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1.
Ann Surg Oncol ; 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32239339

RESUMO

BACKGROUND: This study aimed to evaluate the feasibility of a wait-and-see strategy for non-small cell lung cancer (NSCLC) patients with special pleural dissemination lesions (r-pM1a and s-pM1a). Furthermore, the study characterized genomic alternations about disease progression. METHODS: For this study, 131 NSCLC patients with a diagnosis of pM1a were retrospectively selected. Survival differences were evaluated among patients treated with three different initial postoperative treatments: chemotherapy, targeted therapy, and wait-and-see strategy. Whole-exome sequencing (WES) was performed on primary and metastatic tumors of 10 patients with dramatic progression and 13 patients with gradual progression. RESULTS: The wait-and-see group showed better progression-free survival (PFS) than the chemotherapy group (p < 0.001) but PFS similar to that of targeted group (p = 0.984). This pattern persisted in epidermal growth factor receptor (EGFR)-positive patients. For patients with EGFR-negative/unknown status, PFS was longer in the wait-and-see group than in the two treatment groups. Furthermore, better overall survival (OS) was observed for the patients who received chemotherapy or targeted therapy after the wait-and-see strategy than for those who received chemotherapy or targeted therapy immediately. Lymph node status was an independent prognostic factor for PFS and OS. Finally, WES analysis showed that a high genomic instability index (GIS) and chromosome 18q loss were more common in metastatic tumors, and low GIS was significantly associated with better PFS (p = 0.016). CONCLUSIONS: The wait-and-see strategy could be considered for special pM1a patients without lymph nodes metastasis, and patients with a low GIS may be suitable for this strategy.

2.
J Immunother Cancer ; 8(1)2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31959728

RESUMO

BACKGROUND: Immunotherapy has become an important treatment option for patients with advanced non-small cell lung cancer (NSCLC). At present, none of these existing biomarkers can effectively stratify true responders and there is an urgent need for identifying novel biomarkers. Exosomes derived from the serum of patients with cancer have been proven to be reliable markers for cancer diagnosis. Here, we explored the possibility of using plasma-derived exosomal microRNAs as potential biomarkers for optimal selection of patients with advanced EGFR / ALK negative NSCLC to immunotherapy. METHODS: From June 2017 to February 2019, 30 patients with advanced EGFR / ALK wild-type (WT) NSCLC who received PD-1/PD-L1 inhibitors were enrolled. The efficacy evaluation was conducted after every three cycles of treatment according to RECIST 1.1. Plasma samples of these patients were collected before the administration of PD-1/PD-L1 inhibitors as baseline, and after every three cycles if the patients achieved partial response (PR) or complete response. Plasma from seven healthy individuals was also collected as normal control. Exosomes were prepared by ultracentrifugation followed by total RNA extraction, and exosome-derived miRNAs were profiled using small RNA next-generation sequencing followed by differential expression analysis. RESULTS: In order to identify biomarker for better response, all five patients who achieved PR and four patients with progressive disease (PD) at efficacy evaluation were included for differential expression analysis. Based on unsupervised hierarchical clustering, exosomal miRNA expression profile was significantly altered in patients with NSCLC compared with normal controls with a total of 155 differentially expressed exosomal miRNAs. Interestingly, hsa-miR-320d, hsa-miR-320c, and hsa-miR-320b were identified significantly upregulated in the PD groups compared with the PR group at baseline before the treatment. In addition, we identified that hsa-miR-125b-5p, a T-cell suppressor, showed a trend of increased expression in the PD group at baseline and was significantly downregulated in the post-treatment plasma exosomes compared with pre-treatment samples of the PR patients. CONCLUSION: Patients with NSCLC represent unique plasma exosomal miRNA profiles. Hsa-miR-320d, hsa-miR-320c, and hsa-miR-320b were identified as potential biomarkers for predicting the efficacy of immunotherapy in advanced NSCLCs. When T-cell suppressor hsa-miR-125b-5p was downregulated during the treatment, the patients may obtain increased T-cell function and respond well to immunotherapy.

3.
Ann Thorac Surg ; 109(4): 1040-1046, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31926158

RESUMO

BACKGROUND: Patients undergoing thoracic lung wedge resection could benefit from tubeless strategies. However, postoperative pneumothorax is a primary limiting factor for such strategies. Accordingly, we evaluated the safety and efficacy of the prophylactic use of an air-extraction catheter as an improved drainage strategy and compared the findings with those for chest tube drainage in patients undergoing thoracic wedge resection. METHODS: Patients undergoing thoracic wedge resection between August 2017 and October 2018 were enrolled in this single-center, randomized, open-label, noninferiority trial. Patients who received an improved drainage strategy involving the use of a prophylactic air-extraction catheter were randomized to the intervention group, whereas those who underwent routine chest tube drainage were assigned to the control group. Analysis was based on the per-protocol population. The primary outcome was the incidence of pneumothorax on postoperative day 1. Secondary outcomes included patient recovery and related complications, including pleural effusion, lung infection, numeric rating scale score for pain, postoperative chest tube or catheter removal, postoperative hospitalization, and chest tube reinsertion. RESULTS: A total of 96 patients were randomized. Baseline demographic and clinical characteristics were similar between groups. The incidence of pneumothorax in the intervention and control groups was 10.0% and 9.1%, respectively (noninferiority, P = 1.00). In addition, there were no significant between-group differences in secondary outcomes. A significantly lower pain score was observed in the intervention group (P = .001). CONCLUSIONS: The improved drainage strategy is not inferior to standard chest tube drainage after thoracic wedge resection and should be popularized.

4.
J Thorac Oncol ; 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31972351

RESUMO

INTRODUCTION: Leptomeningeal carcinomatosis (LMC) occurs frequently in anaplastic lymphoma kinase (ALK)-rearranged NSCLC and develops acquired resistance to ALK tyrosine kinase inhibitors (ALK TKIs). This study aimed to clarify the resistance mechanism to alectinib, a second-generation ALK TKI, in LMC and test a novel therapeutic strategy. METHODS: We induced alectinib resistance in an LMC mouse model with ALK-rearranged NSCLC cell line, A925LPE3, by continuous oral alectinib treatment, established A925L/AR cells. Resistance mechanisms were analyzed using several assays, including Western blot and receptor tyrosine kinase array. We also measured amphiregulin (AREG) concentrations in cerebrospinal fluid from patients with ALK-rearranged NSCLC with alectinib-refractory LMC by enzyme-linked immunosorbent assay. RESULTS: A925L/AR cells were moderately resistant to various ALK TKIs, such as alectinib, crizotinib, ceritinib, and lorlatinib, compared with parental cells in vitro. A925L/AR cells acquired the resistance by EGFR activation resulting from AREG overexpression caused by decreased expression of microRNA-449a. EGFR TKIs and anti-EGFR antibody resensitized A925L/AR cells to alectinib in vitro. In the LMC model with A925L/AR cells, combined treatment with alectinib and EGFR TKIs, such as erlotinib and osimertinib, successfully controlled progression of LMC. Mass spectrometry imaging showed accumulation of the EGFR TKIs in the tumor lesions. Moreover, notably higher AREG levels were detected in cerebrospinal fluid of patients with alectinib-resistant ALK-rearranged NSCLC with LMC (n = 4), compared with patients with EGFR-mutated NSCLC with EGFR TKI-resistant LMC (n = 30), or patients without LMC (n = 24). CONCLUSIONS: These findings indicate the potential of novel therapies targeting both ALK and EGFR for the treatment of ALK TKI-resistant LMC in ALK-rearranged NSCLC.

5.
Cancer ; 126(2): 373-380, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31769875

RESUMO

BACKGROUND: This study assesses different technologies for detecting epidermal growth factor receptor (EGFR) mutations from circulating tumor DNA in patients with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC) from the AURA3 study (NCT02151981), and it evaluates clinical responses to osimertinib and platinum-pemetrexed according to the plasma T790M status. METHODS: Tumor tissue biopsy samples were tested for T790M during screening with the cobas EGFR Mutation Test (cobas tissue). Plasma samples were collected at screening and at the baseline and were retrospectively analyzed for EGFR mutations with the cobas EGFR Mutation Test v2 (cobas plasma), droplet digital polymerase chain reaction (ddPCR; Biodesix), and next-generation sequencing (NGS; Guardant360, Guardant Health). RESULTS: With cobas tissue test results as a reference, the plasma T790M positive percent agreement (PPA) was 51% (110 of 215 samples) by cobas plasma, 58% (110 of 189) by ddPCR, and 66% (136 of 207) by NGS. Plasma T790M detection was associated with a larger median baseline tumor size (56 mm for T790M-positive vs 39 mm for T790M-negative; P < .0001) and the presence of extrathoracic disease (58% for M1b-positive vs 39% for M0-1a-positive; P = .002). Progression-free survival (PFS) was prolonged in randomized patients (tissue T790M-positive) with a T790M-negative cobas plasma result in comparison with those with a T790M-positive plasma result in both osimertinib (median, 12.5 vs 8.3 months) and platinum-pemetrexed groups (median, 5.6 vs 4.2 months). CONCLUSIONS: PPA was similar between ddPCR and NGS assays; both were more sensitive than cobas plasma. All 3 test platforms are suitable for routine clinical practice. In patients with tissue T790M-positive NSCLC, an absence of detectable plasma T790M at the baseline is associated with longer PFS, which may be attributed to a lower disease burden.

6.
J Clin Oncol ; 38(3): 286-287, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31804870
7.
Thorac Cancer ; 11(2): 346-352, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31794146

RESUMO

BACKGROUND: Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare and unique subtype of lung cancer. However, the prevalence of driver alterations, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, and the response of tyrosine kinase inhibitor (TKIs) in PLELC has not been thoroughly investigated. METHOD: We retrospectively reviewed the genetic profiles and treatment course of 330 PLELC patients at the Guangdong Lung Cancer Institute (GLCI) from 1st January, 2008 to 30th December, 2018. We searched and analyzed related literature published in PubMed and Web of Science from 1st January, 2000 and 31th August, 2019 based on their mention of "driver mutations" and "the response of TKIs to mutant PLELC". RESULTS: Genetic alterations of EGFR/ALK were tested in 203 patients (203/330, 61.5%). Five patients (5/175, 2.9%) had EGFR mutation and three patients (3/140, 2.1%) had ALK alteration. From the total of 15 articles identified from electronic searches, 1071 PLELC cases mentioned the driver mutations. EGFR mutation and ALK rearrangement were detected in 15 patients and one patient, respectively. In total, there were four EGFR/ALK mutant PLELC patients who received targeted therapy as palliative treatment at the GLCI and in the literature. However, there was disease progression in all cases one month after use of TKIs. CONCLUSION: The mutation rates of EGFR and ALK were low in PLELC. EGFR and ALK TKIs showed limited response in EGFR/ALK mutant PLELC. Further studies are needed to explore other molecular targets to optimize the therapeutic strategy for PLELC.

8.
Lung Cancer ; 139: 118-123, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31775086

RESUMO

OBJECTIVES: The 2015 World Health Organization classification defines pulmonary large-cell neuroendocrine carcinoma (LCNEC) as a high-grade neuroendocrine carcinoma. However, the clinical characteristics and prognostic factors of pure LCNEC and combined LCNEC remain unclear. Hence, we performed a multi-center retrospective study to compare the clinical outcomes of pure versus combined LCNEC. MATERIALS AND METHODS: Data from 381 patients with pulmonary LCNEC admitted to 17 Chinese institutes between 2009 and 2016 were collected retrospectively. Clinical characteristics and prognosis were analyzed among patients receiving adjuvant (adjuvant group; n = 56) and first-line (first-line group; n = 146) chemotherapy, as well as among patients receiving small cell lung cancer (SCLC) and non-SCLC (NSCLC) chemotherapy regimens. The Kaplan-Meier method and multivariable Cox regression were used to identify clinicopathological variables that might influence patient outcomes. RESULTS: Expression levels of neuroendocrine markers (synaptophysin, chromogranin-A, CD56) were associated with patients' prognosis in the total study cohort. In the adjuvant group, median disease-free survival was non-significantly longer for SCLC-based regimens than for NSCLC-based regimens (P = 0.112). In the first-line group, median progression-free survival was significantly longer for SCLC-based regimens than for NSCLC-based regimens (11.5 vs. 7.2 months, P = 0.003). Among patients with combined LCNEC, adenocarcinoma was the most common combined component, accounting for 70.0 % of cases. Additionally, median overall survival was non-significantly shorter for combined LCNEC than for pure LCNEC (P = 0.083). CONCLUSION: The SCLC regimen is a more effective choice, as either first-line or adjuvant chemotherapy, when compared to the NSCLC regimen for LCNEC treatment. Further studies are needed to clarify the survival differences between patients with pure-, and combined LCNEC.

9.
Int J Clin Oncol ; 25(2): 267-273, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31587134

RESUMO

BACKGROUND: Bevacizumab was demonstrated to have efficacy in patients with non-small cell lung cancer (NSCLC) and brain metastases. However, cerebral toxicities were a major concern. This study aims to investigate the efficacy and risk factors of toxicity of bevacizumab in brain metastases. METHODS: All patients with advanced NSCLC hospitalized in our institute were screened and only those, who underwent bevacizumab administration after the diagnosis of brain metastases, were included. RESULTS: Fifty-one patients, who were treatment naïve or pretreated prior to bevacizumab regimens, were enrolled. Regardless of treatment lines, the objective response rate (ORR) was 62.7% (32/51), progression free survival (PFS) and overall survival were 6.2 months (95%CI, 5.0-7.4) and 14.0 months (95%CI, 9.6-18.4), respectively, and intracranial PFS was 7.8 months (95%CI, 7.1-8.5). For 41 patients with measurable brain metastatic lesions, the intracranial ORR was 46.3% (19/41). Ten patients (19.6%, 10/51) experienced cerebral toxicities (seven cases of grade 1 and three cases of grade 3), including cerebral or intratumoral hemorrhage and ischemic stroke. Cardiovascular disease was the risk factor contributing to cerebral toxicities (OR 16.645; 95%CI, 2.443-113.430; P = 0.004). CONCLUSIONS: This retrospective study shows that bevacizumab has efficacy and favorable toxicity in patients with NSCLC and brain metastases and cardiovascular disease might be a risk factor for cerebral toxicity.

10.
Curr Opin Oncol ; 32(1): 68-77, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31714259

RESUMO

PURPOSE OF REVIEW: The objective of this review is to discuss the strength and limitations of tissue and liquid biopsy and functional imaging to capture spatial and temporal tumor heterogeneity either alone or as part of a diagnostic framework in non-small cell lung cancer (NSCLC). RECENT FINDINGS: NSCLC displays genetic and phenotypic heterogeneity - a detailed knowledge of which is crucial to personalize treatment. Tissue biopsy often lacks spatial and temporal resolution. Thus, NSCLC needs to be characterized by complementary diagnostic methods to resolve heterogeneity. Liquid biopsy offers detection of tumor biomarkers and for example, the classification and monitoring of EGFR mutations in NSCLC. It allows repeated sampling, and therefore, appears promising to address temporal aspects of tumor heterogeneity. Functional imaging methods and emerging image analytic tools, such as radiomics capture temporal and spatial heterogeneity. Further standardization of radiomics is required to allow introduction into clinical routine. SUMMARY: To augment the potential of precision therapy, improved diagnostic characterization of tumors is pivotal. We suggest a comprehensive diagnostic framework combining tissue and liquid biopsy and functional imaging to address the known aspects of spatial and temporal tumor heterogeneity on the example of NSCLC. We envision how this framework might be implemented in clinical practice.

11.
BMC Cancer ; 19(1): 1051, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694572

RESUMO

BACKGROUND: Local consolidative treatment (LCT) is important for oligometastasis, defined as the restricted metastatic capacity of a tumor. This study aimed to determine the effects and prognostic heterogeneity of LCT in oligometastatic non-small cell lung cancer. METHODS: This retrospective study identified 436 eligible patients treated for oligometastatic disease at the Guangdong Provincial People's Hospital during 2009-2016. A Cox regression analysis was used to identify potential predictors of overall survival (OS). After splitting cases randomly into training and testing sets, risk stratification was performed using recursive partitioning analysis with a training dataset. The findings were confirmed using a validation dataset. The effects of LCT in different risk groups were evaluated using the Kaplan-Meier method. RESULTS: The T stage (p = 0.001), N stage (p = 0.008), number of metastatic sites (p = 0.031), and EGFR status (p = 0.043) were identified as significant predictors of OS. A recursive partitioning analysis was used to establish a prognostic risk model with the following four risk groups: Group I included never smokers with N0 disease (3-year OS: 55.6%, median survival time [MST]: 42.8 months), Group II included never smokers with N+ disease (3-year OS: 32.8%, MST: 26.5 months), Group III included smokers with T0-2 disease (3-year OS: 23.3%, MST: 19.4 months), and Group IV included smokers with T3/4 disease (3-year OS: 12.5%, MST: 11.1 months). Significant differences in OS according to LCT status were observed in all risk groups except Group IV (p = 0.45). CONCLUSIONS: Smokers with T3/4 oligometastatic non-small cell lung cancer may not benefit from LCT.

12.
J Extracell Vesicles ; 8(1): 1663666, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31579436

RESUMO

In this study, we evaluated the diagnostic value and molecular characteristics of plasma extracellular vesicles (EVs)-derived miRNAs for patients with solitary pulmonary nodules (SPNs), particularly ground-glass nodules (GGNs). This study was registered at www.clinicaltrials.gov under registration number NCT03230019. Small RNA sequencing was performed to assess plasma EVs miRNAs in 59 patients, including 12 patients with benign nodules (2017, training set). MiRNA profiles of 40 an additional individuals were sequenced (2018, validation set). Overall, 16 pure GGNs, 21 mixed GGNs, and 42 solid nodules were included, with paired post-operative plasma samples available for 20 patients. The target miRNA/reference miRNA ratio was used to construct a support vector machine (SVM) model. The SVM model with the best specificity showed 100% specificity in both the training and validation sets independently. The model with the best sensitivity showed 100% and 96.9% sensitivity in the training and validation sets, respectively. Principal component analysis revealed that pure GGN distributions were distinct from those of solid nodules, and mixed GGNs had a diffuse distribution. Among differentially expressed miRNAs, miR-500a-3p, miR-501-3p, and miR-502-3p were upregulated in tumor tissues and enhanced overall survival. The SVM classifier accurately distinguished malignant GGNs and benign nodules. The distinct profile characteristics of miRNAs provided insights into the feasibility of EVs miRNAs as prognostic factors in lung cancer.

14.
J Thorac Dis ; 11(8): E109-E111, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31559076
15.
J Thorac Oncol ; 14(11): 1912-1923, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31446140

RESUMO

BACKGROUND: Understanding the genomic landscape and immune microenvironment features of preinvasive and early invasive lung adenocarcinoma may provide critical insight and facilitate development of novel strategies for early detection and intervention. METHODS: A total of 80 tumor tissue samples and 30 paired histologically normal lung tissue samples from 30 patients with adenocarcinoma in situ (AIS) (n = 8), minimally invasive adenocarcinoma (MIA) (n = 8), and invasive adenocarcinoma (IAC) (n = 14) were subjected to multiregion whole exome sequencing and immunohistochemistry staining for CD8 and programmed death ligand 1 (PD-L1). RESULTS: All tumors, including AIS, exhibited evidence of genomic intratumor heterogeneity. Canonical cancer gene mutations in EGFR, erb-b2 receptor tyrosine kinase 2 gene (ERBB2), NRAS, and BRAF were exclusively trunk mutations detected in all regions within each tumor, whereas genes associated with cell mobility, gap junction, and metastasis were all subclonal mutations. EGFR mutation represented the most common driver alterations across AIS, MIA, and IAC, whereas tumor protein p53 gene (TP53) was identified in MIA and IAC but not in AIS. There was no difference in PD-L1 expression among AIS, MIA, and IAC, but the CD8 positivity rate was higher in IAC. Tumors positive for both PD-L1 and CD8 had a larger proportion of subclonal mutations. CONCLUSIONS: Mutations in EGFR, ERBB2, NRAS, and BRAF are early clonal genomic events during carcinogenesis of lung adenocarcinoma, whereas TP53 and cell mobility, gap junction, and metastasis-related genes may be late events associated with subclonal diversification and neoplastic progression. Genomic intratumor heterogeneity and immunoediting are common and early phenomena that may have occurred before the acquisition of invasion.

16.
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
17.
Lung Cancer ; 135: 188-195, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31446994

RESUMO

OBJECTIVES: Most lung cancer diagnoses occur in elderly patients, who are underrepresented in clinical trials. We present a pooled analysis of safety and efficacy in elderly patients (≥75 years) who received pembrolizumab (a programmed death 1 inhibitor) for advanced non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1)‒positive tumors. METHODS: The pooled analysis included patients aged ≥18 years with advanced NSCLC with PD-L1-positive tumors from the KEYNOTE-010 (NCT01905657), KEYNOTE-024 (NCT02142738), and KEYNOTE-042 (NCT02220894) studies. In KEYNOTE-010, patients were randomized to pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or docetaxel, as second- or later-line therapy. In KEYNOTE-024 and KEYNOTE-042, patients were randomized to first-line pembrolizumab 200 mg Q3W or platinum-based chemotherapy. Overall survival (OS) was estimated by the Kaplan-Meier method, and safety data were summarized in elderly patients (≥75 years). RESULTS: The analysis included 264 elderly patients with PD-L1-positive tumors (PD-L1 tumor proportion score [TPS] ≥1%); among these, 132 had PD-L1 TPS ≥ 50%. Pembrolizumab improved OS among elderly patients with PD-L1 TPS ≥ 1% (hazard ratio [HR], 0.76 [95% CI, 0.56-1.02]) and PD-L1 TPS ≥ 50% (HR, 0.40 [95% CI, 0.25-0.64]). Pembrolizumab as first-line therapy also improved OS among elderly patients with PD-L1 TPS ≥ 50% (from KEYNOTE-024 and KEYNOTE-042) compared with chemotherapy (HR, 0.41 [95% CI, 0.23‒0.73]). Pembrolizumab was associated with fewer treatment-related adverse events (AEs) in elderly patients (overall, 68.5% vs 94.3%; grade ≥3, 24.2% vs 61.0%) versus chemotherapy. Immune-mediated AEs and infusion reactions were more common with pembrolizumab versus chemotherapy (overall, 24.8% vs 6.7%; grade 3‒4: 9.4% vs 0%; no grade 5 events). CONCLUSIONS: In this pooled analysis of elderly patients with advanced NSCLC with PD-L1‒positive tumors, pembrolizumab improved OS versus chemotherapy, with a more favorable safety profile. Outcomes with pembrolizumab in patients ≥75 years were comparable to those in the overall populations in the individual studies.

18.
J Thorac Dis ; 11(7): 2754-2762, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31463103

RESUMO

Background: We aimed to validate the tumor (T) descriptors of visceral pleural invasion (VPI) for T1 tumors (<3 cm) in the 8th edition of the tumor-node-metastasis (TNM) classification system and the prognostic value of VPI for resected T1a tumors. Methods: The external cohort consisted of 23,501 patients with resected pN0 non-small cell lung cancer (NSCLC) selected from the Surveillance, Epidemiology, and End Results (SEER) database (2010 to 2013). The classification of T1 tumors with VPI was investigated using survival curves. The internal cohort consisted of patients diagnosed with pN0 NSCLC between 2011 and 2013 at Guangdong Lung Cancer Institute. The prognostic value of VPI for T1a tumors (<1 cm) was further assessed in these two cohorts. Results: The overall survival (OS) and lung cancer-specific survival (LCSS) of the T1-VPI group and groups of each T stage (size only) were compared in the external (SEER) cohort. There were no significant survival differences between the T1-VPI and T2a groups (OS: P=0.706; LCSS: P=0.792) and T1-VPI and T2b groups, although the latter showed a trend toward lower P-values (OS: P=0.117; LCSS: P=0.094). In the internal cohort, a significant difference in OS was observed between patients with T1-VPI and those with T2b (P=0.049). Among patients with T1a tumors and VPI in the SEER database, the prognosis of the non-sub-lobectomy group was superior to that of the sub-lobectomy group, with intrathoracic recurrence as the predominant relapse pattern of T1 tumors with VPI (69.2%). Conclusions: T1 tumors (<3 cm) with VPI can be staged as T2a in the 8th TNM staging system and surgical resection of T1a tumors is a concern when VPI is present.

19.
Future Oncol ; 15(24): 2795-2805, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31313942

RESUMO

Aim: We evaluated reasons for dacomitinib dose reduction (DR) and examined adverse event (AE) incidence, key efficacy end points (progression-free survival [PFS]/overall survival [OS]), and pharmacokinetics in dose-reducing patients in the ARCHER 1050 trial. Patients & methods: Newly diagnosed patients with EGFR mutation-positive, advanced non-small-cell lung cancer received oral dacomitinib (45 mg once-daily [QD]), with stepwise toxicity-managing DR (30 and 15 mg QD) permitted. Results: Skin toxicities (62.7%) were the most common DR-leading AEs. The AE incidence and severity decreased following DRs. Initial plasma dacomitinib exposure (45 mg QD) was generally lower in patients remaining at 45 mg QD compared with dose-reducing patients. Median PFS and OS were similar in all dacomitinib-treated patients and dose-reducing patients. Conclusion: Tolerability-guided dose modifications enabled patients to continue with dacomitinib and benefit from PFS/OS improvement. Trial registration number: NCT01774721.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinonas/administração & dosagem , Quinazolinonas/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Mutação/genética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos
20.
Future Oncol ; 15(26): 3003-3014, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31339357

RESUMO

Aim: Osimertinib is a third-generation, irreversible, oral EGFR tyrosine kinase inhibitor. We report real-world effectiveness and safety data. Patients & methods: EGFR T790M positive advanced non-small-cell lung cancer adults, who received ≥1 prior EGFR tyrosine kinase inhibitor, received osimertinib 80 mg daily. Primary effectiveness outcome: overall survival. Secondary effectiveness outcomes included: investigator-assessed clinical response, progression-free survival, time-to-treatment discontinuation. Results: At data cutoff, 3015 patients had enrolled: 57.1% had investigator-assessed response (95% CI: 55.2-58.9). Median progression-free survival: 11.1 months (95% CI: 11.0-12.0) and median time-to-treatment discontinuation: 13.5 months (95% CI: 12.6-13.9). Interstitial lung disease/pneumonitis-like events reported in 28 (1%) patients. Conclusion: Osimertinib demonstrated clinical effectiveness similar to efficacy observed in the clinical trial program with no new safety signals.


Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Acrilamidas/administração & dosagem , Acrilamidas/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Substituição de Aminoácidos , Compostos de Anilina/administração & dosagem , Compostos de Anilina/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Receptores ErbB/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do Tratamento
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