Studies Of Tyrosine Kinase Inhibitors Research Articles

Pharmacovigilance study of tyrosine kinase inhibitors: Analysis of adverse reactions

The aim of the study is to analyze reports of adverse drug reactions published in the scientific literature occurring during and after the use of kinase inhibitors for the treatment of rheumatologic diseases to determine their type, frequency, and severity. The search was conducted in the MEDLINE and PubMed databases from January 2005 to May 2022. We found a total of 291 publications, from which we selected suitable ones for data extraction. We conducted descriptive and variation analyses as the main statistical analyses. We determined mean values, standard deviation, minimum, maximum, and 95% confidence intervals. The PICOS tool was used to evaluate the results. The analyzed population includes patients with rheumatologic and oncologic diseases. There is a significant interest in the drug safety of kinase inhibitors, as they represent a rapidly evolving and reliable pharmacological class. Clarifying the safety profile of their representatives remains important. In-depth review of full-text publications shows that the high frequency of reported serious ADRs is rather due to increased interest in reporting and publishing these cases than to their high frequency of occurrence.

A real-world study of tyrosine kinase inhibitors plus anti-PD-1 immunotherapy with or without chemoembolization for hepatocellular carcinoma patients with main portal vein invasion.

Although systemic therapies are recommended for hepatocellular carcinoma (HCC) patients with main portal vein (MPV) invasion and preserved liver function, the outcome is limited. In the real-world, chemoembolization is a commonly used local treatment for advanced HCC. To evaluate whether the additional chemoembolization treatment yields survival benefits compared to systemic therapy for HCC patients with MPV invasion and preserved liver function (Child-Pugh score ≤ B7) in a real-world study from multiple centers. Between January 2020 and December 2022, 91 consecutive HCC patients with MPV invasion who received either systemic medical therapy (i.e., tyrosine kinase inhibitors (TKIs) plus anti-PD-1 immunotherapy, S group, n = 43) or in combination with chemoembolization treatment (S-T group, n = 48) from five centers were enrolled in the study. The primary outcome was overall survival (OS), and the secondary outcomes were progression-free survival (PFS) and treatment response. Adverse events (AEs) related to treatment were also recorded. Survival curves were constructed with the Kaplan-Meier method and compared using the log-rank test. The baseline characteristics were comparable between the two groups. The mean number of chemoembolization sessions per patient was 2.1 (range 1-3). The median OS was 10.0months and 8.0months in the S-T group and S group, respectively (P = 0.254). The median PFS between the two groups was similar (4.0months vs. 4.0months, P = 0.404). The disease control rate between the S-T and S groups were comparable (60.4% vs. 62.8%, P = 0.816). Although no chemoembolization-related deaths occurred, 13 grade 3-4 AEs occurred in the S-T group. The results of the real-world study demonstrated that additional chemoembolization treatment did not yield survival benefits compared to TKIs plus anti-PD-1 immunotherapy for the overall patients with advanced HCC and MPV invasion.

Molecular docking studies of tyrosine kinase inhibitors: Exemplified protocol to advance pharmaceutical education in medicinal chemistry

Background: One of the essential goals of pharmacy education is to extend professional learning to pharmacists, pharmacy students and educators. Medicinal chemistry is a major component of this professional learning. Nowadays, computer-aided drug design (CADD) is considered a cornerstone in drug discovery platforms. However, this computational drug design is not crystal-clear to pharmacy students and pharmacists. In this study, a molecular docking process was established to advance pharmaceutical education in the medicinal chemistry field. Method: CADD is available in the syllabus of Iraqi pharmacy schools however the software packages are not available for the students to practice the docking process. Five different compounds were designed and docked by employing the Genetic Optimisation of Ligand Docking (GOLD) software and the scores were recorded. Results: Pharmacy students would use this exemplified docking to enhance their understanding of the medicinal chemistry module. Conclusion: This educational docking study was successfully performed to advance the pharmacy education.

CML-246: Systematic Literature Review of the Efficacy of Available Interventions for Patients with Chronic-Phase (CP) Chronic Myeloid Leukemia (CML) Who Have Previously Been Treated with ≥2 Lines of Tyrosine Kinase Inhibitors (TKIs)

Context and Objective Despite several TKIs being available as standard of care for CP-CML patients, survival rates are low once patients move beyond their second line of treatment. This study aimed to systematically capture and summarize evidence on treatment outcomes for CP-CML patients previously treated with ≥2 lines of TKIs. Methods The search was conducted in November 2019 within Embase, MEDLINE, and Cochrane, to identify studies of TKIs, allogeneic stem cell transplantation (allo-SCT), omacetaxine, and hydroxycarbamide in the target population. Outcomes of interest were complete cytogenetic response (CCyR), major molecular response (MMR), as well as 4-log (MR4), 4.5-log (MR4.5), and 5-log (MR5) reductions in BCR-ABL ratio, and survival (progression-free [PFS] and overall [OS]). Results Seven single-arm trials and 12 observational studies were included, with no randomized controlled trial (RCT) of relevance being identified. Six studies featured multiple interventions, all of which were observational. Seven studies evaluated dasatinib, seven nilotinib, six bosutinib, five ponatinib, one omacetaxine, one imatinib, and one allo-SCT. Sample sizes ranged between 10 and 270 patients. Median age and proportion of males ranged from 33 to 68 years and from 45% to 65%, respectively. Among the seven studies reporting on performance status, patients had an ECOG score of either 0 or 1. Between 0% and 54% of patients were in CCyR at study entry. Median PFS and median OS were not reached with ponatinib, bosutinib, dasatinib, or nilotinib, were not reported with allo-SCT, and were 9.6 and 33.9 months with omacetaxine. CCyR, MMR, MR4, and MR4.5 rates (reported in 18, 18, five, and five studies respectively) ranged from 5% to 81%, 8% to 72%, 20% to 57%, and 16% to 57%. No study reported MR5. Conclusions No RCT has been conducted in this population. Since most included studies were observational, with known associated risks of bias, there is a clear need for data generation through RCTs. Long-term outcomes were generally poor; differences in prognostic factors at baseline may explain part of the heterogeneity in the reported outcomes. Comparative evidence on the efficacy of interventions is needed to aid clinicians in managing this heavily pretreated population.

The current role for adjuvant and neoadjuvant therapy in renal cell cancer.

Here we explore the recent and relevant trials for treatment of renal cell cancer (RCC) in the adjuvant and neoadjuvant settings as well as recent updates to the guidelines for RCC management. Most phase III studies of tyrosine kinase inhibitors in the adjuvant setting have been negative. Notably, sunitinib received regulatory approval by the FDA after showing improved disease-free survival in high risk populations. Recent improvements in the genetic classification and understanding of RCC molecular and genetic disorder will hopefully improve patient selection. Meanwhile, recent advances in metastatic RCC treatment, particularly with the combination of tyrosine kinase inhibitors and immune checkpoint inhibitors, have given rise to hope that advances can be made by moving these treatment strategies forward to the adjuvant or neoadjuvant settings. In the absence of a clinical trial, observation remains the standard of care. Based on the S-TRAC data, sunitinib is approved for use in the adjuvant setting, and can be considered under select circumstances. Although there is optimism for checkpoint monotherapy and combination therapy in the adjuvant or neoadjuvant setting, ongoing studies will determine clinical benefit and tolerability in this setting. Therefore, for patients with high risk of recurrent disease clinical trials of checkpoint inhibitor therapy are viable options.

Epidermal growth factor receptor tyrosine kinase inhibitors combined with thoracic radiotherapy or chemoradiotherapy for advanced or metastatic non-small cell lung cancer: A systematic review and meta-analysis of single-arm trials.

Background:Preclinical in vitro experiments demonstrated that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) might have synergistic effect in combination with radiotherapy on Non-small cell lung cancer (NSCLC), but the clinical trials showed inconsistence results in NSCLC patients with EGFR status unknow or mutations. This study aimed to determine if added TKIs to Thoracic radiotherapy (TRT) improve primary disease response rate (RR) and survival outcomes in advanced or metastatic NSCLC.Methods:We searched MEDLINE, EMBASE, and Cochrane Library from January 2000 to December 2017 for eligible studies where patients received concurrent EGFR TKIs and TRT or CRT. Concerned outcomes were primary tumor RR, overall survival (OS), and adverse events (AEs). The meta-analysis was performed using Stata software (version 12.0). Random effects models were used to pool outcomes across studies. Sensitivity analysis was performed to determine if the results would be different.Results:We found 16 prospective clinical trials with mature results for meta-analyses. Twelve studies including 446 patients reported the RR and survival outcomes of TRT combined TKIs. The CR, PR, SD, and PD, respectively, were 0.06 (95% CI 0.03–0.09, I2 = 0%), 0.44 (95% CI 0.38–0.49, I2 = 64.9%), 0.29 (95% CI 0.24–0.34, I2 = 78.4%), and 0.15 (95% CI 0.11–0.19, I2 = 84.2%). One- and 2-year OS, respectively, were 0.52 (95% CI 0.44–0.60, I2 = 38.8%) and 0.26 (95% CI 0.18–0.33, I2 = 0%). Four studies including 182 patients reported the RR and survival outcomes of CRT combined TKIs. The pooled CR, PR, SD, and PD, respectively, were 0.12 (95% CI 0.02–0.22, I2 = 69.1%), 0.41 (95% CI 0.27–0.55, I2 = 71.6%), 0.31 (95% CI 0.16–0.46, I2 = 79%), and 0.14 (95% CI −0.01–0.30, I2 = 87.8%). Only 1 study reported the survival event rate, 1- and 2-year OS, respectively, were 0.83 (95% CI 0.71–0.94) and 0.67 (95% CI 0.54–0.81). There were not severe adverse events (SAEs) reported either TRT combined TKIs or CRT combined TKIs.Conclusion:There is evidence, albeit of low quality, that added the TKIs to TRT or CRT may improve RR and survival outcomes in patients with EGFR mutant status unknown advanced or metastatic NSCLC relative to other studies of TKIs alone, TRT alone or CRT.

Abstract 2201: Preclinical development of novel pyrazolo[3,4-d]pyrimidines structure-based TKIs for the treatment of glioblastoma

Abstract The aim of this study was the preclinical development of a set of pyrazolo[3,4-d]pyrimidine structure-based small molecules ATP-competitive SRC inhibitors for the therapy of glioblastoma (GBM), a rare but extremely aggressive and infiltrative glial tumor with a very limited response to therapies. Ongoing preclinical and clinical studies of tyrosine kinase inhibitors (TKIs) for the therapy of GBM identified SRC family inhibitors as a significant and effective therapeutic strategy (i.e. dasatinib, bosutinib, PP2). In vitro Screening: From the wide in-house synthesized pyrazolo[3,4-d]pyrimidines’ library, nine compounds have been selected to be formulated and tested in in vitro and in vivo GBM pharmacological models. Among all the examined formulations, the prodrug approach has been applied to the candidate drugs, introducing the N-methylpiperazine moiety by a carbamate-based linker (in vivo enzymatically hydrolysable). Drugs and corresponding prodrugs have been screened on the basis of their SRC Ki and in vitro ADME properties. GBM U87 cell assays showed IC50 in the sub-micromolar range (1.5 - 15.0 µM) for almost all compounds and improved cellular uptake of the prodrugs in respect to the corresponding drugs. PK and Toxicity: After that, the most promising compound has been selected for further in vitro assays and in vivo tests. In vivo pharmacokinetics and pharmacodynamics have been evaluated for the compound by various formulations, routes of administration and dosages. In all cases investigated, the compound has been proved to reach the brain. As expected, prodrug plasmatic MRT and AUC confirmed the realization of an extended release formulation that allows a higher overall exposure to the drug. In addition, considering an estimated oral bioavailability of 40.4% and a 11-fold higher Cmax in respect to i.v. and i.p. administration, the oral route can be identified as the most advantageous for the compound for GBM treatment. Moreover, an acute toxicity study revealed that the LD50 for i.v. toxicity is more than 100 mg/kg with a good tolerability. In vivo Efficacy Tests: The selected compound and its prodrug were orally administered in GBM orthotopic mouse model and results indicated a median survival rate 10% greater for prodrug-treated mice in respect to drug-treated mice and 35% greater in respect to control group. The combination effect of the compound and radiotherapy was also investigated in subcutaneous U87 xenografted mice model and resulted in a reduction of the tumor growth close to 80% in respect to the control growth. Conclusions: Taking into account all the data collected regarding their pharmacological properties, pyrazolo[3,4-d]pyrimidines SRC inhibitors class of compounds deserve further investigation to show its potential to become a new therapy for GBM. Citation Format: Arianna Mancini, Anna Lucia Fallacara, Claudio Zamperini, Giulia Iovenitti, Alessio Molinari, Enrico Rango, Adriano Angelucci, Silvia Schenone, Maurizio Botta. Preclinical development of novel pyrazolo[3,4-d]pyrimidines structure-based TKIs for the treatment of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2201.

Medullary Thyroid Cancer: Clinical Characteristics and New Insights into Therapeutic Strategies Targeting Tyrosine Kinases.

Medullary thyroid carcinoma (MTC) is a hyperplasia of thyroid C-cells, accounting for 5-10% of all thyroid cancers. MTCs may appear as sporadic or hereditary forms, and several molecules and signaling pathways have been found to function defectively in MTC cells. Tyrosine kinases are the most well-studied molecules that have abnormal function in these tumor cells. Due to their limited response, chemotherapeutic agents and radiation therapy are not effective in treating patients with advanced metastatic MTC. In the past decade, significant attention has been given to the utilization of multikinase inhibitors as targeted therapeutic agents for treating MTC patients, with the most promising results arising from the study of tyrosine kinase inhibitors, which generally bind to the ATP binding sites of these kinases. Two drugs-vandetanib and cabozantinib-are approved for the treatment of aggressive advanced MTC; however, the potential for toxicities and adverse effects of these agents on patient quality of life need to be considered against any therapeutic gain. According to recent data, it appears that inhibition of only one receptor or molecule in a pathway is not as effective as simultaneous inhibition of different pathways, indicating the need to use combination therapy. The main purpose of this review is to describe the clinical characteristics, molecular mechanisms, and current molecular and targeted therapeutic strategies active in clinical trials for advanced MTC treatment.

Stem Cell Transplantation for Chronic Myeloid Leukemia (CML): Current Indications and Perspectives

The introduction of tyrosine kinase inhibitors (TKIs) has reduced the indications for allogeneic stem cell transplants (SCT) in patients with chronic myeloid leukemia (CML) from 1500/year in 2000 to approximately 500/year in 2010. The recently updated indications by the European Leukemia Network include advanced-phase CML and nonresponders to second-line TKIs. Changes in transplant programs, over the past decade, have resulted in a significant reduction in transplant related mortality and this has expanded the transplant option to older patients, who may be eligible for SCT. Transplantation for blastic phase CML remains a challenge due to the high rate of post-transplant relapses. Thus, in view of this issue, several studies of TKIs after allogeneic SCT have been undertaken with encouraging results. In conclusion, allogeneic SCT remains a therapeutic option for selected patients with CML and is currently being integrated with the use of TKIs both before and after transplantation.

Targeted molecular therapy in peripheral T-cell lymphomas

Peripheral T-cell lymphomas (PTCLs) are rare neoplasms constituting a heterogeneous group of diseases. At present, available chemotherapy regimens that have improved outcomes in B-cell lymphomas appear to be less efficacious in the context of PTCLs and, thus, alternative strategies are warranted. In the last few years, based on the recent, deeper understanding of PTCL biology, several molecules and/or pathways have been proposed for targeted therapy in this setting, including surface antigens, tyrosine kinases, the NF-κB pathway, folate metabolism, histone modification and others. Of particular interest, histone deacetylase and proteasome inhibitors, as well as novel chemotherapeutic agents such as pralatrexate, have already demonstrated efficacy in PTCL therapy. In addition, a strong biological rationale and early clinical evidence supports the future study of tyrosine kinase inhibitors in this setting. In this article, the authors review the available literature on targeted therapy in PTCLs and also, based on their own experience, discuss potential opportunities in this intriguing area.

Systemic Sclerosis 2011

Systemic Sclerosis 2011

Ongoing under-reporting of clinically relevant safety data in phase II studies of tyrosine kinase inhibitors

Ongoing under-reporting of clinically relevant safety data in phase II studies of tyrosine kinase inhibitors

Reply: Ongoing under-reporting of clinically relevant safety data in phase II studies of tyrosine kinase inhibitors

Reply: Ongoing under-reporting of clinically relevant safety data in phase II studies of tyrosine kinase inhibitors

Somatic EGFR mutations and efficacy of tyrosine kinase inhibitors in NSCLC

Early clinical studies of tyrosine kinase inhibitors (TKIs) that target the EGFR in patients with advanced non-small-cell lung cancer (NSCLC) showed that some patients experienced rapid, durable, complete or partial responses. These data were the basis for attempts to identify specific subgroups of patients who would further benefit from these agents. The discovery of somatic mutations in EGFR that correlated with sensitivity to TKIs identified a plausible explanation for these observations. Clinical and pathological factors such as female sex, never having smoked, Asian origin and adenocarcinoma histology correlate with the presence of EGFR mutations and objective responses to TKIs in patients with NSCLC. Recent studies in metastatic colorectal cancer highlighted that somatic mutations in KRAS represent a negative predictor of response to anti-EGFR monoclonal antibodies; KRAS mutations also represent an important mechanism of resistance to TKIs in NSCLC. Many large clinical studies are currently investigating the predictive and prognostic value of EGFR mutational status and other candidate biomarkers. We summarize the literature and present an overview of the field of anti-EGFR therapy in NSCLC, focusing on the influence of somatic EGFR mutations on selection of patients for TKI therapy and the influence of EGFR pathway regulation.

Targeted cancer therapy: The prime time show in oncology

Targeted cancer therapy: The prime time show in oncology

In Vitro Expansion of Polycythemia Vera Progenitors Favors Expansion of Erythroid Precursors without JAK2 V617F Mutation.

A single acquired point mutation of JAK2 1849G>T (V617F), a tyrosine kinase with a key role in signal transduction from growth factor receptors, is found in 70%–97% of patients with polycythemia vera (PV). In the studies of tyrosine kinase inhibitors on JAK2 1849G>T (see Gaikwad et all abstract at this meeting) we decided to study the possible therapeutic effect of these agents using native in vitro expanded cells from peripheral blood. To our surprise, the in vitro expansion of PV progenitors preferentially augmented cells without JAK2 1849G>T mutation.We used a 3 step procedure to amplify erythroid precursors in different stages of differentiation from the peripheral blood of 5 PV patients previously found to be homozygous or heterozygous for the JAK2 1849G>T mutation. In the first step (days 1–7), 106/ml MNCs were cultured in the presence of Flt-3 (50 ng/ml), Tpo (100 ng/ml), and SCF (100 ng/ml). In the second step (days 8–14), the cells obtained on day 7 were re-suspended at 106/ml in the same medium with SCF (50 ng/ml), IGF-1 (50 ng/ml), and 3 units/ml Epo. In the third step, the cells collected on day 14 were re-suspended at 106/ml and cultured for two more days in the presence of the same cytokine mixture as in the step 2 but without SCF. The cultures were incubated at 37oC in 5% CO2/95% air atmosphere and the medium renewed every three days to ensure good cell proliferation. The expanded cells were stained with phycoerythrin-conjugated anti-CD235A (glycophorin) and fluorescein isothiocyanate-conjugated anti-human-CD71 (transferrin receptor) monoclonal antibodies and analyzed by flow cytometry. The cells were divided by their differential expression of these antigens into 5 subgroups ranging from primitive erythroid progenitors (BFU-Es and CFU-Es) to polychromatophilic and orthochromatophilic erythroblasts; over 70% of harvested cells were early and late basophilic erythroblasts. The proportion of JAK2 1849G>T mutation in clonal PV granulocytes (GNC) before in vitro expansion and in expanded erythroid precursors was quantitated by pyrosequencing (Jelinek, Blood in press) and is depicted in the Table.These data indicate that in vitro expansion of PV progenitors favors expansion of erythroid precursors without JAK2 V617F mutation. Since three PV samples were from females with clonal granulocytes, erythrocytes, and platelets, experiments were underway to determine if the in vitro expanded erythroid cells were clonal PV cells without JAK2 V617F mutation, or derived from polyclonal rare circulating normal hematopoietic progenitors.The Proportion of JAK2 T AllelePatientsGNC T Allele (%)Expanded Cells T Allele (%)PV1 (Female)8110PV2 (Male)7728PV3 (Male)4442PV4 (Female)7819PV5 (Female)7828

The doctor's role in advocacy

In his Rock Carling lecture last year, entitled “Fads in medical care policy and politics: the rhetoric and reality of managerialism”, Theodore Marmor spoke of the “linguistic muddle” and “conceptual confusion” that marked the organisation of medicine during the past decade. Business ideology infiltrated health care when costs spiralled and governments reconsidered their longstanding commitment to the welfare state. As professors were deposed by chief executive officers, and as the fog of human-resources jargon obscured an emptiness of serious thought, so mediocrity became the benchmark for running a health service. Priorities shifted. Quality was eroded by a concern for quantity, effectiveness gave way to efficiency, and notions of professionalism were subsumed by mission statements. Morale collapsed, cynicism became commonplace. Medical professionalism in the new millennium: a physicians' charterPublished simultaneously in Ann Intern Med 2002; 136: 243–46. Full-Text PDF BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective studyDifferent mutations within the kinase domain of BCR-ABL can be responsible for refractoriness of Ph+ leukaemia to STI571. Mutation in the BCR-ABL kinase domain might be a frequent mechanism of STI571 resistance in lymphoid disease. Full-Text PDF Relation between resistance of Philadelphia-chromosome-positive acute lymphoblastic leukaemia to the tyrosine kinase inhibitor STI571 and gene-expression profiles: a gene-expression studyWe have shown the clinical relevance of gene expression data for the pretreatment assessment of acute lymphoblastic leukaemia. Our results have implications for future clinical studies of tyrosine kinase inhibitors. Full-Text PDF

Relation between resistance of Philadelphia-chromosome-positive acute lymphoblastic leukaemia to the tyrosine kinase inhibitor STI571 and gene-expression profiles: a gene-expression study

The ABL tyrosine kinase inhibitor STI571 is a promising agent for treatment of advanced Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukaemia. However, resistance to this drug develops within a few months in most patients. We aimed to predict resistance to STI571. Total RNA was extracted from 25 bone-marrow samples from 19 patients with Ph+ acute lymphoblastic leukaemia who were enrolled into a phase II study. 17 samples were obtained before STI571 treatment was started: ten from individuals who were classified as good responders to STI571 (sensitive), and seven from individuals who did not to respond to STI571 (primary resistance). Eight samples were obtained from patients during treatment with STI571. We analysed six matched samples, which were obtained before and during treatment with STI571. Oligonucleotide microarray analysis of samples was done with high-density microarrays. We identified 95 genes whose expression could be used to predict sensitivity of leukaemic cells to STI571. On this basis, all the STI571-sensitive samples could clearly be distinguished from the resistant cases. 56 highly differentially expressed genes were identified in leukaemic cells that were secondarily resistant to STI571. Resistant leukaemic cells expressed high levels of Bruton's tyrosine kinase and two ATP synthetases (ATP5A1 and ATP5C1), and showed significantly reduced expression of the proapoptotic gene BAK1 and the cell-cycle control gene p15 INK4b. We have shown the clinical relevance of gene expression data for the pretreatment assessment of acute lymphoblastic leukaemia. Our results have implications for future clinical studies of tyrosine kinase inhibitors.