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Background: Afatinib and Osimertinib are first-line treatments for EGFR-mutated advanced non-small cell lung cancer (NSCLC), but their comparative efficacies and the patient groups that benefit the most remain unclear. This multicenter retrospective study evaluated the efficacy of first-line Afatinib and Osimertinib in NSCLC patients with EGFR 19del and no brain metastases at diagnosis., Methods: The primary endpoints were time on treatment (ToT) and overall survival (OS). Survival analyses were performed for three groups: Afatinib followed by Osimertinib, Afatinib followed by other therapies, and Osimertinib (alone or followed by other therapies). Rebiopsy practices, including T790M mutation detection, were also analyzed in patients with disease progression on Afatinib., Results: Among 97 Afatinib-treated and 60 Osimertinib-treated patients, Osimertinib showed a significantly longer ToT (23.3 vs. 16.5 months; p = 0.007). Median OS was numerically higher for Afatinib with sequential Osimertinib (40.5 vs. 34.6 months for Osimertinib; p = 0.473). Osimertinib demonstrated advantages, with fewer brain metastases upon progression and fewer adverse effects. In the Afatinib group, 64% of patients with disease progression underwent rebiopsy, with 39% testing positive for T790M mutation and subsequently receiving Osimertinib. Rebiopsy was most frequently performed on the lung parenchyma using non-surgical methods., Conclusions: In this real-world study, Osimertinib achieved a significantly longer ToT compared to Afatinib in NSCLC patients with EGFR 19del and no brain metastases. The sequential use of Afatinib followed by Osimertinib showed a trend toward improved OS, highlighting the importance of rebiopsy for identifying T790M mutations to guide subsequent therapy.

Introduction: Comprehensive next-generation sequencing (NGS) of non-small-cell lung cancer specimens can identify oncogenic driver mutations and their corresponding targeted therapies. Plasma cell-free DNA (cfDNA) genotyping is easy to perform; however, false negatives cannot be overlooked. We explored malignant pleural effusion (MPE), a rich source of cfDNA, as a non-inferior alternative to tumor tissues for genotyping., Methods: We conducted a prospective trial including 39 patients with newly diagnosed stage IV lung adenocarcinoma who presented with MPE. Tissue tests matching hotspot variants, including EGFR, ALK, and ROS1, were compared with the AlphaLiquid100 of PE-cfDNA., Results: Among the 39 PE-cfDNA samples successfully sequenced, 32 (82.1%) had a PE cell-block tumor content of < 10%. Standard tissue or cell-block testing for EGFR, ALK, and ROS1 identified 20 mutations (51.3%), whereas PE cfDNA identified 25 mutations (64.1%). Five EGFR mutations were observed in PE cfDNA but not in Cobas EGFR owing to coverage or insufficient tumor content issues. The overall rate of oncogenic mutations identified in the PE cfDNA was 92.3%, and the mutation distribution was as follows: even with a very low cfDNA input, high detection rates could be achieved. Otherwise, most patients harbored co-mutations. Comparison of pleural fluid NGS with traditional testing revealed differences in accuracy. We also followed up with patients with EGFR-sensitizing mutations who had a treatment response rate of 97.2% after 3 months., Conclusions: Genotyping of MPE supernatant cfDNA is feasible in clinical practice, in addition to plasma and tumor testing, to improve diagnostic yield and extend patients' benefit from targeted therapies., (© 2024. The Author(s).)

Objective: Reports of tuberculosis (TB) during anticancer treatment with immune checkpoint inhibitors (ICIs) are increasing. However, it is not clear whether the use of ICIs is a significant risk factor for TB, including reactivation or latent TB infection (LTBI)., Methods: To determine the risk of TB reactivation in patients with lung cancer who use ICIs or tyrosine kinase inhibitors (TKIs), we conducted a retrospective study using a hospital-based cancer registry. In addition, we monitored patients with cancer using ICI or TKI in a multicenter prospective study to check the incidence of LTBI., Results: In the retrospective study, several demographic factors were imbalanced between the ICI and TKI groups: the ICI group was younger, had more males, exhibited more squamous cell carcinoma in histology rather than adenocarcinoma, had fewer EGFR mutations, and received more chemotherapy. Propensity score matching was used to control for confounding factors, and we found that the incidence of TB was higher among patients with lung cancer who received ICIs than among those who received TKIs (2298 vs 412 per 100 000 person-years, P = .0165). Through multivariable analysis, group (ICI vs TKI) was the independent risk factor for TB development (adjusted hazard ratio (aHR): 6.29, 95% CI, 1.23-32.09, P = .0269). In the prospective cohort, which included 72 patients receiving ICIs and 50 receiving TKIs, we found that the incidence of positive seroconversion of LTBI by interferon gamma release assay (IGRA) was significantly higher in patients receiving ICIs (18% vs 0%, aHR: 9.88, P = 0.035) under multivariable Cox regression., Conclusion: The use of ICIs may be linked to a higher likelihood of TB reactivation and LTBI than individuals solely receiving TKIs as anticancer therapy. Consequently, the implementation of a screening program for TB reactivation and LTBI among patients undergoing ICI treatment could prove advantageous by enabling early detection and prompt treatment of the infection., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are used as the standard first-line treatment for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, the impact of comorbidities and treatment toxicities on quality of life (QoL) was seldom investigated., Objective: We aimed to investigate the association of comorbidities, adverse events (AEs), and QoL in treatment-naïve advanced NSCLC patients receiving EGFR-TKI treatments., Methods: This multi-center prospective observational study was conducted to evaluate QoL and AEs at baseline, the 2nd, 4th, 12th, and 24th week. Clinical characteristics, comorbidities, and pre-treatment laboratory data were recorded. QoL was assessed by using the summary score of the EORTC QLQ-C30 and the dermatology life quality index. The impact of comorbidities, neutrophil-to-lymphocyte ratio (NLR), and AEs on QoL was analyzed by generalized estimating equations., Results: A total of 121 patients were enrolled. Diarrhea (p = 0.033), anorexia (p < 0.001), and NLR ≥4 (p = 0.017) were significantly associated with a QoL impairment. Among skin toxicities, acneiform rash (p = 0.002), pruritus (p = 0.002), visual analogue scale for pruritus (≥3 and < 7, p = 0.006; ≥7, p = 0.001) and pain (1-3, p = 0.041) were associated with a QoL impairment. No significant association was found between comorbidities and QoL changes., Conclusion: Diarrhea, anorexia, skin pain, and pruritus may cause a deterioration in QoL in patients receiving EGFR-TKI therapy. NLR may be a potential predictive factor for QoL impairment. Aggressive management and close monitoring for these clinical factors are crucial to improve QoL., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jung-Yueh Chen has received honoraria for speeches from AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Eli Lilly, Novartis, Pfizer, Roche, and Chugai Pharmaceutical. Yu-Feng Wei has received honoraria for speeches from Boehringer Ingelheim, Eli Lilly, AstraZeneca, Novartis, Pfizer, Roche, and Chugai Pharmaceutical. Sheng-kai Liang has received honoraria for speeches from Roche, AstraZeneca, Pfizer, Merck Sharp & Dohme, Novartis, and Boehringer Ingelheim. Kuan-Yu Chen has received honoraria for speeches from Pfizer, Novartis, Merck Sharp & Dohme, AstraZeneca, Roche, Boehringer Ingelheim, Daiichi Sankyo, Chugai Pharmaceutical, and Bristol-Myers Squibb, as well as travel/accommodation/meeting expenses from Merck Sharp & Dohme, Chugai Pharmaceutical, and Boehringer Ingelheim. Chia-Yu Chu has received honoraria for speeches from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Pfizer, Roche. Tzu-Yi Chuang, Chia-Hung Tu, Yu-Jo Yeh declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Background: In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis. We aimed to assess the efficacy of low-dose CT (LDCT) screening among never-smokers, who had other risk factors for lung cancer., Methods: The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) was a nationwide, multicentre, prospective cohort study done at 17 tertiary medical centres in Taiwan. Eligible individuals had negative chest radiography, were aged 55-75 years, had never smoked or had smoked fewer than 10 pack-years and stopped smoking for more than 15 years (self-report), and had one of the following risk factors: a family history of lung cancer; passive smoke exposure; a history of pulmonary tuberculosis or chronic obstructive pulmonary disorders; a cooking index of 110 or higher; or cooking without using ventilation. Eligible participants underwent LDCT at baseline, then annually for 2 years, and then every 2 years up to 6 years thereafter, with follow-up assessments at each LDCT scan (ie, total follow-up of 8 years). A positive scan was defined as a solid or part-solid nodule larger than 6 mm in mean diameter or a pure ground-glass nodule larger than 5 mm in mean diameter. Lung cancer was diagnosed through invasive procedures, such as image-guided aspiration or biopsy or surgery. Here, we report the results of 1-year follow-up after LDCT screening at baseline. The primary outcome was lung cancer detection rate. The p value for detection rates was estimated by the χ 2 test. Univariate and multivariable logistic regression analyses were used to assess the association between lung cancer incidence and each risk factor. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of LDCT screening were also assessed. This study is registered with ClinicalTrials.gov, NCT02611570, and is ongoing., Findings: Between Dec 1, 2015, and July 31, 2019, 12 011 participants (8868 females) were enrolled, of whom 6009 had a family history of lung cancer. Among 12 011 LDCT scans done at baseline, 2094 (17·4%) were positive. Lung cancer was diagnosed in 318 (2·6%) of 12 011 participants (257 [2·1%] participants had invasive lung cancer and 61 [0·5%] had adenocarcinomas in situ). 317 of 318 participants had adenocarcinoma and 246 (77·4%) of 318 had stage I disease. The prevalence of invasive lung cancer was higher among participants with a family history of lung cancer (161 [2·7%] of 6009 participants) than in those without (96 [1·6%] of 6002 participants). In participants with a family history of lung cancer, the detection rate of invasive lung cancer increased significantly with age, whereas the detection rate of adenocarcinoma in situ remained stable. In multivariable analysis, female sex, a family history of lung cancer, and age older than 60 years were associated with an increased risk of lung cancer and invasive lung cancer; passive smoke exposure, cumulative exposure to cooking, cooking without ventilation, and a previous history of chronic lung diseases were not associated with lung cancer, even after stratification by family history of lung cancer. In participants with a family history of lung cancer, the higher the number of first-degree relatives affected, the higher the risk of lung cancer; participants whose mother or sibling had lung cancer were also at an increased risk. A positive LDCT scan had 92·1% sensitivity, 84·6% specificity, a PPV of 14·0%, and a NPV of 99·7% for lung cancer diagnosis., Interpretation: TALENT had a high invasive lung cancer detection rate at 1 year after baseline LDCT scan. Overdiagnosis could have occurred, especially in participants diagnosed with adenocarcinoma in situ. In individuals who do not smoke, our findings suggest that a family history of lung cancer among first-degree relatives significantly increases the risk of lung cancer as well as the rate of invasive lung cancer with increasing age. Further research on risk factors for lung cancer in this population is needed, particularly for those without a family history of lung cancer., Funding: Ministry of Health and Welfare of Taiwan., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: In RELAY, a randomized, double-blind, phase III trial investigating the efficacy and safety of ramucirumab+erlotinib (RAM+ERL) or ERL+placebo (PBO) in patients with untreated, stage IV, epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), RAM+ERL demonstrated superior progression-free survival (PFS) versus PBO+ERL, with no new safety signals., Objective: The aim of this paper was to report efficacy and tolerability findings for the Taiwanese participants of RELAY., Patients and Methods: Patients were randomized 1:1 to RAM+ERL or ERL+PBO. Primary endpoint was investigator-assessed PFS. Secondary endpoints included objective response rate (ORR), duration of response (DoR) and tolerability. Data for the current analysis are reported descriptively., Results: In RELAY, 56 Taiwanese patients were enrolled; 26 received RAM+ERL, 30 received ERL+PBO. The demographic profile of the Taiwanese subgroup was consistent with that of the overall RELAY population. Median PFS for RAM+ERL/ERL+PBO, respectively, was 22.05 months/13.40 months (unstratified hazard ratio 0.4; 95% confidence interval 0.2-0.9); ORR was 92%/60%; median DoR was 18.2 months/12.7 months. All patients experienced one or more treatment-emergent adverse events (TEAEs); those most commonly reported were diarrhea and dermatitis acneiform (58% each) for RAM+ERL and diarrhea (70%) and paronychia (63%) for PBO+ERL. Grade ≥  3 TEAEs were experienced by 62%/30% of RAM+ERL/PBO+ERL patients, respectively, and included dermatitis acneiform (19%/7%), hypertension (12%/7%), and pneumonia (12%/0%)., Conclusions: PFS for the Taiwanese participants of RELAY receiving RAM+ERL versus ERL+PBO was consistent with that in the overall RELAY population. These results, together with no new safety signals and a manageable safety profile, may support first-line use of RAM+ERL in Taiwanese patients with untreated EGFR-mutant stage IV NSCLC., Trial Registration: www., Clinicaltrials: gov , NCT02411448., (© 2023. The Author(s).)

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are commonly used to treat advanced non-small cell lung cancer (NSCLC). A rapid and reliable method for measuring plasma and cerebrospinal fluid (CSF) concentrations of EGFR-TKIs is needed for therapeutic drug monitoring. By using UHPLC‒MS/MS with multiple reaction monitoring mode, we developed a method for rapidly determining the plasma and CSF concentrations of gefitinib, erlotinib, afatinib, and osimertinib. Protein precipitation was employed to remove protein interference for plasma and CSF matrix. The LC‒MS/MS assay was validated to be satisfactory in terms of linearity, precision, and accuracy. This method was successfully applied to measure plasma (n = 44) and CSF (n = 6) concentrations of EGFR-TKIs in NSCLC patients. The chromatographic separation was achieved by a Hypersil Gold aQ column within 3 min. The median plasma concentrations were 325.76, 1981.50, 42.62, 40.27, and 340.92 ng/ml for gefitinib erlotinib, afatinib 30 mg/day, afatinib 40 mg/day, and osimertinib, respectively. The CSF penetration rates were 2.15% for the patients receiving erlotinib therapy, 0.59% for afatinib, 0.08-1.12% for osimertinib 80 mg/day, and 2.18% for those receiving osimertinib 160 mg/day. This assay helps to predict the effectiveness and toxicities of EGFR-TKIs in the pursuit of precision medicine for lung cancer patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The imbalance of gut microbiota, dysbiosis, is associated with various malignant diseases. This study aimed to identify the characteristics of gut microbiota in age-matched treatment-naïve non-small-cell lung cancer (NSCLC) patients and healthy individuals to investigate possible gut-microbe-related pathways involved in the development of NSCLC. Methods: We enrolled 34 age-matched NSCLC patients and 268 healthy individuals. Hypervariable V3−V4 amplicons of 16S rRNA in freshly collected fecal samples were sequenced. Diversity, microbial composition, functional pathways, smoking history, and gut-microbe-related comorbidities were analyzed to assess the factors associated with the risk of NSCLC. Results: Microbial alpha diversity was decreased in the patients with NSCLC, and beta diversity was significantly different between the patients and controls (p < 0.001). After adjustments for sex, smoking history, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, and 11 abundant microbes with significant differences between the patients and controls, the enrichment of Anaerotruncus spp. and Bacteroides caccae was associated with an increased risk of NSCLC (p = 0.003 and 0.007, respectively). The areas under receiver operating characteristic curves were 71.4% and 66.9% for Anaerotruncus spp. and Bacteroides caccae, respectively (both p < 0.001). Furthermore, the abundance of Bacteroides caccae was positively correlated with steroid hormone biosynthesis (p < 0.001), N-glycan biosynthesis (p = 0.023), glycosaminoglycan degradation (p < 0.001), lipoic acid metabolism (p = 0.039), peroxisome (p < 0.001), and apoptosis (p < 0.001), but inversely related to glycerolipid metabolism (p < 0.001). Anaerotruncus spp. was positively associated with decreased biosynthesis of ansamycin only (p = 0.001). No overlapping signaling pathways were modulated by Bacteroides caccae or Anaerotruncus spp. Conclusions: Our results revealed that fecal Anaerotruncus spp. and Bacteroides caccae were abundant and may be associated with the risk of NSCLC regardless of sex, smoking history, and gut-microbe-related comorbidities. Further investigations on the mechanism underlying the potential association between gut dysbiosis and the development of NSCLC are warranted.

Backgrounds: Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy (CT) are the standard of care for first-line therapy in metastatic non-small cell lung cancer (NSCLC) patients without actionable mutations. The safety ranking of different ICI and CT combination regimens has not been investigated. This study was aimed to provide a toxicity profile and safety ranking of different ICI and CT combination regimens., Methods: We performed comprehensive searches of phase 2 and 3 randomized clinical trials (RCTs) comparing different ICI regimens (alone or combination) or CT for the first-line treatment of advanced NSCLC. Outcomes of interest were the cumulative incidence of any treatment-related adverse events (TRAEs), grade 3-5 TRAEs (grade 3-5), any immune-related adverse events (irAEs), and grade 3-5 irAEs (grade 3-5). Odds ratios and 95% credible intervals were calculated as summary statistics to quantify the effect of different ICI combination regimens., Results: We included 21 RCTs from 2016 to 2021 with a total of 12,626 patients. The incidence of any TRAEs and grade 3-5 TRAEs ranked from high to low were ICI-CT (probability: 88.3% and 87.1%), ICI-ICI-CT (66.2% and 73.9%), CT alone (77.7% and 86.6%), ICI-ICI (98.9% and 99.2%), and ICI monotherapy (99.7% and 100%). Adding CT to ICI regimens resulted in a higher incidence of any grade or grade 3-5 TRAEs compared to ICI-ICI combinations or ICI monotherapy. However, ICI-ICI-CT combinations did not result in a higher incidence of TRAEs than ICI-CT combinations. For any irAEs and grade 3-5 irAEs, the ranking was ICI-ICI (probability: 97.6% and 99.8%), ICI monotherapy (97.2% and 99.8%), ICI-CT (99.5% and 99.9%), and CT alone (99.9% and 100%). Notably, the incidence of any grade and grade 3-5 irAEs was lower when adding CT to ICI monotherapy., Conclusion: Lack of head-to-head comparisons, these findings provide evidence for clinical decision-making when considering different ICI combination regimens for advanced NSCLC patients., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: RELAY was a global, double-blind, placebo-controlled phase III study that demonstrated superior progression-free survival (PFS) for ramucirumab plus erlotinib (RAM + ERL) versus placebo plus erlotinib (PBO + ERL) in the first-line treatment of patients with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) mutation-positive, metastatic non-small-cell lung cancer (NSCLC)., Objective: This article provides an in-depth analysis of the safety profile of RAM + ERL versus PBO + ERL observed in RELAY., Methods: Eligible patients met these criteria: stage IV NSCLC; EGFR exon 19 deletion or exon 21 substitution (L858R) mutation; Eastern Cooperative Oncology Group performance status 0 or 1; and no central nervous system metastases. Patients were randomized (1:1) to receive erlotinib 150 mg/day orally plus either ramucirumab 10 mg/kg intravenously or matching placebo once every 2 weeks, until disease progression or unacceptable toxicity. The primary endpoint was PFS. Safety was evaluated based on reported treatment-emergent adverse events (AEs) and clinical laboratory assessments., Results: The safety population comprised 446 patients (221 in RAM+ERL arm; 225 in PBO + ERL arm) who received at least one dose of study drug between January 2016 and February 2018. The overall incidence of grade ≥ 3 AEs was higher with RAM + ERL than with PBO + ERL, primarily driven by grade 3 hypertension. Grade ≥ 3 dermatitis acneiform and diarrhea were also reported more frequently in the RAM + ERL arm. The increased incidence of AEs with RAM + ERL was easily detected through routine monitoring and managed through dose adjustments and appropriate supportive care., Conclusion: This in-depth safety analysis from RELAY supports that RAM + ERL, irrespective of the increased incidence of AEs, does not affect a patient's ability to benefit from treatment., Clinical Trial Registration Number: NCT02411448., (© 2021. The Author(s).)

Background: Limited studies have focused on the impact of the coexistence of small cell lung cancer (SCLC) and chronic obstructive pulmonary disease (COPD). The study was to examine the impact of COPD on mortality in SCLC patients., Methods: We analyzed SCLC patients from the Taiwan Cancer Registry Database between January 1, 1997, and December 31, 2015. The COPD population was composed of patients with a COPD diagnosis before the diagnosis of SCLC. The control group was composed of randomly selected SCLC patients without COPD who were propensity score matched with those with concomitant COPD according to age, sex, index date, cancer staging and comorbidities at a 1:1 ratio., Results: Among 9425 SCLC patients in the database, eligible subjects were divided into the COPD group (n = 4235) and the non-COPD group (n = 2334). Compared to patients in the non-COPD group, the patients in the COPD group were older (71.4 versus 65.7 years, p<0.0001), had a lower percentage of stage IV disease (60.1% versus 68.3%, p<0.0001) and had more comorbidities. After matching, there were 1457 patients in each group. Older age, lower body mass index (BMI), and some comorbidities were associated with higher mortality, and comorbid COPD was associated with lower 1-year mortality in SCLC patients. Multivariate analysis identified older age, lower BMI, and concomitant congestive heart failure or diabetes as risk factors for OS., Conclusion: A diagnosis of COPD was associated with reduced 1-year mortality in SCLC patients, but no significant difference after 1-year in this population., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Liao et al.)

Background: Limited treatment options exist for relapsed advanced lung squamous cell carcinoma (SCC), leading to poor outcomes compared with adenocarcinoma. This study aimed to investigate the efficacy of second-line afatinib versus chemotherapy in patients with advanced lung SCC who progressed after first-line chemotherapy., Methods: In this retrospective, multisite cohort study, we recruited patients with initial locally advanced or metastatic lung SCC from four institutes in Taiwan between June 2014 and October 2020. The primary endpoint of this study was progression-free survival (PFS), and the secondary endpoints were the objective response rate (ORR), disease control rate (DCR), and overall survival (OS)., Results: The present study enrolled 108 patients: 19 received second-line afatinib, and 89 received second-line chemotherapy. The median ages were 71 and 67 years, respectively. PFS was significantly longer among patients who received afatinib than among those who received chemotherapy (median 4.7 months [95% confidence interval (CI), 0.1-7.5] vs. 2.6 months [95% CI, 0.9-6.7]; hazard ratio (HR) 0.53 [95% CI 0.32-0.88], p = 0.013). Compared with the chemotherapy group, OS was longer in the afatinib group but did not reach significance (median 16.0 months [95% CI, 6.1-22.0] vs. 12.3 months [6.2-33.9]; HR 0.65 [95% CI 0.38-1.11], p = 0.112)., Conclusions: Afatinib offered a longer PFS and comparable OS to chemotherapy in advanced lung SCC patients in a real-world setting, it may be considered as a 2nd line alternative treatment choice for immunotherapy unfit advanced lung SCC patients., (© 2021. The Author(s).)

Introduction: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non-small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear., Methods: This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients' clinicopathologic characteristics and treatment outcomes were analyzed., Results: Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. Five (16%) ALK mutations (L1196M ×2, I1171T, D1203N, G1269A/F1174L) and 3 possible bypass mutations (NRAS G12V, EGFR R108K, PIK3CA E545K) were found in 32 crizotinib-resistant cancers. Four (22%) ALK mutations (G1128A, G1202R, G1269A, I1171T/E1210K) and 3 possible bypass mutations (KIT D820E, MET E1012∗, EGFR P265&#95;C291del) were found in 18 ceritinib-resistant cancers. Four (17%) ALK mutations (G1202R ×2, W1295C, G1202R/L1196M) and 1 possible bypass mutation (EGFR P753S) were found in 24 alectinib-resistant cancers. Two (11%) ALK mutations (G1202R/G1269A ×2) and 2 possible bypass mutations (BRAF V600E, MET D1246N) were found in 18 lorlatinib-resistant cancers. In patients with simultaneous paired tissue and cfDNA samples (n = 20), mutations were identified in 9 (45%) and 6 (30%) cases, respectively; the concordance rate was 45%., Conclusions: The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: YTL has received speaking honoraria from ACT Genomics, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Manudipharma, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and TTY Biopharm; and travel expense from Pfizer. CLC has received speaking honoraria from Chugai Pharmaceutical, Novartis, and Pfizer. SYW has received speaking honoraria from Boehringer Ingelheim, Merck Sharp & Dohme, Merck KGaA, Novartis, and Sanofi; and travel expense from Bristol-Myers Squibb and TTY Biopharm. HPC has received speaking honoraria from AstraZeneca, Chugai Pharmaceutical, Novartis, and Pfizer. CHC has received honoraria from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche, and Takeda. JYS has been an advisory board member for AstraZeneca, Roche, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Ono Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, Cstone Pharmaceuticals, Janssen Pharmaceutica, and Takeda. JYS has received speaking honoraria from AstraZeneca, Roche, Boehringer-Ingelheim, Eli Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Ono Pharmaceutical, Chugai Pharmaceutical, and Bristol-Myers Squibb; and travel expense from Roche, Boehringer Ingelheim, Pfizer, Merck Sharp & Dohme, Chugai Pharmaceutical, and Bristol-Myers Squibb. The remaining authors declare no conflict of interest. Results from this study were presented, in part, at the 2020 Annual Congress of Taiwan Society of Pulmonary and Critical Care Medicine in Taipei, Taiwan, December 12, 2020., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This meta-analysis investigated the clinical benefits of chemo-immunotherapy in extensive-stage small-cell lung cancer (ES-SCLC). Seven randomized controlled trials with a total of 2862 patients were analyzed. Compared with chemotherapy alone, chemo-immunotherapy provided a better progression-free survival (PFS) with a hazard ratio (HR) of 0.81, p < 0.00001, and overall survival (OS) with a HR of 0.82, p < 0.0001; however, the incidence of treatment-related adverse effects (TRAEs) was significantly increased. Subgroup analyses showed that good performance status, cisplatin-based chemotherapy, without brain metastases at baseline and non-Asian populations were associated with greater benefits in OS from chemo-immunotherapy. Chemo-immunotherapy demonstrated better PFS and OS compared with chemotherapy alone as first line treatment in ES-SCLC, but additional TRAEs should be closely monitored.

Aim: S-1 combined with cisplatin is known to be noninferior to taxanes plus platinum as the first-line treatment for patients with advanced nonsmall cell lung cancer (NSCLC) in the Japanese population. This study aimed to evaluate the efficacy and safety profiles of oral S-1 plus cisplatin (SP) in Taiwanese patients., Methods: Patients with previously untreated stage IIIB or IV NSCLC were prospectively recruited to receive 40-60 mg of S-1 twice daily on days 1-21 plus 60 mg/m 2 of cisplatin on day 8 in a 5-week cycle for up to six cycles., Results: A total of 55 patients from five cancer centers in Taiwan were enrolled. Among the 46 evaluable patients, those administered with SP achieved disease control rate of 69.6% (partial response, 19.6%; stable disease, 50.0%), with median overall survival and progression-free survival (PFS) of 15.1 and 5.7 months, respectively. Moreover, a better survival trend was observed in epidermal growth factor receptor mutation-positive patients versus mutation-negative patients treated with SP (PFS, 8.6 vs 5.6 months). The most commonly observed treatment-related adverse events (AEs) were nausea (41.8%), followed by decreased appetite, anemia, and diarrhea. Grade of ≥3 AEs related to the study treatment occurred in 11 patients (20.0%). No febrile neutropenia or treatment-related death was found in this study., Conclusions: This study demonstrated that SP is an effective and safe first-line regimen for Taiwanese patients with advanced NSCLC., (© 2019 John Wiley & Sons Australia, Ltd.)

Introduction: Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor (TKI). Durvalumab is an anti-programmed death ligand 1 monoclonal antibody. The phase III open-label CAURAL trial (NCT02454933) investigated osimertinib plus durvalumab versus osimertinib monotherapy in patients with EGFR-TKI sensitizing and EGFR T790M mutation-positive advanced NSCLC and disease progression after EGFR-TKI therapy., Methods: Patients were randomly assigned 1:1 to receive orally administered osimertinib (80 mg once daily) with or without durvalumab (10 mg/kg administered intravenously every 2 weeks) until progression. Treatment could continue beyond progression, providing clinical benefit continued (judged by the investigator). The amended primary objective was to assess the safety and tolerability of osimertinib plus durvalumab; efficacy was an exploratory objective., Results: CAURAL recruitment was terminated early because of increased incidence of interstitial lung disease-like events in the osimertinib plus durvalumab arm from the separate phase Ib TATTON trial (NCT02143466). At termination of CAURAL recruitment, 15 patients had been randomly assigned to treatment with osimertinib and 14 to treatment with osimertinib plus durvalumab. The most common AEs were diarrhea (53% [grade ≥3 in 6% of patients]) in the osimertinib arm and rash (67% [grade ≥3 in 0 patients]) in the combination arm. One patient who had been randomized to the combination arm reported grade 2 interstitial lung disease while receiving osimertinib monotherapy (after discontinuing durvalumab therapy after one dose). The objective response rates were 80% in the osimertinib arm and 64% in the combination arm., Conclusion: Limited patient numbers preclude formal safety and efficacy comparisons between the two treatment arms. The combination of programmed cell death 1/programmed death ligand 1 inhibitors and EGFR-TKIs as therapy for NSCLC is not well understood, but it requires a careful approach if considered in the future., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: As the first-line treatment, afatinib is commonly used in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, dose adjustments are frequently required. The optimal dose of afatinib for brain metastasis has seldom been investigated., Patients and Methods: From May 2014 to March 2017, treatment-naive patients with advanced EGFR-mutated NSCLC and brain metastases at diagnosis who received afatinib therapy were retrospectively enrolled. Clinical data was reviewed and analyzed, including age, gender, performance status, smoking history, EGFR mutation status, initial doses of afatinib, average daily doses of afatinib, and best intracranial treatment responses., Results: A total of 74 patients were included for analysis. The overall intracranial objective response rate (IORR) and intracranial disease control rate (IDCR) were 81.1% and 95.9%, respectively. For patients treated with afatinib alone (N = 45), no significant difference between an initial daily dose of 30 mg (N = 15) and 40 mg (N = 30) (30 mg vs. 40 mg, IORR: 86.7% vs. 80.0%; P = .581 and IDCR: 93.3% vs. 93.3%; P = 1.000, respectively). The IORRs were 75.0%, 91.7%, 80.0%, and 85.7% (P = .707), and the IDCRs were 93.8%, 100.0%, 90.0%, and 85.7% (P = .638) in patients with an average daily dose of 40 mg (N = 16), < 40 mg and > 30 mg (N = 12), 30 mg (N = 10), and < 30 mg and > 20 mg (N = 7), respectively. No significant differences in intracranial treatment responses between groups treated with afatinib alone or afatinib plus local treatments., Conclusion: Dose reduction may not affect intracranial treatment responses to afatinib therapy, either alone or combined with local treatments, in patients with advanced EGFR-mutated NSCLC and brain metastases., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Our population-based research aimed to clarify the association between chronic kidney disease (CKD) and mortality risk in patients with lung cancer., Design: Retrospective cohort study SETTING: National health insurance research database in Taiwan PARTICIPANTS: All (n=1 37 077) Taiwanese residents who were diagnosed with lung cancer between 1997 and 2012 were identified. Eligible patients with baseline CKD (n=2269) were matched with controls (1:4, n=9076) without renal disease according to age, sex and the index day of lung cancer diagnosis., Methods: The cumulative incidence of death was calculated by the Kaplan-Meier method, and the risk determinants were explored by the Cox proportional hazards model., Results: Mortality occurred in 1866 (82.24%) and 7135 (78.61%) patients with and without CKD, respectively (P=0.0001). The cumulative incidences of mortality in patients with and without chronic renal disease were 72.8% vs 61.6% at 1 year, 82.0% vs 76.6% at 2 years and 88.9% vs 87.2% at 5 years, respectively. After adjusting for multiple confounding factors including age and comorbidities, Cox regression analysis revealed that CKD was associated with an increased risk of mortality (adjusted HR 1.38; 95% CI 1.29 to 1.47). Stratified analysis further showed that the association was consistent across patient subgroups., Conclusion: Comorbidity associated with CKD is a risk factor for mortality in patients with lung cancer., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose: We aimed to summarize the imaging findings of 25 patients with gefitinib-related interstitial lung disease (ILD), and identify the factors related to prognosis of gefitinib-related ILD in patients with non-small-cell-lung cancer., Materials and Methods: Diagnosis of gefitinib-induced ILD by at least two chest radiologists was based on a review and analysis of the chest radiography and CT findings plus clinical data in the medical records. All patients were diagnosed with Stage III - IV non-small-cell carcinoma (adenocarcinoma (n = 24), bronchioalveolar cell carcinoma (n = 1)) and essential clinical data such as gefitinib as first-line use and survival status were recorded and analyzed to determine whether these were prognosis predictors. The imaging findings were classified into four patterns according to the previous largest study in Japan., Results: The 25 chest radiographs were classified as Pattern A (n = 8), Pattern B (n = 3), Pattern C (n = 6), and pattern D (n = 8). Likewise the 23 CT images were classified as pattern A (n = 8; 34.8%), B (n = 3; 13%), C (n = 5; 21.7%), and D (n = 7; 30.4%). The mortality rate was significantly higher in patients with pattern D than in patients with the other patterns. Pattern D imaging findings were also significantly correlated with non first-line use of gefitinib (p = 0.007)., Conclusions: We found an increase in mortality rate in patients with gefitinib associated ILD/pattern D compared to other radiological patterns. Familiarity with these imaging patterns can facilitate early and accurate diagnosis and help physicians gauge clinical prognosis of gefitinib-related ILD.