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Molecular Oncology Apr 2018The molecular mechanism of action of the HER2-targeted antibody trastuzumab is only partially understood, and the direct effects of trastuzumab on the gastric cancer...
The molecular mechanism of action of the HER2-targeted antibody trastuzumab is only partially understood, and the direct effects of trastuzumab on the gastric cancer signaling network are unknown. In this study, we compared the molecular effect of trastuzumab and the HER kinase inhibitor afatinib on the receptor tyrosine kinase (RTK) network and the downstream-acting intracellular kinases in gastric cancer cell lines. The molecular effects of trastuzumab and afatinib on the phosphorylation of 49 RTKs and 43 intracellular kinase phosphorylation sites were investigated in three gastric cancer cell lines (NCI-N87, MKN1, and MKN7) using proteome profiling. To evaluate these effects, data were analyzed using mixed models and clustering. Moreover, proliferation assays were performed. Our comprehensive quantitative analysis of kinase activity in gastric cancer cell lines indicates that trastuzumab and afatinib selectively influenced the HER family RTKs. The effects of trastuzumab differed between cell lines, depending on the presence of activated HER2. The effects of trastuzumab monotherapy were not transduced to the intracellular kinase network. Afatinib alone or in combination with trastuzumab influenced HER kinases in all cell lines; that is, the effects of monotherapy and combination therapy were transduced to the intracellular kinase network. These results were confirmed by proliferation analysis. Additionally, the MET-amplified cell line Hs746T was identified as afatinib nonresponder. The dependence of the effect of trastuzumab on the presence of activated HER2 might explain the clinical nonresponse of some patients who are routinely tested for HER2 expression and gene amplification in the clinic but not for HER2 activation. The consistent effects of afatinib on HER RTKs and downstream kinase activation suggest that afatinib might be an effective candidate in the future treatment of patients with gastric cancer irrespective of the presence of activated HER2. However, MET amplification should be taken into account as potential resistance factor.
Topics: Afatinib; Cell Line, Tumor; Enzyme Activation; Humans; Receptor, ErbB-2; Stomach Neoplasms; Trastuzumab
PubMed: 29325228
DOI: 10.1002/1878-0261.12170 -
European Journal of Cancer (Oxford,... Apr 2024The combination of gemcitabine/nab-paclitaxel is an established standard treatment in the first-line treatment of metastatic ductal adenocarcinoma of the pancreas...
PURPOSE
The combination of gemcitabine/nab-paclitaxel is an established standard treatment in the first-line treatment of metastatic ductal adenocarcinoma of the pancreas (mPDAC). Afatinib, an oral second-generation pan ErbB family tyrosine kinase inhibitor, has shown promising pre-clinical signs in the treatment of pancreatic cancer. The aim of this phase 1b trial was to determine the maximum tolerated dose (MTD) of afatinib in combination with gemcitabine/nab-paclitaxel in patients with mPDAC.
METHODS
Treatment naïve patients (≥18 years) with histologically proven mPDAC and good performance status (ECOG 0/1) were enrolled to receive gemcitabine/nab-paclitaxel in combination with afatinib. Treatment was continued until disease progression, or unacceptable toxicity. The primary endpoint MTD was determined using a 3 + 3 design. Treatment started at dose level 0 with intravenous gemcitabine/nab-paclitaxel 1000 mg/m / 125 mg/m (day 1, 8, 15 of a 28-day cycle) + oral afatinib 30 mg daily. At dose level + 1 afatinib was increased to 40 mg. Secondary endpoints included safety parameters and exploratory endpoints evaluated treatment efficacy.
RESULTS
Twelve patients were included in this trial, and 11 patients were treated and analysed in the safety and full analysis set (FAS). At dose level 0 the first three patients did not experience a dose-limiting toxicity (DLT). At dose leve (DL) + 1 two patients experienced a DLT. Accordingly, enrolment continued at DL 0 with three more patients, of which one experienced DLT (skin rash ≥ CTCAE grade 3). Seven patients (63.6%) experienced at least one treatment-emergent serious adverse event (TESAE), with four patients (36.4%) experiencing TESAEs grade 3-5 related to the study medication. In the FAS, the objective response rate (ORR) was 36.4%, median progression-free survival (PFS) was 3.5 months and median overall survival in nine evaluable patients was 7.5 months.
CONCLUSIONS
In this phase 1b clinical trial, the MTD of gemcitabine/nab-paclitaxel (1000 mg/m / 125 mg/m) and afatinib (30 mg) was established. In a cohort of 11 patients, the combination showed an acceptable safety profile.
Topics: Humans; Gemcitabine; Afatinib; Deoxycytidine; Paclitaxel; Albumins; Pancreatic Neoplasms; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38401449
DOI: 10.1016/j.ejca.2024.113926 -
Cellular Physiology and Biochemistry :... 2018The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor afatinib is primarily utilized for the treatment of non-small cell lung carcinoma. The drug is at...
BACKGROUND/AIMS
The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor afatinib is primarily utilized for the treatment of non-small cell lung carcinoma. The drug is at least partially effective by triggering suicidal tumor cell death. Side effects of afatinib treatment include anemia. At least in theory, afatinib induced anemia could be secondary to stimulation of suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling potentially stimulating eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), induction of oxidative stress, and increase of ceramide abundance. The present study explored, whether afatinib induces eryptosis and, if so, whether its effect involves Ca2+ entry, oxidative stress, and/or ceramide.
METHODS
Flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, reactive oxygen species (ROS) abundance from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies.
RESULTS
A 48 hours exposure of human erythrocytes to afatinib (≥ 4 µg/ml) significantly increased the percentage of annexin-V-binding cells and significantly decreased forward scatter. Afatinib significantly increased Fluo3-fluorescence, DCFDA fluorescence and ceramide abundance. The effect of afatinib on annexin-V-binding and forward scatter was significantly blunted by removal of extracellular Ca2+.
CONCLUSIONS
Afatinib triggers phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to Ca2+ entry, oxidative stress, and ceramide.
Topics: Afatinib; Anemia; Calcium Signaling; Eryptosis; Erythrocyte Membrane; Humans; Phospholipids; Quinazolines
PubMed: 29913444
DOI: 10.1159/000490221 -
Journal of Experimental & Clinical... Jun 2019Glioblastoma (GBM) is an aggressive brain tumor with universal recurrence and poor prognosis. The recurrence is largely driven by chemoradiation resistant cancer stem...
BACKGROUND
Glioblastoma (GBM) is an aggressive brain tumor with universal recurrence and poor prognosis. The recurrence is largely driven by chemoradiation resistant cancer stem cells (CSCs). Epidermal growth factor receptor (EGFR) and its mutant EGFRvIII are amplified in ~ 60% and ~ 30% of GBM patients, respectively; however, therapies targeting EGFR have failed to improve disease outcome. EGFRvIII-mediated cross-activation of tyrosine kinase receptor, cMET, regulates GBM CSC maintenance and promote tumor recurrence. Here, we evaluated the efficacy of pan-EGFR inhibitor afatinib and Temozolomide (TMZ) combination on GBM in vitro and in vivo.
METHODS
We analyzed the effect of afatinib and temozolomide (TMZ) combination on GBM cells U87MG and U251 engineered to express wild type (WT) EGFR, EGFRvIII or EGFRvIII dead kinase, CSCs isolated from U87 and U87EGFRvIII in vitro. The therapeutic utility of the drug combination was investigated on tumor growth and progression using intracranially injected U87EGFRvIII GBM xenografts.
RESULTS
Afatinib and TMZ combination synergistically inhibited the proliferation, clonogenic survival, motility, invasion and induced senescence of GBM cells compared to monotherapy. Mechanistically, afatinib decreased U87EGFRvIII GBM cell proliferation and motility/invasion by inhibiting EGFRvIII/AKT, EGFRvIII/JAK2/STAT3, and focal adhesion kinase (FAK) signaling pathways respectively. Interestingly, afatinib specifically inhibited EGFRvIII-cMET crosstalk in CSCs, resulting in decreased expression of Nanog and Oct3/4, and in combination with TMZ significantly decreased their self-renewal property in vitro. More interestingly, afatinib and TMZ combination significantly decreased the xenograft growth and progression compared to single drug alone.
CONCLUSION
Our study demonstrated significant inhibition of GBM tumorigenicity, CSC maintenance in vitro, and delayed tumor growth and progression in vivo by combination of afatinib and TMZ. Our results warrant evaluation of this drug combination in EGFR and EGFRvIII amplified GBM patients.
Topics: Afatinib; Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; ErbB Receptors; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Mice; Neoplastic Stem Cells; Proto-Oncogene Proteins c-met; Signal Transduction; Temozolomide; Xenograft Model Antitumor Assays
PubMed: 31215502
DOI: 10.1186/s13046-019-1264-2 -
Thoracic Cancer Apr 2021Afatinib is an ErbB family blocker approved for the treatment of epidermal growth factor receptor mutation-positive nonsmall-cell lung cancer. A pivotal trial...
Afatinib is an ErbB family blocker approved for the treatment of epidermal growth factor receptor mutation-positive nonsmall-cell lung cancer. A pivotal trial demonstrated significant clinical benefits with manageable toxicity of afatinib as a second-line treatment option in squamous cell carcinoma of the lung (SCC) which led to approval in >60 countries. However, these results were derived from a controlled study conducted in selected patients and are not necessarily representative of the real-world use of this drug. In addition, data on afatinib use after immunotherapy in this clinical setting are lacking. The aim of this study is to evaluate the treatment outcomes and safety of afatinib as a second- or later-line treatment for SCC and to identify potential predictive biomarkers. As a real-world observational study, 130 eligible patients with advanced SCC, who progressed after platinum-based chemo- and immunotherapy, will be enrolled. Treatment outcomes and safety data will be collected for both the retrospective and prospective cohorts, and molecular profiling using tissue and plasma will be performed for the prospective cohort. The primary endpoint is time to treatment failure, and the secondary endpoints are objective response rate, progression-free survival, overall survival, and safety. Comparison of clinical outcomes with respect to the different programmed death-ligand 1 expression and molecular characteristics will also be carried out. This study will provide additional evidence on the usefulness of afatinib as a subsequent treatment, as well as feasible molecular biomarkers to predict its efficacy in this clinical setting.
Topics: Afatinib; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Female; Humans; Immunotherapy; Male; Prospective Studies; Retrospective Studies; Treatment Outcome
PubMed: 33586312
DOI: 10.1111/1759-7714.13880 -
Cancer Medicine Sep 2021The optimal sequence for the administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for treating non-small cell lung cancer (NSCLC)...
Sequential treatment of afatinib and osimertinib or other regimens in patients with advanced non-small-cell lung cancer harboring EGFR mutations: Results from a real-world study in South Korea.
OBJECTIVES
The optimal sequence for the administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for treating non-small cell lung cancer (NSCLC) is still unclear. This study aimed to evaluate the efficacy of sequential afatinib and osimertinib treatment in patients with NSCLC harboring EGFR mutations.
MATERIALS AND METHODS
Electronic records of patients with EGFR-mutated NSCLC, who were administered afatinib and osimertinib (group A) or other chemotherapy (group B) between October 2014 and 2019, across 16 hospitals in South Korea were reviewed. The primary outcome, time on treatment (TOT), secondary outcome, and overall survival (OS) were estimated using the Kaplan-Meier method and log-rank test. Multivariate analyses were performed using the Cox proportional hazards model.
RESULTS
Of the 737 patients who received frontline afatinib treatment, 324 with complete records were selected (group A: 126, group B: 198). All patients in group A were T790M positive after afatinib, while patients in group B were all negative or unknown. The median TOT was 35.4 months (95% confidence interval [CI]: 27.7-45.6) in group A and 20.8 months (95% CI: 19.4-24.0) in group B. The median TOT with afatinib was 13.0 months (95% CI: 12.0-13.9) overall and 15.7 months (95% CI: 13.9-17.3) in group A. The 2- and 3-year survival rates were 86.0 and 69.3% in group A and 75.9 and 55.3% in group B, respectively.
CONCLUSION
Sequential afatinib and osimertinib treatment resulted in better survival rates than treatment with afatinib followed by other chemotherapies.
Topics: Acrylamides; Afatinib; Aged; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Mutation; Republic of Korea
PubMed: 34258882
DOI: 10.1002/cam4.4127 -
Medicine Dec 2020Afatinib is an epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI) with proven efficacy for treating patients with advanced or metastatic non-small...
A randomized, multi-center, open-label study to compare the safety and efficacy between afatinib monotherapy and combination therapy of afatinib and HAD-B1 for the locally advanced or metastatic NSCLC patients with EGFR mutations.
BACKGROUND
Afatinib is an epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI) with proven efficacy for treating patients with advanced or metastatic non-small cell lung cancer (NSCLC). Unfortunately, responses are limited by acquired resistance. Because traditional Korean medicine may have synergistic effects when combined with chemotherapy or radiotherapy, the aim of our study is to elucidate the efficacy and safety of afatinib plus HangAmDan-B1 (HAD-B1) combination therapy in the treatment of patients with NSCLC, as well as EGFR mutations, who need afatinib therapy.
METHODS/DESIGN
This study is a randomized, multi-center, open clinical trial. A total of 178 eligible subjects, recruited at 8 centers, are randomly assigned to take Afatinib (20-40 mg) ± HAD-B1 (0.972 g/day) for 48 weeks. In the test group, HAD-B1 and afatinib will be used in combination. The primary outcome is a comparison of progression-free survival (PFS) between afatinib monotherapy and afatinib plus HAD-B1 combination therapy in patients with local advanced or metastatic (Stage IIIA, B, C/IV) NSCLC. Secondary outcomes are the overall survival rates, clinical responses, tumor size reductions, health-related qualities of life, and safety.
DISCUSSION
The result of this clinical trial will provide evidence for the efficacy and safety of using HAD-B1 in the treatment of EGFR-positive patients with locally advanced or metastatic NSCLC who require afatinib therapy.
TRIAL REGISTRATION
Clinical Research Information Service (CRIS), Republic of Korea (ID: KCT0005414), on September 23, 2020.
Topics: Humans; Afatinib; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Lung Neoplasms; Neoplasm Staging; Quality of Life; Survival Analysis; Multicenter Studies as Topic; Randomized Controlled Trials as Topic
PubMed: 33285743
DOI: 10.1097/MD.0000000000023455 -
Cancer Research and Treatment Oct 2023This study aimed to report the final analysis of time-on-treatment (TOT) and overall survival (OS) in patients with advanced-stage epidermal growth factor receptor...
PURPOSE
This study aimed to report the final analysis of time-on-treatment (TOT) and overall survival (OS) in patients with advanced-stage epidermal growth factor receptor (EGFR)+ non-small cell lung cancer (NSCLC) who received sequential afatinib and osimertinib and to compare the outcomes with other second-line regimens (comparator group).
MATERIALS AND METHODS
In this updated report, the existing medical records were reviewed and rechecked. TOT and OS were updated and analyzed according to clinical features using the Kaplan-Meier method and log-rank test. TOT and OS were compared with those of the comparator group, in which most patients received pemetrexed-based treatments. A multivariable Cox proportional hazard model was used to evaluate features that could affect survival outcomes.
RESULTS
The median observation time was 31.0 months. The follow-up period was extended to 20 months. A total of 401 patients who received first-line afatinib were analyzed (166 with T790M+ and second-line osimertinib, and 235 with unproven T790M and other second-line agents). Median TOTs on afatinib and osimertinib were 15.0 months (95% confidence interval [CI], 14.0 to 16.1) and 11.9 months (95% CI, 8.9 to 14.6), respectively. The median OS in the osimertinib group was 54.3 months (95% CI, 46.7 to 61.9), much longer than that in the comparator group. In patients who received osimertinib, the OS was longest with Del19+ (median, 59.1; 95% CI, 48.7 to 69.5).
CONCLUSION
This is one of the largest real-world studies reporting the encouraging activity of sequential afatinib and osimertinib in Asian patients with EGFR+ NSCLC who acquired the T790M mutation, particularly Del19+.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Afatinib; Lung Neoplasms; ErbB Receptors; Protein Kinase Inhibitors; Mutation
PubMed: 37218139
DOI: 10.4143/crt.2023.493 -
Thoracic Cancer May 2021We report a subgroup analysis of afatinib with respect to its efficacy, safety, and the long-term survival of patients in a Named Patient Use program at a single...
BACKGROUND
We report a subgroup analysis of afatinib with respect to its efficacy, safety, and the long-term survival of patients in a Named Patient Use program at a single institution.
METHODS
We analyzed 60 patients with stage IV non-small cell lung cancer (NSCLC) who had been treated with ≥1 line of platinum-based chemotherapy and had activating epidermal growth factor receptor (EGFR) mutations or disease control for ≥6 months with prior EGFR inhibitors. Afatinib was started on a daily dose of 50 mg, which was decreased according to the adverse events and tolerability.
RESULTS
A total of 13 patients achieved partial remission, whereas 33, 12, and two showed stable disease, had progression, and were not evaluable, respectively, resulting in an objective response rate and disease control rate of 21.7% and 76.7%, respectively. The median progression-free survival (PFS) was 5.4 (95% confidence interval [CI]: 4.0-7.7) months and median overall survival (OS) was 10.1 (8.5-13.6) months. Toxicities leading to drug discontinuation were experienced by four patients (6.7%). Grade 3 diarrhea occurred in 10 patients (16.7%), and afatinib dose reductions were required in 35 patients. The PFS and OS were significantly longer for patients whose dose was reduced to 40 or 30 mg than for those without dose reduction (7.0 vs 3.1 months and 13.5 vs 8.1 months, respectively, p < 0.05).
CONCLUSIONS
The efficacy of afatinib was similar to that identified in the global data without unexpected adverse events. Survival analyses support the currently approved dose of afatinib as first-line treatment for NSCLC.
Topics: Afatinib; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Erlotinib Hydrochloride; Female; Gefitinib; Humans; Lung Neoplasms; Male; Middle Aged; Progression-Free Survival; Protein Kinase Inhibitors
PubMed: 33811467
DOI: 10.1111/1759-7714.13957 -
The Oncologist Jan 2021Neuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan-ErbB family inhibitor that may be an...
BACKGROUND
Neuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan-ErbB family inhibitor that may be an effective treatment for NRG1 fusion-driven tumors.
PATIENTS AND METHODS
This report summarizes pertinent details, including best tumor response to treatment, for six patients with metastatic NRG1 fusion-positive tumors treated with afatinib.
RESULTS
The six cases include four female and two male patients who ranged in age from 34 to 69 years. Five of the cases are patients with lung cancer, including two patients with invasive mucinous adenocarcinoma and three patients with nonmucinous adenocarcinoma. The sixth case is a patient with colorectal cancer. NRG1 fusion partners for the patients with lung cancer were either CD74 or SDC4. The patient with colorectal cancer harbored a novel POMK-NRG1 fusion and a KRAS mutation. Two patients received afatinib as first- or second-line therapy, three patients received the drug as third- to fifth-line therapy, and one patient received afatinib as fifteenth-line therapy. Best response with afatinib was stable disease in two patients (duration up to 16 months when combined with local therapies) and partial response (PR) of >18 months in three patients, including one with ongoing PR after 27 months. The remaining patient had a PR of 5 months with afatinib 40 mg/day, then another 6 months after an increase to 50 mg/day.
CONCLUSION
This report reviews previously published metastatic NRG1 fusion-positive tumors treated with afatinib and summarizes six previously unpublished cases. The latter include several with a prolonged response to treatment (>18 months), as well as the first report of efficacy in NRG1 fusion-positive colorectal cancer. This adds to the growing body of evidence suggesting that afatinib can be effective in patients with NRG1 fusion-positive tumors.
KEY POINTS
NRG1 fusions activate ErbB signaling and have been identified as oncogenic drivers in multiple solid tumor types. Afatinib is a pan-ErbB family inhibitor authorized for the treatment of advanced non-small cell lung cancer that may be effective in NRG1 fusion-driven tumors. This report summarizes six previously unpublished cases of NRG1 fusion-driven cancers treated with afatinib, including five with metastatic lung cancer and one with metastatic colorectal cancer. Several patients showed a prolonged response of >18 months with afatinib treatment. This case series adds to the evidence suggesting a potential role for afatinib in this area of unmet medical need.
Topics: Adult; Afatinib; Aged; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neuregulin-1; Oncogene Proteins, Fusion; Protein Kinase Inhibitors
PubMed: 32852072
DOI: 10.1634/theoncologist.2020-0379