Star Formation Feedback and Metal Enrichment History Of The Intergalactic Medium

Using hydrodynamic simulations we compute the metal enrichment history of the intergalactic medium (IGM). We show that galactic superwind (GSW) feedback can transport metals to the IGM and that the properties of simulated metal absorbers match observations. The distance of influence of GSW is typically limited to >0.5Mpc and within regions of overdensity >10. Most CIV and OVI absorbers are located within shocked regions of elevated temperature (T>2x10^4K), overdensity (>10), and metallicity ([-2.5,-0.5]). OVI absorbers have typically higher metallicity, lower density and higher temperature than CIV absorbers. For OVI absorbers collisional ionization dominates over the entire redshift range z=0-6, whereas for CIV absorbers the transition occurs at moderate redshift z~3 from collisionally dominated to photoionization dominated. We find that the observed column density distributions for CIV and OVI in the range log N cm^2=12-15 are reasonably reproduced by the simulations. The evolution of mass densities contained in CIV and OVI lines, Omega_CIV and Omega_OVI, is also in good agreement with observations, which shows a near constancy at low redshifts and an exponential drop beyond redshift z=3-4. For both CIV and OVI, most absorbers are transient and the amount of metals probed by CIV and OVI lines of column log N cm^2=12-15 is only ~2% of total metal density at any epoch. While gravitational shocks from large-scale structure formation dominate the energy budget (80-90%) for turning about 50% of IGM to the warm-hot intergalactic medium (WHIM) by z=0, GSW feedback shocks are energetically dominant over gravitational shocks at z > 1-2. Most of the so-called "missing metals" at z=2-3 are hidden in a warm-hot (T=10^{4.5-7}K) gaseous phase, heated up by GSW feedback shocks. Their mass distribution is broadly peaked at $\delta=1-10$ in the IGM, outside virialized halos.Comment: 52 pages, 26 figures, published in the Astrophysical Journal, 2011, ApJ, 731, 1

Energy viability study of Microgrides in non-interconnected areas of the department of Cauca (Colombia)

Trabajo de Grado (Profundización)The feasibility of implementing a hybrid renewable energy system as a single microgrid that supplies the energy needs of a region isolated from the conventional network is studied, taking as a case the township of San Isidro in the Municipality of López de Micay located in the Department of Cauca (Colombia).1. INTRODUCTION 2. PROBLEM STATEMENT 3. OBJECTIVES 4. CONCEPTUAL FRAMEWORK 5. THEORETICAL FRAMEWORK 6. STATE OF ART 7. METHODOLOGY FOR SELECTING THE BEST ENERGY SYSTEMS FOR THE ISOLATED MICROGRID 8. APPLICATION OF THE METHODOLOGY 9. RESULTS 10. VALIDATION OF RESULTS 11. DESCRIPTION OF RESULTS 12. CONCLUSIONS AND FUTURE WORK REFERENCES ANNEXESMaestríaMagister en Ingeniería y Gestión de la Innovació

Visuo‐spatial processing is linked to cortical glutamate dynamics in Parkinson's disease – a 7 Tesla functional MRS study

Background and purpose: Cognitive decline is a frequent and debilitating non-motor symptom for patients with Parkinson's disease (PD). Metabolic alterations in the occipital cortex during visual processing may serve as a biomarker for cognitive decline in patients with PD.Methods: Sixteen patients with PD (Unified Parkinson's Disease Rating Scale Part 3, OFF, 38.69 ± 17.25) and 10 age- and sex-matched healthy controls (HC) underwent 7-T functional magnetic resonance spectroscopy (MRS) utilizing a visual checkerboard stimulation. Glutamate metabolite levels during rest versus stimulation were compared. Furthermore, correlates of the functional MRS response with performance in visuo-cognitive tests were investigated.Results: No differences in static MRS between patients with PD and HC were detected, but a dynamic glutamate response was observed in functional MRS in HC upon visual stimulation, which was blunted in patients with PD (F1,22 = 7.13, p = 0.014; η2p= 0.245). A diminished glutamate response correlated with poorer performance in the Benton Judgment of Line Orientation test in PD (r = -0.57, p = 0.020).Conclusions: Our results indicate that functional MRS captures even subtle differences in neural processing linked to the behavioral performance, which would have been missed by conventional, static MRS. Functional MRS thus represents a promising tool for studying molecular alterations at high sensitivity. Its prognostic potential should be evaluated in longitudinal studies, prospectively contributing to earlier diagnosis and individual treatment decisions.Keywords: biomarker; cognitive decline; functional magnetic resonance spectroscopy; visuo-cognition

Pirtobrutinib (LOXO-305), a Next-Generation, Highly Selective, Non-Covalent Bruton’s Tyrosine Kinase Inhibitor in Previously Treated Mantle Cell Lymphoma and Other Non-Hodgkin Lymphomas: Phase 1/2 BRUIN Study

Presentation during EHA2021 : E-Poster Presentation - Session title: Aggressive Non-Hodgkin lymphoma - ClinicalBackgroundDespite the marked efficacy of covalent BTK inhibitors (BTKi) in MCL, WM, and MZL, the development of resistance and discontinuation for adverse events can lead to treatment failure. Moreover, pharmacological liabilities of these agents such as low oral bioavailability or short half-life, can lead to suboptimal BTK target coverage and ultimately result in acquired resistance in some patients (pts). To address these limitations, pirtobrutinib (LOXO-305), a highly selective, non-covalent BTKi that inhibits both WT and C481-mutated BTK with equal low nM potency was developed.AimsTo evaluate safety and efficacy of pirtobrutinib in previously treated MCL and other NHLs.MethodsBRUIN is a multicenter phase 1/2 trial (NCT03740529) enrolling pts with advanced B-cell malignancies who have received >2 prior therapies. Oral pirtobrutinib was dose escalated in a standard 3+3 design in 28-day cycles. The primary endpoint was MTD/RP2D identification. Efficacy evaluable pts included all dosed pts who underwent their first response evaluation or discontinued therapy. Safety was assessed in all pts (n=323). Response was assessed according to Lugano Classification or iWWM. ResultsAs of 27 September 2020, 323 pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, and 66 other B-cell lymphomas) were treated on 7 dose levels (25-300mg QD). Median age was 69 (range 50-87) years for MCL pts, 68 (42-84) for WM pts, and 68 (27-86) for other NHLs pts. Median number of prior lines of therapy was 3 (range, 1-8) for MCL, 3 (2-11) for WM, and 4 (2-10) for other NHLs. 93% of MCL, 70% of WM and 36% other NHL pts had received a prior BTKi. Pirtobrutinib demonstrated high oral exposures, with doses ≥100mg QD exceeding the BTK IC90 for the entirety of the dosing interval. No DLTs occurred. Consistent with pirtobrutinib’s selectivity, the only treatment emergent adverse events regardless of attribution or grade in >10% of pts (n=323) were fatigue (20%), diarrhea (17%) and contusion (13%). Grade 3 atrial fibrillation/flutter was not observed; 1 pt had grade 3 hemorrhage in the setting of mechanical trauma. Responses were observed at the first dose level of 25mg QD. A RP2D of 200mg QD was selected. At the efficacy cutoff date, 35 (57%) MCL pts, 18 (69%) WM pts and 34 (52%) other NHL pts remained on therapy. Among the 52 efficacy evaluable prior BTKi treated MCL pts, the ORR was 52% with 13 CR, 14 PR and 9 SD. Median follow up was 6 months (range 0.7-18.3+) for MCL. Responses in MCL were observed in 9/14 pts (64%) with prior autologous or allogeneic transplant, and 2 of 2 with prior CAR-T cell therapy. Among the 19 efficacy-evaluable pts with WM, the ORR was 68% (9 PR, 4 MR, 3 SD), and 69% in prior BTKi treated pts. 10 of 13 WM responders were ongoing (follow-up time from initial response: 0.8-9.2 months). For the 55 efficacy-evaluable other NHL pts, best response was as follows: DLBCL - 24% ORR (4 CR, 2 PR, 2 SD, 12 PD, 5 NE), FL - 50% ORR (2 CR, 2 PR, 1 SD, 3 PD), MZL - 22% ORR (2 PR, 7 SD), Richter’s transformation - 75% ORR (6 PR, 1 SD, 1 NE) and Other (2 B-PLL, 3 Low grade transformation) 1 SD, 2 PD, 2 NE.ConclusionPirtobrutinib demonstrated promising efficacy in MCL pts following multiple prior lines of therapy, including a covalent BTKi. Pirtobrutinib also showed efficacy in previously treated other NHLs. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index

ABCL-040: Pirtobrutinib (LOXO-305), a Next-Generation, Highly Selective, Non-Covalent Bruton's Tyrosine Kinase Inhibitor in Previously Treated Mantle Cell Lymphoma and Other Non-Hodgkin Lymphomas: Phase 1/2 BRUIN Study Results

International audienc

Seasonal changes in diet and chemical defense in the Climbing Mantella frog (Mantella laevigata).

Poison frogs acquire chemical defenses from the environment for protection against potential predators. These defensive chemicals are lipophilic alkaloids that are sequestered by poison frogs from dietary arthropods and stored in skin glands. Despite decades of research focusing on identifying poison frog alkaloids, we know relatively little about how environmental variation and subsequent arthropod availability impacts alkaloid loads in poison frogs. We investigated how seasonal environmental variation influences poison frog chemical profiles through changes in the diet of the Climbing Mantella (Mantella laevigata). We collected M. laevigata females on the Nosy Mangabe island reserve in Madagascar during the wet and dry seasons and tested the hypothesis that seasonal differences in rainfall is associated with changes in diet composition and skin alkaloid profiles of M. laevigata. The arthropod diet of each frog was characterized into five groups (i.e. ants, termites, mites, insect larvae, or other) using visual identification and cytochrome oxidase 1 DNA barcoding. We found that frog diet differed between the wet and dry seasons, where frogs had a more diverse diet in the wet season and consumed a higher percentage of ants in the dry season. To determine if seasonality was associated with variation in frog defensive chemical composition, we used gas chromatography / mass spectrometry to quantify alkaloids from individual skin samples. Although the assortment of identified alkaloids was similar across seasons, we detected significant differences in the abundance of certain alkaloids, which we hypothesize reflects seasonal variation in the diet of M. laevigata. We suggest that these variations could originate from seasonal changes in either arthropod leaf litter composition or changes in frog behavioral patterns. Although additional studies are needed to understand the consequences of long-term environmental shifts, this work suggests that alkaloid profiles are relatively robust against short-term environmental perturbations

LOXO-305, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated Mantle Cell Lymphoma, Waldenström's Macroglobulinemia, and Other Non-Hodgkin Lymphomas: Results from the Phase 1/2 BRUIN Study

Background: Covalent BTK inhibitors (BTKi) have transformed the management of MCL, WM, and MZL. Despite the marked efficacy of covalent BTKi, treatment failure can occur through the development of resistance and discontinuation for adverse events. Covalent BTKi also share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover, ultimately manifesting as acquired resistance in some patients (pts). To address these limitations, LOXO-305, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. The aim of the BRUIN trial was to define the safety and early efficacy of LOXO-305 in pts with B-cell malignancies. Here we report these data in pts with previously treated MCL, WM, and other NHLs. Methods: BRUIN is a multicenter phase 1/2 trial (NCT 03740529) enrolling pts with advanced B-cell malignancies who have received >2 prior therapies. Dose was escalated according to a standard 3+3 design with LOXO-305 dosed orally in 28-day cycles. The primary endpoint was MTD/RP2D identification. Intra-patient dose-escalation to previously cleared dose levels was permitted. Efficacy evaluable pts included all dosed pts who underwent their first response evaluation or discontinued therapy. Response was assessed every 8 weeks from cycle 3, and every 12 weeks from cycle 13 and was measured according to Lugano Classification or iWWM. Safety was assessed in all pts (CLL/SLL and NHL, n=186). Results: As of 30 April 2020, 186 pts with B-cell malignancies (94 CLL/SLL, 38 MCL, 19 DLBCL, 17 WM, 6 FL, 5 MZL, and 7 Other [B-PLL and Richter's transformation]) were treated on 7 dose levels (25mg to 300mg QD). Among the 92 pts with NHL, the median age was 68 (range 27-87) years. Median number of prior lines of therapy was 2 for MCL (range 2-8), and 3 for other NHLs (range 2-11). 92% of MCL pts had received a prior BTKi; 87% received at least an anti-CD20 antibody, chemotherapy, and BTKi; 10 pts had received SCT/CAR-T; 71% of WM pts had received a prior BTKi. LOXO-305 demonstrated high oral exposures, with doses ≥100mg QD exceeding the BTK IC90 for the entirety of the dosing interval. There were no DLTs or dose reductions. Consistent with LOXO-305's selectivity, the only treatment emergent adverse events regardless of attribution or grade seen in >10% of pts (n=186) were fatigue (n=29, 16%) and diarrhea (n=28, 15%). Responses were observed at the first dose level of 25mg QD. A RP2D of 200mg QD was selected for future studies. At the efficacy cutoff date, 24 MCL pts (63%) and 35 other NHL pts (65%) remained on therapy. Among the 35 efficacy-evaluable MCL pts treated across all dose levels, the ORR was 51% including 9 CRs, 9 PRs, 7 SDs, 8 PDs, and 2 NEs. An additional 3 MCL pts were awaiting initial radiologic assessment. Among the subset of 20 efficacy evaluable MCL pts who started at the RP2D (200mg QD), the ORR was 65% including 7 CRs, 6 PR, 4 SDs, 1 PD and 2 NEs. Of the 18 responding pts treated at any dose, all except 2 remain on therapy, with the longest followed responding pt on treatment for 14 months and ongoing. Of the 2 responding pts who have discontinued treatment, 1 progressed and 1 achieved a CR and electively discontinued treatment to undergo allogeneic stem cell transplant. Responses in MCL have been observed in pts who received prior cell therapy, including 3 of 7 patents with prior SCT, and 1 of 2 with prior CAR-T. Among the 15 efficacy-evaluable pts with WM, the ORR was 60% (1 VGPR, 4 PRs, 4 MRs, 5 SDs, 1 NE), and also 60% in the subset with prior BTKi treatment. 8 of 9 WM responders were ongoing (follow-up time from initial response: 0.1-4.8 months). For the remaining 29 efficacy-evaluable other NHL pts, best response was as follows: DLBCL (3 CRs, 1 SD, 6 PDs, 5 NEs), FL (3 PRs, 1 SD, 1 PD), MZL (2 PRs, 1 SD) and Other [5 Richter's transformation, 1 B-PLL] (2 PRs, 2 SDs, 2 NEs). Conclusion: LOXO-305 demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL pts following multiple prior lines of therapy, including covalent BTKi. Early efficacy was also observed in BTK-treated WM, as well as heavily pretreated other NHLs. LOXO-305 was well tolerated and exhibited a wide therapeutic index. Disclosures Wang: Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Loxo Oncology: Consultancy, Research Funding; Verastem: Research Funding; Molecular Templates: Research Funding; Dava Oncology: Honoraria; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding; Nobel Insights: Consultancy; VelosBio: Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Targeted Oncology: Honoraria; Juno: Consultancy, Research Funding; BioInvent: Research Funding; Lu Daopei Medical Group: Honoraria; OncLive: Honoraria; Beijing Medical Award Foundation: Honoraria; MoreHealth: Consultancy; Guidepoint Global: Consultancy; Acerta Pharma: Research Funding; Pulse Biosciences: Consultancy. Shah:Cell Vault: Research Funding; Miltenyi Biotec: Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Incyte: Consultancy; Lily: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Verastim: Consultancy; TG Therapeutics: Consultancy. Alencar:Genentech, Celgene, KITE, Loxo Oncology at Lilly: Consultancy. Gerson:Loxo: Research Funding; Pharmacyclics: Consultancy; Abbvie: Consultancy; Genentech: Consultancy. Fakhri:University of California San Francisco: Current Employment. Jurczak:MeiPharma: Research Funding; Roche: Research Funding; Takeda: Research Funding; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months; Pharmacyclics: Research Funding; Bayer: Research Funding; Janssen: Research Funding; Acerta: Research Funding; TG Therapeutics: Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment. Tan:Sir Charles Gairdner Hospital and Linear Clinical Research: Current Employment. Lewis:Sir Charles Gairdner Hospital and Linear Clinical Research: Current Employment. Fenske:Medical College of Wisconsin: Current Employment. Coombs:Novartis: Honoraria; Octapharma: Honoraria; LOXO Oncology: Honoraria; MEI Pharma: Honoraria; AstraZeneca: Honoraria; Genentech: Honoraria; Abbvie: Consultancy, Honoraria. Flinn:Calithera Biosciences: Research Funding; Loxo: Research Funding; IGM Biosciences: Research Funding; Takeda: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche: Research Funding; Gilead Sciences: Consultancy, Research Funding; Agios: Research Funding; Karyopharm Therapeutics: Research Funding; Incyte: Research Funding; BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Curio Science: Consultancy; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; Nurix Therapeutics: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Research Funding; Teva: Research Funding; Constellation Pharmaceuticals: Research Funding; Great Point Partners: Consultancy; Forma Therapeutics: Research Funding; Iksuda Therapeutics: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Infinity Pharmaceuticals: Research Funding; Acerta Pharma: Research Funding; AbbVie: Consultancy, Research Funding; Janssen: 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; Merck: Research Funding; Celgene: Research Funding; ArQule: Research Funding; Kite Pharma: Consultancy, Research Funding; Forty Seven: Research Funding. Le Gouill:Loxo Oncology at Lilly: Consultancy; Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria. Palomba:Celgene: Honoraria; Pharmacyclics: Honoraria; Genentech: Research Funding; Novartis: Honoraria; Merck: Honoraria; Juno Therapeutics, a Bristol-Meyers Squibb Company: Honoraria, Research Funding; Regeneron: Research Funding. Woyach:Janssen, Pharmacyclics, AstraZeneca, Abbvie, Arqule: Consultancy; Pharmacyclics, Janssen, Morphosys, Karyopharm, Verastem, Abbvie, Lox: Research Funding; Pharmacyclics LLC, an AbbVie Company, AbbVie, Janssen, AstraZeneca, ArQule: Honoraria. Lamanna:Columbia University Medical Center: Current Employment; MingSight: Other: Institutional research grants, Research Funding; Octapharma: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bei-Gene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Abbvie: Consultancy, Membership on an entity

LOXO-305, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated CLL/SLL: Results from the Phase 1/2 BRUIN Study

Background: Covalent BTK inhibitors (BTKi) have transformed the management of CLL/SLL. Despite the marked efficacy of covalent BTKi, treatment failure can occur through the development of resistance and discontinuation for adverse events. The activity of covalent BTK inhibitors is markedly reduced or absent in the presence of BTK cysteine binding site (C481) mutations. Moreover, these agents share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover, ultimately manifesting as acquired resistance in some patients (pts). To address these limitations, LOXO-305, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. The aim of the BRUIN trial was to define the safety and early efficacy of LOXO-305 in pts with B-cell malignancies. Here we report these data in pts with previously treated CLL/SLL. Methods: BRUIN is a multicenter phase 1/2 trial (NCT 03740529) enrolling pts with advanced B-cell malignancies who have received >2 prior therapies. Dose was escalated according to a standard 3+3 design with LOXO-305 dosed orally in 28-day cycles. The primary endpoint was MTD/RP2D identification. Intra-patient dose-escalation to previously cleared dose levels was permitted. Efficacy evaluable pts included all dosed pts who underwent their first response evaluation or discontinued therapy. Response was assessed every 8 weeks from cycle 3, and every 12 weeks from cycle 13 and was measured according to the iwCLL 2018 criteria, including PR with lymphocytosis (PR-L). Safety was assessed in all pts (CLL/SLL and NHL, n=186). Results: As of 30 April 2020, 186 pts with B-cell malignancies (94 CLL/SLL, 38 MCL, 19 DLBCL, 17 WM, 6 FL, 5 MZL, and 7 Other [B-PLL and Richter's transformation]) were treated on 7 dose levels (25mg to 300mg QD). Among the 94 pts with CLL/SLL, the median age was 69 (range 36-84) years and median number of prior therapies was 4 (range 1-10). 84% of CLL/SLL pts had received a prior BTKi, and 69% had received an anti-CD20 antibody, chemotherapy, and BTKi. In addition, 21% had received a PI3K inhibitor and 31% venetoclax. At enrollment, central molecular characterization for high-risk features in available samples revealed 17p deletion in 21% (13/63), TP53 mutation in 30% (27/91), and unmutated IGHV in 84% (51/61). LOXO-305 demonstrated high oral exposures, with doses ≥100mg QD exceeding the BTK IC90 for the entirety of the dosing interval. There were no DLTs or dose reductions. Consistent with LOXO-305's selectivity, the only treatment-emergent adverse events regardless of attribution or grade seen in >10% of pts (n=186) were fatigue (n=29, 16%) and diarrhea (n=28, 15%). Responses were observed at the first dose level of 25mg QD. A RP2D of 200mg QD was selected for future studies. At the efficacy cutoff date, 88 CLL/SLL pts (94%) remained on therapy and 65 CLL/SLL pts were efficacy-evaluable (58 BTKi-treated, 7 BTKi-naïve). Median follow up time was 3 months (range 0.1-13) for all pts and 6.7 months for responders. The ORR was 57%, with 23 PRs, 14 PR-Ls, 26 SDs, 1 PD, and 1 NE (Figure). An additional 29 pts were ongoing and awaiting initial radiologic assessment. As has been observed with covalent BTK inhibitors, responses deepened over time; among pts with at least 6 months of follow-up (n=26), the ORR was 77%. Response rate was not influenced by the presence or absence of a pretreatment BTK C481 mutation, the reason for prior BTKi discontinuation (i.e. progression vs intolerance), or other classes of prior therapy received (including a covalent BTK and BCL2 inhibitor). Of the 37 responding pts, all except 2 remain on therapy (1 progressed and 1 achieved a PR and electively discontinued treatment to undergo an allogeneic stem cell transplant). The longest-followed responding patient has been on treatment for 13.5 months and is ongoing. Responding pts with BTK C481 mutations demonstrated corresponding decreases in mutant disease burden by ddPCR. Conclusion: LOXO-305 demonstrated promising efficacy in heavily pretreated, poor-prognosis CLL/SLL pts following multiple prior lines of therapy including covalent BTKi and a BCL2 inhibitor. Importantly, the activity of LOXO-305 was not restricted to pts with BTK C481 mutations. LOXO-305 was well tolerated and exhibited a wide therapeutic index. Figure Disclosures Mato: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding. Coombs:Abbvie: Consultancy, Honoraria; Genentech: Honoraria; AstraZeneca: Honoraria; MEI Pharma: Honoraria; LOXO Oncology: Honoraria; Octapharma: Honoraria; Novartis: Honoraria. Shah:TG Therapeutics: Consultancy; Celgene: Consultancy, Honoraria; Incyte: Consultancy; Cell Vault: Research Funding; Kite Pharma: Consultancy, Honoraria; Miltenyi Biotec: Honoraria, Research Funding; Verastim: Consultancy; Lily: Consultancy, Honoraria. Lamanna:Oncternal, Verastem, TG Therapeutics: Other: Institutional research grants, Research Funding; MingSight: Other: Institutional research grants, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Columbia University Medical Center: Current Employment; Bei-Gene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Loxo: Research Funding; Octapharma: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno: Other: Institutional research grants, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lech-Marańda:Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, AbbVie, Sanofi: Consultancy; Roche, Amgen, Gilead: Speakers Bureau. Eyre:Gilead: Consultancy, Honoraria, Other: travel support; Janssen: Consultancy, Honoraria, Other: travel support; KITE, AZ, Loxo Oncology at Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support. Woyach:Janssen, Pharmacyclics, AstraZeneca, Abbvie, Arqule: Consultancy; Pharmacyclics, Janssen, Morphosys, Karyopharm, Verastem, Abbvie, Lox: Research Funding; Pharmacyclics LLC, an AbbVie Company, AbbVie, Janssen, AstraZeneca, ArQule: Honoraria. Cheah:Celgene, F. Hoffmann-La Roche, Abbvie, MSD: Research Funding; Celgene, F. Hoffmann-La Roche, MSD, Janssen, Gilead, Ascentage Pharma, Acerta, Loxo Oncology, TG therapeutics: Honoraria. Roeker:AbbVie: Other: spouse with minority ownership interest ; Abbott Laboratories: Other: spouse with minority ownership interest ; American Society of Hematology: Research Funding. Fakhri:University of California San Francisco: Current Employment. Tam:Janssen: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria; AbbVie: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding. Gerson:Genentech: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy; Loxo: Research Funding. Alencar:Genentech, Celgene, KITE, Loxo Oncology at Lilly: Consultancy. Abdel-Wahab:Merck: Consultancy; Janssen: Consultancy; Envisagenics Inc.: Current equity holder in private company; H3 Biomedicine Inc.: Consultancy, Research Funding. Ghia:MEI: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; Celgene/Juno: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; BeiGene: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Research Funding; ArQule: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Adaptive, Dynamo: Consultancy, Honoraria. Schuster:Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria. Chen:Loxo Oncology at Lilly: Current Employment. Nair:Loxo Oncology at Lilly: Current Employment. Tsai:Loxo Oncology at Lilly: Current Employment. Ku:Loxo Oncology at Lilly: Current Employment. Brown:Abbvie, Acerta, AstraZeneca, Beigene, Invectys, Juno/Celgene, Kite, Morphosys, Novartis, Octapharma, Pharmacyclics, Sunesis, TG Therapeutics, Verastem: Consultancy; Janssen, Teva: Speakers Bureau; Gilead, Loxo, Sun, Verastem: Research Funding. Jurczak:Bayer: Research Funding; Janssen: Research Funding; MeiPharma: Research Funding; Pharmacyclics: Research Funding; Roche: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment; Jagiellonian Univers

CLL-039: Pirtobrutinib (LOXO-305), a Next-Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated CLL/SLL: Results from the Phase 1/2 BRUIN Study

Despite the marked efficacy of covalent BTK inhibitors (BTKi) in CLL/SLL, the development of resistance and discontinuation for adverse events can lead to treatment failure. Low oral bioavailability or short half-life of these agents can lead to suboptimal BTK target coverage and ultimately result in acquired resistance in some patients (pts). Pirtobrutinib (LOXO-305) is a highly selective, non-covalent BTKi that inhibits both WT and C481-mutated BTK with equal, low nM potency. To evaluate pirtobrutinib safety and efficacy in pts with CLL/SLL. BRUIN is an ongoing multi-center phase 1/2 trial (NCT03740529). Enrollment was initiated 21 March 2019. Global: community hospitals, and academic medical centers. As of 27 September 2020, 323 previously treated pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, and 66 other B-cell lymphomas) were enrolled. Oral pirtobrutinib (7 dose escalation levels: 25–300mg once daily) in 28-day cycles. Determining the maximum tolerated dose/recommended phase 2 dose (RP2D), safety profile, and efficacy based on response assessment using disease-specific criteria (iwCLL2018 for CLL/SLL) per protocol. Pirtobrutinib demonstrated high oral exposures, with doses ≥100mg QD exceeding BTK IC90 for the entirety of the dosing interval. No DLTs occurred. The only treatment-emergent adverse events, regardless of attribution or grade seen in ≥10% of pts (n=323), were fatigue (20%), diarrhea (17%), and contusion (13%). An RP2D of 200 mg QD was selected for future studies. The ORR (per iwCLL 2018) was 63%, with 69 PRs, 19 PR-Ls, 45 SDs, 1 PD, and 5 discontinued prior to first response assessment. Responses deepened over time among pts with ≥10 months of follow-up (n=29; 86% ORR). ORR was not influenced by the reason for prior BTKi discontinuation (i.e., progression vs intolerance) or other classes of prior therapy received (including a covalent BTK and a BCL2 inhibitor). The longest followed responding pt continues on treatment for 17.8+ months. Pirtobrutinib showed promising efficacy in pre-treated CLL/SLL pts, was well-tolerated, and exhibited a wide therapeutic index