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Pharmaceutics Jan 2024Dacomitinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the treatment of patients with advanced non-small-cell...
Dacomitinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) and EGFR-activating mutations. Proton-pump inhibitors decreased dacomitinib exposure. This analysis summarizes the effect of Histamine-2 receptor antagonists (H2RAs) on dacomitinib exposure. A within-patient comparison of the steady-state trough concentrations (C) of dacomitinib and its active metabolite and active moiety with and without concomitant use of H2RAs was conducted using a linear mixed effects model with pooled data from 11 clinical studies in patients with NSCLC. An oral absorption physiologically based pharmacokinetic (PBPK) model was constructed and verified using clinical pharmacokinetic (PK) data after a single dose of dacomitinib in healthy volunteers to estimate the effect of gastric pH altered by an H2RA on dacomitinib's PKs. The adjusted geometric mean of the dacomitinib C of the dacomitinib parent, metabolite and active moiety following co-administration with an H2RA was approximately 86%, 104% and 100% relative to that following dacomitinib 45 mg administration without an H2RA ( > 0.05). The PBPK modeling showed negligible change in dacomitinib maximum concentration (C) and area under the drug concentration-time curve (AUC) over 0-24 h after H2RA administration when compared with those administered dacomitinib alone. Co-administration of an H2RA with dacomitinib is not expected to have any clinically relevant effect on dacomitinib exposure.
PubMed: 38258127
DOI: 10.3390/pharmaceutics16010118 -
Molecules (Basel, Switzerland) Jan 2024Paclitaxel is still used as a standard first-line treatment for ovarian cancer. Although paclitaxel is effective for many types of cancer, the emergence of...
Paclitaxel is still used as a standard first-line treatment for ovarian cancer. Although paclitaxel is effective for many types of cancer, the emergence of chemoresistant cells represents a major challenge in chemotherapy. Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity. Additionally, we confirmed that dacomitinib inhibits chemoresistance in paclitaxel-resistant ovarian cancer HeyA8-MDR cells. Collectively, our research indicated that dacomitinib effectively resensitized paclitaxel in SKOV3-TR cells by inhibiting EGFR signaling and elevating intracellular ROS levels.
Topics: Female; Humans; Paclitaxel; Reactive Oxygen Species; Ovarian Neoplasms; Apoptosis; ErbB Receptors; Fluoresceins; Quinazolinones
PubMed: 38202856
DOI: 10.3390/molecules29010274 -
JTO Clinical and Research Reports Dec 2023To compare the performance of droplet digital polymerase chain reaction (ddPCR) and plasma next-generation sequencing (NGS) in detecting clearance of plasma EGFR (pEGFR)...
Brief Report: Droplet Digital Polymerase Chain Reaction Versus Plasma Next-Generation Sequencing in Detecting Clearance of Plasma EGFR Mutations and Carcinoembryonic Antigen Levels as a Surrogate Measure.
INTRODUCTION
To compare the performance of droplet digital polymerase chain reaction (ddPCR) and plasma next-generation sequencing (NGS) in detecting clearance of plasma EGFR (pEGFR) mutations.
METHODS
Patients with treatment-naive advanced EGFR-mutated lung cancer treated with first-line tyrosine kinase inhibitors (TKIs) were included. pEGFR were measured at baseline and first response assessment using ddPCR and NGS. Clearance of pEGFR was defined as undetectable levels after a positive baseline result. Results were correlated with time-to-treatment failure (TTF). In exploratory analysis, corresponding change in carcinoembryonic antigen (CEA) levels was evaluated.
RESULTS
Between January 1, 2020, and December 31, 2021, 27 patients were recruited. Ex19del comprised 74% (20 of 27) and L858R 26% (seven of 27). Osimertinib was used in 59% (16 of 27), dacomitinib 4% (one of 27), and gefitinib/erlotinib 37% (10 of 27). Sensitivity of ddPCR and NGS in detecting pEGFR mutation at baseline was 70% (19 of 27) and 78% (21 of 27), respectively ( = 0.16). All patients with detectable pEGFR by ddPCR were detected by NGS.At a median of 8 (range 3-24) weeks post-TKI initiation, clearance of pEGFR was achieved in 68% (13 of 19) and 71% (15 of 21) using ddPCR and NGS, respectively. Concordance between ddPCR and NGS was 79% (kappa = 0.513, = 0.013). Clearance of pEGFR was associated with longer median TTF (not reached versus 6 months, = 0.03) and median decrease in CEA levels by 70% from baseline.In another cohort of 124 patients, decrease in CEA levels by greater than 70% within 90 days of TKI initiation was associated with doubling of both TTF and overall survival.
CONCLUSIONS
Plasma NGS trended toward higher sensitivity than ddPCR in detecting pEGFR, although both had similar concordance in detecting pEGFR clearance. Our results support using NGS at diagnosis and interchangeability of NGS and ddPCR for monitoring, whereas CEA could be explored as a surrogate for pEGFR clearance.
PubMed: 38162173
DOI: 10.1016/j.jtocrr.2023.100599 -
Journal of Microscopy and Ultrastructure 2023Gastrointestinal (GIT) mucositis is a common problem associated with chemotherapy. Dacomitinib is a chemotherapeutic drug that treats nonsmall cell lung cancer. It...
INTRODUCTION
Gastrointestinal (GIT) mucositis is a common problem associated with chemotherapy. Dacomitinib is a chemotherapeutic drug that treats nonsmall cell lung cancer. It irreversibly binds to the receptors at the ileal epithelial cells, leading to mucosal injury. Baicalin (BA) is a flavonoid with anti-inflammatory, antifibrosis, and antibarrier disruption properties.
AIM
This work aimed to investigate the possible protective effects of BA on dacomitinib-induced ileal mucositis in rats by histological and immunohistochemical studies.
MATERIALS AND METHODS
60 Wistar rats (8-12 weeks) were used (180-200 g) and divided into 6 groups (10 rats each). Group 1: Control; Group 2 (dacomitinib): Rats received dacomitinib 7.5 mg/kg/day orally; Group 3 (dacomitinib + carboxyl methylcellulose [CMC]): Rats received dacomitinib 7.5 mg/kg/day and 0.5% CMC orally; Group 4 (dacomitinib + BA low dose): Rats received low-dose BA 30 mg/kg/day and 7.5 mg/kg/day dacomitinib orally; Group 5 (dacomitinib + BA mid dose): Rats received mid-dose BA 60 mg/kg/day and 7.5 mg/kg/day dacomitinib orally; Group 6 (dacomitinib + BA high dose): Rats received high-dose BA 100 mg/kg/day and 7.5 mg/kg/day dacomitinib orally.
RESULTS
Dacomitinib group showed short villi, desquamated epithelium, congested blood vessels, inflammatory cellular infiltrations, dilated lacteals, and wide spaces between the crypts. There is a significant increase in collagen fibers and number of tumor necrosis factor-alpha and proliferating cell nuclear antigen-positive cells. Further, there were lost epithelial cadherin (E-cadherin) and epidermal growth factor receptor immunohistochemical reaction. The previous findings were ameliorated by BA in a dose-dependent manner.
CONCLUSION
BA has a protective effect through its anti-inflammatory, antifibrosis, and antibarrier disruption effects. Hence, BA is considered as a promising new drug for the treatment of chemotherapy-associated GIT problems, especially dacomitinib.
PubMed: 38025187
DOI: 10.4103/jmau.jmau_115_20 -
ESMO Open Dec 2023Dacomitinib showed superior progression-free survival (PFS) and overall survival compared to gefitinib in patients with advanced non-small-cell lung cancer (NSCLC)...
INTRODUCTION
Dacomitinib showed superior progression-free survival (PFS) and overall survival compared to gefitinib in patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations in the ARCHER1050 study. However, because that study did not include patients with brain metastases, the efficacy of dacomitinib in patients with brain metastases has not been clarified.
PATIENTS AND METHODS
This single-arm phase II study enrolled 30 patients with treatment-naïve advanced NSCLC harboring activating EGFR mutations from January 2021 to June 2021 and started them on dacomitinib (45 mg/day). All patients had non-irradiated brain metastases with a diameter of ≥5 mm. The primary endpoint was confirmed intracranial objective response rate (iORR).
RESULTS
Patients had exon 19 deletions (46.7%) and L858R mutations in exon 21 (55.3%). The confirmed iORR was 96.7% (29/30), with an intracranial complete response of 63.3%. Median intracranial PFS (iPFS) was not reached, with 12- and 18-month iPFS rates of 78.6% [95% confidence interval (CI) 64.8% to 95.4%] and 70.4% (95% CI 54.9% to 90.1%), respectively. In the competing risk analysis, the 12-month cumulative incidence of intracranial progression was 16.7%. Regarding the overall efficacy for intracranial and extracranial lesions, the overall ORR was 96.7%, and the median PFS was 17.5 months (95% CI 15.2 months-not reached). Grade 3 or higher treatment-related adverse events were reported in 16.7% of patients, and 83.3% required a reduced dacomitinib dose to manage adverse events. However, none permanently discontinued dacomitinib treatment due to treatment-related adverse events.
CONCLUSIONS
Dacomitinib has outstanding intracranial efficacy in patients with EGFR-mutant NSCLC with brain metastases.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; ErbB Receptors; Brain Neoplasms
PubMed: 38016250
DOI: 10.1016/j.esmoop.2023.102068 -
BMC Cancer Oct 2023About 10% of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are harbored as uncommon mutations. This study aimed to...
BACKGROUND
About 10% of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are harbored as uncommon mutations. This study aimed to explore the efficacy and safety of dacomitinib, a second-generation EGFR tyrosine kinase inhibitor (EGFR-TKIs), in treating uncommon EGFR-mutated advanced NSCLC.
METHODS
Treatment-naïve advanced NSCLC patients treated with dacomitinib at Hunan Cancer Hospital with uncommon EGFR mutations were evaluated. The primary endpoint was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety.
RESULT
Between December 2019 and December 2021, a total of 16 patients was included. Median PFS was 14.0 (95% CI 4.32-23.7) months, and median OS was not reached. ORR was 68.8% (95% CI 41.3 to 89.0%) and DCR was 93.8% (95%CI 69.8 to 99.8%), including three achieving complete remission (CR) and eight achieving partial remission (PR). Median PFS for patients with brain metastasis was 9.0 (95%CI 6.9 to 11.1) months. Intracranial ORR was 100%, including 2 CR and 4 PR. Major treatment-related adverse events (TRAEs) included rash (87.5%), paronychia (62.5%), oral ulcers (50.0%), and diarrhea (50.0%), none of which were ≥ grade 3 TRAEs.
CONCLUSIONS
Dacomitinib showed good activity and manageable toxicity in NSCLC patients with uncommon EGFR mutations.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Cohort Studies; Antineoplastic Agents; Protein Kinase Inhibitors; ErbB Receptors; Mutation
PubMed: 37840124
DOI: 10.1186/s12885-023-11465-2 -
Neuro-oncology Advances 2023Glioblastoma (GBM) is a highly aggressive and invasive brain tumor associated with high patient mortality. A large fraction of GBM tumors have been identified as...
BACKGROUND
Glioblastoma (GBM) is a highly aggressive and invasive brain tumor associated with high patient mortality. A large fraction of GBM tumors have been identified as epidermal growth factor receptor () amplified and ~50% also are mutant positive. In a previously reported multicenter phase II study, we have described the response of recurrent GBM (rGBM) patients to dacomitinib, an EGFR tyrosine kinase inhibitor (TKI). As a continuation of that report, we leverage the tumor cargo-encapsulating extracellular vesicles (EVs) and explore their genetic composition as carriers of tumor biomarker.
METHODS
Serum samples were longitudinally collected from EGFR-amplified rGBM patients who clinically benefitted from dacomitinib therapy (responders) and those who did not (nonresponders), as well as from a healthy cohort of individuals. The serum EV transcriptome was evaluated to map the RNA biotype distribution and distinguish GBM disease.
RESULTS
Using long RNA sequencing, we show enriched detection of over 10 000 coding RNAs from serum EVs. The EV transcriptome yielded a unique signature that facilitates differentiation of GBM patients from healthy donors. Further analysis revealed genetic enrichment that enables stratification of responders from nonresponders prior to dacomitinib treatment as well as following administration.
CONCLUSION
This study demonstrates that genetic composition analysis of serum EVs may aid in therapeutic stratification to identify patients with dacomitinib-responsive GBM.
PubMed: 37811539
DOI: 10.1093/noajnl/vdad104 -
Clinical and Translational Science Dec 2023This study aimed to evaluate the bioequivalence between test tablet dacomitinib and reference product Vizimpro® under fasting and fed conditions and assess their... (Randomized Controlled Trial)
Randomized Controlled Trial
This study aimed to evaluate the bioequivalence between test tablet dacomitinib and reference product Vizimpro® under fasting and fed conditions and assess their pharmacokinetic (PK) and safety profiles for gaining marketing approval of the new generic drug. A single-center, randomized, open-label, single-dose, two-treatment, two-period, crossover bioequivalence study was conducted in healthy Chinese subjects. Eligible healthy subjects randomly received a single 45 mg dose of test or reference formulations with an administration sequence of test tablet (T), reference tablet (R), or (RT), under both fasting and fed conditions, and each single administration was followed by a 21-day washout period. Plasma concentrations and corresponding non-compartmental PK parameters of dacomitinib were determined. The 90% confidence intervals of the geometric mean ratio (GMR) (test/reference) for C , AUC , and AUC , respectively, were 97.75%-119.99%, 101.00%-115.09%, and 100.27%-113.90% under fasting conditions and 95.20%-104.94%, 97.24%-102.23%, and 97.27%-101.88% under fed conditions, which were within the limits of 80%-125%. Under fasting and fed conditions, the PK characteristics of the test dacomitinib tablet and reference Vizimpro® were comparable; the two formulations of dacomitinib were demonstrated to be bioequivalent and well-tolerated in healthy Chinese volunteers.
Topics: Humans; Therapeutic Equivalency; Cross-Over Studies; Healthy Volunteers; Fasting; Tablets; China
PubMed: 37786330
DOI: 10.1111/cts.13653 -
Translational Cancer Research Aug 2023Accumulating evidence has shown that dacomitinib has potential activities for patients with non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor... (Review)
Review
The treatment of patients with non-small cell lung cancer carrying uncommon mutations, mutations, or brain metastases: a systematic review of pre-clinical and clinical findings for dacomitinib.
BACKGROUND
Accumulating evidence has shown that dacomitinib has potential activities for patients with non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor () mutations, human epidermal growth factor receptor 2 () mutations, or central nervous system (CNS) metastases.
METHODS
This study aimed to give a systematic review on its potential applications in the above settings by searching MEDLINE/PubMed, Embase, Cochrane Library, American Society of Clinical Oncology.org, European Society for Medical Oncology.org, and ClinicalTrials.gov.
RESULTS
The literature search yielded 649 publications in total. According to our findings, dacomitinib exhibited promising efficacy in patients with major uncommon mutations (including G719X, S768I, and L861Q). Both exon 20 insertional mutation (Ex20ins) and Ex20ins demonstrated significant internal heterogeneity in response to dacomitinib, among which specific subtypes (including D770delinsGY, A763_Y764insFQEA, and M774delinsWLV) were highly sensitive. Other uncommon mutations including 18del and L747P have also been shown responsive to dacomitinib. Interestingly, limited studies suggested dacomitinib application on certain first or third generation tyrosine kinase inhibitors (TKIs)' resistant secondary mutations. Last but not least, both pre-clinical and clinical data indicated that dacomitinib has an encouraging intracranial tumor control ability, regardless of uncommon mutations.
CONCLUSIONS
Dacomitinib demonstrated good disease control on patients with NSCLC harboring major uncommon mutations and specific or mutation subtypes, and selective clinical application of dacomitinib is considerable in this setting, especially for those with intracranial metastases.
PubMed: 37701115
DOI: 10.21037/tcr-23-95 -
Journal of Immunotherapy and Precision... Aug 2023Osimertinib is the treatment of choice for epidermal growth factor receptor ()-mutated advanced non-small-cell lung cancer (NSCLC). Because of its high price, many... (Review)
Review
INTRODUCTION
Osimertinib is the treatment of choice for epidermal growth factor receptor ()-mutated advanced non-small-cell lung cancer (NSCLC). Because of its high price, many low-income countries, such as Syria, cannot provide osimertinib, which makes it difficult to choose the appropriate treatment for these patients. This study aimed to review articles that assessed tyrosine kinase inhibitors (TKIs) for advanced NSCLC and developed an appropriate treatment plan for Syrian patients.
METHODS
An electronic literature search was conducted of published phase II and III studies that assessed the efficacy of EGFR-TKIs for advanced NSCLC between January 2003 and May 2022.
RESULTS
Seventeen articles were reviewed. The results were similar when erlotinib or icotinib was compared with gefitinib. Progression-free survival and overall survival for afatinib and dacomitinib were longer than for gefitinib, with small significant differences. Osimertinib was the only TKI that showed efficacy against the T790M mutation, which showed an improvement over the first- and second-generation TKIs. Osimertinib as a first-line therapy is not cost-effective compared with first- and second-generation TKIs.
CONCLUSION
Osimertinib is the preferred first-line treatment in patients with advanced mutated NSCLC. First- and second-generation TKIs are still considered good options, especially in low-income countries that cannot cover the costs of osimertinib.
PubMed: 37637235
DOI: 10.36401/JIPO-22-29