Small Tyrosine Kinase Inhibitors Research Articles

A multicenter real-world study on the efficacy and safety of anlotinib-based treatment for metastatic breast cancer.

e13120 Background: Anlotinib is a multi-targeted small molecule receptor tyrosine kinase (RTK) inhibitor that inhibits angiogenesis. There is only one phase II study on the use of anlotinib in advanced breast cancer (MBC). Therefore, this study aims to analyze its efficacy and safety in the treatment of BC in the real world. It has been approved for the treatment of advanced non-small cell lung cancer and soft tissue sarcoma. There is limited research on the use of anlotinib in advanced breast cancer (MBC). Methods: This study retrospectively analyzed the clinical data of MBC patients who received anlotinib treatment at four domestic centers from January 2021 to December 2023. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Kaplan-Meier analysis was used to analyze PFS and OS, and Cox regression model was used to analyze the hazard ratios (HRs) of anlotinib-based treatment on PFS and OS in different subgroups of patients. A p-value <0.05 was considered statistically significant. Results: A total of 153 MBC patients receiving anlotinib-based treatment were included from four centers. The median age was 51 years (range: 22-76), and the median number of prior lines of therapy was 3. The median PFS was 7.7 months (range: 5.2-10.1 months), and the median OS was 28.0 months (range: 21.4-34.9 months). The median ORR and DCR were 19.6% and 60.1%, respectively. The ORR for HR+/HER2- and triple-negative breast cancer patients was 11.6% and 28.8%, respectively, DCR for HR+/HER2- and triple-negative breast cancer (TNBC) patients was 55.8% and 59.6%, respectively. The median PFS was 9.0 months (range: 6.0-11.9 months) for HR+/HER2- patients and 5.3 months (range: 3.5-7.0 months) for TNBC patients, while the median OS was 33.0 months (range: 24.4-41.5 months) and 14.0 months (range: 9.5-18.4 months), respectively. In the subgroup analysis, age <60 years, initial stage IV disease, Ki67≤60%, and treatment with PD-L1 monoclonal antibodies-based regimen were associated with PFS benefit. ECOG <2 and treatment with PD-L1 monoclonal antibodies-based regimen were associated with prolonged OS. Among the 31 patients with brain metastases receiving anlotinib treatment, 11 had active brain metastases and 20 had stable brain metastases. The median PFS was 8.0 months. The intracranial ORR was 12.9%, and the intracranial DCR was 61.3%. No serious adverse events or treatment-related deaths occurred. Grade I/II adverse reactions included hand-foot syndrome (22.2%) and fatigue (19.6%), while grade III/IV adverse reactions included fatigue (6.5%) and decreased neutrophil count (5.2%). Three patients required dose reduction due to intolerable adverse reactions, and nine patients discontinued treatment. Conclusions: Anlotinib demonstrates good antitumor activity and safety in the treatment of MBC. When combined with chemotherapy or immunotherapy, it can improve PFS and OS without significantly increasing toxicity. In particular, it shows promising intracranial ORR and PFS in patients with brain metastases. Clinical trial information: NCT04541420 .

Abstract 5953: DUSP6 is a novel target in neuroendocrine tumors

Abstract Background: Neuroendocrine tumors (NETs) are rare malignancies derived from enterochromaffin cells of the diffuse neuroendocrine system and most frequently observed in the gastrointestinal tract and bronchopulmonary system. Surgery is the major treatment for localized NETs. In high-grade NETs, treatment opportunities include chemotherapeutic drugs such as temozolomide (TEM), and capecitabine and small-molecule targeted therapies such as everolimus or sunitinib. Despite promising initial responses, most patients develop therapy resistance by unknown mechanisms. Therefore, there is a pressing need to apprehend the mechanisms of resistance to improve the therapeutic efficacy of the current treatments. Phosphatases are emerging and novel targets in human malignancies and their modulation yields significant anti-tumor activities. Dual specificity phosphatase 6 (DUSP6) is a MAPK phosphatase and mainly binds to and dephosphorylates extracellular signal-regulated kinase (ERK)1/2. DUSP6 expression is increased in several malignancies, correlating with distant metastases and a worse clinical outcome. Moreover, DUSP6 mediates resistance to certain chemotherapeutics and small molecular tyrosine kinase inhibitors and its blockade increases therapeutic sensitivity. The current study aimed to investigate the contribution of DUSP6 to therapy resistance in the NET models. Material and Methods: Using Western blot analysis, the expression of DUSP6 was measured in 8 clinical samples of small bowel neuroendocrine tumors, the NET cell lines BON-1, H69, IMR-32, QGP and H524 and two PDX models, 1452 (rectal neuroendocrine) and 913 (pancreatic neuroendocrine). The effects of DUSP6 depletion on cell viability were explored using a pharmacological inhibitor, BCI, and its siRNA-mediated knockdown. Moreover, BCI-mediated apoptotic cell death was measured by an annexin V/PI staining assay. Results: DUSP6 expression was positive in 5 out of 8 clinical samples, 4 NET cell lines and both the PDX models. BCI treatment induced an apoptotic response in the NET models and synergistically increased sensitivity to TMZ and cisplatin in 1452 cells., RNAi-mediated depletion of DUSP6 also increased sensitivity to sunitinib and triggered TMZ-induced apoptotic cell death in 1452 cells, which was associated with changes in (O6-Methylguanine-DNA-methyltransferase) MGMT expression. These findings suggest that DUSP6 is an important therapeutic target in neuroendocrine tumors and its blockade is a promising therapeutic approach to enhance the therapeutic index of current treatments. Citation Format: Majid Momeny, Vahid Khalaj, Solmaz AghaAmiri, Po Hien Ear, Servando Hernandez Vargas, Sukhen Ghosh, Ali Azhdarinia. DUSP6 is a novel target in neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5953.

Abstract B004: Clinico-genomic characteristics of breast cancer brain metastasis: A multi-institutional analysis from AACR Project GENIE BPC

Abstract Purpose: The presence of Her2 amplification is associated with an increased risk of developing brain metastases. Brain metastases in breast cancer can be particularly challenging and have significant implications for prognosis and treatment. Common Her2-targeted therapies and small tyrosine kinase inhibitors have demonstrated the ability to penetrate the blood brain barrier and be effective in treating brain metastases. We investigated the clinico-genomic characteristics and the prognosis of brain metastasis in patients with breast cancer. Experimental design: Patients with breast cancer whose tumors underwent targeted sequencing from 2013-2018 at age 56 years old or younger at three institutions from the American Association of Cancer Research Genomics Evidence Neoplasia Information Exchange Biopharma Collaborative (AACR Project GENIE BPC) registry were selected for data curation. The PRISSMM data model was used for real world outcomes including overall survival. We analyzed clinical and genomic characteristics, treatment, and clinical outcome data among patients with and without brain metastases, stratified by Her2 amplification and hormone-receptor status (Her2+ vs. Her2-/HR+ vs. triple-negative breast cancer (TNBC)). We explored the top 20 most frequently altered genes that were included on at least 20% of sequencing panels. Results: A total of 1019 patients with breast cancer along with their receptor subtype information were included in the study (110 patients were excluded due to either post- mortem sequencing or unknown receptor subtype). Among them, 336 (33%) patients were identified to have developed brain metastasis (n=87 with Her2+; n=181 with Her2-/HR+; and n=68 with TNBC). At time of advanced disease, the brain was the first and only distant site of disease in 41/336 (12%) and detected with extracranial sites of disease in 22/336 (7%) patients. For patients presenting with stage I-III breast cancer, the cumulative incidence of brain metastasis at 5 years from breast cancer diagnosis was higher in those with TNBC (35%; 95% CI: 25, 50) as compared to 24% (95% CI: 16, 37) and 21% (95% CI: 15, 29) for those with Her2+ and Her2-/HR+ subtypes, respectively. Median overall survival from brain metastasis was significantly longer (log-rank p<0.001) for those with Her2+ disease (19m, 95% CI: 13, 36) compared to those with Her2-/HR+ (8.9m, 95% CI: 6.3, 15) or TNBC (7.4m, 95% CI: 4.6, 11). Among patients who ever developed brain metastases, IKZF3 alterations occurred in 71% (20/28) of Her2+ patients but did not occur in either Her2- subtype. Additionally, frequencies of CDK12, MYC, and PTEN alterations differed across subtypes. Conclusions: Brain involvement at metastatic presentation conferred a higher risk of death than brain-sparing metastases. Triple negative and Her2+ histologies were associated with higher risk of brain involvement at metastasis presentation. Further exploration by treatment received across receptor subtypes and genomic alterations will be presented. Citation Format: Samantha Brown, Hannah E. Fuchs, Jessica A. Lavery, Katherine S. Panageas, Nelson S. Moss. Clinico-genomic characteristics of breast cancer brain metastasis: A multi-institutional analysis from AACR Project GENIE BPC [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B004.

Dendritic cell vaccination in combination with erlotinib in a patient with inoperable lung adenocarcinoma: a case report

BackgroundSatisfactory treatment for patients with unresectable advanced lung cancer has not yet been established. We report a case of unresectable advanced lung cancer (stage IIIb: T2aN3M0) treated with a total of 15 doses of dendritic cells pulsed with a Wilms’ tumor 1 and mucin 1 vaccine in combination with erlotinib, a small molecule epidermal growth factor receptor tyrosine kinase inhibitor, for more than 699 days without recurrence or metastasis.Case presentationA 63-year-old Korean woman was diagnosed with lung adenocarcinoma by pathology and computed tomography. The adenocarcinoma showed an epidermal growth factor receptor (EGFR) mutation, no anaplastic lymphoma kinase expression, and less than 1% expression of programmed death ligand 1. She received erlotinib alone for approximately 1 month. She then received erlotinib and the dendritic cells pulsed with Wilms’ tumor 1 and mucin 1 vaccine. The diameter of the erythema at the vaccinated sites was 30 mm at 48 hours after the first vaccination. Moreover, it was maintained at more than 20 mm during the periods of vaccination. These results suggested the induction of antitumor immunity by the vaccine. Remarkably, the tumor size decreased significantly to 12 mm, a 65.7% reduction, after combined therapy with eight doses of the dendritic cells pulsed with Wilms’ tumor 1 and mucin 1 vaccine and erlotinib for 237 days based on fluorodeoxyglucose uptake by positron emission tomography/computed tomography and computed tomography. Interestingly, after 321 days of combination therapy, the clinical findings improved, and no tumor was detected based on computed tomography. Validation of the tumor’s disappearance persisted for at least 587 days after treatment initiation, without any indication of recurrence or metastasis.ConclusionStandard anticancer therapy combined with the dendritic cells pulsed with Wilms’ tumor 1 and mucin 1 vaccine may have therapeutic effects for such patients with unresectable lung adenocarcinoma.

Tumor microenvironment responsive nano-platform for overcoming sorafenib resistance of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a malignant tumor, which seriously jeopardizes human health. The 5-year relative survival rate of HCC is only about 18%. Sorafenib, a small molecule multi-targeted tyrosine kinase inhibitor (MTKI), has been classified as the first-line treatment scheme for HCC and has significantly extended the median survival time for patients with advanced HCC. Nevertheless, the emergence of sorafenib resistance has substantially hampered its further clinical application. Herein, the nano-platform based on phototherapy and small molecular targeted therapy (SMTT) was devised to overcome the sorafenib resistance and reduce the adverse effects. Hollow mesoporous manganese dioxide (H–MnO2) was prepared by hard template method, and the prepared H–MnO2 was used to load sorafenib and Chlorin e6 (Ce6). Subsequently, the nanoparticle (NPs) were modified with dopamine to optimize biocompatibility. The final prepared NPs (MCS NPs) exhibit regular spherical shape with a hydrated particle size of approximately 97.02 nm. MCS NPs can not only possess tumor microenvironment (TME) stimuli-responsive drug release performance but also can enhance the efficacy of photodynamic therapy and reverse sorafenib resistance by alleviating tumor hypoxia. Under the action of phototherapy (Ce6) combined with molecular targeted therapy (sorafenib), MCS NPs manifest a satisfactory antitumor effect for sorafenib-sensitive or sorafenib-resistant HCC cells, and retain the antiangiogenic properties of sorafenib. In the nude mouse subcutaneous tumor model constructed with sorafenib-resistant cells, MCS NPs demonstrated superior tumor imaging ability and excellent biocompatibility. The tumor inhibition rate of the MCS NPs group without laser irradiation was 53.4 %, while the MCS NPs group with laser irradiation was as high as 100 %. The novel smart TME-responsive nano-platform shows great potential for overcoming sorafenib resistance and realizes multimodality imaging and therapy of HCC.

Orelabrutinib for the treatment of relapsed or refractory marginal zone lymphoma: A phase 2, multicenter, open-label study.

Marginal zone lymphoma (MZL) is an indolent type of non-Hodgkin lymphoma that develops through pathological B cell receptor signaling. Orelabrutinib, a new-generation oral small molecule Bruton's tyrosine kinase inhibitor, was evaluated in relapsed/refractory (r/r) MZL patients. Previously treated r/r MZL patients received orelabrutinib 150 mg once daily in a phase 2, multicenter, single-arm study conducted in China. The primary endpoint was overall response rate (ORR) assessed by an Independent Review Committee (IRC) based on the Lugano 2014 classification. Other efficacy, safety, and pharmacokinetic profiles were evaluated as secondary outcome measures. A total of 111 patients were enrolled, of which 90 patients had MZL confirmed by central pathology review, who were mainly with extra-nodal MZL of mucosa-associated lymphoid tissue (MALT, 46.7%) and nodal MZL (35.6%). The majority had late-stage disease, with stage IV accounting for 75.6%. After a median follow-up duration of 24.3 months, the IRC-assessed ORR was 58.9% (95% confidence interval [CI], 48.0-69.2), with rates of complete response and partial response being 11.1% and 47.8%, respectively. The IRC-assessed median duration of response was 34.3 months, and the IRC-assessed median progression-free survival (PFS) was not reached with a 12-month PFS rate of 82.8% (95% CI, 72.6-89.5). The rate of overall survival at 12 months was 91.0% (95% CI, 82.8-95.4). Common all-grade treatment-related adverse events (TRAEs) included anemia (27.9%), neutrophil count decrease (23.4%), white blood cell count decrease (18.0%), platelet count decrease (17.1%), blood present in urine (16.2%), rash (14.4%), and upper respiratory tract infection (10.8%). Thirty-four patients (30.6%) experienced grade 3 or higher TRAEs. Serious TRAEs occurred in 18 patients (16.2%), of which pneumonia (5.4%) was the most common. Seven patients (6.3%) discontinued orelabrutinib due to TRAEs. Orelabrutinib demonstrated high response rates with durable disease remission and was well tolerated in Chinese patients with r/r MZL.

The Maverick trial: A phase 2 study of abivertinib in patients (pts) with metastatic castration resistant prostate cancer (mCRPC).

TPS5106 Background: Abivertinib is a potent, small molecule third-generation tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), Bruton tyrosine kinase (BTK) receptor, and bone marrow tyrosine kinase gene on chromosome X (BMX). Abivertinib irreversibly binds to the BTK receptor, preventing the phosphorylation of the receptor, and also BMX. The adrenal-permissive HSD3B1(1245C) allele, which is present in upwards of 50% of men with prostate cancer, encodes a 3βHSD1 enzyme missense that up-regulates the rate-limiting step of androgen biosynthesis from extragonadal precursor steroids and promotes poor clinical outcomes. 3βHSD1 must be phosphorylated by BMX for androgen biosynthesis. Preclinical studies suggest BMX inhibition blocks 3βHSD1, androgen biosynthesis and CRPC in xenograft models. These provide the rationale for use of the combination of abivertinib and abiraterone to block residual androgen synthesis that escapes abiraterone inhibition. Methods: The Maverick Trial is a multicenter, open-label phase 2 study within the US Dept of Defense Prostate Cancer Clinical Trials Consortium (DOD PCCTC) of abivertinib with abiraterone in pts with mCRPC harboring the adrenal-permissive HSD3B1(1245C) allele (germline heterozygous or homozygous). HSD3B1 status will be confirmed centrally prior to enrollment via CLIA testing at the Cleveland Clinic. The study includes two cohorts: abiraterone-naïve and abiraterone-progressing. There will be cap of 50% of accrual in each cohort for pts heterozygous for the HSD3B1(1245C) allele. An interim futility analysis is embedded in each cohort, and toxicity rates will be continuously monitored for early stoppage according to predefined rules. Pts receive continuous treatment with abivertinib 200 mg BID with abiraterone 1000 mg QD + prednisone 5 mg BID until radiographic progression, unacceptable toxicity, intercurrent illness, or other reason, such as subject withdrawal. The primary endpoint is 6-month rPFS defined as percent of subjects alive and without progression by RECIST version 1.1 for measurable disease and PCWG3 criteria for bone metastases. Secondary and exploratory endpoints include objective response rate, duration of response, PSA progression, pharmacokinetics, pharmacodynamic tissue changes, and mechanisms of response and resistance to therapy via sequential tissue and blood sampling. The study is currently open at 1 site and will activate at 9 additional sites. It is sponsored by Sorrento Therapeutics, Inc, and managed by the Prostate Cancer Clinical Trials Consortium. Trial Registration: NCT05361915 Funding Source: Sorrento Therapeutics, Inc, the trial’s sponsor who is funding the trial. Clinical trial information: NCT05361915 .

Tyrosine kinase inhibitors in HER2-positive breast cancer brain metastases: A systematic review and meta-analysis.

Small tyrosine kinase inhibitors (TKIs) show activity against breast cancer brain metastases (BCBM) of the human epidermal growth factor receptor 2 (HER2)-positive subtype. This meta-analysis aimed to objectively explore the efficacy and safety of TKIs. Electronic databases were searched for relevant clinical trials. We conducted a pairwise meta-analysis, pooled analysis, and estimated summary survival curves to compare survival outcomes following TKIs therapy for BCBM patients using Stata version 16.0 or R x64 4.0.5. Thirteen clinical trials involving 987 HER2-positive BCBM patients were analyzed. A trend of longer progression-free survival (PFS) was observed in the TKI-containing arm compared to the non-TKI-containing arm (hazard ratio = 0.64, 95% confidence interval [CI]: 0.35-1.15, p = 0.132), although the difference is not statistically significant. Summary survival curves reported the summary median PFS and overall survival were 7.9 months and 12.3 months. Subgroup analysis revealed that TKIs combined with capecitabine (TKI + Cap) regimens resulted in improved survival outcomes. Tucatinib may be more effective in BCBM patients. The main grade 3-5 adverse events (AEs) were diarrhea (22%, 95% CI: 14%-32%), neutropenia (11%, 95% CI: 5%-18%), hepatic toxicity (7%, 95% CI: 1%-16%), and sensory neuropathy (6%, 95% CI: 2%-12%). TKIs therapy improved the survival outcomes of HER2-positive BCBM patients, especially when combined with capecitabine and tolerable AEs. We also identified the clinical value of tucatinib, which appears to be the most favorable TKI drug for BCBM patients.

Testing modalities for ALK-driven lung cancer: A narrative review

ABSTRACT Anaplastic lymphoma kinase (ALK) rearranged non-small-cell lung cancer (NSCLC) comprises a distinct molecular entity with a reported global prevalence of 5–7%. The development and rapid approvals of small molecule ALK tyrosine kinase inhibitors (TKIs) have led to the development of diagnostic strategies with robust methodology and superior attributes. Owing to myriad alterations which can be present in the ALK gene in NSCLC, it is important to understand the principal attributes as well as limitations of each to aid in optimal therapeutic decision making. To prepare this review, we used the keywords, “ALK detection,” “ALK NGS,” “ALK TKI,” and “EML4 (echinoderm microtubule-associated protein-like 4)-ALK,” to search within scientific databases like Scopus, PubMed, and Embase. We chose 55 articles that we identified from this search. Detection of ALK is an essential frontline diagnostic test as per all international and national recommendations. The various modalities available include immunohistochemistry, fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, and DNA/RNA-based next-generation sequencing. Each has its own advantages and limitations with respect to test metrics like sensitivity and specificity, as well as ease of use, availability, and cost. This is a detailed review of these various techniques and their attributes.

DCZ19931, a novel multi-targeting kinase inhibitor, inhibits ocular neovascularization

Neovascularization is a prominent cause of irreversible blindness in a variety of ocular diseases. Current therapies for pathological neovascularization are concentrated on the suppression of vascular endothelial growth factors (VEGF). Despite the remarkable efficacy of anti-VEGF drugs, several problems still exist, including ocular complications and drug resistance. Thus, it is still required to design novel drugs for anti-angiogenic treatment. This study aimed to investigate the anti-angiogenic effects of a small molecule multi-target tyrosine kinase inhibitor, DCZ19931, on ocular neovascularization. The results showed that administration of DCZ19931 at the tested concentrations did not cause obvious cytotoxicity and tissue toxicity. DCZ19931 could reduce the size of choroidal neovascularization (CNV) lesions in laser-induced CNV model and suppress ocular neovascularization in oxygen-induced retinopathy (OIR) model. DCZ19931 could suppress VEGF-induced proliferation, migration, and tube formation ability of endothelial cells, exhibiting similar anti-angiogenic effects as Ranibizumab. DCZ19931 could reduce the levels of intercellular cell adhesion molecule-1 (ICAM-1) expression in vivo and in vitro. Network pharmacology prediction and western blots revealed that DCZ19931 exerted its anti-angiogenic effects through the inactivation of ERK1/2-MAPK signaling and p38-MAPK signaling. In conclusion, this study indicates that DCZ19931 is a promising drug for anti-angiogenic therapy for ocular diseases.

The Multi-Kinases Inhibitor ARQ531 Enhanches Anti-MM Activity of Imids By Dual Deregulation of MAP- and Cyclin-Dependent Kinases Activities

Introduction: Kinases inhibitors are emerging as promising therapeutic tools for various blood tumors. We previously reported that a novel small tyrosine kinase inhibitor, ARQ531, constrains leukemia cells proliferation and survival by disrupting multiple tumor-addicted programs based on its kinase inhibition profile. As result we pursued its application in pre-clinical models of Multiple Myeloma (MM). Methods: Inhibitory effects of ARQ531 on cell viability were investigated in a panel of MM cell lines and primary tumor cells (collected from NDMM and RRMM patients) by CellTiterGlo luminescent assay over a range of drug concentrations and time. Specific transcriptomic profiling of ARQ531-treated MM cells was performed by RNA-Seq analysis. Molecular mechanism of this small molecule on MM cells was further investigated by qPCR and western blot analyses. The therapeutic efficacy of ARQ531 combination with different anti-MM drugs was also explored and CalcuSyn software was employed to confirm synergistic effects. Mice engrafted with MM cells were used to determine in-vivo anti-MM activity of ARQ531 in combination with lenalidomide. Results: ARQ531 inhibited cell viability of MM cell lines (n=20) with IC50 value of 3±1 µM. Furthermore, inhibitory effects of ARQ531 on cell viability were evaluated in a panel of primary MM cells with different mutational status (including those with RAS mutations), with an IC50s value ranging from 0.9 to 4 µM. Consistent with the effect on cell viability, ARQ531 increased the apoptotic rate of MM cells tested. Moreover, anti-MM effects of ARQ531were not reduced in presence of bone marrow stromal cells (BMSCs), and, more importantly such treatment showed a good therapeutic window. A transcriptome profiling analysis of ARQ 531-treated cells demonstrates wide oncogenic transcriptional programs dysregulation, as well as specific interference with kinases involved in cell cycle progression including MAP Kinases and CDK. Given that these kinases are targetable resistance mechanisms for immunomodulatory drugs (IMiDs) in MM, we combined ARQ531 with lenalidomide, pomalidomide or iberdomide observing synergistic effects. Different gene-editing approaches further supported ARQ531-identified profiling as crucial for observed anti-MM activity of tested drugs. We also confirmed that co-treatment in vivo leads to impaired engraftment and prolonged survival in a MM xenograft mouse model, by disrupting key cell proliferation pathways including c-MYC. Conclusions: Our data show that the small multi-kinases inhibitor ARQ531 has a promising therapeutic activity against MM in preclinical models thus supporting the feasibility of targeting oncogenic driven programs in MM cells with ARQ531 alone or in combinations with IMiDs.

Safety, Tolerability, and Pharmacokinetic Profile of Single and Multiple Ascending Doses of GB5121, a CNS-Penetrant BTK Inhibitor, in Healthy Subjects

Background: GB5121 is an oral, brain-penetrant, potent, highly selective, irreversible, small molecule Bruton's tyrosine kinase inhibitor (BTKi) in development for hematologic malignancies with CNS involvement. Preclinical studies demonstrated that GB5121 exhibited several characteristics differentiating it from other BTKis, including rapid equilibrium into the brain, increased brain target occupancy, and fast inactivation rate. These characteristics combined with GB5121's kinase selectivity and activity in in vitro and in vivo DLBCL models support its clinical investigation in BTK-driven CNS lymphomas. This first-in-human study was designed to evaluate the single- and multiple-dose safety, tolerability, pharmacokinetics (PK; including CNS penetrance) and pharmacodynamics (PD), the effect of food, drug interactions, and cardiac safety of GB5121 to inform dosing and concomitant medications in clinical studies. Methods: This is an ongoing Phase 1, double-blind, randomized, placebo-controlled, single ascending and multiple ascending dose (SAD, MAD) study in healthy subjects, with staggered dose escalations and adaptive dose selection. Safety is assessed throughout the study and PK and PD are characterized using serial blood samples collected up to 48 hours post-dose for GB5121 plasma concentrations, BTK target occupancy (TO), and target engagement (TE). Cerebrospinal fluid (CSF) samples are collected at 2 hours post-dose to characterize the relationship between GB5121 plasma concentrations and CNS penetrance. GB5121 PK parameters (e.g., AUClast, AUCinf, Cmax, Tmax, t1/2) are estimated by standard noncompartmental methods. Results: Preliminary PK results from 3 completed SAD cohorts are presented, including 23 subjects (7 receiving 5 mg, 8 receiving 15 mg, and 8 receiving 45 mg: randomized in a 3:1 ratio to receive GB5121 or placebo) in a fed state (moderate-fat meal). A review of blinded safety data thus far indicated that the study drug was generally well tolerated with no serious adverse events or early study discontinuations reported. PK parameters are presented in Table 1. GB5121 was rapidly absorbed following oral administration with mean plasma Tmax ranging from 1-2 hours and exhibited a terminal half-life of approximately 3 hours. Single-dose GB5121 exposure (AUCinf) increased in a greater than dose-proportional manner from 5 to 15 mg and near dose-proportional from 15 to 45 mg. Mean GB5121 CSF:unbound plasma concentration ratios approximated 1, indicating unimpeded access of unbound drug in plasma into the CNS. The observed GB5121 plasma exposure, CNS penetrance, and preliminary TO and TE PD data were consistent with that of a translational PK/PD model. Conclusions: Data from the first 3 SAD cohorts in healthy subjects indicated that low doses of GB5121 provided plasma exposure and CSF penetrance adequate to drive desired BTK inhibition in the CNS. Blinded safety data indicated that single-dose study drug administration was well tolerated across the dose range. PD analysis and additional evaluations are ongoing and final results will be presented. The safety and PK profiles of GB5121 support its continued evaluation in the ongoing Phase 1b/2 open-label, international study in adult subjects with relapsed/refractory primary/secondary CNS lymphoma, or primary vitreoretinal lymphoma (STAR CNS; NCT05242146). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Fostamatinib in Elderly Patients with Immune Thrombocytopenia: A Single-Center, Real-World Case Series

Background: Fostamatinib is an oral small molecule spleen tyrosine kinase (Syk) inhibitor that was approved for treatment of adult patients with immune thrombocytopenia (ITP) in second-line therapy [1]. Syk inhibition prevents cytoskeletal rearrangements during phagocytosis allowing platelet survival in ITP. The efficacy of fostamatinib in adults with chronic ITP has been established in phase 3 clinical trials [2], and further studies have established fostamatinib as an effective second-line treatment [3]. However, fostamatinib treatment in elderly patients with ITP has not been well established. These individuals pose a particular challenge with a higher risk of bleeding [4], having multiple comorbidities, and may be at increased risk of toxicity from treatments such as fostamatinib. Methods: We performed a retrospective review of all elderly patients (age greater than or equal to 65 years) who had started on fostamatinib between June 1, 2021 and May 31, 2022 for the treatment of ITP at a single tertiary care centre to evaluate its efficacy and safety. Results: Seven patients, median age 80 years (range 78 - 94), four women and three men, all Caucasian background, with various comorbidities started fostamatinib 100mg oral twice daily as second or subsequent line therapy. Patients had a diagnosis of ITP for a median 6 years (range approximately 6 months - 30 years), had six comorbidities (range 2 - 14), and experienced 2 unique prior lines of ITP therapy (range 1 to 6). Over 1290 days of fostamatinib exposure, two patients required dose escalation to 150mg oral twice daily while five patients remained on initial starting dose of 100mg twice daily in partial or complete response. The median platelet count at time of initiating fostamatinib was 25 x 109/L (range less than 10 - 193). Median time to response (defined any first platelet count greater than or equal to 30 x 109/L) was 19 days (range 0 - 181 days) with two patients responding rapidly (5 days and 19 days). Two patients required dose escalation, rescue therapy, and these same two patients discontinued fostamatinib after 175 days and 216 days of treatment. Treatment was tolerated in all patients with no thromboembolic events observed. One death was noted and unrelated to treatment. In keeping with the current recommendations, dose reduction was not required in any of the patients despite their advanced age. Conclusions: Fostamatinib was effective and safe for the majority of our very elderly patients with ITP in second and subsequent line therapies over a cumulative 1290 days of exposure.

The Efficacy and Safety of Fostamatinib in Elderly Patients with Immune Thrombocytopenia: A Single-Center, Real-World Case Series.

Fostamatinib is a small molecule spleen tyrosine kinase (Syk) inhibitor that was approved for the treatment of adult patients with immune thrombocytopenia (ITP) in second-line therapy. Syk inhibition prevents cytoskeletal rearrangements during phagocytosis, allowing platelet survival in ITP. However, fostamatinib treatment in elderly patients with ITP has not been well established. We performed a retrospective review of all elderly patients (age greater than or equal to 65 years) who had started on fostamatinib for the treatment of ITP at a single tertiary care centre to evaluate its efficacy and safety. Seven patients, median age 80 years (range 78-94), four women and three men, all of Caucasian background, with various comorbidities, started fostamatinib 100 mg orally twice daily as second or subsequent line therapy. Patients had a diagnosis of ITP for a median of 6 years (range approximately 6 months-30 years), had six comorbidities (range 2-14), and experienced 2 unique prior lines of ITP therapy (range 1 to 6). Over 1290 days of fostamatinib exposure, two patients required dose escalation to 150 mg orally twice daily, while five patients remained on the initial starting dose of 100 mg twice daily. The median platelet count at the time of initiating fostamatinib was 25 × 109/L (range less than 10-193). The median time to response (defined as any first platelet count greater than or equal to 30 × 109/L) was 19 days (range 0-181 days), with two patients responding rapidly (5 days and 19 days). Two patients required dose escalation and rescue therapy, and these same two patients discontinued fostamatinib after 175 days and 216 days of treatment. Treatment was tolerated in all patients with no thromboembolic events observed. One death was noted and unrelated to treatment. Overall, fostamatinib was effective and safe for the majority of these very elderly patients with ITP.

Management and Treatment of Non-small Cell Lung Cancer with MET Alteration and Mechanisms of Resistance.

MET-driven tumors are a heterogenous group of non-small cell lung cancers (NSCLC) with activating mutations. Pathologic activation of MET can be achieved with increased number of gene copies overexpression, or decreased protein degradation through several mechanisms, including mutations, amplifications, or fusions. Besides its role as primary driver, MET activation might also mediate resistance to kinase inhibitors in NSCLC with various other actionable alterations. While checkpoint inhibitors have modest efficacy in MET-driven tumors, several approaches of targeted blockade are available. Among them the most promising are small tyrosine kinase inhibitors, antibody-drug conjugates, and bispecific antibodies. Unfortunately, resistance is virtually inevitable. Resistance to small kinase inhibitors might be mediated by kinase domain mutations or activation of shunting cascades. Various resistance mechanisms might be present in one patient, making it overcoming an unresolved problem.

Establishment and validation of a LC-MS/MS method for the determination of anlotinib in human plasma: Application to therapeutic drug monitoring.

Anlotinib is a novel small molecule multitarget tyrosine kinase inhibitor for the treatment of several cancers. We developed and validated a highly sensitive, rapid and stable high-performance liquid chromatography-mass spectrometrymethod for the determination of anlotinib in human plasma with anlotinib-d5 as a stable isotopically labeled internal standard (SIL-IS). To explore the feasibility of therapeutic drug monitoring in the treatment of tumors with anlotinib, human plasma samples were prepared by protein precipitation. The mobile phases comprised of (A) 5.0mm NH4 AC aqueous solution containing 0.1% formic acid and (B) 100% methanol containing 0.1% formic acid. A gradient mobile phase system was adopted for chromatographic separation using a BEH C18 (2.1 × 50 mm, 1.7μm) column. A positive ion pattern was chosen for quantification under multiple reaction monitoring mode. The ion pairs were detected at m/z 408.2→339.1 and m/z 413.4→344.3 for anlotinib and anlotinib-d5 (SIL-IS), respectively. The total run time was 5.0min. The calibration curve was found to be linear within a plasma concentration range of 2-400 ng·ml-1 . The precision and accuracy, matrix effect, extraction recovery and stability were all validated and met the requirements of international guidelines. The proposed methods were successfully applied to support therapeutic drug monitoring in breast and thyroid cancer patients receiving anlotinib for therapy. Clinical data showed that in the 12 mg dose group, the mean plasma concentrations of anlotinib in breast cancer patients and thyroid cancer patients were 87.1 and 118.8ng·ml-1 , respectively. The data demonstrate that the peak concentration of anlotinib may be related to the different tumor types in patients.

Magic Bullets: The Coming Age of Meaningful Pharmacological Control of the Corneal Responses to Injury and Disease.

Corneal injuries from chemical burns, mechanical trauma, infections, immunological rejections, surgical complications, and some diseases are commonly associated with persistent epithelial defects (PED), neurotrophic epitheliopathy, scarring fibrosis, corneal neovascularization (CNV), and/or corneal endothelial damage that lead to vision loss. Several Food and Drug Administration (FDA) approved medications have recently become available, are currently in clinical trials, or are likely to enter clinical trials in the near future. For example, a 2-week course of topical human recombinant nerve growth factor is frequently an effective treatment for corneal neurotrophic epitheliopathy associated with PEDs. Topical losartan, an angiotensin converting enzyme II receptor antagonist that also inhibits TGF beta signaling, has been shown to effectively decrease myofibroblast generation and scarring fibrosis in alkali burn injury and Descemetorhexis rabbit models. Small molecule topical tyrosine kinase inhibitors, such as sunitinib and axitinib, FDA approved as chemotherapeutic agents to treat specific cancers, have also been found to be effective topical inhibitors of CNV in animal and human trials. Rho-kinase inhibitors, such as ripasudil and netarsudil, that are currently approved agents for the treatment of glaucoma in some countries, have been shown to stimulate corneal endothelial proliferation in animal studies and human trials, and may accelerate the regeneration of Descemet's membrane. These agents, as well as other drugs in development, will be used in targeted combinations to treat corneal pathophysiology associated with epithelial healing disorders, stromal scarring fibrosis, CNV, and corneal endothelial injury during the next decade.

FGF receptor inhibitor BGJ398 partially rescues osteoarthritis-like phenotype in older high molecular weight FGF2 transgenic mice via multiple mechanisms

We have used Basic Fibroblast Growth Factor (FGF2) transgenic mice as experimental models for human X-linked hypophosphatemia (XLH)-related degenerative osteoarthritis (OA) to investigate the pathogenesis of the disease and to test potential pharmacotherapies for treatment. This study tested the efficacy of BJG398, a small molecule fibroblast growth factor receptor tyrosine kinase (FGFRTK) inhibitor, to rescue the knee joint osteoarthritis phenotype in High Molecular Weight fibroblast growth factor 2 transgenic (HMWTgFGF2) mice. BJG398 was administered in vivo to 8-month-old female HMWTgFGF2 mice for six weeks. Histomorphometry, immunohistochemistry and micro-CT were used to examine the knee joints in BGJ398-treated and control mice. We assessed: Fibroblast Growth Factor 23 (FGF23) expression and FGFR1 activity; Matrix metalloproteinase 13 (MMP13) and Aggrecanase2 (ADAMTS5) expression; then signaling by SMAD1/5/8-pSMAD6, pERK1/2 and Runt-related transcription factor 2 (RUNX2). Using PrimePCR arrays, we identified a contributing role for major target genes in the TGFB/BMP2 signaling pathway that were regulated by BGJ398. BGJ398 inhibited HMWFGF2/FGF23-induced increase in bone morphogenic protein receptor-1, bone morphogenic protein-2 and 4 and Serine peptidase inhibitor, clade E, member 1. The results from Micro-CT and histology show BGJ398 treatment rescued the OA changes in subchondral bone and knee articular cartilage of HMWTgFGF2 mice. The gene expression and signal transduction results provide convincing evidence that HMWFGF2 generates OA through FGFRTK with characteristic downstream signaling that defines OA, namely: increased FGF23-FGFR1 activity with BMP-BMPR, activation of pSMAD1/5/8-RUNX2 and pERK signaling pathways, then upregulation of MMP13 and ADAMTS5 to degrade matrix. BGJ398 treatment effectively reversed these OA molecular phenotypes, providing further evidence that the OA generated by HMWFGF2 in the transgenic mice is FGFR-mediated and phenocopies the OA found in the Hyp mouse homolog of XLH with a spontaneous mutation in the Phex (phosphate regulating endopeptidase on the X chromosome) gene and human XLH-OA. Overall, the results obtained here explain how the pleotropic effects of FGF2 emanate from the different functions of HMW protein isoforms for cartilage and bone homeostasis, and the pathogenesis of XLH-degenerative osteoarthropathy. BGJ398 inhibits HMWFGF2-induced osteoarthritis via multiple mechanisms. These results provided important scientific evidence for the potential application of BGJ398 as a therapeutic agent for osteoarthritis in XLH.

Are off-target effects of imatinib the key to improving beta-cell function in diabetes?

The small tyrosine kinase (TK) inhibitor imatinib mesylate (Gleevec, STI571) protects against both type 1 and type 2 diabetes, but as it inhibits many TKs and other proteins, it is not clear by which mechanisms it acts. This present review will focus on the possibility that imatinib acts, at least in part, by improving beta-cell function and survival via off-target effects on beta-cell signaling/metabolic flow events. Particular attention will be given to the possibility that imatinib and other TK inhibitors function as inhibitors of mitochondrial respiration. A better understanding of how imatinib counteracts diabetes will possibly help to clarify the pathogenic role of beta-cell signaling events and mitochondrial function, and hopefully leading to improved treatment of the disease.

P11.58.A Case of a complex neurocutaneous syndrome characterized by extensive peripheral nerve sheath tumors and somatic ERBB2 mutation

Abstract Schwannomatosis is a rare genetic tumor predisposition syndrome characterized by the presence of multiple non-intradermal schwannomas and the definitive absence of vestibular nerve involvement. Though considered benign, the burden of tumors can cause significant morbidity in the form of motor dysfunction and refractory neuropathic pain. Treatment is focused on mitigating these symptoms, which includes resection of offending tumors when feasible and anti-angiogenesis therapy with bevacizumab. Options for targeted medical therapies are lacking. Schwannomatosis is molecularly distinct from the other neurofibromatoses and by definition lacks constitutional mutations in NF1 and NF2. Instead, constitutional mutations in SMARCB1 or LZTR1 are often the “first hit” in tumorigenesis. Activating mutations in ERBB2 (also designated HER2) have been identified as oncogenic drivers in peripheral nerve sheath tumors in patients who lack these typical constitutional tumor suppressor gene mutations. Here we report a case of extensive peripheral nerve sheath tumors in the setting of apparent somatic mosaicism of an ERBB2 mutation. A 48-year-old man with history of chronic back pain presented with diffuse enlarging soft tissues masses primarily involving the left neck and occiput. Examination revealed areas of cutaneous heterogeneous hyperpigmentation, decreased muscle bulk and dorsiflexor weakness in the bilateral lower extremities, and steppage gait. Neuroimaging showed extensive T2 hyperintense, mildly enhancing masses within the bilateral thoracic and lumbar spine neuroforamina, intercostal nerves, paraspinal musculature, and lumbosacral plexus. Tissue from two separate tumor sites was morphologically consistent with schwannoma with some features of neurofibroma. Immunohistochemistry revealed partial loss of staining for SMARCB1. Whole exome sequencing (WES) on blood and tumor tissue did not show pathogenic germline or somatic variants for NF1, NF2, SMARCB1, LZTR1, or an array of tumor predisposition syndromes. WES on tumor tissue from both sites however did reveal a somatic ERBB2 variant (p.D769Y), suggesting mosaicism. ERBB2 D769Y has previously been classified as an activating mutation that confers sensitivity to some small molecule receptor tyrosine kinase inhibitors. Patients with ERRB2-mutated peripheral nerve sheath tumors may have broader therapeutic options in the variety of available tyrosine kinase inhibitors studied in other cancers.