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Annals of Oncology : Official Journal... Jan 2017Analysis of circulating cell-free DNA (cfDNA) is under intensive investigation for its potential to identify tumor somatic mutations. We have now explored the usefulness...
Monitoring of somatic mutations in circulating cell-free DNA by digital PCR and next-generation sequencing during afatinib treatment in patients with lung adenocarcinoma positive for EGFR activating mutations.
BACKGROUND
Analysis of circulating cell-free DNA (cfDNA) is under intensive investigation for its potential to identify tumor somatic mutations. We have now explored the usefulness of such liquid biopsy testing with both the digital polymerase chain reaction (dPCR) and next-generation sequencing (NGS) during treatment of patients with the epidermal growth factor receptor (EGFR) inhibitor afatinib.
PATIENTS AND METHODS
Eligible patients had advanced lung adenocarcinoma with EGFR activating mutations and were treated with afatinib. Plasma samples were collected before and during (4 and 24 weeks) afatinib treatment as well as at disease progression. Tumor and plasma DNA were analyzed by dPCR and NGS.
RESULTS
Thirty-five patients were enrolled. The objective response rate and median progression-free survival (PFS) were 77.1% and 13.8 months, respectively. Tumor and plasma DNA were available for 32 patients. dPCR and NGS detected EGFR activating mutations in 81.3% and 71.9% of baseline cfDNA samples, respectively. In 19 patients treated with afatinib for ≥24 weeks, the number of EGFR mutant alleles detected in cfDNA by dPCR declined rapidly and markedly after treatment onset, becoming undetectable or detectable at only a low copy number (<10 copies per milliliter) at 4 weeks. Median PFS was slightly longer for patients with undetectable EGFR mutant alleles in cfDNA at 4 weeks than for those in whom such alleles were detectable (14.3 versus 10.0 months). A total of 45 somatic mutations was identified in baseline tumor DNA, and 30 (66.7%) of these mutations were identified in cfDNA by NGS. Allele frequency for somatic mutations in cfDNA determined by NGS changed concordantly during afatinib treatment with the number of EGFR mutant alleles determined by dPCR.
CONCLUSIONS
Monitoring of cfDNA by dPCR is informative for prediction of afatinib efficacy, whereas that by NGS is reliable and has the potential to identify mechanisms of treatment resistance.
Topics: Adenocarcinoma; Adenocarcinoma of Lung; Afatinib; Circulating Tumor DNA; ErbB Receptors; Female; High-Throughput Nucleotide Sequencing; Humans; Liquid Biopsy; Lung Neoplasms; Male; Mutation; Neoplasm Staging; Polymerase Chain Reaction; Prospective Studies; Quinazolines
PubMed: 28177428
DOI: 10.1093/annonc/mdw531 -
Nature Communications Aug 2023Afatinib, an irreversible ErbB-family blocker, could improve the survival of advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer patients...
Afatinib, an irreversible ErbB-family blocker, could improve the survival of advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer patients (NSCLCm+). This phase II trial (NCT04201756) aimed to assess the feasibility of neoadjuvant Afatinib treatment for stage III NSCLCm+. Forty-seven patients received neoadjuvant Afatinib treatment (40 mg daily). The primary endpoint was objective response rate (ORR). Secondary endpoints included pathological complete response (pCR) rate, pathological downstaging rate, margin-free resection (R0) rate, event-free survival, disease-free survival, progression-free survival, overall survival, treatment-related adverse events (TRAEs). The ORR was 70.2% (95% CI: 56.5% to 84.0%), meeting the pre-specified endpoint. The major pathological response (MPR), pCR, pathological downstaging, and R0 rates were 9.1%, 3.0%, 57.6%, and 87.9%, respectively. The median survivals were not reached. The most common TRAEs were diarrhea (78.7%) and rash (78.7%). Only three patients experienced grade 3/4 TRAEs. Biomarker analysis and tumor microenvironment dynamics by bulk RNA sequencing were included as predefined exploratory endpoints. CISH expression was a promising marker for Afatinib response (AUC = 0.918). In responders, compared to baseline samples, increasing T-cell- and B-cell-related features were observed in post-treatment tumor and lymph-node samples, respectively. Neoadjuvant Afatinib is feasible for stage III NSCLC+ patients and leads to dynamic changes in the tumor microenvironment.
Topics: Humans; Afatinib; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Lung Neoplasms; Mutation; Neoadjuvant Therapy; Protein Kinase Inhibitors; Tumor Microenvironment
PubMed: 37537219
DOI: 10.1038/s41467-023-40349-z -
The Oncologist Apr 2021Afatinib and selumetinib can be combined in continuous and intermittent dosing schedules, albeit at lower doses than approved for monotherapy. Maximum tolerated dose for...
LESSONS LEARNED
Afatinib and selumetinib can be combined in continuous and intermittent dosing schedules, albeit at lower doses than approved for monotherapy. Maximum tolerated dose for continuous and intermittent schedules is afatinib 20 mg once daily and selumetinib 25 mg b.i.d. Because the anticancer activity was limited, further development of this combination is not recommended until better biomarkers for response and resistance are defined.
BACKGROUND
Antitumor effects of MEK inhibitors are limited in KRAS-mutated tumors because of feedback activation of upstream epidermal growth factor receptors, which reactivates the MAPK and the phosphoinositide 3-kinase-AKT pathway. Therefore, this phase I trial was initiated with the pan-HER inhibitor afatinib plus the MEK inhibitor selumetinib in patients with KRAS mutant, PIK3CA wild-type tumors.
METHODS
Afatinib and selumetinib were administered according to a 3+3 design in continuous and intermittent schedules. The primary objective was safety, and the secondary objective was clinical efficacy.
RESULTS
Twenty-six patients were enrolled with colorectal cancer (n = 19), non-small cell lung cancer (NSCLC) (n = 6), and pancreatic cancer (n = 1). Dose-limiting toxicities occurred in six patients, including grade 3 diarrhea, dehydration, decreased appetite, nausea, vomiting, and mucositis. The recommended phase II dose (RP2D) was 20 mg afatinib once daily (QD) and 25 mg selumetinib b.i.d. (21 days on/7 days off) for continuous afatinib dosing and for intermittent dosing with both drugs 5 days on/2 days off. Efficacy was limited with disease stabilization for 221 days in a patient with NSCLC as best response.
CONCLUSION
Afatinib and selumetinib can be combined in continuous and intermittent schedules in patients with KRAS mutant tumors. Although target engagement was observed, the clinical efficacy was limited.
Topics: Afatinib; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Humans; Lung; Lung Neoplasms; Mutation; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras)
PubMed: 33296125
DOI: 10.1002/onco.13631 -
Journal of Neuro-oncology Dec 2021Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Amplification or overexpression of the epidermal growth factor receptor gene,...
BACKGROUND
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Amplification or overexpression of the epidermal growth factor receptor gene, part of the ErbB family, occur in approximately 40% and 60% of patients with GBM, respectively. We present data from a dose-finding study of the ErbB inhibitor afatinib in combination with radiotherapy (RT), with or without temozolomide (TMZ), in patients with GBM.
METHODS
This was a phase I, open-label, 3 + 3 dose-escalation trial in patients with newly-diagnosed, histologically-confirmed grade 4 malignant glioma and proven O-methylguanine-DNA methyltransferase gene promoter methylation status. The primary endpoint was the maximum tolerated dose (MTD) of continuous daily afatinib when given in combination with RT, with (regimen M) or without (regimen U) concomitant TMZ treatment.
RESULTS
Fifty-five patients were enrolled; 36 received ≥ 1 dose of trial medication (regimen M, n = 20, regimen U, n = 16). Afatinib was discontinued by all patients during the study. Reasons for afatinib discontinuation (regimen M/U) included disease progression (45%/50%), dose-limiting toxicity (10%/0%), and other adverse events (AEs; 35%/38%). The most frequently reported AEs with either regimen were diarrhea and rash, with no new safety signals identified. The MTD was determined as afatinib 30 mg in combination with daily TMZ and RT, and afatinib 40 mg in combination with RT alone.
CONCLUSIONS
This study identified the MTD for afatinib in combination with RT, with and without TMZ, in patients with GBM. Further studies of afatinib in patients with GBM are warranted and should be based on appropriate biomarker-based preselection.
TRIAL REGISTRATION
NCT00977431 (first posted September 15, 2009).
Topics: Adult; Afatinib; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Dacarbazine; Glioblastoma; Humans; Temozolomide; Treatment Outcome
PubMed: 34787778
DOI: 10.1007/s11060-021-03877-6 -
Future Oncology (London, England) Aug 2022This plain language summary reports the findings of a recent review of fusion-positive tumors. (Review)
Review
WHAT IS THIS STUDY ABOUT?
This plain language summary reports the findings of a recent review of fusion-positive tumors.
WHAT ARE FUSIONS?
A gene fusion occurs when two genes join to create a new gene. This rearrangement of DNA can change the processes within normal cells and lead to cancer. One of these gene fusions involves the gene. fusions have been reported in several types of cancers. These are known as fusion-positive cancers.
WHAT TREATMENTS ARE AVAILABLE FOR PEOPLE WITH FUSION-POSITIVE CANCER?
One drug that has been studied in people with fusion-positive cancer is called afatinib. People with several cancer types have received afatinib in clinical trials, and some people have responded to afatinib. Further studies are required to understand how effective afatinib and other treatments are for fusion-positive cancer.
Topics: Afatinib; Biology; Humans; Language; Lung Neoplasms; Neuregulin-1; Oncogene Proteins, Fusion
PubMed: 35876504
DOI: 10.2217/fon-2022-0073 -
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 -
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 -
Biomedicine & Pharmacotherapy =... Feb 2021Currently, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were approved for the treatment of non-small cell lung cancer (NSCLC) patients...
Currently, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were approved for the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR mutation. However, some lung cancer patients fail to respond and eventually develop drug resistance. Therefore, new therapeutic strategies are needed to improve the outcomes for substantial clinical benefit. Here we aimed to explore the combination of vinorelbine with the second EGFR-TKI afatinib in NSCLC cells with or without EGFR mutation. The three cells of H1975, HCC827, and H460 were assessed for the combination of vinorelbine and afatinib. Vinorelbine combined with afatinib synergistically inhibited the three lung cancer cells growth without aggravating adverse effect on the normal lung cells. The combination of low doses of vinorelbine and afatinib suppressed the cancer cell proliferation by cell colony formation assay and significantly induced cell apoptosis. The anti-apoptotic proteins Bcl-xL and Bcl-2 showed significant reduction after the drug combination treatment, while the pro-apoptotic protein Bax as well as apoptosis indicators cytochrome C and cleaved PARP were observed a notable increasing. EGFR downstream pathways including AKT, ERK, JNK, and p38 were highly active and p53 was inactive in the three lung cancer cells, favoring tumor growth. The low doses of vinorelbine plus afatinib blocked the phosphorylation of AKT, ERK, JNK, and p38, but restored the expression of p53. Our findings suggested that the combination of vinorelbine and afatinib could be recommended as a therapeutic regimen for treatment of NSCLC with or without EGFR mutation.
Topics: Afatinib; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Synergism; ErbB Receptors; Humans; Lung Neoplasms; Signal Transduction; Tumor Suppressor Protein p53; Vinorelbine
PubMed: 33360044
DOI: 10.1016/j.biopha.2020.111144 -
Cancer Nov 2022Afatinib is the only currently approved EGFR-tyrosine kinase inhibitors for advanced non-small cell lung cancer (NSCLC) patients with EGFR G719X/L861Q/S768I. However,...
BACKGROUND
Afatinib is the only currently approved EGFR-tyrosine kinase inhibitors for advanced non-small cell lung cancer (NSCLC) patients with EGFR G719X/L861Q/S768I. However, there are limited real-world data concerning the benefits and resistance mechanisms of afatinib in patients with these nonclassical mutations. To fill this gap, the present study was conducted.
METHODS
All NSCLC patients treated with afatinib were screened, and patients with EGFR G719X/L861Q/S768I were enrolled into the analysis. Either tumor tissue or blood specimens were detected by the commercial next-generation sequencing (NGS) panels or amplification-refractory mutation system (ARMS)-polymerase chain reaction (PCR) to figure out the mutation genotype.
RESULTS
A total of 106 advanced NSCLC patients with EGFR G719X/L861Q/S768I received afatinib treatment. The benefits of afatinib exhibited heterogeneity in different mutation genotypes. Notably, at baseline, NGS testing was performed in 59 patients, and TP53 was the most frequently coexisting mutation. Patients with TP53 mutations obtained fewer survival benefits than those with TP53 wild-type. A total of 68 patients ultimately experienced progression, and 27 patients received NGS testing to clarify the potential resistance mechanisms. EGFR-T790M, CDK4 amplification, FGFR1 amplification, PIK3CA, MET amplification, RET fusions, HER2, and BRAF mutations were identified in three (11.1%), three (11.1%), three (11.1%), three (11.1%), three (11.1%), one (3.7%), one (3.7%), and one (3.7%) of the cases, respectively. Five patients underwent ARMS-PCR testing for detecting EGFR-T790M mutation, and only one patient was T790M-positive.
CONCLUSIONS
The present study elucidated the differential benefits of afatinib within different mutation genotypes and first revealed the spectrum of potential resistance mechanisms in patients with EGFR G719X/L861Q/S768I. The results of this study may provide practical clinical information that can guide optimal treatment in this setting.
Topics: Afatinib; Carcinoma, Non-Small-Cell Lung; Class I Phosphatidylinositol 3-Kinases; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf
PubMed: 36069292
DOI: 10.1002/cncr.34451 -
Onkologie 2013Non-small cell lung cancer (NSCLC) consists of several histomorphologically defined phenotypes that display an enormous genetic variability. In recent years, epidermal... (Review)
Review
Non-small cell lung cancer (NSCLC) consists of several histomorphologically defined phenotypes that display an enormous genetic variability. In recent years, epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma has emerged as a unique subset of NSCLC in terms of etiopathogenesis and tumor biology. Since the introduction of the reversible EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib, patients with metastatic EGFR mutation-positive lung cancer can be offered a therapeutic alternative that has proven its superiority over standard platinum-based chemotherapy. However, primary or acquired resistance limits the therapeutic success of these targeted agents. Irreversible inhibitors targeting all ErbB family receptor tyrosine kinases, such as afatinib and dacomitinib, have been developed to confer sustained disease control in ErbB-dependent cancers. The large LUX-Lung 3 phase III trial recently reported afatinib to be clearly superior over the most effective platinum doublet in patients with EGFR mutation-positive lung cancer. To fully exploit the clinical activity of afatinib, proactive management of its gastrointestinal and dermatologic toxicities is advised.
Topics: Adenocarcinoma; Afatinib; Antineoplastic Combined Chemotherapy Protocols; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Humans; Lung Neoplasms; Mutation; Polymorphism, Single Nucleotide; Quinazolines
PubMed: 24051929
DOI: 10.1159/000354627