RESUMO
INTRODUCTION: Central nervous system (CNS) metastases are common in non-small cell lung cancer (NSCLC), yet clinical trials of new drugs in advanced NSCLC have varying inclusion and exclusion criteria for CNS disease. The true extent of variation in CNS-related enrollment criteria in NSCLC clinical trials has not been documented. METHODS: We performed a systematic search of the ClinicalTrials.gov website to characterize interventional drug trials enrolling adult patients with advanced NSCLC. RESULTS: Of 413 open trials, 78 (19%) strictly excluded patients with leptomeningeal disease (LMD). Separate from LMD, patients with any history of CNS metastases were strictly excluded in 59 trials (14%), allowed after local treatment in 169 (41%), and allowed with no prior treatment in 106 (26%). No explicit mention of CNS disease was made in 79 trials (19%). In multivariate analysis looking at trial phase, location, sponsor, and treatment type, only sponsor was statistically significant, with pharmaceutical industry-sponsored trials having higher odds of excluding patients with brain metastases than did university or investigator-initiated trials (OR = 2.262, 95% confidence interval: 1.063-4.808, p = 0.0342) CONCLUSIONS: With 14% to 19% of trials excluding any history of LMD or CNS parenchymal metastatic disease and 41% of trials permitting CNS disease only after prior CNS-directed treatment, direct evidence of activity of a treatment on CNS disease cannot be reliably generated in most NSCLC trials. Given the high frequency of CNS disease in NSCLC and only sponsor being associated with specific CNS exclusion criteria, sponsors should consider tailoring trial designs to explore CNS benefit more explicitly.
Assuntos
Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Ensaios Clínicos como Assunto/estatística & dados numéricos , Neoplasias Pulmonares/patologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Sistema de Registros , Adulto JovemRESUMO
INTRODUCTION: The objective of this study was to determine whether the addition of ramucirumab to first-line paclitaxel-carboplatin chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) resulted in a 6-month progression-free survival (PFS) rate that compares favorably with the historic rate for bevacizumab combined with paclitaxel-carboplatin in this patient population. METHODS: In this phase II, single-arm, open-label, multicenter study, 40 patients with advanced NSCLC received ramucirumab (10 mg/kg intravenous [IV]) followed by paclitaxel (200 mg/m IV) and carboplatin area under the curve = 6 on day 1 every 21 days as first-line therapy. Therapy continued for up to six cycles. Patients not experiencing withdrawal criteria may have continued ramucirumab monotherapy every 3 weeks. The primary endpoint was PFS at 6 months, with 80% power to detect a 6-month PFS rate of at least 55%. RESULTS: The 6-month PFS rate was 59.0% and the objective response rate was 55.0%. The most common treatment-related adverse events were fatigue, peripheral neuropathy, nausea, epistaxis, and myalgia. Single-nucleotide polymorphism (SNP) rs2981582 on the FGFR-2gene had significant associations with improved overall survival, PFS, and best overall response (p values without multiplicity adjustment were 0.0059, 0.0429, and 0.0392, respectively). CONCLUSION: Ramucirumab in combination with paclitaxel-carboplatin resulted in a 6-month PFS rate and safety profile that compared favorably with the historical control. In addition, no deaths were associated with this treatment. Furthermore, we describe an association of SNP on FGFR-2 gene with survival and response. These findings warrant further clinical investigation in patients with NSCLC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatina/administração & dosagem , Carboplatina/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , RamucirumabAssuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Carcinomatose Meníngea/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Relação Dose-Resposta a Droga , Cloridrato de Erlotinib , Éxons , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Carcinomatose Meníngea/genética , Carcinomatose Meníngea/patologia , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/administração & dosagem , Quinazolinas/uso terapêutico , Deleção de Sequência , Resultado do TratamentoRESUMO
The diagnostic testing, treatment and prognosis of non-small cell lung cancer (NSCLC) has undergone a paradigm shift since the discovery of sensitizing mutations in the epidermal growth factor receptor (EGFR) gene in a subset of NSCLC patients. Several additional oncogenic mutations, including gene fusions and amplifications, have since been discovered, with a number of drugs that target each specific oncogene. This review focuses on oncogenes in NSCLC other than EGFR and their companion "targeted therapies." Particular emphasis is placed on the role of ALK, ROS1, RET, MET, BRAF, and HER2 in NSCLC.
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Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismoAssuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Mutação/genética , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND: Crizotinib produces high response rates and prolonged PFS in ALK+ NSCLC. Retrospective analyses suggest enhanced sensitivity to pemetrexed in crizotinib naive ALK+ NSCLC. Cross-resistance between crizotinib and pemetrexed has not been previously investigated. PATIENTS AND METHODS: Patients with stage IV ALK+ NSCLC treated with PEM-CRIZ, or CRIZ-PEM were identified. Overall PFS and PFS excluding central nervous system events (eCNS) were compared. RESULTS: Objective response rates in evaluable patients were 66% (PEM-CRIZ) and 75% (CRIZ-PEM) for pemetrexed and 84% (CRIZ-PEM) and 66% (PEM-CRIZ) for crizotinib. For PEM-CRIZ (n = 29), median PFS and eCNS PFS were both 6 months with pemetrexed, and 10 and 14.5 months, respectively, with crizotinib. For CRIZ-PEM (n = 9), median PFS and eCNS PFS were 4.5 and 3 months, respectively, with pemetrexed, and 8.5 and 7.5 months, respectively, with crizotinib. There was a statistically significant increase in the risk of an overall PFS event with pemetrexed when administered after crizotinib (P = .0277; hazard ratio [HR], 2.5898; 95% confidence interval [CI], 1.1100-6.0424), but differences in the risk of an eCNS PFS event were not significant (P = 0.4913; HR, 1.3521; 95% CI, 0.5727-3.1920). Neither overall nor eCNS PFS for patients while taking crizotinib was associated with a sequence effect relative to pemetrexed. CONCLUSION: Crizotinib and pemetrexed are active drugs in ALK+ NSCLC. PFS benefit appeared higher with crizotinib than with pemetrexed. PFS benefit from pemetrexed was less after crizotinib compared with before crizotinib, however, this difference was only statistically significant for overall and not eCNS PFS. Pemetrexed exposure did not seem to affect crizotinib outcomes.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quimioterapia Combinada , Glutamatos/administração & dosagem , Guanina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Adulto , Idoso , Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Crizotinibe , Intervalo Livre de Doença , Interações Medicamentosas , Feminino , Guanina/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pemetrexede , Receptores Proteína Tirosina Quinases/metabolismo , Estudos Retrospectivos , Adulto JovemRESUMO
Metastatic non-small cell lung cancer remains a disease with a high annual incidence and annual mortality worldwide, with limitations in first-line treatment past a fixed amount of platinum doublet chemotherapy for patients that do not harbor a targetable genetic abnormality such as an EGFR mutation or ALK gene rearrangement. Previous attempts to extend first-line treatment past 4-6 cycles of conventional cytotoxic chemotherapy have been disappointing, resulting in diminished quality of life and increased toxicity without improvement of progression-free or overall survival. Several advances in third-generation chemotherapy and targeted agents have generated a renewed interest in maintenance therapy, with several randomized phase III trials reporting a significant improvement in progression-free and overall survival with manageable toxicity profiles. The availability of new chemotherapy agents, tyrosine kinase inhibitors, and immunotherapy agents with a more tolerable or nonoverlapping toxicity profile have resulted in improvements in progression-free survival and median overall survival in maintenance settings with specific agents such as pemetrexed and erlotinib. Patients who are responding to first-line therapy, have not suffered a detrimental decrease in quality of life or performance status, and understand the risks and benefits of further immediate chemotherapy should be considered for maintenance treatment.
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quimioterapia de Manutenção/métodos , Animais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Quimioterapia de Manutenção/tendências , Ensaios Clínicos Controlados Aleatórios como Assunto/métodosRESUMO
PURPOSE: Oncogenic gene fusions involving the 3' region of ROS1 kinase have been identified in various human cancers. In this study, we sought to characterize ROS1 fusion genes in non-small cell lung cancer (NSCLC) and establish the fusion proteins as drug targets. EXPERIMENTAL DESIGN: An NSCLC tissue microarray (TMA) panel containing 447 samples was screened for ROS1 rearrangement by FISH. This assay was also used to screen patients with NSCLC. In positive samples, the identity of the fusion partner was determined through inverse PCR and reverse transcriptase PCR. In addition, the clinical efficacy of ROS1 inhibition was assessed by treating a ROS1-positive patient with crizotinib. The HCC78 cell line, which expresses the SLC34A2-ROS1 fusion, was treated with kinase inhibitors that have activity against ROS1. The effects of ROS1 inhibition on proliferation, cell-cycle progression, and cell signaling pathways were analyzed by MTS assay, flow cytometry, and Western blotting. RESULTS: In the TMA panel, 5 of 428 (1.2%) evaluable samples were found to be positive for ROS1 rearrangement. In addition, 1 of 48 patients tested positive for rearrangement, and this patient showed tumor shrinkage upon treatment with crizotinib. The patient and one TMA sample displayed expression of the recently identified SDC4-ROS1 fusion, whereas two TMA samples expressed the CD74-ROS1 fusion and two others expressed the SLC34A2-ROS1 fusion. In HCC78 cells, treatment with ROS1 inhibitors was antiproliferative and downregulated signaling pathways that are critical for growth and survival. CONCLUSIONS: ROS1 inhibition may be an effective treatment strategy for the subset of patients with NSCLC whose tumors express ROS1 fusion genes.