BACKGROUND/AIM: We investigated efficacy differences for afatinib versus gefitinib in non-small-cell lung cancer (NSCLC) according to epidermal growth factor receptor (EGFR) mutations. PATIENTS AND METHODS: We retrospectively analysed data for 343 patients with NSCLC with performance status 1 having EGFR mutations treated with gefitinib or afatinib. Overall response rate (ORR) was tested by Fisher's exact test. Overall (OS) and progression-free (PFS) survival were estimated by Kaplan-Meier method. RESULTS: ORR did not differ in any group or subgroup. Among all patients, we observed significantly longer PFS for those treated with afatinib vs. gefitinib (median 13.4 vs. 9.5 months, p=0.026), but only a nonsignificant trend was observed for OS. We showed nonsignificant trends of better PFS and OS using afatinib for exon 19 deletion and L858R subgroups. We observed no significant PFS differences for other EGFR mutations but a nonsignificant trend towards better OS for those treated with afatinib. CONCLUSION: Afatinib led to longer PFS for patients with common EGFR mutations but not for those with rare mutations.

• Klíčová slova
• Afatinib, NSCLC, gefitinib, real world data,
• MeSH
• afatinib terapeutické užití   MeSH
• dospělí MeSH
• erbB receptory genetika   MeSH
• gefitinib terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mutace MeSH
• nádory plic farmakoterapie   genetika   mortalita   patologie   MeSH
• nemalobuněčný karcinom plic farmakoterapie   genetika   mortalita   patologie   MeSH
• progrese nemoci MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• afatinib MeSH
• EGFR protein, human MeSH Prohlížeč
• erbB receptory MeSH
• gefitinib MeSH

OBJECTIVES: Patients with head and neck squamous cell carcinoma (HNSCC) can experience severe symptom burden and/or difficulty swallowing, leading to problems with treatment adherence/administration. In LUX-Head and Neck 1 (LH&N1; NCT01345682), second-line afatinib improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic HNSCC. We report adherence and safety across pre-specified and additional subgroups potentially linked to afatinib PFS benefit in LH&N1 (p16 status, smoking history), and afatinib adherence, safety and efficacy by administration (oral versus feeding tube; post-hoc analysis). METHODS: Patients were randomized (2:1) to afatinib (40 mg/day) or intravenous methotrexate (40 mg/m2/week). RESULTS: Among 320 afatinib-treated and 160 methotrexate-treated patients, 83-92% and 76-92% (of patients with data available) across all subgroups took ≥80% of treatment. Across p16 status and smoking history subgroups, the most common treatment-related adverse events (AEs) were diarrhea (70-91%), rash/acne (72-84%), stomatitis (34-73%) with afatinib; and included stomatitis (39-100%), fatigue (22-50%), nausea (19-36%) with methotrexate. Dose reduction decreased AE incidence/severity. Baseline characteristics were generally similar between oral/feeding tube (n = 276/n = 46) groups. 89%/89% (of patients with data available) took ≥80% of assigned afatinib. Median PFS was 2.6 versus 2.7 months (hazard ratio: 0.997; 95% confidence interval: 0.72-1.38). The most common afatinib-related AEs were: rash/acne (74% versus 74%), diarrhea (73% versus 65%), stomatitis (40% versus 30%). CONCLUSION: Subgroup analyses of LH&N1 demonstrate that afatinib has predictable and manageable safety across patient subgroups, with high treatment adherence, and is effective via oral and feeding tube administration.

• Klíčová slova
• Adherence, Afatinib, Feeding tube, HNSCC, Methotrexate, Recurrent/metastatic, Safety,
• MeSH
• adherence a compliance při léčbě MeSH
• afatinib terapeutické užití   MeSH
• chinazoliny aplikace a dávkování   MeSH
• dlaždicobuněčné karcinomy hlavy a krku farmakoterapie   metabolismus   MeSH
• erbB receptory metabolismus   MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   metabolismus   MeSH
• methotrexát aplikace a dávkování   MeSH
• nádory hlavy a krku farmakoterapie   metabolismus   MeSH
• přežití bez známek nemoci MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• afatinib MeSH
• chinazoliny MeSH
• erbB receptory MeSH
• methotrexát MeSH

INTRODUCTION: Exon 18-T719X EGFR mutation in non-small cell lung cancer is rare, only 1-5% of all EGFR mutations. The efficacy of EGFR tyrosin kinase inhibitors in tumours with uncommon mutations is still unclear and the prediction of response of such tumours to therapy remains unexplored. CASE: A 71-year-old woman with no previous smoking history with disseminated lung adenocarcinoma with exon 18-T719X EGFR mutation was treated with afatinib. A partial response was achieved in 2 months, progression-free survival was 19 months. The dose of afatinib was reduced to 30mg/day after 3 months due to skin toxicity and stomatitis grade 2. Next reduction to 20mg/day was performed after 10 subsequent months due to leucopenia and neutropenia grade 2. CONCLUSION: With this patient, a partial response which lasted 19 months despite 50% reduction of the afatinib dose was achieved. Key words: afatinib - non-small cell lung cancer - epidermal growth factor-mutation receptor - treatment outcome - drug toxicity This article was supported by Boehringer Ingelheim. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 27. 9. 2018 Accepted: 1. 10. 2018.

• Klíčová slova
• afatinib - non-small cell lung cancer - epidermal growth factor-mutation receptor - treatment outcome - drug toxicity This article was supported by Boehringer Ingelheim. The authors declare they have no potential conflicts of interest concerning drugs, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 27. 9. 2018 Accepted: 1. 10. 2018, products,
• MeSH
• adenokarcinom plic farmakoterapie   genetika   MeSH
• afatinib MeSH
• erbB receptory genetika   MeSH
• exony MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• mutace MeSH
• nádory plic farmakoterapie   genetika   MeSH
• nemalobuněčný karcinom plic farmakoterapie   genetika   MeSH
• přežití bez známek nemoci MeSH
• protinádorové látky terapeutické užití   MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• afatinib MeSH
• EGFR protein, human MeSH Prohlížeč
• erbB receptory MeSH
• inhibitory proteinkinas MeSH
• protinádorové látky MeSH

Biofilms are complex microbial communities that tend to attach to either biotic or abiotic surface. Enclosed in a self-produced extracellular polymeric substance (EPS) matrix, the biofilms often cause persistent infections. The objective of this study was to investigate the antibiofilm activity of dimethyl sulfoxide (DMSO) and afatinib against Gram-negative pathogens. Test microorganisms used in this study were Escherichia coli ATCC 1299, Pseudomonas aeruginosa ATCC 10145, and Salmonella typhimurium ATCC 14028. Biofilms were developed in 96-well microplate at 37°C for 24 h. Following removal of non-adherent cells, analysis of biofilm viability, biofilm biomass, and extracellular polymeric substances (EPS) matrix were performed using resazurin assay, crystal violet assay, and attenuated total reflectance fourier transform infrared (ATR-FTIR) spectroscopy, respectively. Bradford protein assay was conducted to determine the total amount of EPS proteins. The results demonstrated that both 32% DMSO alone and its combination with 3.2 μg/mL afatinib were effective in killing biofilm cells and reducing biofilm biomass. IR spectral variations of EPS matrix of biofilms in the range between 1700 and 900 cm-1 were also observed. Reduction in EPS proteins verified the chemical modifications of EPS matrix. In conclusion, 32% DMSO alone and its combination with 3.2 μg/mL afatinib showed remarkable antibiofilm activities against Gram-negative pathogens. It was suggested that the biofilm inhibition was mediated by the chemical modification of EPS matrix.

• Klíčová slova
• Afatinib, Antibiofilm, Dimethyl sulfoxide, Gram-negative pathogen,
• MeSH
• afatinib MeSH
• antibakteriální látky farmakologie   MeSH
• biofilmy účinky léků   MeSH
• chinazoliny farmakologie   MeSH
• dimethylsulfoxid farmakologie   MeSH
• Escherichia coli účinky léků   fyziologie   MeSH
• Pseudomonas aeruginosa účinky léků   fyziologie   MeSH
• Salmonella typhimurium účinky léků   fyziologie   MeSH
• spektroskopie infračervená s Fourierovou transformací MeSH
• synergismus léků MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• afatinib MeSH
• antibakteriální látky MeSH
• chinazoliny MeSH
• dimethylsulfoxid MeSH

BACKGROUND: Patients with sensitive EGFR mutations are already being treated with first and second generation tyrosine kinase inhibitors (TKIs). However, resistance to these drugs occurs over time, and over half of all cases is caused by a mutation (T790M) in the EGFR kinase domain. Osimertinib offers a new treatment option that overcomes this problem. Unfortunately, resistance to this drug also develops after several months of treatment and is caused by another mutation (C797S) in EGFR. CASE REPORT: Our case report provides evidence for the progressive development of EGFR-TKI resistance in a patient with a deletion of exon 19 in the EGFR gene. First, based on a mutation (T790M) identified after afatinib treatment and a subsequent mutation (C797S) mutation identified after osimertinib treatment. We mention overcoming this resistance (C797S) mutation by using 4th generation EGFR-TKI and other alternative procedures (chemotherapy, immunotherapy, and combinations of older EGFR-TKI generations). We also mention a rare case of peritoneal metastasis that occurred after previous treatment with osimertinib that we attempted to ameliorate by using erlotinib because the impaired condition of the patient did not allow treatment by chemotherapy. There are documented cases in which erlotinib has been successfully given to patients with peritoneal metastases and patients with the EGFR mutation C797S following progression to afatinib. This was not the case in our patient, probably because of the remaining EGFR mutation T790M. CONCLUSION: In our case report, erlotinib did not show efficacy after progression to osimetinib. Nowadays, chemotherapy is the only possible treatment in patients with good a performance status. The next-generation of TKIs are undergoing promising developments.Key words: EGFR - deletion on exon 19 - mutation T790M - mutation C797S - afatinib - osimertinibSubmitted: 12. 9. 2017Accepted: 12. 10. 2017 This project was supported by grant AZV 17-30 748A. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

• MeSH
• afatinib terapeutické užití   MeSH
• akrylamidy MeSH
• aniliny MeSH
• chemorezistence genetika   MeSH
• erbB receptory genetika   MeSH
• erlotinib terapeutické užití   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• mutace MeSH
• piperaziny terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• afatinib MeSH
• akrylamidy MeSH
• aniliny MeSH
• EGFR protein, human MeSH Prohlížeč
• erbB receptory MeSH
• erlotinib MeSH
• inhibitory proteinkinas MeSH
• osimertinib MeSH Prohlížeč
• piperaziny MeSH