Comparative efficacy and safety of first-line EGFR-TKIs for advanced non-small cell lung cancer：a network meta-analysis / 中华疾病控制杂志

Objective To compare the efficacy and safety of gefitinib, erlotinib, and afatinib in the first-line treatment of advanced non-small cell lung cancer (NSCLC). Methods PubMed, EMBASE, and The Cochrane Library were searched to identify the relevant literatures published from December 2008 to December 2018. Bayesian network meta-analysis was carried out to rank the three treatments. Results A total of ten eligible studies involving 2275 patients were enrolled. In terms of efficacy, the surface under the cumulative ranking (SUCRA) indicated that erlotinib performed best in progression-free survival(PFS)(0.88), afatinib performed best in objective response rate(ORR)(0.82) and disease control rate(DCR) (0.86), gefitinib performed worst in PFS (0.45), ORR(0.42), and DCR(0.45). For safety, the differences of grade 3 or 4 adverse events rate (OR=0.29,95%CI:0.08-0.98) and discontinuation rate(OR=0.14,95%CI:0.01-0.8) between erlotinib and the platinum-based doublet chemotherapy were statistically significant. The ranking results also supported that erlotinib was the safest. SUCRA results suggested that gefitinib (0.31) had a lower grade 3 or 4 adverse events rate than afatinib (0.57), and the possibility of discontinuation in gefitinib (0.44) was similar to that of afatinib (0.41). Conclusion Erlotinib might be the preferred first-line treatment for advanced NSCLC after weighing and balancing the benefits and risks.

Potential life years not saved due to lack of access to anti-EGFR tyrosine kinase inhibitors for lung cancer treatment in the Brazilian public healthcare system: Budget impact and strategies to improve access. A pharmacoeconomic study

ABSTRACT BACKGROUND: Lung cancer is the fourth most common cancer in Brazil. In the 2000s, better understanding of molecular pathways led to development of epidermal growth factor receptor (EGFR)-targeted treatments that have improved outcomes. However, these treatments are unavailable in most Brazilian public healthcare services (Sistema Único de Saúde, SUS). OBJECTIVE: To assess the potential number of years of life not saved, the budget impact of the treatment and strategies to improve access. DESIGN AND SETTING: Pharmacoeconomic study assessing the potential societal and economic impact of adopting EGFR-targeted therapy within SUS. METHODS: We estimated the number of cases eligible for treatment, using epidemiological data from the National Cancer Institute. We used data from a single meta-analysis and from the Lung Cancer Mutation Consortium (LCMC) study as the basis for assessing differences in patients' survival between use of targeted therapy and use of chemotherapy. The costs of targeted treatment were based on the national reference and were compared with the amount reimbursed for chemotherapy through SUS. RESULTS: There was no life-year gain with EGFR-targeted therapy in the single meta-analysis (hazard ratio, HR, 1.01). The LCMC showed that 1,556 potential life-years were not saved annually. We estimated that the annual budget impact was 125 million Brazilian reais (BRL) with erlotinib, 48 million BRL with gefitinib and 52 million BRL with afatinib. Their incremental costs over chemotherapy per life-year saved were 80,329 BRL, 31,011 BRL and 33,225 BRL, respectively. A drug acquisition discount may decrease the budget impact by 30% (with a 20% discount). A fixed cost of 1,000 BRL may decrease the budget impact by 95%. CONCLUSION: Reducing drug acquisition costs may improve access to EGFR-targeted therapy for lung cancer.

Development of a competitive enzyme-linked immunosorbent assay for therapeutic drug monitoring of afatinib / 药物分析学报

Afatinib is an oral tyrosine kinase inhibitor (TKI) approved for treating advanced non-small cell lung cancer. It is necessary to develop a simple quantification method for TKIs in order to facilitate therapeutic drug monitoring (TDM) in clinical settings. This study sought to develop a simple and sensitive com-petitive enzyme-linked immunosorbent assay (ELISA) to quantify afatinib in plasma for routine phar-macokinetic applications. An anti-afatinib antibody was obtained using (S)-N-4-(3-chloro-4-fluor-ophenyl)-7-(tetrahydrofuran-3-yloxy)-quinazoline-4,6-diamine (CTQD), which has the same sub-structure as afatinib, as a hapten. Enzyme labeling of afatinib with horseradish peroxidase was similarly performed using CTQD. A simple competitive ELISA for afatinib was developed based on the principle of direct competition between afatinib and the enzyme marker for the anti-afatinib antibody, which had been immobilized on the plastic surface of a microtiter plate. Plasma afatinib concentrations below the limit of quantification of 30 pg/mL were reproducibly measurable. Also, the values of plasma afatinib levels measured from 20 patients were comparable with those measured by high-performance liquid chromatography, and there was a strong correlation between the values determined by both methods (Y = 0.976X – 0.207, r = 0.975). As indicated by its specificity and sensitivity, this newly developed ELISA for afatinib is an important tool for TDM and studies of the pharmacokinetics of afatinib.

Efficacy and Safety of Afatinib for EGFR-mutant Non-small Cell Lung Cancer, Compared with Gefitinib or Erlotinib / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: We tried to evaluate whether there are any specific features in treatment outcomes of firstline afatinib in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), compared with gefitinib or erlotinib. MATERIALS AND METHODS: We analyzed patients treated with first-line afatinib, gefitinib, or erlotinib for advanced EGFR-mutant NSCLC at Samsung Medical Center between 2014 and 2016. RESULTS: In total, 467 patients received first-line afatinib (n=165), gefitinib (n=230), or erlotinib (n=72). Afatinib was used more often in patients with tumors harboring deletion in exon 19 (Del19), whereas the gefitinib group had more elderly, females, and never smokers. The median progression-free survival (PFS) time for afatinib, gefitinib, and erlotinib was 19.1 months, 13.7 months, and 14.0 months, respectively (p=0.001). The superior PFS of afatinib was more remarkable in subgroups of Del19 or uncommon EGFR mutations. Overall toxicity profiles of the three drugs were comparable, though more grade 3 or 4 toxicities were detected in afatinib (7.3%) compared with gefitinib (2.6%) or erlotinib (1.8%). The common grade 3 or 4 toxicities of afatinib included diarrhea (3.0%), paronychia (2.4%), and skin rash (1.8%). Dose modification was more frequently required in patients treated with afatinib (112/165, 68%), compared with gefitinib (5/230, 2%) and erlotinib (4/72, 6%). Interestingly, however, dose reduction in the afatinib group did not impair its efficacy in terms of PFS (dose reduction vs. no reduction group, 23.5 months vs. 12.4 months). CONCLUSION: First-line afatinib showed satisfactory efficacy data and manageable toxicity profiles.

Determination and Pharmacokinetic Study of Afatinib in Rat Plasma by UPLC-MS/MS / 中国药师

Objective: To establish an accurate and selective UPLC-MS/MS) method for the determination of afatinib in rat plas-ma. Methods: Protein precipitating by acetonitrile was used to prepare the samples. A CORTECS BEH C18column ( 50 mm × 2. 1 mm, 1. 6 μm) was used to separate the analytes at 40℃. The mobile phase consisted of acetonitrile and water (0. 1% formic acid) with the flow rate of 0. 4 ml·min-1. The analytes were quantified by multiple reaction monitoring ( MRM) mode with positive electrospray ionization, while the target fragment ions were m/z 486. 19→112. 1 for afatinib and m/z 557. 3→112. 15 for neratinib (IS). Results: The calibration curve obtained good linearity for afatinib within the range of 1–200 ng·ml-1(r=0. 998 1), and the LLOQ in rat plasma was 1. 0 ng/ml. The intra-and inter-day precisions were both≤9. 51% . The recovery of afatinib from plasma was above 77. 1% . After intragastric administration and intravenous administration of afatinib in rats, the t1/2was 7. 19 h and 2. 69 h, Cmax was 97. 78 ng·ml-1and 123. 37 ng·ml-1,and AUC(0-∞)was 1 505. 4 ng·ml-1·h and 405. 55 ng·ml-1·h, respectively. Con-clusion: The validated method can be applied in the pharmacokinetic study of afatinib at the intragastric and intravenous dosage of 10 and 2 mg·kg-1, respectively.

Formulation and Efficacy of Liposome-encapsulated Afatinib for Therapy of Non-small Cell Lung Cancer / 中国肺癌杂志

BACKGROUND@#Afatinib, a second-generation irreversible epidermal growth factor inhibitor receptor for the development of non-small cell lung cancer and secondary drug resistance, has low bioavailability and adverse reactions due to current oral administration. The aim of this study was to prepare a novel drug delivery system, afatinib liposome, and to establish a method for the determination of encapsulation efficiency.@*METHODS@#Four different preparation methods were used to prepare afatinib liposomes, and the optimal preparation process was determined by comparing the encapsulation efficiency and particle size.@*RESULTS@#It has been verified that sephadex microcolumn centrifugation can be used to purify afatinib liposomes, and UV spectrophotometry can be employed to determine the entrapment efficiency of liposomes. Among different preparation methods, the encapsulation efficiency of afatinib liposomes prepared by ammonium sulfate gradient method was 90.73% and the average particle size was 108.6 nm.@*CONCLUSIONS@#Ammonium sulfate gradient method can be successfully applied to prepare afatinib liposomes that performed higher encapsulation efficiency and smaller particle size. The UV spectrophotometry employed to determine the liposome encapsulation efficiency was easy operation and with high accuracy.

Efficacy of Afatinib in a Previously-Treated Patient with Non-Small Cell Lung Cancer Harboring HER2 Mutation: Case Report

Human epidermal growth factor receptor 2 (HER2) mutation in non-small cell lung cancer (NSCLC) is an oncogenic driver that possibly becomes a druggable target to HER2-targeted therapy. The benefit of HER2-targeted therapy is much less defined especially in eastern populations. We provide evidence of clinical benefit of afatinib in a 50-year-old Asian woman with HER2-mutant NSCLC who previously failed cytotoxic chemotherapy and gefitinib treatment. Next-generation sequencing of the tumor tissue revealed a HER2 exon 20 mutation (c.2437A > G), which has never been reported. The patient was treated with afatinib for more than four months. She showed rapid radiologic response within a month, and maintained stable state until the last dose of afatinib.

Custo-efetividade do afatinibe versus pemetrexede associado a cisplatina, erlotinibe e gefitinibe no tratamento de primeira linha de pacientes com câncer de pulmão não pequenas células localmente avançado ou metastático, com mutação do receptor do fator de crescimento epidermoide (EGFR+), na perspectiva do Sistema de Saúde Suplementar do Brasil / Cost-effectiveness of afatinib versus pemetrexed plus cisplatin, erlotinib and gefitinib as first line treatment in patients with locally advanced or metastatic epidermal growth factor receptor mutation (EFGR+) non-small cell lung cancer in the Brazilian private healthcare system

Objetivo: Comparar os custos e efetividade do afatinibe versus pemetrexede associado a cisplatina (PEM/CIS), erlotinibe e gefitinibe no tratamento de primeira linha de pacientes com câncer de pulmão não pequenas células (CPNPC) com mutação no receptor de fator de crescimento epidermoide (EGFR+) localmente avançado ou metastático, no Sistema de Saúde Suplementar brasileiro. Métodos: O modelo de Markov foi utilizado para estimar anos de vida livres de progressão (PFLY), anos de vida (LY), anos de vida ajustados pela qualidade (QALY) e desfechos clínicos por sete anos. Utilizaram-se dados de sobrevida, segurança e utilidade dos estudos LUX-Lung 1, 3 e 6 e LUCEOR. A eficácia comparativa versus gefitinibe e erlotinibe foi estimada utilizando modelos bayesianos de comparação indireta. A utilização dos recursos foi estimada por painel de especialistas, e custos diretos foram estimados utilizando-se bases de dados oficiais. Resultados: Afatinibe mostrou aumento da sobrevida livre de progressão (0,41 PFLY), sobrevida global (0,16 LY) e qualidade de vida (0,21 QALY) com custo incremental (R$ 8.549), resultando em razão de custo-efetividade incremental (RCEI) de R$ 20.639/PFLY. Comparado ao erlotinibe, o afatinibe mostrou aumento de 0,46 PFLY, 0,13 LY e 0,20 QALY, com menor custo (-R$ 21.327). Comparado ao gefitinibe, o afatinibe mostrou incrementos de 0,53 PFLY, 0,37 LY, 0,34 QALY, com custo incremental de R$ 24.890, resultando em RCEI de R$ 46.709/PFLY. Considerando-se três vezes o PIB per capita como limiar de custo-efetividade (R$ 86.628), o afatinibe é custo-efetivo versus PEM/CIS e gefitinibe e dominante quando comparado ao erlotinibe. Conclusão: Sugere-se que o afatinibe é uma opção custo-efetiva quando comparado ao PEM/CIS, erlotinibe e gefitinibe no tratamento de primeira linha de pacientes com CPNPC EGFR+.

Objective: To compare costs and effectiveness of afatinib versus pemetrexed plus cisplatin (PEM/ CIS), erlotinib and gefitinib, as first line treatment in patients with locally advanced or metastatic epidermal growth factor receptor mutation (EGFR+) non-small cell lung cancer (NSCLC) in the Brazilian Private Healthcare System. Methods: A Markov model was used to estimate 7year progression-free life years (PFLY), life years (LY), quality-adjusted life years (QALY) and clinical outcomes of afatinib. Partitioned survival, safety and utility data from the LUX-Lung 1, 3 and 6 and LUCEOR trials were used. Comparative effectiveness versus gefitinib and erlotinib was estimated using Bayesian indirect treatment comparison. Resource use was estimated by an expert panel and direct costs were estimated from official databases. Results: Compared with PEM/CIS, afatinib was associated with increased progression free survival (0.41 PFLY), increased overall survival (0.16 LY) and increased quality of life (0.21 QALY) with incremental cost (BRL 8,549), resulting in an incremental cost-effectiveness ratio (ICER) of BRL 20.639/PFLY. Compared to erlotinib, afatinib was associated with additional 0.46 PFLY, 0.13 LY and 0.20 QALYs with lower cost (- BRL 21,327). When compared to gefitinib, afatinib was associated with incremental 0.53 PFLY, 0.37 LY and 0.34 QALY and increased cost (BRL 24,890), resulting in an ICER of BRL 46,709/PFLY. Considering 3 PIB per capita as a threshold (BRL 86,628), afatinib is a cost-effective technology versus PEM/CIS and gefitinib and dominant when compared to erlotinib. Conclusion: Findings suggest that afatinib is a cost-effective option, when compared to PEM/CIS, erlotinib and gefitinib, as first line treatment in EGFR+ NSCLC patients.

Effect of afatinib on the proliferation and apoptosis of human breast cell lines and its mechanisms / 中国肿瘤临床

Objective:To investigate the effect of afatinib, a tyrosine kinase inhibitor, on the proliferation, cell cycle, and apoptosis of human breast cell lines, and compare its effects with those of gefitinib. Methods:Three human breast cell lines, MCF-7, T47D, and MDA-MB-231, were cultured as cell models. A methyl thiazolyl tetrazolium assay was utilized to measure cell viability. Flow cytometer was used to analyze the cell cycle arrest (PI staining) and apoptosis rates (Annexin-V/PI staining). The protein expression was detected by Western blot analysis. Results:The proliferation of three human breast cell lines was significantly inhibited by afatinib, and the IC50 levels of MCF-7, T47D, and MDA-MB-231 were 0.101, 0.141, and 0.887μmol/L, respectively. The G0/G1 phase cell ratio increased con-siderably 24 h after afatinib was added to T47D or MDA-MB-231. The cell apoptosis rate also increased in the two cell lines (88.9%and 58.1%). The cleavage of apoptosis pathway proteins PARP and caspase-3 was also promoted by afatinib. Phosphorylation of EGFR was significantly inhibited by afatinib in the MDA-MB-231 cell line. Finally, the inhibition effect of afatinib was stronger than that of gefi-tinib. Conclusion: Afatinib could significantly inhibit the proliferation of breast cancer cells and promote apoptosis. The effect was dose-dependent. Afatinib was a more effective tyrosine kinase inhibitor as compared with gefitinib.

Advances in clinical application of afatinib in advanced non-small cell lung cancer based on the LUX-Lung trials / 肿瘤

Afatinib which is orally administered is an irreversible inhibitor of theepidermal growth factor receptor (EGFR) family tyrosine kinase. TheLUX-Lung 7 trial has shown that in the first-line treatment of patientswith advanced EGFR -mutant lung adenocarcinoma, afatinib couldsignificantly improve the progression-free survival (PFS) and the timeto treatment failure (TTF) as compared with gefitinib, but failed toachieve clinical benefit for the overall survival (OS). As compared withpemetrexed plus cisplatin regimen (LUX-Lung 3 trial) and gemcitabineplus cisplatin regimen (LUX-Lung 6 trial), afatinib could significantlyprolong the PFS, but not the OS. However, it is worth noting that bothLUX-Lung 3 trial and LUX-Lung 6 trial have shown that in the subgroup of patients with 19 exon deletion mutation of EGFR , the OS was significantly prolonged whenreceiving afatinib treatment versus chemotherapy. In addition, in the second-line treatment ofadvanced squamous-cell lung carcinoma, afatinib has shown to significantly prolong the PFSand OS as compared with erlotinib, regardless of EGFR mutation status (LUX-Lung 8 trial). Sideeffects of afatinib treatment in patients with NSCLC could be prevented by lowering the dose.In conclusion, afatinib can be used in the first-line treatment for patients with EGFR -mutantadvanced NSCLC, and also can be used in the second-line treatment of squamous-cell lungcarcinoma with progression after platinum-based chemotherapy.

Practical recommendation for rash and diarrhea management in Indian patients treated with tyrosine kinase inhibitors for the treatment of non‑small cell lung cancer.

Tyrosine kinase inhibitors (TKIs) are a pharmaceutical class of small molecules, orally available with manageable safety profile, approved worldwide for the treatment of several neoplasms, including lung, breast, kidney and pancreatic cancer as well as gastro‑intestinal stromal tumours and chronic myeloid leukaemia. In recent years, management of lung cancer has been moving towards molecular‑guided treatment, and the best example of this new approach is the use of the tyrosine kinase inhibitors (TKIs) in patients with mutations in the epidermal growth factor receptor (EGFR). The identification of molecular predictors of response can allow the selection of patients who will be the most likely to respond to these tyrosine kinase inhibitors (TKIs). Gastrointestinal (GI) adverse events (AEs) are frequently observed in patients receiving EGFR tyrosine kinase inhibitor therapy and are most impactful on the patient’s quality of life. Dermatologic side effects are also relatively common among patients treated with EGFR inhibitors. Evidence has emerged in recent years to suggest that the incidence and severity of rash, positively correlated with response to treatment. These skin disorders are generally mild or moderate in severity and can be managed by appropriate interventions or by reducing or interrupting the dose. Appropriate and timely management make it possible to continue a patient’s quality of life and maintain compliance; however if these adverse events (AEs) are not managed appropriately, and become more severe, treatment cessation may be warranted compromising clinical outcome. Strategies to improve the assessment and management of TKI related skin AEs are therefore essential to ensure compliance with TKI therapy, thereby enabling patients to achieve optimal benefits. This article provides a consensus on practical recommendation for the prevention and management of diarrhoea and rash in Non‑Small Cell Lung Cancer (NSCLC) patients receiving TKIs.

Afatinib Reduces STAT6 Signaling of Host ARPE-19 Cells Infected with Toxoplasma gondii

Specific gene expressions of host cells by spontaneous STAT6 phosphorylation are major strategy for the survival of intracellular Toxoplasma gondii against parasiticidal events through STAT1 phosphorylation by infection provoked IFN-γ. We determined the effects of small molecules of tyrosine kinase inhibitors (TKIs) on the growth of T. gondii and on the relationship with STAT1 and STAT6 phosphorylation in ARPE-19 cells. We counted the number of T. gondii RH tachyzoites per parasitophorous vacuolar membrane (PVM) after treatment with TKIs at 12-hr intervals for 72 hr. The change of STAT6 phosphorylation was assessed via western blot and immunofluorescence assay. Among the tested TKIs, Afatinib (pan ErbB/EGFR inhibitor, 5 µM) inhibited 98.0% of the growth of T. gondii, which was comparable to pyrimethamine (5 µM) at 96.9% and followed by Erlotinib (ErbB1/EGFR inhibitor, 20 µM) at 33.8% and Sunitinib (PDGFR or c-Kit inhibitor, 10 µM) at 21.3%. In the early stage of the infection (2, 4, and 8 hr after T. gondii challenge), Afatinib inhibited the phosphorylation of STAT6 in western blot and immunofluorescence assay. Both JAK1 and JAK3, the upper hierarchical kinases of cytokine signaling, were strongly phosphorylated at 2 hr and then disappeared entirely after 4 hr. Some TKIs, especially the EGFR inhibitors, might play an important role in the inhibition of intracellular replication of T. gondii through the inhibition of the direct phosphorylation of STAT6 by T. gondii.

Afatinib-Induced Acute Fatal Pneumonitis in Metastatic Lung Adenocarcinoma / 가정의학회지

Afatinib is an oral tyrosine kinase inhibitor (TKI) that inhibit Endothelial Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and HER4. The common side effects of EGFR TKI are rash, acne, diarrhea, stomatitis, pruritus, nausea, and loss of appetite. Drug induced pneumonitis is the less common adverse effects of EGFR TKI. Afatinib, 2nd generation EGFR TKI is anticipated to overcome drug resistance from 1st generation EGFR TKI according to preclinical study, and several studies are being conducted to compare clinical efficacy between 1st and 2nd EGFR TKI. Several cases of rug induced acute fatal pneumonitis were reported after use of erlotinib or gefitinib. However, a case of acute fatal pneumonitis associated with afatinib was note reported except drug induced pneumonitis in other clinical study. Here, we present a cases of acute severe pneumonitis related with afatinib in metastatic lung adenocarcinoma with literature review.

Afatinib-Induced Acute Fatal Pneumonitis in Metastatic Lung Adenocarcinoma / 가정의학회지

Afatinib is an oral tyrosine kinase inhibitor (TKI) that inhibit Endothelial Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and HER4. The common side effects of EGFR TKI are rash, acne, diarrhea, stomatitis, pruritus, nausea, and loss of appetite. Drug induced pneumonitis is the less common adverse effects of EGFR TKI. Afatinib, 2nd generation EGFR TKI is anticipated to overcome drug resistance from 1st generation EGFR TKI according to preclinical study, and several studies are being conducted to compare clinical efficacy between 1st and 2nd EGFR TKI. Several cases of rug induced acute fatal pneumonitis were reported after use of erlotinib or gefitinib. However, a case of acute fatal pneumonitis associated with afatinib was note reported except drug induced pneumonitis in other clinical study. Here, we present a cases of acute severe pneumonitis related with afatinib in metastatic lung adenocarcinoma with literature review.

New First-line Treatment Drug for Advanced Non-small Cell Lung Cancer-Afatinib / 中国药师

Afatinib is an irreversible inhibitor for the ErbB family of tyrosine kinases with oral administration. In two randomized, open-label and multinational phase III trials, the progression-free survival was significantly prolonged by afatinib compared with peme-trexed plus cisplatin (LUX-Lung 3) or gemcitabine plus cisplatin (LUX-Lung 6) in the treatment-naive patients with advanced non-small cell lung cancer ( NSCLC) with activating EGFR mutations. The patient-reported symptoms such as cough and dyspnoea, and certain health-related quality of life after the treatment by afatinib were also better than those treated by control dugs. Afatinib was ap-proved by FDA in July 2013 as the first-line treatment drug for the patients with metastatic NSCLC with EGFR exon 19 deletions or exon 21 (L858R) mutations. The action mechanisms, pharmacokinetics, clinical trials and adverse events were reviewed in this paper.

Advance in research for afatinib and its analogues, the multi-target tyrosine kinase inhibitor / 中国药学杂志

OBJECTIVE: To review the lastest research progress afatinih and its analogues, which are multi-target tyrosine kinase inhibitor. METHODS: By consulting references, the synthesis afatinib, the design, synthesis and antitumor activity its analogues are summarized, the antitumor activity, structure-activity relationship, pharmacokinetic research, adverse reaction are also summarized. RESULTS: The research progress afatinib and its analogues was comprehensively summarized. CONCLUSION: Although afatinib has much adverse reaction, it still has a good prospect and its analogues may be worth further studying.