ALBERT

Description: Background: Tislelizumab is a humanized IgG4 monoclonal antibody with high affinity/specificity for programmed cell death protein 1 (PD-1). Tislelizumab was specifically engineered to minimize binding to FcɤR on macrophages, thereby abrogating antibody-dependent phagocytosis, a potential mechanism of T-cell clearance and resistance to anti-PD-1 therapy (Dahan 2015). Results of tumor growth inhibition studies suggest that tislelizumab had superior antitumor activity compared with nivolumab in mice transplanted with human cancer cells and peripheral blood mononuclear cells. Favorable results with other PD-1 inhibitors in patients with relapsed or refractory (R/R) classical HL (cHL) provide a strong rationale to investigate tislelizumabin this disease. Methods: BGB-A317-203 (clinicaltrials.gov NCT03209973) is a single-arm, open-label, multicenter, phase 2 study of tislelizumab in Chinese patients with R/R cHL; all patients received tislelizumab 200 mg intravenously every 3 weeks until progression or unacceptable toxicity. Patients were eligible if they (a) failed to achieve a response or progressed after autologous stem cell transplant (ASCT) or (b) received ≥2 prior systemic chemotherapy regimens for cHL and were ineligible for ASCT. Diagnosis of cHL was confirmed in all patients by central pathologic review.The primary endpoint was overall response rate (ORR) determined using the Lugano criteria (Cheson, 2014) as assessed by an independent review committee (IRC). Key secondary endpoints included progression-free survival (PFS), duration of response, rate of complete response (CR), time to response, safety, and tolerability. Treatment emergent adverse events (TEAEs) were summarized according to NCI-CTCAE v4.03. Results: In total, 70 patients were enrolled from 11 Chinese centers; patient characteristics are shown in the Table. With a data cutoff date of 25 May 2018, the median follow-up was 7.9 months (range, 3.4 to 12.7). The IRC-assessed ORR was 85.7%, based on PET-CT scans. A total of 43 patients (61.4%) achieved CR, 38 of whom were in CR at the first on-study response assessment. At data cutoff, 53 patients remained on treatment and 17 had discontinued (11 for progressive disease [PD]; 4 for TEAEs; 1 withdrew consent; 1 due to pregnancy). The estimated 6-month PFS rate was 80%. The most frequently reported (≥15%) TEAEs due to any cause were pyrexia (52.9%), hypothyroidism (30.0%), increased weight (28.6%), upper respiratory tract infection (27.1%) and cough (17.1%). Grade ≥3 TEAEs reported in ≥2 patients were upper respiratory tract infection (2.9%) and pneumonitis (2.9%). Immune-related TEAEs were reported in 23 patients (32.9%); Grade ≥3 in 5 patients (7.1%): pneumonitis (n=2), organizing pneumonia, nephritis (focal segmental glomerulosclerosis) and increased creatine phosphokinase (each n=1). There were no Grade 5 TEAEs. TEAEs that led to treatment discontinuation in 4 patients (5.7%) included pneumonitis (n=2), organizing pneumonia (n=1), and focal segmental glomerulosclerosis (n=1). One patient died on study due to PD. Conclusions: In this study, tislelizumab therapy was shown to be highly active resulting in a high CR rate in patients with R/R cHL who had failed or were ineligible for ASCT. Tislelizumab was generally well-tolerated in Chinese patients with R/R cHL. The safety profile was generally consistent with that of other PD-1 inhibitors for the treatment of cHL. Disclosures Song: Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Liu:West China Hospital of Sichuan University: Employment. Guo:BeiGene (Shanghai) Co., LTD: Employment. Yang:BeiGene (Beijing) Co., Ltd.: Employment. Elstrom:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Huang:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Novotny:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Wei:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Zhu:Beijing Cancer Hospital: Employment.

Description: 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 160 mg of oral zanubrutinib 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 published previously). 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. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

Description: 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.

Description: Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was 〉95% at all doses. Sustained complete (〉95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in 〉2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

Description: Background: Investigational Bruton tyrosine kinase (BTK) inhibitor zanubrutinib has demonstrated greater selectivity vs other TEC and EGFR family kinases in biochemical assays and favorable pharmacokinetic/pharmacodynamic properties in preclinical studies. In phase 1 testing, high plasma concentrations were achieved, resulting in complete and sustained 24-hour BTK inhibition in blood and lymph nodes in patients treated at 160 mg twice daily (bid; Tam et al. Blood 2016;128:642). A recent update of clinical data suggested that complete and sustained 24-hour BTK occupancy is associated with durable responses in patients with non-Hodgkin lymphomas (Tam et al. Blood 2017;130:152). Here, we present updated safety and efficacy data from patients with mantle cell lymphoma (MCL). Methods: Study AU-003 is a global, open-label, multicenter, phase 1b trial investigating zanubrutinib in patients with B-cell malignancies. After dose escalation, the expansion phase enrolled disease specific cohorts at the recommended phase 2 dose of zanubrutinib (320 mg/day once daily or 160 mg bid). Treatment emergent adverse events (TEAEs) were summarized according to NCI CTCAE v4.03 and response was assessed per International Conference on Malignant Lymphoma criteria (Cheson et al. J Clin Oncol 2014;32:3059). Positron-emission tomographic (PET) scan was not required for response assessment. Results: As of 28 Feb 2018, 43 patients were enrolled: 38 relapsed/refractory and 5 treatment-naïve (Table). Median follow-up was 10.3 months (range, 0.1-39.2). Twenty patients have discontinued treatment (12 due to progressive disease; 8 due to TEAEs). Most common TEAEs of any cause (≥15% of patients) included diarrhea (30.2%), petechiae/purpura/contusion (30.2%), upper respiratory tract infection (27.9%), constipation (18.6%), fatigue (18.6%), and rash (16.3%). Two cases of atrial fibrillation/flutter (4.7%) and 3 cases of major hemorrhage (7.0%; renal hematoma, gastrointestinal hemorrhage, and tumor hemorrhage, all grade 3) were reported. Most common grade ≥3 TEAEs of any cause (≥2 patients) included anemia (7.0%), cellulitis (7.0%), pneumonia (7.0%), myalgia (7.0%), neutropenia (4.7%), back pain (4.7%), peripheral edema (4.7%), hypertension (4.7%), and acute kidney injury (4.7%). Fourteen patients experienced ≥1 serious TEAE (SAE) of any cause; SAEs occurring in 〉1 patient included pneumonia (7.0%) and cellulitis (4.7%). Nine TEAEs led to discontinuation of zanubrutinib in 8 patients: pneumonia, cognitive disorder, antineutrophil cytoplasmic antibody-positive vasculitis and acute kidney injury (same patient), joint effusion, and myelodysplastic syndrome; 3 of the 9 were fatal TEAEs designated by the investigator as unrelated to zanubrutinib including pneumonia, congestive cardiac failure, and cerebral infarction. Three patients who had not yet reached their first response assessment were not evaluable for response. As shown in the Table, overall response rate was 90.0% (n=36/40) including 20.0% (n=8) with complete response. Response was based on computed tomography (CT) scan alone for the majority of patients as PET was not required. The 4 non-responders included 1 with progressive disease, 1 with stable disease, and 2 patients who discontinued because of TEAEs (pneumonia, congestive cardiac failure) before the first response assessment. Median progression-free survival was 18.0 months (Table, Figure). Conclusions: Zanubrutinib monotherapy was demonstrated to be highly active in patients with relapsed/refractory MCL, with a safety profile consistent with that of previous reports of zanubrutinib. Disclosures Tam: Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding. Wang:MoreHealth: Consultancy; Novartis: Research Funding; Dava Oncology: Honoraria; Kite Pharma: Research Funding; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Research Funding; Acerta Pharma: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Simpson:Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Research Funding; BeiGene: Research Funding; Merck: Honoraria, Research Funding; Acerta: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria, Research Funding; Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; MSD: Honoraria. Opat:Gilead: 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, Other, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Support, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Support, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Support, Research Funding; Amgen: Research Funding; Mundipharma: Honoraria; Beigene: Other: Clinical Trial Support; Epizyme: Other: Clinical Trial Support; Merck & Co., Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support and travel expenses; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Support, Research Funding. Cull:Takeda Australia: Other: Travel Expenses; Amgen Australia: Other: Travel Expenses; AbbVie (Australia): Membership on an entity's Board of Directors or advisory committees. Munoz:Alexion: Consultancy; Kite: Consultancy, Honoraria, Speakers Bureau; Gilead: Speakers Bureau; Juno: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy, Honoraria; Bayer: Consultancy, Speakers Bureau; Genentech: Consultancy, Honoraria. Phillips:Gilead: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy, Research Funding; Abbvie: Research Funding; Genentech: Consultancy. Kim:Novartis: Research Funding; Roche: Research Funding; Celltrion: Research Funding; Takeda: Research Funding; Kyowa-Kirin: Research Funding; Mundipharma: Research Funding; J&J: Research Funding. Hilger:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Huang:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Novotny:BeiGene (Beijing) Co., Ltd.: Employment, Equity Ownership. Trotman:PCYC: Research Funding; Janssen: Other: Unremunerated member of Ad Board, Research Funding; Celgene: Other: Unremunerated member of Ad Board, Research Funding; Takeda: Other: Unremunerated member of Ad Board; F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; Beigene: Research Funding.