Osimertinib then chemotherapy in EGFR-mutated lung cancer with osimertinib third-line rechallenge (OCELOT-cohort A interim analysis). This ongoing multicenter Phase II trial is evaluating third-line (3L) osimertinib rechallenge in patients with epidermal growth factor receptor mutation–positive (EGFR+) advanced non-small cell lung cancer (NSCLC) after first-line osimertinib and second-line platinum-based chemotherapy, in a setting where palliative chemotherapy such as docetaxel is the current standard of care. The interim analysis of 58 evaluable patients showed an objective response rate (ORR) of 3.4 percent, median progression-free survival (PFS) of 1.9 months, median time to treatment failure (TTF) of 4.0 months, and median overall survival (OS) of 4.6 months. The confirmed stable disease rate was 25 percent, 35.1 percent of patients remained on 3L osimertinib at six months with treatment beyond progression allowed at physician discretion, and patients had a median of 518 days on first-line osimertinib with a median osimertinib-free interval of 232 days. Time off osimertinib was predictive of improved OS and TTF, and 3L osimertinib demonstrated excellent tolerability consistent with historical data. Overall, 3L osimertinib rechallenge demonstrated modest efficacy but clinically meaningful disease control in a subset of heavily pretreated patients.
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Prognostic role of exosome in patients with Stage IIIA(N2) non-small cell lung cancer treated with perioperative durvalumab in addition to neoadjuvant chemotherapy in the trial SAKK 16/14. This Phase II trial evaluated exosomal dynamics as prognostic biomarkers in patients with resectable Stage IIIA(N2) NSCLC treated with perioperative durvalumab plus neoadjuvant cisplatin/docetaxel followed by surgery and adjuvant durvalumab. Exosomes, defined as extracellular vesicles (EVs), were isolated from serial serum samples at five time points, and bead-based flow cytometry was used to quantify programmed death-ligand 1 (PD-L1), PanEV, pan-cytokeratin (PanCK), epithelial cell adhesion molecule (EpCAM), and CD45. There was a trend toward decreasing EV mean fluorescence intensity at postneoadjuvant chemotherapy, and current smokers exhibited significantly lower PanEV levels than nonsmokers. At the post-therapy time point after four cycles of adjuvant durvalumab, the area under the receiver operating characteristic curve (AUC) for PD-L1+ PanEV+ EV–bead complexes was 0.875, and higher levels of PanEV+ PanCK+ EV–bead complexes were significantly associated with shorter OS and event-free survival, with similar adverse trends observed for PanEV+ PanCK+ and EpCAM+ PanEV+ profiles at baseline and post-therapy. These results demonstrate the feasibility of exosome-based liquid biopsy in NSCLC and suggest that elevated post-treatment PanEV/PanCK EV signatures might identify patients at higher risk for worse outcomes.
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Global quantitative assessment of multidisciplinary team care in early-stage NSCLC. This global online survey described multidisciplinary team (MDT) access and dynamics in the treatment of Stage I to IIIB NSCLC among 529 physicians from 11 countries. Most respondents reported lung cancer–specific MDT meetings, although 18.0 percent participated only in noncancer type–specific MDTs, and only 37.2 percent stated MDT care was used for all patients with early-stage NSCLC (highest in the United Kingdom at 69.8%). MDTs met at least weekly in 74.5 percent of cases, 49.7 percent of discussions lasted between 30 to 60 minutes, 86.8 percent of MDTs included at least five specialties, and roughly half of physicians reported that final treatment decisions were made jointly. Cases less likely to be discussed included tumors localized within the lung or very early-stage disease (33.6%) and situations requiring immediate treatment (39.9%), while the most frequently cited drivers of MDT success were multispecialty representation (67.7%), availability of complete diagnostic information (51.6%), and effective communication (42.9%). Key barriers included lack of complete diagnostic or biomarker information (50.9%) and delayed referral between centers (31.2%). Overall, 96.6 percent of physicians agreed that MDT discussions provide at least some benefit for outcomes in early-stage NSCLC, underscoring broad recognition of MDT value and the need to address structural and informational barriers in an increasingly complex treatment landscape.
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Sex and gender in NSCLC immunotherapy: integrated evidence from systematic review and real-world analysis. This study assessed sex-based differences in tumor genomics, immune checkpoint inhibitor (ICI) efficacy, toxicity, and trial representation in NSCLC through a structured review of 112 studies and a retrospective analysis of a late-line ICI cohort. The literature showed that women with NSCLC more frequently harbor actionable mutations, such as EGFR and anaplastic lymphoma kinase (ALK) alterations, contributing to greater benefit from tyrosine kinase inhibitors (TKI), whereas ICI monotherapy trials reported more pronounced OS benefit in men (hazard ratio [HR]: 0.72 vs. 0.86 in women), potentially reflecting sex-related immune differences. Across studies, immune-related adverse events (irAEs), particularly thyroiditis and pneumonitis, were 1.5 to 2 times more common in women than in men. In the retrospective German cohort of 342 patients (244 men, 98 women) treated with at least two cycles of late-line ICI, women were significantly younger at ICI initiation (63.0 vs. 65.6 years; p=0.01). Overall irAE incidence was higher in women (43.9% vs. 34.4%; p=0.13), with hyperthyroidism and nausea/vomiting significantly more frequent among women. There were no significant sex-based differences in number of ICI cycles or OS, indicating that while survival outcomes might be similar. Female patients with NSCLC experience a distinct and more frequent toxicity profile with ICI therapy, supporting the need for sex-stratified analyses and tailored toxicity monitoring in precision immuno-oncology.
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Risk factors for developing brain metastases among patients with NSCLC: a retrospective study. This retrospective single-center cohort study evaluated risk factors for developing metachronous brain metastases (BM) among patients with NSCLC who had a negative baseline brain magnetic resonance imaging (MRI). Among 426 patients, 138 (32%) developed BM, and those who developed BM were more often younger, women, nonsmokers, had better performance status (PS), and more frequently had adenocarcinoma histology and positivity for oncogenic drivers EGFR, ALK, or ROS1. Fine-Gray competing risk analyses showed time to develop BM was shorter in younger patients, women, nonsmokers, those with PS of 1 or less, adenocarcinoma, or an oncogene driver, and the highest BM risk was observed in women with driver-positive tumors, nonsmoker women, and women with PS of 1 or less. These findings suggest that patients who are younger, female, nonsmokers, and who have adenocarcinoma with oncogene drivers are particularly prone to earlier and more frequent development of BM despite a negative baseline brain MRI.
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AI-based classification of oligometastatic NSCLC: assessing organ-specific detection and its clinical implications. This study described an artificial intelligence (AI) pipeline designed to classify oligometastatic versus non-oligometastatic metastatic NSCLC (mNSCLC), defined as mNSCLC with five or fewer metastases in three or fewer organs, by automatically counting metastases on baseline computed tomography and MRI scans. The approach focused on the most frequently involved organs in mNSCLC, using organ-specific models: UNETR++, a three-dimensional segmentation architecture combining convolutional and transformer components, for lung, liver, and bone metastases; a pretrained nnU-Net for brain metastases; and a two-stage segmentation-plus-classification strategy for adrenal gland and lymph node metastases. Where possible, models were trained on publicly available imaging datasets, and an in-house dataset of annotated images from patients with NSCLC was created with radiologist collaboration for validation. On training data, UNETR++ models correctly predicted lesion counts in 92 percent of lung cases, 58 percent of liver cases, and 100 percent of bone cases, with misclassifications typically differing from the true count by only ±1. The pipeline showed promise for automated classification of oligometastatic NSCLC and is intended to support prospective trials to strengthen individualized treatment strategies and improve patient outcomes.
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Single-organ oligometastatic NSCLC. This retrospective study evaluated outcomes in patients with oligometastatic NSCLC defined as metastatic disease confined to a single organ, using data from 638 patients who underwent computed tomography–based staging. Among these, 209 patients (32.7%) had single-organ disease, most commonly involving the contralateral lung (27%), brain (22%), bone (22.5%), or adrenal gland (8.7%), and median OS for the overall cohort was 18 months, with shorter OS reported in those with liver (median OS: 8.2 months) and adrenal (median OS: 8.6 months) metastases. Patients with oncogene-addicted tumors had markedly prolonged survival, with median OS of 55 months for EGFR-mutated disease and 40 months for ALK-positive disease compared with 12 months in patients without driver mutations (p=0.01). Nonsmokers experienced better outcomes than smokers (median OS: 21 vs. 10 months; p=0.04) and the addition of ICIs to chemotherapy significantly improved PFS despite shorter follow-up (HR: 0.44, p=0.008). Only 26 percent of patients received local therapy (ie, surgery, radiotherapy, or both) to metastatic sites, which was not associated with a significant survival benefit. Overall, patients with single-organ metastatic NSCLC demonstrated improved survival and a significant subset achieved extended survival.
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Real-world benefit of chemoimmunotherapy in patients with low PD-L1 NSCLC: impact of clinical trial eligibility status. This multicenter retrospective cohort study evaluated first-line ICI plus chemotherapy (ICI-Chemo) versus chemotherapy alone in 728 patients in Japan with Stage IIIB/IIIC or IV NSCLC (PD-L1 tumor proportion score: 1–49% and EGFR/ALK wildtype), stratified by trial eligibility based on pivotal Phase III trial criteria. ICI-Chemo improved OS compared with chemotherapy in both trial-eligible and ineligible groups, with median OS of 25.1 versus 18.5 months in eligible patients and 18.2 versus 14.9 months in ineligible patients. Median PFS was also longer with ICI-Chemo in both eligibility strata. Within the ineligible cohort, PS of 2 or greater and squamous cell carcinoma histology were independently associated with poor outcomes, and no OS benefit from ICI-Chemo was observed in these subgroups. Safety was comparable between eligible and ineligible patients receiving ICI-Chemo, with no significant increase in severe adverse events in the ineligible group. Overall, ICI-Chemo provided a survival benefit for patients with low PD-L1 NSCLC regardless of formal trial eligibility, but the findings suggest that patients with PS of 2 or greater or squamous cell carcinoma might derive limited benefit, supporting broader inclusion criteria alongside careful patient selection in real-world practice.
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