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1.
Cancer Commun (Lond) ; 39(1): 69, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699150

RESUMO

BACKGROUND: Gefitinib, as the first epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC), has been proved to significantly improve the progression-free survival (PFS) in the first-line setting but suffers from resistance 7-10 months after treatment initiation. Apatinib (YN968D1), a potent vascular endothelial growth factor receptor (VEGFR) 2-TKI, specifically binds to VEGFR2 and leads to anti-angiogenetic and anti-neoplastic effect. Concurrent inhibition of VEGFR and EGFR pathways represents a rational approach to improve treatment responses and delay the onset of treatment resistance in EGFR-mutant NSCLC. This ACTIVE study aims to assess the combination of apatinib and gefitinib as a new treatment approach for EGFR-mutant NSCLC as a first-line setting. METHODS: This multicenter, randomized, double-blind, placebo-controlled phase III study (NCT02824458) has been designed to assess the efficacy and safety of apatinib or placebo combined with gefitinib as a first-line treatment for patients with EGFR-mutant advanced NSCLC. A total of 310 patients with EGFR-mutation (19del or 21L858R), pathological stage IIIB to IV non-squamous NSCLC were to be enrolled. The primary endpoint is investigator assessment of PFS, and the secondary endpoints include independent radiological central (IRC)-confirmed PFS, overall survival (OS), objective response rate (ORR), disease control rate (DCR), time to progressive disease (TTPD), duration of response (DoR), quality of life (QoL) and safety. The patients are randomized in a 1:1 ratio to receive gefitinib (250 mg, p.o. q.d.) plus apatinib (500 mg, p.o. q.d.) or gefitinib plus placebo, given until disease progression or intolerable adverse events. Exploratory biomarker analysis will be performed. This study is being conducted across China and comprises of 30 participating centers. Enrollment commenced in August 2017 and finished in December 2018, most of the patients are in the follow-up period. ANTICIPATED OUTCOMES AND SIGNIFICANCE: The present study will be the first to evaluate the efficacy and safety profile of the combination of apatinib plus gefitinib as a first-line therapy for patients with EGFR-positive advanced non-squamous NSCLC. Importantly, this trial will provide comprehensive evidence on the treatment of EGFR-TKIs combined with antiangiogenic therapy. Trial registration Clinicaltrials.gov NCT02824458. Registered 23 June 2016.

2.
Lung Cancer ; 137: 100-107, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31568886

RESUMO

OBJECTIVES: Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare subtype of primary lung cancer. Due to the lack of prospective studies, the optimal first-line chemotherapy regimens and survival outcomes remain unclear. MATERIALS AND METHODS: This real-world, retrospective study enrolled consecutive patients with unresectable pulmonary LELC. The survival outcomes, prognosis, and comparative efficacy of different chemotherapy regimens were investigated. RESULTS: In total, 127 patients were included in the analyses. The first-line chemotherapy regimens included gemcitabine plus platinum (GP, n = 19 [15.0%]), taxanes plus platinum (TP, n = 70 [55.1%]) and pemetrexed plus platinum (AP, n = 38 [30.0%]). 25 (19.7%) patients underwent palliative thoracic radiotherapy. 60 (47.2%) patients had detectable baseline Epstein-Barr virus (EBV) DNA. For the entire cohort, objective response was obtained in 41 patients (32.3%). Median progression-free survival (PFS) and overall survival (OS) were 7.7 months (95% CI, 6.6-8.8) and 36.7 months (95% CI, 30.9-42.5), respectively. Among the three chemotherapy regimens, GP achieved the highest response rate (GP, 63.2% vs. TP, 30.0% vs. AP, 21.1%; p = 0.005). Median PFS in the GP group (8.8 months) was also significantly longer than that in the TP group (7.9 months) and AP group (6.4 months) (p = 0.031). In the multivariate model, cycles of first-line chemotherapy (p < 0.001), palliative thoracic radiotherapy (p < 0.001), and chemotherapy regimens (p = 0.031) remained independent prognostic factors for PFS; while cycles of first-line chemotherapy (p = 0.002), baseline EBV DNA (p = 0.033) and palliative thoracic radiotherapy (p = 0.041) were significantly associated with OS. CONCLUSION: Gemcitabine-based chemotherapy and palliative thoracic radiotherapy are active in pulmonary LELC. These data provide added evidence for the similarity between pulmonary LELC and nasopharyngeal carcinoma in endemic area. Randomized controlled studies are needed to further define the standard-of-care for patients with advanced pulmonary LELC.

4.
Nat Commun ; 10(1): 3108, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311932

RESUMO

Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare and distinct subtype of primary lung cancer characterized by Epstein-Barr virus (EBV) infection. Herein, we reported the mutational landscape of pulmonary LELC using whole-exome sequencing, targeted deep sequencing and single-nucleotide polymorphism arrays. We identify a low degree of somatic mutation but widespread existence of copy number variations. We reveal predominant signature 2 mutations and frequent loss of type I interferon genes that are involved in the host-virus counteraction. Integrated analysis shows enrichment of genetic lesions affecting several critical pathways, including NF-κB, JAK/STAT, and cell cycle. Notably, multi-dimensional comparison unveils that pulmonary LELC resemble NPC but are clearly different from other lung cancers, natural killer/T-cell lymphoma or EBV-related gastric cancer in terms of genetic features. In all, our study illustrates a distinct genomic landscape of pulmonary LELC and provides a road map to facilitate genome-guided personalized treatment.

5.
Int J Epidemiol ; 48(3): 743-750, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31219597

RESUMO

BACKGROUND: We aimed to investigate whether more years spent in education are causally associated with a lower risk of lung cancer, through a two-sample Mendelian randomization study. METHODS: The main analysis used publicly available genetic summary data from two large consortia [International Lung Cancer Consortium (ILCCO) and Social Science Genetic Association Consortium (SSGAC)]. Genetic variants used as instrumental variables for years of education were derived from SSGAC. Finally, genetic data from three additional consortia (TAG, GLGC, GIANT) were analysed to investigate whether education could causally alter common lung cancer risk factors. The exposure was the genetic predisposition to higher levels of education, measured by 73 single nucleotide polymorphisms from SSGAC. The primary outcome was the risk of lung cancer (11 348 events in ILCCO). Secondary outcomes based on different histological subtypes were also examined. Analyses were performed using the package TwoSampleMR in R. RESULTS: Genetic predisposition towards 3.6 years of additional education was associated with a 52% lower risk of lung cancer (odds ratio 0.48, 95% confidence interval 0.34 to 0.66; P = 1.02 × 10 - 5). Sensitivity analyses were consistent with a causal interpretation in which major bias from genetic pleiotropy was unlikely. The Mendelian randomization assumptions did not seem to be violated. Genetic predisposition towards longer education was additionally associated with less smoking, lower body mass index and a favourable blood lipid profile. CONCLUSIONS: Our study indicated that low education is a causal risk factor in the development of lung cancer. Further work is needed to elucidate the potential mechanisms.

6.
BMC Cancer ; 19(1): 595, 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31208370

RESUMO

BACKGROUND: Epidermal growth factor receptor exon 20 insertion (EGFRex20ins) mutations represent approximately 4-12% of EGFR mutations and are generally refractory to the 1st and 2nd generation EGFR tyrosine kinase inhibitors (TKIs). Development of effective therapies for patients with EGFRex20ins mutant non-small-cell lung carcinoma (NSCLC) represents a great unmet need. Preclinical models have shown that osimertinib is active in NSCLC harboring EGFRex20ins, while the antitumor activity of osimertinib remains to be evaluated in patients with EGFRex20ins mutations. METHODS: Tumor genotyping was performed in 2316 Chinese NSCLC cases with targeted next generation sequencing (NGS) covering the whole exons of EGFR gene. The frequency and genetic characteristics of EGFRexon20ins mutations were analyzed. Furthermore, six patients with specific EGFRexon20ins mutations and receiving osimertinib 80 mg once daily were retrospectively included to assess the antitumor activity and safety of monotherapy osimertinib. RESULTS: EGFRex20ins mutations were identified in 4.8% (53/1095) of EGFR mutant NSCLC and 2.3% (53/2316) of all NSCLC cases. The most frequently identified EGFRexon20ins is A767_V769dup (17/53,32.1%). We found that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Four patients with osimertinib therapy achieved partial response and the rest stable disease. Median progression free survival (PFS) was 6.2 months (95% confidence interval 5.0-12.9 months; range 4.9-14.6 months). The most common adverse events (AEs) were diarrhea (2/6), pruritis (2/6), stomatitis (1/6) and nausea (1/6). No grade 3 or more AEs were documented. CONCLUSIONS: This study revealed that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Furthermore, our study firstly demonstrated promising antitumor activity of osimertinib in certain EGFRex20ins mutant advanced NSCLC patients, indicating that osimertinib treatment for EGFRex20ins positive patients deserves further study.

9.
Future Oncol ; 15(21): 2479-2488, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31238738

RESUMO

Aim: Stage I small-cell lung cancer (SCLC) is a potentially curable disease that needs timely and multidisciplinary management. The aim of this study was to evaluate the probability of cause-specific mortality for patients with stage I SCLC. Material & methods: We identified patients in the SEER database and constructed a proportional subdistribution hazard model to evaluate cancer-specific mortality. A nomogram was built based on Fine and Gray competing risk regression model. Results: A total of 864 stage I SCLC patients were identified. The 5-year cumulative incidence of SCLC-specific mortality was 56.2%, while that for other causes of death was 17.3%. The c-index for the prognostic prediction model was 0.66. Besides, the nomogram was well calibrated. Conclusion: Our nomogram might serve as a reference for clinicians when evaluating the prognosis of stage I SCLC.

10.
Oncologist ; 24(7): 891-e431, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31048330

RESUMO

LESSONS LEARNED: Nivolumab treatment at doses of 3 mg/kg once every 2 weeks (Q2W), 240 mg Q2W, and 360 mg once every 3 weeks was well tolerated in the Chinese population, with no new safety signals identified.Comparison of intensive pharmacokinetic profiles of nivolumab at 3 mg/kg Q2W in Chinese versus global populations revealed no ethnic differences of nivolumab treatment.Nivolumab shows promising preliminary antitumor activity in nasopharyngeal carcinoma. BACKGROUND: This phase I/II study investigated the safety and pharmacokinetics (PK) of nivolumab (anti-programmed cell death-1 monoclonal antibody) in Chinese patients with nasopharyngeal carcinoma (NPC) and other solid tumors. METHODS: A dose evaluation phase (3 mg/kg once every 2 weeks [Q2W]) was followed by a cohort expansion phase (3 mg/kg Q2W or flat doses of 240 mg Q2W or 360 mg once every 3 weeks). RESULTS: In the dose evaluation phase, 8/8 patients completed one cycle with no dose-limiting toxicities. At data cutoff, 46/51 patients were evaluable for safety (all cohorts). Treatment-related adverse events (TRAEs) occurred in 35 (76%) patients and were primarily grade 1-2; one patient (3 mg/kg Q2W) discontinued because of study drug toxicity. Intensive PK profiles at 3 mg/kg, 240 mg, and 360 mg were well characterized at single and multiple doses of nivolumab. An objective response was determined in six (6/46) patients, four (4/32) of whom had NPC tumors. CONCLUSION: Nivolumab monotherapy at 3 mg/kg and flat doses of 240 mg and 360 mg were well tolerated in this Chinese patient population, with PK profiles at 3 mg/kg being similar to those of global patients. Preliminary efficacy results showed promising antitumor activity of nivolumab in advanced NPC.

11.
J Immunother Cancer ; 7(1): 120, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053172

RESUMO

Pembrolizumab monotherapy has become the preferred treatment for patients with advanced non-small cell lung carcinoma (NSCLC) and a programmed cell death-ligand 1 (PD-L1) tumor proportion score (TPS) of at least 50%. However, little is known about the value of adding chemotherapy to pembrolizumab in this setting. Therefore, we performed an indirect comparison for pembrolizumab plus chemotherapy versus pembrolizumab, using the frequentist methods. The primary outcomes were overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Data were retrieved from randomized trials comparing pembrolizumab plus chemotherapy or pembrolizumab monotherapy against chemotherapy. Five trials involving 1289 patients were included. Direct meta-analysis showed that both pembrolizumab plus chemotherapy (ORR: relative risk (RR) 2.16; PFS: hazard ratio (HR) 0.36; OS: HR 0.51) and pembrolizumab alone (ORR: RR 1.33; PFS: HR, 0.65; OS: HR 0.67) improved clinical outcomes compared with chemotherapy. Indirect comparison showed that pembrolizumab plus chemotherapy was superior to pembrolizumab alone, in terms of ORR (RR 1.62, 1.18-2.23) and PFS (HR 0.55, 0.32-0.97). A trend towards improved OS was also observed (HR 0.76, 0.51-1.14). In conclusion, the addition of chemotherapy to pembrolizumab further improves the outcomes of patients with advanced NSCLC and a PD-L1 TPS of at least 50%.

12.
Clin Cancer Res ; 25(16): 5015-5026, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31085721

RESUMO

PURPOSE: Immune checkpoint inhibitors (ICI) have revolutionized cancer management. However, molecular determinants of response to ICIs remain incompletely understood. EXPERIMENTAL DESIGN: We performed genomic profiling of 78 patients with non-small cell lung cancer (NSCLC) who underwent anti-PD-(L)1 therapies by both whole-exome and targeted next-generation sequencing (a 422-cancer-gene panel) to explore the predictive biomarkers of ICI response. Tumor mutation burden (TMB), and specific somatic mutations and copy-number alterations (CNA) were evaluated for their associations with immunotherapy response. RESULTS: We confirmed that high TMB was associated with improved clinical outcomes, and TMB quantified by gene panel strongly correlated with WES results (Spearman's ρ = 0.81). Compared with wild-type, patients with FAT1 mutations had higher durable clinical benefit (DCB, 71.4% vs. 22.7%, P = 0.01) and objective response rates (ORR, 57.1% vs. 15.2%, P = 0.02). On the other hand, patients with activating mutations in EGFR/ERBB2 had reduced median progression-free survival (mPFS) compared with others [51.0 vs. 70.5 days, P = 0.0037, HR, 2.47; 95% confidence interval (CI), 1.32-4.62]. In addition, copy-number loss in specific chromosome 3p segments containing the tumor-suppressor ITGA9 and several chemokine receptor pathway genes, were highly predictive of poor clinical outcome (survival rates at 6 months, 0% vs. 31%, P = 0.012, HR, 2.08; 95% CI, 1.09-4.00). Our findings were further validated in two independently published datasets comprising multiple cancer types. CONCLUSIONS: We identified novel genomic biomarkers that were predictive of response to anti-PD-(L)1 therapies. Our findings suggest that comprehensive profiling of TMB and the aforementioned molecular markers could result in greater predictive power of response to ICI therapies in NSCLC.

13.
J Immunother Cancer ; 7(1): 98, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30944026

RESUMO

High-level tissue tumor mutational burden (tTMB) or blood TMB (bTMB) are associated with better response of immunotherapy in non-small cell lung cancer (NSCLC) patients. However, the correlations of single-region tTMB, multi-region tTMB and bTMB remain to be determined. Moreover, whether intratumor heterogeneity (ITH) has impact on TMB should be clarified. We collected multi-region tumor tissues with matched blood from 32 operative NSCLC and evaluated single-region tTMB, multi-region tTMB and bTMB through a 1021-gene panel sequencing. TMB of > 9 mutations/Mb was classified as high. Besides, we used tTMB fold-change to evaluate the influence of the enrolled region number on tTMB. We found both of single-region tTMB and bTMB showed strong correlations with multi-region tTMB, while the former correlated better (Pearson r = 0.94, P = 2E-84; Pearson r = 0.47, P = 0.0067). It showed extremely high specificity (100%) but low sensitivity (43%) when using bTMB to define TMB-high patients, while most false-negative predictions were in early-stage patients. Compared to single region, we found significantly enhanced tTMB fold-change if taking multi-regions for consideration. However, it showed insignificant tTMB fold-change increase if the included regions' number more than three. Moreover, ITH-high patients had significantly higher tTMB fold-change compared with ITH-low patients (2.32 vs. 1.02, P = 8.879e-05). The conversion rate of tTMB level (tTMB-low to tTMB-high) was numerically higher in ITH-high group than that in ITH-low group (16.67% vs. 3.84%). In summary, single-region tTMB has stronger correlation with multi-region tTMB compared with bTMB. ITH has an impact on tTMB, especially in high-level ITH patients.

14.
Cancer Med ; 8(4): 1817-1825, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30741477

RESUMO

BACKGROUND: Observational studies have shown that excessive dietary fat may be associated with lung carcinogenesis. However, findings from previous studies are inconsistent and it remains unclear whether docosapentaenoic acid (DPA), a kind of polyunsaturated fatty acid, is linked to the risk of lung cancer. The aim of this study is to investigate the causal effect of DPA on lung cancer with Mendelian randomization (MR) method. METHODS: With a two-sample MR approach, we analyzed the summary data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE, 8866 individuals of European ancestry) Consortium and International Lung Cancer Consortium (ILCCO, 11 348 lung cancer cases and 15 861 controls; European ancestry) to assess the possible causal relationship of DPA on the risk of lung cancer. RESULTS: Our results indicated that genetically predicted higher DPA level has a positive association with lung cancer, where 1% higher DPA was associated with a 2.01-fold risk of lung cancer (odds ratio [OR]: 2.01, 95% CI = 1.34-3.01; P = 7.40 × 10-4 ). Additionally, lung cancer was not a causal factor for DPA. The results of MR-Egger regression analysis showed that there was no evidence for the presence of directional horizontal pleiotropy. CONCLUSIONS: Genetically elevated DPA is positively associated with risk of lung cancer, and more work is needed to investigate the potential mechanisms.

15.
Mol Cancer ; 18(1): 7, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30626401

RESUMO

Understanding of intratumor heterogeneity (ITH) among different non-small cell lung cancer (NSCLC) subtypes is necessary. Whether circulating tumor DNA (ctDNA) profile could represent these ITH is still an open question. We performed 181 multi-region tumor tissues sequencing and matched ctDNA sequencing from 32 operative NSCLC to compare ITH among different NSCLC subtypes, including EGFR-mutant lung adenocarcinoma (LUAD), KRAS-mutant LUAD, EGFR&KRAS-wild-type LUAD, and lung squamous cell carcinoma (LUSC), and examine potential value of ctDNA for ITH analysis. ITH is evaluated by ITH index (ITHi). If the somatic genetic alteration is shared by all the tissue regions, it is defined as trunk mutation. Otherwise, it is called branch mutation. The ITHi will be higher, if the tumor has less trunk mutations. We found EGFR-mutant LUAD showed significantly higher ITHi than KRAS-mutant LUAD/wild-type LUAD (P = 0.03) and numerically higher ITH than LUSC. For trunk mutations, driver mutations were identified at a higher proportion than passenger mutations (60% vs. 40%, P = 0.0023) in overall, especially in EGFR-mutant LUAD (86% vs. 14%, P = 0.0004), while it was opposite in KRAS-mutant LUAD (40% vs. 60%, P = 0.18). For branch mutations, the proportions of driver mutations and passenger mutations were similar for each NSCLC subtype. ctDNA analysis showed unsatisfactory detections of tumor-derived trunk and branch mutations (43% vs. 23%, P = 4.53e-6) among all NSCLC subtypes. In summary, EGFR-mutant LUAD has the highest ITH than other NSCLC subtypes, offering further understanding of tumorigenesis mechanisms among different NSCLC subtypes. Besides, ctDNA maybe not an appropriate method to reflect ITH.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , DNA Tumoral Circulante/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , DNA de Neoplasias/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos
16.
J Immunother Cancer ; 6(1): 155, 2018 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-30577837

RESUMO

BACKGROUND: Immune-checkpoint inhibitors plus chemotherapy are emerging as effective first-line treatment in advanced non-small-cell lung carcinoma (NSCLC), but little is known about the magnitude of benefits and potential clinical predictors. METHODS: We performed a meta-analysis of randomized trials that compared PD-1/PD-L1 inhibitor plus chemotherapy with chemotherapy in first line of treatment for advanced NSCLC. The outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and treatment-related adverse events (AEs). A fixed-effect or random-effects model was adopted depending on between-study heterogeneity. RESULTS: Six trials involving 3144 patients were included. PD-1/PD-L1 inhibitor plus chemotherapy was significantly associated with improvement of PFS (hazards ratio [HR], 0.62; 95% CI 0.57-0.67; P < .001), OS (HR, 0.68; 95% CI 0.53-0.87; P = .002) and ORR (relative ratio [RR], 1.56; 95% CI 1.29-1.89; P < .001), irrespective of PD-L1 expression level. The significant predictor(s) for treatment benefit with combination therapy versus chemotherapy alone were PD-L1 expression level for PFS (P < .001); types of checkpoint inhibitor for ORR (P < .001); histology (P = .025), age (P = .038), gender (P < .001), and types of checkpoint inhibitor (P < .001) for OS. In safety analyses, PD-1/PD-L1 inhibitor plus chemotherapy had significantly higher incidence of adverse events (AEs) of grade 3 or higher (RR, 1.14; P = .007), AEs leading to treatment discontinuation (RR, 1.29; P = .022), serious AEs (RR 1.70; P = .006), immune mediated AEs of any grade (RR, 2.37; P < .001), and immune mediated AEs of grade 3 or higher (RR, 3.71; P < .001). CONCLUSIONS: PD-1/PD-L1 inhibitor plus chemotherapy, compared with chemotherapy, is associated with significantly improved PFS, ORR, and OS in first-line therapy in NSCLC, at the expense of increased treatment-related AEs.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Ensaios Clínicos como Assunto , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Resultado do Tratamento
17.
Int J Cancer ; 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30430561

RESUMO

The advent of immunotherapy leads to greater availability of effective subsequent treatments and extended survival in previously treated advanced non-small cell lung cancer (NSCLC), complicating the evaluation of overall survival (OS) in second-line NSCLC trials. Here, we aimed to assess the surrogacy of progression-free survival (PFS) and milestone survival for OS in second-line NSCLC trials investigating chemotherapy, targeted therapy and immunotherapy, respectively. We systemically searched for active-controlled, second-line NSCLC trials. The milestone time point was set at one-year based on pre-analysis. A two-stage meta-analytic validation model was adopted to assess associations between surrogate endpoint (SE) and OS and associations between treatment effects on SE and OS. Treatment effects on SE and OS were expressed as PFS hazard ratios (HRPFS ), 1yr-milestone ratio (Ratio1y-SUR ) and HROS . Subgroup analyses stratified by treatment types and trial publication years evaluated the surrogacy in different clinical contexts. The study included 50 trials with 22,804 patients. One-year survival strongly correlated with OS (R2 [95% confidence interval]: one-year survival -median OS=0.707 [0.704-0.708]; Ratio1y-SUR -HROS =0.829 [0.828-0.831]). No correlation was established between PFS and OS (median PFS-median OS=0.100 [0.098-0.101]; HRPFS -HROS =0.064 [0.059-0.069]), except in immunotherapy subgroup (HRPFS -HROS =0.835 [0.791-0.918]). In subgroup analyses, surrogacy of one-year survival persisted in different clinical contexts, and the disassociation between PFS and OS persisted in recent trials. One-year milestone survival showed strong surrogacy for OS in second-line NSCLC trials. Although no association was identified between PFS and OS, the strong HRPFS -HROS correlation in immunotherapy trials indicates the potential of PFS as a SE in NSCLC trials involving immunotherapies. This article is protected by copyright. All rights reserved.

18.
Lancet Oncol ; 19(10): 1338-1350, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30213452

RESUMO

BACKGROUND: Platinum-based doublet chemotherapy regimens, preferentially gemcitabine plus cisplatin, are generally considered the first-line standard of care for patients with recurrent or metastatic nasopharyngeal carcinoma. However, no consensus has been reached regarding treatment following progression after first-line therapy. Camrelizumab (SHR-1210) is a humanised anti-programmed death-1 (anti PD-1) antibody. We present safety and preliminary antitumour activity of camrelizumab alone as second-line therapy in patients with recurrent or metastatic nasopharyngeal carcinoma and combined with gemcitabine and cisplatin as first-line therapy in this patient population. METHODS: We report the results from two single-arm, phase 1 trials. Both trials included patients aged 18-70 years with histologically or cytologically confirmed nasopharyngeal carcinoma and confirmed metastatic disease or locoreginal recurrence, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients who received at least one previous line of treatment were enrolled at five academic hospitals in China into the dose-escalation and expansion trial to receive camrelizumab monotherapy intravenously at escalating doses of 1 mg/kg, 3 mg/kg, and 10 mg/kg, and a bridging dose of 200 mg per dose once every 2 weeks (monotherapy trial). Treatment-naive patients were enrolled from a single centre in China to receive six cycles of camrelizumab 200 mg (day 1), gemcitabine 1 g/m2 (days 1 and 8), and cisplatin 80 mg/m2 (day 1) every 3 weeks followed by camrelizumab 200 mg maintenance once every 3 weeks (combination trial). The primary endpoint of both trials was the safety and tolerability of the study treatment. Analyses were done per protocol. Both trials are registered with ClinicalTrials.gov, number NCT02721589 (camrelizumab monotherapy trial) and NCT03121716 (camrelizumab combination trial). Both trials are ongoing, but are no longer enrolling patients. FINDINGS: In the camrelizumab monotherapy trial, between March 31, 2016, and Sept 20, 2017, 121 patients were assessed for eligibility, of whom 93 patients were enrolled across the dose-escalation and expansion cohorts and received at least one dose of camrelizumab (safety population). 15 (16%) of 93 patients had treatment-related adverse events of grade 3 or 4, the most common of which were elevated conjugated bilirubin concentration (three [3%] of 93 patients), stomatitis, anaemia, and increased concentrations of aspartate aminotransferase, alanine aminotransferase, and total bilirubin, each of which occurred in two (2%) patients. Eight (9%) patients had a treatment-related serious adverse event. No dose-limiting toxic effects were observed during the dose-escalation phase. 31 (34%; 95% CI 24-44) of 91 evaluable patients on camrelizumab monotherapy had an overall response with a median follow-up of 9·9 months (IQR 8·1-11·7). In the camrelizumab combination trial, between April 18, 2017, and Aug 15, 2017, 24 patients were assessed for eligibility, of whom 23 patients were enrolled and treated (safety population). 20 (87%) of 23 patients had grade 3 or 4 treatment-related adverse events: neutropenia (13 [57%] of 23 patients), anaemia (11 [48%] patients), leucopenia (11 [48%] patients), thrombocytopenia (seven [30%] patients), oedema (two [9%] patients), hyponatraemia (two [9%] patients), hypochloraemia (one [4%] patients), and rash (one [4%] patient). Two patients had treatment-related serious adverse events. No treatment-related deaths occurred in these trials. 20 (91% [95% CI 72-97]) of 22 evaluable patients had an overall response with a median follow-up time of 10·2 months (IQR 9·7-10·8). INTERPRETATION: Camrelizumab is a well tolerated, potential treatment option for patients with recurrent or metastatic nasopharyngeal carcinoma. The combination of camrelizumab plus gemcitabine and cisplatin has a manageable toxicity profile and promising preliminary antitumour activity for this disease in treatment-naive patients. Randomised controlled trials are needed to further establish the role of immune checkpoint inhibition for nasopharyngeal carcinomas. FUNDING: Hengrui Medicine Co, Chinese National Natural Science Foundation project, Science and Technology Program of Guangdong, Pearl River Nova Program of Guangzhou.

19.
Future Oncol ; 14(19): 1933-1941, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30019968

RESUMO

AIM: We compare neurokinin-1 receptor antagonist (NK-1RA)-based triple regimen and conventional duplex regimen for antiemetic efficacy for patients with moderately emetogenic chemotherapy (MEC). Patients & methods: Pooled risk ratios (RRs) were used to evaluate the complete response and no significant nausea. The results were separately analyzed for pure MEC regimens, carboplatin-based regimens and oxaliplatin-based regimens. RESULTS: Ten trials focused on MEC involving 2928 cancer patients using NK-1RA triple regimens or conventional duplex regimen were included. NK-1RA-based triple regimen showed significant better complete responses in overall (RR: 1.14; 95% CI: 1.05-1.24), acute (RR: 1.02; 95% CI: 1.00-1.04) and delayed (RR: 1.13; 95% CI: 1.04-1.23) phase compared with duplex regimen in patients with MEC. Similar results were found for no significant nausea. Subgroup analyses showed that triple regimen showed superior antiemetic efficacy significantly in patients with carboplatin-based chemotherapy, instead of oxaliplatin-based chemotherapy. CONCLUSION: NK-1RA is recommended to use in carboplatin-based chemotherapy, not oxaliplatin-based chemotherapy.


Assuntos
Náusea/tratamento farmacológico , Neoplasias/tratamento farmacológico , Receptores da Neurocinina-1/genética , Vômito/tratamento farmacológico , Adulto , Antieméticos/uso terapêutico , Carboplatina/efeitos adversos , Feminino , Humanos , Quimioterapia de Indução/efeitos adversos , Náusea/induzido quimicamente , Náusea/genética , Náusea/patologia , Neoplasias/complicações , Neoplasias/patologia , Antagonistas do Receptor de Neuroquinina-1/uso terapêutico , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Vômito/induzido quimicamente , Vômito/genética , Vômito/patologia
20.
Cancer Med ; 7(8): 4146-4155, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29971970

RESUMO

Lung cancer patients have an increased risk for committing suicide. But no comprehensive study about the suicide issues among non-small-cell lung cancer (NSCLC) patients has been published. We aimed to estimate the trend of suicide rate and identify the high-risk group of NSCLC patients. Patients diagnosed with primary NSCLC were identified from Surveillance, Epidemiology, and End Results (SEER) database (1973-2013). Suicide mortality rate (SMR) were calculated. Multivariable logistic regression was employed to find out independent risk factors for suicide. Among 495 889 NSCLC patients, 694 (0.14%) of them died from suicide. The suicide mortality rates have significantly decreased (before 1993: 0.21%, 1994-2003: 0.16%, after 2004: 0.09%, P < .001). Male (OR 6.22, 95% CI: 4.96-7.98, P < .001), white (OR 3.89, 95% CI: 2.66-5.97, P < .001), being unmarried (OR 1.43, 95% CI: 1.22-1.67, P < .001), the elderly (60-74 vs <60: OR 1.24, 95% CI: 1.03-1.50, P = .024, >75 vs <60: OR 1.31, 95% CI: 1.05-1.63, P = .018) were independently associated with higher risk of suicide mortality. Surgery (OR: 1.44, 95% CI: 1.19-1.73, P < .001) was also relative with higher risk of suicide. Our study observed significant decrease in suicide mortality among NSCLC patients in US over past decades. Older age, male sex, unmarried status, and surgery were risk factors of committing suicide. Clinicians should be aware of these high-risk groups.

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