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Current Treatment Options in Oncology Dec 2023EGFR tyrosine kinase inhibitors (TKI) should always be considered when treating advanced/metastatic non-small cell lung cancer (NSCLC) with atypical EGFR mutations. The... (Review)
Review
EGFR tyrosine kinase inhibitors (TKI) should always be considered when treating advanced/metastatic non-small cell lung cancer (NSCLC) with atypical EGFR mutations. The first choice of TKI depends on the specific mutation(s) present and its effect on structure and function of the EGFR protein. Afatinib is the only EGFR TKI currently FDA approved for atypical EGFR mutations and has the strongest data to support its use in PACC mutations, a subgroup of atypical EGFR mutations which includes G719X and S7681. Dacomitinib may also be an option for these mutations given similar efficacy to afatinib. In contrast, for classical-like mutations such as L861Q, osimertinib should be considered the first choice given that their behavior mimics that of the classical mutations exon 19 deletion and L858R. Osimertinib should also be utilized in the setting of a concurrent T790M mutation. Superior CNS penetrance and well managed toxicity profile may also be reasons to consider osimertinib. Given that the choice of TKI may depend on the specific mutation, it is crucial that every patient diagnosed with NSCLC undergo comprehensive sequencing to identify these mutations.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Afatinib; ErbB Receptors; Mutation; Protein Kinase Inhibitors
PubMed: 38095779
DOI: 10.1007/s11864-023-01159-z -
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 -
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 -
Nature Reviews. Clinical Oncology Sep 2018
Topics: Afatinib; Carcinogenesis; Cell Transformation, Neoplastic; Humans; Proto-Oncogene Proteins p21(ras)
PubMed: 29985468
DOI: 10.1038/s41571-018-0068-1 -
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 -
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 -
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 -
Journal of Oncology Pharmacy Practice :... Sep 2020Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors represent the standard of care in patients with mutation-positive (m+) non-small cell lung cancer... (Review)
Review
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors represent the standard of care in patients with mutation-positive (m+) non-small cell lung cancer (NSCLC). The availability of several EGFR tyrosine kinase inhibitors approved for use in the first-line or later settings in NSCLC warrants an in-depth understanding of the pharmacological properties of, and clinical data supporting, these agents. The second-generation, irreversible ErbB-family blocker, afatinib, has been extensively studied in the context of m+ NSCLC. Results from the LUX-Lung 3 and 6 studies showed that afatinib was more active and better tolerated than chemotherapy in patients with tumors harboring mutations. Subanalysis of these trials, along with real-world data, indicates that afatinib is active in patients with certain uncommon mutations (S768I/G719X/L861Q) as well as common mutations (Del19/L858R), and in patients with active brain metastases. In LUX-Lung 7, a head-to-head phase IIb trial, afatinib improved progression-free survival and time-to-treatment failure versus the first-generation reversible EGFR tyrosine kinase inhibitor, gefitinib, albeit with a higher incidence of serious treatment-related adverse events. Nevertheless, afatinib is generally well tolerated, and adverse events are manageable through supportive care and a well-defined tolerability-guided dose adjustment scheme. In this review, we provide a detailed overview of the pharmacology, efficacy, and safety of afatinib, discuss treatment sequencing strategies following emergence of different resistance mechanisms, and shed light on the economic impact of afatinib. We also provide a comparison of afatinib with the available EGFR tyrosine kinase inhibitors and discuss its position within treatment strategies for patients with m+ NSCLC.
Topics: Afatinib; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Gefitinib; Humans; Lung Neoplasms; Mutation; Progression-Free Survival; Protein Kinase Inhibitors
PubMed: 32567494
DOI: 10.1177/1078155220931926 -
Lung Cancer (Amsterdam, Netherlands) Oct 2023Adding bevacizumab to first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) prolonged the progression-free survival (PFS), but... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Adding bevacizumab to first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) prolonged the progression-free survival (PFS), but limited data are available for second-generation EGFR-TKIs. AfaBev-CS is a randomized, phase II trial comparing afatinib plus bevacizumab and afatinib alone as first-line treatment.
PATIENTS AND METHODS
Untreated patients with non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations (Del19 or L858R) were enrolled and randomly assigned to receive either afatinib (30 mg) plus bevacizumab (AfaBev group) or afatinib (40 mg) monotherapy (Afa group). The primary endpoint was PFS. The power was >50% under the assumptions of a median PFS of 12 months for the Afa group and hazard ratio (HR) of 0.6 for the AfaBev group.
RESULTS
Between August 2017 and September 2019, 100 patients were enrolled. There was no significant difference in PFS between the groups. The median PFS was 16.3 and 16.1 months for the AfaBev and Afa groups, respectively, with an HR of 0.865 (95% confidence interval [CI], 0.539 to 1.388; p = 0.55). In terms of overall survival, there was no significant difference between the groups (HR, 0.84; 95% CI, 0.39 to 1.83; p = 0.67). The overall response rate was 82.6% and 76.6% in the AfaBev and Afa groups, respectively (p = 0.61). Grade ≥ 3 diarrhea, hypertension, acneiform rash, paronychia, and stomatitis were frequently observed in the AfaBev group.
CONCLUSIONS
This study failed to show efficacy of AfaBev over Afa for improving PFS in untreated patients with EGFR-mutated NSCLC.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Afatinib; Bevacizumab; Lung Neoplasms; ErbB Receptors; Mutation
PubMed: 37651927
DOI: 10.1016/j.lungcan.2023.107349