Factors associated with prolonged progression-free survival of patients treated with first-line afatinib for advanced epidermal growth factor receptor-mutated non-small cell lung cancer.

BACKGROUND: This study aimed to investigate the factors associated with prolonged progression-free survival (PFS) (>36 months) of advanced non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations treated with first-line afatinib. METHODS: We performed a retrospective analysis of data of patients with advanced EGFR-mutated NSCLC receiving first-line afatinib at two tertiary care referral centers, Linkou and Kaohsiung Chang Gung Memorial Hospital, in Taiwan between June 2014 and April 2022. RESULTS: The data of 546 treatment-naïve EGFR-mutated advanced NSCLC patients were analyzed. Median PFS and overall survival were 14.5 months and 27.2 months, respectively. The PFS of 462 patients (84.6%) was less than 36 months and of 84 patients (15.4%) was more than 36 months. The PFS > 36 months group had a significantly higher percentage of patients with uncommon mutations (p = 0.002). The PFS ≤36 months group had significantly higher incidences of bone, liver, and adrenal metastases (all p < 0.05) and a higher rate of multiple distant metastases. Multivariate logistic regression analysis showed that liver metastasis was negatively and independently associated with prolonged PFS (adjusted odds ratio = 0.246 [95% CI: 0.067-0.908], p = 0.035). The median overall survival of the PFS >36 months group was 46.0 months and that of the PFS ≤36 months group was 22.9 months (log-rank test, p < 0.001). CONCLUSIONS: We found that EGFR-mutated NSCLC patients receiving first-line afatinib were prone to shorter PFS if they had distant organ metastasis, especially liver metastasis.

Real-world evidence of lorlatinib therapy in Taiwanese patients with advanced anaplastic lymphoma kinase-positive non-small cell lung cancer.

BACKGROUND: Lorlatinib is a brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) inhibitor indicated for ALK-positive metastatic non-small cell lung cancer (NSCLC). In a global phase II study, patients who experience disease progression despite prior treatment with ALK tyrosine kinase inhibitors (TKIs) was assessed. Herein, we report real-world clinical outcomes of lorlatinib-treated patients with ALK-positive advanced NSCLC who were heavily pretreated and progressed on first- and second-generation ALK-TKIs, in a Taiwanese population under the lorlatinib expanded access program (EAP). METHODS: This multicenter observational study examined the effectiveness and safety of ALK-positive advanced NSCLC patients that progressed from previous second-generation ALK-TKI therapy and received lorlatinib treatment subsequently. Patients who received lorlatinib treatment under EAP between Jul 2017 and Sep 2019 were eligible. Patients were followed for at least one year from the first lorlatinib treatment until study completion. RESULTS: Sixty-three patients were eligible for safety analysis (male: 46.0 %; median age: 52.8 [27.5-78.3] years; brain metastases: 81.0 %). Fifty-four patients with more than one-month lorlatinib treatment were included in the effectiveness analysis. Prior to lorlatinib treatment, 10 patients (18.5 %) received one ALK-TKI, 27 (50.0 %) received two ALK-TKIs, and 17 (31.5 %) received three or more ALK-TKIs. The overall median rwPFS was 9.2 months (95 % confidence interval: 5.3-21.1). The best overall response rate (n = 51) was 13.7 %, with a disease control rate of 80.4 %. CONCLUSION: Lorlatinib exhibits substantial activity and tolerability when used clinically in a later-line setting in a Taiwanese population with ALK-positive advanced NSCLC.

Differential prognostic value of tumor and plasma T790M mutations in EGFR TKI-treated advanced NSCLC.

Background: Substitution of methionine for threonine at codon 790 (T790M) of epidermal growth factor receptor (EGFR) represents the major mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer. We determined the prognostic impact and association of secondary T790M mutations with the outcomes of osimertinib and chemotherapy. Methods: Patients (n = 460) progressing from first-line EGFR-TKI treatment were assessed. Tissue and/or liquid biopsies were used to determine T790M status; post-progression overall survival (OS) was analyzed. Results: Overall, 143 (31.1%) patients were T790M positive, 95 (20.7%) were T790M negative, and 222 (48.2%) had unknown T790M status. T790M status [T790M positive versus T790M negative: hazard ratio (HR) 0.48 (95% confidence interval (CI), 0.32-0.70); p < 0.001, T790M unknown versus T790M negative: HR 1.97 (95% CI, 1.47-2.64); p < 0.001] was significantly associated with post-progression OS. T790M positivity rates were similar for tissue (90/168, 53.6%) and liquid (53/90, 58.9%) biopsies (Fisher's exact test, p = 0.433). Tumor T790M-positive patients had significantly longer post-progression OS than tumor T790M-negative patients (34.1 versus 17.1 months; log-rank test, p = 8 × 10-5). Post-progression OS was similar between plasma T790M-positive and -negative patients (17.4 versus not reached; log-rank test, p = 0.600). In tumor T790M-positive patients, post-progression OS was similar after osimertinib and chemotherapy [34.1 versus 29.1 months; log-rank test, p = 0.900; HR 1.06 (95% CI, 0.44-2.57); p = 0.897]. Conclusion: T790M positivity predicts better post-progression OS than T790M negativity; tumor T790M positivity has a stronger prognostic impact than plasma T790M positivity. Osimertinib and chemotherapy provide similar OS benefits in patients with T790M-positive tumors.

Different prognostic meaning of tumor resistant gene detected from tumor or blood in patients with EGFR-mutant lung cancer The study demonstrates that patients with EGFR-mutant lung cancer who develop resistance due to a secondary T790M mutation, defined by tumor or blood T790M positivity, achieve better survival than patients without secondary T790M mutation; this association was mainly contributed by tumour T790M positivity. Oismertinib and chemotherapy led to similar survival in tumour T790M-positive patients. However, compared to osimertinib, chemotherapy was associated with longer survival in blood T790M-positive patients.

Brain metastasis, EGFR mutation subtype and generation of EGFR-TKI jointly influence the treatment outcome of patient with EGFR-mutant NSCLC.

Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation is brain metastasis (BM)-prone. We determined the impact of this hallmark, along with EGFR subtype and generation of tyrosine kinase inhibitor (TKI) treatment, on patients' outcome. 553 metastatic EGFR-mutant NSCLC patients received front-line EGFR-TKI treatment. Progression-free survival (PFS), overall survival (OS) and secondary T790M rate were analysed. BM was observed in 211 (38.2%) patients. BM (HR 1.20 [95% CI 0.99-1.48]; p = 0.053), ECOG PS 0-1 (HR 0.71 [95% CI 0.54-0.93]; p = 0.014) and afatinib treatment (HR 0.81 [95% CI 0.66-0.99]; p = 0.045) were associated with PFS. Afatinib-treated patients without BM demonstrated a significantly longer PFS (16.3 months) compared to afatinib-treated patients with BM (13.7 months) and to gefitinib/erlotinib-treated patients with (11.1 months) or without BM (14.2 months; p < 0.001). CNS-only progression trended higher in afatinib-treated patients. ECOG PS 0-1 (HR 0.41 [95% CI 0.31-0.56]; p < 0.001) and EGFR L858R mutation (HR 1.46 [95% CI 1.13-1.88]; p = 0.003), but not BM, were the predictors for OS. BM (OR 2.02 [95% CI 1.02-4.08]; p = 0.040), afatinib treatment (OR 0.26 [95% CI 0.12-0.50]; p < 0.001) and EGFR L858R mutation (OR 0.55 [95% CI 0.28-1.05]; p = 0.070) were associated with secondary T790M rate. In BM patients, gefitinib/erlotinib-treated ones with 19 deletion mutation and afatinib-treated ones with L858R mutation had the highest and the lowest T790M rate (94.4% vs. 27.3%, p < 0.001), respectively. BM and generation of EGFR-TKI jointly impact PFS and secondary T790M rate in patients with EGFR-mutant NSCLC, whereas OS was mainly associated with EGFR subtype.

Sequential treatment in advanced epidermal growth factor receptor-mutated lung adenocarcinoma patients receiving first-line bevacizumab combined with 1st/2nd-generation EGFR-tyrosine kinase inhibitors.

Introduction: The clinical outcomes of sequential treatment of advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients with first-line bevacizumab combined with 1st/2nd-generation EGFR-TKIs are unclear. Thus, we aimed to analyze the outcomes of these patients. Methods: Between January 2015 and December 2020, data for 102 advanced EGFR-mutated lung adenocarcinoma patients receiving first-line bevacizumab combined with erlotinib or afatinib followed by treatments at multiple institutions were retrospectively analyzed. All patients with progressive disease (PD) after first-line therapy underwent secondary T790M mutation detection. Results: The secondary T790M mutation positive rate of all study patients was 57.9%. First-line erlotinib use and progression-free survival (PFS) after first-line therapy > 12 months were positively associated with the T790M mutation (P <0.05). The response rates (RRs) to second-line treatments were 51.7% and 22.7% for the osimertinib and nonosimertinib groups, respectively (P = 0.001). The median PFS associated with second-line osimertinib and nonosimertinib therapy was 13.7 and 7.1 months, respectively (hazard ratio (HR) = 0.38; 95% confidence interval (CI), 0.23-0.63; P< 0.001). Patients with a secondary T790M mutation receiving second-line osimertinib treatment had a median overall survival (OS) of 54.3 months, and the median OS was 31.9 months for non-T790M-mutated patients receiving second-line nonosimertinib treatments (HR = 0.36; CI: 0.21-0.62, P < 0.001). Conclusion: The majority of acquired resistance to first-line bevacizumab combined with 1st/2nd-generation EGFR-TKIs is associated with the T790M mutation. Sequential osimertinib treatment in patients with positive secondary T790M mutation is associated with better outcomes among these patients.

Do patient characteristics affect EGFR tyrosine kinase inhibitor treatment outcomes? A network meta-analysis of real-world survival outcomes of East Asian patients with advanced non-small cell lung cancer treated with first-line EGFR-TKIs.

BACKGROUND: Despite the well-established efficacies of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), there is limited real-world evidence comparing their effectiveness according to patients' clinical characteristics. This network meta-analysis (NMA) compared survival outcomes among first-line EGFR-TKIs in different subgroups of East Asian patients with advanced NSCLC. METHODS: This NMA included real-world observational studies reporting outcomes with TKIs in patients aged >65 years, with baseline brain metastasis, with different Eastern Cooperative Oncology Group (ECOG) statuses, or with different common EGFR mutation types. RESULTS: In patients with the EGFR L858R mutation, afatinib resulted in significantly longer progression-free survival (PFS) than erlotinib (hazard ratio [HR]: 0.59, 95% confidence interval [CI]: 0.46-0.75) and gefitinib (HR: 0.41, 95% CI: 0.32-0.53). Similarly, in patients with the EGFR Del19 mutation, afatinib and erlotinib resulted in significantly longer PFS than gefitinib (HR: 0.48 with 95% CI: 0.33-0.71 and HR: 0.54 with 95% CI: 0.36-0.80, respectively). Moreover, afatinib resulted in significantly longer PFS than gefitinib in patients with brain metastasis (HR: 0.53, 95% CI: 0.33-0.87) or ECOG status 0-1 (HR: 0.37, 95% CI: 0.23-0.59). CONCLUSION: This NMA suggests that afatinib results in similar PFS to erlotinib and superior PFS than gefitinib in patients with Del19 mutant NSCLC, aged ≥65 years, with ECOG scores of 0-1, and with baseline brain metastasis.

Clinical outcome analysis of non-small cell lung cancer patients with brain metastasis receiving metastatic brain tumor resection surgery: a multicenter observational study.

Brain metastasis is most common in primary non-small cell lung cancer (NSCLC), and some patients require neurosurgical resection for intracranial disease control. Because advances in systemic therapies for metastatic NSCLC have been developed in the past decade, we aimed to analyze and determine clinical factors associated with the postresection survival of NSCLC patients with brain metastasis who underwent neurosurgery followed by systemic therapy. Between January 2017 and December 2021, data for 93 NSCLC patients with brain metastasis treated with neurosurgery followed by systemic therapy at Linkou, Kaohsiung and Chiayi Chang Gung Memorial Hospitals were retrospectively retrieved for analysis. For all study patients, median postresection survival was 34.36 months (95% confidence interval (CI), 28.97-39.76), median brain metastasis (BM)-free survival was 26.90 months (95% CI, 22.71-31.09), and overall survival (OS) was 41.13 months (95% CI, 34.47-47.52). In multivariate analysis, poor performance status (Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2) and concurrent liver metastasis were identified as independent unfavorable factors associated with significantly shortened postresection survival (P<0.001). The histological type adenocarcinoma was associated with significantly longer postresection survival (P = 0.001). The median postresection survival for adenocarcinoma and nonadenocarcinoma patients was 36.23 and 10.30 months, respectively (hazard ratio (HR) = 0.122; 95% CI, 0.035-0.418; P<0.001); that for patients with and without concurrent liver metastasis was 11.43 and 36.23 months, respectively (HR = 22.18; 95% CI, 5.827-84.459; P<0.001). Patients with preserved ECOG PS, adenocarcinoma histology type and no concurrent liver metastasis appeared to have better postresection survival than nonadenocarcinoma patients. Our results provide counseling and decision-making references for neurosurgery feasibility in NSCLC patients with brain metastasis.

Levels of organophosphate flame retardants and their metabolites among 391 volunteers in Taiwan: difference between adults and children.

Background: Organophosphate flame retardants (OPFRs) are ubiquitous in the environment. The compositions and concentrations of different OPFRs metabolites vary in different environments depending on different human activities. The objective of the present study was to evaluate the exposure of different age groups to OPFRs in Taiwan. Methods: Volunteers provided urine samples and responded to questionnaires including demographic factors, underlying disease, lifestyle information, and occupation from October 2021 to January 2022. OPFR measurements were performed using a Waters Acquity Ultra-Performance Liquid Chromatography system coupled with a Waters Xevo TQ-XS mass spectrometer. Results: A total of 391 volunteers (74 children and 317 adults) were enrolled in this study. The concentrations (presented as µg/g creatinine) of bis(1,3-dichloro-2-propyl) phosphate (BDCPP, p = 0.029) and tri-n-butyl phosphate (TNBP, p = 0.008) were higher in the adult group, while the concentrations of bis-2-chloroethyl phosphate (BCEP, p = 0.024), diphenyl phosphate (DPHP, p < 0.001), tris(1,3-dichloro-2-propyl) phosphate (TDCPP, p = 0.009), and Tris(2-butoxyethyl) phosphate (TBEP, p = 0.007) were higher in the child group. Compared with school age children (>6 years), the concentration of di(2-n-butoxyethyl) phthalate (DBEP, 1.14 vs. 0.20 µg/g creatinine, p = 0.001), DPHP (1.23 vs. 0.54 µg/g creatinine, p = 0.036), TBEP (1.63 vs. 0.29 µg/g creatinine, p < 0.001), and the sum of OPFR metabolites (ΣOPFRs, 6.58 vs. 2.04 µg/g creatinine, p < 0.001) were statistically higher in preschool-aged children. After adjusting for confounding factors, pre-school age [odds ratio (OR): 4.579, 95% confidence interval (CI): 1.389-13.115] and current smoker (OR: 5.328, 95%CI: 1.858-14.955) were independently associated with the risk of ΣOPFRs higher than 90 percentile. Conclusion: This study revealed the distribution of different OPFRs metabolites in children and adults. DBEP, DPHP, TBEP, and ΣOPFR were higher in preschool-aged children. Pre-school age and current smoking status were independent risk factors for ΣOPFRs higher than 90 percentile.

Survival outcomes of east Asian patients with advanced non-small cell lung cancer treated with first-line EGFR tyrosine kinase inhibitors: A network meta-analysis of real-world evidence.

BACKGROUND: The comparative efficacies of different generation tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC) remain largely unknown. Moreover, whether one EGFR-TKI confers superior survival remains unclear, especially in East Asians. We conducted a network meta-analysis (NMA) comparing the survival outcomes of East Asian patients with advanced NSCLC treated with first-line EGFR-TKIs. METHODS: The NMA included observational real-world evidence studies on adult patients with EGFR-mutated advanced NSCLC who received first (gefitinib and erlotinib), second (afatinib), or third (osimertinib) generation EGFR-TKIs as frontline therapy. Studies were identified through an online bibliographic search of Medline articles in the PubMed, SCOPUS, Web of Science, and Cochrane Library databases. RESULTS: For overall survival (OS), afatinib had significantly better hazard ratios (HRs) than osimertinib (HR: 0.46, 95% confidence interval [CI]: 0.23-0.91), gefitinib (HR: 0.56, 95% CI: 0.43-0.72), and erlotinib (HR: 0.71, 95% CI: 0.54-0.92). For progression-free survival (PFS), afatinib had significantly better HRs than gefitinib (HR: 0.45, 95% CI: 0.36-0.56) and erlotinib (HR: 0.63, 95% CI: 0.49-0.81). Moreover, afatinib was most likely to achieve the longest OS (81.3%), followed by erlotinib (13%), osimertinib, and gefitinib. Furthermore, afatinib was most likely to achieve the longest PFS (48.3%), followed by osimertinib (34.9%) and erlotinib. CONCLUSIONS: This real-world evidence shows that afatinib confers better survival than other first-line EGFR-TKIs in East Asian patients with advanced NSCLC.

T790M detection rate after first-line combination therapy with bevacizumab and EGFR-TKIs in advanced NSCLC (TERRA Study).

Real-world data regarding the T790M mutation rate after acquiring resistance to first-line combination therapy with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and bevacizumab in patients with advanced non-small-cell lung cancer (NSCLC) are limited. The present study was aimed at analyzing predictors of acquired T790M mutations in this patient group. A total of 107 patients who received first-line combination therapy with EGFR-TKIs and bevacizumab at 11 tertiary referral centers in Taiwan were enrolled in this multicenter retrospective study. Survival data and genomic test results after acquiring resistance were analyzed. We discovered that patients who received a combination of afatinib, a second generation EGFR-TKI, and bevacizumab showed better progression-free survival (PFS). After disease progression, 59 patients (55.1%) were confirmed to test positive for EGFR T790M. A longer duration of first-line therapy could be a predictor of subsequent T790M mutations. To our knowledge, this is one of the few and early studies to demonstrate the T790M mutation rate after first-line combination therapy with an EGFR-TKI and bevacizumab. Whether the longer PFS afforded by the addition of bevacizumab could lead to subsequent T790M mutations needs further investigation.

E-cadherin expression in the tumor microenvironment of advanced epidermal growth factor receptor-mutant lung adenocarcinoma and the association with prognosis.

BACKGROUND: The expression of programmed death-ligand 1 (PD-L1), tumor-infiltrating lymphocytes (TILs), E-cadherin, and vimentin in lung cancer tumor microenvironment is known to impact patient survival or response to therapy. The expression of these biomarkers may also differ between primary lung tumors and brain metastatic tumors. In this study, we investigated the interaction between these biomarkers in lung tumors with or without concomitant brain metastasis and the interaction with paired brain metastatic tumors. METHODS: The study included 48 patients with stage IV epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma. Sixteen of the forty-eight patients were diagnosed with brain metastasis, while the remaining thirty-two were not. All sixteen patients with brain metastasis had brain tumors. The expression of PD-L1, TILs (CD8+ T lymphocytes and FOXP3+ regulatory T lymphocytes), E-cadherin, and vimentin were evaluated using immunohistochemical (IHC) staining. RESULTS: Patients with brain metastasis exhibited a higher frequency of exon 19 deletion and uncommon EGFR mutations, a higher lung tumor vimentin score, worse progression-free survival (PFS), and overall survival (OS) than patients without brain metastasis. IHC staining showed no difference between paired lung and brain tumors. Patients with low PD-L1 expression had better PFS and OS. After multivariate analysis, higher body mass index, the presence of brain metastasis, bone metastasis, and uncommon EGFR mutations were correlated with worse PFS, while the presence of brain metastasis and high lung tumor E-cadherin score was associated with worse OS. CONCLUSIONS: In patients with stage IV EGFR-mutant lung adenocarcinoma, high E-cadherin expression in the lung tumor might be associated with worse OS. Vimentin expression in the lung tumor was positively related to the risk of brain metastasis.

KEYNOTE-033: Randomized phase 3 study of pembrolizumab vs docetaxel in previously treated, PD-L1-positive, advanced NSCLC.

KEYNOTE-033 (NCT02864394) was a multicountry, open-label, phase 3 study that compared pembrolizumab vs docetaxel in previously treated, programmed death-ligand 1 (PD-L1)-positive, advanced non-small cell lung cancer (NSCLC), with most patients enrolled in mainland China. Eligible patients were randomized (1:1) to pembrolizumab 2 mg/kg or docetaxel 75 mg/m2 every 3 weeks. Primary endpoints were overall survival (OS) and progression-free survival and were evaluated sequentially using stratified log-rank tests, first in patients with PD-L1 tumor proportion score (TPS) ≥50% and then in patients with PD-L1 TPS ≥1% (significance threshold: P < .025, one-sided). A total of 425 patients were randomized to pembrolizumab (N = 213) or docetaxel (N = 212) between 8 September 2016 and 17 October 2018. In patients with a PD-L1 TPS ≥50% (n = 227), median OS was 12.3 months with pembrolizumab and 10.9 months with docetaxel; the hazard ratio (HR) was 0.83 (95% confidence interval [CI]: 0.61-1.14; P = .1276). Because the significance threshold was not met, sequential testing of OS and PFS was ceased. In patients with a PD-L1 TPS ≥1%, the HR for OS for pembrolizumab vs docetaxel was 0.75 (95% CI: 0.60-0.95). In patients from mainland China (n = 311) with a PD-L1 TPS ≥1%, HR for OS was 0.68 (95% CI: 0.51-0.89). Incidence of grade 3 to 5 treatment-related AEs was 11.3% with pembrolizumab vs 47.5% with docetaxel. In summary, pembrolizumab improved OS vs docetaxel in previously treated, PD-L1-positive NSCLC without unexpected safety signals; although the statistical significance threshold was not reached, the numerical improvement is consistent with that previously observed for pembrolizumab in previously treated, advanced NSCLC.

Afatinib in Untreated Stage IIIB/IV Lung Adenocarcinoma with Major Uncommon Epidermal Growth Factor Receptor (EGFR) Mutations (G719X/L861Q/S768I): A Multicenter Observational Study in Taiwan.

BACKGROUND: Real-world clinical experience with afatinib as a treatment for advanced lung adenocarcinoma harboring uncommon epidermal growth factor receptor (EGFR) mutations (G719X, L861Q and S768I) has rarely been reported. OBJECTIVE: We aimed to perform a retrospective multicenter study to analyze afatinib therapy in untreated advanced lung adenocarcinoma harboring uncommon EGFR mutations. PATIENTS AND METHODS: Between May 2014 and June 2021, the data of 90 stage IIIB/IV lung adenocarcinoma patients with uncommon EGFR mutations (G719X/L861Q/S768I) treated with first-line afatinib from the cancer center database of Linkou, Tucheng, and Kaohsiung Chang Gung Memorial Hospitals were retrospectively retrieved and analyzed. RESULTS: Afatinib had an objective response rate (ORR) of 63.3% and a disease control rate (DCR) of 86.7%. The median progression-free survival (PFS) with first-line afatinib therapy was 17.3 months (95% confidence interval (CI), 12.07-22.53), and the median overall survival (OS) was 28.5 months (95% CI, 20.22-36.77) in all study patients. In the multivariate analysis, poor performance (Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2) and brain and liver metastases were independent predictors of unfavorable PFS. The G719X mutation (alone+compound) was an independent predictor of favorable PFS (hazard ratio (HR) = 0.578; 95% CI, 0.355-0.941; P = 0.027). Most afatinib-related adverse events (AEs) were limited to grades 1 and 2 and were manageable. CONCLUSIONS: First-line afatinib therapy is effective and safe for advanced lung adenocarcinoma harboring uncommon EGFR mutations. The G719X mutation was an independent factor associated with a favorable outcome. Poor performance (ECOG PS ≥ 2), brain metastasis, and liver metastasis were predictive factors of shorter PFS with first-line afatinib therapy.

Novel Potential Therapeutic Targets of PTPN Families for Lung Cancer.

Despite the treatment of lung adenocarcinoma (LUAD) having partially improved in recent years, LUAD patients still have poor prognosis rates. Therefore, it is especially important to explore effective biomarkers and exploit novel therapeutic developments. High-throughput technologies are widely used as systematic approaches to explore differences in expressions of thousands of genes for both biological and genomic systems. Recently, using big data analyses in biomedicine research by integrating several high-throughput databases and tools, including The Cancer Genome Atlas (TCGA), cBioportal, Oncomine, and Kaplan-Meier plotter, is an important strategy to identify novel biomarkers for cancer therapy. Here, we used two different comprehensive bioinformatics analysis and revealed protein tyrosine phosphatase non-receptor type (PTPN) family genes, especially PTPN1 and PTPN22, were downregulated in lung cancer tissue in comparison with normal samples. The survival curves indicated that LUAD patients with high transcription levels of PTPN5 were significantly associated with a good prognosis. Meanwhile, Gene Ontology (GO) and MetaCore analyses indicated that co-expression of the PTPN1, PTPN5, and PTPN21 genes was significantly enriched in cancer development-related pathways, including GTPase activity, regulation of small GTPase-mediated signal transduction, response to mechanical stimuli, vasculogenesis, organ morphogenesis, regulation of stress fiber assembly, mitogen-activated protein kinase (MAPK) cascade, cell migration, and angiogenesis. Collectively, this study revealed that PTPN family members are both significant prognostic biomarkers for lung cancer progression and promising clinical therapeutic targets, which provide new targets for treating LUAD patients.

Circadian rhythm-related factors of PER and CRY family genes function as novel therapeutic targets and prognostic biomarkers in lung adenocarcinoma.

The period (PER) and cryptochrome (CRY) families play critical roles in circadian rhythms. The imbalance of circadian factors may lead to the occurrence of cancer. Expressions of PER and CRY family members decrease in various cancers. Nevertheless, expression levels, genetic variations, and molecular mechanisms of PER and CRY family members in lung adenocarcinoma (LUAD) and their correlations with prognoses and immune infiltration in LUAD patients are still unclear. In this study, to identify their biological functions in LUAD development, comprehensive high-throughput techniques were applied to analyze the relationships of expressions of PER and CRY family members with genetic variations, molecular mechanisms, and immune infiltration. The present results showed that transcription levels of PER1 and CRY2 in LUAD were significantly downregulated. High expression levels of PER2, PER3, CRY1, and CRY2 indicated longer overall survival. Some cancer signaling pathways were related to PER and CRY family members, such as cell-cycle, histidine metabolism, and progesterone-mediated oocyte maturation pathways. Expressions of PER and CRY family members significantly affected the infiltration of different immune cells. In conclusion, our findings may help better understand the molecular basis of LUAD, and provide new perspectives of PER and CRY family members as novel biomarkers for LUAD.

Association of smoking status with non-small cell lung cancer patients harboring uncommon epidermal growth factor receptor mutation.

Introduction: Uncommon epidermal growth factor receptor (EGFR) mutations include single and complex mutations. However, the association of the smoking status of patients with uncommon and complex EGFR mutations remains unclear. Methods: This retrospective study evaluates the spectrum of uncommon EGFR mutations and investigates the influence of smoking status on the frequency of various uncommon EGFR mutations using a multi-institutional medical database. Results: Between 2010 and 2019, 5,608 non-small cell lung cancer (NSCLC) patients were analyzed. EGFR mutations were detected in 3,155 (56.3%) patients. Among the 399 (12.6%) patients with uncommon mutations, 198 had single uncommon and 201 complex mutations, including 87 exon 20 insertions, 79 de novo T790M, 70 complex common, and 52 complex uncommon mutations. For comparison, we also included 402 patients with common EGFR mutations. The percentage of ever-smokers was significantly higher in patients with uncommon EGFR mutations than in patients with common EGFR mutations (25.8% vs. 17.4%, p = 0.005). Furthermore, the percentage of ever-smokers was higher in those with a complex mutation than in those with a single uncommon mutation (30.3% vs. 21.2%, p = 0.040). Among patients carrying uncommon EGFR mutations, ever-smokers had significantly more complex uncommon EGFR mutations than never-smokers (22.3% vs. 9.8%, p = 0.002). Among patients carrying G719X, L861Q, and S768I, ever-smokers tended to have complex EGFR mutations more frequently than never-smokers (64.7% vs. 28.7%, 50.0% vs. 18.7%, 88.9% vs. 81.2%, respectively). Conclusions: Our study demonstrates not only a comprehensive spectrum of uncommon EGFR mutations, but also a positive relationship between smoking status and uncommon EGFR mutation frequency, especially complex uncommon EGFR mutations. The results suggest that smoking contributes to the development of complex EGFR mutations.

Clinical outcomes of Atezolizumab Therapy for Previously-Treated Advanced-Stage Non-Small Cell Lung Cancer: A Real-World Study in Taiwan.

Immune checkpoint inhibitors (ICIs) are the standard treatment for non-small-cell lung cancer (NSCLC). We assessed the clinical prognostic factors in NSCLC patients receiving atezolizumab as a second- or later-line (2L+) treatment. Data were retrospectively collected for NSCLC patients treated with atezolizumab from July 2017 to June 2019 at six medical centers in Taiwan. Clinical characteristics, treatment course and responses of patients were recorded. A total of 128 NSCLC patients received 2L+ atezolizumab, and the outcomes included a response rate of 10.2%, median progression-free survival (mPFS) of 3.5 months, and median overall survival (mOS) of 10.7 months. Eleven patients who had received osimertinib treatment before atezolizumab had a shorter mPFS (2.3 versus 3.5 months; p = 0.002) and mOS (4.8 versus 11.2 months; p < 0.001) than those without prior osimertinib treatment. Even for the subgroup of patients with EGFR-mutant non-squamous NSCLC, prior osimertinib was still associated with shorter PFS (2.3 versus 4.1 months; p = 0.006) and OS (4.8 versus 11.7 months; p < 0.001). Multivariate analysis revealed that prior osimertinib treatment correlated with not only shorter PFS (hazard ratio [HR]: 2.94; 95% confidence interval [CI], 1.34-6.47; p = 0.007) but also shorter OS (HR, 3.55; 95% CI, 1.57-8.03; p = 0.002). Patients with prior ICIs treatment (HR, 3.18; p = 0.002) or poor performance status (HR, 2.70; p = 0.001) had shorter OS. In conclusion, osimertinib treatment before atezolizumab therapy was associated with a shorter PFS and a poor prognosis in NSCLC patients in real-world settings. Further studies with larger sample sizes are needed to validate these observations.

Overall Survival Improvement in Patients with Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer and Bone Metastasis Treated with Denosumab.

The impact of an initial skeletal-related event (SRE) and denosumab adjuvant treatment on the survival outcome of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients with bone metastasis remains unclear. This retrospective study included 400 metastatic EGFR-mutated NSCLC patients. Among 190 bone metastasis patients, 61 had initial SREs and 73 received denosumab. We analyzed patient characteristics, SRE-free survival (SRE-FS), and overall survival (OS). In metastatic EGFR-mutated NSCLC, bone metastasis was associated with a poorer OS (21.7 vs. 33.0 months; p < 0.001). Bone metastasis patients with initial SREs at diagnosis had an even shorter OS, compared with those without initial SRE (15.4 vs. 23.6 months; p = 0.026). Denosumab reduced SRE incidence (hazard ratio (HR) 0.57 (95% confidence interval (CI) 0.34−0.94; p = 0.027) and was associated with improved OS (26.6 vs. 20.1 months; p = 0.015). A multivariate analysis demonstrated that denosumab treatment was correlated with a lower incidence of SRE (HR 0.61 (95% CI 0.37−0.98); p = 0.042) and better OS (HR 0.60 (95% CI 0.41−0.88); p = 0.008). In subgroup analyses, denosumab prolonged SRE-FS (HR 0.36 (95% CI 0.19−0.79); p = 0.009) in patients without initial SREs and was related to a better OS (25.3 vs. 12.9 months; p = 0.016) in patients with initial or pre-existing SREs. Osteonecrosis of the jaw was diagnosed in two patients (2.74%) receiving denosumab. Our study confirmed the association between initial SREs and a worse outcome and provided novel evidence of the survival benefit of denosumab for EGFR-mutated NSCLC patients with bone metastasis.

Comparison of afatinib and erlotinib combined with bevacizumab in untreated stage IIIB/IV epidermal growth factor receptor-mutated lung adenocarcinoma patients: a multicenter clinical analysis study.

Background: Although bevacizumab in combination with afatinib or erlotinib is an effective and safe first-line therapy for advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), there are very few clinical data comparing afatinib and erlotinib combined with bevacizumab. We performed a retrospective multicenter analysis for the comparison of two combination therapies. Methods: Between May 2015 and October 2020, data of 135 stage IIIB/IV EGFR-mutated NSCLC patients receiving first-line afatinib or erlotinib combined with bevacizumab combination therapy in Linkou, Keelung, Chiayi, and Kaohsiung Chang Gung Memorial Hospitals were retrieved and retrospectively analyzed. Results: In all, 67 patients received afatinib plus bevacizumab, and 68 patients received erlotinib plus bevacizumab. Afatinib combined with bevacizumab had an objective response rate (ORR) of 82.1% and a disease control rate (DCR) of 97.0%, and the ORR and DCR were 83.8 and 95.6%, respectively, in the erlotinib combined with bevacizumab group (p = 0.798 and p = 1.000). The median progression-free survival was 20.7 and 20.3 months for the afatinib plus bevacizumab group and the erlotinib plus bevacizumab group, respectively [hazard ratio (HR) = 1.02; 95% confidence interval (CI), 0.891-1.953; p = 0.167). The overall survival was 41.9 and 51.0 months for the afatinib plus bevacizumab group and erlotinib plus bevacizumab group, respectively (HR = 1.42; 95% CI, 0.829-2.436; p = 0.201). The secondary EGFR-T790M mutation rates after disease progression were 44% in the afatinib plus bevacizumab group and 58.8% in the erlotinib plus bevacizumab group (p = 0.165). Skin toxicity was the most frequent treatment-related adverse event (AE) in both treatment groups. Diarrhea, an AE, occurred significantly more frequently in the afatinib plus bevacizumab group than in the erlotinib plus bevacizumab group (p < 0.05). Conclusion: Afatinib combined with bevacizumab was equally as effective as erlotinib combined with bevacizumab for untreated advanced EGFR-mutated NSCLC. Prospective clinical studies that explore bevacizumab combined with afatinib or erlotinib for advanced EGFR-mutated NSCLC are warranted.

The different overall survival between single-agent EGFR-TKI treatment and with bevacizumab in non-small cell lung cancer patients with brain metastasis.

Comparison of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) monotherapy or with bevacizumab in real-world non-small cell lung cancer (NSCLC) patients was lacking. 310 patients of advanced NSCLC with common EGFR mutation receiving first-generation EGFR-TKI monotherapy or with bevacizumab were included and propensity-score matched. Progression-free survival (PFS), overall survival (OS) and secondary T790M mutation were analysed. Patients receiving EGFR-TKI and bevacizumab were significantly younger, had better performance status and with high incidence of brain metastasis (55.8%). In the propensity-score matched cohort, PFS (13.5 vs. 13.7 months; log-rank p = 0.700) was similar between the two groups. The OS (61.3 vs. 34.2 months; log-rank p = 0.010) and risk reduction of death (HR 0.42 [95% CI 0.20-0.85]; p = 0.017) were significantly improved in EGFR-TKI plus bevacizumab group. Analysis of treatment by brain metastasis status demonstrated EGFR-TKI plus bevacizumab in patients with brain metastasis was associated with significant OS benefit compared to other groups (log-rank p = 0.030) and these patients had lower early-CNS and early-systemic progressions. The secondary T790M did not significantly differ between EGFR-TKI plus bevacizumab and EGFR-TKI monotherapy groups (66.7% vs. 75.0%, p = 0.460). Forty-one (31.1%) and 31 (23.5%) patients received subsequent osimertinib and chemotherapy, respectively. The post-progression OS of osimertinib and chemotherapy were 22.1 and 44.9 months in EGFR-TKI plus bevacizumab group and were 10.0 and 14.1 months in EGFR-TKI monotherpay group, respectively. First-generation EGFR-TKI with bevacizumab improved treatment efficacy in real-world patients of NSCLC with EGFR mutation. Patients with brain metastasis received additional OS benefit from this treatment.