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OncoTargets and Therapy 2022Previous retrospective studies reported that proton-pump inhibitors (PPIs) may decrease the efficacy of first-generation epidermal growth factor receptor tyrosine kinase...
PURPOSE
Previous retrospective studies reported that proton-pump inhibitors (PPIs) may decrease the efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) including gefitinib and erlotinib. Afatinib had a wider soluble pH range, with possible fewer interactions with antacids. However, clinical data were limited. Thus, this study aimed to evaluate the negative impact of PPIs on afatinib.
PATIENTS AND METHODS
This retrospective cohort study included patients who are newly diagnosed with non-small cell lung cancer (NSCLC) from 2014 to 2019 using the Chang Gung Research Database. We identified patients who were treated with first-line afatinib and analyzed the association between the PPI and afatinib treatment outcomes.
RESULTS
A total of 1418 patients were treated with first-line afatinib and followed up for 6 years. First-line afatinib was administered to 918 eligible patients, and 330 had afatinib with PPIs. The combination use of PPIs and afatinib significantly decreased the overall survival (OS) compared with that of patients using afatinib only (median OS: 33.2 and 25.1 months, < 0.01) and multivariate analyses (Combination use: hazard ratio: 1.29; 1.05-1.59, = 0.01). The percentages of patients who were able to receive 2nd line therapy also significantly decreased in afatinib with PPI cohort.
CONCLUSION
The concurrent use of PPIs was associated with lower OS in patients with EGFR-mutant lung cancer under the first-line afatinib treatment but not associated with TTF.
PubMed: 36597496
DOI: 10.2147/OTT.S387165 -
Thoracic Cancer Nov 2021Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have improved the prognosis of mutant lung cancer; however, the clinical application value of...
BACKGROUND
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have improved the prognosis of mutant lung cancer; however, the clinical application value of TKIs for nonclassical EGFR mutation is unclear, especially for patients with rare uncommon mutations.
METHODS
A retrospective study based on electronic medical records was conducted to collect data on the effectiveness of afatinib in patients with stage IIIB/IV lung adenocarcinoma (LUAD) bearing uncommon mutations between January 2017 and January 2021.
RESULTS
Forty-two patients with uncommon mutations treated with afatinib were enrolled. The objective response rate (ORR) was 50.0% (10 of 20 patients). The median time to treatment failure (TTF) was 11.7 months (95% confidence interval = 8.5-18.3 months). Of the 42 patients, the median TTF was 15.0, 11.7, and 16.6 months in patients with Gly719Xaa (G719X), Ser768Ile (S768I), and Leu861Gln (L861Q) mutations, respectively. In patients with the rare uncommon mutation, the median TTF was 10.0 months, and the ORR was 50.0%. Afatinib demonstrated clinical activity across a set type of specific rare uncommon mutations, including EGFR L747P, A767_V769dup, and L833V/H835L, with a case having a TTF of more than 1 year. Molecular profiling reports of 16 afatinib-resistant biopsy samples were available, and the secondary T790M mutation was detected in one patient with L833V/H835L mutation and one harboring S768I/L858R mutation.
CONCLUSIONS
Our findings suggested that afatinib is effective in patients with uncommon mutations. Mechanisms of afatinib resistance vary and need further investigation.
Topics: Adenocarcinoma of Lung; Adult; Afatinib; Aged; Aged, 80 and over; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Protein Kinase Inhibitors; Retrospective Studies
PubMed: 34549528
DOI: 10.1111/1759-7714.14156 -
Taiwan Journal of Ophthalmology 2024This case discussed a significant ocular side effect, bilateral keratitis, which could be induced by afatinib, an irreversible epidermal growth factor receptor-tyrosine...
This case discussed a significant ocular side effect, bilateral keratitis, which could be induced by afatinib, an irreversible epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). We explored the disease progression of a 52-year-old, stage IV nasopharyngeal carcinoma male patient, who was under afatinib treatment and had experienced progressive bilateral eye dryness and tenderness on increasing afatinib from 40 mg every other day to 40 mg daily. Clinical examination noted bilateral visual acuity reduction, diffuse superficial punctate keratopathy in the right eye, and a central epithelial defect in the left eye. Seidel test results were negative for both eyes, with no corneal infiltration, lagophthalmos, anterior chamber cell precipitation, or retinal lesion. Symptoms subsequently resolved after reducing the frequency of afatinib used, along with intensive ocular hydration. In summary, this case highlighted afatinib's potential link to bilateral keratitis, and early afatinib dose adjustment with supportive medication could significantly reverse the condition.
PubMed: 38654991
DOI: 10.4103/tjo.TJO-D-24-00003 -
Targeted Oncology May 2022Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors are the standard first-line treatment for patients with advanced and recurrent EGFR-positive non-small...
The Difference in Clinical Outcomes Between Osimertinib and Afatinib for First-Line Treatment in Patients with Advanced and Recurrent EGFR-Mutant Non-Small Cell Lung Cancer in Taiwan.
BACKGROUND
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors are the standard first-line treatment for patients with advanced and recurrent EGFR-positive non-small cell lung cancer.
OBJECTIVE
The main objective of the present study was to compare the clinical efficacies between osimertinib and afatinib as first-line treatment in patients with EGFR-mutant non-small cell lung cancer.
METHODS
We retrospectively analyzed patients with advanced and recurrent non-small cell lung cancer who harbored an exon 19 deletion or an exon 21 L858R mutation and were being given either osimertinib or afatinib as first-line treatment from January 2018 to December 2020.
RESULTS
A total of 128 patients were selected for this study. The osimertinib group included 47 patients, while 81 patients received afatinib. The median follow-up time was 20.1 months in the osimertinib group and 22.7 months in the afatinib group. The median progression-free survival was 18.8 months and 13.1 months in the osimertinib and afatinib groups, respectively (hazard ratio 0.75 [95% confidence interval 0.48-1.18]). The median overall survival was not reached in the osimertinib group and was 41.7 months in the afatinib group (hazard ratio 0.79 [95% confidence interval 0.36-1.72]). In patients without brain metastasis, the median progression-free survival was 17.9 months and 17.2 months in the osimertinib and afatinib groups, respectively (hazard ratio 1.02 [95% confidence interval 0.56-1.85]). In patients with brain metastasis at baseline, the median progression-free survival was 22.1 months in the osimertinib group, and 10.9 months in the afatinib group (adjusted hazard ratio 0.45 [95% confidence interval 0.21-0.96]).
CONCLUSIONS
Our research demonstrates that there was no strong evidence showing that patients taking osimertinib as first-line treatment experienced longer median progression-free survival and overall survival than patients treated with afatinib. However, there was a statistical significance revealing that osimertinib provided better median progression-free survival than afatinib in patients with brain metastasis at baseline.
Topics: Acrylamides; Afatinib; Aniline Compounds; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Indoles; Lung Neoplasms; Mutation; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Taiwan
PubMed: 35460474
DOI: 10.1007/s11523-022-00878-x -
Veterinary Research Communications Dec 2023Canine glioma is one of the most common brain tumors with poor prognosis, making effective chemotherapy highly desirable. Previous studies have suggested that ERBB4, a...
Canine glioma is one of the most common brain tumors with poor prognosis, making effective chemotherapy highly desirable. Previous studies have suggested that ERBB4, a signaling molecule involving one of the epidermal growth factor receptors (EGFR), may be a promising therapeutic target. In this study, the anti-tumor effects of pan-ERBB inhibitors, which can inhibit the phosphorylation of ERBB4, were evaluated both in vitro and in vivo using a canine glioblastoma cell line. The results demonstrated that both afatinib and dacomitinib effectively reduced the expression of phosphorylated ERBB4, and significantly decreased the number of viable cells, ultimately prolonging the survival time of orthotopically xenografted mice. Further downstream of ERBB4, afatinib was found to suppress the expression of phosphorylated Akt and phosphorylated Extracellular signal-related kinases1 and 2 (ERK1/2) and induced apoptotic cell death. Thus, pan-ERBB inhibition is a promising therapeutic strategy for the treatment of canine gliomas.
Topics: Animals; Dogs; Mice; Afatinib; ErbB Receptors; Signal Transduction; Phosphorylation; Glioma; Cell Line, Tumor; Dog Diseases
PubMed: 36991174
DOI: 10.1007/s11259-023-10117-x -
Clinical Cancer Research : An Official... Oct 2023The EORTC-90111-24111 phase II window study evaluated afatinib versus no preoperative treatment in patients with primary squamous cell carcinoma of the head and neck...
PURPOSE
The EORTC-90111-24111 phase II window study evaluated afatinib versus no preoperative treatment in patients with primary squamous cell carcinoma of the head and neck (HNSCC). We investigated afatinib-induced tumor and microenvironment modifications by comparing pre- and posttreatment tumor biopsies.
PATIENTS AND METHODS
Thirty treatment-naïve patients with primary HNSCC were randomized. Twenty-five patients received afatinib for 14 days before surgery (40 mg 1×/day) and 5 patients were attributed to the control arm. Biopsies were taken at work-up and during surgery. Good quality RNA samples were used for omics analyses. The control arm was enlarged by samples coming from our previous similar window study.
RESULTS
IHC analyses of afatinib-treated tumor biopsies showed a decrease in pEGFR (P ≤ 0.05) and pERK (P ≤ 0.05); and an increase in CD3+ (P ≤ 0.01) and CD8+ (P ≤ 0.01) T-cell infiltration, and in CD3+ (P ≤ 0.05) T-cell density. RNA sequencing analyses of afatinib-treated tumor samples showed upregulation of inflammatory genes and increased expression scores of signatures predictive of response to programmed cell death protein 1 blockade (P ≤ 0.05). In posttreatment biopsies of afatinib-treated patients, two clusters were observed. Cluster 1 showed a higher expression of markers and gene sets implicated in epithelial-to-mesenchymal transition (EMT) and activation of cancer-associated fibroblasts (CAF) compared with cluster 2 and controls.
CONCLUSIONS
Short-term treatment with afatinib in primary HNSCC induces CD3+ and CD8+ tumor infiltration and, in some patients, EMT and CAF activation. These results open perspectives to overcome resistance mechanisms to anti-HER therapy and to potentiate the activity of immune checkpoint inhibitors.
PubMed: 37531234
DOI: 10.1158/1078-0432.CCR-23-0645 -
Cancer Research and Treatment Apr 2022The aim of this study was to investigate the efficacy of various epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) plus bevacizumab in advanced...
PURPOSE
The aim of this study was to investigate the efficacy of various epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) plus bevacizumab in advanced EGFR-mutant lung adenocarcinoma patients.
MATERIALS AND METHODS
From August 2016 to October 2020, we enrolled advanced lung adenocarcinoma patients harboring exon 19 deletion or L858R receiving gefitinib, erlotinib and afatinib plus bevacizumab as the first-line treatment for the purposes of analysis.
RESULTS
A total of 36 patients were included in the final analysis. Three patients received gefitinib, 17 received erlotinib, and 16 received afatinib combined with bevacizumab as the first-line treatment. The objective response rate was 77.8%, and disease control rate was 94.4%. The overall median progression-free survival (PFS) was 16.4 months, while the median PFS was 17.1 months in patients with exon 19 deletion, and 16.2 months in patients with L858R mutation (p=0.311). Regarding the use of different EGFR-TKIs, the median PFS was 17.1 months in the erlotinib group and 21.6 months in the afatinib group (p=0.617). In patients with brain metastasis at baseline, the median PFS was 18.9 months in the erlotinib group and 16.4 months in the afatinib group (p=0.747). Amongst patients harboring exon 19 deletion, the median PFS was 16.2 months in the erlotinib group and not-reached in the afatinib group (p=0.141). In patients with L858R mutation, the median PFS was 18.9 months in the erlotinib group and 16.2 months in the afatinib group (p=0.481).
CONCLUSION
Our research demonstrates that not only erlotinib combined with bevacizumab, but also afatinib plus bevacizumab as first-line treatment, provides solid clinical efficacy in advanced EGFR-mutant lung adenocarcinoma patients.
Topics: Adenocarcinoma of Lung; Afatinib; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors
PubMed: 34352999
DOI: 10.4143/crt.2021.671 -
Die Pharmazie Feb 2022Patients with prostate cancer often develop resistance to androgen deprivation therapy, a condition called castration-resistant prostate cancer (CRPC). Enzalutamide...
Patients with prostate cancer often develop resistance to androgen deprivation therapy, a condition called castration-resistant prostate cancer (CRPC). Enzalutamide (MDV3100) can prolong the survival of patients with CRPC after chemotherapy, but ∼50% of patients eventually relapse and develop resistance to MDV3100. Thus, it is necessary to explore new treatment methods to improve the therapeutic effect of MDV3100. Tyrosine kinases play an essential role in the pathogenesis of CRPC. MTT assay was used to detect the inhibitory effects of MDV3100 and tyrosine kinase inhibitor on prostate cancer cells. CompuSyn version 1.0 was used to calculate the combination index (CI) values using the Chou-Talalay method. Clone formation and EdU assay were used to detect the effect of afatinib combined with MDV3100 on the proliferation of 22Rv1 cells. RT-qPCR and Western blot were used to explore the mechanism of drug combination. The aim of the present study was to determine the effects of several tyrosine kinase inhibitors (TKIs) when used in combination with MDV3100 . The results demonstrated that TKIs combined with MDV3100 exerted a synergistic effect on a variety of PCa cells. Afatinib combined with MDV3100 could suppress the proliferation and migration of 22RV1 cells, as well as cause their cell cycle arrest and apoptosis. Mechanistically, afatinib effectively reduced the protein expression levels of HER2 and HER3 and inhibited EGFR phosphorylation, thereby enhancing the effect of MDV3100 and suppressing CRPC. These findings suggested that afatinib treatment improved the effect of MDV3100 on 22RV1 cells, highlighting this drug as a potential therapeutic strategy for patients with CRPC.
Topics: Afatinib; Androgen Antagonists; Benzamides; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Humans; Male; Neoplasm Recurrence, Local; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen
PubMed: 35209965
DOI: 10.1691/ph.2022.1948 -
European Journal of Cancer (Oxford,... Jan 2022An increasing number of advanced non-small cell lung cancer (NSCLC) cases are being reported in the ageing population. However, studies on the use of afatinib in elderly...
PURPOSE
An increasing number of advanced non-small cell lung cancer (NSCLC) cases are being reported in the ageing population. However, studies on the use of afatinib in elderly patients are scarce. We conducted a prospective multicentre, single-arm, and open-label phase II trial for low-dose afatinib (30 mg/day) use in elderly patients with NSCLC with EGFR mutation to assess quality-of-life (QOL) and pharmacokinetic (PK)/pharmacogenomic (PGx) parameters.
PATIENTS AND METHODS
The primary end-point was the objective response rate (ORR), and the planned number of registered cases was 35, with a threshold ORR of 50%, an expected ORR of 75%, α of 0.05, and β of 0.1. Secondary end-points were progression-free survival (PFS), overall survival (OS), the incidence rate of adverse events (AEs), QOL survey (FACT-L), and trough plasma concentration of afatinib at steady state (Css) and at the occurrence of clinically significant AEs.
RESULTS
The median age of the patients was 79 years. The ORR was 80.0% and the disease control rate was 91.4%. The median PFS and OS were 15.6 and 29.5 months, respectively. Four patients discontinued because of AEs. Treatment-related death was not observed. No significant change in QOL was observed at baseline and after 4, 8, and 12 weeks. Css was comparable with those in previous reports and was significantly higher in patients with grade 3 AEs. Direct correlations between afatinib treatment and PGx profiles were not observed.
CONCLUSIONS
An afatinib starting dose of 30 mg/day could be an effective and safe treatment option for elderly patients.
Topics: Afatinib; Aged; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Progression-Free Survival; Protein Kinase Inhibitors
PubMed: 34862083
DOI: 10.1016/j.ejca.2021.10.024 -
Cells Dec 2021() exon 20 insertion mutations account for a tenth of all mutations in lung cancers. An important unmet clinical need is the identification of EGFR exon 20 insertion...
EGFR-D770>GY and Other Rare EGFR Exon 20 Insertion Mutations with a G770 Equivalence Are Sensitive to Dacomitinib or Afatinib and Responsive to EGFR Exon 20 Insertion Mutant-Active Inhibitors in Preclinical Models and Clinical Scenarios.
() exon 20 insertion mutations account for a tenth of all mutations in lung cancers. An important unmet clinical need is the identification of EGFR exon 20 insertion mutants that can respond to multiple classes of approved EGFR-TKIs. We sought to characterize variants involving -D770 to -G770 position equivalence changes that structurally allow for response to irreversible 2nd generation EGFR-TKIs. Our group used preclinical models of EGFR exon 20 insertion mutations to probe representative 1st (erlotinib), 2nd (afatinib, dacomitinib), 3rd generation (osimertinib) and EGFR exon 20 insertion mutant-active (poziotinib, mobocertinib) TKIs; we also queried the available clinical literature plus our institutional database to enumerate clinical outcomes. -D770>GY and other insertions with a G770 equivalence were identified at a frequency of 3.96% in separate cohorts of exon 20 insertion mutated lung cancer ( = 429). Cells driven by EGFR-D770>GY were insensitive to erlotinib and osimertinib, displayed sensitivity to poziotinib and dacomitinib and were uniquely sensitive to afatinib and dacomitinib in comparison with other more typical EGFR exon 20 insertion mutations using proliferation and biochemical assays. Clinical cases with -G770 equivalence from the literature and our center mirrored the preclinical data, with radiographic responses and clinical benefits restricted to afatinib, dacomitinib, poziotinib and mobocertinib, but not to erlotinib or osimertinib. Although they are rare, at <4% of all exon 20 insertion mutations, EGFR-G770 equivalence exon 20 insertion mutations are sensitive to approved 2nd generation EGFR TKIs and EGFR exon 20 insertion mutant-active TKIs (mobocertinib and poziotinib). EGFR-D770>GY and other insertions with a G770 equivalence join EGFR-A763_Y764insFQEA as exon 20 insertion mutationsresponsive to approved EGFR TKIs beyond mobocertinib; this data should be considered for clinical care, genomic profiling reports and clinical trial elaboration.
Topics: Afatinib; Amino Acid Sequence; Animals; Cell Line; Disease Models, Animal; ErbB Receptors; Exons; Humans; Lung Neoplasms; Mice; Mutagenesis, Insertional; Mutation; Neoplasm Staging; Protein Kinase Inhibitors; Quinazolinones
PubMed: 34944068
DOI: 10.3390/cells10123561