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1.
Medicine (Baltimore) ; 99(29): e21170, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702875

RESUMO

BACKGROUND: The purpose of the current meta-analysis was to compare the oncological outcomes of pemetrexed versus gefitinib in pre-treated advanced or metastatic non-small cell lung cancer (NSCLC) patients. METHODS: Search the online electronic databases on comparison the effectiveness and adverse effects of pemetrexed versus gefitinib in therapy outcomes of pre-treated NSCLC to September 2019. All studies analyzed the summary odds ratios (ORs) of the main outcomes, including survival efficacy and toxicity complications. RESULTS: In all, 5 trials involving 676 subjects were included, with 332 receiving pemetrexed and 344 using gefitinib. The pooled analysis of overall survival (OS) (OR = 0.97, 95%CI = 0.77-1.21, P = .76) and progression-free survival (PFS) (OR = 1.17, 95%CI = 0.60-2.30, P = .65) showed that pemetrexed did not achieve benefit when compared with gefitinib. In the results of subgroup analysis among the EGFR mutation-positive patients, the comparison of gefitinib therapy versus pemetrexed did show PFS benefit 0.35 (95%CI 0.12-1.01; P = .05). In terms of grade 3 or 4 side effects, a similar toxicity profile of both pemetrexed and gefitinib was shown in the incidence rate of rash (P = .045), fatigue (P = .97), thrombocytopenia (P = .68) and anemia (P = .21) between the 2 groups. CONCLUSION: Pemetrexed was not associated with survival benefit than gefitinib therapy among pre-treated NSCLC patients. While, gefitinib showed superior PFS efficacy than pemetrexed for patients with EGFR mutation-type. Future investigations are required to identify relevant biomarkers in selected patients that would most likely benefit from pemetrexed or gefitinib treatment in pre-treated advanced NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Gefitinibe/normas , Pemetrexede/normas , Idoso , Antineoplásicos/normas , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Gefitinibe/uso terapêutico , Humanos , Masculino , Pemetrexede/uso terapêutico , Intervalo Livre de Progressão
2.
Medicine (Baltimore) ; 99(23): e20510, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32501998

RESUMO

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy is the primary treatment option for patients with non-small cell lung cancer (NSCLC). However, one of the major adverse effects associated with this therapy is skin toxicity, which impacts the patient's quality of life. This study aimed to describe the severities and locations of skin toxicity, and to analyze their association with the quality of life in patients with advanced NSCLC who received EGFR-TKI therapy as first-line treatment.This cross-sectional and correlation study was conducted at a tertiary medical center in northern Taiwan between July 2015 and March 2016. Skin toxicity was assessed and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). The Skindex-16 scale was used to measure the skin disease-related quality of life.A total of 146 NSCLC patients who received EGFR-TKI therapy within the first 3 months of diagnosis were included in this study; 93.2% of these patients experienced skin toxicities. Approximately 70% of the patients developed xerosis and pruritus, while 50% had papulopustular eruptions and paronychia. The mean skin symptom impact score was 5.38 (standard deviation = 2.65). The skin-related quality of life varied widely among the participants but remained acceptable (mean score = 13.96, standard deviation = 16.55). Skin symptoms correlated significantly with poor quality of life (r = 0.50, P < .001). Younger patients and those treated with afatinib were the most affected, reporting the poorest quality of life. Patients who required EGFR-TKI dose reduction had experienced more severe skin symptoms than had patients who did not require it (7.35 vs 5.01, P < .001).Skin toxicity related to EGFR-TKI treatment impacts the quality of life in patients with NSCLC. During the treatment period, skin assessment and tailored management should be incorporated into the daily care plan.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/normas , Pele/efeitos dos fármacos , Afatinib/efeitos adversos , Afatinib/normas , Afatinib/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/psicologia , Correlação de Dados , Estudos Transversais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/fisiopatologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/psicologia , Cloridrato de Erlotinib/efeitos adversos , Cloridrato de Erlotinib/normas , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe/efeitos adversos , Gefitinibe/normas , Gefitinibe/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Qualidade de Vida/psicologia , Pele/fisiopatologia , Inquéritos e Questionários , Taiwan/epidemiologia
3.
PLoS One ; 15(4): e0231413, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32267879

RESUMO

INTRODUCTION: Comparison of the effectiveness and cost-effectiveness of three first-line EGFR-tyrosine kinase inhibitors (TKIs) would improve patients' clinical benefits and save costs. Using real-world data, this study attempted to directly compare the effectiveness and cost-effectiveness of first-line afatinib, erlotinib, and gefitinib. METHODS: During May 2011-December 2017, all patients with non-small cell lung cancer (NSCLC) visiting a tertiary center were invited to fill out the EuroQol five-dimension (EQ-5D) questionnaires and World Health Organization Quality of Life, brief version (WHOQOL-BREF), and received follow-ups for survival and direct medical costs. A total of 379 patients with EGFR mutation-positive advanced NSCLC under first-line TKIs were enrolled for analysis. After propensity score matching for the patients receiving afatinib (n = 48), erlotinib (n = 48), and gefitinib (n = 96), we conducted the study from the payers' perspective with a lifelong time horizon. RESULTS: Patients receiving afatinib had the worst lifetime psychometric scores, whereas the differences in quality-adjusted life expectancy (QALE) were modest. Considering 3 treatments together, afatinib was dominated by erlotinib. Erlotinib had an incremental cost-effectiveness of US$17,960/life year and US$12,782/QALY compared with gefitinib. Acceptability curves showed that erlotinib had 58.6% and 78.9% probabilities of being cost-effective given a threshold of 1 Taiwanese per capita GDP per life year and QALY, respectively. CONCLUSION: Erlotinib appeared to be cost-effective. Lifetime psychometric scores may provide additional information for effectiveness evaluation.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Análise Custo-Benefício , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Afatinib/uso terapêutico , Idoso , Carcinoma Pulmonar de Células não Pequenas/economia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe/uso terapêutico , Humanos , Expectativa de Vida , Neoplasias Pulmonares/economia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pontuação de Propensão , Qualidade de Vida , Taxa de Sobrevida , Taiwan , Centros de Atenção Terciária
4.
Cancer Sci ; 111(5): 1724-1738, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32159882

RESUMO

In a subgroup of Japanese patients in the ARCHER 1050 randomized phase 3 trial, we evaluated the efficacy and safety and determined the effects of dose modifications on adverse events (AE) and therapy management of first-line oral dacomitinib 45 mg compared with oral gefitinib 250 mg, each once daily in 28-d cycles, in patients with EGFR-activating mutation-positive (EGFR-positive; exon 19 deletion or exon 21 L858R substitution mutations) advanced non-small cell lung cancer (NSCLC). The primary endpoint was progression-free survival (PFS; RECIST, version 1.1, by blinded independent review). In 81 Japanese patients (40 dacomitinib, 41 gefitinib), PFS was longer with dacomitinib compared with gefitinib (hazard ratio [HR], 0.544 [95% confidence interval {CI}, 0.307-0.961]; 2-sided P = .0327; median 18.2 for dacomitinib [95% CI, 11.0-31.3] mo, 9.3 [95% CI, 7.4-14.7] mo for gefitinib). The most common Grade 3 AEs were dermatitis acneiform with dacomitinib (27.5%) and increased alanine aminotransferase with gefitinib (12.2%). A higher proportion of patients receiving dacomitinib (85.0%) compared with gefitinib (24.4%) had AEs leading to dose reduction. Incidence and severity of diarrhea, dermatitis acneiform, stomatitis and paronychia were generally reduced after dacomitinib dose reductions and dacomitinib treatment duration was generally longer in patients with a dose reduction in comparison with those without a dose reduction. Our results confirmed the efficacy and safety of first-line dacomitinib in Japanese patients with EGFR-positive advanced NSCLC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinonas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/fisiopatologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Gefitinibe/administração & dosagem , Gefitinibe/efeitos adversos , Gefitinibe/uso terapêutico , Humanos , Japão , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Quinazolinonas/administração & dosagem , Quinazolinonas/efeitos adversos , Resultado do Tratamento
5.
N Engl J Med ; 382(1): 41-50, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31751012

RESUMO

BACKGROUND: Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. A phase 3 trial compared first-line osimertinib with other EGFR-TKIs in patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). The trial showed longer progression-free survival with osimertinib than with the comparator EGFR-TKIs (hazard ratio for disease progression or death, 0.46). Data from the final analysis of overall survival have not been reported. METHODS: In this trial, we randomly assigned 556 patients with previously untreated advanced NSCLC with an EGFR mutation (exon 19 deletion or L858R allele) in a 1:1 ratio to receive either osimertinib (80 mg once daily) or one of two other EGFR-TKIs (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily, with patients receiving these drugs combined in a single comparator group). Overall survival was a secondary end point. RESULTS: The median overall survival was 38.6 months (95% confidence interval [CI], 34.5 to 41.8) in the osimertinib group and 31.8 months (95% CI, 26.6 to 36.0) in the comparator group (hazard ratio for death, 0.80; 95.05% CI, 0.64 to 1.00; P = 0.046). At 3 years, 79 of 279 patients (28%) in the osimertinib group and 26 of 277 (9%) in the comparator group were continuing to receive a trial regimen; the median exposure was 20.7 months and 11.5 months, respectively. Adverse events of grade 3 or higher were reported in 42% of the patients in the osimertinib group and in 47% of those in the comparator group. CONCLUSIONS: Among patients with previously untreated advanced NSCLC with an EGFR mutation, those who received osimertinib had longer overall survival than those who received a comparator EGFR-TKI. The safety profile for osimertinib was similar to that of the comparator EGFR-TKIs, despite a longer duration of exposure in the osimertinib group. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125.).


Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Acrilamidas/efeitos adversos , Idoso , Compostos de Anilina/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Método Duplo-Cego , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/efeitos adversos
6.
Biochem Pharmacol ; 172: 113772, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31866302

RESUMO

Patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer (NSCLC) benefits from EGFR-tyrosine kinase inhibitor (TKI) treatment. However, drug resistance to EGFR-TKIs remains a great challenge. Single nucleotide polymorphisms (SNPs) may significantly influence prognosis of EGFR-TKI therapy. Herein, we hypothesized that the functional SNP in DACT2, coding a pivotal inhibitor of the Wnt/ß-catenin signaling, may affect gene expression, which in turn, impact prognosis of NSCLC treated with EGFR-TKIs. Genotypes of the DACT2 promoter rs9364433 SNP were determined in two independent cohorts consisted of 319 EGFR-TKI treated stage IIIB/IV NSCLC patients. The allele-specific regulation on DACT2 expression by rs9364433 and impacts of DACT2 on gefitinib sensitivity was evaluated in vitro and in vivo. Cox regression analyses demonstrated that rs9364433 was significantly associated with patient survival in both cohorts (all P < 0.05). Reporter gene assays and Electrophoretic Mobility Shift Assays demonstrated that rs9364433 has an allele-specific effect on gene expression modulated by transcription factor TFAP2A. The G allele associated with diminished TFAP2A binding leads to significantly decreased DACT2 expression in NSCLC cell lines and tissues. Consistently, DACT2 could evidently increase the anti-proliferation effect of gefitinib on NSCLC cells. Our findings elucidated potential clinical implications of DACT2, which may result in better understanding and outcome assessment of EGFR-TKI treatments.


Assuntos
Adenocarcinoma/tratamento farmacológico , Gefitinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Fator de Transcrição AP-2/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Alelos , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Feminino , Regulação Neoplásica da Expressão Gênica , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Inibidores de Proteínas Quinases/farmacologia , Análise de Regressão , Análise de Sobrevida , Fator de Transcrição AP-2/genética
7.
BMC Cancer ; 19(1): 1203, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31823748

RESUMO

BACKGROUND: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) (e.g. gefitinib) currently remain the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) with activating EGFR mutation. However, acquired resistance to gefitinib, which occurs frequently through unidentified mechanisms, significantly attenuate therapeutic effectiveness. Previous miRNA microarray analysis reveals that expression levels of a conserved oncomiR miR-762 are significantly upregulated in gefitinib-resistant NSCLC cells. We therefore aim to elucidate the role and underlying mechanisms of miR-762 during the pathogenesis of gefitinib resistance. METHODS: miR-762 expression in gefitinib-resistant NSCLC tissues and cells was evaluated using RT-qPCR. The potential regulation of miR-762 expression by IL-6 was studied using pharmacological and biochemical approaches. Effects of miR-762 manipulation on sensitivity to gefitinib was assessed using MTT, apoptotic ELISA and xenograft model. Finally, the posttranscriptional regulation of active BCR related protein (ABR) by miR-762 was determined using luciferase assay and site-directed mutagenesis. RESULTS: miR-762 expression was upregulated in gefitinib-resistant NSCLC tissues and cells, and this upregulation predicted a poor post-chemotherapy prognosis in NSCLC patients. miR-762 upregulation, induced by IL-6 signaling, significantly enhanced cell survival and rendered NSCLC cells unresponsiveness to gefitinib-elicited cell death. We finally provided the evidence that the oncogenic effect of miR-762 was mediated mainly through posttranscriptional repression of ABR in gefitinib-resistant NSCLC cells. CONCLUSIONS: Our findings provide a rationale for future efforts testing miR-762 inhibition and ABR restoration co-treatment in patients with recurrent EGFR mutant NSCLC to therapeutically combat the heterogeneity of EGFR-TKIs resistance mechanisms.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Gefitinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , MicroRNAs/genética , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Linhagem Celular Tumoral , Sobrevivência Celular , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Proteínas Ativadoras de GTPase/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Mutação , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Arch. bronconeumol. (Ed. impr.) ; 55(12): 627-633, dic. 2019. graf
Artigo em Espanhol | IBECS | ID: ibc-186396

RESUMO

Introduction: Lung cancer is a major public health problem, as the second causes of cancer related death worldwide, with relatively low survival rates, and accessible drug resistance. Long non-coding RNAs (LncRNAs) have been identified as activator in lung cancer with elusive mechanisms. We aimed to detect the regulation of LncRNA MALAT1 in the proliferation and gefitinib resistance in lung cancer cells. Methods: MALAT1 in A549 and HCC 1299 human lung adenocarcinoma cell lines was silenced by shRNA or overexpressed using plasmid, and the cell viability and cell proliferation were evaluated by MTT assay and soft agar colony formation assay. RNA levels were detected by RT-PCR, and the protein expression was measured by western blot. The binding between MALAT1 and miR-200a was validated by luciferase reporter assays using pSi-Chech 2 vectors. Results: The cell viability and proliferation of A549 cells transfected with MALAT1 shRNA were significantly lower than the control. The MALAT1 expression in gefitinib resistant A549 cells was upregulated. miR-200a significantly inhibited the fluorescence of pSi-Check 2 vector with MALAT1 gene, suggesting the direct binding between MALAT1 and miR-200a. In addition, LncRNA MALAT1 promotes ZEB1 expression in A549 cells. Conclusion: Our study showed that MALAT1 promoted the proliferation and gefitinib resistance of lung cancer cells by sponging miR-200a, which regulates expression of ZEB1 in the A549 cells. This MALAT1/miR-200a axis could serve as new therapeutic target for lung cancer treatment


Introducción: El cáncer de pulmón es un importante problema de salud pública. Constituye la segunda causa de muerte por cáncer en el mundo y se asocia a tasas de supervivencia relativamente bajas y a resistencia a fármacos accesibles. Los RNA largos no-codificantes (lncRNA) se han identificado como activadores en el cáncer de pulmón con mecanismos aún no esclarecidos. El objetivo de este estudio fue detectar la regulación del LncRNA MALAT1 en la proliferación y la resistencia de las células tumorales de pulmón. Métodos: La expresión de MALAT1 se silenció con un shRNA o se sobreexpresó mediante el uso de un plásmido en las líneas celulares de adenocarcinoma pulmonar humano A459 y HCC. La viabilidad celular y la proliferación se evaluaron mediante un ensayo MTT y el ensayo de formación de colonias en agar blando. Los niveles de RNA se detectaron con RT-PCR y los niveles de proteína se midieron con Western Blot. La unión entre MALAT1 y miR-200a se validó gracias a un ensayo de luciferasa utilizando vectores pSi-Chech 2. Resultados: La viabilidad y la proliferación de las células A549 transfectadas con el shRNA contra MALAT1 resultaron significativamente más bajas que en el control. Se produjo un incremento en la expresión de MALAT1 en las células A549 resistentes a gefitinib. MiR-200a inhibió significativamente la fluorescencia del vector pSi-Check 2 que contenía el gen MALAT1, sugiriendo la unión directa entre MALAT1 y miR-200a. Además, el LncRNA de MALAT1 promovió la expresión de ZEB1 en las células A549. Conclusión: Nuestro estudio demuestra que MALAT1 promovió la proliferación y resistencia a gefitinib en células tumorales de pulmón actuando como "esponja" de miR-200a, que regula la expresión de ZEB1 en células A549


Assuntos
Humanos , MicroRNAs/genética , Proteínas de Ligação a RNA/genética , RNA Longo não Codificante/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/diagnóstico , Resistência a Medicamentos/efeitos dos fármacos , Adenocarcinoma/diagnóstico , Gefitinibe/uso terapêutico , Reação em Cadeia da Polimerase
9.
Future Oncol ; 15(33): 3775-3782, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31709807

RESUMO

Aim: The association of tyrosine kinase inhibitors (TKIs) and local radiotherapy in EGFR-mutated non-small-cell lung cancer patients experiencing disease progression under TKIs could be a valid an option. Patients & methods: We included 131 patients experiencing disease progression during first-line TKI. In group A, patients received TKI beyond progression and site(s) of progression were irradiated; in group B, patients remained on TKI alone beyond progression; and group C stopped TKI at first disease progression. Results: Median overall survival resulted longer in group A versus B and C (p < 0.0001). Group A had a trend toward a longer second progression-free survival (measured from the time of first progression until second progression) versus group B (p = 0.06). Conclusion: TKI beyond progression in association with local ablative treatment is a valid treatment option in oligoprogressive patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia/métodos , Neoplasias Pulmonares/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Ablação por Radiofrequência , Adulto , Afatinib/farmacologia , Afatinib/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Análise Mutacional de DNA , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos da radiação , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Humanos , Pulmão/diagnóstico por imagem , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/efeitos da radiação , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/farmacologia , Estudos Retrospectivos
10.
BMC Cancer ; 19(1): 1006, 2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31655564

RESUMO

BACKGROUND: Non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations often develop brain metastases. Treatment with EGFR-tyrosine kinase inhibitors (TKIs) has shown the effectiveness; however, knowledge of the clinical factors associated with outcomes in NSCLC patients with EGFR mutations remains limited. METHODS: Treatment-naive patients diagnosed with advanced non-squamous NSCLC with brain metastases harboring EGFR mutations and treated with an EGFR-TKI as first-line therapy were enrolled with analysis of their medical records. RESULTS: A total of 134 advanced NSCLC patients with brain metastases harboring EGFR mutations received an EGFR-TKI (gefitinib: 62, erlotinib: 49, and afatinib: 23) as the first-line therapy. Sixty-nine had exon 19 deletions (51.5%), and 56 (41.8%) had L858R mutations. There was no statistically significant difference in progression-free survival (PFS) and overall survival (OS) among the EGFR-TKIs. Significantly shorter OS was noted in patients with multiple brain metastases (hazard ratio [HR]: 2.43, p = 0.007), uncommon EGFR mutations (HR: 3.75, p = 0.009), and liver metastases. Thirty-eight patients (29.1%) received brain radiotherapy for brain metastases before disease progression, and had a significantly longer time until intracranial progression. However, the brain radiotherapy had no statistically significant impact on PFS or OS. CONCLUSIONS: Patients with uncommon mutations, multiple brain metastases, and concomitant liver metastases tended to have shorter OS. Brain radiotherapy could delay the time to intracranial disease progression but had no impact on survival. The different first-line EGFR-TKIs achieved similar treatment responses in terms of PFS and OS in the EGFR-mutated NSCLC patients with brain metastases.


Assuntos
Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Deleção de Sequência/genética , Adulto , Afatinib/farmacologia , Afatinib/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Casos e Controles , Progressão da Doença , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Éxons/genética , Feminino , Seguimentos , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos
11.
Zhongguo Fei Ai Za Zhi ; 22(9): 562-567, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31526459

RESUMO

BACKGROUND: EGFR-tyrosine kinase inhibitors (EGFR-TKIs) were used to treat non-small cell lung cancer (NSCLC) patients with EGFR mutation positive. This study aims to compare the effectiveness of first line TKIs; gefitinib, erlotinib, and afatinib in the treatment of advanced stage NSCLC patients with EGFR mutation positive in the Indonesian population. METHODS: A retrospective cohort study of 88 NSCLC patients with EGFR mutation positive treated with gefitinib (n=59), erlotinib (n=22), and afatinib (n=7) was performed in national cancer hospital in Indonesia.Inclusion criteria were stage IIIb or IV NSCLC with adenocarcinoma subtype. Subjects less than 18 years or with a history of other malignancy were excluded. Outcomes were treatment response, progression-free survival (PFS), and mortality rate. RESULTS: Complete response, partial response, and stable disease were shown in 1.1%, 35.2%, and 31.8% of subjects, respectively. There were 31.8% of subjects developed progressive disease during treatment. Regarding EGFR mutation positive profile, a total of 56.8% subjects had deletion in exon 19, 42% subjects had mutation in exon 21, and rare mutation in exon 18 was found in 3.4% of total subjects. Demography and clinical characteristics had no significant association with the risk of progressive disease. The median PFS of subjects was 11 months (95%CI: 6.8-15.2 months). There was no statistical difference of PFS between treatment groups.
 CONCLUSIONS: Gefitinib, erlotinib, and afatinib have similar effectiveness in advanced stage NSCLC with EGFR mutation positive. Afatinib tends to be associated with longer PFS but further investigation is required.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/farmacologia , Afatinib/farmacologia , Afatinib/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Estudos de Coortes , Intervalo Livre de Doença , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos
12.
Int J Mol Sci ; 20(16)2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31426531

RESUMO

Pneumonitis is the leading cause of death associated with the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) against non-small cell lung cancer (NSCLC). However, the risk factors and the mechanism underlying this toxicity have not been elucidated. Tumor necrosis factor (TNF) has been reported to transactivate EGFR in pulmonary epithelial cells. Hence, we aimed to test the hypothesis that EGFR tyrosine kinase activity regulates TNF-mediated bronchial epithelial cell survival, and that inhibition of EGFR activity increases TNF-induced lung epithelial cell apoptosis. We used surfactant protein C (SPC)-TNF transgenic (tg) mice which overexpress TNF in the lungs. In this model, gefitinib, an EGFR-TKI, enhanced lung epithelial cell apoptosis and lymphocytic inflammation, indicating that EGFR tyrosine kinase prevents TNF-induced lung injury. Furthermore, IL-17A was significantly upregulated by gefitinib in SPC-TNF tg mice and p38MAPK activation was observed, indicative of a pathway involved in lung epithelial cell apoptosis. Moreover, in lung epithelial cells, BEAS-2B, TNF stimulated EGFR transactivation via the TNF-α-converting enzyme in a manner that requires heparin binding (HB)-EGF and transforming growth factor (TGF)-α. These novel findings have significant implications in understanding the role of EGFR in maintaining human bronchial epithelial cell homeostasis and in NSCLC treatment.


Assuntos
Apoptose , Células Epiteliais/metabolismo , Gefitinibe/efeitos adversos , Lesão Pulmonar/metabolismo , Pneumonia/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína ADAM17/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/fisiologia , Receptores ErbB/metabolismo , Gefitinibe/uso terapêutico , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/fisiologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/fisiopatologia , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Transgênicos , Modelos Animais , Pneumonia/induzido quimicamente , Pneumonia/fisiopatologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Fator de Crescimento Transformador alfa , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Future Oncol ; 15(23): 2769-2777, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31401844

RESUMO

Dacomitinib is a second-generation EGFR tyrosine kinase inhibitor (TKI) that irreversibly binds to and inhibits EGFR/Her1, Her2 and Her4 subtypes with an efficacy comparable to other TKIs. In the ARCHER 1050 trial, progression-free survival was improved by dacomitinib compared with gefitinib, supporting dacomitinib as a first-line treatment option for advanced non-small-cell lung cancer with sensitive EGFR mutation. Regarding to the higher adverse events rate, dose reductions did not reduce the efficacy of dacomitinib and could effectively decreased the incidence and severity of adverse events. Considering the evolving landscape of EGFR-mutant non-small-cell lung cancer, future head to head comparison between dacomitinib and osimertinib could provide key information to determine the optimal TKI treatment schedule.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinonas/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Gefitinibe/uso terapêutico , Intervalo Livre de Progressão , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-4/antagonistas & inibidores
14.
Biomed Pharmacother ; 117: 109185, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387179

RESUMO

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is the first-line treatment in non-resectable non-small lung cancer (NSCLC) with EGFR mutation. However, EGFR-TIKs resistance would inevitably develop within 9-14 months after treatment. And, chemotherapy is the main treatment for EGFR-TKIs resistant patients. WEE1 kinase, a G2/M checkpoint regulator, was recently considered as a putative biomarker for the platinum-based chemo-response. The aim of this study is to clarify the relationship between WEE1 kinase and chemosensitivity in EGFR-TKIs resistant NSCLC. WEE1 expression was tested in EGFR-TKIs resistant cell lines (H1299, PC9/G2) and patients' specimens by western blot, qPCR and immunohistochemistry (IHC). In in vitro experiment, WEE1 expression was higher in EGFR-TKIs resistant than EGFR-TKIs sensitive cell lines and was gradually increased following cisplatin or gemcitabine treatment with the enrichment of G2/M cell cycle phase. And, for patients with acquired Icotinib/Gefitinib resistance, 58.4% (7/12) had increased WEE1 expression compared to its initial expression level. In order to explore the impact of WEE1 on chemo-response, WEE1 knockdown was conducted in EGFR-TKIs resistant H1299 and PC9/G2 cells. MTT and colony formation assay showed that the efficacy of cisplatin and gemcitabine was enhanced in the two cell lines after WEE1 knockdown. And, the IC50 value of cisplatin decreased from 8.64 µg/ml to 3.10 µg/ml or 2.38 µg/ml in H1299 and from 3.66 µg/ml to 0.97 µg/ml or 1.18 µg/ml in PC9/G2 after WEE1 knockdown with two specific shRNAs. This study revealed that WEE1 expression was increased after EGFR-TKIs resistance, and WEE1 knockdown could enhance chemosensitivity in EGFR-TKIs resistant NSCLC. It is suggested the combination of WEE1 inhibitor and chemotherapy might improve the clinical outcome of NSCLC patients with acquired EGFR-TKIs resistance.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas de Ciclo Celular/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Éteres de Coroa/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Receptores ErbB/metabolismo , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Quinazolinas/uso terapêutico , RNA Interferente Pequeno/metabolismo
15.
Anticancer Res ; 39(7): 3923-3929, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262922

RESUMO

BACKGROUND/AIM: Treatment with EGFR-tyrosine kinase inhibitor (TKI) shows a durable response against NSCLC harboring EGFR mutation; however, treatment resistance occurs within 1-1.5 years following first-line EGFR-TKIs [first- and second-generation (G) TKIs]. When resistant NSCLC exhibits T790M mutations, osimertinib is the standard therapy. However, intratumoral heterogeneity and clonal evolution may occur in NSCLC. Afatinib may overcome tumor heterogeneity, leading to T790M colonal purity. We aimed to determine whether NSCLC treatment with afatinib followed by osimertinib (afatinib group) provides higher therapeutic efficacy than other 1st-G EFGR-TKIs followed by osimertinib (1st-G group). MATERIALS AND METHODS: This multicenter retrospective study evaluated outcomes between afatinib group and 1st-G group. We analyzed clinical data from NSCLC patients receiving osimertinib after progression following 1st- or 2nd-G EGFR-TKIs between March 28, 2016 and March 31, 2018. Patients with performance status (PS) 0-2 were enrolled to reduce bias of patients' conditions. RESULTS: We enrolled 111 patients treated with osimertinib. The median age was 69 (range: 39-88) years. Out of 111 patients, 33 (29.7%) were men, 100 (90%) had PS 0-1, and 35 (31.5%) were in the afatinib group. The objective RR and DCR were significantly higher in the afatinib group than in the 1st-G group [82.9% vs. 53.9% (p=0.0065); 91.4% vs. 71.1% (p=0.032)]. The median PFS tended higher in the afatinib group than in the 1st-G group (15.6 vs. 8.9 months, p=0.195). CONCLUSION: Afatinib followed by osimertinib may provide better outcomes for T790M-positive NSCLC than 1st-G EGFR-TKIs. Afatinib followed by osimertinib may be a therapeutic option for NSCLC harboring EGFR mutation.


Assuntos
Afatinib/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/uso terapêutico , Gefitinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Acrilamidas , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina , Antineoplásicos/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
17.
Cells ; 8(7)2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31323891

RESUMO

In up to 30% of non-small cell lung cancer (NSCLC) patients, the oncogenic driver of tumor growth is a constitutively activated epidermal growth factor receptor (EGFR). Although these patients gain great benefit from treatment with EGFR tyrosine kinase inhibitors, the development of resistance is inevitable. To model the emergence of drug resistance, an EGFR-driven, patient-derived xenograft (PDX) NSCLC model was treated continuously with Gefitinib in vivo. Over a period of more than three months, three separate clones developed and were subsequently analyzed: Whole exome sequencing and reverse phase protein arrays (RPPAs) were performed to identify the mechanism of resistance. In total, 13 genes were identified, which were mutated in all three resistant lines. Amongst them the mutations in NOMO2, ARHGEF5 and SMTNL2 were predicted as deleterious. The 53 mutated genes specific for at least two of the resistant lines were mainly involved in cell cycle activities or the Fanconi anemia pathway. On a protein level, total EGFR, total Axl, phospho-NFκB, and phospho-Stat1 were upregulated. Stat1, Stat3, MEK1/2, and NFκB displayed enhanced activation in the resistant clones determined by the phosphorylated vs. total protein ratio. In summary, we developed an NSCLC PDX line modelling possible escape mechanism under EGFR treatment. We identified three genes that have not been described before to be involved in an acquired EGFR resistance. Further functional studies are needed to decipher the underlying pathway regulation.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos , Gefitinibe/farmacologia , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Feminino , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/genética , MAP Quinase Quinase 2/metabolismo , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Mutação , NF-kappa B/genética , NF-kappa B/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Regulação para Cima
18.
Cancer Biomark ; 25(4): 361-369, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31306106

RESUMO

BACKGROUND: Gefitinib-resistance in lung cancers has become an intractable clinical problem. However, the mechanisms underlying this resistance are not fully understood. OBJECTIVE: Present study aims to investigate the roles and underlying mechanism of miR-153 in modulating gefitinib resistance in lung cancers. METHODS: In the present study, genes expression of miR-153, MDR-1 and ABCE1 were detected by qRT-PCR and western blot. The cell viability was examined by MTT assays. The regulation of miR-153 on ABCE1 was examined by luciferase reporter gene assays. The interaction of miR-153 and ABCE1 was detected by gene over-expression and siRNA interference technology. RESULTS: The mRNA level of miR-153 was significantly down-regulated in gefitinib-resistance (GR) tissues and HCC827 cells, while the protein level of ABCE1 was up-regulated in GR tissues and HCC827 cells. Besides, miR-153 over-expression evidently increased miR-153 level and suppressed cell viability and multi drug resistance gene (MDR-1) expression in HCC827/Gef cells, while silence of miR-153 caused adverse alterations in HCC827 cells. Luciferase reporter assay results showed that miR-153 directly targeted ABCE1. Further studies showed that ABCE1 over-expression improved the expression of ABCE1 and MDR-1 and increased cell viability in HCC827/Gef cells, while ABCE1 silencing resulted in contrary trends in HCC827 cells. What's more, miR-153 over-expression inhibited tumorigenesis and ABCE1 expression, while increased miR-153 level in tumor tissues. CONCLUSIONS: MiR-153 regulates gefitinib resistance by modulating expression of ABCE1 in lung cancers. Our findings may provide a worthwhile therapeutic target to reverse gefitinib resistance in lung cancers in the future.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/uso terapêutico , Gefitinibe/uso terapêutico , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , MicroRNAs/metabolismo , Antineoplásicos/farmacologia , Gefitinibe/farmacologia , Humanos , Neoplasias Pulmonares/patologia
19.
Lung Cancer ; 133: 10-19, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31200814

RESUMO

OBJECTIVES: In patients with advanced epidermal growth factor receptor mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC), first-line afatinib significantly improved progression-free survival (PFS) and objective response vs. platinum-doublet chemotherapy in the phase III LUX-Lung 3 and LUX-Lung 6 trials, and significantly improved PFS, time to treatment failure and objective response vs. gefitinib in the phase IIb LUX-Lung 7 trial. We report post-hoc analyses of efficacy, safety and patient-reported outcomes (PROs) in afatinib long-term responders (LTRs) in these trials. METHODS: Treatment-naïve patients with stage IIIB/IV EGFRm + NSCLC randomized to afatinib in LUX-Lung 3/LUX-Lung 6/LUX-Lung 7 were included in the analysis. Patients treated with afatinib for ≥ 3 years were defined as LTRs. RESULTS: In LUX-Lung 3, LUX-Lung 6, and LUX-Lung 7, 24/229 (10%), 23/239 (10%) and 19/160 (12%) afatinib-treated patients were LTRs. Baseline characteristics were similar to the study populations, except for the proportions of women (LUX-Lung 3/LUX-Lung 6 only; 92/78% vs. 64% overall) and Del19-positive patients (63-79% vs. 49-58% overall). Median treatment duration among LTRs was 50, 56 and 42 months, and median PFS was 49.5, 55.5, and 42.2 months in LUX-Lung 3/LUX-Lung 6/LUX-Lung 7, respectively. Median overall survival could not be estimated. Frequency of afatinib dose reduction was consistent with the LUX-Lung 3/LUX-Lung 6/LUX-Lung 7 overall populations. PROs were stable in LTRs, with slight improvements after 3 years of afatinib treatment vs. baseline scores. CONCLUSIONS: In the LUX-Lung 3/LUX-Lung 6/LUX-Lung 7 trials, 10-12% of afatinib-treated patients were LTRs. Long-term afatinib treatment was independent of tolerability-guided dose adjustment and had no detrimental impact on safety or PROs.


Assuntos
Afatinib/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Cálculos da Dosagem de Medicamento , Receptores ErbB/genética , Feminino , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação/genética , Metástase Neoplásica , Estadiamento de Neoplasias , Compostos de Platina/uso terapêutico , Análise de Sobrevida , Resultado do Tratamento
20.
Clin Lung Cancer ; 20(5): e576-e583, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31178389

RESUMO

INTRODUCTION: Second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) appear superior to first-generation TKIs in clinical trials, but at the cost of greater toxicity. It is unclear whether real-world patients, who often suffer worse outcomes, experience similar survival benefits. Using population-based data, we aim to characterize outcome differences by type of treatment. PATIENTS AND METHODS: We reviewed all patients with advanced non-small-cell lung cancer who initiated treatment with an EGFR TKI at BC Cancer between 2010 and 2015. A propensity score was generated to account for imbalances in patient characteristics between treatment groups. A Cox proportional hazards model based on the propensity score was then used to estimate effects of treatment on survival. RESULTS: A total of 484 patients were identified for analysis. Patients in the second-generation cohort were younger (62 vs. 67 years), had less baseline central nervous system metastases (9% vs. 22%), and more uncommon EGFR mutations (13% vs. 7%). Patients receiving a second-generation TKI had an improved overall survival (hazard ratio, 0.69; P = .05), driven by the subgroup with an EGFR exon 19 deletion. Patients with a L858R mutation did not appear to derive benefit from a second-generation TKI (hazard ratio, 0.91; P = .74). Overall, 40% of patients receiving a second-generation TKI required a dose reduction, but only 1% required discontinuation. CONCLUSIONS: Second-generation TKIs tended to be chosen over first-generation TKIs as frontline therapy in younger patients with uncommon EGFR mutations and without central nervous system metastases. The survival benefit of a second-generation TKI seen in clinical trials appeared to be generalizable to real-world patients and is a reasonable first-line therapy.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Afatinib/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Estudos de Coortes , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação/genética , Análise de Sobrevida
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