Erratum: Correction of Affiliations in the Article "Validity of Outcome Prediction Scoring Systems in Korean Patients with Severe Adult Respiratory Distress Syndrome Receiving Extracorporeal Membrane Oxygenation Therapy".

This corrects the article on p. 932 in vol. 31, PMID: 27247503.

PAK1 as a Potential Therapeutic Target in Male Smokers with EGFR-Mutant Non-Small Cell Lung Cancer.

P21-activated kinases (PAKs) are serine/threonine protein kinases that contribute to several cellular processes. Here, we aimed to determine the prognostic value of PAK1 and its correlation with the clinicopathological characteristics and five-year survival rates in patients with non-small cell lung cancer (NSCLC). We evaluated PAK1 mRNA and protein expression in NSCLC cells and resected tumor specimens, as well as in healthy human bronchial epithelial cells and adjacent healthy lung tissues, respectively, for effective comparison. Immunohistochemical tissue microarray analysis of 201 NSCLC specimens showed the correlation of PAK1 expression with clinicopathological characteristics. The mRNA and protein expression of PAK1 were 2.9- and 4.3-fold higher in six of seven NSCLC cell types and human tumors (both, p < 0.001) than in healthy human bronchial epithelial BEAS-2B cells and adjacent healthy lung tissues, respectively. Decreased survival was significantly associated with PAK1 overexpression in the entire cohort (χ2 = 8.48, p = 0.0036), men (χ2 = 17.1, p < 0.0001), and current and former smokers (χ2 = 19.2, p < 0.0001). Notably, epidermal growth factor receptor (EGFR) mutation-positive lung cancer patients with high PAK1 expression showed higher mortality rates than those with low PAK1 expression (91.3% vs. 62.5%, p = 0.02). Therefore, PAK1 overexpression could serve as a molecular target for the treatment of EGFR mutation-positive lung cancer, especially among male patients and current/former smokers.

Upregulation of P21-Activated Kinase 1 (PAK1)/CREB Axis in Squamous Non-Small Cell Lung Carcinoma.

BACKGROUND/AIMS: p21-activated Ser/Thr kinase 1 (PAK1) is essential for the genesis and development of many cancers. The purpose of this study was to investigate the role of the PAK1-cyclic AMP response element-binding (CREB) axis in non-small cell lung cancer (NSCLC) tumorigenesis and its related mechanisms. METHODS: Western blot assay and immunohistochemical staining were employed to investigate the PAK1 and CREB expression in the tissue microarray of human squamous NSCLC. Co-immunoprecipitation and immunofluorescence confocal assays were performed to determine the link between PAK1 and CREB. NSCLC xenograft models were used to study oncogenic function of PAK1 in vivo. RESULTS: We observed that PAK1 and CREB expression levels were significantly elevated in human squamous NSCLC-tissue specimens, compared with those in adjacent normal bronchial or bronchiolar epithelial-tissue specimens, as well as their phosphorylated forms, based on western blotting. We showed in vitro that PAK1 knockdown by small-interfering RNA (siRNA) blocked CREB phosphorylation, whereas plasmid-based PAK1 overexpression resulted in CREB phosphorylation at Ser133, based on western blotting. In addition, PAK1 interacted with CREB in co-immunoprecipitation assays. Additionally, our in vitro findings detected by flow cytometry revealed that PAK1 silencing attenuated cell cycle progression, inducing apoptosis. Inhibition of PAK1 expression reduced tumor sizes and masses by modulating CREB expression and activation in xenograft models. CONCLUSION: These results suggest a novel mechanism whereby the PAK1-CREB axis drives carcinogenesis of squamous-cell carcinomas, and have important implications in the development of targeted therapeutics for squamous-cell lung cancer.

Current Status and Future of Lung Donation in Korea.

Lung transplantation is the only effective treatment option for patients with end-stage lung disease. However, donor organ shortage makes timely transplant not possible for all patients, especially in Korea. We investigated the number and utilization of donor lungs by retrospectively reviewing all donor organs registered in the Korea Network for Organ Sharing database from March 2012 to March 2016. The donors were stratified into 4 groups by donor acceptability criteria. A total of 1,304 donors were included. Of those, 295 brain-dead donors (22.6%) consented to lung donation. Among these consented donors, 168 donors (12.9%) were retrieved for lung transplant. Retrieval rate was very low compared with that of the kidney (93.9%), liver (86.3%), and heart (27.3%). The characteristics of utilized donor lungs were: mean age, 40.5 years (range: 18 to 63 years); mean partial pressure of oxygen, 356.5 mmHg; mean smoking history, 5.9 pack-years; and mean body mass index, 22.6 kg/m². The proportion of donors with acceptable condition of the transplanted lungs was only 39.3% (ideal 19, standard 47, marginal 70, unusable 32). Among brain-dead patients who denied to donate lungs (n = 1,009), 82 were potentially acceptable donors (ideal 19, standard 63), which was equal to half of actually transplanted lung donations. Many potential donor lungs, which are currently excluded, may be successfully used in lung transplantation in Korea. The available lung donors must be actively selected and managed to maximize the utilization of this precious resource.

The Utility of Preemptive Distal Perfusion Cannulation During Peripheral Venoarterial Extracorporeal Membrane Oxygenation Support.

OBJECTIVES: We compared the ischemia and rescue rates according to the strategy of distal cannulation. BACKGROUND: Limb ischemia developing during percutaneous venoarterial (VA) extracorporeal membrane oxygenation (ECMO) is a potentially severe complication. Although appropriate use of a distal perfusion cannula can avoid ischemia, evidences about distal cannulation is still lacking. METHODS: Patients who underwent peripheral VA ECMO between January 2010 and August 2015 were reviewed. We classified patients into 2 groups in terms of insertion timing with respect to the onset of ischemia. The preemptive strategy group underwent early insertion of a distal perfusion cannula at commencement of ECMO support. The rescue strategy group underwent delayed cannula insertion after onset of limb ischemia. RESULTS: A total of 151 patients were included in the analysis. Forty-four patients formed the preemptive strategy group and 107 patients formed the rescue strategy group. In total, 10 of 151 (6.7%) patients developed significant limb ischemia, they all were the rescue strategy group (10/107, 9.3%). Of the 10 patients, 2 patients were rescued from limb ischemia after distal cannulation. Otherwise, ischemia was not rescued in the remaining eight patients. Of the latter 8, 3 patient required surgical interventions (2 fasciotomy and 1 below-the-knee amputation) and the other five died from disease aggravation prior to surgical intervention. CONCLUSIONS: Preemptive distal perfusion cannulation is safe and effective when used to prevent lower limb ischemia in patients undergoing femoral cannulation to treat ECMO. However, delayed distal cannulation increases the extent of cannulation site bleeding, without improving the ischemia.

Impact of bloodstream infections on catheter colonization during extracorporeal membrane oxygenation.

There are concerns about secondary extracorporeal membrane oxygenation (ECMO) catheter infections in bacteremic patients. We investigated the association between blood stream infection (BSI) and ECMO catheter colonization. From January 2012 to August 2014, 47 adults who received ECMO support were enrolled. The ECMO catheter tip was cultured at the end of the ECMO procedure. The enrolled patients were classified into two groups according to the presence of BSI during ECMO support and analyzed with respect to ECMO catheter colonization. Of 47 cases, BSI during ECMO was identified in 13 patients (27.7 %). ECMO catheter colonization was identified in 6 (46.2 %) patients in the BSI group and 3 (8.8 %) in the non-BSI group. BSI during ECMO support was independently associated with ECMO catheter colonization [odds ratio (OR) 5.55; 95 % confidence interval (CI) 1.00-30.73; p = 0.049]. The organisms colonizing ECMO catheters in the setting of primary BSI were predominantly Gram-positive cocci and Candida species. Acinetobacter baumannii was the most common colonizing pathogen in the setting of secondary BSI. All the organisms colonizing ECMO catheters were multi-drug resistant organisms, including methicillin-resistant S. aureus, Candida glabrata, and carbapenem-resistant A. baumannii. ECMO catheters may become contaminated with multi-drug resistant pathogens in the presence of BSI. Therefore, ECMO should be applied cautiously in septic patients with bacteremia caused by multi-drug resistant pathogens.

Validity of Outcome Prediction Scoring Systems in Korean Patients with Severe Adult Respiratory Distress Syndrome Receiving Extracorporeal Membrane Oxygenation Therapy.

Recently, several prognostic scoring systems for patients with severe acute respiratory distress syndrome (ARDS) requiring extracorporeal membrane oxygenation (ECMO) have been published. The aim of this study was to validate the established scoring systems for outcome prediction in Korean patients. We retrospectively reviewed the data of 50 patients on ECMO therapy in our center from 2012 to 2014. A calculation of outcome prediction scoring tools was performed and the comparison across various models was conducted. In our study, the overall hospital survival was 46% and successful weaning rate was 58%. The Predicting Death for Severe ARDS on V-V ECMO (PRESERVE) score showed good discrimination of mortality prediction for patients on ECMO with AUC of 0.80 (95% CI 0.66-0.90). The respiratory extracorporeal membrane oxygenation survival prediction (RESP) score and simplified acute physiology score (SAPS) II score also showed fair prediction ability with AUC of 0.79 (95% CI 0.65-0.89) and AUC of 0.78 (95% CI 0.64-0.88), respectively. However, the ECMOnet score failed to predict mortality with AUC of 0.51 (95% CI 0.37-0.66). When evaluating the predictive accuracy according to optimal cut-off point of each scoring system, RESP score had a best specificity of 91.3% and 66.7% of sensitivity, respectively. This study supports the clinical usefulness of the prognostic scoring tools for severe ARDS with ECMO therapy when applying to the Korean patients receiving ECMO.

Impact of Implementation of an Automated Liquid Culture System on Diagnosis of Tuberculous Pleurisy.

This study was conducted to evaluate the impact of implementation of an automated liquid culture system on the diagnosis of tuberculous pleurisy in an HIV-uninfected patient population. We retrospectively compared the culture yield, time to positivity, and contamination rate of pleural effusion samples in the BACTEC Mycobacteria Growth Indicator Tube 960 (MGIT) and Ogawa media among patients with tuberculous pleurisy. Out of 104 effusion samples, 43 (41.3%) were culture positive on either the MGIT or the Ogawa media. The culture yield of MGIT was higher (40.4%, 42/104) than that of Ogawa media (18.3%, 19/104) (P<0.001). One of the samples was positive only on the Ogawa medium. The median time to positivity was faster in the MGIT (18 days, range 8-32 days) than in the Ogawa media (37 days, range 20-59 days) (P<0.001). No contamination or growth of nontuberculous mycobacterium was observed on either of the culture media. In conclusion, the automated liquid culture system could provide approximately twice as high yields and fast results in effusion culture, compared to solid media. Supplemental solid media may have a limited impact on maximizing sensitivity in effusion culture; however, further studies are required.

Prevalence of chronic sputum and associated factors in Korean adults.

Chronic sputum is a troublesome symptom in many respiratory diseases. The prevalence of chronic sputum varies from 1.2% to 13% according to the country. The purpose of this study was to estimate the prevalence of chronic sputum and to find its associated factors in a general Korean population. We analyzed the data of the Korea National Health and Nutrition Examination Survey 2010 and 2011. A total number of 6,783 subjects aged 40 yr or more were enrolled in this study with 3,002 men and 3,781 women. As a result, the prevalence of chronic sputum was 6.3% (n=430). Significant risk factors for chronic sputum by multivariate analysis were: age (≥ 70 yr) (odds ratio [OR], 1.954; 95% confidence interval [CI], 1.308-2.917), current smoking (OR, 4.496; 95% CI, 3.001-6.734), chronic obstructive pulmonary disease (COPD) (OR, 1.483; 95% CI, 1.090-2.018), and tuberculosis (OR, 1.959; 95% CI, 1.307-2.938). In conclusion, the prevalence of chronic sputum in Korea was in the intermediate range compared with other countries. Smoking is a preventable risk factor identified in this study, and major respiratory diseases, such as COPD and tuberculosis, should be considered in subjects with chronic sputum.

Weight calibration in the joint modelling of medical cost and mortality.

Joint modelling of longitudinal and time-to-event data is a method that recognizes the dependency between the two data types, and combines the two outcomes into a single model, which leads to more precise estimates. These models are applicable when individuals are followed over a period of time, generally to monitor the progression of a disease or a medical condition, and also when longitudinal covariates are available. Medical cost datasets are often also available in longitudinal scenarios, but these datasets usually arise from a complex sampling design rather than simple random sampling and such complex sampling design needs to be accounted for in the statistical analysis. Ignoring the sampling mechanism can lead to misleading conclusions. This article proposes a novel approach to the joint modelling of complex data by combining survey calibration with standard joint modelling. This is achieved by incorporating a new set of equations to calibrate the sampling weights for the survival model in a joint model setting. The proposed method is applied to data on anti-dementia medication costs and mortality in people with diagnosed dementia in New Zealand.

Intubated or rigid bronchoscopy under high-flow oxygenation and deep sedation without ventilator or anesthesiologist: A report on a new technique.

As the demand for advanced bronchoscopic procedures increases, prolonged sedation with adequate oxygenation has become essential. Traditionally, these procedures require an anesthesiologist to provide (positive-pressure or jet) ventilator support. However, recent innovations have enabled advanced bronchoscopy under high-flow endotracheal oxygenation and deep sedation without these requirements. Following oropharyngeal lidocaine anaesthesia, deep sedation was induced using fentanyl and remimazolam. Thereafter lidocaine was instilled into the larynx, trachea, and main bronchi using a flexible bronchoscope with a spray catheter. Finally, either an uncuffed endotracheal tube (Case 1) or a rigid bronchoscope (Case 2) was inserted, and advanced bronchoscopic procedures, such as cryobiopsy and stent insertion, were successfully performed without a ventilator or an anesthesiologist. Our novel technique is expected to facilitate the easier and adequate performance of advanced high-level bronchoscopic procedures by pulmonologists, even in resource-limited settings.

Immune Checkpoint Inhibitor Score Predicts Survival Benefit of Immunotherapy in Patients with Non-small Cell Lung Cancer.

BACKGROUND: The use of immune checkpoint inhibitors (ICIs) in patients with advanced lung cancer is increasing. Despite ongoing studies to predict the efficacy of ICIs, its use in clinical practice remains difficult. Thus, we aimed to discover a predictive marker by analyzing blood cell characteristics and developing a scoring system for patients treated with ICIs. METHODS: This was a prospective multicenter study in patients with advanced nonsmall cell lung cancer (NSCLC) who received ICIs as second-line treatment from June 2021 to November 2022. Blood cell parameters in routine blood samples were evaluated using an automated hematology analyzer. Immune checkpoint inhibitor score (IChIS) was calculated as the sum of neutrophil count score and immature granulocyte score. RESULTS: A total of 143 patients from four institutions were included. The treatment response was as follows: partial response, 8.4%; stable disease, 37.1%; and progressive disease, 44.8%. Median progression-free survival and overall survival after ICI treatment was 3.0 and 8.3 months, respectively. Median progression-free survival in patients with an IChIS of 0 was 4.0 months, which was significantly longer than 1.9 months in patients with an IChIS of 1 and 1.0 month in those with an IChIS of 2 (p=0.001). The median overall survival in patients with an IChIS of 0 was 10.2 months, which was significantly longer than 6.8 and 1.8 months in patients with an IChIS of 1 and 2, respectively (p<0.001). CONCLUSION: Baseline IChIS could be a potential biomarker for predicting survival benefit of immunotherapy in NSCLC.

The Real-World Outcome of First Line Atezolizumab in Extensive-Stage Small Cell Lung Cancer: A Multicenter Prospective Cohort Study.

PURPOSE: The addition of immune checkpoint inhibitors to chemotherapy has improved survival outcomes in patients with extensive-stage small cell lung cancer (ES-SCLC). However, their real-world effectiveness remains unknown. Therefore, we investigated the effectiveness of atezolizumab plus chemotherapy in ES-SCLC in actual clinical settings. MATERIALS AND METHODS: In this multicenter prospective cohort study, patients with ES-SCLC receiving or scheduled to receive atezolizumab in combination with etoposide and carboplatin were enrolled between June 2021 and August 2022. The primary outcomes were progression-free survival (PFS) and the 1-year overall survival (OS) rate. RESULTS: A total of 100 patients with ES-SCLC were enrolled from seven centers. Median age was 69 years, and 6% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2. The median PFS was 6.0 months, the 1-year OS rate was 62.2%, and the median OS was 13.5 months. An ECOG PS of 2-3 and progressive disease as the best response were poor prognostic factors for PFS, while an ECOG PS of 2-3 and brain metastasis were associated with poor prognosis for OS. In addition, consolidative thoracic radiotherapy was found to be an independent favorable prognostic factor for OS (hazard ratio, 0.336; p=0.021). Grade ≥ 3 treatment-related adverse events were observed in 7% of patients, with treatment-related deaths occurring in 2% of patients. CONCLUSION: We provided evidence of the favorable real-world effectiveness and safety of atezolizumab plus chemotherapy in ES-SCLC patients, including in the elderly and those with poor ECOG PS. Additional consolidative thoracic radiotherapy may also benefit ES-SCLC patients.

Real-World Outcomes of Crizotinib in ROS1-Rearranged Advanced Non-Small-Cell Lung Cancer.

Real-world data on the use and outcomes of crizotinib in ROS1-rearranged non-small-cell lung cancer (NSCLC) are limited. This study aims to analyze the real-world efficacy of crizotinib in South Korea and explore the utilization of liquid biopsies that implement next-generation sequencing (NGS) using cell-free total nucleic acids. In this prospective multicenter cohort study, 40 patients with ROS1-rearranged NSCLC, either starting or already on crizotinib, were enrolled. Patients had a median age of 61 years, with 32.5% presenting brain/central nervous system (CNS) metastases at treatment initiation. At the data cutoff, 48.0% were still in treatment; four continued with it even after disease progression due to the clinical benefits. The objective response rate was 70.0%, with a median duration of response of 27.8 months. The median progression-free survival was 24.1 months, while the median overall survival was not reached. Adverse events occurred in 90.0% of patients, primarily with elevated transaminases, yet these were mostly manageable. The NGS assay detected a CD74-ROS1 fusion in 2 of the 14 patients at treatment initiation and identified emerging mutations, such as ROS1 G2032R, ROS1 D2033N, and KRAS G12D, during disease progression. These findings confirm crizotinib's sustained clinical efficacy and safety in a real-world context, which was characterized by a higher elderly population and higher rates of brain/CNS metastases. The study highlights the clinical relevance of liquid biopsy for detecting resistance mechanisms, suggesting its value in personalized treatment strategies.

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.

Healthcare utilization of lung cancer patients associated with exposure to fine particulate matter: A Korean cohort study.

BACKGROUND: Higher concentrations of particulate matter (PM) have been shown to cause deterioration of the symptoms of respiratory and cardiovascular disease in several regional studies. Here, we aimed to investigate the healthcare utilization of lung cancer patients associated with short-term exposure to PM at the national level in Korea. METHODS: We extracted the data of 210 558 subjects over a period of 3 years (2015-2017), who were diagnosed with lung cancer before 2015 and benefited from the National Health Insurance Sharing Service. We performed the interpolation method using the geographic information system to calculate the estimated mean PM2.5 and PM10 concentrations by regions and classified three groups as high (upper 10%), intermediate (10%-90%), and low (bottom 10%) based on the mean PM mass concentrations of the month. RESULTS: The monthly average number of outpatient visits was significantly increased in high PM2.5 urban areas (46.296 vs. 50.646, p = 0.015). In high PM2.5 nationwide regions, the monthly average number of emergency admission was significantly increased (0.528 vs. 0.785, p = 0.001). The outpatient visits tended to change with PM2.5 concentration and correlated with PM10 /PM2.5 concentrations in urban and nationwide areas. In high PM2.5 urban regions, there was a significant increase in bronchodilator prescriptions (3.102 vs. 3.758, p = 0.008). Concerning high PM2.5 nationwide regions, there were significantly increased prescriptions of antibiotics, steroids, bronchodilators, antihistamines, and mucolytics. CONCLUSIONS: This study suggests that exposure to PM2.5 is significantly associated with hospital utilization and drug prescription in lung cancer patients.

Initial Tumor Necrosis Factor-Alpha and Endothelial Activation Are Associated with Hemorrhagic Complications during Extracorporeal Membrane Oxygenation.

Studies on inflammatory markers, endothelial activation, and bleeding during extracorporeal membrane oxygenation (ECMO) are lacking. Blood samples were prospectively collected after ECMO initiation from 150 adult patients who underwent ECMO for respiratory failure between 2018 and 2021. After excluding patients who died early (within 48 h), 132 patients were finally included. Their tumor necrosis factor-alpha (TNF-α), tissue factor (TF), soluble thrombomodulin (sTM), and E-selectin levels were measured. A Cox proportional hazards regression model was used to estimate the hazard ratio for hemorrhagic complications during ECMO. The 132 patients were divided into hemorrhagic (n = 23, H group) and non-complication (n = 109, N group) groups. The sequential organ failure assessment score, hemoglobin level, and ECMO type were included as covariates in all Cox models to exclude the effects of clinical factors. After adjusting for these factors, initial TNF-α, TF, sTM, E-selectin, and activated protein C levels were significantly associated with hemorrhagic complications (all p < 0.001). TNF-α, TF, and E-selectin better predicted hemorrhagic complications than the model that included only the aforementioned clinical factors (clinical factors only (area under the curve [AUC]: 0.804), reference; TNF-α (AUC: 0.914); TF (AUC: 0.915); E-selectin (AUC: 0.869)). Conclusions: TNF-α levels were significantly predictive of hemorrhagic complications during ECMO.

Evaluation of Blood Tumor Mutation Burden for the Efficacy of Second-Line Atezolizumab Treatment in Non-Small Cell Lung Cancer: BUDDY Trial.

This study aimed to investigate the feasibility of blood-based biomarkers, including blood tumor mutation burden (bTMB), to predict atezolizumab efficacy in relapsed and advanced non-small cell lung cancer (NSCLC). Stage IV NSCLC patients who had previously received platinum-doublet chemotherapy were recruited and received 1200 mg of atezolizumab every three weeks. Blood was collected to obtain plasma cell-free DNA (cfDNA) before the first cycle (C0) and at the fourth cycle (C4). bTMB was measured by CT-ULTRA in patients with cfDNA over 10 ng. The objective response rate (ORR) of the enrolled 100 patients was 10%, and there was no difference in ORR according to bTMB (cutoff: 11.5 muts/Mb) at C0 (high bTMB: 8.1% vs. low bTMB: 11.1%). However, the C4/C0 bTMB ratio was significantly lower in the durable clinical benefit (DCB) patients. The cfDNA concentration at C0, the C4/C0 ratio of the cfDNA concentration, the highest variant allele frequency (hVAF), and the VAF standard deviation (VAFSD) were significantly lower in the DCB patients. In the multivariate analysis, a high cfDNA concentration at C0 (cutoff: 8.6 ng/mL) and a C4/C0 bTMB ratio greater than 1 were significantly associated with progression-free survival. These results suggest that baseline levels and dynamic changes of blood-based biomarkers (bTMB, cfDNA concentration, and VAFSD) could predict atezolizumab efficacy in previously treated NSCLC patients.

Real-world first-line afatinib for advanced EGFR mutation-positive non-small cell lung cancer in Korea: updated survival data.

Background: Data from clinical trials and real-world studies show that afatinib is effective in treating non-small cell lung cancer (NSCLC) harboring activating mutations in the epidermal growth factor receptor (EGFR) gene. A previous analysis of patients enrolled in the Korean Academy of Tuberculosis and Respiratory Disease (KATRD) EGFR cohort showed that first-line afatinib was well tolerated and effectiveness results were encouraging. At the time of the previous analysis, survival data were not mature. Here we briefly present updated survival data from the cohort. Methods: The study was a retrospective, multicenter (15 sites) review of electronic records of Korean adult patients (aged >20 years) with advanced EGFR mutation-positive NSCLC who initiated first-line afatinib (N=421). Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier survival curves. Results: Overall, median PFS was 20.2 months and median OS was 48.6 months. OS rates at 36 and 60 months were 60.1% and 42.3%, respectively. Presence vs. absence of baseline brain metastases was associated with significantly reduced median PFS (14.9 vs. 28.0 months; P<0.001) and median OS (32.2 vs. 65.6 months; P<0.001). The presence of common baseline EGFR mutations (Del19, L858R) was associated with significantly prolonged median OS (49.6 vs. 30.1 months; P=0.017). In patients stratified by the presence/absence of T790M EGFR mutation, the T790M mutation was associated with significantly reduced median PFS (P=0.0005) but there was no significant difference between groups in survival (P=0.263). There were no significant differences in PFS or OS for patients stratified by afatinib dose reduction or by age group (<70 vs. ≥70 years). Conclusions: Afatinib was effective in Korean patients with EGFR mutation-positive NSCLC with median OS over 4 years. The presence of baseline brain metastases and/or uncommon EGFR mutations were associated with reduced survival. In the absence of baseline brain metastases, median OS was more than 5 years.

Korean Real-World Data on Patients With Unresectable Stage III NSCLC Treated With Durvalumab After Chemoradiotherapy: PACIFIC-KR.

INTRODUCTION: This study aimed to investigate real-world evidence for efficacy and safety of durvalumab consolidation (DC) after chemoradiotherapy (CRT) in patients with unresectable stage III NSCLC. METHODS: Patients with stage III NSCLC who started DC after CRT between September 2018 and December 2020 and were treated at five tertiary hospitals in the Republic of Korea were included. The primary end point was real-world progression-free survival (rwPFS). Secondary end points were overall survival, objective response rate, and adverse events including radiation pneumonitis (RP) and immune-related adverse events (irAEs). RESULTS: A total of 157 patients were enrolled. At the median follow-up of 19.1 months, median rwPFS of DC was 25.9 months (95% confidence interval: 16.5-35.4) and the 1-, 2-, and 3-year rwPFS rates were 59.4%, 51.8%, and 43.5%, respectively. The median overall survival was not mature, and objective response rate of DC was 51.0%. High programmed death-ligand 1 expression (≥50%) and development of RP requiring steroid treatment were significantly associated with longer (p = 0.043) and shorter rwPFS (p = 0.036), respectively. RP, RP requiring steroid treatment, and irAEs developed in 57 (36.3%), 42 (26.8%), and 53 (33.8%) patients, respectively. Among peripheral blood cell counts at the initiation of DC, a high derived monocyte-to-lymphocyte ratio was the most significant risk factor for the development of RP requiring steroid treatment (OR 44.76, 95% CI: 8.89-225.43, p < 0.001) and irAEs (OR 2.85, 95% CI: 1.27-6.41, p = 0.011). CONCLUSIONS: Compared with the outcome of the PACIFIC trial, these real-world data revealed favorable survival benefits of DC after CRT in patients with unresectable stage III NSCLC. Blood-based biomarkers could predict higher-grade RP and irAEs before the initiation of DC.