RESUMEN
INTRODUCTION: The effect of icotinib on non-small cell lung cancer (NSCLC) patients with EGFR exon 19 deletions (19-Del) or L858R point mutation in exon 21 (21-L858R) remains inconsistent. This study aimed to evaluate the efficacy and safety of icotinib in patients with advanced NSCLC harboring these 2 EGFR mutations. METHODS: We retrospectively assessed the clinical effects of first-line icotinib on advanced NSCLC patients with 2 classic EGFR mutations. Kinase activity assays were used to reaffirm the preclinical efficacy. RESULTS: Among 2,757 patients, 2,365 (86%) harbored 19-Del (1,346/2,757, 49%) or 21-L858R (1,019/2,757, 37%) mutation. Patients with 19-Del had a higher response rate (ORR; 67.8 vs. 62.1%; p = 0.0039) and disease control rate (98.5 vs. 97.2%; p = 0.0223) than those with 21-L858R mutation. The median progression-free survival (PFS) in the 19-Del group (22.3 months, 95% confidence interval [CI]: 21.3-23.4) was significantly longer than that in the 21-L858R group (20.4 months, 95% CI: 19.5-21.7) (p = 0.004). In multivariate analysis, mutation types, clinical stage, and smoking history were significant factors for PFS. Additionally, an in vitro study indicated the 50% inhibitory concentrations (IC50) of icotinib was lower for EGFR 19-Del than 21-L858R. CONCLUSION: These results suggest that EGFR 19-Del confers superior PFS and response to the icotinib treatment compared to 21-L858R.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Éteres Corona/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , China , Éteres Corona/administración & dosificación , Éteres Corona/efectos adversos , Relación Dosis-Respuesta a Droga , Receptores ErbB/genética , Exones , Femenino , Humanos , Concentración 50 Inhibidora , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Estudios Retrospectivos , Fumar/epidemiología , Fumar/patologíaRESUMEN
BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are recommended for patients with non-small cell lung cancer with EGFR mutations. However, acquired resistance to EGFR-TKIs seems inevitable and the mechanism of drug resistance has not been fully defined. There is no effective treatment for patients with advanced lung adenocarcinoma who are resistant to TKIs owing to pathologic type conversion. CASE PRESENTATION: We report a patient who was initially diagnosed with lung adenocarcinoma. At first, she was sensitive to the first-generation TKI icotinib. After 17 months of treatment, the patient acquired resistance to icotinib. Moreover, after tumor resection, immunohistochemical analysis showed pathologic change from adenocarcinoma to adenosquamous carcinoma, and next-generation sequencing technology discovered EGFR exon19 p.745-750 del, exon20 p.T790M, and KMT2C exon 18 p.R973G mutations. After video-assisted tumor resection, the patient is receiving osimertinib (AZD 9291). Current overall survival is 60 months. CONCLUSIONS: Surgical intervention may prolong survival time in patients with acquired TKI resistance, especially when there is no evidence of metastasis.
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Adenocarcinoma del Pulmón/tratamiento farmacológico , Carcinoma Adenoescamoso/patología , Éteres Corona/efectos adversos , Resistencia a Antineoplásicos/genética , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Quinazolinas/efectos adversos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Carcinoma Adenoescamoso/inducido químicamente , Carcinoma Adenoescamoso/cirugía , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Pronóstico , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
BACKGROUND: Epidermal growth factor receptor (EGFR) mutation positive (M+) non-small cell lung cancer (NSCLC) is an important subtype of lung cancer comprising 10% to 15% of non-squamous tumours. This subtype is more common in women than men, is less associated with smoking, but occurs at a younger age than sporadic tumours. OBJECTIVES: To assess the clinical effectiveness of single-agent or combination EGFR therapies used in the first-line treatment of people with locally advanced or metastatic EGFR M+ NSCLC compared with other cytotoxic chemotherapy (CTX) agents used alone or in combination, or best supportive care (BSC). The primary outcomes were overall survival and progression-free survival. Secondary outcomes included response rate, symptom palliation, toxicity, and health-related quality of life. SEARCH METHODS: We conducted electronic searches of the Cochrane Register of Controlled Trials (CENTRAL) (2020, Issue 7), MEDLINE (1946 to 27th July 2020), Embase (1980 to 27th July 2020), and ISI Web of Science (1899 to 27th July 2020). We also searched the conference abstracts of the American Society for Clinical Oncology and the European Society for Medical Oncology (July 2020); Evidence Review Group submissions to the National Institute for Health and Care Excellence; and the reference lists of retrieved articles. SELECTION CRITERIA: Parallel-group randomised controlled trials comparing EGFR-targeted agents (alone or in combination with cytotoxic agents or BSC) with cytotoxic chemotherapy (single or doublet) or BSC in chemotherapy-naive patients with locally advanced or metastatic (stage IIIB or IV) EGFR M+ NSCLC unsuitable for treatment with curative intent. DATA COLLECTION AND ANALYSIS: Two review authors independently identified articles, extracted data, and carried out the 'Risk of bias' assessment. We conducted meta-analyses using a fixed-effect model unless there was substantial heterogeneity, in which case we also performed a random-effects analysis as a sensitivity analysis. MAIN RESULTS: Twenty-two trials met the inclusion criteria. Ten of these exclusively recruited people with EGFR M+ NSCLC; the remainder recruited a mixed population and reported results for people with EGFR M+ NSCLC as subgroup analyses. The number of participants with EGFR M+ tumours totalled 3023, of whom approximately 2563 were of Asian origin. Overall survival (OS) data showed inconsistent results between the included trials that compared EGFR-targeted treatments against cytotoxic chemotherapy or placebo. Erlotinib was used in eight trials, gefitinib in nine trials, afatinib in two trials, cetuximab in two trials, and icotinib in one trial. The findings of FASTACT 2 suggested a clinical benefit for OS for participants treated with erlotinib plus cytotoxic chemotherapy when compared to cytotoxic chemotherapy alone, as did the Han 2017 trial for gefitinib plus cytotoxic chemotherapy, but both results were based on a small number of participants (n = 97 and 122, respectively). For progression-free survival (PFS), a pooled analysis of four trials showed evidence of clinical benefit for erlotinib compared with cytotoxic chemotherapy (hazard ratio (HR) 0.31; 95% confidence interval (CI) 0.25 to 0.39 ; 583 participants ; high-certainty evidence). A pooled analysis of two trials of gefitinib versus paclitaxel plus carboplatin showed evidence of clinical benefit for PFS for gefitinib (HR 0.39; 95% CI 0.32 to 0.48 ; 491 participants high-certainty evidence), and a pooled analysis of two trials of gefitinib versus pemetrexed plus carboplatin with pemetrexed maintenance also showed evidence of clinical benefit for PFS for gefitinib (HR 0.59; 95% CI 0.46 to 0.74, 371 participants ; moderate-certainty evidence). Afatinib showed evidence of clinical benefit for PFS when compared with chemotherapy in a pooled analysis of two trials (HR 0.42; 95% CI 0.34 to 0.53, 709 participants high-certainty evidence). All but one small trial showed a corresponding improvement in response rate with tyrosine-kinase inhibitor (TKI) compared to chemotherapy. Commonly reported grade 3/4 adverse events associated with afatinib, erlotinib, gefitinib and icotinib monotherapy were rash and diarrhoea. Myelosuppression was consistently worse in the chemotherapy arms; fatigue and anorexia were also associated with some chemotherapies. Seven trials reported on health-related quality of life and symptom improvement using different methodologies. For each of erlotinib, gefitinib, and afatinib, two trials showed improvement in one or more indices for the TKI compared to chemotherapy. The quality of evidence was high for the comparisons of erlotinib and gefitinib with cytotoxic chemotherapy and for the comparison of afatinib with cytotoxic chemotherapy. AUTHORS' CONCLUSIONS: Erlotinib, gefitinib, afatinib and icotinib are all active agents in EGFR M+ NSCLC patients, and demonstrate an increased tumour response rate and prolonged PFS compared to cytotoxic chemotherapy. We found a beneficial effect of the TKI compared to cytotoxic chemotherapy in adverse effect and health-related quality of life. We found limited evidence for increased OS for the TKI when compared with standard chemotherapy, but the majority of the included trials allowed participants to switch treatments on disease progression, which will have a confounding effect on any OS analysis. Single agent-TKI remains the standard of care and the benefit of combining a TKI and chemotherapy remains uncertain as the evidence is based on small patient numbers. Cytotoxic chemotherapy is less effective in EGFR M+ NSCLC than erlotinib, gefitinib, afatinib or icotinib and is associated with greater toxicity. There are no data supporting the use of monoclonal antibody therapy. Icotinib is not available outside China.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Afatinib/efectos adversos , Afatinib/uso terapéutico , Anciano , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sesgo , Carboplatino/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Cetuximab/efectos adversos , Cetuximab/uso terapéutico , Éteres Corona/efectos adversos , Éteres Corona/uso terapéutico , Clorhidrato de Erlotinib/efectos adversos , Clorhidrato de Erlotinib/uso terapéutico , Femenino , Gefitinib/efectos adversos , Gefitinib/uso terapéutico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Paclitaxel/uso terapéutico , Pemetrexed/uso terapéutico , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Calidad de Vida , Quinazolinas/efectos adversos , Quinazolinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
To explore a better treatment strategy for patients with advanced non-small cell lung cancer harboring sensitive epidermal growth factor receptor mutations, a total of 271 patients were retrospectively analyzed. The patients were divided into two groups: the combination group (58 cases), which received concurrent icotinib, pemetrexed, and platinum treatment, and the sequential group (213 cases), which received the sequential pemetrexed and platinum therapy, followed by icotinib treatment. The primary end points were progression-free survival (PFS) and PFS on the subsequent line of therapy (PFS2). PFS in the combination group was significantly higher compared with that in the sequential group (16.89 months vs. 9.90 months; p < 0.001). PFS in the combination group was also significantly higher than PFS2 in the sequential group (16.89 months vs. 14.05 months; p = 0.009). The overall survival (OS) of the patients was 33.22 months (95% confidence interval (CI): 26.99-37.01) in the combination group and 26.47 months (95% CI: 25.05-26.95) in the sequential group (p < 0.001). The combination group's objective response rate was superior to that of the sequential group (79.31% vs. 52.11%; p < 0.001). Propensity score matching also revealed that icotinib therapy combined with chemotherapy extended the PFS, PFS2, and OS of the patients (p < 0.0001, p = 0.003, and p = 0.001, respectively). The combination group's objective response rate was also better compared with the sequential group (79.31% vs. 51.72%; p = 0.001). In conclusion, our study demonstrated icotinib combined with chemotherapy can improve survival efficacy better than the separated two-line therapy. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? For advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutants, EGFR-tyrosine kinase inhibitors (TKIs) are the standard first-line treatment. Unfortunately, most patients with NSCLC harboring EGFR mutations acquire EGFR-TKI resistance after EGFR-TKI treatment for about 10-14 months. Studies have indicated that chemotherapy plus EGFR-TKIs may have combined effects on the growth of NSCLC cells. However, until now, there has been no study comparing the concurrent and sequential EGFR-TKIs plus chemotherapy. WHAT QUESTION DID THIS STUDY ADDRESS? We retrospectively analyzed the efficacy and safety of concurrent versus sequential icotinib and chemotherapy in untreated NSCLC with sensitive EGFR mutations. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? In the patients with NSCLC with sensitive EGFR mutations, the first-line pemetrexed plus platinum combined with icotinib better improved PFS, PFS2, and objective response rate compared with first-line icotinib and second-line pemetrexed plus platinum. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? The results of this paper provide guidance for the strategy choice in the treatment of patients with NSCLC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Éteres Corona/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Éteres Corona/efectos adversos , Esquema de Medicación , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Pemetrexed/administración & dosificación , Pemetrexed/efectos adversos , Supervivencia sin Progresión , Quinazolinas/efectos adversosRESUMEN
BACKGROUND: This study profiled the somatic genes mutations and the copy number variations (CNVs) in cerebrospinal fluid (CSF)-circulating tumor DNA (ctDNA) from patients with neoplastic meningitis (NM). METHODS: A total of 62 CSF ctDNA samples were collected from 58 NM patients for the next generation sequencing. The data were bioinformatically analyzed by (Database for Annotation, Visualization and Integrated Discovery) DAVID software. RESULTS: The most common mutated gene was TP53 (54/62; 87.10%), followed by EGFR (44/62; 70.97%), PTEN (39/62; 62.90%), CDKN2A (32/62; 51.61%), APC (27/62: 43.55%), TET2 (27/62; 43.55%), GNAQ (18/62; 29.03%), NOTCH1 (17/62; 27.42%), VHL (17/62; 27.42%), FLT3 (16/62; 25.81%), PTCH1 (15/62; 24.19%), BRCA2 (13/62; 20.97%), KDR (10/62; 16.13%), KIT (9/62; 14.52%), MLH1 (9/62; 14.52%), ATM (8/62; 12.90%), CBL (8/62; 12.90%), and DNMT3A (7/62; 11.29%). The mutated genes were enriched in the PI3K-Akt signaling pathway by the KEGG pathway analysis. Furthermore, the CNVs of these genes were also identified in these 62 samples. The mutated genes in CSF samples receiving intrathecal chemotherapy and systemic therapy were enriched in the ERK1/2 signaling pathway. CONCLUSIONS: This study identified genes mutations in all CSF ctDNA samples, indicating that these mutated genes may be acted as a kind of biomarker for diagnosis of NM, and these mutated genes may affect meningeal metastasis through PI3K-Akt signaling pathway.
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ADN Tumoral Circulante/genética , Variaciones en el Número de Copia de ADN , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Pulmonares/genética , Neoplasias Meníngeas/líquido cefalorraquídeo , Mutación , Acrilamidas/administración & dosificación , Adulto , Anciano , Compuestos de Anilina/administración & dosificación , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , ADN Tumoral Circulante/líquido cefalorraquídeo , Fosfatidilinositol 3-Quinasa Clase I/genética , Éteres Corona/administración & dosificación , Éteres Corona/efectos adversos , Femenino , Genes erbB-1 , Humanos , Estado de Ejecución de Karnofsky , Neoplasias Pulmonares/líquido cefalorraquídeo , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/secundario , Persona de Mediana Edad , Tasa de Mutación , Proteínas Proto-Oncogénicas c-akt/genética , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Adulto JovenRESUMEN
BACKGROUND: The epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer has been successfully treated with tyrosine kinase inhibitors (TKIs). Acquired resistance becomes a tough issue when patients fail to respond to the third-generation TKI osimertinib. This study aimed to report a case baring acquired EGFR L858R/L718Q mutation in the central nervous system induced by osimertinib, which was successfully overcome using afatinib. CASE PRESENTATION: A 65-year-old female patient was diagnosed with stage IV non-small-cell lung adenocarcinoma with synchronic brain metastasis in February 2015. Before and during treatment, 416 tumor-related genes were monitored dynamically by liquid biopsies using next-generation sequencing, and the treatment strategy was decided according to the gene status. At baseline, an EGFR L858R mutation in exon 21 was detected, so treatment with icotinib was started. After 8 months, she experienced disease progression with leptomeningeal metastasis and switched to osimertinib based on an acquired EGFR T790 M mutation. After 9 months, her disease progressed and an EGFR L718Q mutation was found in the cerebrospinal fluid. The patient was then challenged with afatinib, and her disease was under control for 4 months. In January 2017, the patient passed away, with an overall survival time of 23 months, 15 months after leptomeningeal metastasis. CONCLUSION: The acquired EGFR L718Q mutation in the cerebrospinal fluid resulted in subsequent resistance to osimertinib and could be partly overcome using afatinib, indicating a promising treatment option in the clinic.
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Acrilamidas/efectos adversos , Afatinib/uso terapéutico , Compuestos de Anilina/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Carcinomatosis Meníngea/secundario , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Acrilamidas/administración & dosificación , Acrilamidas/uso terapéutico , Afatinib/administración & dosificación , Anciano , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/uso terapéutico , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/genética , Éteres Corona/administración & dosificación , Éteres Corona/efectos adversos , Progresión de la Enfermedad , Receptores ErbB/líquido cefalorraquídeo , Receptores ErbB/genética , Resultado Fatal , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/genética , Carcinomatosis Meníngea/genética , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversosRESUMEN
RATIONALE: Mounting evidences reveal that mutation of epidermal growth factor receptor (EGFR) may induce the resistance of tyrosine kinase inhibitors (TKIs). TKI-resistant lung cancer cells are sensitive to inhibition of the EGFR pathway. This case report aimed to characterize the therapeutic benefits of erlotinib, a targeted drug, on an advanced lung cancer patient with somatic EGFR mutation. PATIENT CONCERNS: A 52-year-old non-smoking Chinese woman was suffered from pneumonia-based chest pains, and the patient was diagnosed as advanced lung cancer through medical imaging, thoracoscopy, and pathological examination. DIAGNOSES: Blood tests, pathological examination, thoracoscopy, computed tomography (CT)/positron emission computed tomography (PET) scans, next-generation sequencing (NGS) testing were subjected to the patient's samples before and after targeted drug treatments. INTERVENTIONS: After icotinib-induced resistance, the chemoresistance mechanism was involved in EGFR mutations before being prescribed with erlotinib. OUTCOMES: The therapeutic effectiveness of icotinib for 4-month showed undetected carcinomatous metastasis. The lung tumor sizes were reduced, and improved quality of life (QOL) was described by the patient. Followed by monotherapy with erlotinib for 1.5-year, the icotinib-resistant patient benefited from longer survival rate without tumor enlargement and neoplastic metastasis. In therapeutic duration of erlotinib, T790M mutation of EGFR, R248W mutation of tumor protein p53 (TP53), K844S mutation of retinoblastoma protein 1 (RB1) were identified through NGS test. LESSONS: In conclusion, the anti-cancer benefits of icotinib and erlotinib against advanced lung cancer may contribute to suppress neoplastic growth and metastasis. Further, erlotinib exerts potent efficacy for extended survival rate of patient because detectable mutations may not or limitedly induce erlotinib-resistance. In addition, reduced circulating hormones by menopause may enhance the therapeutic effectiveness of erlotinib.
Asunto(s)
Adenocarcinoma del Pulmón/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Éteres Corona/efectos adversos , Resistencia a Antineoplásicos/genética , Clorhidrato de Erlotinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/efectos adversos , Adenocarcinoma del Pulmón/genética , Receptores ErbB/efectos de los fármacos , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/genética , Persona de Mediana Edad , MutaciónRESUMEN
BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have been emerged as the standard selection in non-small cell lung cancer (NSCLC) patients with EGFR sensitive mutations. However, primary or acquired resistance to EGFR-TKIs seems inevitable, especially to third-generation TKIs, which has appeared absence of effective solutions so far. CASE PRESENTATION: Here we reported a NSCLC patient with EGFR sensitive mutation of deletion within EGFR exon 19, who had been resistant to icotinib and AZD9291 successively after a period of 18 months response duration. Next-generation sequencing (NGS) technique using plasma sample suggested an acquired EGFR Leu792H mutation, rather than C797S one. Interestingly, the patient obtained another 8 months of disease-free duration with symptoms greatly relieved after repeating icotinib administration. The overall survival of the patient has been thirty-six months and still in the extension. CONCLUSION: The presentation of the case may provide some selective therapeutic thoughts for NSCLC patients with acquired EGFR Leu792H mutation suffering resistance to the third-generation TKIs.
Asunto(s)
Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Alelos , Antineoplásicos/uso terapéutico , Éteres Corona/uso terapéutico , Mutación , Quinazolinas/uso terapéutico , Acrilamidas/uso terapéutico , Adenocarcinoma del Pulmón/diagnóstico , Anciano , Sustitución de Aminoácidos , Compuestos de Anilina/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Biomarcadores , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/secundario , Terapia Combinada , Éteres Corona/administración & dosificación , Éteres Corona/efectos adversos , Receptores ErbB/genética , Humanos , Imagen por Resonancia Magnética , Masculino , Metástasis de la Neoplasia , Estadificación de Neoplasias , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Retratamiento , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Recently, targeted agents were reported to improve overall survival, progression-free survival (PFS), response rate, and quality of life compared with cytotoxic chemotherapies, which provides hope for the treatment of non-small-cell lung cancer (NSCLC). The network meta-analysis is applied to compare the efficacies and adverse events of five targeted agents (erlotinib, gefitinib, vandetanib, dacomitinib, and icotinib) for advanced or metastatic NSCLC. Nine eligible randomized controlled trials from PubMed and Cochrane Library database were included. Weighted mean difference, odds ratio, and surface under the cumulative ranking curve (SUCRA) values were evaluated for the efficacy and adverse events of the five targeted agents in the treatment of NSCLC. With regard to efficacy, the overall response rate (ORR) of advanced or metastatic NSCLC patients treated with gefitinib was relatively higher than those treated with placebo. Compared with patients treated with placebo, the disease control rate (DCR) of patients treated with erlotinib and with gefitinib was relatively higher. Furthermore, in terms of PFS and DCR, the SUCRA value of icotinib was the highest among the five targeted drugs. With regard to ORR, the SUCRA value of gefitinib was the highest among the five targeted drugs. In terms of fatigue, rash, and cough, erlotinib had the lowest SUCRA value, whereas vandetanib exhibited the lowest SUCRA value in terms of diarrhea. Our study suggests that the efficacies of gefitinib and icotinib for advanced or metastatic NSCLC were comparatively better, whereas the toxicities of erlotinib and vandetanib were relatively greater.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Éteres Corona/uso terapéutico , Clorhidrato de Erlotinib/uso terapéutico , Gefitinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Quinazolinonas/uso terapéutico , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/secundario , Éteres Corona/efectos adversos , Progresión de la Enfermedad , Clorhidrato de Erlotinib/efectos adversos , Gefitinib/efectos adversos , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Terapia Molecular Dirigida , Metaanálisis en Red , Piperidinas/efectos adversos , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Quinazolinas/efectos adversos , Quinazolinonas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
This study aimed to explore the effect and toxicity of icotinib and whole-brain radiotherapy (IWBRT) for the treatment of brain metastases from nonsmall cell lung cancer (BMNSCLC) with epidermal growth factor receptor (EGFR)-mutant among Chinese Han population.A total of 55 patients with EGFR-mutant BMNSCLC were included. They received orally icotinib (125âmg/tablet, 125âmg each time, 3 times daily) until disease progression. In addition, they also underwent whole-brain radiotherapy (3-Gy fractions once daily, 5 days weekly for a total dose of 30 Gy) in an attempt to extend their survival time. The outcomes consisted of complete response (CR), partial response (PR), stable disease (SD), progress disease (PD), overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). In addition, toxicity was also recorded in this study.The CR, PR, SD, PD, ORR, PFS, and OS were 38.2%, 52.8%, 5.4%, 3.6%, 90.1%, 12.5%, and 48.0% months, respectively. In addition, mild toxicity was observed in this study.This study demonstrated that IWBRT is efficacious with acceptable toxicity for patients with EGFR-mutant BMNSCLC among Chinese Han population.
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Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Irradiación Craneana , Éteres Corona/uso terapéutico , Análisis Mutacional de ADN , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Quinazolinas/uso terapéutico , Anciano , Neoplasias Encefálicas/terapia , China , Terapia Combinada , Éteres Corona/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Quinazolinas/efectos adversos , Dosificación Radioterapéutica , Estudios RetrospectivosAsunto(s)
Corticoesteroides/administración & dosificación , Éteres Corona/efectos adversos , Manejo de la Enfermedad , Síndrome de Hipersensibilidad a Medicamentos/diagnóstico , Síndrome de Hipersensibilidad a Medicamentos/tratamiento farmacológico , Inmunoglobulinas Intravenosas/administración & dosificación , Quinazolinas/efectos adversos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Multi-targeted agents represent the next generation of targeted therapies for solid tumors, and patients with acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs) may also benefit from their combination with TKI therapy. Third-generation targeted drugs, such as osimertinib, are very expensive, thus a more economical solution is required. The aim of this study was to explore the use of apatinib combined with icotinib therapy for primary acquired resistance to icotinib in three patients with advanced pulmonary adenocarcinoma with EGFR mutations. We achieved favorable oncologic outcomes in all three patients, with progression-free survival of four to six months. Unfortunately, the patients ultimately had to cease combination therapy because of intolerable adverse effects of hand and foot syndrome and oral ulcers. Combination therapy of apatinib with icotinib for primary acquired resistance to icotinib may be an option for patients with advanced pulmonary adenocarcinoma with EGFR mutations, but physicians must also be aware of the side effects caused by such therapy.
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Adenocarcinoma del Pulmón/tratamiento farmacológico , Éteres Corona/administración & dosificación , Piridinas/administración & dosificación , Quinazolinas/administración & dosificación , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Éteres Corona/efectos adversos , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Receptores ErbB/genética , Femenino , Síndrome Mano-Pie , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Mutación , Estadificación de Neoplasias , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinazolinas/efectos adversosRESUMEN
BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is the optimal treatment for EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, most patients developed systemic or local progression due to acquired EGFR-TKI resistance. This retrospective study aimed to evaluate the feasibility of continued EGFR-TKI with concurrent radiotherapy (CTCRT) in patients with local progression after front-line EGFR-TKI treatment. METHODS: Advanced NSCLC patients with active EGFR mutation who received EGFR-TKI were treated with CTCRT after local progression. Medical data were analyzed for time to progression (TTP), progression-free survival (PFS), tumor response rate, overall survival (OS) and adverse events. RESULTS: A total of 50 irradiated lesions from 44 patients were included. Median TTP and PFS of measurable lesions (n = 31) were both significantly prolonged after local radiotherapy (TTP1 + TTP2 vs. TTP1: 21.7 vs. 16.0 months, P = 0.010; PFS1 + PFS2 vs. PFS1: 21.3 vs. 16.0 months, P = 0.027). For all lesions (n = 50), objective response rate (ORR) and local tumor control rate (LCR) were 54.0 and 84.0%, respectively. Median OS was 26.6 months. There were no serious adverse events before or after radiotherapy. CONCLUSIONS: The treatment modality of CTCRT is considerable and effective for EGFR-mutant NSCLC patients even with local failure from front-line EGFR-TKI treatment.
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Carcinoma de Pulmón de Células no Pequeñas/terapia , Quimioradioterapia/métodos , Neoplasias Pulmonares/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Quimioradioterapia/efectos adversos , Éteres Corona/administración & dosificación , Éteres Corona/efectos adversos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib/administración & dosificación , Clorhidrato de Erlotinib/efectos adversos , Femenino , Gefitinib , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Estudios Retrospectivos , Terapia Recuperativa/métodosRESUMEN
OBJECTIVE: This study aims to explore the feasibility of icotinib neoadjuvant therapy for nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: This was a retrospective analysis of the clinical data for 63 NSCLC patients (61 cases of adenocarcinoma and two cases of squamous cell carcinoma) receiving surgical resection of lung lesions after oral intake of icotinib from December 2011 to November 2013 in the PLA General Hospital. Preoperative oral intake of the patients was icotinib 125 mg tid, drug side effects were evaluated according to the American National Cancer Institute Common Toxicity Criteria Version 4.0; computed tomography scan was done on the day taking medicine and 2 weeks later to determine tumor changes. After oral intake of Icotinib for 2 to 22 weeks (5 cases for 2 weeks,13 cases for 3 to 22 weeks), all patients receive surgical resection of lung cancer lesions, and testing of removed tumor to evaluate the epidermal growth factor receptor (EGFR) gene mutation status was performed by fluorescence polymerase chain reaction. The patients with sensitive EGFR mutations receive Icotinib as postoperative adjuvant therapy. RESULTS: Side effects of medication within 2 weeks included rash (44.4%, 28/63), dry skin (34.9%, 22/63), diarrhea (14.3%, 9/63), and oral ulcer (1.6%, 1/63); there were no icotinib-associated thoracic surgery complications during the perioperational period. 71.4% patients (45/63) achieve an average reduction of 23.5% ±10.7%(10%-53.5%) after 2 weeks medication of Icotinib(regressive tumor[RT]) .28.6% patients(18/63) achieve stable tumor(ST),enlargement of 8.7% to reduction of 8.7% of the maximum diameter of lung cancer after 2 weeks medication of Icotinib. Of the RT group, 68.9% (31/45) of the tumors were detected with EGFR-sensitive mutation (exon 19 or 21 mutation), 24.4% (11/45) with wild-type EGFR, and three cases of exon 20 mutation. Of the ST group, 77.8% (14/18) were detected with wild-type EGFR, three cases of exon 20 mutation, and one case of exon 19 deletion mutation (tumor reduction by 7.9%). 45 cases in RT group and 1 case with EGFR 19 exon metation in ST group receive Icotinib as adjuvant therapy. Among 45 cases in RT group and 18 cases in ST group, there was no difference in gender, age, smoking history, tumor diameter, tumor differentiation degree, and incidence of side effects (P = 0.076). There was significant difference (P < 0.0001) in terms of symptom remission rate after medication and EGFR gene-sensitive mutation rate in RT and ST groups. CONCLUSION: Icotinib neoadjuvant therapy for NSCLC is safe and feasible, and the reactivity of lung cancer patients to icotinib can be determined within 2 weeks of medication. People sensitive to preoperative selection of drugs can more accurately determine the sensitivity of tumors to drugs, thus providing evidence for postoperative adjuvant therapy.
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Adenocarcinoma/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Éteres Corona/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/administración & dosificación , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adenocarcinoma del Pulmón , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Éteres Corona/efectos adversos , Receptores ErbB/genética , Exones , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Quinazolinas/efectos adversosRESUMEN
BACKGROUND: Icotinib has been previously shown to be non-inferior to gefitinib in non-selected advanced non-small-cell lung cancer patients when given as second- or further-line treatment. In this open-label, randomized, phase 3 CONVINCE trial, we assessed the efficacy and safety of first-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance in lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation. PATIENTS AND METHODS: Eligible participants were adults with stage IIIB/IV lung adenocarcinoma and exon 19/21 EGFR mutations. Participants were randomly allocated (1 : 1) to receive oral icotinib or 3-week cycle of cisplatin plus pemetrexed for up to four cycles; non-progressive patients after four cycles were maintained with pemetrexed until disease progression or intolerable toxicity. The primary end point was progression-free survival (PFS) assessed by independent response evaluation committee. Other end points included overall survival (OS) and safety. RESULTS: Between January 2013 and August 2014, 296 patients were randomized, and 285 patients were treated (148 to icotinib, 137 to chemotherapy). Independent response evaluation committee-assessed PFS was significantly longer in the icotinib group (11.2 versus 7.9 months; hazard ratio, 0.61, 95% confidence interval 0.43-0.87; P = 0.006). No significant difference for OS was observed between treatments in the overall population or in EGFR-mutated subgroups (exon 19 Del/21 L858R). The most common grade 3 or 4 adverse events (AEs) in the icotinib group were rash (14.8%) and diarrhea (7.4%), compared with nausea (45.9%), vomiting (29.2%), and neutropenia (10.9%) in the chemotherapy group. AEs (79.1% versus 94.2%; P < 0.001) and treatment-related AEs (54.1% versus 90.5%; P < 0.001) were significantly fewer in the icotinib group than in the chemotherapy group. CONCLUSIONS: First-line icotinib significantly improves PFS of advanced lung adenocarcinoma patients with EGFR mutation with a tolerable and manageable safety profile. Icotinib should be considered as a first-line treatment for this patient population.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Éteres Corona/uso terapéutico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Éteres Corona/efectos adversos , Receptores ErbB/metabolismo , Exones , Femenino , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Pemetrexed/administración & dosificación , Pemetrexed/efectos adversos , Quinazolinas/efectos adversosRESUMEN
EGFR-TKIs and radiation therapy (RT) are the principal treatment for patients with brain metastases (BM) and EGFR mutant NSCLC. However, the optimal use of brain RT for patients with asymptomatic BM remains undefined. A total of 152 patients were identified. 58 patients were excluded. Of the remaining 97 patients, 56 patients received upfront RT followed by icotinib, including WBRT or SRS. 41 patients received icotinib therapy alone. The mOS from diagnosis of BM was 27.0 months for the whole cohort (95% CI, 23.9-30.1 months). There was no difference in OS between the RT followed by icotinib group and the icotinib alone group (31.9 vs. 27.9 months, P = 0.237), and similar results were found in the SRS subgroup (35.5 vs. 27.9 months, P = 0.12). Patients with the EGFR Del19 mutation had a longer OS than patients with the exon 21 L858R mutation (32.7 vs. 27.4, P = 0.037). Intracranial progression-free survival (PFS) was improved in the patients who received RT followed by icotinib compared to those receiving icotinib alone (22.4 vs. 13.9 months, P = 0.043). Patients with EGFR-mutant adenocarcinoma and BM treated with icotinib exhibited prolonged survival. A longer duration of intracranial control was observed with brain RT.
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Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/terapia , Carcinoma de Pulmón de Células no Pequeñas/terapia , Éteres Corona/uso terapéutico , Receptores ErbB/genética , Neoplasias Pulmonares/terapia , Quinazolinas/uso terapéutico , Radiocirugia/métodos , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Éteres Corona/administración & dosificación , Éteres Corona/efectos adversos , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Radiocirugia/efectos adversosRESUMEN
Tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR) are becoming the standard treatment option for patients with advanced non-small cell lung cancer (NSCLC) harboring an EGFR mutation, but the economic impact of this practice is unclear, especially in a health resource-limited setting. A decision-analytic model was developed to simulate 21-day patient transitions in a 10-year time horizon. The health and economic outcomes of four first-line strategies (pemetrexed plus cisplatin [PC] alone, PC followed by maintenance with pemetrexed, or initial treatment with gefitinib or icotinib) among patients harboring EGFR mutations were estimated and assessed via indirect comparisons. Costs in the Chinese setting were estimated. The primary outcome was the incremental cost-effectiveness ratio (ICER). Sensitivity analyses were performed. The icotinib strategy resulted in greater health benefits than the other three strategies in NSCLC patients harboring EGFR mutations. Relative to PC alone, PC followed by pemetrexed maintenance, gefitinib and icotinib resulted in ICERs of $104,657, $28,485 and $19,809 per quality-adjusted life-year gained, respectively. The cost of pemetrexed, the EGFR mutation prevalence and the utility of progression-free survival were factors that had a considerable impact on the model outcomes. When the icotinib Patient Assistance Program was available, the economic outcome of icotinib was more favorable. These results indicate that gene-guided therapy with icotinib might be a more cost-effective treatment option than traditional chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/economía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Éteres Corona/economía , Éteres Corona/uso terapéutico , Costos de los Medicamentos , Neoplasias Pulmonares/tratamiento farmacológico , Pemetrexed/economía , Pemetrexed/uso terapéutico , Inhibidores de Proteínas Quinasas/economía , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/economía , Quinazolinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , China , Simulación por Computador , Análisis Costo-Beneficio , Éteres Corona/efectos adversos , Supervivencia sin Enfermedad , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Gefitinib , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Modelos Económicos , Terapia Molecular Dirigida/economía , Mutación , Pemetrexed/efectos adversos , Medicina de Precisión/economía , Inhibidores de Proteínas Quinasas/efectos adversos , Años de Vida Ajustados por Calidad de Vida , Quinazolinas/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Icotinib is a new epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that developed and used in China; this work was to evaluate its efficacy and safety in treating non-small cell lung cancer (NSCLC). Clinical studies evaluating the efficacy and safety of icotinib in treating NSCLC were identified from the databases of Medline, Web of Science, Embase and Cochrance Library. Pooled efficacy and safety of icotinib were calculated through a series of predefined search strategies. A total of 15 studies with 2,304 patients were involved in this study. The overall response rate (ORR) and disease control rate (DCR) of icotinib were 40.99% (95% CI: 33.77% to 48.22%) and 77.16% (95% CI: 51.43% to 82.31%). The pooled progression-free survival (PFS) and overall survival (OS) were 7.34 months (95% CI: 5.60 to 9.07) and 14.98 months (95% CI: 9.78 to 20.18). Patients with EGFR mutations exhibited better ORR (OR = 3.67, p < 0.001), DCR (OR = 1.39, p = 0.001) and PFS (11.0 ± 0.76 vs. 1.97 ± 0.82 months). Moreover, patients with rash had a higher ORR (OR = 2.14, p = 0.001) than those without rash. The common adverse effects (AEs) included skin rash (31.4%), diarrhea (14.2%), pruritus (6.7%) and hepatic toxicity (3.8%) and most of them were well tolerated. In conclusion, Icotinib is an effective and well tolerated regimen for Chinese patients with advanced NSCLC. Further randomized trials with large population are required to provide stronger evidence for icotinib in treating NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Éteres Corona/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Éteres Corona/efectos adversos , Diarrea/inducido químicamente , Supervivencia sin Enfermedad , Receptores ErbB/genética , Exantema/inducido químicamente , Humanos , Neoplasias Pulmonares/genética , Mutación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Prurito/inducido químicamente , Quinazolinas/efectos adversos , Resultado del TratamientoRESUMEN
LESSONS LEARNED: This phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity.These findings provide clinicians with evidence for application of higher-dose icotinib. BACKGROUND: Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100-200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC. METHODS: Twenty-six patients with advanced NSCLC were treated at doses of 250-625 mg three times daily The EGFR mutation test was not mandatory in this study. RESULTS: Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (Tmax) ranged from 1 to 3 hours (1.5-4 hours) after multiple doses. The t1/2 was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease. CONCLUSION: This study demonstrated that higher-dose icotinib was well-tolerated, with a MTD of 500 mg. Favorable antitumor activity and pharmacokinetic profile were observed in patients with heavily pretreated, advanced NSCLC.
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Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Éteres Corona/efectos adversos , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/efectos adversos , Adulto , Anciano , Éteres Corona/farmacocinética , Receptores ErbB/genética , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Mutación , Quinazolinas/farmacocinéticaRESUMEN
BACKGROUND: Epidermal growth factor receptor (EGFR) mutations occur in about 50% of Asian patients with non-small cell lung cancer (NSCLC). Patients with advanced NSCLC and EGFR mutations derive clinical benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs). This study assessed the efficacy and safety of adjuvant icotinib without chemotherapy in EGFR-mutated NSCLC patients undergoing resection of stage IB-IIIA. METHODS: Our retrospective study enrolled 20 patients treated with icotinib as adjuvant therapy. Survival factors were evaluated by univariate and Cox regression analysis. RESULTS: The median follow-up time was 30 months (range 24-41). At the data cut-off, five patients (25%) had recurrence or metastasis and one patient had died of the disease. The two-year disease-free survival (DFS) rate was 85%. No recurrence occurred in the high-risk stage IB subgroup during the follow-up period. In univariate analysis, the micropapillary pattern had a statistically significant effect on DFS ( P = 0.040). Multivariate logistic regression analysis showed that there was no independent predictor. Drug related adverse events (AEs) occurred in nine patients (45.0%). The most common AEs were skin-related events and diarrhea, but were relatively mild. No grade 3 AEs or occurrences of intolerable toxicity were observed. CONCLUSIONS: Icotinib as adjuvant therapy is effective in patients harboring EGFR mutations after complete resection, with an acceptable AE profile. Further trials with larger sample sizes might confirm the efficiency of adjuvant TKI in selected patients.