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BACKGROUND: To report the efficacy and safety data of immunotherapy plus angiogenic inhibitors treatment in lung adenocarcinoma patients. METHODS: Eligible patients with pathological or cytological confirmed locally advanced or metastatic lung adenocarcinoma and treated with immune checkpoint inhibitors (ICI) plus angiogenic inhibitors were enrolled. The primary endpoints were progressive free survival (PFS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. RESULTS: A total of 46 consecutive enrolled patients received ICI plus angiogenic inhibitor, and the median follow-up was 9.6 months (range 1.5-32.5). The ORR and DCR were 8.7% (n = 4) and 50% (n = 23), respectively. Median PFS and OS were 2.9 months (95% CI 2.1-3.7) and 12.3 months (95% CI 7.6-17.0), respectively. Patients at stage IVB had an inferior PFS than stage IIIC or IVA (2.8 months vs 4.4 months, P = 0.003). The median PFS of patients who were treated with ICI plus bevacizumab was shorter than ICI plus anlotinib or apatinib (1.2 months vs 3.3 months, P = 0.005). The occurrence of hypertension during the combination treatment has been related to a tendency for prolonged PFS (5.5 months vs 2.6 months; P = 0.05). The overall incidence of treatment-related adverse events (TRAE) was 89.1% (n = 41), and grade 3-4 TRAE was occupied 21.4% (n = 10). CONCLUSION: This study objectively demonstrated that the treatment of ICI and antiangiogenic agents in lung adenocarcinoma could be a promising alternative therapeutic regimen, and the toxic effects were manageable. Subgroup analysis revealed that small molecular angiogenic inhibitors plus ICI and low tumor burden during treatment were better prognostic factors.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Inibidores da Angiogênese , Inibidores de Checkpoint Imunológico , ImunoterapiaRESUMO
BACKGROUND: Furmonertinib (AST2818) is a brain penetrant pan-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both EGFR sensitizing mutations and T790M mutation. We report the pooled central nervous system (CNS) efficacy data of furmonertinib in patients with EGFR T790M mutated non-small cell lung cancer (NSCLC) from two phase 2 studies. METHODS: This was a pooled, post-hoc analysis of two phase 2 studies (NCT03127449 [phase 2a study of furmonertinib], NCT03452592 [phase 2b study of furmonertinib]). In the phase 2a study, patients received furmonertinib 40 mg, 80 mg, 160 mg, or 240 mg orally once daily. In the phase 2b study, all patients received furmonertinib 80 mg orally once daily. CNS efficacy of furmonertinib was analyzed in patients with baseline CNS lesions by an independent review center per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: A total of 132 patients with baseline CNS metastases were included in this analysis. In 52 patients with measurable CNS lesions, CNS objective response rates were zero (0/1), 65% (22/34), 85% (11/13), and 25% (1/4), and CNS disease control rates were zero (0/1), 97% (33/34), 100% (13/13), and 100% (4/4) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively. In patients with measurable or non-measurable CNS lesions, median CNS progression-free survival was 2.8 months (95% confidence interval [CI] 1.4-8.3), 11.6 months (95% CI 8.3-13.8), 19.3 months (95% CI 5.5-not available [NA]), and not reached (95% CI 2.8 months-NA) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively. CONCLUSIONS: Furmonertinib showed promising CNS efficacy in doses of 80 mg orally once daily or higher in patients with EGFR T790M mutated NSCLC. TRIAL REGISTRATION: Both studies were registered on ClinicalTrial.gov. The phase 2a study was registered with NCT03127449 on April 25, 2017; The phase 2b study was registered with NCT03452592 on March 2, 2018.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Receptores ErbB/genética , Inibidores de Proteínas Quinases/efeitos adversos , Mutação , Sistema Nervoso Central/patologia , Ensaios Clínicos Fase II como AssuntoRESUMO
BACKGROUND: As a potential target receptor tyrosine kinase, mesenchymal-epithelial transition factor (MET) exhibits high aberrant expression across various tumors. This study aimed to evaluated the safety, tolerability, efficacy and pharmacokinetics (PK) of BPI-9016M, a novel tyrosine kinase inhibitor (TKI) targeting c-MET, in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS/DESIGN: In this two-part multicenter phase Ib study, eligible patients with locally advanced or metastatic NSCLC harboring c-MET overexpression or MET exon 14 skipping mutation were enrolled into Part A (tested positive for c-MET overexpression [immunohistochemical staining score ≥ 2+]; 300 mg quaque die [QD], 450 mg QD and 600 mg QD cohorts) or Part B (tested positive for MET exon 14 skipping mutation; 400 mg bis in die [BID] cohort), respectively. The primary endpoints were safety, objective response rate (ORR) and disease control rate (DCR), the second endpoints were PK parameters, progression-free survival (PFS) and overall survival (OS). RESULTS: Between March 15, 2017 and September 18, 2021, 38 patients were enrolled (Part A, n = 34; Part B, n = 4). Of 38 patients, 32 (84.2%) patients completed the treatment protocol. As of the data cut-off date on January 27, 2022, all patients reported at least one treatment-emergent adverse event (TEAE). Ninety-two point one percent (35/38) of patients experienced treatment-related adverse events (TRAEs), and grade ≥ 3 TRAEs were observed in 11 (28.9%) patients. The most common TRAEs were elevated alanine aminotransferase (ALT, 14/38, 36.8%) and elevated aspartate aminotransferase (AST, 11/38, 28.9%). Only one (2.6%) patient had treatment-related serious adverse event (SAE) in 600 mg QD cohort due to thrombocytopenia. PK analysis showed BPI-9016M and its main metabolites (M1 and M2-2) reached steady state after seven days of continuous administration. At the dose of 300 mg QD and 450 mg QD, the exposure of BPI-9016M increased with increasing dose. Exposure of BPI-9016M was similar at 450 mg QD and 600 mg QD, which may exhibit a saturation trend. In all patients, ORR and DCR were 2.6% (1/38, 95% confidence interval [CI] 0.1-13.8%) and 42.1% (16/38, 95% CI 26.3-59.2%), respectively. Only one partial response (PR) patient was observed at a dose of 600 mg QD in Part A. In Part B, DCR was 75.0% (3/4, 95% CI 19.4-99.4%). The median PFS and OS in all 38 patients were 1.9 months (95% CI 1.9-3.7) and 10.3 months (95% CI 7.3-not evaluable [NE]), respectively. CONCLUSION: BPI-9016M showed manageable safety profile in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic NSCLC, but showed limited efficacy. TRIAL REGISTRATION: Clinicaltrials.gov NCT02929290 (11/10/2016).
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas c-met/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , ÉxonsRESUMO
BACKGROUND: Antibodies targeting programmed cell death-1(PD1) and its ligand (PDL1) have revolutionized cancer therapy. However, little is known about the preexisted anti-PD1/PDL1 autoantibodies (AAbs) distribution in multiple cancer types, nor is their potential biomarker role for anti-PD1 therapy. METHOD: Plasma anti-PD1/PDL1 AAb IgG and subclasses (IgG1-4) were detected by enzyme-linked immune sorbent assay (ELISA) in 190 cancer patients, covering 10 cancer types (lung, breast, esophageal, colorectal, liver, prostatic, cervical, ovarian, gastric cancers and lymphoma), the comprehensive correlation of AAbs with multiple clinical parameters was analyzed. We further tested these AAbs in 76 non-small cell lung cancer (NSCLC) samples receiving anti-PD1 therapy, the association of AAbs level with survival was analyzed and validated in an independent cohort (n = 32). RESULTS: Anti-PD1/PDL1 AAb IgG were globally detected in 10 types of cancer patients. IgG1 and IgG2 were the major subtypes for anti-PD1/PDL1 AAbs. Correlation analysis revealed a distinct landscape between various cancer types. The random forest model indicated that IgG4 subtype was mostly associated with cancer. In discovery cohort of 76 NSCLC patients, high anti-PD1 IgG4 was associated with a reduced overall survival (OS, p = 0.019), not progression-free survival (PFS, p = 0.088). The negative association of anti-PD1 IgG4 with OS was validated in 32 NSCLC patients (p = 0.032). CONCLUSION: This study reports for the first time the distribution of preexisted anti-PD1/PDL1 AAb IgG and subclasses across 10 cancer types. Moreover, the anti-PD1 AAb IgG4 subclass was identified to associate with OS, which may serve as a potential biomarker for anti-PD1 therapeutic survival benefit in NSCLC patients.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Autoanticorpos , Antígeno B7-H1/metabolismo , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Imunoglobulina G , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
BACKGROUND: Although targeted agents have been gradually applied in the treatment of HER2-mutated non-small cell lung cancer (NSCLC) in recent years, patients' therapeutic demands are far from being met. PATHER2 was the first phase 2 trial to explore the efficacy and safety of the HER2-targeted tyrosine kinase inhibitor (TKI) pyrotinib plus the antiangiogenic agent apatinib in previously treated HER2-altered metastatic NSCLC patients. METHODS: HER2-mutated or HER2-amplified metastatic NSCLC patients who had failed at least first-line chemotherapy or HER2-targeted TKIs received oral pyrotinib 400 mg plus apatinib 250 mg once daily until disease progression, intolerable toxicity, or death. The primary endpoint was the investigator-assessed objective response rate (ORR). RESULTS: Between March 2019 and December 2020, 33 patients were enrolled; 13 (39.4%) presented brain metastases, and 16 (48.5%) had received at least two lines of prior chemotherapy or HER2-targeted TKIs. As of September 20, 2021, the median follow-up duration was 11.3 (range, 3.5-26.0) months. The investigator-assessed ORR was 51.5% (17/33; 95% CI, 33.5 to 69.2%), and the disease control rate was 93.9% (31/33; 95% CI, 79.8 to 99.3%). The median duration of response, progression-free survival, and overall survival were 6.0 (95% CI, 4.4 to 8.6) months, 6.9 (95% CI, 5.8 to 8.5) months, and 14.8 (95% CI, 10.4 to 23.8) months, respectively. The most frequent grade ≥ 3 treatment-related adverse events included diarrhea (3.0%) and hypertension (9.1%). No treatment-related deaths were reported. CONCLUSIONS: Pyrotinib plus apatinib demonstrated promising antitumor activity and a manageable safety profile in HER2-mutated or HER2-amplified metastatic NSCLC patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR1900021684 .
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Acrilamidas , Aminoquinolinas , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Estudos Prospectivos , PiridinasRESUMO
BACKGROUND: Because of rapid disease progression and lack of optimal treatment strategies beyond the second-line, the prognosis of patients with extensive-stage (ES) small cell lung cancer (SCLC) still remains depressing. Alternative treatment strategies are required to improve their prognosis. In this prospective clinical study, we aimed to evaluate the feasibility of single-agent apatinib, a vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, as a treatment option for patients with ES-SCLC after failure of at least two prior chemotherapy regimens. MATERIALS AND METHODS: Twenty-two patients with ES-SCLC treated with 500 mg single-agent apatinib as subsequent-line regimen in our institution from November 2016 to August 2018 were enrolled in the study. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). RESULTS: Clinical outcomes included partial response in 3 patients (13.6%), stable disease in 18 patients (81.8%), and disease progression in 1 patient (4.5%), with an ORR of 13.6% and DCR of 95.5%. The median PFS and OS were 5.4 and 10.0 months, respectively. Apatinib demonstrated a manageable toxicity profile, with grade I-III secondary hypertension and proteinuria as the most common AEs. No grade IV and V AEs were observed among the patients. Multivariate analysis revealed secondary hypertension as an independent predictor of OS (p = .047); however, the association became insignificant after Q correction (p = .455). CONCLUSIONS: Apatinib was safe and effective in the management of patients with ES-SCLC and can be considered as a treatment option after failure of at least two prior chemotherapy regimens. ClinicalTrials.gov identifier. NCT02995187 IMPLICATIONS FOR PRACTICE: This study indicated the acceptable toxicity profile and promising efficacy of apatinib in the management of patients with extensive-stage small cell lung cancer after failure from at least two prior chemotherapy regimens. Secondary hypertension can be a potential prognostic factor for apatinib treatment.
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Antineoplásicos , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Antineoplásicos/efeitos adversos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Estudos Prospectivos , Piridinas , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Fator A de Crescimento do Endotélio VascularRESUMO
Objective: Based on epidemiological field data, this study was to develop a prediction model which can be used as a preliminary screening tool to identify pregnant women who were at high risk of offspring congenital heart disease (CHD) in Nanchong City, and be beneficial in guiding prenatal management and prevention. Methods: A total of 367 children with CHD and 367 children without congenital malformations aged 0 to 14 years old were recruited from the Affiliated Hospital of North Sichuan Medical College and Nanchong Central Hospital between March 2016 and November 2018. Using the SPSS 22.0 case-control matching module, the controls were matched to the cases at a rate of 1:1, according to the same gestational age of child (premature delivery or full-term), the maternal age of pregnancy (less than 1 year). 327 matched case-control pairs were analyzed by SPSS 22. Univariate and multivariate analysis were performed to find the important maternal influencing factors of offspring CHD. A logistic regression disease prediction model was constructed as the final predictors, and Hosmer-Lemeshow goodness of fit test and receiver operating characteristic (ROC) curve were used to evaluate the model. Results: 654 subjects (327 cases and 327 controls) were matched. The 25 variables were analysed. The logistic regression model established in this study was as follows: Logit(P)= -2.871+(0.686×respiratory infections)+(1.176×water pollution)+(1.019×adverse emotions during pregnancy) - (0.617×nutrition supplementation). The Hosmer-Lemeshow chi-square value was 7.208 (df = 6), with a nonsignificant p value of 0.302, which indicates that the model was well-fitted. The calibration plot showed good agreement between the bias-corrected prediction and the ideal reference line. Area under the ROC curve was 0.72 (95% CI: 0.681~0.759), which means that the predictive power of the model set fitted the data. Conclusion: In Nanchong city, more attention should be paid to mother who had a history of respiratory infections, exposure to polluted water, adverse emotions during pregnancy and nutritional deficiency. The risk model might be an effective tool for predicting of the risk of CHD in offspring by maternal experience during pregnancy, which can be used for clinical practise in Nanchong area.
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Cardiopatias Congênitas/epidemiologia , Fatores de Risco de Doenças Cardíacas , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , China/epidemiologia , Ecocardiografia , Estudos de Viabilidade , Feminino , Idade Gestacional , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/etiologia , Humanos , Lactente , Recém-Nascido , Modelos Logísticos , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Análise Multivariada , Gravidez , Complicações na Gravidez/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Efeitos Tardios da Exposição Pré-Natal/etiologia , Curva ROC , Infecções Respiratórias/epidemiologia , Medição de Risco/métodos , Poluição Química da Água/efeitos adversos , Poluição Química da Água/estatística & dados numéricosRESUMO
Background This phase I trial was primarily conducted to determine the maximum tolerated dose (MTD) of apatinib combined with docetaxel in advanced lung adenocarcinoma patients with wild-type EGFR who have failed to first-line platinum-based chemotherapy, and to evaluate the safety and tolerability of apatinib plus docetaxel. Methods This was a single-center, open-label, dose-escalating phase I trial. The study used a standard 3 + 3 dose escalation design with the primary aim of determining the MTD. Twelve patients with advanced lung adenocarcinoma were enrolled, the primary endpoint was safety. Two doses of apatinib, 250 mg/day (level 1) and 500 mg/day (level 2), were evaluated in combination with 60 mg/m2 doxetacel every 3 weeks. Six patients have been treated at levels 1 and 2, respectively. Optimal dose of apatinib was determined by dose-limiting toxicity (DLT). Results Six patients have been treated at levels 1 and 2. At level 1, one of six patients experienced grade 3 acneiform rash as DLTs. At level 2, two patients experienced grade 3 hypertension and one experienced grade 3 nasal bleeding. MTD and recommended dose for phase II study was 250 mg/day. Most frequent adverse events of any grade were bilirubin elevation, hypertension, alanine aminotransferase elevation, transglutaminase elevation, hand foot syndrome and fatigue. The median progression-free survival was 2.76 month. Moreover, three patients had developed progressive disease and the mean duration of response was 2.79 months. Conclusion Apatinib plus docetaxel was well tolerated and showed promising efficacy in advanced lung adenocarcinoma. This combination therapy may represent a potent therapeutic option for advanced lung adenocarcinoma patients with wild-type EGFR.
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Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Docetaxel/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Adulto , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Docetaxel/efeitos adversos , Receptores ErbB , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Receptores de Fatores de Crescimento do Endotélio Vascular , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the efficacy and safety profile of first-line bevacizumab (Bev)-containing pemetrexed-platinum chemotherapy in a real-world Chinese cohort with advanced non-squamous non-small cell lung cancer (NS-NSCLC). METHODS: A total of 415 eligible patients with NS-NSCLC who received first-line pemetrexed-platinum chemotherapy at National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between February 2010 and September 2017 were reviewed retrospectively: 309 Bev(-) and 106 Bev(+) cases. Bev was administered at 7.5 mg/kg every 3 weeks in the Bev(+) group. To reduce the risk of a selection bias, a propensity score-matching (PSM) was conducted and 105 pairs of Bev(-) and Bev(+) cases were identified. RESULTS: The median duration of follow-up was 15.8 months. The median progression-free survival (PFS) was prolonged significantly in the Bev(+) group than in the Bev(-) group in overall (9.8vs. 7.8 months, P=0.006) and PSM pairs (9.8 vs. 6.6 months, P<0.001). Moreover, patients receiving maintenance therapy with pemetrexed plus Bev had longer PFS than those interrupted after induction chemotherapy, or those receiving mono-maintenance with pemetrexed (12.3vs. 4.8 vs. 8.6 months; P<0.001). Multivariate analyses revealed Bev to be one of the favorable prognostic factors for PFS, along with the predictor of maintenance therapy. CONCLUSIONS: First-line induction and maintenance therapy with Bev (7.5 mg/kg every 3 weeks) combined with pemetrexed-platinum chemotherapy was efficacious and superior to non-Bev chemotherapy in Chinese patients with advanced NS-NSCLC.
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The incidence and mortality of hepatocellular carcinoma (HCC) is high, but the mechanisms underlying the growth and progression of HCC have not been elucidated. Recently, the ZIC family member 5 (ZIC5) is emerging as an oncogene in various types of tumors. However, its expression and biological role in HCC have not been reported. This study first demonstrated that ZIC5 was up-regulated in HCC specimens, and high ZIC5 expression indicated poor prognosis of HCC patients. In addition, over-expressed ZIC5 promoted the proliferation, migration and invasion of HCC cell lines Huh7 and HepG2 in vitro and in vivo, while ZIC5 knockdown achieved the opposite effects. Actually, ZIC5 increased the expression of genes participating in Wnt/ß-catenin pathway such as ß-catenin and CyclinD1. ZIC5 also promoted ß-catenin to enter the nucleus of HCC cells. Furthermore, silencing ß-catenin abated the promoting role of ZIC5 in HCC. Overall, this study reveals a novel mechanism of ZIC5/ß-catenin that mediates the invasion and metastasis of HCC and ZIC5 serves as a novel indicator for prognosis of HCC patients.
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Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Adulto , Idoso , Carcinoma Hepatocelular/patologia , Proteínas de Ligação a DNA , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Células Tumorais CultivadasRESUMO
OBJECTIVE: To investigate the clinical features of patients with non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor (EGFR) mutations, and the treatment outcomes of EGFR tyrosine kinase inhibitors (TKIs) in these patients. METHODS: We retrospectively analyzed the data of 128 NSCLC patients pathologically diagnosed with uncommon EGFR mutation in the Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College and Beijing Hospital from January 2010 to December 2015, including 40 advanced patients who received EGFR-TKI. RESULTS: Among the total 128 patients, 11 patients were non-adenocarcinoma, including squamous carcinoma (3.9%), adenosquamous carcinoma (2.3%), large cell carcinoma (0.8%), and composite neuroendocrine carcinoma (1.6%). Single mutations accounted for 75.0% (96/128), including G719X (29.7%), S768I (18.0%), 20 exon insertion (13.3%), L861Q (12.5%),De novo T790M (0.8%), and T725 (0.8%). Thirty-two patients harbored complex mutations. Forty advanced patients received EGFR-TKI, the objective response rate (ORR) was 20.0%, the disease control rate (DCR) was 85.0%, and the progression-free survival (PFS) was 6.4 [95% confidence interval (95% CI), 4.8-7.9] months. The exploratory analysis of tumor response and PFS in 33 patients with G719X/S768I/L861Q subtypes showed that ORR was 21.2% (7/33), the DCR was 93.9% (31/33), and PFS was 7.6 (95% CI, 5.8-9.4) months. Patients with exon 20 insertion mutation andDe novo T790M experienced rapid disease progression with PFS no more than 2.7 months. CONCLUSIONS: Uncommon EGFR-mutant NSCLCs are heterogeneous, EGFR-TKIs can have different efficacy in this specific subtype, and thus further individual assessment is required for each case.
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The aim of this study was to evaluate the efficacy and safety of the combination of docetaxel (TXT) plus tamoxifen (TAM) in advanced non-small-cell lung cancer (NSCLC) patients who had received platinum-based first-line chemotherapy. A total of 120 advanced NSCLC patients pretreated with platinum-based chemotherapy were randomized into two treatment groups (the TXT and TXT+TAM groups) in a 1 : 1 ratio. Reversal of P-glycoprotein (P-gp) expression, tumor response, progression-free survival, overall survival, and safety were evaluated on an intention-to-treat basis. The median number of cycles of allocated chemotherapy was four in each treatment group (range: 2-6 cycles). The overall response rate and disease control rate in the TXT+TAM group were significantly higher than those in the TXT group (36.7 vs. 15.0% for overall response rate, P=0.007; 85.0 vs. 68.3% for disease control rate, P=0.031). The combination of TXT and TAM could effectively reverse P-gp expression in tumor tissues and provide a significant survival benefit for advanced NSCLC patients compared with TXT alone (11.6 vs. 9.1 months, P=0.030). In addition, in the TXT+TAM group, patients achieving P-gp reversal had a significantly greater median progression-free survival and overall survival than nonreversal patients. Furthermore, the combined therapy showed a safety profile comparable to that of TXT. The combination of TXT and TAM may be an effective and safe treatment option for advanced NSCLC patients who have already developed P-gp-mediated multidrug resistance.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Tamoxifeno/administração & dosagem , Taxoides/administração & dosagemRESUMO
OBJECTIVE: This phase I study was to evaluate safety, maximum tolerated dose, pharmacokinetics and preliminary antitumor activity of chidamide, a novel subtype-selective histone deacetylase (HDAC) inhibitor, in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Ten patients received oral chidamide 20, 25, or 30 mg twice per week continuously with paclitaxel (175 mg/m(2)) and carboplatin [area under the curve (AUC) 5 mg/mL/min] administered in a 3-week cycle. Patients with response and stable disease after four cycles maintained chidamide monotherapy until disease progression or unacceptable toxicity. Blood samples were collected for pharmacokinetic analysis after the first single oral of chidamide and first combination treatment in cycle 1 from all patients. RESULTS: Two dose-limiting toxicities were recorded in the 30 mg cohort, including thrombocytopenia and prolonged neutropenia in the first cycle. Grade 3/4 neutropenia in any cycle was observed in all patients, but was not associated with significant complications. Other grade 3/4 hematologic toxicities included thrombocytopenia and leucopenia. No significant changes were observed in pharmacokinetic parameters for both chidamide and paclitaxel. One patient in the 20 mg cohort had confirmed partial response (PR). Two out of 5 patients with brain metastases had intracranial complete remission after 4-cycle treatment. CONCLUSIONS: Chidamide combined with paclitaxel and carboplatin was generally tolerated without unanticipated toxicities or clinically relevant pharmacokinetic interactions. The recommended dose for chidamide in this combination was established at 20 mg, and a phase II trial is ongoing with this regimen in patients with advanced NSCLC.
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Simotinib is a novel oral small-molecule tyrosine kinase inhibitor that has demonstrated equal or superior antineoplastic activities to erlotinib in preclinical studies. In support of a clinical pharmacokinetic study, a sensitive and accurate liquid chromatography (LC) method with mass spectrometry detection using multiple reaction monitoring (MRM) in positive ion mode was developed and validated for the quantification of simotinib in human plasma. The sample preparation procedure involved a simple protein precipitation with methanol. Erlotinib was used as the internal standard. The optimal chromatographic behavior was achieved on a Zorbax SB-C8 column (2.1 mm × 100 mm, 3.5 µm) using a mixture of 0.1% formic acid with 10 mM ammonium formate/methanol (20:80, v/v) as the mobile phase. The total LC analysis time per injection was 4 min with a flow rate of 0.2 mL/min. The recovery was greater than 90% and no significant matrix effect was observed. The assay was validated over the concentration range of 1-1,000 ng/mL. The intra- and interday precision and accuracy of the quality control samples at low, medium, and high concentration levels showed at most 9.4% relative standard deviation (RSD) and -7.4 to 7.4% relative errors (RE). Assay selectivity, freeze/thaw stability, storage stability, and dilution effects were also assessed. The method is now used to support clinical pharmacokinetic studies in patients with non-small cell lung cancer (NSCLC) after oral administration of simotinib.
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Antineoplásicos/sangue , Quinazolinas/sangue , Compostos de Espiro/sangue , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida/métodos , Monitoramento de Medicamentos/métodos , Humanos , Limite de DetecçãoRESUMO
INTRODUCTION: Treatment options for second-generation (2nd-gen) ALK tyrosine kinase inhibitor (TKI)-resistant patients are limited. We evaluated the safety, pharmacokinetics, and efficacy of ficonalkib (SY-3505), a third-generation (3rd-gen) ALK TKI, in patients with advanced ALK-positive non-small cell lung cancer. METHODS: This first-in-human, phase 1/2 study (Chinese Clinical Trial Registry identifier: ChiCTR1900025619; ClinicalTrials.gov identifier: NCT05257512) had two parts. Phase 1 included a dose-escalation phase (25-800 mg quaque die [QD]) and a dose-expansion phase (500 mg QD or 600 mg QD). Phase 2 enrolled patients treated at recommended phase 2 dose. Primary end points were safety in phase 1 and objective response rate (ORR) in phase 2. RESULTS: Between April 21, 2020, and August 31, 2023, a total of 127 patients with advanced ALK-positive non-small cell lung cancer were enrolled, with 62 in phase 1. Ficonalkib was well absorbed and tolerated, with one dose-limited toxicity event occurring at 800 mg QD. Treatment-related adverse events occurred in 85.5% of patients, with 19.4% experienced greater than or equal to grade 3 events. The ORR was 38.3% (23 of 60, 95% confidence interval [CI]: 26.1%-51.8%) in phase 1, and 600 mg QD was established as recommended phase 2 dose. In phase 2, a total of 65 patients received ficonalkib at 600 mg QD. In total, 88 patients received ficonalkib at 600 mg QD in phase 1/2, and all had received prior 2nd-gen ALK TKI treatment. Furthermore, 90.9% of the patients experienced treatment-related adverse events and 14.8% experienced greater than or equal to grade 3 events. The ORR in efficacy-assessable patients who received ficonalkib at 600 mg QD was 47.5% (38 of 80, 95% CI: 36.2%-59.0%), with an intracranial ORR of 37.5% (12 of 32, 95% CI: 21.1%-56.3%) in these patients with measurable brain lesions at baseline. CONCLUSIONS: Ficonalkib (SY-3505) was well tolerated, with favorable safety profiles and promising efficacy in patients resistant to prior 2nd-gen ALK TKI.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Masculino , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Adulto , Idoso , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/genética , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagemRESUMO
OBJECTIVE: To retrospectively analyze the efficacy and safety of osimertinib combined with anlotinib in the treatment of advanced non-small-cell lung cancer (NSCLC) after drug resistance, and to explore the related factors affecting the efficacy. METHODS: The clinical data of 34 patients with advanced NSCLC who received osimertinib combined with anlotinib as three or more lines of treatment in the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from June 2019 to March 2022 were collected, and the therapeutic efficacy and safety were analyzed. RESULTS: A total of 34 advanced NSCLC patients met the inclusion criteria. The objective response rate was 20.6%, the disease response rate was 88.2%, the median overall survival was 19.0 months, and the median progression-free survival was 6.0 months. The common adverse events were mainly grade 1-2, and only three cases (11.1%) of adverse events were grade 3, including hypertension, proteinuria, and vomiting. No grade 4 or above adverse events were observed. Multivariate Cox regression analysis showed that the Eastern Cooperative Oncology Group Performance Status score and bone metastasis were independent prognostic factors for osimertinib combined with anlotinib as three or more lines of treatment in advanced NSCLC. CONCLUSIONS: Osimertinib combined with anlotinib as three or more lines of treatment in advanced NSCLC was effective and adverse events were tolerable.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Estudos Retrospectivos , Resistência a MedicamentosRESUMO
BACKGROUND: The aim of the study was to explore the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with non-small cell lung cancer (NSCLC). METHODS: Studies that enrolled NSCLC patients treated with two lines of ICIs were included using four databases. The initial line (1L-) and subsequent lines (2L-) of ICIs were defined as 1L-ICI and 2L-ICI, respectively. RESULTS: A total of 17 studies involving 2100 patients were included. The pooled objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and median overall survival (mOS) for 2L-ICIs were 10%, 50%, 3.0 months, and 13.1 months, respectively. The 2L-ICI discontinuation rates caused by toxicities ranged from 0% to 23.5%. Original data were extracted from six studies, covering 89 patients. Patients in whom 1L-ICIs were discontinued following clinical decision (the mPFS of 2L-ICIs was not reach) achieved a more prolonged mPFS of 2L-ICIs than those due to toxicity (5.2 months) and progressive disease (2.1 months) (p < 0.0001). Patients' 1L-PFS for more than 2-years had preferable 2L-ORR (35.0% vs. 9.8%, p = 0.03), 2L-DCR (85.0% vs. 49.0%, p = 0.007), and 2L-mPFS (12.4 vs. 3.0 months, p < 0.0001) than those less than 1-year. Patients administered the same drugs achieved a significantly prolonged mPFS compared with the remaining patients (5.4 vs. 2.3 months, p = 0.0004), and those who did not accept antitumor treatments during the intervals of two lines of ICIs achieved a prolonged mPFS compared to those patients who did accept treatments (7.6 vs. 1.9 months, p < 0.0001). CONCLUSIONS: ICI rechallenge is a useful therapeutic strategy for NSCLC patients, especially suitable for those who achieve long-term tumor remission for more than 2-years under 1L-ICIs.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Inibidores de Checkpoint Imunológico , Bases de Dados Factuais , Intervalo Livre de ProgressãoRESUMO
Objective: This study sought to assess the efficacy and safety of immunotherapy combined with single-agent chemotherapy as a second- or later-line setting for metastatic non-small cell lung cancer (NSCLC) and to provide clinical evidence for this treatment regimen. The predictive value of extracellular vesicle (EV) membrane proteins was explored in patients who underwent this treatment. Methods: Clinical data from patients diagnosed with metastatic NSCLC who received immunotherapy plus single-agent chemotherapy as a second- or later-line setting were retrospectively collected between March 2019 and January 2022. A total of 30 patients met the inclusion criteria, and all were pathologically confirmed to have NSCLC. Short-term efficacy, progression-free survival (PFS), EV markers for response prediction, and adverse events were assessed. Results: Efficacy data were available for all 30 patients and included a partial response in 5 patients, stable disease in 18 patients, and disease progression in 7 patients. The objective response rate was 16.7%, the disease control rate was 76.7%, and the median PFS was 3.2 months. Univariate analysis showed that PFS was not associated with sex, age, smoking status, treatment lines, prior use of immunotherapy, or prior use of antiangiogenic drugs. The EV membrane proteins MET proto-oncogene, receptor tyrosine kinase (c-MET), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor receptor 2 (VEGFR2) at baseline were associated with poor prognosis and correlated with the efficacy of immunotherapy plus chemotherapy. According to the receiver operating characteristics and Kaplan-Meier curve analyses, patients with high c-MET, EGFR, and VEGFR2 expression at baseline had significantly shorter PFS than those with low expression. In addition, VEGFR2 expression was increased after combined immunotherapy in responders, which was decreased in non-responders. The most common grade 2 or higher adverse events were neutropenia, gastrointestinal reactions, and thyroid dysfunction, all of which were tolerated. Conclusions: Immunotherapy plus single-agent chemotherapy as a second- or later-line treatment is safe, effective, and tolerable for metastatic NSCLC. EV markers can be used as predictive markers of efficacy in patients with metastatic NSCLC treated with immunotherapy plus chemotherapy to help monitor treatment efficacy and guide treatment decisions.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular , Intervalo Livre de Doença , Mutação , Receptores ErbB/genética , Imunoterapia/efeitos adversosRESUMO
Introduction: The treatment response to neoadjuvant immunochemotherapy varies among patients with potentially resectable non-small cell lung cancers (NSCLC) and may have severe immune-related adverse effects. We are currently unable to accurately predict therapeutic response. We aimed to develop a radiomics-based nomogram to predict a major pathological response (MPR) of potentially resectable NSCLC to neoadjuvant immunochemotherapy using pretreatment computed tomography (CT) images and clinical characteristics. Methods: A total of 89 eligible participants were included and randomly divided into training (N=64) and validation (N=25) sets. Radiomic features were extracted from tumor volumes of interest in pretreatment CT images. Following data dimension reduction, feature selection, and radiomic signature building, a radiomics-clinical combined nomogram was developed using logistic regression analysis. Results: The radiomics-clinical combined model achieved excellent discriminative performance, with AUCs of 0.84 (95% CI, 0.74-0.93) and 0.81(95% CI, 0.63-0.98) and accuracies of 80% and 80% in the training and validation sets, respectively. Decision curves analysis (DCA) indicated that the radiomics-clinical combined nomogram was clinically valuable. Discussion: The constructed nomogram was able to predict MPR to neoadjuvant immunochemotherapy with a high degree of accuracy and robustness, suggesting that it is a convenient tool for assisting with the individualized management of patients with potentially resectable NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Terapia Neoadjuvante , Nomogramas , ImunoterapiaRESUMO
Current management of small cell lung cancer (SCLC) remains challenging. Effective biomarkers are needed to subdivide patients presenting distinct treatment response and clinical outcomes. An understanding of heterogeneous phenotypes of aneuploid CD31- circulating tumor cells (CTCs) and CD31+ circulating tumor endothelial cells (CTECs) may provide novel insights in the clinical management of SCLC. In the present translational and prospective study, increased cancer metastasis-related cell proliferation and motility, accompanied with up-regulated mesenchymal marker vimentin but down-regulated epithelial marker E-cadherin, were observed in both lentivirus infected SCLC and NSCLC cells overexpressing the stemness marker CD44v6. Aneuploid CTCs and CTECs expressing CD44v6 were longitudinally detected by SE-iFISH in 120 SCLC patients. Positive detection of baseline CD44v6+ CTCs and CD44v6+ CTECs was significantly associated with enhanced hepatic metastasis. Karyotype analysis revealed that chromosome 8 (Chr8) in CD44v6+ CTCs shifted from trisomy 8 towards multiploidy in post-therapeutic patients compared to pre-treatment subjects. Furthermore, the burden of baseline CD44v6+ CTCs (t0) or amid the therapy (t1-2), the ratio of baseline CD31+ CTEC/CD31- CTC (t0), and CTC-WBC clusters (t0) were correlated with treatment response and distant metastases, particularly brain metastasis, in subjects with limited disease (LD-SCLC) but not in those with extensive disease (ED-SCLC). Multivariate survival analysis validated that longitudinally detected CD44v6+/CD31- CTCs was an independent prognostic factor for inferior survival in SCLC patients. Our study provides evidence for the first time that comprehensive analyses of CTCs, CTECs, and their respective CD44v6+ subtypes enable clinical stratification and improve prognostic prediction of SCLC, particularly for potentially curable LD-SCLC.