Background China is the world's largest consumer of tobacco and has a large smoking-related chronic disease burden. In this nationwide study, we aimed to evaluate smoking prevalence and its implication on chronic diseases in the Chinese population. Methods We collected data from serial cross-sectional National Health Service Surveys done in China in 2003, 2008, and 2013. These surveys cover all 31 provinces, autonomous regions, and municipalities in mainland China, and use multistage stratified cluster sampling. We divided mainland China into east, central, and west regions and then sampled counties from each region stratified by urban and rural areas. All respondents aged 15 years or older in the selected households were eligible. We analysed the variation in smoking prevalence from 2003 to 2013, further identified risk factors for smoking, and assessed the association between smoking and chronic diseases by using multiple logistic regression. Findings The number of individuals interviewed and involved in the study was 153 450 in 2003, 145 223 in 2008, and 229 676 in 2013. The standardised smoking prevalence in China was consistently high, with a proportion of current smokers of 26.0% (95% CI 25.8-26.2) in 2003, 24.9% (24.8-25.1) in 2008, and 25.2% (25.1-25.4) in 2013 (p value for trend 0.5062). For men, prevalence was 48.4% (48.1-48.7) in 2003, 47.0% (46.6-47.4) in 2008, and 47.2% (46.9-47.5) in 2013. For women, prevalence was 3.1% (3.0-3.2) in 2003, 2.3% (2.2-2.5) in 2008, and 2.7% (2.6-2.8) in 2013. Smoking prevalence varied in different regions, and we identified four major patterns. While a consistently high proportion of Chinese men smoked, the standardised smoking prevalence in women younger than 40 years increased from 1.0% in 2003 to 1.6% in 2013. Moreover, the smoking prevalence among adolescent smokers aged 15-24 years increased from 8.3% in 2003 to 12.5% in 2013. Alcohol consumption was closely linked to smoking in adolescents (odds ratio 7.5, 95% CI 6.9-8.1). Risk factors for adolescent smoking were having older family members who smoke (1.9, 1.8-1.9) and low level education (1.3, 1.2-1.4). Increased risks of chronic diseases were related to smoking (1.1, 1.0-1.1), with higher risks related to early smoking initiation (1.1, 1.0-1.1) and long-term smoking (1.2, 1.2-1.3). Interpretation The implementation of tobacco control policies in China since the signing of the WHO Framework Convention on Tobacco Control in 2003 has not been effective in reducing smoking prevalence. Smoking prevalence among adolescents of both genders has increased substantially and there has been a steady increase among young women. More practical and effective policies targeting adolescents and women are urgently needed. Action is needed to prevent the large and growing smoking-related chronic disease burden further increasing as China's population ages. Copyright (c) 2018 Elsevier Ltd. All rights reserved.
Background Genetic variation has an important role in the development of non-small-cell lung cancer (NSCLC). However, genetic factors for lung cancer have not been fully identified, especially in Chinese populations, which limits the use of existing polygenic risk scores (PRS) to identify subpopulations at high risk of lung cancer for prevention. We therefore aimed to identify novel loci associated with NSCLC risk, and generate a PRS and evaluate its utility and effectiveness in the prediction of lung cancer risk in Chinese populations. Methods To systematically identify genetic variants for NSCLC risk, we newly genotyped 19 546 samples from Chinese NSCLC cases and controls from the Nanjing Medical University Global Screening Array Project and did a metaanalysis of genome-wide association studies (GWASs) of 27 120 individuals with NSCLC and 27 355 without NSCLC (13 327 cases and 13 328 controls of Chinese descent as well as 13 793 cases and 14 027 controls of European descent). We then built a PRS for Chinese populations from all reported single-nucleotide polymorphisms that have been reported to be associated with lung cancer risk at genome-wide significance level. We evaluated the utility and effectiveness of the generated PRS in predicting subpopulations at high-risk of lung cancer in an independent prospective cohort of 95 408 individuals from the China Kadoorie Biobank (CKB) with more than 10 years' follow-up. Findings We identified 19 susceptibility loci to be significantly associated with NSCLC risk at p <= 5.0 x 10(-8), including six novel loci. When applied to the CKB cohort, the PRS of the risk loci successfully predicted lung cancer incident cases in a dose-response manner in participants at a high genetic risk (top 10%) than those at a low genetic risk (bottom 10%; adjusted hazard ratio 1.96, 95% CI 1.53-2.51; p(trend) = 2.02 x 10(-9)). Specially, we observed consistently separated curves of lung cancer events in individuals at low, intermediate, and high genetic risk, respectively, and PRS was an independent effective risk stratification indicator beyond age and smoking pack-years. Interpretation We have shown for the first time that GWAS-derived PRS can be effectively used in discriminating subpopulations at high risk of lung cancer, who might benefit from a practically feasible PRS-based lung cancer screening programme for precision prevention in Chinese populations.
Background Anaplastic lymphoma kinase-positive (ALK-positive) disease occurs in approximately 5% of all patients with non-small-cell lung cancer, with a similar incidence reported in Asian patients. This study is the first phase 3 randomised trial recruiting only Asian patients to compare alectinib with crizotinib as a first-line treatment for ALK-positive non-small-cell lung cancer with 600 mg of alectinib twice per day. This study assessed consistency of the progression-free survival benefit with the global phase 3 ALEX study. Methods In this randomised, open-label, phase 3 study done at 21 investigational sites in China, South Korea, and Thailand, Asian patients, aged 18 years or older, with ALK-positive non-small-cell lung cancer were randomly assigned (2: 1) to twice-daily oral alectinib (600 mg) or crizotinib (250 mg). Patients were randomly assigned via a block-stratified (block size three) randomisation procedure, done centrally via an interactive voice or web response system, with stratification by Eastern Cooperative Oncology Group performance status and baseline CNS metastases. Clinical staff and the funder's drug safety and medical monitoring staff had access to treatment assignments. The independent review committee was masked to treatment assignment, and funder personnel did not have access to efficacy and safety summaries by treatment group, before the formal reporting of study results. Patients with asymptomatic CNS metastases were permitted. The primary endpoint was investigator-assessed progression-free survival. The primary analysis population for efficacy was the intention-to-treat population, defined as all randomly assigned patients. The primary analysis population for safety was defined as all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02838420. Findings Between Aug 3, 2016, and May 16, 2017, 187 patients were randomly assigned to treatment: 125 to alectinib and 62 to crizotinib. Median follow-up was 16.2 months (IQR 13.7-17.6) in the alectinib group, and 15.0 months (12.5-17.3) in the crizotinib group. Investigator-assessed progression-free survival was significantly prolonged with alectinib versus crizotinib (hazard ratio [HR] 0.22, 95% CI 0.13-0.38; p< 0.0001; median progression-free survival not estimable vs 11.1 months). Independent review committee-assessed progression-free survival was also significantly longer in the alectinib group compared with the crizotinib group (HR 0.37, 0.22-0.61; p< 0.0001). The proportion of patients who achieved an objective response was 114 (91%) of 125 with alectinib, and 48 (77%) of 62 with crizotinib, with a longer duration of response for alectinib than crizotinib (HR 0.22, 95% CI 0.12-0.40; p< 0.0001). Time to CNS progression (cause-specific HR 0.14) and the percentage of patients who achieved a CNS objective response with measurable or non-measurable baseline CNS lesions were improved (32 [73%] of 44 patients treated with alectinib vs five [22%] of 23 patients treated with crizotinib). Despite longer treatment duration with alectinib than crizotinib (14.7 months vs 12.6 months, respectively), fewer patients had grade 3-5 adverse events (36 [29%] of 125 vs 30 [48%] of 62, respectively) or serious adverse events (19 [15%] of 125 vs 16 [26%] of 62, respectively). Interpretation Our results align with ALEX, confirming the clinical benefit of 600 mg of alectinib twice per day as a first-line treatment for ALK-positive non-small-cell lung cancer. Copyright (c) 2019 Elsevier Ltd. All rights reserved.
Background The IMpower150 trial showed significant improvements in progression-free and overall survival with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) versus the standard-of-care bevacizumab plus carboplatin plus paclitaxel (BCP) in chemotherapy-naive patients with non-squamous non-small-cell lung cancer. Here, we report the efficacy of ABCP or atezolizumab plus carboplatin plus paclitaxel (ACP) versus BCP in key patient subgroups. Methods IMpower150 was a randomised, open-label, phase 3 study done at 240 academic medical centres and community oncology practices across 26 countries worldwide. Patients with chemotherapy-naive metastatic nonsmall-cell lung cancer were randomly assigned (1: 1: 1) to receive ABCP, ACP, or BCP every three weeks. The co-primary endpoints were overall survival and investigator-assessed progression-free survival in intention-to-treat wild-type patients (patients with epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK] genetic alterations were excluded). Efficacy was assessed in key subgroups within the intention-to-treat population, including patients with EGFR mutations (both sensitising and non-sensitising; EGFR-positive) previously treated with one or more tyrosine kinase inhibitors and patients with baseline liver metastases. Overall survival in the intention-to-treat population was included among secondary efficacy endpoints. Exploratory endpoints included the proportion of patients achieving an objective response in the intention-to-treat population, including EGFR-positive patients and patients with baseline liver metastases. Data are reported as per the Jan 22, 2018, data cutoff date, at which the number of coprimary prespecified overall survival events was met in the ABCP versus BCP groups. This trial is registered with ClinicalTrials. gov, number NCT02366143, and is ongoing. Findings Between March 31, 2015, and Dec 30, 2016, 1202 patients were enrolled. 400 patients were randomly assigned to ABCP, 402 to ACP, and 400 to BCP. In EGFR-positive patients (124 of 1202), median overall survival was not estimable (NE; 95% CI 17.0-NE) with ABCP (34 of 400) and 18.7 months (95% CI 13.4-NE) with BCP (45 of 400; hazard ratio [HR] 0.61 [95% CI 0.29-1.28]). Improved overall survival with ABCP versus BCP was observed in patients with sensitising EGFR mutations (median overall survival NE [95% CI NE-NE] with ABCP [26 of 400] vs 17.5 months [95% CI 11.7-NE] with BCP [32 of 400]; HR 0.31 [95% CI 0.11-0.83]) and in the intention-to-treat population (19.8 months [17.4-24.2] vs 14.9 months [13.4-17.1]; HR 0.76 [0.63-0.93]). Improved median overall survival with ABCP versus BCP was seen in patients with baseline liver metastases (13.3 months [11.6-NE] with ABCP [52 of 400] vs 9.4 months [7.9-11.7] with BCP [57 of 400]; HR 0.52 [0.33-0.82]). Median overall survival was 21.4 months (95% CI 13.8-NE) with ACP versus 18.7 months (95% CI 13.4-NE) with BCP in EGFR-positive patients (HR 0.93 [95% CI 0.51-1.68]). No overall survival benefit was seen with ACP versus BCP in patients with sensitising EGFR mutations (HR 0.90 [95% CI 0.47-1.74]), in the intention-to-treat population (HR 0.85 [0.71-1.03]), or in patients with baseline liver metastases (HR 0.87 [0.57-1.32]). In the intention-to-treat safety-evaluable population, grade 3-4 treatment-related events occurred in 223 (57%) patients in the ABCP group, in 172 (43%) in the ACP group, and in 191 (49%) in the BCP group; 11 (3%) grade 5 adverse events occurred in the ABCP group, as did four (1%) in the ACP group, and nine (2%) in the BCP group. Interpretation Improved survival was noted for patients treated with ABCP compared with those given BCP in the intention-to-treat population, and in patients with baseline liver metastases. The overall survival signal in the subgroup of patients with EGFR sensitising mutations warrants further study. Copyright (c) 2019 Elsevier Ltd. All rights reserved.
Background Adjuvant chemotherapy after radical resection of stage IIIA non-small-cell lung cancer (NSCLC) has quite poor outcomes. We aimed to investigate whether adjuvant erlotinib therapy improves 2-year disease-free survival compared with chemotherapy in epidermal growth factor receptor (EGFR) mutation-positive stage IIIA NSCLC. Methods In this randomised, open-label, phase 2 trial, eligible patients aged 18-75 years who had undergone complete (RO) resection of histologically or pathologically confirmed stage IIIA EGFR mutation-positive NSCLC and had not received any previous anticancer therapies were enrolled. Patients were randomly assigned (1:1) to receive either adjuvant erlotinib (150 mg once daily administered orally) or vinorelbine and cisplatin chemotherapy (four cycles of vinorelbine [25 mg/m(2) intravenously on days 1 and 8 of each 21-day cycle] plus cisplatin [75 mg/m(2) intravenously on day 1 of each 21-day cycle]). Randomisation was done by Simon's minimisation with a random element and was stratified by EGFR activating mutation type (exon 19 vs 21), histology (adenocarcinoma vs non-adenocarcinoma), and smoking status (smoker vs non-smoker). The primary endpoint in the unblinded intention-to-treat analysis was 2-year disease-free survival. This ongoing study is registered with ClinicalTrials.gov , number NCT01683175. Findings Between Sept 8, 2012, and May 21, 2015, 102 patients from 16 centres across China were enrolled and randomly assigned to receive erlotinib (n=51) or chemotherapy (n=51). Median follow-up was 33.0 months (IQR 17-8-43-1). 2-year disease-free survival was 81.4% (95% CI 69.6-93.1) in the erlotinib group and 44.6% (26 -9-62- 4) in the chemotherapy group (relative risk 1.823 [95% CI 1.194-2.784; p=0.0054). The difference in 2-year disease-free survival between the groups was 36.7% (95% CI 15 - 5-58- 0; p=0.0007). Adverse events of any grade occurred in 29 (58%) of 50 patients in the erlotinib group and 28 (65%) of 43 patients in the chemotherapy group. Grade 3 or worse adverse events occurred in six (12%) of 50 patients in the erlotinib group versus 11 (26%) of 43 in the chemotherapy group; the most common of these in the erlotinib group was rash (in two 14%1 of 50 patients) and in the chemotherapy group were decreased neutrophil count (in seven [16%] of 43 patients) and myelosuppression (in four [9%]). No treatment-related deaths were reported. Interpretation Adjuvant erlotinib improved 2-year disease-free survival in patients with EGFR mutation-positive stage IIIA NSCLC compared with chemotherapy, with a better tolerability profile. This study suggests that tyrosine kinase inhibitors could have a potentially important role as adjuvant therapy in EGFR mutation-positive stage IIIA NSCLC. However, this trial was a phase 2 study. Mature overall survival data are also needed. Ongoing studies will hopefully confirm the role of adjuvant EGFR tyrosine kinase inhibitor therapy in patients with NSCLC. Copyright (C) 2018 Elsevier Ltd. All rights reserved.
Background Human airway organoids are three-dimensional cultures derived from stem cells, which self-organise in ex-vivo conditions to form so-called mini-airways. The cellular morphology of these cultures is physiologically similar to the human airway, with cilia, goblet cells, and dub cells facing the inner lumen and basal cells situated at the outer layer. The aim of this study was to compare replication competence, tissue tropism, and host responses elicited by human and avian strains of influenza A virus in ex-vivo human bronchus and human airway organoids. Methods Between Sept 29, 2016, and Jan 4, 2017, we obtained ex-vivo cultures of the human bronchus and cultured human airway organoids from lung stem cells obtained from human lung tissues removed as part of the routine clinical care of patients undergoing surgical resection at the Department of Cardiothoracic Surgery, University of Hong Kong, Queen Mary Hospital, Hong Kong. We compared viral replication competence, tissue tropism, and cytokine and chemokine induction of avian influenza A viruses isolated from humans (Sh2/H7N9, H5N1/483, H5N6/39715), and human H1N1pdm/415742 in airway organoids and ex-vivo bronchus explant cultures. Findings Virus tropism and replication kinetics of human and avian influenza A viruses in human airway organoids mimicked those found in ex-vivo cultures of human bronchus explants. In both airway organoids and bronchus explants, influenza A H1N1 subtype (H1N1) and avian influenza A H7N9 viruses replicated to significantly higher titres than did the highly pathogenic avian influenza (HPAI) H5N1, whereas HPAI H5N6 replication was moderate. H1N1, H7N9, and H5N6 viruses infected ciliated cells and goblet cells, but not basal cells in both airway organoids and bronchus explants. The expression of cytokines, interleukin 6, and interferon beta, and the chemokine regulated-on-activation, normal T-cell expressed and secreted, was significantly higher in human airway organoids infected with HPAI H5N1 virus than H1N1pdm/415742, Sh2/H7N9, and H5N6/39715 viruses, and the expression of monocyte chemoattractant protein-1 was significantly higher in human organoids infected with HPAI H5N1 virus than H1N1pdm/415742 and Sh2/H7N9 viruses. Interpretation Human airway organoid cultures provided results that were comparable to those observed in human ex-vivo bronchus cultures, and thus provide an alternative physiologically relevant experimental model for investigating virus tropism and replication competence that could be used to assess the pandemic threat of animal influenza viruses. Copyright (C) 2018 Elsevier Ltd. All rights reserved.
Background Because of the rapid change in economic development and lifestyle in China, and the ageing population, concerns have grown that chronic obstructive pulmonary disease (COPD) could become epidemic. An up-to-date nationwide estimation of COPD prevalence in China is needed. Methods We did a cross-sectional survey of a nationally representative sample of individuals from mainland China aged 40 years or older. The primary outcome was COPD, defined according to the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) lung function criteria. Findings Between Dec 29, 2014, and Dec 31, 2015, 66 752 adults were recruited to the study population. The estimated standardised prevalence of COPD was 13.6% (95% CI 12.0-15.2). The prevalence of COPD differed significantly between men and women (19.0%, 95% CI 16.9-21.2 vs 8.1%, 6.8-9.3; p< 0.0001), mainly because of a significant difference in smoking status between men and women (current smokers 58.2% vs 4.0%). The prevalence of COPD differed by geographic region, with the highest prevalence in southwest China (20.2%, 95% CI 14.7-25.8) and the lowest in central China (10.2%, 8.2-12.2). Among adults with COPD, 56.4% (95% CI 53.7-59.2) had mild disease (GOLD stage I), 36.3% (34.3-38.3) had moderate disease (GOLD stage II), 6.5% (5.5-7.4) had severe disease (GOLD stage III), and 0.9% (0.6-1.1) had very severe disease (GOLD stage IV). Interpretation In a large, nationally representative sample of adults aged 40 years or older, the estimated overall prevalence of COPD in China in 2014-15 was 13.6%, indicating that this disease has become a major public-health problem. Strategies aimed at prevention and treatment of COPD are needed urgently.
Background Detection of EGFR mutations in tumour tissue is the gold-standard approach to ascertain if a patient will benefit from treatment with an EGFR tyrosine kinase inhibitor. However, if tissue is scant, another strategy is to use circulating tumour DNA (ctDNA), but this method needs validation in clinical trials. We did a prospective clinical trial to assess ctDNA-based EGFR mutation detection as a selection criterion for patients with lung adenocarcinoma receiving gefitinib as first-line treatment. Methods BENEFIT is a multicentre, single-arm, phase 2 clinical trial at 15 centres in China. Patients aged 18-75 years with stage IV metastatic lung adenocarcinoma and EGFR mutations detected in ctDNA were given oral gefitinib 250 mg once daily as first-line treatment. The primary endpoint was the proportion achieving an objective response. Secondary endpoints included median progression-free survival and safety. Next-generation sequencing (NGS) of a 168-gene panel was used for genetic analysis of baseline blood samples. The primary efficacy analysis was done by intention to treat in patients who had at least one post-baseline tumour assessment. The safety analysis was done in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov,numberNCT02282267. Findings Between Dec 25, 2014, and Jan 16, 2016, 426 patients were screened for the trial, of whom 188 with EGFR mutations in ctDNA were enrolled and received gefitinib. 183 patients had one or more post-baseline tumour assessment and were included in the primary efficacy analysis. Median follow-up was 14.5 months (IQR 12.2-16.5). At the time of data cutoff (Jan 31, 2017), 152 patients had progressive disease or had died. The proportion achieving an objective response was 72.1% (95% CI 65.0-78.5). Median progression-free survival was 9.5 months (95% CI 9.07-11.04). Of 167 patients with available blood samples, 147 (88%) showed clearance of EGFR mutations in ctDNA at week 8, and median progression-free survival was longer for these patients than for the 20 patients whose EGFR mutations persisted at week 8 (11.0 months [95% CI 9.43-12.85] vs 2.1 months [1.81-3.65]; hazard ratio [HR] 0.14, 95% CI 0.08-0.23; p<0.0001). From baseline NGS data in 179 patients, we identified three subgroups of patients: those with EGFR mutations only (n=58), those with mutations in EGFR and tumour-suppressor genes (n=97), and those with mutations in EGFR and oncogenes (n=24). Corresponding median progression-free survival in these subgroups was 13.2 months (95% CI 11.5-15.0), 9.3 months (7.6-11.0), and 4.7 months (1.9-9.3), respectively (EGFR mutations only vs mutations in EGFR and tumour-suppressor genes, HR 1.78, 95% CI 1.23-2.58; p=0.002; EGFR mutations only vs mutations in EGFR and oncogenes, 2.66, 1.58-4.49; p=0.0003). The most common grade 3 or 4 adverse events were hepatic function abnormalities (n=24). Serious adverse events were reported in 17 (9%) patients. No unexpected safety events for gefitinib were recorded. Interpretation Detection of EGFR mutations in ctDNA is an effective method to identify patients who might benefit from first-line gefitinib treatment. Further analyses of dynamic alterations of EGFR mutations and accompanying gene aberrances could predict resistance to gefitinib. Copyright (C) 2018 Elsevier Ltd. All rights reserved.
Background The protection conferred by influenza vaccination is generally thought to last less than a year, necessitating annual revaccination. However, the speed with which influenza vaccine effectiveness might decline during a year is unknown, which is of particular importance for locations with year-round influenza activity. We aimed to assess how influenza vaccine effectiveness changes by time intervals between vaccination and admission to hospital, taking advantage of almost year-round circulation of influenza in Hong Kong. Methods In this test-negative case-control study, we analysed vaccine effectiveness in children (aged 6 months to 17 years) who were admitted to hospital in Hong Kong over 5 consecutive years (2012-17). We included those who were admitted to general wards in four public hospitals in Hong Kong with a fever (>= 38 degrees C) and any respiratory symptom, such as runny nose, cough, or sore throat. We used direct immunofluorescence assay and reverse transcription PCR to detect influenza virus infection, and recorded children's influenza immunisation history. We compared characteristics of positive cases and negative controls and examined how vaccine effectiveness changed by time between vaccination and admission to hospital with regression analyses. Findings Between Sept 1, 2012, and Aug 31, 2017, we enrolled 15 695 children hospitalised for respiratory infections, including 2500 (15.9%) who tested positive for influenza A or B and 13 195 (84.1%) who tested negative. 159 (6.4%) influenza-positive cases and 1445 (11.0%) influenza-negative cases had been vaccinated. Most vaccinations were done by December of each influenza vaccination season. Influenza-related admissions to hospital occurred year-round, with peaks in January through March in most years and a large summer peak in 2016; pooled vaccine effectiveness for children of all ages was 79% (95% CI 42-92) for September to December, 67% (57-74) for January to April, and 43% (25-57) for May to August. Vaccine effectiveness against influenza A or B was estimated as 79% (95% CI 64-88) within 0 . 5-2 months of vaccination, 60% (46-71) within > 2-4 months, 57% (39-70) within > 4-6 months, and 45% (22-61) within > 6-9 months. In separate analyses by type and subtype, we estimated that vaccine effectiveness declined by 2-5 percentage points per month. Interpretation Influenza vaccine effectiveness decreased during the 9 months after vaccination in children in Hong Kong. Our findings confirm the importance of annual vaccination in children. Influenza vaccines that provide broader and longer-lasting protection are needed to provide year-round protection in regions with irregular influenza seasonality or lengthy periods of influenza activity. Copyright (C) 2018 Elsevier Ltd. All rights reserved.
Background For patients with non-small-cell lung cancer (NSCLC) and multiple brain metastases, whole-brain irradiation (WBI) is a standard-of-care treatment, but its effects on neurocognition are complex and concerning. We compared the efficacy of an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), icotinib, versus WBI with or without chemotherapy in a phase 3 trial of patients with EGFR-mutant NSCLC and multiple brain metastases. Methods We did a multicentre, open-label, parallel randomised controlled trial (BRAIN) at 17 hospitals in China. Eligible participants were patients with NSCLC with EGFR mutations, who were naive to treatment with EGFR-TKIs or radiotherapy, and had at least three metastatic brain lesions. We randomly assigned participants (1:1) to either icotinib 125 mg orally (three times per day) or WBI (30 Gy in ten fractions of 3 Gy) plus concurrent or sequential chemotherapy for 4-6 cycles, until unacceptable adverse events or intracranial disease progression occurred. The randomisation was done by the Chinese Thoracic Oncology Group with a web-based allocation system applying the Pocock and Simon minimisation method; groups were stratified by EGFR gene mutation status, treatment line (first line or second line), brain metastases only versus both intracranial and extracranial metastases, and presence or absence of symptoms of intracranial hypertension. Clinicians and patients were not masked to treatment assignment, but individuals involved in the data analysis did not participate in the treatments and were thus masked to allocation. Patients receiving icotinib who had intracranial progression only were switched to WBI plus either icotinib or chemotherapy until further progression; those receiving icotinib who had extracranial progression only were switched to icotinib plus chemotherapy. Patients receiving WBI who progressed were switched to icotinib until further progression. Icotinib could be continued beyond progression if a clinical benefit was observed by the investigators (eg, an improvement in cognition or intracranial pressure). The primary endpoint was intracranial progression-free survival (PFS), defined as the time from randomisation to either intracranial disease progression or death from any cause. We assessed efficacy and safety in the intention-to-treat population (all participants who received at least one dose of study treatment), hypothesising that intracranial PFS would be 40% longer (hazard ratio [HR] 0.60) with icotinib compared with WBI. This trial is registered with ClinicalTrials.gov, number NCT01724801. Findings Between Dec 10, 2012, and June 30, 2015, we assigned 176 participants to treatment: 85 to icotinib and 91 to WBI. 18 withdrew from the WBI group before treatment, leaving 73 for assessment. Median follow-up was 16.5 months (IQR 11.5-21.5). Median intracranial PFS was 10.0 months (95% CI 5.6-14.4) with icotinib versus 4.8 months (2.4-7.2) with WBI (equating to a 44% risk reduction with icotinib for an event of intracranial disease progression or death; HR 0.56, 95% CI 0.36-0.90; p=0.014). Adverse events of grade 3 or worse were reported in seven (8%) of 85 patients in the icotinib group and 28 (38%) of 73 patients in the WBI group. Raised concentrations of alanine aminotransferase and rash were the most common adverse events of any grade in both groups, occurring in around 20-30% of each group. At the time of final analysis, 42 (49%) patients in the icotinib group and 37 (51%) in the WBI group had died. 78 of these patients died from disease progression, and one patient in the WBI group died from thrombogenesis related to chemotherapy. Interpretation In patients with EGFR-mutant NSCLC and multiple brain metastases, icotinib was associated with significantly longer intracranial PFS than WBI plus chemotherapy, indicating that icotinib might be a better.rst-line therapeutic option for this patient population.