Covalent Bruton Tyrosine Kinase Inhibitor Research Articles

Novel Mechanisms of Acalabrutinib Resistance in Patients with Chronic Lymphocytic Leukemia By Whole Genome Methylome Sequencing

Novel Mechanisms of Acalabrutinib Resistance in Patients with Chronic Lymphocytic Leukemia By Whole Genome Methylome Sequencing

Three-Year Follow-up of the Ascend Trial: Acalabrutinib Vs Rituximab Plus Idelalisib or Bendamustine in Relapsed/Refractory Chronic Lymphocytic Leukemia

Three-Year Follow-up of the Ascend Trial: Acalabrutinib Vs Rituximab Plus Idelalisib or Bendamustine in Relapsed/Refractory Chronic Lymphocytic Leukemia

Preliminary Efficacy and Safety of MK-1026, a Non-Covalent Inhibitor of Wild-Type and C481S Mutated Bruton Tyrosine Kinase, in B-Cell Malignancies: A Phase 2 Dose Expansion Study

Preliminary Efficacy and Safety of MK-1026, a Non-Covalent Inhibitor of Wild-Type and C481S Mutated Bruton Tyrosine Kinase, in B-Cell Malignancies: A Phase 2 Dose Expansion Study

Discovery of 1-Amino-1H-imidazole-5-carboxamide Derivatives as Highly Selective, Covalent Bruton's Tyrosine Kinase (BTK) Inhibitors.

Bruton's tyrosine kinase (BTK) inhibitors suppressing the aberrant activation of BTK have led to a paradigm shift in the therapy of B-cell malignancies. However, there is an urgent need to discover more selective covalent BTK inhibitors owing to the off-target adverse effects of the approved inhibitor, ibrutinib. Herein, we disclose the discovery and preliminary activity studies of novel BTK inhibitors carrying 1-amino-1H-imidazole-5-carboxamide as a hinge binder. The most potent BTK inhibitor 26 demonstrates impressive selectivity, favorable pharmacokinetic properties, and robust antitumor efficacy in vivo, which indicates its potential as a novel therapeutic option for B-cell lymphomas. Importantly, to the best of our knowledge, this is the first example of a 1-amino-1H-imidazole-5-carboxamide scaffold used as the hinge binder of kinase inhibitors, which will largely expand the chemical diversity of kinase inhibitors.

Evaluation of vecabrutinib as a model for noncovalent BTK/ITK inhibition for treatment of chronic lymphocytic leukemia

AbstractCovalent Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib, have proven to be highly beneficial in the treatment of chronic lymphocytic leukemia (CLL). Interestingly, the off-target inhibition of IL-2-inducible T-cell kinase (ITK) by ibrutinib may also play a role in modulating the tumor microenvironment, potentially enhancing the treatment benefit. However, resistance to covalently binding BTK inhibitors can develop as the result of a mutation in cysteine 481 of BTK (C481S), which prevents irreversible binding of the drugs. In the present study we performed preclinical characterization of vecabrutinib, a next-generation noncovalent BTK inhibitor that has ITK-inhibitory properties similar to those of ibrutinib. Unlike ibrutinib and other covalent BTK inhibitors, vecabrutinib showed retention of the inhibitory effect on C481S BTK mutants in vitro, similar to that of wild-type BTK. In the murine Eμ-TCL1 adoptive transfer model, vecabrutinib reduced tumor burden and significantly improved survival. Vecabrutinib treatment led to a decrease in CD8+ effector and memory T-cell populations, whereas the naive populations were increased. Of importance, vecabrutinib treatment significantly reduced the frequency of regulatory CD4+ T cells in vivo. Unlike ibrutinib, vecabrutinib treatment showed minimal adverse impact on the activation and proliferation of isolated T cells. Lastly, combination treatment with vecabrutinib and venetoclax augmented treatment efficacy, significantly improved survival, and led to favorable reprogramming of the microenvironment in the murine Eμ-TCL1 model. Thus, noncovalent BTK/ITK inhibitors, such as vecabrutinib, may be efficacious in C481S BTK mutant CLL while preserving the T-cell immunomodulatory function of ibrutinib.

Discovery of Covalent Bruton's Tyrosine Kinase Inhibitors with Decreased CYP2C8 Inhibitory Activity

Bruton's tyrosine kinase (BTK) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage. Evidence has shown that inhibition of BTK has clinical benefit for the treatment of a wide array of autoimmune and inflammatory diseases. Previously we reported the discovery of a novel nicotinamide selectivity pocket (SP) series of potent and selective covalent irreversible BTK inhibitors. The top molecule 1 of that series strongly inhibited CYP2C8 (IC50 =100 nM), which was attributed to the bridged linker group. However, our effort on the linker replacement turned out to be fruitless. With the study of the X-ray crystal structure of compound 1, we envisioned the opportunity of removal of this liability via transposition of the linker moiety in 1 from C6 to C5 position of the pyridine core. With this strategy, our optimization led to the discovery of a novel series, in which the top molecule 18 A displayed reduced CYP inhibitory activity and good potency. To further explore this new series, different warheads besides acrylamide, for example cyanamide, were also tested. However, this effort didn't lead to the discovery of molecules with better potency than 18 A. The loss of potency in those molecules could be related to the reduced reactivity of the warhead or reversible binding mode. Further profiling of 18 A disclosed that it had a strong hERG (human Ether-a-go-go Related Gene) inhibition, which could be related to the phenoxyphenyl group.

Discovery of AS-1763: A Potent, Selective, Noncovalent, and Orally Available Inhibitor of Bruton's Tyrosine Kinase.

Although Bruton's tyrosine kinase (BTK) has been recognized as a validated drug target for the treatment of B-cell malignances, the emergence of clinical resistance to the first-generation covalent BTK inhibitors is becoming a serious concern. As a part of our effort to develop noncovalent BTK inhibitors, a series of novel pyrrolopyrimidines was identified as noncovalent inhibitors of both the wild-type and C481S mutant BTKs. Subsequent lead optimization led to the identification of an orally available, potent, and selective BTK inhibitor 13f (AS-1763) as a next-generation noncovalent BTK inhibitor. With significant efficacies in vivo tumor xenograft models, AS-1763 has advanced to phase 1 clinical trials.

Discovery of novel BTK PROTACs for B-Cell lymphomas

Bruton's tyrosine kinase (BTK) is a key drug target for B-cell related malignancies. Irreversible covalent BTK inhibitors have been approved for the treatment of B-cell malignancies, yet BTK C481S mutation at the covalent binding site has caused drug-resistance of BTK covalent binding inhibitors. The proteolysis targeting chimera (PROTAC) technology increases the sensitivity to drug-resistant targets compared to classic inhibitors, which provides a new strategy for mutant BTK related B-cell malignancies. ARQ531, a reversible non-covalent BTK inhibitor that inhibits wild type (WT) and mutated BTK with high selectivity, could be an ideal warhead for PROTACs targeting the mutant BTK. Herein, we designed a novel series of PROTACs using the selective non-covalent BTK inhibitor ARQ531 as warhead, with the goal of improving the degradation of both wild-type and C481S mutant BTKs, and increasing the selectivity of BTK over other kinases. This effort will provide some basis for further preclinical study of BTK PROTACs as a novel strategy for treatment of B-cell lymphomas.

How to Sequence Therapies in Waldenström Macroglobulinemia.

There are multiple treatment options in patients with Waldenström macroglobulinemia, including chemotherapy, monoclonal antibodies, proteasome inhibitors, and covalent Bruton tyrosine kinase (BTK) inhibitors. The choice of therapy should take into account the patient's clinical presentation, comorbidities, and preferences. A thorough discussion should take place to outline the administration, safety, and efficacy of the regimens under consideration. The patient's genomic profile can provide insightful information for the treatment selection. In the frontline and relapsed settings, we favor ibrutinib monotherapy over chemoimmunotherapy or proteasome inhibitor-based regimens in patients with MYD88 and without CXCR4 mutations. For patients with MYD88 and CXCR4 mutations or without MYD88 or CXCR4 mutations, chemoimmunotherapy or proteasome inhibitor-based regimens are favored, but efficacy data with ibrutinib in combination with rituximab and with novel covalent BTK inhibitors are emerging. Autologous stem cell transplant should be considered in special cases in the relapsed setting. Participation in clinical trials is positively encouraged in WM patients in frontline and relapsed settings. Agents of interest include the BCL2 antagonist venetoclax, the CXCR4 inhibitor mavorixafor, and the non-covalent BTK inhibitors pirtobrutinib and ARQ-531.

Structure-Function Relationships of Covalent and Non-Covalent BTK Inhibitors.

Low-molecular weight chemical compounds have a longstanding history as drugs. Target specificity and binding efficiency represent major obstacles for small molecules to become clinically relevant. Protein kinases are attractive cellular targets; however, they are challenging because they present one of the largest protein families and share structural similarities. Bruton tyrosine kinase (BTK), a cytoplasmic protein tyrosine kinase, has received much attention as a promising target for the treatment of B-cell malignancies and more recently autoimmune and inflammatory diseases. Here we describe the structural properties and binding modes of small-molecule BTK inhibitors, including irreversible and reversible inhibitors. Covalently binding compounds, such as ibrutinib, acalabrutinib and zanubrutinib, are discussed along with non-covalent inhibitors fenebrutinib and RN486. The focus of this review is on structure-function relationships.

Abstract 1267: Combination therapy of JNJ-67856633, a novel, first-in-class MALT1 protease inhibitor, and JNJ-64264681, a novel BTK inhibitor, for the treatment of B-cell lymphomas

Abstract Background: Constitutive activation of the classical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) pathway is a clear driver of B-cell non-Hodgkin lymphomas (NHL). Bruton's Tyrosine Kinase (BTK) and Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), which lies downstream of BTK, are key mediators of the classical NF-κB signaling pathway activated by BCR and TCR receptors. JNJ-67856633 is a first-in-class MALT1 protease inhibitor. JNJ-64264681 is a BTK inhibitor with improved selectivity against BTK. Blocking the BCR pathway at multiple points using these two orally bioavailable compounds could enhance clinical activity in B-cell lymphoma patients. Methods: JNJ-67856633 and JNJ-64264681 are currently being evaluated in phase 1 clinical trials designed to establish safety, PK, PD and the Recommended Phase 2 Dose (RP2D) of each agent. Results: JNJ-67856633 is a potent, selective, orally bioavailable, allosteric inhibitor of MALT1 protease activity. The compound inhibits proliferation of activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) cell lines bearing CD79b or CARD11 mutations as well as models mimicking resistance to covalent BTK inhibitors. JNJ-67856633 exhibits potent tumor growth inhibition in two human DLBCL xenograft models, OCI-Ly3 and OCI-Ly10, and mutation selected patient derived DLBCL xenografts. Furthermore, treatment with JNJ-67856633 leads to dose dependent inhibition of the generation of Tregs (CD4+CD25+FoxP3+) following CD3/28 stimulation in vitro, suggesting a potential immune modulatory role of MALT1 inhibition. JNJ-64264681 is an orally active small molecule that is a potent, selective, and irreversible covalent BTK inhibitor. JNJ-64264681 inhibits the growth of CD79b-mutant DLBCL cell lines in vitro and potently inhibits tumor growth in xenograft- or patient-derived DLBCL models in vivo. Treatment with JNJ-64264681 and JNJ-67856633 administered together demonstrated statistically significant tumor growth inhibition compared with vehicle control in two CD79b mutant mouse lymphoma models, one based on a DLBCL cell line (OCI-Ly10) and one based on a patient-derived DLBCL model (LY2298). In both models, the combination showed increased growth inhibition compared with single agents and tumor regression in the combination arm. Synergistic anti-proliferative activity was observed in three DLBCL cell lines carrying CD79b mutations and one MCL cell line. Conclusions: Taken together, the in vitro and in vivo data for JNJ-67856633 and JNJ-64264681 suggest that combination therapy can increase the anti-tumor effect of the monotherapies and provide a more sustained response, offering strong support for clinical investigation of the combination of these two novel agents. A phase 1b combination study is scheduled to initiate. Citation Format: Ulrike Philippar, Lorena Fontan, Ivo Cornelissen, Haopeng Rui, Sriram Balasubramanian, Marcello Gaudiano, Mariette Bekkers, Luc Van Nuffel, Tianbao Lu, Tianbao Lu, John Wiener, Mark Tichenor, Tony Greway, Kathryn Packman, Bie Verbist, Yusri Elsayed, Ricardo Attar, Jacqueline Bussolari, John Gerecitano. Combination therapy of JNJ-67856633, a novel, first-in-class MALT1 protease inhibitor, and JNJ-64264681, a novel BTK inhibitor, for the treatment of B-cell lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1267.

Preclinical Mechanisms of Topical PRN473, a Bruton Tyrosine Kinase Inhibitor, in Immune-Mediated Skin Disease Models.

The expression of Bruton tyrosine kinase (BTK) in B cells and innate immune cells provides essential downstream signaling for BCR, Fc receptors, and other innate immune cell pathways. The topical covalent BTK inhibitor PRN473 has shown durable, reversible BTK occupancy with rapid on-rate and slow off-rate binding kinetics and long residence time, resulting in prolonged, localized efficacy with low systemic exposure in vivo. Mechanisms of PRN473 include inhibition of IgE (FcεR)-mediated activation of mast cells and basophils, IgG (FcγR)-mediated activation of monocytes, and neutrophil migration. In vivo, oral PRN473 was efficacious and well tolerated in the treatment of canine pemphigus foliaceus. In this study, we evaluated in vitro selectivity and functionality, in vivo skin Ab inflammatory responses, and systemic pharmacology with topically administered PRN473. Significant dose-dependent inhibition of IgG-mediated passive Arthus reaction in rats was observed with topical PRN473 and was maintained when given 16 h prior to challenge, reinforcing extended activity with once-daily administration. Similarly, topical PRN473 resulted in significant dose-dependent inhibition of the mouse passive cutaneous anaphylaxis IgE-mediated reaction. Multiday treatment with topical PRN473 in rodents resulted in low-to-no systemic accumulation, suggesting that efficacy was mainly due to localized exposure. Reduced skin Ab inflammatory activity was also confirmed with oral PRN473. These preclinical studies provide a strong biologic basis for targeting innate immune cell responses locally in the skin, with rapid onset of action following once-daily topical PRN473 administration and minimal systemic exposure. Dose-dependent inhibition in these preclinical models of immune-mediated skin diseases support future clinical studies.

CG '806, a First-in-Class Non-Covalent Pan-FLT3/BTK Inhibitor, Exerts Superior Potency Against B-Cell Malignant Cells

CG'806 is a non-covalent pan-FMS like tyrosine kinase 3 (FLT3)/Bruton's tyrosine kinase (BTK) multi-kinase inhibitor that potently inhibits wild type (WT) and mutant forms of FLT3 and BTK. As described previously (2017 AACR Hematologic Malignancies abstract #25 and #44), CG'806 inhibits on FLT3-ITD-driven acute myeloid leukemia (AML) and other forms of AML. Because CG'806 targets the WT BTK (IC50 = 8 nM) and the C481S-BTK (IC50 = 2.5 nM), which is a mutant form resistant to ibrutinib and other covalent BTK inhibitors, this small molecule was profiled for its actions on various types of B-cell malignancies in which B cell receptor (BCR) and BTK signaling are reported to play pivotal pathogenic roles. Against 10 malignant B-cell lines, while CG'806 reduced the level of BTK-Y223 phosphorylation, it was less potent than ibrutinib. In contrast, CG'806 was 50-6,000 times more potent (lower IC50) in the ability to kill the malignant B cells across all tested cell lines evaluated by MTS-based assays of cell proliferation and inhibition of colony formation. Hence, the efficacy of killing malignant B cells by CG'806 and by ibrutinib did not correlate with the degree of BTK inhibition. Pathway analyses (KinomeScan and immunoblotting) demonstrated that CG'806, in addition to inhibiting intracellular BTK, potently inhibited the activity of aurora kinases A, B and C, phospho-H3S10, FLT3 and ERK that are differentially expressed and operative in various cell lines representing mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), B-acute lymphocytic leukemia (B-ALL) and Burkitt's lymphoma. Indeed, measuring BrdU incorporation and Annexin V by flow cytometry, CG'806 directly induced polyploidy and triggered apoptosis in malignant B cells at picomolar (pM) to low nanomolar (nM) concentrations, while ibrutinib potently inhibited BTK activity but was unable to induce apoptosis at lower than micromolar (µM) concentrations. These data distinguish CG'806 from ibrutinib and other covalent and non-covalent BTK inhibitors, and illustrate that CG'806 has activity across a wide range of malignant B cell lines including those intolerant, refractory or resistant (due to the presence of a BTK-C481S mutation) to ibrutinib and other BTK inhibitors. [Display omitted] DisclosuresZhang:Aptose Biosciences, Inc.: Employment. Local:Aptose Biosciences, Inc.: Employment. Benbatoul:Aptose Biosciences, Inc.: Employment. Folger:Aptose Biosciences, Inc.: Employment. Sheng:Aptose Biosciences, Inc.: Employment. Howell:Aptose Biosciences, Inc.: Membership on an entity's Board of Directors or advisory committees. Rice:Aptose Biosciences, Inc.: Employment, Equity Ownership, Patents & Royalties.

Pooled Analysis of Safety Data from Clinical Trials Evaluating Acalabrutinib Monotherapy in Hematologic Malignancies

Pooled Analysis of Safety Data from Clinical Trials Evaluating Acalabrutinib Monotherapy in Hematologic Malignancies

Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Updated Results from the Phase 1/2 ACE-CL-001 Study

Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Updated Results from the Phase 1/2 ACE-CL-001 Study

Efficacy and Safety of Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma in the Phase 2 ACE-LY-004 Study

Efficacy and Safety of Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma in the Phase 2 ACE-LY-004 Study

Acalabrutinib with Obinutuzumab in Relapsed/Refractory and Treatment-Naive Patients with Chronic Lymphocytic Leukemia: The Phase 1b/2 ACE-CL-003 Study

▪Background : Bruton tyrosine kinase (BTK) inhibitors have greatly improved the survival of patients with chronic lymphocytic leukemia (CLL). Combining BTK inhibitors with engineered CD20 antibodies, such as obinutuzumab, is hypothesized to increase rapidity and depth of response. Acalabrutinib (ACP-196) is a highly selective covalent inhibitor of BTK. The selectivity of acalabrutinib enables twice-daily dosing and potentially enhanced BTK occupancy over 24 hours. This Phase 1b/2 trial evaluated the activity and tolerability of acalabrutinib in combination with obinutuzumab in relapsed/refractory (R/R) and symptomatic, treatment-naive (TN) patients with CLL.Methods: Key eligibility criteria included diagnosis of CLL or small lymphocytic leukemia, measurable nodal disease, Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 and age ≥18 years. Patients were eligible for the R/R cohort if they had ≥1 prior treatment or the TN cohort if previously untreated and ≥65 years of age or <65 years of age and chemoimmunotherapy ineligible. All patients met IWCLL 2008 criteria for treatment. Previous treatment with ibrutinib or another BTK inhibitor was permitted if the patient discontinued for a reason other than on-treatment disease progression. Concomitant use of vitamin K antagonists was excluded. In 28-day cycles, acalabrutinib was administered orally at 100 mg BID or 200 mg QD (n=15, all later switched to 100 mg BID) until progressive disease (PD); obinutuzumab was administered intravenously on days 1 (100 mg), 2 (900 mg), 8 and 15 (1000 mg) of cycle 2 and day 1 (1000 mg) of cycles 3 to 7. The primary endpoints were overall response rate (ORR), defined as partial response + complete response (CR), and safety. Secondary endpoints included duration of response (DOR), time to response (TTR), progression-free survival (PFS) and pharmacodynamics.Results: As of April 28, 2017, 19 TN and 26 R/R patients had been treated. The median age of all patients was 61 years (range, 42 to 76). Baseline characteristics in TN and R/R patients respectively included ECOG PS ≤1 (both 100%), bulky lymph nodes ≥5 cm (53% and 50%), del(17p) (4/18 [22%] and 5/26 [19%]), del11q (5/18 [28%] and 9/26 [35%]) and unmutated IGHV (9/17 [53%] and 17/26 [65%]). Higher median BTK occupancy at trough was observed with 100 mg BID vs 200 mg QD dosing on cycle 1 day 2 (96% vs 87%; p<0.0001) and on cycle 2 day 1 (97% vs 91%; p=0.001). Median follow-up was 17.8 months (range, 1.0 to 23.4) in TN patients and 21.2 months (range, 15.8 to 27.5) in R/R patients. ORR was 95% and 92% in TN and R/R patients, respectively (Table). CR was achieved in 3 (16%) TN patients and 2 (8%) R/R patients. In TN and R/R patients, median TTR was 2.8 months. Time to CR for the 3 TN patients was 5.6, 10.2, and 10.2 months, and for the 2 R/R patients was 10.2 and 15.7 months, respectively. Median DOR was not reached in TN or R/R patients; the 18-month DOR rate was 86% and 94% in TN and R/R patients, respectively. Median PFS (Figure) was not reached in either cohort. Most patients remain on treatment at the time of cut off (89% and 92% of TN and R/R patients, respectively). Study treatment was discontinued in 2/19 TN patients (11%; 1 metastatic squamous cell carcinoma which pre-existed trial therapy, and 1 Richter transformation [RT] at 15.8 months in a patient with del(17p)) and in 2/26 R/R patients (8%; both due to RT at 18.4 and 24.0 months, respectively). In all patients, the most common AEs (≥40%) of any grade were upper respiratory tract infection (69%), diarrhea (65%), nausea (62%), maculopapular rash (58%), increased weight (54%), cough, headache, and infusion-related reaction (50% each), contusion, vomiting, and constipation (42% each). Grade 3/4 AEs (≥5% of all patients) included decreased neutrophil count (24%), decreased platelet count (9%), increased weight and syncope (7% each). There were no cases of major hemorrhage, defined as Grade ≥3, serious AEs and/or any grade or seriousness of central nervous system hemorrhage, or Grade ≥3 contusion or petechiae. One patient (2%) experienced atrial fibrillation (Grade 3) which did not lead to treatment discontinuation.Conclusions: Treatment with acalabrutinib plus obinutuzumab was well-tolerated and yielded high response rates that deepened over time in both R/R and TN patients. Most patients (41/45 [91%]) remain on treatment with a median follow-up of 21 months. [Display omitted] DisclosuresWoyach:Morphosys Inc: Research Funding; Karyopharm Inc: Research Funding; Janssen: Honoraria. Jones:Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Acerta: Honoraria, Research Funding; Genentech: Research Funding; Merck: Research Funding. Covey:Astra-Zeneca: Equity Ownership; Acerta: Employment, Equity Ownership. Hamdy:Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acalabrutinib related patents. Izumi:Acerta Pharma: Employment, Equity Ownership. Patel:Acerta Pharma: Employment. Wang:Acerta Pharma: Employment, Equity Ownership; Astra Zeneca: Equity Ownership. Byrd:Acerta Pharma: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Janssen: Research Funding.

Molecular Pathways Associated with Ibrutinib Resistance in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is an aggressive and incurable subtype of B-cell lymphoma and constitutive activation of the B-cell receptor pathway is a hallmark of B-cell lymphomas. Bruton's tyrosine kinase (BTK) is a critical component of the B-cell receptor pathway, and ibrutinib, a first-in-class, once-daily, and oral covalent inhibitor of BTK, was developed to reduce/silence B-cell receptor pathway activity, leading to clinically remarkable anti-tumor activity. In our prior multiple-center phase II clinical trial, the overall response rate in relapsed/refractory MCL patients was 68%, with a median progression free survival (PFS) of 13.9 months, surpassing the effectiveness of other therapies. The follow-up data demonstrate the durability of responses and confirm the unprecedented single-agent activity of ibrutinib in relapsed/refractory MCL. Although ibrutinib is extremely efficacious in patients with relapsed/refractory MCL, ibrutinib-treated patients who experience disease progression die within 12 months.We used RNASeq to compare gene expression profiles between ibrutinib-sensitive and -resistant patient samples, and a molecular signature strongly associated with ibrutinib-resistant clinical responses was generated. As a new prognostic predictor for ibrutinib treatment, this molecular signature in combination with the MCL International Prognostic Index (MIPI) stratified the therapeutic outcome of MCL patients. In addition, gene set enrichment analysis (GSEA) revealed the marked upregulation of components of the c-Myc and mTOR signaling pathways in the ibrutinib-resistant patient samples, indicating that the activation of the pathways may mediate ibrutinib resistance. Furthermore, the gene expression of numerous members of metabolic pathways was significantly upregulated, including the OXPHOS pathway, the citric acid cycle, and pyruvate metabolism, suggesting that metabolic reprogramming may play a major role in ibrutinib resistance. To determine the effects of targeting these pathways, the PI3K/AKT/mTOR or OXPHOS signaling pathways were inhibited in both MCL cell lines and ibrutinib-resistant MCL patient-derived xenograft (PDX) models, greatly reducing MCL cell viability and tumor burden, respectively. Furthermore, synergistic combinations using agents targeting these two pathways are currently being investigated in both in vitro and in vivo models.In conclusion, we identified a molecular signature associated with ibrutinib resistance that may eventually be used as a prognostic indicator of ibrutinib response. In addition, these studies indicate that metabolic reprogramming mediated by the mTOR pathway may underlie ibrutinib resistance in MCL. DisclosuresWang:Celgene: Honoraria, Research Funding; Acerta Pharma: Consultancy, Research Funding; Juno Therapeutics: Research Funding; BeiGene: Research Funding; Dava Oncology: Honoraria; Pharmacyclics: Research Funding; Onyx: Research Funding; Kite Pharma: Research Funding; Asana Biosciences: Research Funding; Proteolix: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Updated results of the selective Bruton tyrosine kinase (BTK) inhibitor TG-1701, as monotherapy and in combination with ublituximab and umbralisib (U2) in patients (pts) with B-cell malignancies.

7525 Background: TG-1701 is a selective, covalent BTK inhibitor administered once daily (QD). Both the “U2” combination (anti-CD20 mAb ublituximab + the PI3Kδ-CK1ε inhibitor umbralisib) and BTK inhibition are highly active in treatment-naïve (TN) and relapsed/refractory (R/R) CLL, each having previously demonstrated superiority over standard chemoimmunotherapy. Here we report the results of the dose escalation of TG-1701 monotherapy and TG-1701+U2. Methods: Pts with R/R CLL and lymphoma were enrolled in a Ph 1 study initially evaluating dose escalation (DE) of oral TG-1701 QD continuously administered in 28-day cycles (100, 200, 300, and 400 mg). After characterizing the safety profile of TG-1701 monotherapy, we implemented a parallel DE arm of TG-1701+U2. Select dose levels of TG-1701 monotherapy were expanded in CLL, MCL and Waldenström's (WM). All pts were treated until disease progression. The primary objectives are to characterize the safety profile and define the recommended Ph 2 doses for the drugs alone and in combination. Results: As of 03 February 2021, 123 pts were treated with TG-1701: 25 in the monotherapy DE arm, 61 in the 200 mg disease-specific cohorts (20 CLL [5 TN], 21 MCL [4 TN], 20 WM [8 TN]), 20 in the 300 mg CLL cohort (4 TN), and 17 in the 1701+U2 DE arm. The median # of prior therapies was 1 (range, 1 - 10). All pts were BTKi-naïve. All 123 pts were evaluable for safety. TG-1701 was well tolerated and the maximum tolerated dose (MTD) for monotherapy was not reached at 400 mg (demonstrating near 100% saturation of the BTK at all dose levels studied). Treatment emergent adverse events (TEAE) of clinical interest included atrial fibrillation (AF 4.0% of pts, G ≥3 in 1 case), G ≥3 hypertension (2.4%), and bleeding events (18.7%, all G1-2). No cases of ventricular tachyarrhythmia were reported. TEAEs leading to TG-1701 dose reduction occurred in 6.5% of pts. TEAEs leading to treatment discontinuation occurred in 1.6% of pts (AF, COVID-19). At the data cut-off, 119 pts were evaluable for response, including 40 in DE (Table). The median duration of response has not been reached among responders overall. The median follow-up (mFU range) was 15.9 mos (1.3 - 28.6+) in DE and 8.5 mos (1.4 -15.6+) in disease-specific cohorts. Conclusions: TG-1701 exhibits an encouraging safety and efficacy profile. The combination of 1701+U2 has been well tolerated and dose escalation continues. The combination shows enhanced depth of response over TG-1701 monotherapy. Recruitment to this study continues. Response per investigator review by treatment group. Clinical trial information: NCT03671590. [Table: see text]

Acalabrutinib: A Selective Bruton Tyrosine Kinase Inhibitor for the Treatment of B-Cell Malignancies.

Bruton tyrosine kinase (BTK) is a validated target for treatment of B-cell malignancies, and oral inhibitors of BTK have emerged as a standard of care for these diseases. Acalabrutinib is a second generation, highly selective, potent, covalent BTK inhibitor that exhibits minimal off-target activity in in vitro assays, providing the potential to improve tolerability over the first-in-class BTK inhibitor, ibrutinib. Acalabrutinib was approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) in the US in 2017 and 2019, respectively. Acalabrutinib is also undergoing trials for other B-cell malignancies, both as monotherapy and in combinations. In this review, we discuss results from clinical trials evaluating the efficacy and safety of acalabrutinib in patients with CLL, MCL, and Waldenstrom’s macroglobulinemia. Recent phase 3 data showed that acalabrutinib improved progression-free survival (PFS) compared with rituximab plus idelalisib or rituximab plus bendamustine in patients with relapsed/refractory CLL, and acalabrutinib with or without obinutuzumab improved PFS compared with chlorambucil plus obinutuzumab in patients with treatment-naïve CLL. Overall, acalabrutinib had a tolerable safety profile, with most adverse events being grade 1/2 severity (most commonly headache and diarrhea) and a low rate of discontinuation due to adverse events.