Association between ergonomic risk exposures and insomnia symptoms: a mediation analysis of the 5th Korean working conditions survey.

BACKGROUND: This study investigates the relationship between ergonomic risk exposures and insomnia symptoms, using data representative of Korea's general working population. METHODS: Data from the 5th Korean Working Conditions Survey were used for this study. The eligible population (employees) for the current study was 37,026. Insomnia symptoms were estimated using the minimal insomnia symptom scale (MISS) questionnaire. Logistic regression analysis was conducted to explore the association between ergonomic risks and insomnia symptoms. RESULTS: All the investigated ergonomic risks increased odd ratios (ORs) for insomnia symptoms: Tiring or painful positions (OR, 1.64; 95% CI, 1.43-1.88); lifting or moving heavy loads (OR, 2.33; 95% CI, 1.99-2.71); long periods of standing (OR, 1.47; 95% CI, 1.29-1.69); and repetitive hand or arm movements (OR, 1.46; 95% CI, 1.29-1.67). The mediated proportion of musculoskeletal pain was 7.4% (95% CI, 5.81-10.13), and the mediated proportion of feeling of exhaustion was 17.5% (95% CI, 5.81-10.13). CONCLUSIONS: This study provides evidence for the relationship between ergonomic risks and insomnia symptoms, for which musculoskeletal pains and the feeling of exhaustion may be potential mediators.

Risk adjustment model for tuberculosis compared to non-tuberculosis mycobacterium or latent tuberculosis infection: Center for Personalized Precision Medicine of Tuberculosis (cPMTb) cohort database.

BACKGROUND: The Center for Personalized Precision Medicine of Tuberculosis (cPMTb) was constructed to develop personalized pharmacotherapeutic systems for tuberculosis (TB). This study aimed to introduce the cPMTb cohort and compare the distinct characteristics of patients with TB, non-tuberculosis mycobacterium (NTM) infection, or latent TB infection (LTBI). We also determined the prevalence and specific traits of polymorphisms in N-acetyltransferase-2 (NAT2) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) phenotypes using this prospective multinational cohort. METHODS: Until August 2021, 964, 167, and 95 patients with TB, NTM infection, and LTBI, respectively, were included. Clinical, laboratory, and radiographic data were collected. NAT2 and SLCO1B1 phenotypes were classified by genomic DNA analysis. RESULTS: Patients with TB were older, had lower body mass index (BMI), higher diabetes rate, and higher male proportion than patients with LTBI. Patients with NTM infection were older, had lower BMI, lower diabetes rate, higher previous TB history, and higher female proportion than patients with TB. Patients with TB had the lowest albumin levels, and the prevalence of the rapid, intermediate, and slow/ultra-slow acetylator phenotypes were 39.2%, 48.1%, and 12.7%, respectively. The prevalence of rapid, intermediate, and slow/ultra-slow acetylator phenotypes were 42.0%, 44.6%, and 13.3% for NTM infection, and 42.5%, 48.3%, and 9.1% for LTBI, respectively, which did not differ significantly from TB. The prevalence of the normal, intermediate, and lower transporter SLCO1B1 phenotypes in TB, NTM, and LTBI did not differ significantly; 74.9%, 22.7%, and 2.4% in TB; 72.0%, 26.1%, and 1.9% in NTM; and 80.7%, 19.3%, and 0% in LTBI, respectively. CONCLUSIONS: Understanding disease characteristics and identifying pharmacokinetic traits are fundamental steps in optimizing treatment. Further longitudinal data are required for personalized precision medicine. TRIAL REGISTRATION: This study registered ClinicalTrials.gov NO. NCT05280886.

Occupational physical activity, not leisure-time physical activity, is associated with increased high-sensitivity C reactive protein levels.

OBJECTIVE: This study aims to explore the association between physical activity and high-sensitivity C reactive protein, based on different types of physical activity-occupational and leisure time. METHODS: Using cross-sectional data from the Korea National Health and Nutrition Examination Survey 2015-2018, we explored the association between different types of self-reported physical activity and high levels of high-sensitivity C reactive protein (>3 mg/L). We estimated the ORs for high-level high-sensitivity C reactive protein using multiple logistic regression models after adjusting for covariates from 12 970 eligible subjects (mean age 44.8). RESULTS: Compared with subjects who did not engage in moderate-to-vigorous level of occupational physical activity (OPA), the group that engaged in moderate-to-vigorous level of OPA showed a significantly high OR (1.32, 95% CI (1.03 to 1.69)), whereas the group that engaged in moderate-to-vigorous level of leisure-time physical activity (LPA) yielded a low OR (0.84, 95% CI (0.69 to 1.01)). The group that engaged in moderate-to-vigorous level of OPA but not LPA showed a significantly high OR (1.76, 95% CI (1.27 to 2.45)) compared with subjects who engaged in moderate-to-vigorous level of LPA but not in OPA. CONCLUSIONS: OPA is directly associated with high C reactive protein levels, suggesting that it increases the risk of inflammation.

The relationship between the pattern of shift work and sleep disturbances in Korean firefighters.

PURPOSE: Sleep disturbances are prevalent in firefighters, but the relationship between patterns of shift work and sleep disturbances has not yet been investigated. Here, this relationship has been evaluated in Korean firefighters. METHODS: A cross-sectional study was conducted using an online questionnaire, which captured demographic, psychosocial and work-related characteristics. Sleep disturbance was assessed using the insomnia severity index (ISI). The relationship between insomnia and work-related factors (including type of shift work and the frequency of emergency events and off-duty work which means overtime work on off days) was analyzed. RESULTS: A total of 9810 firefighters completed the survey, representing approximately 21.5% of all Korean firefighters; data from 9738 subjects were included in the analysis. All firefighter roles were significantly associated with insomnia; the odds ratio (OR) was 2.456 (95% confidence interval [CI] 1.461-4.128) for fire suppression and 1.871 (95% CI 1.105-3.167) for the emergency medical services and rescue. However, the pattern of shift work did not show a statistically significant relationship. The OR increased along with the frequency of emergency events and off-duty work (p value for trend < 0.05). CONCLUSIONS: This study found a significant association between the frequency of emergency and off-duty work and insomnia in Korean firefighters, whereas the pattern of shift work showed no significant relationship. Therefore, measures to reduce the frequency of emergency and off-duty work are required to prevent sleep disturbances in firefighters.

Impact of Epidermal Growth Factor Receptor Mutation on Clinical Outcomes of Nintedanib Plus Docetaxel in Patients with Previously Treated Non-Small Cell Lung Cancer from the Korean Named Patient Program.

OBJECTIVES: Anti-angiogenic agents are reported to exert clinical activity on epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancers. We evaluated the clinical outcomes of nintedanib and docetaxel in refractory NSCLC according to EGFR mutation status during the Korean nintedanib named patient program. METHODS: Docetaxel was administered either 75 or 37.5 mg/m2 on D1, D8 q every 3 weeks for 4-6 cycles plus nintedanib 200 mg orally twice daily until disease progression or unacceptable toxicity. RESULTS: Sixty-two patients were enrolled for study. Twenty-eight patients with activating EGFR mutations progressed after EGFR-tyrosine kinase inhibitors (TKI) therapy and 25 out of 28 patients showing progression after platinum doublet chemotherapy were enrolled. The objective response rate was 29% and median PFS and OS were 3.9 months and 11.7 months. Based on the EGFR mutation status, the objective response rate was 39.3 vs. 21.9% (EGFR mut(+) vs. EGFR mut(-), p = 0.142) and median PFS was 6.5 vs. 3.3 months (EGFR mut(+) vs. EGFR mut(-), p = 0.009). No treatment-related deaths were reported. The most frequent drug-related adverse events (AE) were neutropenia (53.2%) and diarrhea (37.1%). Treatment in 12 patients (19.3%) was permanently discontinued due to AEs without disease progression. CONCLUSIONS: Our data indicated that nintedanib-docetaxel combination could be considered to be effective treatment in EGFR TKI-resistant EGFR mutant NSCLC.

A Prospective Observational Study Evaluating the Correlation of c-MET Expression and EGFR Gene Mutation with Response to Erlotinib as Second-Line Treatment for Patients with Advanced/Metastatic Non-Small-Cell Lung Cancer.

OBJECTIVES: We aimed to evaluate the prevalence and predictive role of c-MET expression and EGFR mutation in the efficacy of erlotinib in non-small-cell lung cancer (NSCLC). METHODS: We prospectively recruited 196 patients with stage IV or recurrent NSCLC treated with erlotinib after failure of first-line chemotherapy. Immunohistochemistry was used to evaluate c-MET overexpression, silver in situ hybridization (SISH) to assess gene copy number, and real-time polymerase chain reaction to detect EGFR mutations, respectively, in tumor tissue. RESULTS: The major histologic type was adenocarcinoma (66.8%). c-MET was overexpressed in 55.8% (87/156) and dominant in females as well as non-squamous histology. Although c-MET gene amplification and high polysomy were observed in 2.0% (3/152) and 11.2% (17/152), they did not correlate with any characteristics. EGFR mutation was detected in 13.1% (20/153). The objective response rate of erlotinib was higher (61.1 vs. 3.7%, p < 0.001) and the median progression-free survival (PFS) was longer (10.2 vs. 1.9 months, p < 0.001) in EGFR-sensitizing mutations. However, c-MET positivity did not show a significant correlation with response to erlotinib or PFS. CONCLUSION: We reconfirmed EGFR mutation as a strong predictive marker of NSCLC. However, c-MET positivity was not associated with response or PFS, although c-MET overexpression correlated with some clinical characteristics.

Evaluation for Fatigue and Accident Risk of Korean Commercial Bus Drivers.

Many Korean bus drivers work long hours, which causes fatigue and increased risk of accidents during driving. Their fatigue due to long working hours may cause a significant accident accompanied by injuries of the general population. The present study aimed to evaluate the fatigue and accident risk in Korean commercial bus drivers. The subjects were 16 city and express bus drivers with various work schedules: 2 shifts (2 shifts in a day), WR (duty-off), W2R (duty-duty-off), and W4R2 (duty-duty-duty-duty-off-off). We measured the subjects' heart rate in their workplace during their work and calculated relative heart rate (RHR) and maximum acceptable work time (MAWT), the maximum amount of time for which workers can sustain their workload without physical fatigue. Fatigue and risk index, which is a tool for assessing the risk from fatigue in the safety critical workers, was calculated using the subjects' work schedule. RHR ranged from 9.7 to 21.8% and MAWT was shorter than each subject's actual work hours. Fatigue (45.2-54.4) and risk indices (1.8) were high in WR schedule, which were higher than recommended value (30-35 for fatigue index and < 1.6 for risk index). According to these findings, Korean bus drivers worked long hours beyond their physical abilities, and the fatigue and risk indices were high, especially in WR schedule. It is necessary to prepare the policies to reduce the fatigue and accident risk in the Korean bus drivers including regulation for bus drivers' driving time restriction.

Belotecan/cisplatin versus etoposide/cisplatin in previously untreated patients with extensive-stage small cell lung carcinoma: a multi-center randomized phase III trial.

BACKGROUND: No novel chemotherapeutic combinations have demonstrated superior efficacy to etoposide/cisplatin (EP), a standard treatment regimen for extensive-stage small cell lung carcinoma (ES-SCLC) over the past decade. We aimed to compare the efficacy and safety of belotecan/cisplatin (BP) and EP regimens in chemotherapy- and radiotherapy-naïve patients with previously untreated ES-SCLC. METHODS: We conducted a multi-center, randomized, open-label, parallel-group, phase III clinical study. A total of 157 patients were recruited at 14 centers with 147 patients meeting the inclusion/exclusion criteria and randomized to either BP (n = 71) or EP (n = 76) treatment arms. A non-inferior response rate (RR) in the BP arm, analyzed by intent-to-treat analysis according to Response Evaluation Criteria in Solid Tumors version 1.0 criteria, was used as the primary endpoint. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: In the BP arm, one patient had a complete response, 41 had a partial response (PR), and 17 had stable disease (SD). In the EP arm, 35 patients had PR and 28 had SD. The RR in the BP arm was non-inferior to the EP regimen in patients with ES-SCLC (BP: 59.2 %, EP: 46.1 %, difference: 13.1 %, 90 % two-sided confidence interval: -0.3-26.5, meeting the predefined non-inferiority criterion of -15.0 %). No significant differences in OS or PFS were observed between the treatment arms. Hematologic toxicities, including grade 3/4 anemia and thrombocytopenia, were significantly more prevalent in the BP arm than the EP arm. CONCLUSIONS: The RR to the BP regimen was non-inferior to the EP regimen in chemotherapy- and radiotherapy-naïve patients with previously untreated ES-SCLC. Hematologic toxicities were significantly more prevalent in the BP group, indicating that BP should be used with care, particularly in patients with a poor performance status. Further studies assessing PFS and OS are required to validate the superiority of the BP regimen. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00826644 . Date of Registration: January 21, 2009.

Work-related musculoskeletal diseases and the workers' compensation.

The Industrial Accident Compensation Insurance Act (IACIA) regulates the workers' compensation insurance system and the standards for the recognition of occupational diseases (ODs). Since its establishment in 1994, the IACIA has been amended several times. Before 2008, the approval of compensation for work-related musculoskeletal diseases (WMSDs) was decided based on the recommendation of consultants of the Korea Workers' Compensation and Welfare Service (COMWEL). The IACIA was amended in 2008, and since then, the approval of compensation for occupational injuries has been decided based on the recommendation of COMWEL consultants, whereas the approval of compensation for ODs was decided based on the judgment of Committee on Occupational Diseases Judgment (CODJ) which was established in 2008. According to the 2013 amendment to the IACIA, degenerative musculoskeletal diseases among workers engaged in musculoskeletal-burdening work should be considered compensable ODs. Despite some commendable changes to the workers' compensation insurance system, other significant issues persist. To resolve these issues, related organizations including the associations of orthopedic surgery, neurosurgery, and occupational and environmental medicine; Ministry of Employment and Labor; and COMWEL need to work cooperatively.

Association between social jetlag and self-rated health: Evidence from Korean representative working population.

BACKGROUND: Social jetlag is a circadian misalignment that arises from a discrepancy between activity/sleep schedules on school/work days and free days. This study explored the correlation between social jetlag and self-rated health (SRH) in a representative sample of Korea. METHODS: This study included 8259 working population in the Korea National Health and Nutrition Examination Survey, 2016-2018. Social jetlag was calculated as the difference between the midpoint of sleep time on work day and work-free day. Five-point Likert scale of SRH was used to assess subjective health perception on general health conditions. Multiple logistic regression analysis was performed to calculate the odds ratios (ORs) and 95 % confidence interval (CI) for poor SRH in the 1-2 h or longer than 2 h social jetlag groups compared to that in the reference group (less than 1 h), after adjusting for age, sex, marital status, occupation, household income, and weekly working hours. RESULTS: The proportions of those with <1 h, 1-2 h, >2 h of social jetlag were 63.80 %, 25.67 %, and 10.53 %, respectively. The risk of poor SRH increased as social jetlag increased. Greater social jetlag was significantly associated with an increased likelihood of reporting poor SRH. The adjusted ORs for the groups with social jetlag between 1 and <2 h, and >2 h were 1.100 (95 % CI = 0.935-1.295), and 1.503 (95 % CI = 1.097-1.727), respectively. Moreover, the OR trend was statistically significant (p for trend = 0.008). CONCLUSION: This study found that social jetlag and poor SRH were significantly related in the Korean working population.

Population pharmacokinetic model of rifampicin for personalized tuberculosis pharmacotherapy: Effects of SLCO1B1 polymorphisms on drug exposure.

BACKGROUND: Rifampicin (RIF) exhibits high pharmacokinetic (PK) variability among individuals; a low plasma concentration might result in unfavorable treatment outcomes and drug resistance. This study evaluated the contributions of non- and genetic factors to the interindividual variability of RIF exposure, then suggested initial doses for patients with different weight bands. METHODS: This multicenter prospective cohort study in Korea analyzed demographic and clinical data, the solute carrier organic anion transporter family member 1B1 (SLCO1B1) genotypes, and RIF concentrations. Population PK modeling and simulations were conducted using nonlinear mixed-effect modeling. RESULTS: In total, 879 tuberculosis (TB) patients were divided into a training dataset (510 patients) and a test dataset (359 patients). A one-compartment model with allometric scaling for effect of body size best described the RIF PKs. The apparent clearance (CL/F) was 16.6% higher among patients in the SLCO1B1 rs4149056 wild-type group than among patients in variant group, significantly decreasing RIF exposure in the wild-type group. The developed model showed better predictive performance compared with previously reported models. We also suggested that patients with body weights of <40 kg, 40-55 kg, 55-70 kg, and >70 kg patients receive RIF doses of 450, 600, 750, and 1050 mg/day, respectively. CONCLUSIONS: Total body weight and SLCO1B1 rs4149056 genotypes were the most significant covariates that affected RIF CL/F variability in Korean TB patients. We suggest initial doses of RIF based on World Health Organization weight-band classifications. The model may be implemented in treatment monitoring for TB patients.

Real-world outcome of crizotinib for anaplastic lymphoma kinase-positive lung cancer: Multicenter retrospective analysis in South Korea.

BACKGROUND: About 3%-5% of non-small cell lung cancer (NSCLC) presents positive anaplastic lymphoma kinase (ALK). Recently, several target agents have been approved as a treatment for ALK-positive NSCLC. This study aimed to analyze the real-world efficacy and outcome when administered crizotinib, the first approved target agent for ALK-positive NSCLC, according to first- or late-line treatment. METHODS: A total of 290 patients with ALK-positive advanced NSCLC who were treated with crizotinib in 15 institutions in South Korea from January 2009 to December 2018 were enrolled. RESULTS: The median age of patients was 57.0 years, and 50.3% were male. The median follow-up duration was 29.3 months. Among them, 113 patients received crizotinib as first-line therapy. The objective response rate (ORR) was 60.1% (57.0% for first-line recipients, 61.8% for second-/later-line). Median (95% CI) progression-free survival (PFS) was 13.7 (11.6-17.0) months. For first-line recipients, overall survival (OS) was 26.3 (17.6-35.0) months. No significant difference in ORR, PFS and OS, according to the setting of crizotinib initiation, was observed. In a multivariate Cox regression analysis, old age, male gender, initially metastatic, and number of metastatic organs were associated with poor PFS and OS. The most common adverse events were nausea and vomiting, and severe adverse event leading to dose adjustment was hepatotoxicity. CONCLUSIONS: ORR, PFS, OS, and adverse event profiles were comparable to previous clinical trials. Our findings could aid in the efficient management of ALK-positive lung cancer patients.

Gender-specific influence of socioeconomic status on the prevalence of migraine and tension-type headache: the results from the Korean Headache Survey.

BACKGROUND: Socioeconomic status plays an important role in pain coping strategy. Its influence on migraine and tension-type headache may differ by gender. This study aimed to evaluate how socioeconomic status affects the prevalence of migraine and tension-type headache by gender. METHODS: We used data from the Korean Headache Survey, a population-based sample of Koreans aged 19-69 years. Education level, district size, and household income were evaluated as socioeconomic variables. RESULTS: Among 1507 participants, the 1-year prevalence rates of migraine and tension-type headache were 8.7% [95% confidence interval (CI) 1.9-4.6%] and 29.1% (95% CI 25.7-32.5%) in women and 3.2% (95% CI 1.9-4.6%) and 32.5% (95% CI 29.1-35.9%) in men, respectively. In women, multiple regression analysis found that living in rural areas was related to higher prevalence of migraine [odds ratio (OR) 4.52, 95% CI 1.85-11.02] and lower prevalence of tension-type headache (OR 0.29, 95% CI 0.15-0.58) and college-level education was related to lower prevalence of tension-type headache (OR 0.37, 95% CI 0.18-0.74). In men, multiple regression analysis failed to reveal significant influences of any socioeconomic variable on the prevalence of migraine or tension-type headache. CONCLUSIONS: The influence of socioeconomic status on migraine and tension-type headache differs by gender, with women being more susceptible to socioeconomic influence.

Working hours and the regulations for night shift workers.

There are several types of shift work in Korea: rotating shift, 24-hour shift, day-night shift, fixed night work, and.so on. As a result of analyzing the 8th Korea National Health and Nutrition Examination Survey and the 6th Korean Working Condition Survey, Korean shift workers accounted for 11.6%-13.9% of wage workers. Weekly working hours of shift workers were 57.69 ± 1.73 (24-hours shift) and 49.97 ± 0.67 (fixed night shift), which were significantly longer than day workers. To prevent health consequences of night work, many countries regulate the working hours of night work not to exceed 7-9 hours a day. However, Korea does not regulate working hours for night work, and some occupations may work more hours than the prescribed overtime hours. To prevent health consequences and reduce working hours for Korean night shift workers, it is necessary to regulate the working hours of night shift workers by law.

Social jetlag and risk of depression: Results from the Korea National Health and Nutrition Examination Survey.

BACKGROUND: Social jetlag, which is the mismatch between endogenous rhythm and social timing, is prevalent among the working population. Social jetlag may result in mood changes; however, evidence of relationship between social jetlag and depressive disorders has not been fully verified. Hence, this study aimed to investigate the association between social jetlag and depressive symptoms in a representative working population of South Korea. METHODS: This study included 5447 Korean employees in the Korea National Health and Nutrition Examination Survey. Social jetlag was calculated as the difference between the midpoint of sleep time on weekdays and free days. Depressive symptoms were assessed using Patient Health Questionnaire-9. Multiple logistic regression was used to estimate the odds ratio after adjusting for confounding factors. Moreover, social jetlag and continuous depression scores were evaluated using linear regression and generalized additive models. RESULTS: The proportion of the participants who had >2 h of social jetlag was 10.26 %. Depressive symptoms increased as social jetlag increased. Multiple logistic regression analysis showed that the adjusted OR (95 % confidence interval) for 1 to 2 h of social jetlag was 1.355 (0.891-2.059) and for >2 h was 1.859 (1.084-3.187), which <1 h was reference. LIMITATIONS: This study used a cross-sectional design and measurements were based on self-reported scales. CONCLUSION: This study found that social jetlag and depressive symptoms were significantly related in the Korean working population.

Development of algorithm for work intensity evaluation using excess overwork index of construction workers with real-time heart rate measurement device.

Background: The construction workers are vulnerable to fatigue due to high physical workload. This study aimed to investigate the relationship between overwork and heart rate in construction workers and propose a scheme to prevent overwork in advance. Methods: We measured the heart rates of construction workers at a construction site of a residential and commercial complex in Seoul from August to October 2021 and develop an index that monitors overwork in real-time. A total of 66 Korean workers participated in the study, wearing real-time heart rate monitoring equipment. The relative heart rate (RHR) was calculated using the minimum and maximum heart rates, and the maximum acceptable working time (MAWT) was estimated using RHR to calculate the workload. The overwork index (OI) was defined as the cumulative workload evaluated with the MAWT. An appropriate scenario line (PSL) was set as an index that can be compared to the OI to evaluate the degree of overwork in real-time. The excess overwork index (EOI) was evaluated in real-time during work performance using the difference between the OI and the PSL. The EOI value was used to perform receiver operating characteristic (ROC) curve analysis to find the optimal cut-off value for classification of overwork state. Results: Of the 60 participants analyzed, 28 (46.7%) were classified as the overwork group based on their RHR. ROC curve analysis showed that the EOI was a good predictor of overwork, with an area under the curve of 0.824. The optimal cut-off values ranged from 21.8% to 24.0% depending on the method used to determine the cut-off point. Conclusion: The EOI showed promising results as a predictive tool to assess overwork in real-time using heart rate monitoring and calculation through MAWT. Further research is needed to assess physical workload accurately and determine cut-off values across industries.

Recommendation of pharmacokinetics/pharmacodynamics target of ethambutol to suppress tuberculosis resistance: A population pharmacokinetics study on a large prospective cohort.

BACKGROUND: The ability of ethambutol (EMB) to suppress bacterial resistance has been demonstrated in a time-dependent manner. Through the development of a population pharmacokinetics (PK) model, this study aimed to suggest the PK/pharmacodynamics (PD) target and identify the significant covariates that influence interindividual variability (IIV) in the PK of EMB. METHODS: In total, 837 patients from 20 medical centres across Korea were enrolled in this study. The non-linear mixed-effect method was used to establish and validate the population PK model. RESULTS: A two-compartment model with transit compartment absorption was sufficient to describe the PK of EMB. Body weight and renal function were identified as significant covariates that affect IIV of the apparent clearance (CL/F) of EMB. Patients with moderate renal function showed 35% and 55% lower CL/F (CL/F 89.9 L/h) compared with those with mild and normal renal function, respectively. All the renal function groups with simulated doses ranging from 800 to 1200 mg achieved area under the curve over minimum inhibitory concentration (MIC) >119, and maintained T>MIC for >23 h for MIC of 0.5 µg/mL. Based on our simulation result, it is suggested that doses of 800, 1000, and 1200 mg should obtain the T>MIC target of 4, 6, and 8 h, respectively. This model was validated internally and externally. CONCLUSION: This study provides insight into the PK/PD indexes of EMB for three different renal function groups and T>MIC targets for different doses. The results could be used to provide optimal-dose suggestions for EMB.

Real-world analysis of first-line afatinib in patients with EGFR-mutant non-small cell lung cancer and brain metastasis: survival and prognostic factors.

Background: Overall survival (OS) in patients with non-small cell lung cancer (NSCLC) and brain metastases (BMs) is poor. We aimed to identify prognostic factors and ascertain treatment outcomes of first-line afatinib for patients with epidermal growth factor receptor (EGFR)-mutant NSCLC with BM in a real-world setting. Methods: This retrospective observational study reviewed electronic records of patients with EGFR-mutant NSCLC who received first-line afatinib treatment between October 2014 and October 2019 in 16 hospitals across South Korea. The Kaplan-Meier method estimated time on treatment (TOT) and OS; multivariate analyses were performed using Cox proportional hazards (PH) models. Results: Among 703 patients who received first-line afatinib, 262 (37.3%) had baseline BM. Of 441 patients without baseline BM, 92 (20.9%) developed central nervous system (CNS) failure. Compared with patients without CNS failure, those with CNS failure during afatinib treatment were younger (P=0.012), had a higher Eastern Cooperative Oncology Group (ECOG) performance status (PS) (P<0.001), increased metastatic site involvement (P<0.001), advanced stage disease (P<0.001), with liver metastasis (P=0.008) and/or bone metastasis (P<0.001) at baseline. Cumulative incidence of CNS failure in years 1, 2 and 3 was 10.1%, 21.5% and 30.0%, respectively. In multivariate analysis, cumulative incidence was significantly higher in patients with ECOG PS ≥2 (P<0.001), uncommon EGFR mutations (P=0.001), and no baseline pleural metastasis (P=0.017). Median TOT was 16.0 months (95% CI: 14.8-17.2) and, in patients with CNS failure, without CNS failure, and with baseline BM was 12.2, 18.9, and 14.1 months, respectively (P<0.001). Median OS was 52.9 months (95% CI: 45.4-60.3) and, in patients with CNS failure, without CNS failure, and with baseline BM was 29.1, 67.3 and 48.5 months, respectively (P<0.001). Conclusions: First-line afatinib in the real-world setting showed clinically meaningful effectiveness in patients with EGFR-mutant NSCLC and BM. CNS failure was a poor prognostic factor for TOT and OS correlating with younger age, poor ECOG PS, higher metastatic number, advanced disease stage, uncommon EGFR mutations, and baseline liver and/or bone metastases.

Real-World Study of Osimertinib in Korean Patients with Epidermal Growth Factor Receptor T790M Mutation-Positive Non-Small Cell Lung Cancer.

PURPOSE: Although osimertinib is the standard-of-care treatment of epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer, real-world evidence on the efficacy of osimertinib is not enough to reflect the complexity of the entire course of treatment. Herein, we report on the use of osimertinib in patients with EGFR T790M mutation-positive non-small cell lung cancer who had previously received EGFR tyrosine kinase inhibitor (TKI) treatment in Korea. MATERIALS AND METHODS: Patients with confirmed EGFR T790M after disease progression of prior EGFR-TKI were enrolled and administered osimertinib 80 mg daily. The primary effectiveness outcome was progression-free survival, with time-to-treatment discontinuation, treatment and adverse effects leading to treatment discontinuation, and overall survival being the secondary endpoints. RESULTS: A total of 558 individuals were enrolled, and 55.2% had investigator-assessed responses. The median progression-free survival was 14.2 months (95% confidence interval [CI], 13.0 to 16.4), and the median time-to-treatment discontinuation was 15.0 months (95% CI, 14.1 to 15.9). The median overall survival was 36.7 months (95% CI, 30.9 to not reached). The benefit with osimertinib was consistent regardless of the age, sex, smoking history, and primary EGFR mutation subtype. However, hepatic metastases at the time of diagnosis, the presence of plasma EGFR T790M, and the shorter duration of prior EGFR-TKI treatment were poor predictors of osimertinib treatment. Ten patients (1.8%), including three with pneumonitis, had to discontinue osimertinib due to severe adverse effects. CONCLUSION: Osimertinib demonstrated its clinical effectiveness and survival benefit for EGFR T790M mutation-positive in Korean patients with no new safety signals.

Final Report on Real-World Effectiveness of Sequential Afatinib and Osimertinib in EGFR-Positive Advanced Non-Small Cell Lung Cancer: Updated Analysis of the RESET Study.

PURPOSE: This study aimed to report the final analysis of time-on-treatment (TOT) and overall survival (OS) in patients with advanced-stage epidermal growth factor receptor (EGFR)+ non-small cell lung cancer (NSCLC) who received sequential afatinib and osimertinib and to compare the outcomes with other second-line regimens (comparator group). MATERIALS AND METHODS: In this updated report, the existing medical records were reviewed and rechecked. TOT and OS were updated and analyzed according to clinical features using the Kaplan-Meier method and log-rank test. TOT and OS were compared with those of the comparator group, in which most patients received pemetrexed-based treatments. A multivariable Cox proportional hazard model was used to evaluate features that could affect survival outcomes. RESULTS: The median observation time was 31.0 months. The follow-up period was extended to 20 months. A total of 401 patients who received first-line afatinib were analyzed (166 with T790M+ and second-line osimertinib, and 235 with unproven T790M and other second-line agents). Median TOTs on afatinib and osimertinib were 15.0 months (95% confidence interval [CI], 14.0 to 16.1) and 11.9 months (95% CI, 8.9 to 14.6), respectively. The median OS in the osimertinib group was 54.3 months (95% CI, 46.7 to 61.9), much longer than that in the comparator group. In patients who received osimertinib, the OS was longest with Del19+ (median, 59.1; 95% CI, 48.7 to 69.5). CONCLUSION: This is one of the largest real-world studies reporting the encouraging activity of sequential afatinib and osimertinib in Asian patients with EGFR+ NSCLC who acquired the T790M mutation, particularly Del19+.