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Background: Understanding cancer treatment–related cardiovascular (CV) events is important for cancer care; however, comprehensive evaluation of CV events in patients with lung cancer is limited. This study aimed to assess the cumulative incidence and associated risks of various CV event types in patients with non–small cell lung cancer (NSCLC). Methods: A total of 7868 individuals aged 40 years and older, recently diagnosed with NSCLC (2007–2018), were assessed with data obtained from the National Cancer Center, Korea. This study included nine types of CV events. A 2‐year cumulative incidence function (CIF) of CV events was estimated, with death as a competing event. The associated risks were assessed by subdistribution hazard ratio (sHR) in the Fine–Gray competing risks model. Results: CV events were observed in 7.8% of patients with NSCLC, with the most frequently observed types being atrial fibrillation and flutter (AF) (2.7%), venous thromboembolic disease (2.0%), and cerebrovascular disease (CeVD) (1.5%). Overall, all CV events were highest in the group treated with systemic therapy (CIF, 10.6%; 95% confidence interval [CI], 9.5%–11.8%), followed by those treated with surgery (CIF, 10.0%; 95% CI, 8.6%–11.6%); the incidence of AF (CIF, 5.7%; 95% CI, 4.6%–7.0%) was highest in patients treated with surgery. Individuals treated with systemic therapy were found to exhibit a higher CeVD risk than those treated with surgery (sHR, 4.12; 95% CI, 1.66–10.23). Among the patients who underwent surgery, those with lobectomy and pneumonectomy had a higher AF risk (vs. wedge resection/segmentectomy; sHR, 7.79; 95% CI, 1.87–32.42; sHR, 8.10; 95% CI, 1.60–40.89). Conclusions: These findings revealed treatment‐related CV event risks in patients with NSCLC, which suggests that the risk of AF in surgery and CeVD in systemic therapy should be paid more attention to achieve a better prognosis and improve cancer survivorship outcomes. Plain Language Summary: Atrial fibrillation and flutter (AF) is the most common cardiovascular event, particularly at a high risk in patients with non–small cell lung cancer (NSCLC) undergoing surgery.Patients receiving surgery with poor performance status, diagnosed with regional stage, and undergoing lobectomy or pneumonectomy are at a high risk of AF.Systemic/radiotherapy is associated with cerebrovascular and ischemic heart disease in patients with NSCLC. This study revealed that cardiovascular events occurred in approximately 8% of patients with non–small cell lung cancer during 2‐year treatment periods, with atrial fibrillation and flutter, venous thromboembolic disease, and cerebrovascular disease being the most common types. The findings further emphasize the importance of monitoring atrial fibrillation in patients receiving surgery and cerebrovascular disease in those treated with systemic therapy to enhance cancer care and survivorship outcomes. [ABSTRACT FROM AUTHOR]

Purpose The female sex is reported to have a higher risk of adverse events (AEs) from cytotoxic chemotherapy. Few studies examined the sex differences in AEs and their impact on the use of medical services during adjuvant chemotherapy. This sub-study aimed to compare the incidence of any grade and grade = 3 AEs, healthcare utilization, chemotherapy completion rate, and dose intensity according to sex. Materials and Methods This is a sub-study of a multicenter cohort conducted in Korea that evaluated the impact of healthcare reimbursement on AE evaluation in patients who received adjuvant chemotherapy between September 2013 and December 2016 at four hospitals in Korea. Results A total of 1,170 patients with colorectal, gastric, or non-small cell lung cancer were included in the study. Female patients were younger, had fewer comorbidities, and experienced less postoperative weight loss of > 10%. Females had significantly higher rates of any grade AEs including nausea, abdominal pain, stomatitis, vomiting, and neutropenia, and experienced more grade = 3 neutropenia, nausea, and vomiting. The dose intensity of chemotherapy was significantly lower in females, and they also experienced more frequent dose reduction after the first cycle. Moreover, female patients receiving platinum-containing regimens had significantly higher rates of unscheduled outpatient visits. Conclusion Our study found that females experienced a higher incidence of multiple any-grade AEs and severe neutropenia, nausea, and vomiting, across various cancer types, leading to more frequent dose reductions. Physicians should be aware of sex differences in AEs for chemotherapy decisions. [ABSTRACT FROM AUTHOR]

Background: Companion diagnostic tests play a crucial role in guiding treatment decisions for patients with non‐small cell lung cancer (NSCLC). The Oncomine Dx Target Test (ODxTT) Multi‐CDx System has emerged as a prominent companion diagnostic method. However, its efficacy in detecting driver gene mutations, particularly rare mutations, warrants investigation. Aims: This study aimed to assess the performance of the ODxTT in detecting driver gene mutations in NSCLC patients. Specifically, we aimed to evaluate its sensitivity in detecting epidermal growth factor receptor (EGFR) mutations, a key determinant of treatment selection in NSCLC. Materials and Methods: We conducted a retrospective analysis of NSCLC patients who underwent testing with the ODxTT at Keio University Hospital between May 2020 and March 2022. Patient samples were subjected to both DNA and RNA tests. Driver gene mutation status was assessed, and instances of missed mutations were meticulously examined. Results: Of the 90 patients, five had nucleic acid quality problems, while 85 underwent both DNA and RNA tests. Driver gene mutations were detected in 56/90 (62.2%) patients. Of the 34 patient specimens, driver mutations were not detected using the ODxTT; however, epidermal growth factor receptor (EGFR) mutations were detected using polymerase chain reaction‐based testing in two patients, and a KRAS mutation was detected by careful examination of the sequence data obtained using the ODxTT in one patient. For the above three cases, carefully examining the gene sequence information obtained using the ODxTT could identify driver mutations that were not mentioned in the returned test results. Additionally, we confirmed comparable instances of overlook results for EGFR mutations in the dataset from South Korea, implying that this type of oversight could occur in other countries using the ODxTT. EGFR mutation was missed in ODxTT in Japan (6.3%, 2/32), South Korea (2.0%, 1/49), and overall (3.7%, 3/81). Conclusion: Even if sufficient tumor samples are obtained, rare EGFR mutations (which are excluded from the ODxTT's genetic mutation list) might not be detected using the current ODxTT system due to the program used for sequence analysis. However, such rare EGFR mutations can still be accurately detected on ODxTT's sequence data using next‐generation sequencing. [ABSTRACT FROM AUTHOR]

Background: ONO‐4538‐52/TASUKI‐52 was performed in Japan, Korea, and Taiwan to determine the oncological effectiveness and safety of combining nivolumab or placebo with bevacizumab plus platinum chemotherapy for the initial (first‐line) treatment of patients with advanced non‐squamous non‐small cell lung cancer (nsNSCLC). At the interim analysis (minimum follow‐up, 7.4 months), the independent radiology review committee‐assessed progression‐free survival was significantly longer in the nivolumab arm, but overall survival (OS) data were immature. Methods: Here, we present the updated OS data. Patients with treatment‐naïve stage IIIB/IV or recurrent nsNSCLC without driver mutations in ALK, EGFR, or ROS1, were randomized 1:1 to receive either nivolumab or placebo. Patients in both arms received paclitaxel, carboplatin, and bevacizumab, administered 3‐weekly for a maximum of 6 cycles. Nivolumab/placebo and bevacizumab were subsequently continued until disease progression or unacceptable toxicity. Results: Overall, 550 patients were randomized. At the time of the analysis (minimum follow‐up: 19.4 months), the median OS was longer in the nivolumab arm than in the placebo arm (30.8 vs. 24.7 months; hazard ratio 0.74, 95% confidence interval 0.58–0.94). The 12‐month OS rates were 81.3% vs. 76.3% in the nivolumab vs. placebo arms, respectively. The respective 18‐month OS rates were 69.0% vs. 61.9%. Conclusion: Nivolumab plus platinum chemotherapy and bevacizumab demonstrated longer OS vs. the placebo combination. We believe this regimen is viable as a standard, first‐line treatment for patients with advanced nsNSCLC without driver mutations in ALK, EGFR, or ROS1. [ABSTRACT FROM AUTHOR]

Background: We aimed to examine whether patients with de novo and relapsed/progressed stage IIIB–IV non-small cell lung cancer (NSCLC) without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations have different prognoses. Methods: This retrospective study analyzed the Health Insurance Review and Assessment claims data in South Korea from 2013 to 2020. Patients with stage IIIB–IV NSCLC without EGFR or ALK mutations who received first-line palliative therapy between 2015 and 2019 were identified. Overall survival (OS), time to first subsequent therapy (TFST), and time to second subsequent therapy (TSST) were estimated using the Kaplan–Meier method. Multivariate Cox regression analysis was used to reveal the impact of de novo versus relapsed/progressed disease on OS. Treatment patterns, including treatment sequence, top five most frequent regimens, and time to treatment discontinuation, were described in both groups. Results: Of 14,505 patients, 12,811 (88.3%) were de novo, and 1,694 (11.7%) were relapsed/progressed. The median OS in the de novo group was 11.0 versus 11.5 months in the relapsed/progressed group (P = 0.002). The ongoing treatment probability was higher in relapsed/progressed patients than in de novo patients from 6.4 months since the initiation of first-line treatment (P < 0.001). Median TSST was shorter in the de novo group than in the relapsed/progressed group (9.5 vs. 9.9 months, P < 0.001). In multivariate analysis, de novo disease was associated with shorter OS (hazard ratio 1.07; 95% confidence interval 1.01–1.14). The overall treatment patterns for de novo and relapsed/progressed patients were similar. Conclusions: De novo patients had poorer OS and TSST after the initiation of palliative therapy than relapsed/progressed patients. These findings suggest that the stage of the disease at the time of initial diagnosis should be considered in observational studies and clinical trials as a prognostic factor. [ABSTRACT FROM AUTHOR]

Purpose The impact of epidermal growth factor receptor (EGFR) mutation in locally advanced non-small cell lung cancer (NSCLC) remains controversial. This study was conducted to investigate the clinical outcomes and recurrence patterns after definitive chemoradiotherapy (CRT) in patients with unresectable stage III non-squamous-cell lung cancer according to EGFR mutation status. Materials and Methods We retrospectively reviewed 604 patients with pathologically confirmed stage III NSCLC who were treated with definitive CRT and were examined for EGFR mutation at Samsung Medical Center, Korea, from January 2013 to December 2018. Among them, we identified 236 patients with stage III non-squamous-cell lung cancer who were treated with definitive CRT and were examined for EGFR mutation status. We analyzed the frequency of EGFR mutation, progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and recurrence pattern. Results Among 236 patients, EGFR mutation was detected in 71 patients (30.1%) and the median follow-up duration was 41.7 months. There were no significant differences in PFS (9.9 vs. 10.9 months, p=0.236), and ORR to CRT (93.0% vs. 90.3%, p=0.623) according to EGFR mutation status. However, the EGFR mutant group showed significantly higher recurrence (88.7% vs. 75.2%, p=0.022), distant metastasis (76.1% vs. 61.2%, p=0.036) rates, especially brain (38.0% vs. 12.7%, p < 0.001), and better median OS (59.2 vs. 41.3 months, p=0.037) compared with patients without EGFR mutation. Conclusion Patients with EGFR mutation-positive unresectable stage III non-squamous lung cancer exhibited higher recurrence and distant metastasis rates, especially brain metastasis. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is representative of a high frequency and high mortality disease and ranks at the top in incidence and mortality in Korea, when excluding thyroid cancer. In this manuscript, we focused on current targeted therapies for lung cancer used widely in the medical field. Current Concepts: The majority of patients with lung cancer cannot be treated with surgery only and require chemotherapeutics or radiation therapy. Currently, classical chemotherapeutic agents, targeted agents, and immune checkpoint inhibitors are the most widely used. Recently, the Research and Development of antibodydrug conjugates is gaining attention, and this may become a more widely prescribed treatment in the future. Among the available treatment options, targeted therapy is becoming increasingly feasible and widespread for treating inoperable lung cancers, where driver mutations have been identified, and for adjuvant or neoadjuvant therapies. Next-generation sequencing (NGS) improves the ability to identify driver mutations that were previously difficult to detect and can also be performed on blood samples where no cancer tissue is available for testing. This makes it possible to identify therapeutic targets for targeted therapy more rapidly. Discussion and Conclusion: The most common type of lung cancer in Korea is adenocarcinoma, for which a driver mutation has been identified. Newly developed drugs target previously problematic mutations or cancer cell lines that have acquired resistance induced during the treatment process. The survival rate of patients with lung cancer is expected to improve with the development of tailored treatments for targets identified from the NGS data of the patient. This paper will help clinicians understand the current state of targeted therapies for lung cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Despite the dynamic treatment landscape for EGFR mutant-positive metastatic non-small cell lung cancer (EGFRm+ mNSCLC), most of the earlier studies have focused on US or Western populations. Objective: The objective of this study was to explore real-world treatment patterns and outcomes of South Korean patients with EGFRm+ mNSCLC. Methods: Retrospective chart review of adult patients with EGFRm+ mNSCLC who received systemic treatment between January-2019 and June-2019. Results: A total of 162 patients were included from 21 hospitals, with a median follow-up of 15.6 months. Median age was 65.0 years, 22% had central nervous system metastasis, and 57% and 38% had exon 19 deletion and exon 21 L858R, respectively. Among 144 patients (89%) who received first-line EGFR-tyrosine kinase inhibitor, afatinib was most the common (44%), followed by gefitinib (28%) and erlotinib (13%). First-line chemotherapy was more common when an EGFR-mutation was detected after versus before first-line treatment initiation (31% vs 5%). Discontinuation of first-line treatment was mostly due to disease-progression (81%) and toxicity (7%). Among 58 (78%) patients who received second-line treatment, osimertinib was the most common (40%). Most (60%) patients reported ≥1 Grade ≥3 adverse event during first-line treatment. Following initiation of first-line treatment, physician visits and chest X-rays were the most frequent healthcare utilisation events. Rates of emergency-room visits and hospitalization were 12% and 16%, respectively, with a mean length-of-stay of 10.4 days. At 12 months, overall survival rate was 95%, and numerically worse for patients with exon 21 versus 19 mutations. Conclusions: Characteristics and clinical outcomes of Korean patients with EGFRm+ mNSCLC in real-world practice were comparable to those observed in clinical trials. As osimertinib was not reimbursed for first-line treatment before study completion, further investigation is warranted to explore evolving treatment practice. [ABSTRACT FROM AUTHOR]

Background: This study evaluated whether an addition of bevacizumab to erlotinib improves clinical outcomes in patients with advanced EGFR‐mutated non–small cell lung cancer (NSCLC). Methods: This is an open‐label, multicenter, randomized Phase 2 study in South Korea. Chemonaïve patients with Stage IIIB/IV NSCLC with EGFR 19 deletion or L858R mutation were eligible. Asymptomatic brain metastasis (BM) was enrolled without local treatment. Patients received either erlotinib plus bevacizumab or erlotinib. Results: Between December 2016 and March 2019, 127 patients were randomly assigned to receive erlotinib plus bevacizumab (n = 64) or erlotinib (n = 63). Fifty‐nine (46.5%) patients had baseline BM. Fewer patients in the erlotinib plus bevacizumab arm received radiotherapy for BM than in the erlotinib arm (10.3% vs. 40.0%). A trend toward longer progression‐free survival (PFS) was observed in the erlotinib plus bevacizumab arm compared with the erlotinib alone arm; however, it was not statistically significant (median PFS, 17.5 months vs. 12.4 months; hazard ratio [HR], 0.74; 95% CI, 0.51–1.08; p =.119). The unplanned subgroup analysis showed a longer PFS with erlotinib plus bevacizumab in patients with BM (median PFS, 18.6 months vs. 10.3 months; HR, 0.54; 95% CI, 0.31–0.95; p =.032). Grade 3 or worse adverse events occurred in 56.6% of the erlotinib plus bevacizumab arm and 20.6% of the erlotinib arm. Conclusions: Although it was not statistically significant, a trend to improvement in PFS was observed in patients with erlotinib plus bevacizumab compared to erlotinib alone. Plain Language Summary: A randomized Phase 2 study compared erlotinib with or without bevacizumab in previously untreated patients with advanced non–small cell lung cancer with EGFR mutation. The erlotinib plus bevacizumab failed to improve median progression‐free survival compared with the erlotinib alone. However, the progression‐free survival benefit from erlotinib plus bevacizumab was found in patients with brain metastasis with no severe hemorrhagic adverse effects. A trend to improvement in progression‐free survival was observed in patients with advanced EGFR‐mutated non–small cell lung cancer treated with erlotinib plus bevacizumab compared with erlotinib alone. The progression‐free survival benefit from erlotinib plus bevacizumab was most significant in patients with brain metastasis with no severe hemorrhagic adverse effects. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose This study aimed to provide the clinical characteristics, prognostic factors, and 5-year relative survival rates of lung cancer diagnosed in 2015. Materials and Methods The demographic risk factors of lung cancer were calculated using the KALC-R (Korean Association of Lung Cancer Registry) cohort in 2015, with survival follow-up until December 31, 2020. The 5-year relative survival rates were estimated using Ederer II methods, and the general population data used the death rate adjusted for sex and age published by the Korea Statistical Information Service from 2015 to 2020. Results We enrolled 2,657 patients with lung cancer who were diagnosed in South Korea in 2015. Of all patients, 2,098 (79.0%) were diagnosed with non–small cell lung cancer (NSCLC) and 345 (13.0%) were diagnosed with small cell lung cancer (SCLC), respectively. Old age, poor performance status, and advanced clinical stage were independent risk factors for both NSCLC and SCLC. In addition, the 5-year relative survival rate declined with advanced stage in both NSCLC (82%, 59%, 16%, 10% as the stage progressed) and SCLC (16%, 4% as the stage progressed). In patients with stage IV adenocarcinoma, the 5-year relative survival rate was higher in the presence of epidermal growth factor receptor (EGFR) mutation (19% vs. 11%) or anaplastic lymphoma kinase (ALK) translocation (38% vs. 11%). Conclusion In this Korean nationwide survey, the 5-year relative survival rates of NSCLC were 82% at stage I, 59% at stage II, 16% at stage III, and 10% at stage IV, and the 5-year relative survival rates of SCLC were 16% in cases with limited disease, and 4% in cases with extensive disease. [ABSTRACT FROM AUTHOR]

Background: Tumor spread through airspaces (STAS) is a recently determined pathologic phenomenon of lung cancer with significant prognostic impact. This study aimed to analyze the unexplored correlation between preoperative biopsy procedure and a higher risk of STAS and its impact on STAS-related outcomes in resected stage I non-small cell lung cancer (NSCLC).Research Question: Does preoperative biopsy procedure affect the risk of STAS and STAS-related outcomes in surgically treated stage I NSCLC?Study Design and Methods: We examined 2,169 patients who underwent surgery for pathologic stage I NSCLC from January 2011 through December 2019 at the Seoul National University Bundang Hospital, a tertiary center in South Korea. Factors including percutaneous needle biopsy (PCNB) and bronchoscopic biopsy were assessed for determining the association between preoperative biopsy procedure and an elevated risk of STAS. In addition, the impact of preoperative biopsy on STAS-related prognosis (recurrence and lung cancer-specific mortality) was evaluated with multivariate Cox regression analyses.Results: STAS findings were positive in 638 of 2,169 patients (29.4%). An insignificant association was found between preoperative biopsy (both PCNB and bronchoscopic biopsy) and STAS. After adjustments for preoperative tumor biopsy, STAS was a significant risk factor for cancer recurrence (hazard ratio [HR], 1.72; 95% CI, 1.20-2.48). Additionally, sublobar resection remained a significant risk factor for recurrence (HR, 3.20; 95% CI, 1.65-6.21) and lung cancer-specific mortality (HR, 12.71; 95% CI, 3.68-43.92) in patients with positive STAS findings. However, this association was insignificant for patients without STAS. Preoperative biopsy was not a significant risk factor for either recurrence and mortality, regardless of STAS positivity.Interpretation: Preoperative biopsy in stage I NSCLC neither was associated with an elevated risk of STAS nor influenced the prognosis related to STAS. Physicians can be less apprehensive about performing preoperative biopsy in relationship to STAS. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that gut microbiota dysbiosis adversely affects the efficacy of immune checkpoint inhibitors (ICIs). Our objective was to investigate the association between concomitant use of proton pump inhibitors (PPIs) and ICIs, and poor prognosis in patients with nonsmall cell lung cancer (NSCLC). We conducted a cohort study using a completely enumerated lung cancer cohort from a nationwide healthcare database in South Korea. We identified 2963 patients treated with ICIs as second‐line or later therapy for stage ≥IIIB NSCLC. PPI use was ascertained within 30‐days before and on the date of ICI initiation, and nonuse was defined as no prescription of PPIs during this period. Using national vital statistics in South Korea, we assessed the risk of all‐cause mortality associated with concomitant PPI use through a propensity score‐matched Cox proportional hazard model. Among 1646 patients included after 1:1 propensity score‐matching, concomitant PPI use was associated with a 28% increased risk of all‐cause mortality, compared to nonuse (adjusted hazard ratio [HR] 1.28; 95% confidence intervals [CIs], 1.13‐1.46). We observed an increased risk when we restricted the analysis to new users of PPI (adjusted HR = 1.64; 95% CI = 1.25‐2.17). Subgroup analysis showed that PPI use was associated with high mortality risk among patients with viral hepatitis (adjusted HR = 2.72; 95% CI = 1.54‐4.78; Pinteraction =.048). Our study indicates that PPI use is associated with poor prognosis in NSCLC patients treated with ICIs. Further prospective studies are required to determine the risk‐benefit balance of concomitant use of PPIs and ICIs. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) have shown significant improvements in patients with advanced non–small cell lung cancer (NSCLC). One of the major issues with ICIs is determining the optimal treatment duration. Methods: This multicenter, retrospective study analyzed clinical outcomes in patients with NSCLC who completed 2 years of ICI therapy or were treated for more than 6 months and then discontinued ICIs without disease progression at 11 medical centers in Korea between August 2017 and December 2020. Results: Ninety‐six patients who completed 2 years of ICIs were reviewed. The median durations of treatment and follow‐up were 24.0 and 33.9 months, respectively. The objective response rate (ORR) was 85.4%. The median progression‐free survival (PFS) and overall survival (OS) periods were not reached. After completion, the PFS and OS rates were 81.1% and 96.4%, respectively, at 12 months. Forty‐three patients were identified who discontinued ICIs without disease progression: 26 (60.5%) for adverse events and 17 (39.5%) for other causes. The median durations of treatment and follow‐up were 10.5 and 21.2 months, respectively. The ORR was 90.7%. The median PFS and OS periods were not reached. After discontinuation, the PFS and OS rates were 71.0% and 90.0%, respectively, at 12 months. Conclusions: A significantly high proportion of patients who completed 2 years of ICI therapy continued to experience long‐term PFS. Even if ICIs are discontinued after 6 months in patients without disease progression, they may achieve a durable response and facilitate long‐term survival. Lay Summary: The optimal treatment duration for immune checkpoint inhibitors (ICIs) remains to be determined.This study reports the long‐term outcomes of patients with non–small cell lung cancer who completed 2 years of ICI therapy or achieved a durable response after the discontinuation of ICIs without disease progression in real‐world practice.A significantly high proportion of patients who completed 2 years of ICIs continued to experience long‐term progression‐free survival.In addition, even if ICIs are discontinued after 6 months in patients without disease progression, they may achieve a durable response and facilitate long‐term survival. A significantly high proportion of patients who complete 2 years of immune checkpoint inhibitors (ICIs) continue to experience long‐term progression‐free survival. Even if ICIs are discontinued after 6 months in patients without disease progression, they may achieve a durable response and facilitate long‐term survival. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Cancer organoid-based diagnosis reactivity prediction (CODRP) index-based anticancer drug sensitivity test in ALK-rearrangement positive non-small cell lung cancer (NSCLC)" published in the Journal of Experimental & Clinical Cancer Research. The correction pertains to the funding section of the original article. The authors clarify that the research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government, the Commercialization Promotion Agency for R&D Outcomes (COMPA), and the Korea Medical Device Development Fund. The correction does not impact the overall findings or conclusions of the article. [Extracted from the article]

Purpose The optimal treatment for patients with stage III non-small cell lung cancer (NSCLC) remains controversial. This study aimed to investigate prognostic factors and clinical outcome in stage III NSCLC using real-world clinical data in the Korean population. Materials and Methods Among 8,110 patients with lung cancer selected from 52 hospitals in Korea during 2014-2016, only patients with stage III NSCLC were recruited and analyzed. A standardized protocol was used to collect clinical information and Cox proportional hazards models were used to identify risk factors for mortality. Results A total of 1,383 patients (46.5% had squamous cell carcinoma and 40.9% had adenocarcinoma) with stage III NSCLC were enrolled, and their median age was 70 years. Regarding clinical stage, 548 patients (39.6%) had stage IIIA, 517 (37.4%) had stage IIIB, and 318 (23.0%) had stage IIIC. Pertaining to the initial treatment method, the surgery group (median survival period, 36 months) showed better survival outcomes than the non-surgical treatment group (median survival period, 18 months; p=0.001) in patients with stage IIIA. Moreover, among patients with stage IIIB and stage IIIC, those who received concurrent chemotherapy and radiation therapy (CCRT; median survival period, 24 months) showed better survival outcomes than those who received chemotherapy (median survival period, 11 months), or radiation therapy (median survival period, 10 months; p < 0.001). Conclusion While surgery might be feasible as the initial treatment option in patients with stage IIIA NSCLC, CCRT showed a beneficial role in patients with stage IIIB and IIIC NSCLC. [ABSTRACT FROM AUTHOR]

Purpose Survival probability changes over time in cancer survivors. This study examined conditional survival in patients undergoing curative resection for non-small cell lung cancer (NSCLC). Materials and Methods Five-year conditional recurrence-free survival (CRFS), conditional overall survival (COS), and conditional relative survival (CRS) up to 10 years after surgery were calculated in patients who underwent NSCLC resection from 1994 to 2016. These rates were stratified according to age, sex, year of diagnosis, pathological stage, tumor histology, smoking status, comorbidity, and lung function. Results Five-year CRFS increased from 65.6% at baseline to 90.9% at 10 years after surgery. Early differences in 5-year CRFS according to stratified patient characteristics disappeared, except for age: older patients exhibited persistently lower 5-year CRFS. Five-year COS increased from 72.7% to 78.3% at 8 years and then decreased to 75.4% at 10 years. Five-year CRS increased from 79.0% at baseline to 86.8% at 10 years. Older age and higher pathologic stage were associated with lower 5-year COS and CRS up to 10 years after surgery. Female patients, those with adenocarcinoma histology, non-smokers, patient without comorbidities and had good lung function showed higher COS and CRS. Conclusion CRFS improved over time, but significant risk remained after 5 years. CRS slightly improved over time but did not reach 90%, suggesting significant excess mortality compared to the general population. Age and stage remained significant predictors of conditional survival several years after surgery. Our conditional survival estimates should help clinicians and patients make informed treatment and personal life decisions based on survivorship status. [ABSTRACT FROM AUTHOR]

Objectives: The optimal sequence for the administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for treating non‐small cell lung cancer (NSCLC) is still unclear. This study aimed to evaluate the efficacy of sequential afatinib and osimertinib treatment in patients with NSCLC harboring EGFR mutations. Materials and methods: Electronic records of patients with EGFR‐mutated NSCLC, who were administered afatinib and osimertinib (group A) or other chemotherapy (group B) between October 2014 and 2019, across 16 hospitals in South Korea were reviewed. The primary outcome, time on treatment (TOT), secondary outcome, and overall survival (OS) were estimated using the Kaplan–Meier method and log‐rank test. Multivariate analyses were performed using the Cox proportional hazards model. Results: Of the 737 patients who received frontline afatinib treatment, 324 with complete records were selected (group A: 126, group B: 198). All patients in group A were T790M positive after afatinib, while patients in group B were all negative or unknown. The median TOT was 35.4 months (95% confidence interval [CI]: 27.7−45.6) in group A and 20.8 months (95% CI: 19.4−24.0) in group B. The median TOT with afatinib was 13.0 months (95% CI: 12.0−13.9) overall and 15.7 months (95% CI: 13.9−17.3) in group A. The 2‐ and 3‐year survival rates were 86.0 and 69.3% in group A and 75.9 and 55.3% in group B, respectively. Conclusion: Sequential afatinib and osimertinib treatment resulted in better survival rates than treatment with afatinib followed by other chemotherapies. [ABSTRACT FROM AUTHOR]

• Incidence of tuberculosis in lung cancer patients receiving chemotherapy is high. • Immune checkpoint inhibitors did not pose additional risk for tuberculosis among them. • Prolonged use of steroid showed a tendency to increase the risk of tuberculosis. • Previous history of tuberculosis was a significant risk factor for tuberculosis. The aim of this study was to investigate the risk of TB in advanced non-small cell lung cancer (NSCLC) patients treated with Immune checkpoint inhibitors (ICI) after a platinum-based chemotherapy. A nationwide population-based retrospective cohort study using National health insurance dataset was designed. Patients who were diagnosed as lung cancer between September 1st, 2017 and August 31st, 2018 in South Korea were selected. Among them, those with NSCLC who initiated a platinum-based chemotherapy within 3 months were finally included and followed up until December 31st, 2018. Patients who received nivolumab, pembrolizumab, and atezolizumab within study period were classified as the ICI group. Cox proportional hazard model with time-varying covariates was used to determine effects of the duration of conventional chemotherapy, ICI, and consecutive use of systemic steroid on TB. A total of 6335 patients were enrolled with 3568.7 years of total follow-up period. Among them, 899 patients underwent ICI treatment. Within the follow-up period, 15 TB cases were identified in the ICI group (incidence: 2582.5 per 100,000 person-years) and 63 TB cases were found in the conventional chemotherapy group (incidence: 2108.5 per 100,000 person-years). In a multivariable Cox proportional hazard model, treatment with ICI was not a significant risk factor for TB development (hazard ratio (HR): 1.21, 95 % confidence interval (CI): 0.45−3.26, p = 0.700). Instead, prolonged use of steroid was associated with an increased TB risk (HR: 1.91, 95 %CI: 0.89−4.08, p = 0.095), although its statistical significance was dependent on the operational definition of the effect duration. Previous TB history and older age were independent risk factors for TB disease. In this real-world study, additional treatment with ICI did not increase the risk of TB in advanced NSCLC patients who underwent a cytotoxic chemotherapy. However, TB incidence in these patients was high regardless of ICI treatment. Systemic Treatments. [ABSTRACT FROM AUTHOR]

Purpose As the aging of society progresses, the proportion of extremely older lung cancer patients has also increased; However, studies of these patients with non-small cell lung cancer are limited. Therefore, we investigated the initial treatment modalities and survival outcomes for patients aged 80 years or over. Materials and Methods We included a multicenter retrospective cohort from the Korean Association for Lung Cancer Registry, which surveys 10% of the newly diagnosed lung cancer patients across 52 hospitals in Korea. We analyzed and compared the 2014-2016 data of the non-small cell lung cancer patients aged ≥ 80 years and those aged < 80 years. Results Of the 6,576 patients reviewed, 780 patients were aged ≥ 80 years, and 5,796 patients were aged < 80 years. In the patients aged ≥ 80 years, surgery and radiation therapy resulted in longer patient survival among those with a resectable tumor (stage I-II) than the best supportive care (median survival, not reached [surgery] vs. 32.2 months [radiation therapy] vs. 11.43 months [best supportive care]). The duration of survival in patients with advanced-stage (IV) lung cancers was higher after chemotherapy than after the best supportive care (median survival, 8.63 months vs. 2.5 months). Patients with stage IV adenocarcinoma who received targeted therapy had better survival than those who did not (median survival, 9.0 months vs. 4.3 months). Conclusion Even in extremely older patients, active treatments, such as surgery, radiation therapy, and chemotherapy, can result in better survival outcomes than the best supportive care. [ABSTRACT FROM AUTHOR]

Background: Post hoc analysis of the LUX-Lung 3 and 6 (LL3/6) Phase III trials showed that tolerability-guided dose-adjustments of afatinib reduced treatment-related adverse events (TRAEs) without affecting progression-free survival (PFS) in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). The current post hoc analysis evaluated outcomes of tolerability-guided dose adjustments of afatinib in patients enrolled in the LL3/6/7 trials in Chinese centers. Patients and Methods: Patients enrolled in LL3/6/7 had advanced EGFR mutation-positive NSCLC. LL3 and LL7 recruited patients globally (including China) and LL6 enrolled Asian patients from China, Thailand, and South Korea. In LL3 and LL6, patients were randomized to afatinib 40 mg/day or cisplatin-based chemotherapy. In the Phase IIb LL7 trial, patients were randomized to afatinib 40 mg/day or gefitinib. Tolerability-guided dose adjustments were permitted for TRAEs, and PFS was the primary endpoint. This post hoc analysis pooled data from patients enrolled in Chinese centers in LL3/6/7 and analyzed the frequency and severity of TRAEs before and after afatinib dose reductions during the first 6 months. PFS and overall survival (OS) were compared for patients who had a dose reduction in the first 6 months and those who did not. Results: Overall, 299 patients were enrolled in Chinese centers; 68 (23%) had afatinib dose reductions to < 40 mg/day in the first 6 months. Prior to dose reduction, 55/68 patients (81%) experienced grade ≥ 3 TRAE versus 13/68 (19%) after dose reduction. Grade ≥ 3 TRAEs were much more common in patients with than in those without dose reduction. Median PFS was 11.0 months in both groups, and median OS did not differ significantly: 23.1 months in patients with a dose reduction and 26.9 months in those without a dose reduction. Conclusion: Tolerability-guided afatinib dose adjustment is an effective strategy to reduce TRAEs without affecting efficacy in Chinese patients. [ABSTRACT FROM AUTHOR]

Purpose: Although immune checkpoint inhibitors have been shown to be effective in many clinical trials, real-world data remain limited. We investigated the outcomes of non-small cell lung cancer (NSCLC) patients who received nivolumab, with an emphasis on hyper-progressive disease (HPD). Methods: This retrospective study enrolled stage IV NSCLC patients who received nivolumab after progression on prior chemotherapy between July 2016 and June 2018 at a single center in Korea. HPD was defined by response evaluation criteria in solid tumors as progression at the first evaluation, with a ≥ two-fold increase in the tumor growth rate during nivolumab treatment. Results: A total of 83 patients with a median age of 60 years were enrolled [squamous, 25(30%) and non-squamous, 58(70%)]. The median progression-free survival (PFS) and overall survival (OS) were 2.6 months [95% confidence interval (CI) 0.82–4.31] and 8.6 months (95% CI 5.56–11.59), respectively. HPD developed in 16 (19.2%). The median OS of HPD patients was 2.2 months (95% CI 0.92–3.75) compared with 4.1 months for progressive disease (PD) patients without HPD (95% CI 1.54–6.67). Among patients with pleura or pericardium metastasis, increased effusion was seen more frequently in HPD patients compared with PD patients without HPD [90% (9/10) vs. 28.6% (4/14); p = 0.005]. HPD patients also showed a significant decrease in circulating albumin after treatment with nivolumab (p = 0.030). Conclusion: Although the efficacy of nivolumab in real-world patients was comparable to that seen in clinical trials, clinicians should be aware of HPD because it is not uncommon and represents a worse prognosis. [ABSTRACT FROM AUTHOR]

Purpose The introduction of immune checkpoint inhibitors represents a major advance in the treatment of lung cancer, allowing sustained recovery in a significant proportion of patients. Nivolumab is a monoclonal anti--programmed death cell protein 1 antibody licensed for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy. In this study, we describe the demographic and clinical outcomes of patients with advanced NSCLC treated with nivolumab in the Korean expanded access program. Materials and Methods Previously treated patients with advanced nonsquamous and squamous NSCLC patients received nivolumab at 3 mg/kg every 2 weeks up to 36 months. Efficacy data including investigator-assessed tumor response, progression data, survival, and safety data were collected. Results Two hundred ninety-nine patients were treated across 36 Korean centers. The objective response rate and disease control rate were 18% and 49%, respectively; the median progression- free survival was 2.1 months (95% confidence interval [CI], 1.87 to 3.45), and the overall survival (OS) was 13.2 months (95% CI, 10.6 to 18.9). Patients with smoking history and patients who experienced immune-related adverse events showed a prolonged OS. Cox regression analysis identified smoking history, presence of immune-related adverse events as positive factors associated with OS, while liver metastasis was a negative factor associated with OS. The safety profile was generally comparable to previously reported data. Conclusion This real-world analysis supports the use of nivolumab for pretreated NSCLC patients, including those with an older age. [ABSTRACT FROM AUTHOR]

• This study is to construct a big data-based cohort of NSCLC. • This cohort enables rapid and comprehensive analysis of data of NSCLC patients. • This study showed real-world treatment patterns and clinical outcomes of stage III NSCLC. Until the recent approval of immunotherapy after completing concurrent chemoradiotherapy (CCRT), there has been little progress in treating unresectable stage III non-small cell lung cancer (NSCLC). This prompted us to search real-world data (RWD) to better understand diagnosis and treatment patterns, and outcomes. This non-interventional observational study used a unique, novel algorithm for big data analysis to collect and assess anonymized patient electronic medical records from a clinical data warehouse (CDW) over a 10-year period to capture real-world patterns of diagnosis, treatment, and outcomes of stage III NSCLC patients. We describe real-world patterns of diagnosis and treatment of patients with newly-diagnosed stage III NSCLC, and patients' characteristics, and assessment of treatment outcomes. We analyzed clinical variables from 23,735 NSCLC patients. Stage III patients (N = 4138, 18.2 %) were diagnosed as IIIA (N = 2,547, 11.2 %) or IIIB (N = 1,591. 7.0 %). Treated stage III patients (N = 2530, 61.1 %) had a median age of 64.2 years, were mostly male (78.5 %) and had an ECOG performance status of 1 (65.2 %). Treatment comprised curative-intent surgery (N = 1,254, 49.6 %) with 705 receiving neoadjuvant therapy; definitive CRT (N = 648, 25.6 %); palliative CT (N = 270, 10.7 %), or thoracic RT (N = 170, 6.7 %). Median OS (range) for neoadjuvant, surgery, CRT, palliative chemotherapy, lung RT alone, and supportive care was 49.2 (42.0–56.5), 52.5 (43.1–61.9), 30.3 (26.6–34.0), 14.7 (13.0–16.4), 8.8 (6.2–11.3), and 2.0 (1.0–3.0) months, respectively. This unique in-house algorithm enabled a rapid and comprehensive analysis of big data through a CDW, with daily automatic updates that documented real-world PFS and OS consistent with the published literature, and real-world treatment patterns and clinical outcomes in stage III NSCLC patients. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is an independent risk factor for lung cancer (LC) development; however, its effect on recurrence after curative surgery remains unclear. Objectives: This study aimed to determine the impact of IPF on recurrence-free survival following curative surgical resection of stage I–III non-small cell lung cancer (NSCLC) and investigate the effects of patient and surgical factors on the risk of recurrence. Methods: We reviewed retrospectively collected data of patients with surgically resected stage I–III NSCLC from two tertiary care hospitals in South Korea. By propensity score matching, patients with IPF (LC with IPF) were matched to those without IPF (LC without IPF). Results: In total, 3416 patients underwent surgical resection, and 96 were diagnosed with underlying IPF. In the LC with IPF group, 89.6% patients were men, and the average age was 69.7 years. Sublobar resection was performed more frequently in the LC with IPF group than in the LC without IPF group, while the rate of mediastinal lymph node dissection and dissected node number were lower in the former group. The 5-year recurrence-free survival rate was significantly lower in the LC with IPF group (49.2%) than in the LC without IPF group (69.1%; P<0.001). Multivariable Cox regression analysis revealed that IPF and postoperative stage III were independent risk factors for recurrence. Conclusions: IPF may increase the risk of recurrence after curative surgical treatment for NSCLC. Close surveillance for recurrence is mandatory for patients with underlying IPF. [ABSTRACT FROM AUTHOR]

Background: The risk stratification value of the 6-min walk test (6MWT) to decide the feasibility of surgical resection is not well elucidated in patients with non-small cell lung cancer (NSCLC) and moderately decreased lung function.Objective: This study aimed to determine the role of the 6MWT in predicting postoperative cardiopulmonary complications in patients with NSCLC who underwent lobectomy and had moderately decreased lung function.Methods: The data were obtained from a prospective cohort study called Coordinate Approach to Cancer Patient's Health for Lung Cancer (CATCH-LUNG). Patients who underwent lobectomy for NSCLC were classified into two groups according to predicted postoperative pulmonary function (low-risk group or moderate-risk group); each group was then further classified into short-distance (< 400 m) or long-distance (≥ 400 m) groups according to a 6-min walk distance. The main end point of this study was the incidence of postoperative cardiopulmonary complications occurring within the first 30 postoperative days. A multivariable logistic regression model was used to compare the postoperative cardiopulmonary complications among the four groups.Results: The adjusted ORs for any postoperative pulmonary complications, postoperative cardiac complications, and postoperative cardiopulmonary complications in patients with moderate-risk/short-distance relative to those with low-risk/long-distance were 10.26 (95% CI, 2.37-44.36), 5.65 (95% CI, 1.39-22.90), and 7.84 (95% CI, 2.24-27.46), respectively. However, these complications were not different between the patients with moderate-risk/long-term distance and those with low-risk/long-distance. Among patients in the moderate-risk group, those in the short-distance group had a significantly higher risk of postoperative cardiopulmonary complications compared with those in the long-distance group (adjusted OR, 4.95; 95% CI, 1.37-17.93).Conclusions: Patients with NSCLC with moderate-risk/short-distance were at greater risk of developing postoperative cardiopulmonary complications; it may be feasible, however, for patients with NSCLC and moderate-risk/long-distance to undergo lobectomy compared with those with low-risk/long-distance. Our study suggests that the 6MWT could provide additional information in identifying optimal candidates for lung resection surgery of NSCLC.Trial Registry: ClinicalTrials.gov; No.: NCT03705546; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Objective: ASTRIS is a large real-world, open-label, multinational clinical study of osimertinib in patients with epidermal growth factor receptor (EGFR) T790M mutation-positive advanced non-small cell lung cancer (NSCLC) who have previously received a tyrosine kinase inhibitor (TKI). We report data from the Korean ASTRIS subgroup.Methods: Adult patients with locally advanced or metastatic NSCLC with a confirmed T790M mutation, WHO performance status of 0-2 and prior EGFR-TKI therapy, received osimertinib 80 mg once daily. Efficacy outcomes were overall survival (OS), investigator-assessed response rate (RR) and progression-free survival (PFS), and time to treatment discontinuation (TTD).Results: At data cut-off (20 October 2017), 466 Korean patients were enrolled. Baseline EGFR molecular testing was mainly performed on biopsied tissue (75.1%). Baseline mutations co-occurring with T790M included exon 19 deletions (60.7%) and L858R (32.8%). 1-year OS was 82.7% (OS data not matured at data cut-off). Overall, RR was 71.0%, median PFS was 12.4 months and median TTD was 15.0 months. In patients with/without CNS metastases, RR was 68.0% and 79.6%, respectively; median PFS, 10.8 and 11.0 months, respectively; and median TTD, 11.2 and 14.7 months, respectively. Overall, 31.1% of patients experienced ≥1 adverse event (AE), leading to dose modification (12.0%), discontinuation (5.2%) or death (2.8%). Serious AEs (24.9%) included pulmonary embolism (1.7%), pleural effusion (1.7%), and pneumonia (1.5%).Conclusion: In this real-world subgroup analysis of Korean patients in the ASTRIS study, osimertinib demonstrated comparable clinical efficacy to that attained in the global ASTRIS study and other clinical trials, with no new safety concerns. [ABSTRACT FROM AUTHOR]

Olmutinib (Olita™) is an orally bioavailable third generation epidermal growth factor receptor tyrosine kinase inhibitor. Olmutinib was approved in South Korea in May 2016 for the treatment of patients suffering from locally advanced or metastatic epidermal growth factor receptor T790M mutation‐positive non‐small cell lung cancer. Reactive olmutinib intermediates may be responsible for the severe side effects associated with the treatment. However, literature review revealed no previous reports on the structural identification of reactive olmutinib metabolites. In this work, the formation of reactive olmutinib metabolites in rat liver microsomes was investigated. Methoxylamine, glutathione, and potassium cyanide were used as capturing agents for aldehyde, iminoquinones, and iminium intermediates, respectively. The stable complexes formed were identified using liquid chromatography–tandem mass spectrometry. The major phase I metabolic pathway observed in vitro was hydroxylation of the piperazine ring. Seven potential reactive intermediates were characterized, including three iminium ions, three iminoquinones, and one aldehyde. Based on the findings, various bioactivation pathways were postulated. Hence, identifying the reactive intermediates of olmutinib that may be the cause of severe side effects can provide new insights, leading to improved treatments for patients. [ABSTRACT FROM AUTHOR]

Purpose Human epidermal growth factor receptor 2 (HER2) alterations are found in approximately 1%-3% of non-small cell lung cancers (NSCLCs). We evaluated the clinical features and outcomes of NSCLC harboring HER2 alteration detected by next-generation sequencing (NGS) in Korea. Materials and Methods A total of 1,108 patients who were diagnosed with NSCLC between December 2015 and December 2017 were screened and analyzed by NGS. Medical records were reviewed retrospectively to analyze the clinical characteristics and outcomes from various treatments. Results HER2 alterations were identified in 36 NSCLC patients. Of the patients, 22 (61.1%) had an exon 20 in-frame insertion mutation, 15 (41.7%) had HER2 amplification, and one had both. The median patient age was 58 years, 55.6% were male, and 50.0% were never-smokers. Adenocarcinoma was predominant (88.9%). The most common metastatic site was bone (58.3%), and 66.7% of patients were stage IV at initial diagnosis. Six patients (16.7%) had a coexistent sensitizing epidermal growth factor receptor (EGFR) mutation, and two patients (5.6%) had anaplastic lymphoma kinase (ALK) rearrangement. With a median 14 months of follow-up, the median progression-free survival of first-line treatment was 6 months (95% confidence interval, 4.172 to 7.828), and median overall survival was not reached. The proportions of adenocarcinoma, never-smokers, and metastasis to the liver were higher in the exon 20 in-frame insertion mutation group, whereas coexistence of EGFR mutation was more frequently found in the HER2 amplification group. Conclusion HER2-altered NSCLC showed distinct clinical features. Moreover, different characteristics were identified between the HER2 in-frame insertion mutation group and the HER2 amplification group. [ABSTRACT FROM AUTHOR]

Purpose Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR sensitizing mutation and EGFR T790M and has demonstrated efficacy in non-small cell lung cancer (NSCLC) central nervous system (CNS) metastases. We present results of a subgroup analysis of Korean patients from the pooled data of two global phase II trials: AURA extension (NCT01802632) and AURA2 (NCT02094261). Materials and Methods Enrolled patients had EGFR T790M-positive NSCLC and disease progression during or after EGFR-TKI therapy. Patients received osimertinib 80 mg orally once daily until disease progression. The primary endpoint was objective response rate (ORR). Results In total, 66 Korean patients received osimertinib treatment with a median treatment duration of 19 months. In the evaluable-for-response population (n=62), ORR was 74% (95% confidence interval [CI], 61.5 to 84.5) and median duration of response was 9.8 months (95% CI, 7.1 to 16.8). In the full analysis set (n=66), median progression-free survival was 10.9 months (95% CI, 8.3 to 15.0; data cutoff November 1, 2016), and median overall survival was 29.2 months (95% CI, 24.8 to 35.7; data cutoff May 1, 2018). Eight patients with CNS metastases were evaluable for response, none of whom showed CNS progression. The most common adverse events were rash (53%), cough (33%), paronychia, diarrhea, and decreased appetite (each 32%). Conclusion Efficacy and safety profiles of osimertinib in this subgroup are consistent with the global phase II pooled population, which supports osimertinib as a recommended treatment for Korean patients with T790M positive NSCLC. [ABSTRACT FROM AUTHOR]

Background: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) given EGFR tyrosine kinase inhibitors (TKIs) inevitably become resistant to first-generation or second-generation drugs. We assessed the safety, tolerability, pharmacokinetics, and activity of lazertinib-an irreversible, third-generation, mutant-selective, EGFR TKI-in patients with advanced NSCLC progressing after EGFR TKI therapy.Methods: This first-in-human, open-label, multicentre, phase 1-2 study had three parts: dose escalation, dose expansion, and dose extension; here, we report results on dose escalation and dose expansion. The study was done in 14 hospitals in Korea. Eligible patients were aged 20 years or older and had advanced NSCLC harbouring an activating EGFR mutation and progressing after first-generation or second-generation EGFR TKI treatment, a defined tumour T790M mutation status, an Eastern Cooperative Oncology Group performance status of 0-1, at least one measurable extracranial lesion, defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and adequate organ function. Patients were enrolled to seven dose-escalation cohorts according to a rolling six design; five cohorts were expanded. Patients were given oral lazertinib 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, 240 mg, or 320 mg once daily continuously in 21-day cycles. Primary endpoints were safety and tolerability and secondary endpoints included objective response in evaluable patients. This study is registered with ClinicalTrials.gov, NCT03046992, and the phase 2 extension study is ongoing.Findings: Between Feb 15, 2017, and May 28, 2018, 127 patients were enrolled into the dose escalation group (n=38) and dose expansion group (n=89). No dose-limiting toxicities occurred. There was no dose-dependent increase in adverse events. The most commonly reported adverse events were grade 1-2 rash or acne (in 38 [30%] of 127 patients) and pruritus (in 34 [27%]). Grade 3 or grade 4 adverse events occurred in 20 (16%) patients, with the most common being grade 3 pneumonia (four [3%]). Treatment-related grade 3 or 4 adverse events occurred in four (3%) patients; treatment-related serious adverse events were reported in six patients (5%). There were no adverse events with an outcome of death and no treatment-related deaths. The proportion of patients achieving an objective response by independent central review assessment was 69 (54%; 95% CI 46-63) of 127.Interpretation: Lazertinib had a tolerable safety profile and showed promosing clinical activity in patients with NSCLC progressing on or after EGFR TKI therapy. Our findings provide a rationale for further clinical investigations.Funding: Yuhan Corporation. [ABSTRACT FROM AUTHOR]

Background: This study aimed to assess the effect of antibiotics on the clinical outcomes of patients with solid cancers undergoing treatment with immune checkpoint inhibitors (ICIs).Methods: The medical records of 234 patients treated with ICIs for any type of solid cancer between February 2012 and May 2018 at the Seoul St. Mary's Hospital were retrospectively reviewed. The data of patients who received antibiotics within 60 days before the initiation of ICI treatment were analyzed. The patients' responses to ICI treatment and their survival were evaluated.Results: Non-small-cell lung carcinoma was the most common type of cancer. About half of the patients were treated with nivolumab (51.9%), and cephalosporin (35.2%) was the most commonly used class of antibiotics. The total objective response rate was 21%. Antibiotics use was associated with a decreased objective response (odds ratio 0.466, 95% confidence interval [CI] 0.225-0.968, p = 0.040). The antibiotics group exhibited shorter progression-free survival (PFS) and overall survival (OS) than the no antibiotics group (median PFS: 2 months vs. 4 months, p < 0.001; median OS: 5 months vs. 17 months, p < 0.001). In the multivariate analysis, antibiotics use was a significant predictor of patient survival (PFS: hazard ratio [HR] 1.715, 95% CI 1.264-2.326, p = 0.001; OS: HR 1.785, 95% CI 1.265-2.519, p = 0.001).Conclusions: The use of antibiotics may affect the clinical outcomes of patients with solid cancers treated with ICIs. Careful prescription of antibiotics is warranted in candidates who are scheduled for ICI treatment.Trial Registration: Not applicable (retrospective study). [ABSTRACT FROM AUTHOR]

• We examined PD-L1 level dynamics after concurrent chemoradiation therapy (CCRT). • We retrospectively analyzed stage III NSCLC patients treated by CCRT and surgery. • Increased PD-L1 level post-CCRT was associated with shorter overall survival (OS). • Most patients had increased CD8+ TIL density post-CCRT, accompanied by longer OS. The treatment for stage III non-small cell lung cancer (NSCLC) is quite variable because stage III NSCLC is a heterogenous disease. Programmed death ligand 1 (PD-L1) and CD8+ tumor infiltrating lymphocytes (TILs) are thought to be related to treatment outcome in many tumors. To improve treatment outcome in stage III NSCLC, it is necessary to obtain data on PD-L1 expression and CD8+ TIL counts following CCRT and their relationship to treatment outcome. We retrospectively enrolled 43 patients with stage III NSCLC treated with neoadjuvant CCRT followed by surgery at Yonsei Cancer Center Severance Hospital in Korea between June 2008 and October 2010. PD-L1 level and CD8+ TIL numbers in tumors following CCRT were analyzed by immunohistochemistry, and their association with patient survival was evaluated with Kaplan-Meier method. More than half patients (52%) showed up- or downregulation of PD-L1 expression, and most patients (81%) showed change in CD8+ TIL counts by CCRT. Patients with PD-L1 expression following CCRT tended to have shorter recurrence free survival (RFS) (P = 0.182) or overall survival (OS) (P = 0.215) compared to the ones without PD-L1 expression. In the survival analysis with pre-CCRT specimens, neither RFS nor OS showed statistically significant differences. Patients with increased CD8+ TIL counts following CCRT regardless of pathological response strongly showed longer OS (median: not reached vs. 14.2 months for others; P = 0.017). CCRT dynamically alters PD-L1 expression and CD8+ TIL numbers in stage III NSCLC. Our data provide a rationale for combining CCRT and immunotherapy for the treatment of potentially resectable NSCLC. [ABSTRACT FROM AUTHOR]

Purpose The aim of this study was to investigate epidemiology, clinical characteristics and sex differences of patients with lung cancer using nationwide registry in Korea. Materials and Methods The Korean Association for Lung Cancer developed a registry in cooperation with the Korean Central Cancer Registry, and surveyed about 10% of lung cancer cases. For this first survey of cases diagnosed in 2014, cases were selected through a systematic sampling method. Results Total 2,621 lung cancer patients were surveyed, and the median patient age was 70 years. During the study period, adenocarcinoma was the most frequent histologic type, the proportion of female patients was 28.4%, and women had a better prognosis (median survival, not reached vs. 13 months; p<0.001) than did men for non-small cell lung cancer. The proportion of never-smokers was 36.4%, and never-smoking was more prevalent in women than in men (87.5 vs. 16.0%, p<0.001). Epidermal growth factor receptor (EGFR) mutations were found in 36.8% of stage IV adenocarcinoma patients, and higher in female compared to male patients (51.2 vs. 26.6%, p<0.001). In addition, patients with EGFR mutation showed better survival (median survival, 18 vs. 8 months; p<0.001) than patients without EGFR mutation in these patients. Conclusion This is the first survey to gather unbiased nationwide lung cancer statistics in Korea. More than one-third of lung cancer patients had no smoking history. Female had a high proportion of non-smoker, more adenocarcinoma with EGFR mutation and generally better prognosis than male. [ABSTRACT FROM AUTHOR]

Purpose: Immune checkpoint inhibitors (ICI) have shown marked responses in patients with non-small cell lung cancer (NSCLC) in clinical trials. However, because such trials comprise cohorts selected based on specific criteria, it is unclear if their results represent routine clinical practice. Methods: We examined 155 patients with advanced NSCLC who were administered either nivolumab or pembrolizumab at Yonsei Cancer Center, Korea between March 2014 and January 2019. Patient characteristics, EGFR/ALK mutation status, metastatic locations, response to ICIs, and adverse events were retrospectively analyzed. Results: The median age was 64 years and 72.9% of patients were male; former or current smokers constituted 67.1% of the subjects. Adenocarcinoma was predominant (67.7%), and 50.3% of the patients underwent ≥ 2 previous treatments. Twenty-three patients (14.8%) were EGFR mutation- or ALK rearrangement-positive. The objective response rate (ORR) was 23.9% [95% confidence interval (CI) 17.4–31.4%]; the median progression-free survival (PFS) and overall survival (OS) were 3.06 (95% CI 1.893–4.21) and 10.25 (95% CI 5.39–15.11) months, respectively. Multivariate analysis identified ECOG performance status, EGFR mutation/ALK rearrangement status, liver metastasis and PD-L1 proportion as independent predictors of OS. Furthermore, 61.9% of the patients had adverse events of any grade; 38.1% had immune-related adverse events that were associated with PFS and OS on multivariate analysis. Conclusions: The real-world ORR, PFS, OS, and adverse event profiles were comparable to previous clinical trials despite the patients' different baseline characteristics. Our findings can aid in establishing effective immunotherapeutic management of NSCLC in routine clinical practice. [ABSTRACT FROM AUTHOR]

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. 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. 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). 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. F Hoffmann-La Roche. [ABSTRACT FROM AUTHOR]

Background: Cholesterol plays an important role in the action of opioid analgesics, but its association with postoperative pain has not been clarified. Our study examined the association of pre- and postoperative total serum cholesterol (TSC), and change between the pre- and postoperative TSC levels with postoperative pain outcomes in patients with non-small cell lung cancer (NSCLC) who underwent video-assisted thoracoscopic surgery (VATS) lobectomy. Methods: We retrospectively reviewed medical records of patients with NSCLC who underwent VATS lobectomy at the Seoul National University Bundang Hospital in South Korea. We sought to determine the association between preoperative TSC, TSC on postoperative day (POD) 0-1, and pre- and postoperative changes in TSC by comparing numeric rating scale (NRS) scores on POD 0, 1, and 2 and total morphine equivalent consumption on POD 0-2. Multivariate linear regression analyses were used, and P < 0.05 was considered statistically significant. Results: A total of 1,720 patients with NSCLC who underwent VATS lobectomy were included in the analysis. The change in TSC, preoperative TSC, and postoperative TSC showed no associations with morphine equivalent consumption on POD 0-2 (P > 0.05). In addition, the changes in TSC, preoperative TSC, and postoperative TSC were not associated with postoperative NRS pain score on POD 0, 1, and 2 (P > 0.05). Conclusions: Our results indicated that no significant association was observed between pre- and postoperative TSC level and postoperative pain outcome after VATS lobectomy of the lung. [ABSTRACT FROM AUTHOR]

Purpose Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for approximately 4% of all EGFRmutations. Given the rarity of this mutation, its clinical outcomes are not fully established. Materials and Methods Between 2009 and 2017, non-small cell lung cancer (NSCLC) patients who showed an exon 20 insertion were retrospectively reviewed for clinical characteristics and outcomes, including responses to chemotherapy (CTx) or targeted therapy. Results Of 3,539 NSCLC patients who harbored an activating EGFR mutation, 56 (1.6%) had an exon 20 insertion. Of the advanced NSCLC patients, 27 of 1,479 (1.8%) had an exon 20 insertion. The median overall survival was 29.4 months (95% confidence interval 9.3 to 49.6) for 27 advanced NSCLC patients. The 22 patients who received systemic CTx achieved a 50.0% response rate and a 77.2% disease control rate, with 4.2 months of progressionfree survival. Six patients received EGFR tyrosine kinase inhibitors (TKIs). Three of the four patients that had only an exon 20 insertion showed progressive disease, while one showed stable disease. The other two patients had an exon 20 insertion and another EGFRmutation and achieved a partial response. Conclusion The incidence of an exon 20 insertion mutation is rare in Korea and occasionally accompanied by other common EGFR mutations. Although the response to systemic CTx. in these patients is comparable to that of patients with other mutations, the response rate to firstor second-generation EGFR TKIs is quite low. Therefore, the development of a more efficient agent is urgently needed. [ABSTRACT FROM AUTHOR]

• Lazertinib showed comparable efficacy and safety in real-world clinical settings. • Lazertinib demonstrated durable disease control both systematic and intracranially. • The most common adverse event was paresthesia which was manageable by dose modification. • Further development of lazertinib in 1st line is highly warranted. Lazertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that provides a high level of selectivity for sensitizing and p.Thr790Met (T790M) EGFR mutations. We aimed to collect real-world data regarding the efficacy and safety of lazertinib. This study included patients treated with lazertinib for T790M-mutated non-small cell lung cancer who had previously been treated with an EGFR-TKI. The primary outcome measure was progression-free survival (PFS). Additionally, this study evaluated overall survival (OS), time-to-treatment failure (TTF), duration of response (DOR), objective response rate (ORR) and disease control rate (DCR). Drug safety was also assessed. In a study of 103 patients, 90 received lazertinib as a second- or third-line therapy. The ORR and DCR were 62.1% and 94.2%, respectively. The median follow-up duration was 11.1 months, and the median PFS period was 13.9 (95% confidence interval [CI], 11.0–not reached [NR]) months. OS, DOR, and TTF had not yet been determined. In a subgroup of 33 patients with evaluable brain metastases, the intracranial DCR and ORR were 93.5% and 57.6%, respectively. The median intracranial PFS period was 17.1 (95% CI, 13.9–NR) months. Approximately 17.5% of patients had dose modification or discontinuation due to adverse events, with the most common being grade 1 or 2 paresthesia. The efficacy and safety of lazertinib were recapitulated in a real-world study reflecting routine clinical practice in Korea, showing durable disease control both systematically and intracranially, with manageable side effects. [ABSTRACT FROM AUTHOR]

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Background: As targeted therapy becomes increasingly important, diagnostic techniques for identifying targeted biomarkers have also become an emerging issue. The study aims to evaluate the cost-effectiveness of treating patients as guided by epidermal growth factor receptor (EGFR) mutation status compared with a no-testing strategy that is the current clinical practice in South Korea. Methods: A cost-utility analysis was conducted to compare an EGFR mutation testing strategy with a no-testing strategy from the Korean healthcare payer’s perspective. The study population consisted of patients with stage 3b and 4 lung adenocarcinoma. A decision tree model was employed to select the appropriate treatment regimen according to the results of EGFR mutation testing and a Markov model was constructed to simulate disease progression of advanced non-small cell lung cancer. The length of a Markov cycle was one month, and the time horizon was five years (60 cycles). Results: In the base case analysis, the testing strategy was a dominant option. Quality-adjusted life-years gained (QALYs) were 0.556 and 0.635, and total costs were $23,952 USD and $23,334 USD in the no-testing and testing strategy respectively. The sensitivity analyses showed overall robust results. The incremental cost-effectiveness ratios (ICERs) increased when the number of patients to be treated with erlotinib increased, due to the high cost of erlotinib. Conclusion: Treating advanced adenocarcinoma based on EGFR mutation status has beneficial effects and saves the cost compared to no testing strategy in South Korea. However, the cost-effectiveness of EGFR mutation testing was heavily affected by the cost-effectiveness of the targeted therapy. [ABSTRACT FROM AUTHOR]

Among the non-small cell lung cancer (NSCLC) patients who visited Severance Hospital, Seoul, Korea from July 2005 to October 2018, patients with idiopathic pulmonary fibrosis (IPF) or non-specific interstitial pneumonia (NSIP) in chest CT image were enrolled in this study. 84 patients were definite + possible IPF group, 42 patients were intermediate, and 25 patients were definite NISP + possible NSIP group. CT findings of ILD in lung cancer patients could be helpful in predicting of prognosis. [Extracted from the article]