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: Background: The Bruton tyrosine kinase (BTK) inhibitor zanubrutinib,has demonstrated greater selectivity for BTK versus other TEC- and EGFR-family 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 blood and lymph node biopsies from patients treated at 160 mg twice daily (bid; Tam et al. Blood 2016;128:642), and was associated with durable responses in patients with non-Hodgkin lymphoma (Tam et al. Blood 2017;130:152). Here, we present initial safety and efficacy data from a phase 2 trial of zanubrutinib in patients with relapsed or refractory mantle cell lymphoma (R/R MCL). Methods: Conducted in China, BGB-3111-206 (clinicaltrials.gov NCT03206970) is a pivotal, single-arm, open-label, multicenter phase 2 study. Patients with R/R MCL aged 18-75 years and with 1-4 prior treatment regimens received zanubrutinib 160 mg bid until disease progression (PD) or unacceptable toxicity. The primary objective is to evaluate the efficacy of zanubrutinib as measured by overall response rate (ORR) assessed by an Independent Review Committee (IRC). Response was assessed with PET-CT scans (in subjects with FDG-avid disease) and CT or MRI scans (in subjects with FDG non-avid disease) at each response assessment and for confirmation of complete response (CR) per the International Conference on Malignant Lymphoma (Lugano) criteria (Cheson, 2014). Key secondary endpoints included progression free survival (PFS), time to response (TTR), duration of response (DOR) and safety. Treatment-emergent adverse events (TEAEs) were assessed according to NCI CTCAE v4.03. Results: As of 27 March 2018, 86 patients with R/R MCL were enrolled and treated. Patient characteristics are summarized in the Table. Over one-half (52.3%) of patients were refractory to their last prior therapy. Median follow-up was 36 weeks (range,1-56) at the data cut. Twenty-one patients discontinued zanubrutinib (13 for PD; 6 for TEAEs; 1 withdrew consent; and 1 per investigator's discretion). One patient was not evaluable for response due to a lack of central pathologic confirmation of MCL. Of the 85 evaluable patients, ORR per the IRC was 84% (n=71; Table), with CR reported in 59% of patients (n=50). The estimated event-free rate for responders was 90% at 24 weeks after response. In total, 12 patients have progressed; the estimated PFS rate was 82% at 24 weeks. The most frequent (≥15%) TEAEs due to any cause included decreased neutrophil count (31.4%), upper respiratory tract infection (29.1%), rash (29.1%), decreased platelet count (22.1%), and decreased white blood cell (WBC) count (17.4%). Grade ≥3 TEAEs due to any cause reported in 〉 2 patients included decreased neutrophil count (11.6%), lung infection (5.8%), anemia (4.7%), and decreased WBC count (3.5%). Petechia/purpura/contusion and hematuria were each reported in 4 patients (4.7%, all grade 1/2); major hemorrhage (serious or grade ≥3 bleeding or central nervous system bleeding of any grade)was reported in 1 patient (1.2%); no cases of atrial fibrillation/flutter or tumor lysis syndrome were reported. Six patients died within 30 days of last study treatment, 1 from PD, 4 due to Grade 5 TEAEs and 1 due to a Grade 5 event that was not treatment emergent. TEAEs leading to discontinuation of zanubrutinib included (n=1 each): infection, pneumonia, lung infection, interstitial lung disease, and twoGrade 5 TEAEs (cerebral hemorrhage and road traffic accident). Conclusions: Zanubrutinib was shown to be highly active in patients with R/R MCL, as demonstrated by a high rate of CR documented by PET-based imaging. Zanubrutinib was generally well-tolerated, consistent with previous reports of zanubrutinib treatment in patients with various B-cell malignancies. Disclosures Song: Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Zhou:Affiliated Cancer Hospital of Zhengzhou University: Employment; Health and Family Planning Commission of Henan Province: Patents & Royalties: Scientific and technological innovative talents "51282" Project leaders; Henan Cancer Hospital: Consultancy, Employment; Natural Science Foundation of China: Research Funding. Jin:College of Medicine, Zhejiang University: Employment; The National Natural Science Foundation of China: Research Funding. Guo:BeiGene (Shanghai) Co., LTD: Employment. Wang:BeiGene (Shanghai) Co., LTD: Employment. Hilger:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Huang:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Novotny:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Osman:BeiGene USA: Employment, Equity Ownership. Zhu:Beijing Cancer Hospital: Employment.

Abstract: Introduction Prognosis for relapsed and refractory large B-cell lymphoma (r/r LBCL) is poor, and treatment remains challenging. Relmacabtagene autoleucel (relma-cel) is a CD19-directed 4-1BB/CD3z chimeric antigen receptor T cell (CAR-T) product manufactured in China. RELIANCE study is the first CAR-T study with CD19 as target that got IND approved by the authority in China. Initial findings of the pivotal Phase 2 single-arm, multicenter RELIANCE trial demonstrated high response rates and low rates of CAR-T-associated toxicity with relma-cel treatment in heavily pretreated patients (pts) with r/r LBCL (NCT04089215; Ying et al. Cancer Med 2020;10:999-1011). Long-term follow-up data for the RELIANCE study are presented. Materials & Methods Fifty-nine adults (age ≥18 years) with heavily pretreated (≥2 prior therapies), measurable and histologically confirmed r/r LBCL were randomized to receive lymphodepletion chemotherapy (LDC: fludarabine 25 mg/m 2 + cyclophosphamide 250 mg/m 2 daily×3) followed by a single infusion of autologous CAR+ T cells at a dose of 100×10 6 or 150×10 6. Pts were evaluated for efficacy using Lugano criteria and for toxicity using Common Terminology Criteria for Adverse Events v4.03 and for cytokine release syndrome (CRS) using Lee et al. (Blood 2014;124(2):188-95). Primary endpoint was 3-month objective response rate (ORR); key secondary endpoints included complete response rate (CRR) at 3 months, duration of response (DOR), progression-free survival (PFS), overall survival (OS) and treatment-emergent adverse event (TEAE) profile. The data cutoff date was December 31, 2020. Results At the time of analysis, all 59 pts (median age 56.0 years, range 18-75 years) were at least 15 months post-treatment with relma-cel (7 pts completed trial, 34 pts on study, 18 pts withdrew). Among the modified intent-to-treat (mITT) population of 58 efficacy-evaluable pts, best ORR was 77.6%, with a best CRR of 51.7%; ORR and CRR at 3-month-postdose landmark were 60.3% and 44.8%, respectively. With a median follow-up of 17.9 months (range 0.3-25.6 months), median PFS (mITT) was 7.0 months (95% CI 4.8-not reached [NR]). Median PFS was NR (95% CI 8.8 months-NR) for pts with compete response (CR) at 3 months, the 6-, 12-, 18- and 24-month PFS rates were 80.8%, 69.2%, 69.2% and 69.2%, respectively (Figure). PFS was associated with objective response or CR at 1, 3, 6, and 12 months (log-rank test, p≤0.002). Median OS was NR (95% CI NR-NR) for both the mITT population and pts with CR at 3 months (12-month OS rate, 76.8% and 92.3%, respectively). Median DOR was NR (95% CI 4.9 months-NR) for the mITT population and (95% CI 8.0 months-NR) for pts with CR at 3 months. Levels of CAR-T cells declined to below the level of quantification (BLQ) in 41 (69.5%) pts, among whom nearly 40% had sustained response. Median time from documentation of CAR-T BLQ to disease progression was 6.1 months (95% CI 1.8-NR). Treatment-related TEAEs were reported in 93.2% of pts and were primarily grade 1-2 (89.8% pts); 54.2% of pts had grade ≥3 TEAEs. Pyrexia was the most common TEAE, reported in 59.3% of pts (all grade 1-2). The most common grade ≥3 treatment-related TEAEs were neutrophil count decrease (30.5%) and white blood cell (WBC) count decrease (13.6%). Presence of cytopenia at day 29 (78.0%) was significantly associated with WBC count after LDC, change in serum albumin between days 1 and 4 and serum interleukin 8 after LDC (p & lt;0.05). The incidence of CRS and neurotoxicity (NT) was 47.5% and 20.3%, respectively, both primarily grade 1-2. There were no CRS- or NT-related deaths. Occurrence of grade ≥2 CRS or NT (11.9% and 6.8%, respectively) was significantly associated with fold-change of platelet count on day 4 compared with baseline and day 1 absolute neutrophil count (p & lt;0.03). There were no treatment-related deaths. Conclusions These are the first data of long-term follow-up CD19 CAR-T study with IND approval in China reported. With nearly 18 months of median follow-up, the RELIANCE pivotal registered study demonstrated durable responses, high rates of OS and PFS, and no new safety profile found in r/r LBCL pts. Based on these data, relma-cel is undergoing approval in China. Figure: Kaplan-Meier estimates of (A) PFS and (B) OS by 3-month tumor response PR, partial response Figure 1 Figure 1. Disclosures Zhang: JW Therapeutics: Current Employment. Yang: JW Therapeutics: Current Employment. Zhou: JW Therapeutics: Current Employment. Zheng: JW Therapeutics: Current Employment.

Abstract: 7529 Background: RELIANCE study is the first pivotal CD19 CAR-T study that got IND approval by the authority in China (NCT04089215). Initial findings of this study demonstrated high response rates and low rates of CAR-T–associated toxicity with Relmacabtagene autoleucel (Carteyva, also known as Relma-cel, JWCAR029) treatment in heavily pretreated patients with Relapsed/Refractory (r/r) large B-cell lymphoma (LBCL) (Ying et al. Cancer Med, 2020). Here we provide 2-year follow-up result of RELIANCE study. Methods: 59 adults (age ≥18 years) with ≥2 prior therapies r/r LBCL were randomized to receive lymphodepletion chemotherapy followed by a single infusion of Carteyva at a dose of 100×10 6 or 150×10 6 CAR+T cells, patients were evaluated for efficacy using Lugano criteria (Cheson 2014), for toxicity using CTCAE v4.03 and for cytokine release syndrome (CRS) using Lee et al. criteria (Blood 2014). Primary endpoint was 3-month objective response rate (ORR); key secondary endpoints included complete response rate (CRR) at 3 months, duration of response (DOR), progression-free survival (PFS), overall survival (OS) and treatment-emergent adverse event (TEAE) profile. Results: The cutoff date was December 22, 2021. All 59 patients (median age 56.0 years, range 18–75 years) were post-treatment with Carteyva, among of them 26 patients completed trial, 8 patients on study, 25 patients withdrew. Among the modified intent-to-treat (mITT) population of 58 efficacy-evaluable patients, best ORR and CRR was 77.6% and 53.5%, respectively. The median follow-up was 24 months(95% CI 23.9-24.1), median PFS and DOR was 7 months (95% CI 4.76–24.15) and 20.3 months (95% CI 4.86–NA), median OS was NA (95% CI NA–NA). 2-year PFS, DOR and OS rates were 38.3%, 38.1% and 69.0%, respectively. 91.5% patients reported treatment–related TEAEs with 72.9% patients had Grade ≥3, among this, the most common Grade ≥3 AE were neutropenia (42.4%) and leukopenia (22%). CRS and NT of any grade occurred in 47.5% and 20.3% of patients (Grade 3–4 CRS, 5.1%; Grade 3–4 NT, 3.4%). Median onset of CRS and NT was 4 (1–10) days and 8.5 (2–11) days, After Day 90, 6(10.2%) patients reported AEs Grade ≥3, the most common were lymphocytopenia 2(3.4%), neutropenia 2(3.4%) and leukopenia 1(1.7%). Grade ≥ 3 infections occurred in 2(3.4%) patients, which was gastroenteritis and herpes zoster. 17 (28.8%) patients died in this study, 12(20.3%) due to disease progression. Conclusions: As the longest follow-up term of CD19+ CAR T cell study in heavily pretreated patients with r/r LBCL in China, Carteyva demonstrated durable responses with a high 2-year OS rate, the median OS not yet reached for responding patients, and a manageable safety profile. These data continue supporting the compelling clinical benefit-risk profile of Carteyva for r/r LBCL patients. Clinical trial information: NCT04089215.

Abstract: Currently, no CAR-T product has been approved for use in China despite having hundreds of active CAR-T trials. Relma-cel (JWCAR029) is a CAR-T product with a CAR construct comprised of a binding domain, derived from a murine CD19-specific mAb (FMC63), a CD3ζ activation domain, and a 4-1BB costimulatory domain, and manufactured in China with a commercial-ready, highly automated, single train process to select, activate, transduce and expand both CD4 and CD8 cells to a wide range of doses with consistent product attributes. Relma-cel was evaluated in the first prospective, single-arm, multi-center, pivotal study (RELIANCE Trial) of CAR-T therapy conducted under Chinese IND to support an NMPA-accepted BLA submission in r/r large B-cell lymphoma (LBCL) (NCT 04089215) and the preliminary results are presented herein. Eligible adult patients had measurable, histologically confirmed r/r LBCL, failed at least 2 prior therapies, including anthracycline and anti-CD20 agents, and not had allogeneic transplant within 90 days or primary CNS lymphoma. Patients were randomized to receive either 100×106 (low dose) or 150×106 (high dose) CAR+ T cells as a single infusion following fludarabine 25 mg/m2 & cyclophosphamide 250 mg/m2 daily×3 as lymphodepletion. Patients were evaluated for efficacy (Lugano criteria, 2014), safety (CRS by Lee 2014, and all other events by CTCAE v4.03), and PK (by qPCR and flow cytometry). The protocol pre-specified and regulatory authority-agreed primary endpoint was 3 month ORR by landmark analysis to exclude a 3-month 20% ORR (Michael, 2017). Secondary endpoints included best overall response rate (BOR), duration of response (DOR), progression free survival (PFS), overall survival (OS), frequency/severity of AEs and CAR-T cell expansion. Investigators adjudicated disease response and progression based on imaging studies, pathology and clinical data; a sensitivity analysis was also conducted using an independent review committee adjudication. Between May 2018 and Dec 2019, 69 patients were screened, and 59 enrolled and treated with relma-cel, with median age of 56.0 years (18-75), 59.3% ECOG 1-2, and included several LBCL subtypes (DLBCL NOS 69.5%, TFL 15.3%, DHL/THL 5.1%, and PMBCL 6.8%) and nearly all with poor risk disease (81.4% treatment refractory, 45.8% ≥3 lines of prior therapies, 42.4% requiring bridging therapy, 39% IPI≥3). The median doses administered in low and high dose groups were 99.7×106 (range, 80.1-101.3) and 150.0×106 (range, 120.0-156.4) CAR+ T cells, respectively. Among the 58 efficacy evaluable patients, the primary analysis demonstrated a 3 month ORR of 58.6% (95% CI, 44.9-71.4) (the excluded patient had product that did not meet viability threshold criterion, but achieved CR at D29 that is ongoing for & gt;1 year). As of Jun 17, 2020 data cut-off, BOR was 75.9% (95% CI, 62.8-86.1) with CR rate of 51.7% (95% CI, 38.2-65.1). With a median follow-up of 8.9 months, median OS were not reached, and 6 month DOR, PFS and OS were 60.0%, 54.2% and 90.8%, respectively. No improvement in efficacy outcomes was observed in the high dose group. Of 59 treated patients, grade ≥3 AEs occurring in & gt;5% of patients were cytokine release syndrome (CRS), febrile neutropenia and lung infection (all, 5.1%). Grade ≥3 lab abnormalities in & gt;10% of patients were neutrophil count decreased (30.5%), white blood cell count decreased (13.6%), leukopenia (10.2%) and neutropenia (10.2%). The rates of CRS, neurotoxicity (NT), death, and the use of tocilizumab/steroids are shown in Table 1. All events of CRS and NT resolved except for 1 patient with grade 4 CRS ongoing at the time of death as the result of sepsis at day 8. As of data cut off, no cases of severe cytopenia or severe infections occurred beyond 30 days of infusion. The two dose groups did not differ significantly in PK parameters (see Table 1). The RELIANCE Trial provided the first demonstration of licensure-quality CAR-T manufacturing and clinical trial data generation in r/r patients originating in China. These results with relma-cel demonstrate similar preliminary response rates and PK profiles while providing the potential for an improved toxicity profile in heavily-pre-treated patients with r/r DLBCL having poor risk features relative to other CD19-specific CAR-Ts approved in the US and EU. Figure Disclosures Zhang: JW Therapeutics (Shanghai) Co. Ltd: Current Employment, Current equity holder in private company. Yang:JW Therapeutics (Shanghai) Co. Ltd: Current Employment, Current equity holder in private company. Zhou:JW Therapeutics (Shanghai) Co. Ltd: Current Employment, Current equity holder in private company. Zheng:JW Therapeutics (Shanghai) Co. Ltd: Current Employment, Current equity holder in private company.

Abstract: Background: Chidamide is a novel benzamide class of histone deacetylase (HDAC) inhibitor. In a pivotal phase 2 trial with refractory or relapsed peripheral T-cell lymphoma (PTCL), chidamide produced ORR 28% with CR 14% leading to its approval by the China Food and Drug Administration in 2014 for refractory or relapsed PTCL. We sought to assess the safety, tolerability and efficacy of the novel histone deacetylase inhibitor chidamide in combination with CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) (Chi-CHOEP) for previously untreated PTCL. Patients and methods: This was a prospective, multicenter, single-arm Phase 1b - 2 clinical trial conducted exclusively in China. In the phase 1b study, three dose levels of chidamide were explored. In the phase 2 portion, patients were treated at the RP2D. The primary endpoint of the Phase 1b was determination of the maximum tolerated dose (MTD), dose limiting toxicities (DLT) and RP2D. The primary endpoint of the phase 2 study was determination of the overall response rate (ORR). Results: A total of 82 patients were enrolled between March 2016 and Dec 2017 at 17 sites across China. The cutoff date for the analysis was July 2018. In phase 1b dose-escalation study, 15 patients were treated and the second dose cohort (20 mg biw) was declared the MTD and thus the RP2D. Subsequently, 67 patients were enrolled and treated at the RP2D in the phase 2 part of the study. Overall, among 82 enrolled patients in the entire phase 1b/2 study, the median number of cycles per person was five (range 1-8) and the relative dose intensity was 75.4%. The most common toxicities in the Phase 1b/2 study included leucopenia, anemia, and neutropenia. No reactivation of Epstein-Barr virus or Hepatitis B virus was observed. For entire phase 1b/2 study of 82 patients, the ORR was 68.3% with a CR rate of 43.9%. In the phase 2 part of the study, the ORR was 73.2% with 47.8% CR. with a median follow-up of 12.7 months (range 0.3-30.8 months), the median PFS for entire phase 1b/2 study was 17.4 months and the 1-year PFS was 52.9%. The median OS had not yet been reached, and the 1-year OS was 74.5%. In the phase 2 study, the median PFS was 17.4 months and the 1-year PFS was 53.6%. The median OS had not yet been reached, and the 1-year OS was 76.3%. Conclusion: Chi-CHOEP is an effective and feasible novel regimen for untreated PTCL. These data warrant further investigation in a randomized phase 3 study. This trial was registered at www.clinicaltrials.gov as #NCT02987244. Disclosures No relevant conflicts of interest to declare.

Abstract: Background: Bruton tyrosine kinase (BTK) is one of the key kinases implicated in the pathogenesis of multiple B cell malignancies. Orelabrutinib is a novel, highly selective and potent irreversible BTK inhibitor with minimal activities against other kinases (ITK, EGFR, ERBB2, etc.). As thus orelabrutinib may avoid off-target related adverse events and shall have improved safety profiles comparing to other BTK inhibitors. Here we present the safety profile of orelabrutinib analyzed based on data from 5 ongoing clinical studies in B cell malignancies (Table 1). Methods: Safety data of 266 patients (pts) from 5 ongoing orelabrutinib monotherapy studies were pooled and analyzed. All pts have been treated with at least one dose of oral orelabrutinib at ≥150 mg daily. The analysis includes the frequency and severity of adverse events (AEs), AEs of special interest, and AEs leading to treatment discontinuation or dose modifications. Results: Safety data were pooled from 266 pts with median age of 60 years (range 35.0-79.0, 69.2% males). The median duration of exposure was 11.0 months (range 0.2-22.0). The most common (occurring in ≥15% of pts) AEs were neutropenia (28.6%), thrombocytopenia (25.9%), Upper respiratory tract infection (24.4%), leukopenia (18.0%), anemia (16.2%) and rash (15.8%). Treatment related serious AEs (SAEs) were reported in 14.7% pts. The most common treatment related SAEs included thrombocytopenia (3.0%), lung infection (3.0%), pneumonitis (1.9%), anemia (1.1%) and lymphadentis (0.8%), The safety profiles were comparable in pts with various subtypes of B cell malignancies. It's noted that orelabrutinib has much less frequency of BTK off-target related adverse events, such as atrial fibrillation, diarrhea, major hemorrhage etc. Among all 266 pts, only one patient was reported with one episode of transient grade 1 atrial fibrillation, and no grade ≥3 atrial fibrillation was observed. Diarrhea of any grade was 7.1% and only one case (0.4%) was reported as grade 3. The major hemorrhage, defined as serious or ≥ G3 bleeding of any site, or central nervous system bleeding of any grade, was rarely observed; as only one case of cerebral hemorrhage, in 65-year-old male patient with more than 10 years hypertension was reported; the other three cases were subcutaneous hemorrhage, vitreous hemorrhage and vitreous hemorrhage/retinal hemorrhage. The later 2 cases of vitreous hemorrhage and/or retinal hemorrhage were resulted from posterior vitreous detachment and macular degeneration and both events were assessed as unlikely related to the treatment. Among 266 pts, the second primary malignancies were reported in only one pt with r/r MCL during orelabrutinib treatment. Grade ≥3 infection occurred in 41 pts (15.4%); most common infections were upper respiratory tract infection and lung infection. Most of the AEs were occurred during the early treatment, the frequency of the new event occurrence was significantly decreased during the later cycles. Dose reductions due to AEs occurred in 15 pts (5.6%), and treatment discontinuation due to AEs in 5.3% of pts with 2.3% related to orelabrutinib. Conclusions: Orelabrutinib shows excellent safety profiles and tolerability across various B-cell malignancies in long-term treatment. These data suggested orelabrutinib as a favorable treatment choice including the combinational therapy for B-cell malignancies. . Disclosures Zhu: Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Zhao:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment. Xu:Beijing InnoCare Pharma Tech Co., Ltd: Current Employment.