BACKGROUND The most common EGFR mutations are in-frame deletions in exon 19 and point mutations in exon 21.Cases with classical EGFR mutations show a good response to EGFR tyrosine kinase inhibitors(TKIs),the standard...BACKGROUND The most common EGFR mutations are in-frame deletions in exon 19 and point mutations in exon 21.Cases with classical EGFR mutations show a good response to EGFR tyrosine kinase inhibitors(TKIs),the standard first-line treatment.With the development of next generation sequencing,some uncommon genomic mutations have been detected.However,the effect of TKIs on such uncommon EGFR mutations remains unclear.CASE SUMMARY Here,we report a case of rare EGFR co-mutation in non-small cell lung cancer and the efficacy of afatinib on this EGFR co-mutation.A 64-year-old woman was diagnosed with thoracolumbar and bilateral local rib bone metastases,bilateral pulmonary nodules,and pericardial and left pleural effusion.The pathological diagnosis was lung adenocarcinoma.To seek potential therapeutic regimens,rare co-mutation comprising rare EGFR G724S/R776H mutations and amplification were identified.The patient experienced a significant clinical response with a progression-free survival of 17 mo.CONCLUSION A case of non-small cell lung cancer with rare EGFR G724S/R776H mutations and EGFR amplification responds well to TKI treatment.展开更多
Objective: Several predictors of survival have been identified in EGFR-positive non-small cell lung cancer(NSCLC) patients treated with first generation EGFR inhibitors. Prognostic models of survival outcomes with afa...Objective: Several predictors of survival have been identified in EGFR-positive non-small cell lung cancer(NSCLC) patients treated with first generation EGFR inhibitors. Prognostic models of survival outcomes with afatinib have not been evaluated.Methods: A prognostic tool for overall survival(OS)/progression free survival(PFS) based on pre-treatment clinicopathological factors was developed for EGFR-positive advanced NSCLC patients treated with first-line afatinib using penalised regression of individual-participant data from LUX-Lung 3 and 6(n = 468). Favourable, intermediate and poor risk groups were identified and externally validated using LUX-Lung 1(n = 390) and LUX-Lung 2(n = 129) trials that initiated afatinib following previous chemotherapy or EGFR inhibitor treatment.Results: Discriminative performance was good in the development and validation cohorts. For patients treated with first-line afatinib, the median OS for the favourable, intermediate and poor risk groups were > 47.7, 29.3 and 16.4 months, respectively, and the median PFS were 17.3, 13.2 and 8.3 months, respectively. The improvement in median OS with afatinib use compared to chemotherapy was > 12.4 months for the favourable risk group, whereas no OS benefit was apparent for the poor risk group. The improvement in median PFS with afatinib use compared to chemotherapy was 10.2 months for the favourable risk group and 3.2 months for the poor risk group.Conclusions: A prognostic tool was developed and validated to identify favourable, intermediate and poor risk groups for OS/PFS in EGFR-positive advanced NSCLC patients treated with afatinib. The prognostic groups can inform the likely absolute OS/PFS benefit expected from afatinib compared to chemotherapy in first-line treatment.展开更多
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 ...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 competitive enzyme-linked immunosorbent assay(ELISA) to quantify afatinib in plasma for routine pharmacokinetic applications. An anti-afatinib antibody was obtained using(S)-N-4-(3-chloro-4-fluorophenyl)-7-(tetrahydrofuran-3-yloxy)-quinazoline-4,6-diamine(CTQD), which has the same substructure 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=0.976 X – 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.展开更多
Glucocorticoids(GC)are widely used to counter the adverse events during cancer therapy;nonetheless,previous studies pointed out that GC may reduce the efficacy of chemotherapy on cancer cells,especially in epidermal g...Glucocorticoids(GC)are widely used to counter the adverse events during cancer therapy;nonetheless,previous studies pointed out that GC may reduce the efficacy of chemotherapy on cancer cells,especially in epidermal growth factor receptor(EGFR)-targeted therapy of head and neck squamous cell carcinoma(HNSCC)remaining to be elucidated.The primary aim of the present study was to probe into the GC-induced resistance of EGFR-targeted drug afatinib and the underlying mechanism.HNSCC cell lines(HSC-3,SCC-25,SCC-9,and H-400)and the human oral keratinocyte(HOK)cell lines were assessed for GC receptor(GR)expression.The promoting tumor growth effect of GC was evaluated by the CCK-8 assay and flow cytometry.Levels of signaling pathways participants GR,mTOR,and EGFR were determined by quantitative polymerase chain reaction and western blotting.GC increased the proliferation of HNSCC cells in a GR-dependent manner and promoted AKT/mTOR signaling.But GC failed in counteracting the inhibition of rapamycin in the mTOR signaling pathway.Besides,GC also induced resistance to EGFR-targeted drug afatinib through AKT/mTOR instead of the EGFR/ERK signaling pathway.Thus,GCs reduce the efficacy of afatinib on HNSCC,implicating a cautious use of glucocorticoids in clinical practice.展开更多
BACKGROUND Epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs)have been adopted as the standard of care for non-small cell lung cancer(NSCLC)patients harboring EGFR sensitizing mutations.Besides the...BACKGROUND Epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs)have been adopted as the standard of care for non-small cell lung cancer(NSCLC)patients harboring EGFR sensitizing mutations.Besides the two common mutations exon 19 deletion and L858R,which together comprise approximately 85%of EGFR mutations in NSCLC,rare EGFR mutations also exist,including point mutations,deletions,and insertions spanning EGFR exons 18-25.However,the responsiveness of uncommon EGFR mutations to EGFR TKIs remains elusive and attracts increasing interest.CASE SUMMARY Herein,we report a 55-year-old male patient with stage IV NSCLC harboring a rare EGFR L833F-L861Q compound mutation in cis.The patient achieved a partial response to first-line treatment with afatinib and a progression-free survival of 10 mo.After afatinib failure,the patient received multiple line treatments with chemotherapy.Upon disease progression,the heavily pretreated patient was treated with osimertinib and bevacizumab,and both lung lesion and brain metastases were stable for more than 3 mo.He had an overall survival of 25 mo.CONCLUSION Our case revealed that both afatinib and the osimertinib+bevacizumab combination demonstrated clinical efficacy in NSCLC harboring an EGFR L833FL861Q compound mutation.The results provide more therapeutic options for patients with rare compound mutations.展开更多
Objective:To investigate the clinical efficacy of bevacizumab combined with afatinib in the treatment of non-small cell lung cancer.Methods: Ninety-eight patients with non-small cell lung cancer admitted to our hospit...Objective:To investigate the clinical efficacy of bevacizumab combined with afatinib in the treatment of non-small cell lung cancer.Methods: Ninety-eight patients with non-small cell lung cancer admitted to our hospital from December 2015 to December 2017 were randomly divided into the control group (49 cases) and the experimental group (49 cases). The group was treated with conventional first-line chemotherapy (pemetrexed plus carboplatin). The experimental group was treated with bevacizumab plus afatinib. The therapeutic effects of the two groups were observed. Immune function, angiogenesis related indicators and incidence of adverse reactions.Results: The levels of CD3+, CD4+, CD4+/CD8+, IgG, IgM, IgA, VEGF, BFGF and HDGF were not significantly different between the two groups. After treatment, both groups were reduced, and the experimental group CD3+, CD4+, The levels of CD4+/CD8+, IgG, IgM and IgA were significantly higher than those of the control group. The levels of VEGF, BFGF and HDGF were significantly lower than those of the control group. The effective rate of the experimental group was significantly higher than that of the control group. There was no significant difference in the rate.Conclusion: Bevacizumab combined with afatinib can effectively improve the therapeutic effect of patients with non-small cell lung cancer. It has been the expression of angiogenic factors, improve the immune function of patients and increase the adverse reactions of patients, which is worthy of clinical promotion.展开更多
A simple, controlled, robust and scalable three-stage manufacturing process of Afatinib Dimaleate was assessed and optimized leading to improved yield and quality. The synthetic process involves sequence of reactions ...A simple, controlled, robust and scalable three-stage manufacturing process of Afatinib Dimaleate was assessed and optimized leading to improved yield and quality. The synthetic process involves sequence of reactions as nitro-reduction, amidation and salification. The developed and optimized route was demonstrated on 300 g scale with over all isolated yield of 84% for Afatinib free base. The developed process has the capability to control not only the process related impurities but also the degradation impurities. One new impurity was identified during the process development studies and characterized as acetamide impunity, chemically known as (S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) acetamide. Other impurities were identified as degradation impurities, Process impurities and were labeled as 1-(4-((3-chloro-4-fluorophenyl) amino)-7-(((S)-tetrahydrofuran-3-yl) oxy) quinazoline-6-yl)-5-Hydroxypyrrolidin- 2-one (hydroxy impurity), Afatinib N-Oxide impurity and N4-(3-chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro- 3-furanyl] oxy]-4,6-quinazolinediamine (Intermediate-1).展开更多
Gallbladder cancer(GBC)is a malignancy of biliary tract which is infrequent in developed countries but common in some specific geographical regions of developingCurrently,GBC has a low early diagnosis rate and an extr...Gallbladder cancer(GBC)is a malignancy of biliary tract which is infrequent in developed countries but common in some specific geographical regions of developingCurrently,GBC has a low early diagnosis rate and an extremely poor prognosis,leading to major problems for treatment of GBC.Liver invasion and metastasis one of the main causes of its poor prognosis,with its average overall survival of 6 months.展开更多
Aims:The study aimed to evaluate the effectiveness and adverse events of tyrosine kinase inhibitors(TKIs)in the first-line treatment of advanced non-small cell lung cancer(NSCLC)with epidermal growth factor receptor(E...Aims:The study aimed to evaluate the effectiveness and adverse events of tyrosine kinase inhibitors(TKIs)in the first-line treatment of advanced non-small cell lung cancer(NSCLC)with epidermal growth factor receptor(EGFR)mutations.Methods:A retrospective study on advanced NSCLC patients with EGFR mutations treated with TKIs as a first-line therapy at Nghe An Oncology Hospital,Vietnam between January 2017 and August 2023.The primary endpoints included objective response rate,progression-free survival,and tolerability.The secondary endpoint was overall survival.Results:A total of 211 patients received first-line treatment with Erlotinib(n=74),Gefitinib(n=85),Afatinib(n=34)or Osimertinib(n=18).The overall response rate was 76.7%,with Osimertinib at 83.4%,Afatinib at 73.6%,Erlotinib at 77.1%,and Gefitinib at 76.5%.The median progression-free survival in the Gefitinib group was 12.2 months(95%CI:11.1-13.2),13.4 months(95%CI:10.6-16.2)in the Erlotinib group,18.4 months(95%CI:10.1-26.8)in the Afatinib group and 25.3 months in the Osimertinib group(p=0.001).The median overall survival was 21.8 months(95%Cl:15.0-28.4)in the Gefitinib group,30 months(95%Cl:19.1-40.9)in the Erlotinib group(p=0.154).Most drug-related adverse events were grade 1 or 2.Diarrhea was the most frequent adverse event in the Afatinib group at 44.1%;rash was most common in the Erlotinib group at 60.8%;paronychia(31.8%),and interstitial lung disease(3.5%)were most frequent in the Gefitinib group.Conclusion:The TKIs as first-line therapies for advanced NSCLC patients with EGFR mutated are highly effective,prolong survival,and are well tolerated.展开更多
文摘BACKGROUND The most common EGFR mutations are in-frame deletions in exon 19 and point mutations in exon 21.Cases with classical EGFR mutations show a good response to EGFR tyrosine kinase inhibitors(TKIs),the standard first-line treatment.With the development of next generation sequencing,some uncommon genomic mutations have been detected.However,the effect of TKIs on such uncommon EGFR mutations remains unclear.CASE SUMMARY Here,we report a case of rare EGFR co-mutation in non-small cell lung cancer and the efficacy of afatinib on this EGFR co-mutation.A 64-year-old woman was diagnosed with thoracolumbar and bilateral local rib bone metastases,bilateral pulmonary nodules,and pericardial and left pleural effusion.The pathological diagnosis was lung adenocarcinoma.To seek potential therapeutic regimens,rare co-mutation comprising rare EGFR G724S/R776H mutations and amplification were identified.The patient experienced a significant clinical response with a progression-free survival of 17 mo.CONCLUSION A case of non-small cell lung cancer with rare EGFR G724S/R776H mutations and EGFR amplification responds well to TKI treatment.
基金supported by a grant from Cancer Council South Australia’s Beat Cancer Project on behalf of its donors and the State Government through the Department of Health (Grant No.1159924 and 1127220)funded by a Postdoctoral Fellowship from the National Breast Cancer Foundation, Australia (Grant No.PF-17-007)
文摘Objective: Several predictors of survival have been identified in EGFR-positive non-small cell lung cancer(NSCLC) patients treated with first generation EGFR inhibitors. Prognostic models of survival outcomes with afatinib have not been evaluated.Methods: A prognostic tool for overall survival(OS)/progression free survival(PFS) based on pre-treatment clinicopathological factors was developed for EGFR-positive advanced NSCLC patients treated with first-line afatinib using penalised regression of individual-participant data from LUX-Lung 3 and 6(n = 468). Favourable, intermediate and poor risk groups were identified and externally validated using LUX-Lung 1(n = 390) and LUX-Lung 2(n = 129) trials that initiated afatinib following previous chemotherapy or EGFR inhibitor treatment.Results: Discriminative performance was good in the development and validation cohorts. For patients treated with first-line afatinib, the median OS for the favourable, intermediate and poor risk groups were > 47.7, 29.3 and 16.4 months, respectively, and the median PFS were 17.3, 13.2 and 8.3 months, respectively. The improvement in median OS with afatinib use compared to chemotherapy was > 12.4 months for the favourable risk group, whereas no OS benefit was apparent for the poor risk group. The improvement in median PFS with afatinib use compared to chemotherapy was 10.2 months for the favourable risk group and 3.2 months for the poor risk group.Conclusions: A prognostic tool was developed and validated to identify favourable, intermediate and poor risk groups for OS/PFS in EGFR-positive advanced NSCLC patients treated with afatinib. The prognostic groups can inform the likely absolute OS/PFS benefit expected from afatinib compared to chemotherapy in first-line treatment.
文摘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 competitive enzyme-linked immunosorbent assay(ELISA) to quantify afatinib in plasma for routine pharmacokinetic applications. An anti-afatinib antibody was obtained using(S)-N-4-(3-chloro-4-fluorophenyl)-7-(tetrahydrofuran-3-yloxy)-quinazoline-4,6-diamine(CTQD), which has the same substructure 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=0.976 X – 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.
基金supported by the Research Funding(No.RCDWJS 2020-20)Research and Development Program(RD-02-202002)from West China School/Hospital of Stomatology Sichuan University+1 种基金the Natural Science Foundation of China(81902784&81872207)Sichuan Provincial Fund of China(2022YFSY0058).
文摘Glucocorticoids(GC)are widely used to counter the adverse events during cancer therapy;nonetheless,previous studies pointed out that GC may reduce the efficacy of chemotherapy on cancer cells,especially in epidermal growth factor receptor(EGFR)-targeted therapy of head and neck squamous cell carcinoma(HNSCC)remaining to be elucidated.The primary aim of the present study was to probe into the GC-induced resistance of EGFR-targeted drug afatinib and the underlying mechanism.HNSCC cell lines(HSC-3,SCC-25,SCC-9,and H-400)and the human oral keratinocyte(HOK)cell lines were assessed for GC receptor(GR)expression.The promoting tumor growth effect of GC was evaluated by the CCK-8 assay and flow cytometry.Levels of signaling pathways participants GR,mTOR,and EGFR were determined by quantitative polymerase chain reaction and western blotting.GC increased the proliferation of HNSCC cells in a GR-dependent manner and promoted AKT/mTOR signaling.But GC failed in counteracting the inhibition of rapamycin in the mTOR signaling pathway.Besides,GC also induced resistance to EGFR-targeted drug afatinib through AKT/mTOR instead of the EGFR/ERK signaling pathway.Thus,GCs reduce the efficacy of afatinib on HNSCC,implicating a cautious use of glucocorticoids in clinical practice.
文摘BACKGROUND Epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs)have been adopted as the standard of care for non-small cell lung cancer(NSCLC)patients harboring EGFR sensitizing mutations.Besides the two common mutations exon 19 deletion and L858R,which together comprise approximately 85%of EGFR mutations in NSCLC,rare EGFR mutations also exist,including point mutations,deletions,and insertions spanning EGFR exons 18-25.However,the responsiveness of uncommon EGFR mutations to EGFR TKIs remains elusive and attracts increasing interest.CASE SUMMARY Herein,we report a 55-year-old male patient with stage IV NSCLC harboring a rare EGFR L833F-L861Q compound mutation in cis.The patient achieved a partial response to first-line treatment with afatinib and a progression-free survival of 10 mo.After afatinib failure,the patient received multiple line treatments with chemotherapy.Upon disease progression,the heavily pretreated patient was treated with osimertinib and bevacizumab,and both lung lesion and brain metastases were stable for more than 3 mo.He had an overall survival of 25 mo.CONCLUSION Our case revealed that both afatinib and the osimertinib+bevacizumab combination demonstrated clinical efficacy in NSCLC harboring an EGFR L833FL861Q compound mutation.The results provide more therapeutic options for patients with rare compound mutations.
文摘Objective:To investigate the clinical efficacy of bevacizumab combined with afatinib in the treatment of non-small cell lung cancer.Methods: Ninety-eight patients with non-small cell lung cancer admitted to our hospital from December 2015 to December 2017 were randomly divided into the control group (49 cases) and the experimental group (49 cases). The group was treated with conventional first-line chemotherapy (pemetrexed plus carboplatin). The experimental group was treated with bevacizumab plus afatinib. The therapeutic effects of the two groups were observed. Immune function, angiogenesis related indicators and incidence of adverse reactions.Results: The levels of CD3+, CD4+, CD4+/CD8+, IgG, IgM, IgA, VEGF, BFGF and HDGF were not significantly different between the two groups. After treatment, both groups were reduced, and the experimental group CD3+, CD4+, The levels of CD4+/CD8+, IgG, IgM and IgA were significantly higher than those of the control group. The levels of VEGF, BFGF and HDGF were significantly lower than those of the control group. The effective rate of the experimental group was significantly higher than that of the control group. There was no significant difference in the rate.Conclusion: Bevacizumab combined with afatinib can effectively improve the therapeutic effect of patients with non-small cell lung cancer. It has been the expression of angiogenic factors, improve the immune function of patients and increase the adverse reactions of patients, which is worthy of clinical promotion.
文摘A simple, controlled, robust and scalable three-stage manufacturing process of Afatinib Dimaleate was assessed and optimized leading to improved yield and quality. The synthetic process involves sequence of reactions as nitro-reduction, amidation and salification. The developed and optimized route was demonstrated on 300 g scale with over all isolated yield of 84% for Afatinib free base. The developed process has the capability to control not only the process related impurities but also the degradation impurities. One new impurity was identified during the process development studies and characterized as acetamide impunity, chemically known as (S)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((tetrahydrofuran-3-yl) oxy) quinazolin-6-yl) acetamide. Other impurities were identified as degradation impurities, Process impurities and were labeled as 1-(4-((3-chloro-4-fluorophenyl) amino)-7-(((S)-tetrahydrofuran-3-yl) oxy) quinazoline-6-yl)-5-Hydroxypyrrolidin- 2-one (hydroxy impurity), Afatinib N-Oxide impurity and N4-(3-chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro- 3-furanyl] oxy]-4,6-quinazolinediamine (Intermediate-1).
文摘Gallbladder cancer(GBC)is a malignancy of biliary tract which is infrequent in developed countries but common in some specific geographical regions of developingCurrently,GBC has a low early diagnosis rate and an extremely poor prognosis,leading to major problems for treatment of GBC.Liver invasion and metastasis one of the main causes of its poor prognosis,with its average overall survival of 6 months.
文摘Aims:The study aimed to evaluate the effectiveness and adverse events of tyrosine kinase inhibitors(TKIs)in the first-line treatment of advanced non-small cell lung cancer(NSCLC)with epidermal growth factor receptor(EGFR)mutations.Methods:A retrospective study on advanced NSCLC patients with EGFR mutations treated with TKIs as a first-line therapy at Nghe An Oncology Hospital,Vietnam between January 2017 and August 2023.The primary endpoints included objective response rate,progression-free survival,and tolerability.The secondary endpoint was overall survival.Results:A total of 211 patients received first-line treatment with Erlotinib(n=74),Gefitinib(n=85),Afatinib(n=34)or Osimertinib(n=18).The overall response rate was 76.7%,with Osimertinib at 83.4%,Afatinib at 73.6%,Erlotinib at 77.1%,and Gefitinib at 76.5%.The median progression-free survival in the Gefitinib group was 12.2 months(95%CI:11.1-13.2),13.4 months(95%CI:10.6-16.2)in the Erlotinib group,18.4 months(95%CI:10.1-26.8)in the Afatinib group and 25.3 months in the Osimertinib group(p=0.001).The median overall survival was 21.8 months(95%Cl:15.0-28.4)in the Gefitinib group,30 months(95%Cl:19.1-40.9)in the Erlotinib group(p=0.154).Most drug-related adverse events were grade 1 or 2.Diarrhea was the most frequent adverse event in the Afatinib group at 44.1%;rash was most common in the Erlotinib group at 60.8%;paronychia(31.8%),and interstitial lung disease(3.5%)were most frequent in the Gefitinib group.Conclusion:The TKIs as first-line therapies for advanced NSCLC patients with EGFR mutated are highly effective,prolong survival,and are well tolerated.
