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Anticancer Research Apr 2022Afatinib is a standard treatment for patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Osimertinib...
BACKGROUND/AIM
Afatinib is a standard treatment for patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Osimertinib can overcome the treatment resistance-associated EGFR T790M mutation, and the sequence of afatinib followed by osimertinib is an effective therapeutic strategy for NSCLC patients. This study comprehensively evaluated the outcomes of sequential therapy following frontline afatinib and identified predictive factors for T790M mutation acquisition.
PATIENTS AND METHODS
Data from patients with advanced NSCLC treated with frontline afatinib at a Taiwanese hospital group from June 2014 to March 2018 were retrospectively reviewed. The EGFR T790M mutation was detected by tissue sequencing or liquid biopsy. The patients' clinicopathological features were collected, and univariate and multivariate analyses were performed to identify potential predictive and prognostic factors.
RESULTS
A total of 635 patients treated with afatinib were enrolled in this study. Until August 2021, 553 patients experienced progression, and 225 patients underwent T790M mutation testing. The T790M positive rate was 54.2%. Both exon 19 deletion and progression-free survival were associated with T790M positivity. Osimertinib was found to be effective in T790M-positive but not T790M-negative NSCLC. The median overall survival (OS) was 61.8 months for patients with T790M mutation undergoing later-line osimertinib compared with 30.1 months for patients without T790M mutation undergoing chemotherapy only. Osimertinib independently prolonged OS after afatinib progression.
CONCLUSION
This study confirmed the efficacy of sequential afatinib and osimertinib treatment. T790M mutation detection and osimertinib availability are important for prolonging survival in patients with NSCLC harboring EGFR mutations.
Topics: Afatinib; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Retrospective Studies
PubMed: 35347039
DOI: 10.21873/anticanres.15697 -
Lung Cancer (Amsterdam, Netherlands) Dec 2021Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard of care for EGFR mutation-positive non-small cell lung cancer (NSCLC). However,...
BACKGROUND
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard of care for EGFR mutation-positive non-small cell lung cancer (NSCLC). However, optimal sequence of treatment has yet to be defined. Overall survival (OS) is influenced by the availability/use of subsequent therapy after first-line treatment. Emergence of T790M is the main mechanism of resistance to afatinib and second-line osimertinib could be a treatment option in this instance.
METHODS
In this non-interventional, global study (NCT04179890), existing medical/electronic records were identified for consecutive EGFR TKI-naïve patients with EGFR mutation-positive NSCLC (Del19 or L858R) treated with first-line afatinib and second-line osimertinib in regular clinical practice (n = 191; all T790M-positive). The primary objective was time to treatment failure (TTF). Key secondary objectives were OS and objective response rate (ORR).
RESULTS
At the start of afatinib treatment, median age (range) was 62 years (34-88). Fifty-five percent of patients were female and 67% were Asian. ECOG PS (0/1/≥2) was 31%/57%/12%. Fourteen percent of patients had brain metastases. At the start of osimertinib treatment, ECOG PS (0/1/≥2) was 25%/61%/14% and 14% had brain metastases (rising to 29% at the end of osimertinib treatment). The source of biopsy material (solid/liquid) was 86%/3% at the start of afatinib and 54%/33% at start of osimertinib. Mutations were mainly detected with PCR methods. Overall, median TTF was 27.7 months (95% CI: 24.0-30.2) and median OS was 36.5 months (95% CI: 32.9-41.8). ORR with afatinib and osimertinib was 74% and 45%. TTF, OS and ORR were generally consistent across subgroups.
CONCLUSION
Sequential afatinib and osimertinib demonstrated encouraging activity in patients with EGFR mutation-positive NSCLC and acquired T790M. Activity was observed across all subgroups, including patients with poor ECOG PS or brain metastases. ECOG PS and incidence of brain metastases remained stable prior to, and after, afatinib treatment.
Topics: Acrylamides; Afatinib; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lung Neoplasms; Middle Aged; Mutation; Protein Kinase Inhibitors
PubMed: 34649106
DOI: 10.1016/j.lungcan.2021.09.009 -
Integrative Cancer Therapies 2022In epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC), acquired resistance to EGFR tyrosine kinase inhibitors (TKI) leads to disease...
In epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC), acquired resistance to EGFR tyrosine kinase inhibitors (TKI) leads to disease progression. Strategies to overcome the resistance are required in treatment for advanced lung cancer. In this study, we investigated the therapeutic effect of afatinib and HangAmDan-B1 (HAD-B1) co-administration in gefitinib-resistant NSCLC using HCC827-GR, NSCLC cell line with gefitinib resistance, and the HCC827-GR cell implanted mouse model. HAD-B1 consists of 4 herbs, Radix, , C. A. Mey, and Birdwood, and has been reported to be effective in patients with advanced lung cancer in clinical practice. Our findings demonstrated that HAD-B1 combined with afatinib markedly inhibited cell proliferation and induced apoptosis compared to afatinib monotherapy and HAD-B1 monotherapy. Inhibition of HCC827-GR cell proliferation by HAD-B1 occurred through MET amplification and reduced phosphorylation, and the synergistic effect of afatinib and HAD-B1 induced cell cycle arrest and apoptosis in HCC827-GR cells via the downregulation of ERK and mTOR signaling pathways. In hematology and biochemistry tests, HAD-B1 alleviated the toxicity of tumor. In conclusion, HAD-B1 combined with afatinib would be a promising therapeutic strategy for NSCLC with EGFR-TKI resistance.
Topics: Animals; Mice; Carcinoma, Non-Small-Cell Lung; Afatinib; Gefitinib; Lung Neoplasms; Quinazolines; ErbB Receptors; Cell Line, Tumor; Drug Resistance, Neoplasm; Mutation
PubMed: 36565160
DOI: 10.1177/15347354221144311 -
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 -
Scientific Reports Dec 2023There is no strong and reliable predictive biomarker in head and neck squamous cell carcinoma (HNSCC) for EGFR inhibitors. We aimed to identify predictive and... (Randomized Controlled Trial)
Randomized Controlled Trial
There is no strong and reliable predictive biomarker in head and neck squamous cell carcinoma (HNSCC) for EGFR inhibitors. We aimed to identify predictive and pharmacodynamic biomarkers of efficacy of afatinib, a pan-HER tyrosine kinase inhibitor, in a window-of-opportunity trial (NCT01415674). Multi-omics analyses were carried out on pre-treatment biopsy and surgical specimen for biological assessment of afatinib activity. Sixty-one treatment-naïve and operable HNSCC patients were randomised to afatinib 40 mg/day for 21-28 days versus no treatment. Afatinib produced a high rate of metabolic response. Responders had a higher expression of pERK1/2 (P = 0.02) and lower expressions of pHER4 (P = 0.03) and pRB1 (P = 0.002) in pre-treatment biopsy compared to non-responders. At the cellular level, responders displayed an enrichment of tumor-infiltrating B cells under afatinib (P = 0.02). At the molecular level, NF-kappa B signaling was over-represented among upregulated genes in non-responders (P < 0.001; FDR = 0.01). Although exploratory, phosphoproteomics-based biomarkers deserve further investigations as predictors of afatinib efficacy.
Topics: Humans; Afatinib; Squamous Cell Carcinoma of Head and Neck; Quinazolines; Head and Neck Neoplasms; Biomarkers; Protein Kinase Inhibitors
PubMed: 38110561
DOI: 10.1038/s41598-023-49887-4 -
JAMA Ophthalmology Feb 2024Epidermal growth factor receptor inhibitors (EGFRis) have been reported to be associated with cutaneous and ocular side effects; however, there is limited evidence of an...
IMPORTANCE
Epidermal growth factor receptor inhibitors (EGFRis) have been reported to be associated with cutaneous and ocular side effects; however, there is limited evidence of an association between EGFRi treatment and keratitis.
OBJECTIVE
To determine the association between EGFRi treatment and agents and the risk of new-onset keratitis among patients with lung cancer.
DESIGN, SETTING, AND PARTICIPANTS
This US population-based cohort study examined TriNetX data of patients with lung cancer treated with or without EGFRis between May 1, 2003, and October 30, 2023.
EXPOSURES
Treatment with EGFRis, including the first-generation agents gefitinib and erlotinib, the second-generation agent afatinib, and the third-generation agent osimertinib.
MAIN OUTCOMES AND MEASURES
The risk of new-onset keratitis among patients with lung cancer receiving EGFRi treatment was determined using logistic and Cox proportional hazards regression.
RESULTS
Among 1 388 108 patients with lung cancer, 22 225 received EGFRis (mean [SD] age, 69.7 [10.6] years; 62.8% females and 37.2% males). Patients treated with EGFRis had a higher risk of keratitis than nonexposed patients (hazard ratio [HR], 1.520; 95% CI, 1.339-1.725). Subtypes of EGFRi-associated keratitis included keratoconjunctivitis (HR, 1.367; 95% CI, 1.158-1.615), superficial keratitis (HR, 1.635; 95% CI, 1.306-2.047), and corneal ulcer (HR, 2.132; 95% CI, 1.515-3.002). Patients taking afatinib had a higher risk of keratitis (HR, 2.229; 95% CI, 1.480-3.356).
CONCLUSIONS AND RELEVANCE
These findings suggest that patients with lung cancer treated with EGFRis may have an increased risk of new-onset keratitis, especially with the second-generation EGFRi afatinib, supporting the need for prompt diagnosis and management of EGFRi-associated ocular issues to prevent serious complications or treatment disruptions.
Topics: Male; Female; Humans; Aged; Lung Neoplasms; Afatinib; Cohort Studies; ErbB Receptors; Keratitis; Protein Kinase Inhibitors; Mutation
PubMed: 38206621
DOI: 10.1001/jamaophthalmol.2023.6089 -
Clinical Cancer Research : An Official... Jun 2020Fanconi anemia rare disease is characterized by bone marrow failure and a high predisposition to solid tumors, especially head and neck squamous cell carcinoma (HNSCC)....
PURPOSE
Fanconi anemia rare disease is characterized by bone marrow failure and a high predisposition to solid tumors, especially head and neck squamous cell carcinoma (HNSCC). Patients with Fanconi anemia with HNSCC are not eligible for conventional therapies due to high toxicity in healthy cells, predominantly hematotoxicity, and the only treatment currently available is surgical resection. In this work, we searched and validated two already approved drugs as new potential therapies for HNSCC in patients with Fanconi anemia.
EXPERIMENTAL DESIGN
We conducted a high-content screening of 3,802 drugs in a FANCA-deficient tumor cell line to identify nongenotoxic drugs with cytotoxic/cytostatic activity. The best candidates were further studied and for efficacy and safety.
RESULTS
Several FDA/European Medicines Agency (EMA)-approved anticancer drugs showed cancer-specific lethality or cell growth inhibition in Fanconi anemia HNSCC cell lines. The two best candidates, gefitinib and afatinib, EGFR inhibitors approved for non-small cell lung cancer (NSCLC), displayed nontumor/tumor IC ratios of approximately 400 and approximately 100 times, respectively. Neither gefitinib nor afatinib activated the Fanconi anemia signaling pathway or induced chromosomal fragility in Fanconi anemia cell lines. Importantly, both drugs inhibited tumor growth in xenograft experiments in immunodeficient mice using two Fanconi anemia patient-derived HNSCCs. Finally, toxicity studies in -deficient mice showed that administration of gefitinib or afatinib was well-tolerated, displayed manageable side effects, no toxicity to bone marrow progenitors, and did not alter any hematologic parameters.
CONCLUSIONS
Our data present a complete preclinical analysis and promising therapeutic line of the first FDA/EMA-approved anticancer drugs exerting cancer-specific toxicity for HNSCC in patients with Fanconi anemia.
Topics: Afatinib; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Fanconi Anemia; Female; Gefitinib; Head and Neck Neoplasms; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Squamous Cell Carcinoma of Head and Neck; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 32005748
DOI: 10.1158/1078-0432.CCR-19-1625 -
European Journal of Cancer (Oxford,... Jul 2023This phase I/expansion study assessed the safety, pharmacokinetics and preliminary antitumor activity of afatinib in paediatric patients with cancer.
AIM
This phase I/expansion study assessed the safety, pharmacokinetics and preliminary antitumor activity of afatinib in paediatric patients with cancer.
METHODS
The dose-finding part enroled patients (2-<18 years) with recurrent/refractory tumours. Patients received 18 or 23 mg/m/d afatinib orally (tablet or solution) in 28-d cycles. In the maximum tolerated dose (MTD) expansion, eligible patients (1-<18 years) had tumours fulfilling ≥2 of the following criteria in the pre-screening: EGFR amplification; HER2 amplification; EGFR membrane staining (H-score>150); HER2 membrane staining (H-score>0). The primary end-points were dose-limiting toxicities (DLTs), afatinib exposure, and objective response.
RESULTS
Of 564 patients pre-screened, 536 patients had biomarker data and 63 (12%) fulfilled ≥2 EGFR/HER2 criteria required for inclusion in the expansion part. A total of 56 patients were treated (17 in the dose-finding and 39 in the expansion part). DLTs were observed in one of six MTD-evaluable patients receiving 18 mg/m²/d and in two of five MTD-evaluable patients receiving 23 mg/m²/d; 18 mg/m²/d was defined as the MTD. There were no new safety signals. Pharmacokinetics confirmed exposure consistent with the approved dose in adults. One partial response (-81% per Response Assessment in Neuro-Oncology) was observed in a patient with a glioneuronal tumour harbouring a CLIP2::EGFR fusion; unconfirmed partial responses were observed in two patients. In total, 25% of patients experienced objective response or stable disease (95% confidence interval: 14-38).
CONCLUSION
Targetable EGFR/HER2 drivers are rare in paediatric cancers. Treatment with afatinib led to a durable response (>3 years) in one patient with a glioneuronal tumour with CLIP2::EGFR fusion.
Topics: Child; Humans; Afatinib; Antineoplastic Combined Chemotherapy Protocols; ErbB Receptors; Neoplasms; Child, Preschool; Adolescent
PubMed: 37178647
DOI: 10.1016/j.ejca.2023.04.007 -
Scientific Reports Nov 2023Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation is brain metastasis (BM)-prone. We determined the impact of this hallmark, along...
Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation is brain metastasis (BM)-prone. We determined the impact of this hallmark, along with EGFR subtype and generation of tyrosine kinase inhibitor (TKI) treatment, on patients' outcome. 553 metastatic EGFR-mutant NSCLC patients received front-line EGFR-TKI treatment. Progression-free survival (PFS), overall survival (OS) and secondary T790M rate were analysed. BM was observed in 211 (38.2%) patients. BM (HR 1.20 [95% CI 0.99-1.48]; p = 0.053), ECOG PS 0-1 (HR 0.71 [95% CI 0.54-0.93]; p = 0.014) and afatinib treatment (HR 0.81 [95% CI 0.66-0.99]; p = 0.045) were associated with PFS. Afatinib-treated patients without BM demonstrated a significantly longer PFS (16.3 months) compared to afatinib-treated patients with BM (13.7 months) and to gefitinib/erlotinib-treated patients with (11.1 months) or without BM (14.2 months; p < 0.001). CNS-only progression trended higher in afatinib-treated patients. ECOG PS 0-1 (HR 0.41 [95% CI 0.31-0.56]; p < 0.001) and EGFR L858R mutation (HR 1.46 [95% CI 1.13-1.88]; p = 0.003), but not BM, were the predictors for OS. BM (OR 2.02 [95% CI 1.02-4.08]; p = 0.040), afatinib treatment (OR 0.26 [95% CI 0.12-0.50]; p < 0.001) and EGFR L858R mutation (OR 0.55 [95% CI 0.28-1.05]; p = 0.070) were associated with secondary T790M rate. In BM patients, gefitinib/erlotinib-treated ones with 19 deletion mutation and afatinib-treated ones with L858R mutation had the highest and the lowest T790M rate (94.4% vs. 27.3%, p < 0.001), respectively. BM and generation of EGFR-TKI jointly impact PFS and secondary T790M rate in patients with EGFR-mutant NSCLC, whereas OS was mainly associated with EGFR subtype.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Afatinib; Erlotinib Hydrochloride; Gefitinib; ErbB Receptors; Lung Neoplasms; Protein Kinase Inhibitors; Mutation; Treatment Outcome; Brain Neoplasms
PubMed: 37989860
DOI: 10.1038/s41598-023-45815-8 -
Pharmacology 2022A simple, sensitive, rapid, and practical 2-dimensional liquid chromatography (2D-LC) method was developed and validated for the quantification of a 500-μL afatinib...
INTRODUCTION
A simple, sensitive, rapid, and practical 2-dimensional liquid chromatography (2D-LC) method was developed and validated for the quantification of a 500-μL afatinib sample extracted from human plasma.
METHODS
The plasma samples were pretreated with acetonitrile for protein precipitation. The mobile phase consisted of a first-dimensional mobile phase (acetonitrile, methanol, and 25 mmol/L ammonium phosphate in a ratio of 25:25:50, V/V/V) and a second-dimensional mobile phase (acetonitrile and 10 mmol/L ammonium phosphate in a ratio of 25:75, V/V). The average recovery of the plasma samples was stable and reproducible (98.56%-100.02%).
RESULTS
The analyte was sufficiently stable for handling and analysis. The calibration curve was linear, ranging from 10.93 to 277.25 ng/mL with regression equation y = 804.60 x - 4,169.87 (R2 = 0.999). The relative standard deviations for accuracy and precision studies were within ±2.30% and <3.41%, respectively (intra- and interday). Finally, the validated method was successfully employed to determine the drug levels in plasma from the patients treated with afatinib. In clinical assessment, the patients with gastric cancer were orally administered with 30 or 40 mg per day of afatinib, which resulted in large plasma concentrations, ranging from 5.52 to 45.16 ng/mL.
CONCLUSION
The results indicated that this method was useful for the therapeutic drug monitoring of afatinib and suitable for the assessment of the risks and benefits of chemotherapy in patients with non-small cell lung cancer.
Topics: Acetonitriles; Afatinib; Carcinoma, Non-Small-Cell Lung; Chromatography, High Pressure Liquid; Chromatography, Liquid; Humans; Lung Neoplasms; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 35086096
DOI: 10.1159/000521181