Abstract: 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 & gt;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 & gt;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's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno: 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; Loxo: Research Funding; Oncternal, Verastem, TG Therapeutics: Other: Institutional research grants, Research Funding. Cohen:Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy. Ghia:Gilead: Consultancy, Honoraria, Research Funding; ArQule: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene/Juno: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; MEI: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Adaptive, Dynamo: Consultancy, Honoraria; Novartis: Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Eyre:KITE, AZ, Loxo Oncology at Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: travel support; AbbVie: Consultancy, Honoraria, Other: travel support; Gilead: Consultancy, Honoraria, Other: travel support. Yin: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. Mato:Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Cheah:Celgene, F. Hoffmann-La Roche, MSD, Janssen, Gilead, Ascentage Pharma, Acerta, Loxo Oncology, TG therapeutics: Honoraria; Celgene, F. Hoffmann-La Roche, Abbvie, MSD: Research Funding.

Abstract: Time to progression of disease (POD) after first-line (1L) therapy is prognostic in mantle cell lymphoma (MCL), although studies have included a broad range of 1L, second-line (2L), and subsequent lines of therapy. The purpose of this study was to evaluate the factors predicting outcomes in patients with relapsed/refractory (R/R) MCL exclusively initiating 2L Bruton’s tyrosine kinase inhibitors (BTKis) after 1L rituximab-containing therapy. Patients were accrued from 8 international centers (7 main, 1 validation cohort). Multivariable models evaluating the association between time to POD and clinical/pathologic factors were constructed and converted into nomograms and prognostic indexes predicting outcomes in this population. A total of 360 patients were included, including 160 in the main cohort and 200 in the validation cohort. Time to POD, Ki67 ≥ 30%, and MCL International Prognostic Index (MIPI) were associated with progression-free survival (PFS2) and overall survival (OS2) from the start of 2L BTKis. C-indexes were consistently ≥0.68 in both cohorts. Web/application-based calculators based on nomograms and prognostic indexes to estimate PFS2 and OS2 were constructed. The 2L BTKi MIPI identifies 3 groups with distinct 2-year PFS2, including high risk (14%), intermediate risk (50%), and low risk (64%). Time to POD, Ki67, and MIPI are associated with survival outcomes in patients with R/R MCL receiving 2L BTKis. Simple clinical models incorporating these variables may assist in planning for alternative therapies such as chimeric antigen receptor T-cell therapy, allogeneic stem cell transplantation, or novel agents with alternative mechanisms of action.

Abstract: To expedite the translation of biologic discoveries into novel therapeutics, there is a pressing need for panels of in vivo models that capture the molecular complexity of human disease. While traditional cell lines and genetically engineered mouse models are useful tools, they are insufficient to assess the broad diversity of human tumors within a context that recapitulates in situ biology. Patient-derived xenografts (PDXs), generated by transplanting primary human tumor cells into immune-deficient NOD.Cg-Prkdcscid/Il2rgtm1Wjl/SzJ (NSG) mice, surmount some of the limitations of these traditional platforms and have been increasingly utilized as tools for preclinical investigation. However, the infrastructure required to generate, bank, and characterize PDX models limits their availability to only a few investigators. To address this issue, we established a repository of PDX models of leukemia and lymphoma, which we have named the Public Repository of Xenografts (PRoXe). At the time of this writing, PRoXe contains 213 independent lines that have been passaged through mice once (P0), 123 of which have been repassaged in a second generation (P1) or further repassaged. The repository encompasses AML, B- and T-ALL, and B- and T-cell non-Hodgkin lymphoma (NHL) across a range of cytogenetic- and molecularly-defined subtypes (Table 1). PRoXe is extensively annotated with patient-level information, including demographics, phase of treatment, prior therapies, tumor immunophenotye, cytogenetics, and molecular diagnostics. PDX lines available for distribution are characterized by immunophenotyping, whole transcriptome sequencing (RNAseq), and targeted exon sequencing of ~300 genes. To confirm fidelity of engrafted tumors to their corresponding clinical samples, lymphomas were morphologically assessed in P0 mice by H & E and, when pathologic adjudication was required, by immunohistochemistry. Xenografted leukemias were compared to their original tumors immunophenotypically. Unsupervised hierarchical clustering was performed on 132 of these lines based on transcriptome sequencing data and demonstrated 94% concordance between classification of the PDX lines by RNA expression and by the annotated clinical-pathologic diagnoses. Discordant cases highlighted unusual variants, such as B-ALL with aberrant expression of myeloid markers and a follicular lymphoma that underwent blastic transformation in the mouse. Multiple lines have been luciferized and confirmed to home to bone marrow, spleen, and liver. Existing lines from PRoXe have already been shared with more than ten academic laboratories and multiple industrial partners. All of the data referenced here are freely available through a customized web-based search application at http://proxe.org, and lines can be requested for in vitro or in vivo experiments. We are actively expanding the size of PRoXe to allow for large pre-clinical studies that are powered to detect differences across genetically defined subsets. Thus, we are happy to host additional lines from outside investigators on PRoXe and thereby expand the availability of these valuable reagents. Finally, we have made the source code for PRoXe (in R Shiny) open-access, so that other investigators can establish their own portals. Table 1. WHO diagnostic entities encompassed within PRoXe at P1 or later, or P0 or later for B-ALLs. WHO Classification - number of lines per diagnostic entity AML, Other Myeloid, and Ambiguous Lineage [n=32] ALL [n=107] AML - recurrent gene mutations 6 B-ALL - NOS 44 AML - MDS-related changes 5 B-ALL - MLL-rearranged 11 AML - NOS 4 B-ALL - BCR-ABL 10 AML - MLLT3-MLL 2 B-ALL - hyperdiploidy 9 Acute myelomonocytic leukemia 1 B-ALL - TEL-AML1 8 Acute monocytic leukemia 1 B-ALL - E2A-PBX1 3 AML unable to classify 2 B-ALL unable to classify 1 Blastic plasmacytoid dendritic cell neoplasm 8 T-ALL 21 Mixed phenotype, MLL rearranged 1 B/myeloid acute leukemia 1 Myelodysplastic syndrome 1 Mature B cell neoplasms[n=11] Mature T and NK cell neoplasms [n=4] DBLCL - NOS 4 Angioimmunoblastic T-cell lymphoma 1 Mantle cell lymphoma 3 Adult T-cell leukemia/lymphoma 1 Extranodal marginal zone lymphoma 1 Extranodal NK/T-cell lymphoma 1 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL 3 SŽzary syndrome 1 Disclosures Konopleva: Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Etchin:Karyopharm: Research Funding. Lane:Stemline Therapeutics, Inc.: Research Funding. Stone:Abbvie: Consultancy; Novartis: Research Funding; Celator: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Agios: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Merck: Consultancy; Karyopharm: Consultancy; Roche/Genetech: Consultancy; Pfizer: Consultancy; AROG: Consultancy; Juno: Consultancy.