 43 of 53 pts with CR or PR still retained CR or PR. As data cutoff, eleven (17.9%) pts had disease progression, the median PFS was not achieved. Three pts died data as data cutoff, the median OS was not achieved. Among the 61 treated pts, 48 (95.1%) pts experienced at least 1 treatment-emergent adverse events (TEAEs), with the most common TEAEs being neutrophil count decreased (49.2%), white blood cell count decreased (32.8%). Twenty-seven patients (44.3%) experienced grade ≥ 3 TEAEs, the most common grade ≥ 3 TEAEs was neutrophil count decreased (n = 10, 16.4%). Conclusions: Parsaclisib demonstrated promising efficacy, and acceptable safety profile. These results suggest that parsaclisib could benefit 3 rd or higher line Follicular lymphoma patients. Clinical trial information: NCT04298879.

Abstract: Although Bruton tyrosine kinase (BTK) inhibitors have demonstrated promising efficacy in patients with Waldenström macroglobulinemia (WM), data in Asian populations are scarce. This trial is the first to investigate the effect of a BTK inhibitor in Chinese patients with relapsed/refractory (R/R) WM. Patients and Methods: Patients with R/R WM with at least one prior regimen were enrolled into this single-arm, multicenter, phase II study (NCT03332173) and received zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. The primary endpoint was major response rate (MRR), as assessed by an independent review committee. Secondary endpoints included progression-free survival, overall response rate, duration of major response, and safety. Results: Forty-four patients were enrolled. After a median follow-up of 33.0 (range, 3.2–36.5) months, MRR in all patients was 69.8%, with very good partial response or better in 32.6% of patients. All mutation groups benefited from zanubrutinib treatment (MRR in patients with MYD88L265P mutation, 73%; MRR in patients with MYD88 wild type mutation, 50%). A higher response rate was seen in the MYD88L265P/CXCR4WT population, compared with the other populations. Median progression-free survival and median duration of major response were not reached. The most frequently reported grade ≥3 treatment-emergent adverse events (AEs) were neutrophil count decreased (31.8%), and platelet count decreased and pneumonia (20.5% each). No case of atrial fibrillation/flutter occurred. Conclusions: Zanubrutinib achieved a high rate of response that was durable and deep in patients with R/R WM across all subgroups, and potentially confers a positive benefit–risk profile for WM.

Abstract: Reactivation of hepatitis B virus (HBV) infection is a well-recognized complication in patients with chronic or resolved HBV infection undergoing anticancer therapy. There is a risk of HBV reactivation after infusion of chimeric antigen receptor (CAR) T cells for patients with refractory/relapsed (R/R) multiple myeloma (MM). Methods We administered B cell maturation antigen (BCMA) CAR-T cell by infusion to nine patients with R/R MM with chronic or resolved HBV infection. Patient serum was analyzed to determine the expression of five components of HBV and the copy number of HBV DNA. HBV reactivation was defined if a patient re-exhibited hepatitis B surface antigen (HBsAg) or HBV DNA regrowth after CAR-T therapy. Results In one patient who was HBsAg-positive, no HBV reactivation was observed during the follow-up period of 9.8 months after administration of anti-HBV drugs before and after CAR-T therapy. Among eight patients with MM who had resolved HBV infection, two patients administered prophylactic anti-HBV drugs did not exhibit HBV reactivation. Of the six patients who did not use prophylactic antiviral drugs, five did not exhibit HBV reactivation, while one showed recurrence of HBsAg without detection of HBV DNA or damage to liver function. The best objective response rate was 100%, and the progression-free survival (PFS) at 12 months was of 88.89% (median PFS was not observed). Conclusions These findings showed that BCMA CAR-T cell therapy could be used in patients with R/R MM with chronic or resolved HBV infection and that antiviral drugs should be administered in these patients during CAR-T cell therapy.

Abstract: Introduction Zanubrutinib is a highly specific, potent BTK inhibitor with minimal off-target inhibition of other kinases such as EGFR, JAK3, TEC and ITK. Zanubrutinib has shown 100% BTK occupancy, sustained over 24-hours, in both the peripheral blood and lymph node biopsies from patients treated at 160 mg twice daily and achieves durable responses in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (Tam 2019). In a phase 2 study conducted in patients with relapsed/refractory (R/R) CLL/SLL, treatment with zanubrutinib resulted in an overall response rate (ORR) of 85%. In addition, duration of response (DOR), progression free survival (PFS) and overall survival (OS) of zanubrutinib monotherapy at 12 months were 93%, 87% and 96%(Xu 2020). Here, we present the pooled analysis to evaluate the impact of number of prior lines of therapy on outcomes of zanubrutinib treatment for CLL/SLL patients. Methods Our analysis was based on a pooled data including CLL/SLL patients treated with zanubrutinib monotherapy in two phase 1 studies (ClinicalTrials.gov NCT02343120, and ClinicalTrials.gov NCT03189524) and one phase 2 study (ClinicalTrials.gov NCT03206918), with median study follow-up time of 29.2, 21.1 and 15.1 months, respectively. Firstly, efficacy and safety outcomes were compared between the treatment naïve (TN) and relapsed/refractory (R/R) groups. Secondly, patients with 1 prior therapy were compared to patients with ≥ 2 prior therapies within the R/R setting. To control confounding in each analysis, entropy balancing was used to create a weighted sample where the baseline covariates were balanced between groups (Hainmueller 2012). In each weighted sample, the efficacy outcomes of zanubrutinib included complete response rate (CRR), ORR (defined as the achievement of complete response [CR], or CRi, partial response [PR] , nodular PR, PR with lymphocytosis), PFS and OS. The difference between groups in CRR and ORR was investigated by logistic regression, and those in PFS and OS by Cox proportional hazards models and log-rank test. The 24-month PFS and OS rates were calculated by the Kaplan-Meier method. The extent of exposure and safety profile of each group were summarized. Results The analysis data consisted of 19 TN patients, 93 patients with 1 prior therapy, and 99 patients with ≥ 2 prior therapies. Seven patients were excluded due to missing baseline covariates. In the weighted samples, all baseline covariates were balanced between groups. After weighting, the effective sample sizes were 19 and 31 for the TN and the R/R groups respectively. The median follow-up times were 31.3 and 20.9 months for the TN and R/R group, respectively; 54.4%, 18.8% and 26.8% of the patients in the R/R group had 1, 2 and & gt;2 prior lines of therapy. The ORR and CRR were higher in TN group, compared with R/R groups (100% vs. 92.1% in ORR [p & lt;0.001] and 21.05% vs. 6.7% in CRR [p=0.09] ). PFS of the TN group was superior to the R/R group (p = 0.13; HR 0.33 [95% CI: 0.10, 1.09]; Figure 1a). The 24-month PFS rate was 100% in the TN group and 79.1% in the R/R group. The OS was comparable between two groups. And safety profile was similar for both groups. After weighting, the effective sample sizes were 77 and 85 for the 1 prior therapy and the ≥ 2 prior therapies groups respectively. The median follow-up times were 17.1 and 15.8 months for the 1 prior therapy and the ≥ 2 prior therapies groups; 56.5%, 20.6% and 22.9% of the patients in the ≥ 2 prior therapies group were treated with 2, 3 and & gt;3 prior lines of therapy. The ORR was numerically higher in the 1 prior therapy group, compared with ≥ 2 prior therapies group (97.0% vs. 88.3%; p=0.05). The CRR was comparable in two groups (9.8% vs. 8.4%; p=0.75). The PFS of 1 prior therapy group was significantly longer than that in ≥ 2 prior therapies group (p & lt;0.001; HR 0.15 [95% CI: 0.05, 0.45]; Figure 1b), and 24-month PFS rates were 94.6% and 75.3%, respectively. The OS was comparable between two groups. And safety profile was similar for both groups. Conclusion Zanubrutinib administered in the early lines, including treatment of naïve patients and patients with 1 prior therapy, led to higher overall response rates and greater durability of therapeutic benefit. Safety profile was similar across all lines of therapy. References Tam CS, et al. Blood. 2019; 134 (11): 851-859. Xu W, et al. J Hematol Oncol. 2020; 13 (1): 48. Hainmueller, J. Political Analysis. 2012; 20(1): 25-46. Disclosures Tam: BeiGene: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Seymour:Morphosys: Consultancy, Honoraria; Mei Pharma: Consultancy, Honoraria; Gilead: Consultancy; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Nurix: Honoraria. Zhou:Henan Cancer Hospital: Current Employment. Opat:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: 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; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Research Funding. Trotman:Celgene: Research Funding; Takeda: Research Funding; BeiGene: Research Funding; F. Hoffmann-La Roche: Research Funding; PCYC: Research Funding. Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company. Lu:BeiGene: Current Employment, Current equity holder in publicly-traded company. OffLabel Disclosure: Zanubrutinib in treatment-naive CLL/SLL

Abstract: Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with a high initial response rate followed almost invariably by relapse. Here we report the pooled data from 2 studies, BGB-3111-AU-003 and BGB-3111-206, to explore the efficacy of zanubrutinib monotherapy in relapsed/refractory (R/R) MCL. A total of 112 patients were included. Median follow-up durations were 24.7 and 24.9 months for BGB-3111-AU-003 and BGB-3111-206, respectively. Overall response rate (ORR) and complete response (CR) rate were 84.8% and 62.5%, and median duration of response, progression-free survival (PFS) and overall survival (OS) were 24.9, 25.8 and 38.2 months, respectively. After weighting, the PFS (median: NE vs. 21.1 months, P  = 0.235) and OS (median: NE vs. 38.2 months, P  = 0.057) were similar but numerically better in the second-line than later-line group. Zanubrutinib was well-tolerated with treatment discontinuation and dose reduction for adverse events in 12.5% and 2.7% of patients, respectively. Hypertension, major hemorrhage and atrial fibrillation/flutter rates were 11.6%, 5.4% and 1.8%, respectively. Zanubrutinib is efficacious in R/R MCL, with a favorable safety profile.