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Current Oncology (Toronto, Ont.) May 2023Afatinib, the world's first irreversible ErbB family (containing four different cancer cell epidermal growth factor receptors, including EGFR, HER2, ErbB3, and ErbB4)... (Review)
Review
Afatinib, the world's first irreversible ErbB family (containing four different cancer cell epidermal growth factor receptors, including EGFR, HER2, ErbB3, and ErbB4) inhibitor, is a second-generation oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). It can be used as a first-line treatment for locally advanced or metastatic non-small-cell lung cancer (NSCLC) with an EGFR-sensitive mutation or for patients with locally advanced or metastatic squamous lung cancer whose disease progresses during or after platinum-containing chemotherapy. Currently, with the use of third-generation EGFR-TKIs, afatinib is no longer clinically indicated as the first choice for patients with NSCLC who have EGFR-sensitive mutations. However, afatinib showed a considerable inhibitory effect in NSCLC patients with uncommon EGFR mutations (G719X, S768I, and L861Q) according to a combined post hoc analysis of the LUX-Lung2/3/6 trials. With the development of genetic testing technology, the detection rate of uncommon EGFR mutations is increasing. The aim of this paper is to describe in detail the sensitivity of rare EGFR mutations to afatinib and to provide information and a reference for those suffering from advanced NSCLC who have uncommon EGFR mutations.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Afatinib; Lung Neoplasms; Protein Kinase Inhibitors; ErbB Receptors; Mutation
PubMed: 37366888
DOI: 10.3390/curroncol30060405 -
Biochemical Pharmacology Dec 2023Esophageal squamous cell carcinoma (ESCC) is a highly aggressive tumor with significant heterogeneity in incidence and outcomes. The role of Neuregulin 1 (NRG1) in ESCC...
Esophageal squamous cell carcinoma (ESCC) is a highly aggressive tumor with significant heterogeneity in incidence and outcomes. The role of Neuregulin 1 (NRG1) in ESCC and its contribution to aggressiveness remain unknown. This study aims to investigate the functions and molecular mechanisms of NRG1 in ESCC as well as the treatment strategy for ESCC with overexpression of NRG1. We firstly demonstrated the upregulation of NRG1 and a negative correlation trend between patients' overall survival (OS) and the expression level of NRG1 in esophageal cancer. And then we found NRG1 promoted cell proliferation, migration, inhibited apoptosis, and accelerated tumorigenesis and metastasis in ESCC using cell lines and xenograft models. Furthermore, we discovered that NRG1 activated the NF-κB/MMP9 signaling pathway, contributing to the metastatic phenotype in ESCC. Finally, we show that afatinib (FDA approved cancer growth blocker) could inhibit ESCC with overexpressed NRG1 and down-regulation of NRG1 along with afatinib treatment provides higher efficient strategy. This study uncovers the critical role and molecular mechanism of NRG1 in ESCC tumorigenesis and metastasis, suggesting its potential as a novel biomarker for ESCC treatment.
Topics: Humans; Esophageal Squamous Cell Carcinoma; Esophageal Neoplasms; Afatinib; Carcinoma, Squamous Cell; Neuregulin-1; Carcinogenesis; Cell Transformation, Neoplastic; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Cell Movement
PubMed: 37989416
DOI: 10.1016/j.bcp.2023.115920 -
Expert Review of Anticancer Therapy Jul 2020Afatinib is a second-generation epidermal growth factor receptor () tyrosine kinase inhibitor, acting as an irreversible and multitarget blocker of ErbB family members.... (Comparative Study)
Comparative Study Review
INTRODUCTION
Afatinib is a second-generation epidermal growth factor receptor () tyrosine kinase inhibitor, acting as an irreversible and multitarget blocker of ErbB family members. Afatinib is currently approved for advanced non-small-cell lung cancer (NSCLC) harboring common and uncommon sensitizing mutations and for squamous NSCLC patients progressing after first-line platinum-based chemotherapy.
AREAS COVERED
This review summarizes the efficacy and safety profile of afatinib compared with chemotherapy and other EGFR TKIs, in order to evaluate its characteristics and potential role in the increasingly complex treatment landscape of -mutant lung cancer. Future perspectives and innovative drug combinations are also discussed.
EXPERT OPINION
Afatinib has been demonstrated to improve efficacy and quality of life compared with chemotherapy with a toxicity profile. However, in recent years, the increasing availability of different treatment options for advanced -mutant NSCLC has made the current treatment scenario more complicated, with an increasing need of new and scientific data. In this light, the identification and validation of potential clinicopathological and/or molecular predictors of benefit, as well as the clarification of resistance mechanisms, may help to clarify the most appropriate treatment strategies and sequences for -mutant patients.
Topics: Afatinib; Animals; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Quality of Life
PubMed: 32529917
DOI: 10.1080/14737140.2020.1776119 -
Oncotarget Mar 2024Here, I suggest that while first-line osimertinib extends median progression-free survival (PFS) in EGFR-mutant lung cancer compared to first-generation TKIs, it reduces...
Here, I suggest that while first-line osimertinib extends median progression-free survival (PFS) in EGFR-mutant lung cancer compared to first-generation TKIs, it reduces individual PFS in 15-20% of patients compared to first-generation TKIs. Since detecting a single resistant cell before treatment is usually impossible, osimertinib must be used in all patients as a first-line treatment, raising median PFS overall but harming some. The simplest remedy is a preemptive combination (PC) of osimertinib and gefitinib. A comprehensive PC (osimertinib, afatinib/gefitinib, and capmatinib) could dramatically increase PFS for 80% of patients compared to osimertinib alone, without harming anyone. This article also explores PCs for MET-driven lung cancer.
Topics: Humans; Gefitinib; Acrylamides; Afatinib; Lung Neoplasms; Aniline Compounds; Indoles; Pyrimidines
PubMed: 38497774
DOI: 10.18632/oncotarget.28569 -
Clinical Lung Cancer Sep 2023Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has limited treatment options for patients with EGFR-mutated non-small-cell lung...
BACKGROUND
Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has limited treatment options for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Although osimertinib or afatinib alone induced drug-resistant clones with EGFR secondary mutation in a preclinical model, its combination prevented the appearance of these mutations. We investigated alternating-dose therapy of osimertinib and afatinib in patients with EGFR-mutant NSCLC in a single-arm Phase II trial.
METHODS
Treatment-naïve patients with stage IV NSCLC harboring an activating EGFR mutation were enrolled. Alternating cycles of osimertinib (80 mg/day) followed by afatinib (20 mg/day) were administered every 8 weeks. Genomic analysis was performed using circulating tumor DNA obtained before and after the treatment.
RESULTS
Among the 46 enrolled patients, the median progression-free survival was 20.2 months. The overall response rate was 69.6%. The median overall survival was not reached. Among the 26 plasma samples obtained after the acquisition of resistance, 3 showed an increased MET gene copy number, and 1 showed BRAF mutation. Meanwhile, no EGFR secondary mutation was detected.
CONCLUSION
The efficacy of our treatment was not significantly different from osimertinib alone, as reported previously in untreated advanced NSCLC patients with EGFR mutations. Although the sample size was limited, this treatment may prevent the emergence of EGFR secondary mutations that trigger drug resistance. Further studies are warranted to establish the significance of this treatment.
CLINICAL TRIAL REGISTRATION
jRCTs051180009.
Topics: Humans; Lung Neoplasms; Afatinib; Carcinoma, Non-Small-Cell Lung; Protein Kinase Inhibitors; ErbB Receptors; Mutation
PubMed: 37344331
DOI: 10.1016/j.cllc.2023.05.008 -
Journal of Thoracic Oncology : Official... May 2024ERBB2 amplification in lung cancer remains poorly characterized. HER2 (encoded by ERBB2) is a transmembrane tyrosine kinase capable of ligand-independent dimerization...
INTRODUCTION
ERBB2 amplification in lung cancer remains poorly characterized. HER2 (encoded by ERBB2) is a transmembrane tyrosine kinase capable of ligand-independent dimerization and signaling when overexpressed, and a common cause of HER2 overexpression is ERBB2 amplification. Here, we evaluated the clinicopathologic and genomic characteristics of ERBB2-amplified NSCLC and explored a HER2 antibody-drug conjugate (ADC) therapeutic strategy.
METHODS
Our institutional next-generation DNA sequencing data (OncoPanel) from 5769 NSCLC samples (5075 patients) were queried for cases having high-level ERBB2 amplification (≥6 copies). Clinical and demographic characteristics were extracted from the electronic medical records. Efficacy of the pan-ERBB inhibitor afatinib or HER2 ADCs (trastuzumab deruxtecan and trastuzumab emtansine) was evaluated in NSCLC preclinical models and patients with ERBB2 amplification.
RESULTS
High-level ERBB2 amplification was identified in 0.9% of lung adenocarcinomas and reliably predicted overexpression of HER2. ERBB2 amplification events are detected in two distinct clinicopathologic and genomic subsets of NSCLC: as the sole mitogenic driver in tumors arising in patients with a smoking history or as a concomitant alteration with other mitogenic drivers in patients with a light or never smoking history. We further reveal that trastuzumab deruxtecan is effective therapy in in vitro and in vivo preclinical models of NSCLC harboring ERBB2 amplification and report two cases of clinical activity of an anti-HER2 ADC in patients who acquired ERBB2 amplification after previous targeted therapy.
CONCLUSIONS
High-level ERBB2 amplification reliably predicts HER2 overexpression in patients with NSCLC, and HER2 ADC is effective therapy in this population.
Topics: Humans; Lung Neoplasms; Receptor, ErbB-2; Carcinoma, Non-Small-Cell Lung; Female; Male; Gene Amplification; Middle Aged; Animals; Immunoconjugates; Aged; Mice; Trastuzumab; Prevalence; Afatinib; Ado-Trastuzumab Emtansine; Camptothecin
PubMed: 38154514
DOI: 10.1016/j.jtho.2023.12.019 -
Neoplasia (New York, N.Y.) Sep 2023Afatinib, as the first-line treatment for non-small cell lung cancer (NSCLC), causes severe gastrointestinal adverse reactions that greatly affect patients' quality of...
Afatinib, as the first-line treatment for non-small cell lung cancer (NSCLC), causes severe gastrointestinal adverse reactions that greatly affect patients' quality of life and even potentially result in treatment discontinuation. Multiple dose adjustments and concomitant use of anti-diarrheal medications are commonly employed to manage diarrhea, also allowing for a recovery period between each adjustment. However, these approaches are based on empirical guidance and still have limitations. This study aims to explore reliable approaches to alleviate diarrhea by focusing on two strategies: adjusting the dosing regimen of afatinib itself and implementing combination therapy. In this study, we firstly revealed a dose-dependent relationship between afatinib-induced diarrhea and gastrointestinal epithelial damage, resulting in atrophy, reduced expression of tight junction proteins, and increased permeability. We further found that even after discontinuation of the medication, although the severity of diarrhea had improved to baseline, the tight junction proteins and permeability of the intestinal epithelium did not fully recover, and the pharmacokinetics studies showed that drug absorption significantly increased than normal. This indicated the recovery period was longer than expected and may accelerate the occurrence of subsequent episodes of diarrhea. Hence, it would be prudent to consider adjustments to the starting dose or the recovery interval. Furthermore, we initially investigated the relationship between DPP enzyme and afatinib-induced diarrhea and found a significant decrease in plasma DPP enzyme activity following afatinib-induced diarrhea. Subsequently, we conducted continuous treatment with sitagliptin and observed significant improvement in afatinib-induced diarrhea. We observed that sitagliptin can promote the production of anti-inflammatory factors, increase the expression of intestinal epithelial tight junction proteins, and improve intestinal microbiota, further validating the mechanism through the use of GLP-2 as GLP-2 receptor inhibitor. In conclusion, sitagliptin exhibits promising potential as a therapeutic option for managing afatinib-induced diarrhea. Taken together, our study provides valuable insights into alleviating afatinib-induced diarrhea through both afatinib medication adjustment and sitagliptin combination therapy.
Topics: Rats; Animals; Afatinib; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Sitagliptin Phosphate; Quality of Life; ErbB Receptors; Diarrhea
PubMed: 37567055
DOI: 10.1016/j.neo.2023.100922 -
Proceedings of the National Academy of... Apr 2024High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES)....
High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES). Human papillomavirus DNA was detected in 65.6% (42/64) of the tumors. Recurrent mutations were identified in and The top mutated genes included / and a gene not yet implicated in NETc. Somatic CNV analysis identified two copy number gains (3q27.1 and 19q13.12) and five copy number losses (1p36.21/5q31.3/6p22.2/9q21.11/11p15.5). Also, gene fusions affecting the and genes were identified in one of the eight samples subjected to RNA sequencing. To resolve evolutionary history, multiregion WES in NETc admixed with adenocarcinoma cells was performed (i.e., mixed-NETc). Phylogenetic analysis of mixed-NETc demonstrated that adenocarcinoma and neuroendocrine elements derive from a common precursor with mutations typical of adenocarcinomas. Over one-third (22/64) of NETc demonstrated a mutator phenotype of C > T at CpG consistent with deficiencies in , a member of the base excision repair (BER) pathway. Mutations in the PI3K/AMPK pathways were identified in 49/64 samples. We used two patient-derived-xenografts (PDX) (i.e., NET19 and NET21) to evaluate the activity of pan-HER (afatinib), PIK3CA (copanlisib), and ATR (elimusertib) inhibitors, alone and in combination. PDXs harboring alterations in the ERBB2/PI3K/AKT/mTOR/ATR pathway were sensitive to afatinib, copanlisib, and elimusertib ( < 0.001 vs. controls). However, combinations of copanlisib/afatinib and copanlisib/elimusertib were significantly more effective in controlling NETc tumor growth. These findings define the genetic landscape of NETc and suggest that a large subset of these highly lethal malignancies might benefit from existing targeted therapies.
Topics: Humans; Female; Uterine Cervical Neoplasms; Afatinib; Phylogeny; Phosphatidylinositol 3-Kinases; Neuroendocrine Tumors; Mutation; Class I Phosphatidylinositol 3-Kinases; Adenocarcinoma; Carcinoma, Neuroendocrine; DNA Mutational Analysis
PubMed: 38625939
DOI: 10.1073/pnas.2321898121 -
Cancer Chemotherapy and Pharmacology Oct 2023Because of the large interindividual variability of afatinib pharmacokinetics and adverse events, we evaluated the effects of polymorphisms in pregnane X receptor...
Effects of polymorphisms in pregnane X receptor and ABC transporters on afatinib in Japanese patients with non-small cell lung cancer: pharmacogenomic-pharmacokinetic and exposure-response analysis.
PURPOSE
Because of the large interindividual variability of afatinib pharmacokinetics and adverse events, we evaluated the effects of polymorphisms in pregnane X receptor (NR1I2) and ABC transporters (ABCB1, ABCG2, and ABCC2) on the pharmacokinetics of afatinib.
METHODS
The steady-state area under the concentration-time curve (AUC) of afatinib was analyzed using blood sampling just prior to and at 1, 2, 4, 6, 8, 12, and 24 h on day 15 after administration.
RESULTS
The median oral clearance (CL/F) of afatinib in patients with the NR1I2 7635A allele was significantly lower than those in patients with the 7635G/G genotype (42.0 and 60.0 L/h, respectively, P = 0.025). There were no significant differences in afatinib CL/F between genotypes for NR1I2 8055C > T, -25385C > T, ABCB1, ABCG2, and ABCC2 polymorphisms. Based on the area under the receiver-operating characteristic curve, the threshold afatinib AUC value for prediction of dose reduction or withdrawal was 689 ng·h/mL at the best sensitivity (81.0%) and specificity (72.7%). In multivariate logistic regression analysis, an afatinib AUC above 689 ng·h/mL was independently associated with increased risk of dose reduction or withdrawal (OR: 11.66, P = 0.012).
CONCLUSIONS
The NR1I2 7635A allele was related to a lower afatinib CL/F. Based on the AUC of 689 ng h/mL and CL/F, the optimal doses for patients with the NR1I2 7635G/G genotype and 7635A allele were recommended to be set at 40 and 30 mg/day, respectively, and subsequent adjustment of the maintenance dose based on the plasma concentrations of afatinib may be necessary to avoid afatinib-related adverse events.
Topics: Humans; Afatinib; Carcinoma, Non-Small-Cell Lung; ATP-Binding Cassette Transporters; Pregnane X Receptor; Pharmacogenetics; East Asian People; Lung Neoplasms; Genotype; Polymorphism, Single Nucleotide
PubMed: 37500985
DOI: 10.1007/s00280-023-04569-w -
Clinical Cancer Research : An Official... Apr 2022EGFR pathway inhibition may promote anti-programmed cell death protein 1 (PD-1) responses in preclinical models, but how EGFR inhibition affects tumor antigen...
PURPOSE
EGFR pathway inhibition may promote anti-programmed cell death protein 1 (PD-1) responses in preclinical models, but how EGFR inhibition affects tumor antigen presentation during anti-PD-1 monotherapy in humans remain unknown. We hypothesized that afatinib, an irreversible EGFR tyrosine kinase inhibitor, would improve outcomes in patients treated with pembrolizumab for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) by promoting antigen presentation and immune activation in the tumor microenvironment.
PATIENTS AND METHODS
The ALPHA study (NCT03695510) was a single-arm, Phase II study with Simon's 2-stage design. Afatinib and pembrolizumab were administered to patients with platinum-refractory, recurrent, or metastatic HNSCC. The primary endpoint was the objective response rate (ORR). The study applied gene expression analysis using a NanoString PanCancer Immune Profiling Panel and next-generation sequencing using FoundationOne CDx.
RESULTS
From January 2019 to March 2020, the study enrolled 29 eligible patients. Common treatment-related adverse events were skin rash (75.9%), diarrhea (58.6%), and paronychia (44.8%). Twelve patients (41.4%) had an objective partial response to treatment. The median progression-free survival was 4.1 months, and the median overall survival was 8.9 months. In a paired tissue analysis, afatinib-pembrolizumab were found to upregulate genes involved in antigen presentation, immune activation, and natural killer cell-mediated cytotoxicity. Unaltered methylthioadenosine phosphorylase and EGFR amplification may predict the clinical response to the therapy.
CONCLUSIONS
Afatinib may augment pembrolizumab therapy and improve the ORR in patients with HNSCC. Bioinformatics analysis suggested the enhancement of antigen presentation machinery in the tumor microenvironment.
Topics: Afatinib; Antibodies, Monoclonal, Humanized; Carcinoma, Squamous Cell; ErbB Receptors; Head and Neck Neoplasms; Humans; Neoplasm Recurrence, Local; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment
PubMed: 35046059
DOI: 10.1158/1078-0432.CCR-21-3025