DLL3-guided therapies in small-cell lung cancer: from antibody-drug conjugate to precision immunotherapy and radioimmunotherapy.

DLL3 acts as an inhibitory ligand that downregulates Notch signaling and is upregulated by ASCL1, a transcription factor prevalent in the small-cell lung cancer (SCLC) subtype SCLC-A. Currently, the therapeutic strategies targeting DLL3 are varied, including antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR) T-cell therapies. Although rovalpituzumab tesirine (Rova-T) showed promise in a phase II study, it failed to produce favorable results in subsequent phase III trials, leading to the cessation of its development. Conversely, DLL3-targeted BiTEs have garnered significant clinical interest. Tarlatamab, for instance, demonstrated enhanced response rates and progression-free survival compared to the standard of care in a phase II trial; its biologics license application (BLA) is currently under US Food and Drug Administration (FDA) review. Numerous ongoing phase III studies aim to further evaluate tarlatamab's clinical efficacy, alongside the development of novel DLL3-targeted T-cell engagers, both bispecific and trispecific. CAR-T cell therapies targeting DLL3 have recently emerged and are undergoing various preclinical and early-phase clinical studies. Additionally, preclinical studies have shown promising efficacy for DLL3-targeted radiotherapy, which employs ß-particle-emitting therapeutic radioisotopes conjugated to DLL3-targeting antibodies. DLL3-targeted therapies hold substantial potential for SCLC management. Future clinical trials will be crucial for comparing treatment outcomes among various approaches and exploring combination therapies to improve patient survival outcomes.

Tracheopathia osteochondroplastica-A benign disorder with a daunting appearance.

Tracheopathia osteochondroplastica (TO) is a rare and benign condition. It typically manifests as multiple osteocartilaginous nodules in the submucosa of the central airway. TO-related clinical symptoms and physical signs are nonspecific. The bronchoscopic examination is helpful in establishing the diagnosis. Treatment for TO is mostly conservative and symptom-oriented. The prognosis of TO is generally good, although cases of associated airway stenosis have been reported. In this case report, we describe the clinical, imaging, and histological features, and videoed bronchoscopic findings, of a middle-aged male patient with incidentally diagnosed TO.

Outcomes of surgery and subsequent therapy for central nervous system oligoprogression in EGFR-mutated NSCLC patients.

BACKGROUND: Oligoprogression is an emerging issue in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, the surgical treatment for central nervous system (CNS) oligoprogression is not widely discussed. We investigated the outcomes of craniotomy with adjuvant whole-brain radiotherapy (WBRT) and subsequent therapies for CNS oligoprogression in patients with EGFR-mutated NSCLC. METHODS: NSCLC patients with CNS oligoprogression were identified from a tertiary medical center. The outcomes of surgery with adjuvant WBRT or WBRT alone were analyzed, along with other variables. Overall survival and progression-free survival were analyzed using the log-rank test as the primary and secondary endpoints. A COX regression model was used to identify the possible prognostic factors. RESULTS: Thirty-seven patients with CNS oligoprogression who underwent surgery or WBRT were included in the study after reviewing 728 patients. Twenty-one patients underwent surgery with adjuvant WBRT, and 16 received WBRT alone. The median overall survival for surgery and WBRT alone groups was 43 (95% CI 17-69) and 22 (95% CI 15-29) months, respectively. Female sex was a positive prognostic factor for overall survival (OR 0.19, 95% CI 0.06-0.57). Patients who continued previous tyrosine kinase inhibitors (OR 3.48, 95% CI 1.06-11.4) and induced oligoprogression (OR 3.35, 95% CI 1.18-9.52) were associated with worse overall survival. Smoking history (OR 4.27, 95% CI 1.54-11.8) and induced oligoprogression (OR 5.53, 95% CI 2.1-14.7) were associated with worse progression-free survival. CONCLUSIONS: Surgery combined with adjuvant WBRT is a feasible treatment modality for CNS oligoprogression in patients with EGFR-mutated NSCLC. Changing the systemic-targeted therapy after local treatments may be associated with improved overall survival.

Generation and validation of a predictive model for estimating survival among patients with EGFR-mutant non-small cell lung cancer.

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become the standard therapy for patients with EGFR-mutant non-small cell lung cancer (NSCLC), treatment outcomes vary significantly. Previous studies have indicated that concurrent mutations may compromise the effectiveness of first-line EGFR-TKIs. However, given the high cost of next-generation sequencing, this information is often inaccessible in routine clinical practice. A prediction model based on pre-treatment clinical characteristics may thus offer a more practical solution. This study established a nomogram based on pretreatment clinical characteristics to stratify patients according to optimal treatment strategies. We retrospectively reviewed 761 patients with EGFR-mutant NSCLC who received first- or second-generation EGFR-TKIs at a tertiary referral center between 2010 and 2019. The pretreatment clinical characteristics and progression-free survival data were collected. Using COX proportional hazard regression analysis, we constructed a nomogram based on seven clinically significant prognostic factors: sex, Eastern Cooperative Oncology Group performance status, histology subtype, mutation subtype, stage, and metastasis to the liver and brain. Our nomogram could stratify patients into three groups with different risks for disease progression and was validated in a patient cohort from other hospitals. This risk stratification can provide additional information for determining the optimal first-line treatment strategy for patients with EGFR-mutant NSCLC.

Navigating the challenges of invasive pulmonary aspergillosis in lung cancer treatment: a propensity score study.

Background: Invasive pulmonary aspergillosis (IPA) can negatively impact cancer patients' survival. It remains uncertain whether IPA's impact on patient outcomes varies by treatment approach in advanced lung cancer. Objectives: To explore the association between IPA and outcomes in patients with advanced lung cancer receiving different treatments. Design: A retrospective cohort study. Methods: We enrolled patients with advanced-stage lung cancer between 2013 and 2021 at a college hospital in Taiwan and used the 2021 European Organization for Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium consensus for IPA diagnosis. Multivariable logistic regression was used to identify the IPA risk factors. We compared overall survival (OS) and postgalactomannan (GM) test survival between the IPA and control groups using multivariable Cox proportional hazards regression and the Kaplan-Meier method with propensity score matching (PSM). Results: Among 2543 patients with advanced-stage lung cancer, 290 underwent a GM test, of which 34 (11.7%) were diagnosed with IPA. Patients undergoing chemotherapy (HR = 4.02, p = 0.027) and immunotherapy [hazard ratio (HR) = 3.41, p = 0.076] tended to have IPA. Compared to the control group, the IPA group had shorter median OS (14.4 versus 9.9 months, p = 0.030) and post-GM test survival (4.5 versus 1.9 months, p = 0.003). IPA was associated with shorter OS (log-rank p = 0.014 and 0.018 before and after PSM, respectively) and shorter 1-year and 2-year survival post-GM test (HR = 1.65 and 1.66, respectively). Patients receiving chemotherapy or immunotherapy had a shorter post-GM test survival if they had IPA. Conclusions: IPA tended to be diagnosed more frequently in patients receiving chemotherapy or immune checkpoint inhibitors. Patients diagnosed with IPA are associated with shorter survival. Larger cohort studies are needed to verify the observations.

Single-sized N-functionality graphene quantum dot in tunable dual-modality near infrared-I/II illumination detection and photodynamic therapy under multiphoton nonlinear excitation.

Doping sorted graphene quantum dots (GQDs) with heteroatoms and functionalizing them with amino acid could improve their radiative recombination and two-photon properties-including their excitation-wavelength-independent photoluminescence from the ultraviolet to the near-infrared-I (NIR-I) region, absorption, quantum yield, absolute cross section, lifetime, and radiative-to-nonradiative decay ratio-under two-photon excitation (TPE) at a low excitation energy and short photoexcitation duration, as determined using a self-made optical microscopy system with a femtosecond Ti-sapphire laser. Four types of sorted GQDs were investigated: undoped GQDs, nitrogen-doped GQDs (N-GQDs), amino-functionalized GQDs (amino-GQDs), and N-doped and amino-functionalized GQDs (amino-N-GQDs). Among them, the sorted amino-N-GQDs are effective as a two-photon photosensitizer and generate the highest quantity of reactive oxygen species for the elimination of multidrug-resistant cancer cells through two-photon photodynamic therapy (PDT). Larger amino-N-GQDs result in a greater number of C-N and N-functionalities, leading to a superior photochemical effect and more favorable intrinsic luminescence properties, making the dots effective contrast agents for tracking and localizing cancer cells during in-depth bioimaging in a three-dimensional biological environment under TPE in the NIR-II region. Overall, this study highlights the potential of large amino-N-GQDs as a material for future application to dual-modality two-photon PDT and biomedical imaging.

Low neutrophil-to-lymphocyte ratio predicts overall survival benefit in advanced NSCLC patients with low PD-L1 expression and receiving chemoimmunotherapy.

Although combination therapy including chemotherapy and immune checkpoint inhibitors (ICIs) improves overall survival (OS) of patients with non-small-cell lung cancer (NSCLC), there is a higher incidence of adverse events and treatment discontinuation. Since programmed death-ligand 1 (PD-L1) could not serve as a predictive biomarker, we investigated the neutrophil-to-lymphocyte ratio (NLR) as a predictive biomarker. In our previous research, we demonstrated that a low NLR could predict survival benefits when patients with high PD-L1 expression (> 50%) received chemoimmunotherapy as opposed to immunotherapy alone. In this current study, our objective is to evaluate this predictive capacity in patients with low PD-L1 expression (< 50%). A total of 142 patients were enrolled, 28 receiving combination therapy and 114 receiving chemotherapy alone. Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method and compared using the log-rank test. Patients who received combination therapy had significantly better PFS and OS than those who received monotherapy. In the subgroup of patients with low NLR, those who received combination therapy exhibited extended PFS and OS with clinical significance, which was also confirmed by multivariate Cox regression analysis. Our study demonstrates the potential use of NLR as a biomarker for predicting survival benefits when receiving combination therapy with chemotherapy and ICIs in patients with advanced NSCLC and low PD-L1 expression.

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.

Cigarette smoke increases susceptibility of alveolar macrophages to SARS-CoV-2 infection through inducing reactive oxygen species-upregulated angiotensin-converting enzyme 2 expression.

Alveolar macrophages (AMs) are the drivers of pulmonary cytokine storm in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to investigate clinical-regulatory factors for the entrance protein of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) in AMs. Human AMs were collected from 56 patients using bronchoalveolar lavage. ACE2 expression in AMs was positively correlated with smoking pack-year (Spearman's r = 0.347, P = 0.038). In multivariate analysis, current smoking was associated with increased ACE2 in AMs (ß-coefficient: 0.791, 95% CI 0.019-1.562, P = 0.045). In vitro study, ex-vivo human AMs with higher ACE2 were more susceptible to SARS-CoV-2 pseudovirus (CoV-2 PsV). Treating human AMs using cigarette smoking extract (CSE) increases the ACE2 and susceptibility to CoV-2 PsV. CSE did not significantly increase the ACE2 in AMs of reactive oxygen species (ROS) deficient Cybb-/- mice; however, exogenous ROS increased the ACE2 in Cybb-/- AMs. N-acetylcysteine (NAC) decreases ACE2 by suppressing intracellular ROS in human AMs. In conclusion, cigarette smoking increases the susceptibility to SARS-CoV-2 by increasing ROS-induced ACE2 expression of AMs. Further investigation into the preventive effect of NAC on the pulmonary complications of COVID-19 is required.

Chemotherapy outcomes in EGFR-TKI resistant patients with common and uncommon EGFR mutation: An exploratory retrospective cohort study.

BACKGROUND: Some prospective studies have shown that second-generation tyrosine kinase inhibitors (TKIs) provide better control in patients with non-small cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations. However, studies comparing second-line chemotherapy efficacy between NSCLC patients with common and uncommon EGFR mutations remain rare. This retrospective study compared treatment outcomes in these patients. METHODS: Patients with EGFR-mutated advanced-stage NSCLC who received first-line EGFR-TKIs in a tertiary referral center were retrospectively reviewed between January 2010 and August 2022. Patients with a negative T790M test at disease progression who received second-line chemotherapy were enrolled. We compared progression-free (PFS) and overall (OS) survival between advanced NSCLC patients with common and uncommon EGFR mutations using Kaplan-Meier and log-rank tests. RESULTS: In total, 209 (54.8%) patients had a negative T790M mutation test and received second-line chemotherapy, of which 192 (91.8%) had a common EGFR mutation (exon 19 deletion or exon 21 L858R substitution), and 17 (8.2%) had an uncommon EGFR mutation. Patients with common EGFR mutations had significantly longer PFS than those with uncommon EGFR mutations (4.57 vs. 2.57 months, p = 0.031). A Cox proportional hazard regression analysis controlling for potential confounding factors indicated that an uncommon EGFR mutation was an independent prognostic factor for PFS. CONCLUSION: This study suggests that patients with uncommon EGFR mutations have poorer chemotherapy responses and shorter survival than those with common EGFR mutations. The development of new treatment strategies for these patients remains an unmet need.

Effect of BIM expression on the prognostic value of PD-L1 in advanced non-small cell lung cancer patients treated with EGFR-TKIs.

The role of Programmed Cell Death Ligand 1 (PD-L1) expression in predicting epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) efficacy remains controversial. Recent studies have highlighted that tumor-intrinsic PD-L1 signaling can be modulated by STAT3, AKT, MET oncogenic pathway, epithelial-mesenchymal transition, or BIM expression. This study aimed to investigate whether these underlying mechanisms affect the prognostic role of PD-L1. We retrospectively enrolled patients with EGFR mutant advanced stage NSCLC who received first-line EGFR-TKI between January 2017 and June 2019, the treatment efficacy of EGFR-TKI was assessed. Kaplan-Meier analysis of progression-free survival (PFS) revealed that patients with high BIM expression had shorter PFS, regardless of PD-L1 expression. This result was also supported by the COX proportional hazard regression analysis. In vitro, we further proved that the knockdown of BIM, instead of PDL1, induced more cell apoptosis following gefitinib treatment. Our data suggest that among the pathways affecting tumor-intrinsic PD-L1 signaling, BIM is potentially the underlying mechanism that affects the role of PD-L1 expression in predicting response to EGFR TKI and mediates cell apoptosis under treatment with gefitinib in EGFR-mutant NSCLC. Further prospective studies are required to validate these results.

Spontaneous Breathing and Pendelluft in Patients with Acute Lung Injury: A Narrative Review.

Acute respiratory distress syndrome (ARDS) is characterized by acute-onset rapid-deteriorating inflammatory lung injury. Although the preservation of spontaneous breathing may have physiological benefits in oxygenation, increasing evidence shows that vigorous spontaneous breathing may aggravate lung injury (i.e., patient self-inflicted lung injury). Increased lung stress and pendelluft, which is defined as intrapulmonary gas redistribution without a significant change in tidal volume, are important mechanisms of patient self-inflicted lung injury. The presence of pendelluft may be considered a surrogate marker of vigorous inspiratory effort, which can cause the dependent lung to overstretch. In this review, we summarized three major methods for electrical impedance tomography-based pendelluft monitoring. Future studies are warranted to compare and validate the different methods of pendelluft estimation in patients with ARDS.

The surgical resection of the primary tumor increases survival in patients with EGFR-mutant advanced non-small cell lung cancer: a tertiary center cohort study.

Tumor resection could increase treatment efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). This study aimed to retrospectively analyze patients with advanced EGFR-mutant NSCLC from a Taiwanese tertiary center and receiving EGFR-TKI treatment with or without tumor resection. A total of 349 patients were enrolled. After propensity score matching, 53 EGFR-TKI treated patients and 53 EGFR-TKI treated patients with tumor resection were analyzed. The tumor resection group showed improved progression-free survival (PFS) (52.0 vs. 9.8 months; hazard ratio [HR] = 0.19; p < 0.001) and overall survival (OS) (not reached vs. 30.6 months; HR = 0.14; p < 0.001) compared to the monotherapy group. In the subgroup analysis of patients with newly-diagnosed NSCLC, the tumor resection group showed longer PFS (52.0 vs. 9.9 months; HR = 0.14; p < 0.001) and OS (not reached vs. 32.6 months; HR = 0.12; p < 0.001) than the monotherapy group. In conclusion. the combination of EGFR-TKI and tumor resection provided better PFS and OS than EGFR-TKI alone, and patients who underwent tumor resection within six months had fewer co-existing genomic alterations and better PFS.

Pembrolizumab and Chemotherapy Combination Prolonged Progression-Free Survival in Patients with NSCLC with High PD-L1 Expression and Low Neutrophil-to-Lymphocyte Ratio.

The use of immune checkpoint inhibitors (ICIs) has provided overall survival (OS) benefits in patients with treatment-naïve advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. However, studies comparing ICIs monotherapy with combination therapy either with chemotherapy or radiotherapy in programmed death-ligand 1 high expressors remain limited. This study aimed to retrospectively compare the treatment efficacy of the therapies by studying 47 patients with treatment-naïve advanced NSCLC who received ICI monotherapy (n = 28) or combination therapy either with chemotherapy or radiotherapy (n = 19). Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method and compared using log-rank tests. It was observed that patients who received combination therapy had a better PFS than monotherapy, but no such significant benefit was observed in OS. The difference in PFS was higher in the subgroup of patients with low neutrophil-to-lymphocyte ratio (NLR) than in the high-NLR patient subgroup. This study suggests that pembrolizumab in combination with chemotherapy or radiotherapy could provide a significant benefit in PFS, especially in patients with treatment-naïve advanced NSCLC with low NLR. Furthermore, our study also demonstrates the potential use of NLR as a biomarker for prediction of treatment outcomes in patients with advanced NSCLC receiving combination therapy.

Case report: Salvage capmatinib therapy in KIF5B-MET fusion-positive lung adenocarcinoma with resistance to telisotuzumab vedotin.

Telisotuzumab vedotin is a MET-targeting antibody-drug conjugate that has demonstrated a good treatment response in patients with EGFR wild-type MET-overexpressing non-squamous non-small cell lung cancer. However, patients have been reported to acquire resistance to this drug, and the subsequent therapy has not been standardized. Here, we present a case of a 56-year-old woman diagnosed with KIF5B-MET fusion-positive non-small cell lung cancer who had a durable response to capmatinib after acquired resistance to telisotuzumab vedotin.

Separation of Heart and Lung-related Signals in Electrical Impedance Tomography Using Empirical Mode Decomposition.

BACKGROUND: Electrical impedance tomography (EIT) can be used for continuous monitoring of pulmonary ventilation. However, no proper method has been developed for the separation of pulmonary ventilation and perfusion signals and the measurement of the associated ventilation/ perfusion (V/Q) ratio. Previously, various methods have been used to extract these components; however, these have not been able to effectively separate and validate cardiac- and pulmonary- related images. AIMS: This study aims at validating and developing a novel method to separate cardiac- and pulmonary- related components based on the EIT simulation field of view and to simultaneously reconstruct the individual images instantly. METHODS: Our approach combines the advantages of the principal component analysis (PCA) and processes that originally measure EIT data instead of handling a series of EIT images, thus introducing the empirical mode decomposition (EMD). The PCA template functions for cardiacrelated imaging and intrinsic mode functions (IMFs) of EMD for lung-related imaging are then adapted to input signals. RESULTS: The proposed method enables the separation of cardiac- and lung-related components by adjusting the proportion of the key components related to lung imaging, which are the fourth component (PC4) and the first component (IMF1) in PCA- and EMD-based methods, respectively. The preliminary results on the application of the method to real human EIT data revealed the consistently better performance and optimal computation compared with previous methods. CONCLUSION: This study proposes a novel method for applying EIT to evaluate the best time of V/Q matching on the cardiovascular and respiratory systems; this aspect can be investigated in future research.

Durable Response of Dabrafenib, Trametinib, and Capmatinib in an NSCLC Patient With Co-Existing BRAF-KIAA1549 Fusion and MET Amplification: A Case Report.

BRAF fusions are rare driver oncogenes in non-small cell lung cancer (NSCLC). Similar with BRAF V600E mutation, it could also activate the MAPK signaling pathway. There are a few case reports which had indicated the potential response to BRAF inhibitors and its important role as de novo driver mutation. In addition, the co-occurring MET amplification has been defined as a poor prognostic factor in patients with epidermal growth factor receptor (EGFR) mutant NSCLC. Currently, there are ongoing clinical trials which investigate the MET amplification as a therapeutic target in patients with EGFR mutant NSCLC and acquired resistance to osimertinib, which imply that the MET amplification also had a therapeutic significance. However, the co-occurring MET amplification had not been studied in patients with BRAF fusion before. A 67-year-old man was diagnosed with metastatic poorly-differentiated adenocarcinoma. He received first-line therapy with the combination of pembrolizumab and chemotherapy because the genomic test revealed wild-type EGFR, and negativity of ALK and ROS1 by immunohistochemical stain. Upon disease progression, the next-generation sequencing revealed co-occurring KIAA1549-BRAF fusion and MET amplification. Subsequent dabrafenib, trametinib, and capmatinib combination therapy showed a remarkable treatment effect. The combination therapy targeting the co-occurring driver mutations is a potential effective treatment for NSCLC patients. Further prospective study is still warranted to investigate the role of co-occurring driver mutations and the relevant treatment strategy.

An Observational Study on Treatment Outcomes in Patients With Stage III NSCLC in Taiwan: The KINDLE Study.

INTRODUCTION: Patients with stage III NSCLC represent a very heterogenous group that requires different treatment strategies, especially in patients with N2 (2 nearby lymph nodes having cancer)-positive NSCLC and unresectable EGFR-mutant NSCLC. This real-world study may provide more insights into treatment decisions. METHODS: The KINDLE study is a large, multinational real-world observational study that assessed different treatment strategies in patients with stage III NSCLC. Progression-free survival (PFS) and overall survival (OS) were estimated and compared using Kaplan-Meier and log-rank testing. Patients were classified on the basis of disease stage, resectability, and treatment modalities. RESULTS: The Taiwan subgroup enrolled 200 patients. The median PFS and OS values were similar among patients with stage IIIA and stage IIIB disease, but were significantly better in patients who were deemed as a resectable disease than in those who were deemed as an unresectable disease. In patients with N2-positive NSCLC, patients who underwent surgery had better PFS, but not OS, than patients administered with chemoradiotherapy (CRT) (PFS 13.4 vs. 7.3 mo, hazard ratio [HR] = 0.18, p < 0.001; OS 32.4 vs. 22.0 mo, HR = 0.64, p = 0.215). Among patients with unresectable EGFR-mutant NSCLC, OS was significantly poorer after upfront EGFR-tyrosine kinase inhibitors (TKI) than after upfront CRT with sequential EGFR-TKI (27.4 vs. 49.0 mo, HR = 3.09, p = 0.03). CONCLUSIONS: Our study suggests that surgery could be added as part of therapy for patients with stage III N2-positive NSCLC. Moreover, upfront CRT with sequential EGFR-TKI seems to be appropriate for stage III unresectable EGFR-mutant NSCLC. Further randomized studies are needed to validate these results.