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Background: TTK (also known as MPS1), a dual-specificity serine-threonine kinase, is critical for the spindle assembly checkpoint, chromosome alignment, and error correction in mitosis. Inhibition of TTK causes premature mitotic exit with unattached chromosomes, to result in chromosomal missegregation, aneuploidy, and cell death. CFI-402257 is a potent and highly selective inhibitor of TTK. Robust suppression of tumor growth was achieved upon oral dosing of single agent CFI-402257 in ER+/HER2- cell line and patient derived xenograft models. CFI-402257 demonstrated enhanced cytotoxicity in CDK4/6 inhibitor resistant ER+ breast cancer cell line models compared to parental cell lines, including those with RB1 loss. CFI-402257 has previously exhibited monotherapy and combination efficacy with a tolerable safety profile in ER+/Her2- Breast cancer patients in an ongoing clinical study which is updated here. Methods: This is an ongoing phase I, multi-center, dose escalation study (3+3 design) to determine the safety, tolerability, and maximum tolerated dose of CFI-402257 and to evaluate anti-tumor activity at the recommended phase 2 dose (RP2D). CFI-402257 was dosed once daily on a continuous schedule in 28-day cycles at a starting dose of 5 mg. Dose escalation included patients (pts) with advanced solid tumors. Dose expansion at the RP2D included pts with advanced solid tumors (Cohort A), advanced Her2-negative (ER+ or TNBC) with 1-4 prior lines of chemotherapy for metastatic disease (Cohort B), and ER+/Her2- breast cancer in combination with Fulvestrant (500 mg IM Day 1, 15 and 29 and then every 28 days) who have had prior treatment with an aromatase inhibitor in combination with a CDK4/6 inhibitor (≥ 3 months) and ≤1 prior chemotherapy for metastatic disease (Cohort C). Results: At data cutoff of May 2, 2022, 87 pts were enrolled. 86 pts (66 pts receiving monotherapy and 20 patients receiving combination therapy received ≥1 dose of study therapy and were analyzed for safety. One pt was not dosed due to elevated liver enzymes prior to first dose. The median age for mono was 61 years (range, 35-81) and for combo was 54 (range, 31-70). The median number of prior regimens mono and combo was 5 (range, 0-17; and 1-9, respectively). Tumor types in mono were breast cancer (27 pts), ovarian cancer (7 pts), GI cancer (3 pts), pancreatic cancer (3 pts), and other (30 pts). 20 breast cancer pts were enrolled in the combo. To date, 11 dose levels have been studied (range: 5 to 294 mg) in mono. There were 4 dose limiting toxicities (neutropenia >7days at 168mg/day, febrile neutropenia at 210mg/day, and neutropenia and colitis at 294mg/day, all grade 3). The RP2D of 168 mg was established. 3 pts in mono (biliary obstruction, febrile neutropenia, and pancytopenia) and 0 pts in combo discontinued study due to adverse events (AEs).Treatment emergent adverse events (TEAE’s) occurring in ≥30% of pts were fatigue (31 pts; 47%), nausea (30 pts; 46%), decreased appetite (22 pts; 33%), and diarrhea (21 pts; 32%) in mono; and nausea (11 pts; 55%) and diarrhea (7 pts; 35%) in combo. 35% of mono and 39% of combo AEs were considered related to CFI-402257 by the investigators. Grade ≥3 AEs and serious AEs were reported in 25 pts (38%) and 17 pts (26%), respectively in mono; and 5 pts (25%) and 3 pts (15%) in combo. The investigator assessed best overall response rate (partial response [PR] or better within the efficacy population) of 6% (PR; hepatocellular carcinoma n=1, breast cancer n=2 from n=47) in mono and 18% (PR; n=2 breast cancer) in combo (n=11), with additional patients still to be assessed. Conclusion: CFI-402257 is well tolerated as mono and combination with fulvestrant. Efficacy signals are emerging with pts in the combo cohort demonstrating anti-tumor activity. Additional efficacy will be updated at the time of the presentation. Citation Format: John Hilton, Daniel Renouf, David W. Cescon, Aaron Hansen, Alibiruni Abdul Razak, Lee-Anne Stayner, Trisha A. Denny, Emily Roberts-Thomson, Dih-Yih Chen, Mark Bray, Philippe Bedard. An update to a Phase I trial of CFI-402257, an oral TTK inhibitor, in patients with advanced solid tumors with HER2-negative breast cancer expansion cohorts [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-13.

We hypothesised that zanubrutinib, a highly selective next-generation Bruton tyrosine kinase (BTK) inhibitor, would be a safe and active treatment for patients intolerant of ibrutinib, acalabrutinib, or both. We aimed to assess whether zanubrutinib would prolong treatment duration by minimising treatment-related toxicities and discontinuations in patients with previously treated B-cell malignancies.This ongoing, phase 2, multicentre, open-label, single-arm study was done in 20 centres in the USA. Patients aged 18 or older with previously treated B-cell malignancies (chronic lymphocytic leukaemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenström macroglobulinaemia, or marginal zone lymphoma) who became intolerant of ibrutinib, acalabrutinib, or both, were orally administered zanubrutinib 160 mg twice daily or 320 mg once daily per investigator. The primary endpoint was recurrence and change in severity of ibrutinib or acalabrutinib intolerance events based on investigator-assessed adverse events. Secondary endpoints were investigator-assessed overall response rate; duration of response; disease control rate; and progression-free survival. Analyses included all patients who received any dose of the study drug. This study is registered with ClinicalTrials.gov, NCT04116437.Between Oct 14, 2019, and Sept 8, 2021, 67 patients (36 [54%] men and 31 [46%] women) who were intolerant of ibrutinib (n=57; cohort 1) or of acalabrutinib or acalabrutinib and ibrutinib (n=10; cohort 2) were enrolled. 63 (94%) patients were White, one (2%) had multiple ethnicities, and three (5%) had unreported or unknown ethnicity. Most intolerance events (81 [70%] of 115 for ibrutinib; 15 [83%] of 18 for acalabrutinib) did not recur with zanubrutinib. Of the recurring events, seven (21%) of 34 ibrutinib intolerance events and two (67%) of three acalabrutinib intolerance events recurred at the same severity with zanubrutinib; 27 (79%) ibrutinib intolerance events and one (33%) acalabrutinib intolerance event recurred at a lower severity with zanubrutinib. No events recurred at higher severity. No grade 4 intolerance events recurred. 64 (96%) of 67 patients had one or more adverse events with zanubrutinib; the most common adverse events were contusion (in 15 [22%] of 67 patients), fatigue (14 [21%]), myalgia (ten [15%]), arthralgia (nine [13%]), and diarrhoea (nine [13%]). Atrial fibrillation occurred in three (4%) patients (all grade 2). Eight (12%) of 67 patients had serious adverse events (anaemia, atrial fibrillation, bronchitis, COVID-19, COVID-19 pneumonia, febrile neutropenia, salmonella gastroenteritis, transfusion reaction, trigeminal nerve disorder, and urinary tract infection). No treatment-related deaths occurred. The median follow-up time was 12·0 months (IQR 8·2-15·6). Among the 64 efficacy-evaluable patients, disease control rate was 93·8% (60; 95% CI 84·8-98·3) and overall response rate was 64·1% (41; 95% CI 51·1-75·7). The median duration of response was not reached; the 12-month event-free duration of response rate was 95·0% (95% CI 69·5-99·3). Similarly, median progression-free survival was not reached; 18-month progression-free survival was 83·8% (95% CI 62·6-93·6).Patients intolerant of previous BTK inhibitors have limited treatment options. These results suggest that zanubrutinib, a safe and viable treatment for patients with B-cell malignancies, might fill that unmet need for those who exhibit intolerance to ibrutinib or acalabrutinib.BeiGene.

Summary Background Chemoimmunotherapy is typically the standard of care for patients with Waldenstrom macroglobulinemia; however, infectious and hematologic toxic effects are problematic. Acalabrutinib is a selective, potent Bruton tyrosine-kinase inhibitor. The aim of this trial was to evaluate the activity and safety of acalabrutinib in patients with Waldenstrom macroglobulinemia. Methods This single-arm, multicentre, phase 2 trial was done in 19 European academic centres in France, Italy, Greece, the Netherlands, and the UK, and eight academic centres in the USA. Eligible patients were 18 years or older and had treatment naive (declined or not eligible for chemoimmunotherapy) or relapsed or refractory (at least one previous therapy) Waldenstrom macroglobulinemia that required treatment, an Eastern Cooperative Oncology Group performance status of 2 or less, and received no previous Bruton tyrosine-kinase inhibitor therapy. Patients received 100 mg oral acalabrutinib twice per day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response (at least a minor response) according to the 6th International Workshop for Waldenstrom Macroglobulinemia (IWWM) and the modified 3rd IWWM workshop criteria. The primary outcome and safety were assessed in all patients who received at least one dose of treatment. This study is registered with ClinicalTrials.gov , number NCT02180724 , and is ongoing, but no longer enrolling. Findings Between Sept 8, 2014, and Dec 24, 2015, 122 patients were assessed for eligibility, of which 106 (87%) patients were given acalabrutinib (14 were treatment naive and 92 had relapsed or refractory disease). With a median follow-up of 27·4 months (IQR 26·0–29·7), 13 (93% [95% CI 66–100]) of 14 treatment naive patients achieved an overall response and 86 (93% [86–98]) of 92 relapsed or refractory patients per both the modified 3rd and 6th IWWM criteria. Seven (50%) of 14 treatment naive patients and 23 (25%) of 92 relapsed or refractory patients discontinued treatment on study. Grade 3–4 adverse events occurring in more than 5% of patients were neutropenia (17 [16%] of 106 patients) and pneumonia (7 [7%]). Grade 3–4 atrial fibrillation occurred in one (1%) patient and grade 3–4 bleeding occurred in three (3%) patients. The most common serious adverse events were lower respiratory tract infection (n=7 [7%]), pneumonia (n=7 [7%]), pyrexia (n=4 [4%]), cellulitis (n=3 [3%]), fall (n=3 [3%]), and sepsis (n=3 [3%]). Pneumonia (n=5 [5%]) and lower respiratory tract infection (n=4 [4%]) were considered treatment related. One treatment-related death was reported (intracranial hematoma). Interpretation This study provides evidence that acalabrutinib is active as single-agent therapy with a manageable safety profile in patients with treatment-naive, or relapse or refractory Waldenstrom macroglobulinemia. Further studies are needed to establish its efficacy against current standard treatments and to investigate whether outcomes can be improved with combination therapies. Funding Acerta Pharma.

Background: Bruton tyrosine kinase inhibitors (BTKis) are important tools to treat B-cell malignancies. However, duration of treatment may be limited by adverse events (AEs). Zanubrutinib (zanu) is a BTKi approved for mantle cell lymphoma (MCL) and is in development for other hematologic malignancies. Data from phase 3 head-to-head trials of zanu vs ibrutinib (ibr) in pts with Waldenström macroglobulinemia (WM) or chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) demonstrated that pts treated with zanu showed lower rates of AEs leading to discontinuation (Blood 2020;136(18):2038-50; EHA 2021 LB1900). Preliminary results from BGB-3111-215 (NCT04116437) show that zanu was well-tolerated in pts who discontinued ibr and/or acalabrutinib (acala) treatment due to AEs (EHA 2021 EP642). Here, we report updated results from the BGB-3111-215 study with a median follow-up of 9 months. Methods: This study is an ongoing US, phase 2, multicenter, single-arm, open-label study. The safety and efficacy of zanu monotherapy (160 mg twice daily or 320 mg once daily) were evaluated in pts with B-cell malignancies who met criteria for continued treatment after having become intolerant to prior BTKi therapy. Pts were divided into cohort 1 (pts who were intolerant to ibr only) and cohort 2 (pts who were intolerant to acala alone/and ibr). Pts with documented progressive disease (PD) on prior BTKi therapy were excluded. Efficacy and safety, including recurrence of intolerant AEs to the prior BTKi, were evaluated. AEs were assessed for severity, seriousness, and relation to zanu; as well as dose reductions, holds, or discontinuations. Response was assessed by investigators based on response criteria for their respective indications (Blood 2008;131:2745; J Clin Oncol 2012;30:2820; J Clin Oncol 2014;32:3059; Br J Haemtol 2013;160:171). Disease parameters from study entry were the baseline for response assessment. Mutational analysis was performed on pts who discontinued treatment, and data will be shared once available. To support clinical findings, kinase selectivity was assessed using Kinome profiling at 100X IC50 (against BTK) for zanu, ibr, acala and its major metabolite, M27 (Reaction Biology Corp). Results: As of 7 June 2021 (data cutoff), 57 pts (n=44 CLL/SLL; n=9 WM; n=2 MCL; n=2 marginal zone lymphoma [MZL]) were enrolled in cohort 1, and 7 pts were enrolled in cohort 2 (n=4 CLL; n=1 WM; n=1 MCL; n=1 MZL). All received ≥1 dose of zanu and were analyzed for safety. The median age was 71 years (range, 49-91) in cohort 1 and 71 years (range, 65-76) in cohort 2; median duration of treatment was 8.7 months (range, 0.6-17.9) in cohort 1 and 8.2 months (range, 6.4-11.4) in cohort 2; median number of prior regimens was 1 (range, 1-12) in cohort 1 and 3 (range, 2-5) in cohort 2. Within cohort 2, 5 pts were intolerant to both ibr and acala. Median number of intolerant events per pt for both cohorts 1 and 2 was 2 (range, 1-5). Overall, 73% of pts did not experience recurrence of their ibr or acala intolerant events and 79% of recurrent events recurred at a lower severity (Figure 1). At cutoff, 54 pts remained on treatment. Reasons for treatment discontinuation were AEs (n=4), PD (n=4), physician's decision (n=1), and consent withdrawal (n=1). Grade ≥3 AEs were reported in 18 pts (28%), and serious AEs occurred in 7 pts (11%). AEs requiring dose interruptions occurred in 17 pts (27%), and AEs leading to dose reduction occurred in 3 pts (5%). One death, due to COVID-19, was reported. Pts demonstrated maintained (41%) and improved (53%) response with zanu treatment from their reported best overall response on prior BTKis for a total disease control rate of 94% (including a 42% partial response rate in pts with CLL/SLL, 30% in pts with WM, and a 20% very good partial response rate in pts with WM). Zanu also demonstrated good selectivity by kinase profiling. It showed >50% inhibition on 7/370 kinases, while ibr, acala, and M27 had more off-target binding (17, 15 and 23 kinases, respectively) at their respective 100X IC50 (BTK) concentrations (Figure 2). Conclusion: In pts with B-cell malignancies intolerant to ibr and/or acala, zanu treatment resulted in continued disease control or improved response. Zanu was well-tolerated, and most AEs that led to discontinuation of previous BTKi therapy did not recur or recurred at a lower grade. In support of clinical findings, differentiation between BTKi selectivity profiles favor zanu over ibr and acala. Figure 1 Figure 1. Disclosures Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, and Atara Biotherapeutics, Adaptimmune: Consultancy; Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding; Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, and Atara Biotherapeutics, Adaptimmune: Membership on an entity's Board of Directors or advisory committees. Flinn: Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Levy: Epizyme: Consultancy, Other: Promotional speaker; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Novartis: Consultancy, Other: Promotional speaker; Dova: Consultancy, Other: Promotional speaker; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau. Burke: SeaGen: Consultancy, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; MorphoSys: Consultancy; Bristol Myers Squibb: Consultancy; AstraZeneca: Consultancy; Epizyme: Consultancy; Verastem: Consultancy; Kura: Consultancy; Kymera: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; Roche/Genentech: Consultancy; X4 Pharmaceuticals: Consultancy. Cultrera: Beigene: Research Funding. Yimer: Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau; Janssen: Speakers Bureau; Beigene: Speakers Bureau; GSK: Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Texas Oncology: Current Employment. Chaudhry: Medical Oncology Associates, PS (dba Summit Cancer Centers): Current Employment; Novartis, Immunomedics: Current holder of individual stocks in a privately-held company. Gandhi: TG Therapeutics: Honoraria; Karyopharm Therapeutics: Honoraria; GlaxoSmithKline: Honoraria. Kingsley: Comprehensive Cancer Centers of Nevada: Current Employment. Tumula: Texas Oncology: Current Employment. Manda: Morphosys: Honoraria; Genmab: Current equity holder in publicly-traded company. Chen: BeiGene: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Cohen: BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: Travel, Accommodations, Expenses. By: BeiGene, Ltd: Current Employment. Xu: Beigene: Current Employment; AstraZeneca: Ended employment in the past 24 months. Liu: BeiGene Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Sharman: TG Therapeutics: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy; BMS: Consultancy; AbbVie: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Lilly: Consultancy.

Background: Bruton tyrosine kinase (BTK) inhibitors (BTKi) have been shown to improve outcomes in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); however, adverse events (AEs) were the most common reason for ibrutinib and acalabrutinib discontinuation (median time ≤6 mo; Mato et al, Haematologica 2018;103:874; Yazdy et al, Blood 2019; Supplement1: 4311). Off-target effects of ibrutinib have been implicated in BTKi-related AEs. Zanubrutinib, a BTKi approved for treatment of mantle cell lymphoma (MCL) and in development for other hematologic malignancies, was specifically engineered to optimize selectivity and maximize BTK occupancy. In the head-to-head ASPEN trial of zanubrutinib vs ibrutinib in patients with Waldenström macroglobulinemia (WM), zanubrutinib showed a lower rate of AEs leading to death, discontinuation, dose reduction, and dose holds (Dimopoulos et al, EHA 2020; Abstract S225). We conducted a prospective clinical trial of zanubrutinib in patients with relapsed/refractory B-cell malignancies who have become intolerant to prior BTKi (ibrutinib and/or acalabrutinib) therapy. Methods : In this ongoing phase 2, multicenter, US, single-arm, open-label study (NCT04116437; BGB-3111-215), the safety and efficacy of zanubrutinib monotherapy (160 mg twice daily or 320 mg once daily) is being evaluated in patients with B-cell malignancies who meet requirements for treatment and have become intolerant to prior BTKi therapy. An intolerant event was defined as an unacceptable toxicity where, in the opinion of the investigator (INV), treatment should be discontinued despite optimal supportive care as a result of 1 of the following: grade ≥2 nonhematologic toxicities for >7 days (with or without treatment), grade ≥3 nonhematologic toxicity of any duration, grade 3 neutropenia with infection or fever, or grade 4 hematologic toxicity that persists to the point that the INV chose to stop therapy due to toxicity and not disease progression (PD). All enrolled patients must not have documented PD during prior BTKi therapy. Response assessment was evaluated by INV for CLL per modified International Workshop on CLL criteria (Hallek et al, Blood 2008;131:2745; Cheson et al, J Clin Oncol 2012;30:2820), for SLL, MCL, and marginal zone lymphoma per Lugano criteria (Cheson et al, J Clin Oncol 2014;32:3059), and for WM per modified 6th International Workshop on WM criteria (Owen et al, Br J Haemtol 2013;160:171). Disease parameters (imaging and laboratory parameters) performed at study entry were used as the baseline for response assessment. Results : As of 01 June 2020 (data cutoff), 17 patients with CLL/SLL were enrolled, received ≥1 dose of zanubrutinib, and were analyzed for safety. Median age was 70 years (range, 49-91) and median duration of treatment exposure was 3.02 mo (range, 0.56-7.59). The median number of prior regimens was 1 (range, 1-3). All patients had received ibrutinib. At data cut off, no patients had received acalabrutinib. At data cutoff, 16 patients remained on zanubrutinib treatment. One patient withdrew herself from the study following an AE (grade 3 syncope) unrelated, as per INV, to study treatment. Of the 31 BTKi-related AEs associated with intolerance (Table 1), 30 (96.8%) did not recur, and 1 event (3.2%; atrial fibrillation) recurred at a lower grade (grade 3 vs 2) and for a shorter duration (14 vs 3 days) vs the initial ibrutinib-intolerant event. Ten patients (58.8%) reported ≥1 AE. AEs reported in ≥10% of patients on zanubrutinib included dizziness (n=3; 17.6%) and cough (n=2; 11.8%). Grade ≥3 AEs were reported in 2 patients (11.8%): neutropenia and syncope (n=1 each; 5.9%). AEs of interest included hemorrhage and infections (n=3 each, 17.6%) and anemia, neutropenia, and atrial fibrillation (n=1 each; 5.9%). No AEs led to dose modification or treatment discontinuation. No serious AEs or deaths were reported. As of data cutoff, 10 patients were evaluable for efficacy with ≥1 response assessment. All 10 patients achieved at least stable disease, and 60% of these patients achieved a deepening of response since initiating zanubrutinib. Enrollment is ongoing and the presentation will include additional patients. Conclusions : Zanubrutinib demonstrated efficacy and tolerability in CLL/SLL patients who were intolerant to previous BTKi. These data suggest that zanubrutinib may provide a potential option after intolerance to other BTKi. Disclosures Shadman: Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: 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; Celgene: Research Funding; Atara Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellectar: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding; Sound Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mustang Bio: Research Funding; MophoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Ended employment in the past 24 months; Sunesis: Research Funding; Gilead: Research Funding. Sharman:Celgene: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; BeiGene: Research Funding; Roche: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding. Levy:Amgen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; Baylor University Med Center: Current Employment; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Misleh:Medical Oncology Hematology Consultants (MOHC): Current Employment; High Mark Blue Cross: Membership on an entity's Board of Directors or advisory committees. Zafar:Bristol Meyers Squibb: Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); AstraZeneca: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Karyopharm: Honoraria; Sarah Canon Research Institute: Research Funding; Florida Cancer Specialists and Research Institute: Current Employment. Freeman:Summit Medical Group: Current Employment. Burke:Kura: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Adaptive: Consultancy; Morphosys: Consultancy; Bristol Myers Squibb: Consultancy; Roche: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Astra Zeneca: Consultancy; Verastem: Consultancy; Epizyme: Consultancy; Seattle Genetics: Speakers Bureau; Adaptive Biotechnologies: Consultancy. Cultrera:Amgen: Speakers Bureau; Florida Cancer Specialists + Research Institute: Current Employment; Celgene: Speakers Bureau; AcroTech: Speakers Bureau; Verastem: Speakers Bureau. Yimer:BeiGene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Sanofi: Speakers Bureau; Epizyme: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; Texas Oncology: Current Employment; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Karyopharm: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; TG Therapeutics: Consultancy; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Celgene, a Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees. Chen:BeiGene: Current Employment, Current equity holder in publicly-traded company. Zhang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Cohen:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Ro:BeiGene: Current Employment, Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company. Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Flinn:Iksuda Therapeutics: Consultancy; Loxo: Research Funding; Kite Pharma: Consultancy, Research Funding; Karyopharm Therapeutics: Research Funding; IGM Biosciences: Research Funding; Infinity Pharmaceuticals: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Acerta Pharma: Research Funding; Incyte: Research Funding; Janssen: Consultancy, Research Funding; Great Point Partners: Consultancy; Genentech, Inc.: Research Funding; AstraZeneca: Consultancy, Research Funding; ArQule: Research Funding; Agios: Research Funding; Takeda: Consultancy, Research Funding; Forty Seven: Research Funding; Calithera Biosciences: Research Funding; BeiGene: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Triphase Research & Development Corp.: Research Funding; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Celgene: Research Funding; Merck: Research Funding; Constellation Pharmaceuticals: Research Funding; Curio Science: Consultancy; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; AbbVie: Consultancy, Research Funding; Teva: Research Funding; Pfizer: Research Funding; Nurix Therapeutics: Consultancy; Novartis: Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Forma Therapeutics: Research Funding; F. Hoffmann-La Roche: Research Funding; Gilead Sciences: Consultancy, Research Funding. OffLabel Disclosure: Zanubrutinib has not been approved for R/R CLL/SLL, MZL, and WM in the US

e19506 Background: Many patients (pts) with B-cell malignancies require continuous treatment with Bruton tyrosine kinase inhibitors (BTKi). Adverse events (AEs) are a common reason for ibrutinib (ibr) or acalabrutinib (acala) discontinuation. Early data from BGB-3111-215 showed zanubrutinib (zanu) was well tolerated in pts with B-cell malignancies intolerant to ibr or acala. We report preliminary results with a median follow-up of 4.2 mo. Methods: Pts meeting protocol criteria for intolerance to ibr, acala or both (without documented progressive disease) were given zanu monotherapy (160 mg twice daily or 320 mg once daily). Recurrence of AEs that led to intolerance of prior BTKi and additional safety measures were assessed based on the Common Terminology Criteria for AEs v5.0. Investigators determined responses using disease status at study entry as baseline. Results: As of November 1, 2020 (cutoff), 44 pts (n=34 chronic lymphocytic leukemia/small lymphocytic lymphoma, n=6 Waldenström macroglobulinemia, n=2 mantle cell lymphoma, n=2 marginal zone lymphoma) were enrolled, received ≥1 dose of zanu, and analyzed for safety. Median age was 70.5 y (range, 49-91); median duration of treatment was 4.2 mo (range, 0.1-12.6). Median number of prior regimens was 2 (range, 1-12). Regarding prior BTKi, 39 pts received ibr only, 4 received ibr and acala, and 1 received acala only. The median number of ibr- or acala-intolerant AEs per pt was 2 (range, 1-5). 83% of ibr and 78% of acala intolerant events did not reccur on zanu; Table. At data cutoff, 43 pts remained on treatment; 1 withdrew consent due to zanu-unrelated grade 3 syncope. Overall, 34 pts (77.3%) reported any AE; most commonly reported AEs were myalgia (n=9; 20.5%), contusion (n=8; 18.2%), dizziness (n=7; 15.9%), fatigue (n=7; 15.9%), and cough (n=5; 11.4%). Grade ≥3 AEs were reported in 6 pts (13.6%), serious AEs in 1 pt (2.3%, febrile neutropenia and salmonella infection), AEs requiring dose interruptions in 6 pts (13.6%), and AEs leading to dose reduction in 2 pts (4.5%). No AEs led to zanu discontinuation. No deaths were reported. All efficacy evaluable pts (26/26 [100%]) maintained (10 [38.5%]) or achieved deepening (16 [61.5%]) of their response. Conclusions: Zanu provides an additional treatment option after intolerance to other BTKi, demonstrating tolerability and sustained or improved efficacy. Updated results will be presented. Recurrence and Severity Change of AEs Leading to Ibr or Acala Intolerance. Clinical trial information: NCT04116437. [Table: see text]

TPS8066 Background: Ibrutinib (ibr), a Bruton tyrosine kinase inhibitor (BTKi), was shown to improve patient outcomes in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); however, adverse events (AEs) were the most common reason for discontinuing ibr (50% and 63% of discontinuations in relapse/refractory (R/R) and frontline patients, respectively; Haematologica. 2018:103:874). Zanubrutinib, an approved BTKi for mantle cell lymphoma, was specifically engineered to optimize selectivity. Pooled clinical data from 6 zanubrutinib monotherapy trials in B-cell malignancies (N=682 patients; R/R CLL/SLL [n=91]) suggested that zanubrutinib monotherapy was well tolerated and demonstrated a low rate of treatment discontinuation from AEs (9%; Tam, EHA 2019). Presented here is a trial-in-progress that will evaluate whether zanubrutinib monotherapy may serve as a therapeutic option for patients with CLL/SLL who have become ibr intolerant. Methods: The ongoing phase II, multicenter, US, single-arm, open-label study (NCT04116437, BGB-3111-215) will evaluate zanubrutinib monotherapy (160mg twice daily) as a treatment option for patients with CLL/SLL intolerant to prior ibr treatment. Approximately 60 patients will be enrolled from ~30 community medical centers. Key inclusion criteria include CLL/SLL requiring treatment per International Workshop on CLL criteria ( Blood. 2018;131:2745) before ibr therapy, intolerance to ibr (defined as an unacceptable AE for which, per investigator’s opinion, ibr treatment should be discontinued despite optimal supportive therapy), resolution of ibr-related AEs to grade ≤1 or baseline, and an ECOG PS 0-2. Key exclusion criteria include having an intervening cancer therapy between ibr and zanubrutinib, a documented disease progression during ibr treatment up to the time of enrollment, and a history of central nervous system (CNS) hemorrhage. The primary endpoint is frequency and severity of protocol-specified treatment-emergent AEs (diarrhea, myalgia, muscle spasm, arthralgia, hypertension, fatigue, rash, atrial fibrillation, and hemorrhage excluding CNS hemorrhage). The secondary endpoints include overall response rate, progression-free survival, and patient-reported outcomes. An exploratory endpoint was added to evaluate clinical effects (physical activity, treatment-related symptoms, and quality of life) using a smartphone app. Recruitment is ongoing. Clinical trial information: NCT04116437 .

7501Background: Bruton tyrosine kinase (BTK) is a clinically validated target in WM. Acalabrutinib is a highly selective, potent, covalent BTK inhibitor that we evaluated in a Phase 2 study of pts ...

Background: Bruton tyrosine kinase (BTK) is a critical component of B-cell receptor signaling pathway and a validated therapeutic target for CLL. Acalabrutinib is a highly selective, potent, covalent BTK inhibitor with minimal off-target activity that has been shown to have an overall response rate (ORR) of 95% (85% partial response [PR]; 10% PR with lymphocytosis [PRL]) after a median follow-up of 14.3 months in the relapsed CLL cohort of the Phase 1/2 ACE-CL-001 study. We present an updated analysis of the safety and efficacy results from the TN cohort of CLL patients from ACE-CL-001. Methods: Patients with TN CLL/small lymphocytic lymphoma (SLL) were eligible if they met International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for treatment, had an ECOG performance status of ≤2, and declined or were not appropriate candidates for chemotherapy. Patients received oral acalabrutinib 100 mg twice daily (BID) or 200 mg daily (patients were started on 200 mg QD and then switched to 100 mg BID) until progressive disease or unacceptable toxicity. Safety was the primary endpoint. Secondary endpoints were investigator-assessed overall response rate (ORR) by IWCLL 2008 criteria with modification for lymphocytosis, duration of response (DOR) and progression-free survival (PFS). Time to response (TTR; ≥ PR) and event-free survival (EFS) were exploratory endpoints. Results: A total of 99 patients (100 mg BID, n=62; 200 mg QD, n=37) were treated. The median age was 64 years (range 33-85), 46% of patients had bulky lymph nodes ≥5 cm, 47% had Rai stage III-IV disease at baseline, 10% (9/91) of patients had del(17p), and 62% (57/92) of patients had unmutated IGHV. As of December 1, 2017, the median time on study was 33 (1-39) months, with 91% of patients remaining on study treatment. Nine patients discontinued therapy: adverse events (n=5; 5%), pregnancy, disease progression, patient withdrawal, and initiation of subsequent therapy (n=1 each; 1%). The most common AEs (all grades; >20% of patients) were diarrhea (47%), headache (44%), contusion (34%), upper respiratory tract infection (33%), weight increase (30%), arthralgia (29%), nausea (26%), and cough (23%); the majority of these most common AEs were Grade 1/2. Grade 3/4 AEs occurred in 49% (49/99) of patients, most commonly (>2% of patients) neutropenia (7%), diarrhea (5%), headache (5%), nausea (4%), pneumonia (4%), hypertension (3%), and syncope (3%). Atrial fibrillation and hypertension (all grades vs grade 3/4) occurred in 6% vs 1% of patients and 14% vs 3% of patients, respectively. The most common bleeding events (>15%) were contusion (34%), petechiae (18%), and ecchymosis (16%); all bleeding events (60%) were Grade 1/2 except for 2 Grade 3 events (hematuria, upper gastrointestinal hemorrhage). Approximately 34% (34/99) of patients reported serious AEs (all grades), most commonly (≥5 patients) infection (pneumonia [4 patients], influenza [2 patients], and sinusitis [2 patients]). One grade 5 event (multiorgan failure due to neutropenic sepsis/pneumonia) was reported, which was considered unrelated to acalabrutinib. AEs leading to treatment discontinuation (5%) were secondary malignancies (angiosarcoma, glioblastoma multiforme, small cell lung cancer), neutropenic sepsis (Grade 2), rash (Grade 3), and urinary tract infection (Grade 3). ORR was high (97%) for this patient cohort (Table). Median DOR for the 96 responders (≥ PR) and median PFS for the 99 treated patients were not reached (NR) (95% CI: NR, NR; Figure 1). The 36-month DOR and PFS rate was 99% (95% CI: 91%, 100%) and 98% (95% CI: 92%, 100%), respectively. The EFS (with events defined as progression, death, discontinuation due to AE, or start of new anticancer therapy) was estimated to be 94.9% (95% CI: 88.2%, 97.9%) at 24 months (Figure 2). Median TTR was 3.7 months (range 2-22). For the 5 patients who achieved complete response (CR), the median time to CR was 28 months. One CLL progression was reported. No Richter's transformation occurred. Conclusion: Acalabrutinib monotherapy produced high response rates and demonstrated an acceptable safety profile in patients with TN CLL. Disclosures Furman: Gilead: Consultancy; Loxo Oncology: Consultancy; Acerta: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy; Incyte: Consultancy, Other: DSMB; Janssen: Consultancy; AbbVie: Consultancy. Martin:Gilead: Consultancy; Janssen: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; AstraZeneca: Consultancy; Kite: Consultancy. O'Brien:Janssen: Consultancy; GlaxoSmithKline: Consultancy; Acerta: Research Funding; Pfizer: Consultancy, Research Funding; Alexion: Consultancy; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Vaniam Group LLC: Consultancy; Astellas: Consultancy; Abbvie: Consultancy; Aptose Biosciences Inc.: Consultancy; Gilead: Consultancy, Research Funding; Kite Pharma: Research Funding; Regeneron: Research Funding; TG Therapeutics: Consultancy, Research Funding. Brown:Celgene: Consultancy; Verastem: Consultancy, Research Funding; Janssen: Consultancy; Genentech: Consultancy; Sunesis: Consultancy; Boehringer: Consultancy; Sun Pharmaceutical Industries: Research Funding; Gilead: Consultancy, Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; TG Therapeutics: Consultancy; Roche/Genentech: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees; Loxo: Consultancy. Barrientos:Pharmacyclics/Abbive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Devereux:Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Other: Personal fees. Hillmen:Novartis: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Acerta: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Abbvie: 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. Pagel:Gilead: Consultancy; Pharmacyclics, an AbbVie Company: Consultancy. Chen:Acerta Pharma: Employment. Hamdy:Acerta Pharma: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: various patents for ACP-196. Izumi:Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acerta Pharma, various patents for ACP-196. Patel:Acerta Pharma: Employment, Equity Ownership. Wang:Acerta Pharma: Employment. Jain:Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Pfizer: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Incyte: Research Funding; BMS: Research Funding; ADC Therapeutics: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; BMS: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Infinity: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; ADC Therapeutics: Research Funding; Astra Zeneca: Research Funding; Seattle Genetics: Research Funding; Servier: Research Funding; Verastem: Research Funding; Incyte: Research Funding; Cellectis: Research Funding; Celgene: Research Funding; Adaptive Biotechnologioes: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: 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; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:AbbVie, Inc: Research Funding; Genentech: Research Funding.

The human telomerase reverse transcriptase hTERT is overexpressed in most human tumors and contributes importantly to oncogenesis by maintaining the integrity of telomeric DNA. Despite being a self-antigen, the hTERT enzyme is immunogenic. Peptides derived from hTERT have been shown both in vitro and in vivo to drive the activation and proliferation of peptide-specific T lymphocytes. An HLA-A2-binding peptide from Htert (I540, ILAKFLHWL) has been used to generate peptide-specific T cells in vitro and in vivo in patients that lyse telomerase-positive tumors in an MHC-restricted fashion. Although these and other data suggest that I540 is naturally processed and presented on the surface of certain tumor cells, there are reports that I540-specific T cells, and in particular, T cell clones, do not lyse tumors in vitro. Here, we compared cytotoxic function of I540-specfic T cell clones vs. polyclonal T cell lines, including clones and lines generated from the same donor. We found that I540-specific polyclonal T cell lines lyse telomerase-positive tumors whereas non-specific polyclonal T cell lines and I540-specific T cell clones do not. Estimated TCR avidity for I540, as well as cell surface expression of CD45RO, CD45RA, CD28, CD27, CD57 and CD62L were similar between lines and clones. V beta usage, however, differed such that the majority of the I540-specific TCR repertoire found in polyclonal T cell lines was not represented in clones generated from the same source material. Thus, I540-specific T cells can vary in cytotoxic potential depending on the method of generation, isolation and expansion.

Purpose: High-level expression of the telomerase reverse transcriptase (hTERT) in >85% of human cancers, in contrast with its restricted expression in normal adult tissues, points to hTERT as a broadly applicable molecular target for anticancer immunotherapy. CTLs recognize peptides derived from hTERT and kill hTERT+ tumor cells of multiple histologies in vitro. Moreover, because survival of hTERT+ tumor cells requires functionally active telomerase, hTERT mutation or loss as a means of escape may be incompatible with sustained tumor growth.Experimental Design: A Phase I clinical trial was performed to evaluate the clinical and immunological impact of vaccinating advanced cancer patients with the HLA-A2-restricted hTERT I540 peptide presented with keyhole limpet hemocyanin by ex vivo generated autologous dendritic cells.Results: As measured by peptide/MHC tetramer, enzyme-linked immunospot, and cytotoxicity assays, hTERT-specific T lymphocytes were induced in 4 of 7 patients with advanced breast or prostate carcinoma after vaccination with dendritic cells pulsed with hTERT peptide. Tetramer-guided high-speed sorting and polyclonal expansion achieved highly enriched populations of hTERT-specific cells that killed tumor cells in an MHC- restricted fashion. Despite concerns of telomerase activity in rare normal cells, no significant toxicity was observed. Partial tumor regression in 1 patient was associated with the induction of CD8+ tumor infiltrating lymphocytes.Conclusions: These results demonstrate the immunological feasibility of vaccinating patients against telomerase and provide rationale for targeting self-antigens with critical roles in oncogenesis.

Previous studies have demonstrated that naturally phosphorylated PRL antagonizes the growth-promoting effects of unmodified PRL in two different PRL-responsive cell lines. In this study our aim was to produce a molecular mimic of phosphorylated PRL by substituting a fairly bulky, negatively charged amino acid (glutamate or aspartate) for the normally phosphorylated serine [serine 179 in human PRL (hPRL)]. In addition, because of the marked effect of phosphorylation on biological activity, we investigated the importance of the unmodified serine in the growth-promoting activity of PRL. hPRL complementary DNA was obtained from the American Type Culture Collection and subcloned into pT7-SCII after site-directed mutagenesis using the deoxyuridine approach. Proteins were expressed in Escherichia coli BL21 (DE3) and were primarily found in inclusion bodies. Agonist and antagonist activities of each serine 179 mutant were assessed using the Nb2 bioassay. Compared with standard hPRL, the recombinant wild-type was more active in the Nb2 assay, attesting to both the absence, or low level, of endotoxin contamination in preparations from these cells and the appropriate folding of the molecule. The aspartate and glutamate mutants had no intrinsic agonist activity, but both antagonized the growth-promoting activity of wild-type PRL, with the aspartate mutant proving to be a very effective antagonist. Two hundred picograms per ml of the aspartate mutant negated 75% of the growth response to 400 pg/ml wild-type PRL. When serine 179 was mutated to alanine or valine, mutant PRLs with 0% and 14% of the biological activity of wild-type PRL, respectively, were produced. These results demonstrate 1) that molecular mimicry of the phosphorylated hormone does produce a PRL antagonist, and 2) that the serine at position 179 is crucial to the growth-promoting activity of PRL. The aspartate mutant can now be used to study many aspects of the physiology of PRL.