Search Results (4,623)

Background: Adhesion G protein-coupled receptor D1 (ADGRD1), formerly known as GPR133, has been implicated in tumor-associated signaling; however, its histology-specific clinicopathologic and prognostic significance in non-small cell lung cancer (NSCLC) remains incompletely characterized. Methods: Clinical and survival data from The Cancer Genome Atlas lung adenocarcinoma (TCGA-LUAD) and lung squamous cell carcinoma (TCGA-LUSC) cohorts were integrated with harmonized gene-expression data obtained from the Genomic Data Commons (GDC). ADGRD1 expression was dichotomized using a cohort-specific median cutoff and additionally analyzed as a continuous standardized variable. Clinicopathologic associations, Pearson correlations with prespecified subtype-associated genes, Kaplan–Meier survival analyses, and univariate and multivariable Cox proportional hazards regression analyses were performed. Benjamini–Hochberg false-discovery-rate correction was applied to molecular correlation analyses. Independent validation was performed using GSE30219 and GSE50081, followed by random-effects meta-analysis and proportional hazards sensitivity analyses. Results: High ADGRD1 expression was associated with favorable overall survival (OS) in LUAD in both univariate (HR = 0.542, 95% CI = 0.400–0.734, p < 0.001) and clinically adjusted Cox analyses (HR = 0.543, 95% CI = 0.398–0.740, p < 0.001). Continuous-expression analyses showed concordant results, and the association remained significant in an additional LUAD model incorporating EGFR mutation status (HR = 0.611, 95% CI = 0.391–0.956, p = 0.031). High ADGRD1 expression was also associated with favorable recurrence-free survival (RFS) in LUAD. In contrast, high ADGRD1 expression was associated with adverse OS in LUSC in both univariate (HR = 1.444, 95% CI = 1.099–1.898, p = 0.008) and clinically adjusted analyses (HR = 1.501, 95% CI = 1.137–1.982, p = 0.004), whereas RFS was not significantly different. After false-discovery-rate correction, ADGRD1 correlated positively with TP53 expression in LUAD and inversely with CDKN2A, SOX2, and PIK3CA in LUSC. Independent GEO validation supported the favorable LUAD association (pooled HR = 0.675, 95% CI = 0.538–0.847, p < 0.001), whereas the adverse LUSC association was not independently reproduced (pooled HR = 0.909, 95% CI = 0.686–1.204, p = 0.504). Conclusions: ADGRD1 shows histology-dependent prognostic associations in NSCLC. Its favorable association with survival in LUAD was robust across dichotomized and continuous analyses, multivariable adjustment, EGFR-mutation sensitivity analysis, and independent GEO cohorts. In contrast, the adverse association observed in TCGA-LUSC was not reproduced externally. These findings support further evaluation of ADGRD1 as a subtype-specific prognostic marker, particularly in LUAD. Full article

Emerging liquid biopsy platforms are expanding frontiers in lung cancer care, facilitating real-time molecular insights and addressing some of the limitations of tissue biopsy. While standardization and sensitivity improvements are undergoing continuous refinement in those liquid biopsy techniques that are now established, several advancements are expanding the panorama of its potential future applications. This review offers an overview of the emerging uses of liquid biopsy in the field of lung cancer, with a specific focus on emerging technologies. We comprehensively reviewed the literature through PubMed and Embase, combining keywords and Medical Subject Headings (MeSH) related to small-cell (SCLC) and non-small-cell lung cancer (NSCLC) and liquid biopsy using Boolean operators. The search was limited to publications from 2017 up to 2026. Titles and abstracts underwent manual scrutiny for relevance. We critically analyzed a body of evidence assessing the potential role of liquid biopsy in common and uncommon applications, such as its combination with machine learning and AI and its integration in multiomics approaches or its usage in next-generation technologies—including label-free CTC isolation, DNA fragmentomics and end-motif profiling, four-dimensional proteomics, and unconventional biospecimens—that remain largely unaddressed in prior narrative reviews on this topic. Full article

Background/Objectives: Perioperative chemoimmunotherapy has become an important curative-intent strategy for selected patients with resectable non-small cell lung cancer (NSCLC). However, most pivotal trials evaluate neoadjuvant therapy, surgery, and postoperative immune checkpoint inhibitor (ICI) treatment as an integrated regimen. Whether continued postoperative immunotherapy provides independent incremental benefit for all patients after effective neoadjuvant chemoimmunotherapy and complete resection remains unresolved. This review focuses on the adjuvant-phase dilemma and discusses how postoperative treatment may be refined according to response and residual risk. Methods: We performed a narrative review of major neoadjuvant and perioperative chemoimmunotherapy trials, indirect comparative analyses, pathological-response studies, circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) evidence, immune biomarker studies, and emerging data in driver-positive and real-world populations. Particular attention was given to evidence informing postoperative continuation, de-escalation, or intensification after neoadjuvant chemoimmunotherapy. Results: Current phase III perioperative trials demonstrate clinically meaningful activity but do not isolate the independent contribution of the adjuvant ICI phase. Pathological response provides the most accessible postoperative risk signal: pathologic complete response identifies the deepest-response group, major pathologic response represents an intermediate state, and non-major pathologic response or persistent nodal disease suggests higher relapse risk. ctDNA-based MRD offers dynamic risk refinement and may help identify patients with residual systemic disease, although prospective validation is required before it can guide routine treatment omission or escalation. Programmed death-ligand 1 (PD-L1), tumor mutational burden, tertiary lymphoid structures, B-cell signatures, radiomics, and pathomics may provide complementary information but are not sufficient as standalone decision tools. Driver-positive disease requires molecularly stratified perioperative strategies rather than unselected extrapolation from epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)-negative trials. Conclusions: The key question in resectable NSCLC is shifting from whether perioperative immunotherapy is active to which patients truly require postoperative immunotherapy. Future trials should prospectively test response-guided strategies integrating pathological response, ctDNA-based MRD, immune contexture, baseline risk, and treatment feasibility. Full article

Background: Non-small-cell lung cancer (NSCLC) is a major cause of cancer-related mortality. Current therapies are limited by drug resistance and adverse effects, highlighting the need for new strategies. Panduratin A (PA), a chalcone from Boesenbergia rotunda, has reported anticancer activity. This study investigated the effects of PA in NSCLC cells and whether PA enhances tumor necrosis factor alpha (TNF-α)-associated cell death. Methods: Human NSCLC cell lines A549 and H1299 were treated with PA alone or in combination with TNF-α. Cytotoxicity and apoptosis were assessed using cell-viability assays, cell-number analysis, and flow cytometry. Western blotting was used to evaluate caspase-3 activation and PARP-1 cleavage. Cell-cycle distribution was analyzed to determine the impact of PA on cell-cycle progression. Results: PA reduced cell number and induced cell death in both A549 and H1299 cells, and co-treatment with TNF-α increased apoptosis compared with single-agent treatment. PA increased the G1-phase fraction and, in a concentration-dependent manner, reduced expression of thymidine kinase and cyclin A2, consistent with a G1-associated arrest phenotype. Combination treatment also increased the sub-G1 population. Conclusions: PA promotes apoptosis in NSCLC cells and enhances TNF-α-associated apoptotic cell death in vitro, accompanied by a G1-associated cell-cycle phenotype. These findings provide an in vitro framework for studying natural compounds as modulators of TNF-α-driven apoptosis and support further mechanistic validation in more disease-relevant models. Full article

Background/Objectives: Outcomes in non–small cell lung cancer (NSCLC) remain heterogeneous, even within stage and molecular subtypes. We evaluated whether a Computational Histology Artificial Intelligence (CHAI) biomarker, derived solely from the diagnostic hematoxylin-and-eosin (H&E) whole-slide image (WSI), provides prognostic information independent of established clinicopathologic factors. Methods: Using The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) projects, 914 patients with an evaluable diagnostic digitized whole-slide images (WSI) and outcomes data were stratified by stage and histology and randomly split into a development set (30%, N = 270) and a held-out validation set (70%, N = 644). A CHAI histologic signature was developed and locked on the development set and applied without modification to the validation set. In development, image features were extracted from H&E-stained WSIs and used to train a Cox proportional hazards model to output a CHAI prognostic biomarker score and then dichotomized into high (CHAI positive (+))- and low (CHAI negative (−))-risk groups. The primary endpoint was overall survival (OS), and the secondary endpoint was progression-free interval (PFI). Associations were assessed by Kaplan–Meier and Cox proportional-hazards models and adjusted for traditional clinicopathologic and genomic variables. Results: A total of 644 patients were included in the validation cohort. Median age was 68 (IQR: 60–74), 388 (60%) were male, 317 (49%) had LUAD, 327 (51%) had LUSC, and 57 (9%) were never smokers. CHAI-positive patients had significantly worse OS than CHAI-negative patients (3-year OS: 53% vs. 69%; log-rank p < 0.001). The biomarker remained significantly associated with OS (HR 1.70, 95% CI 1.29–2.24, p < 0.001) and PFI (HR 1.39, 95% CI 1.05–1.84, p = 0.023) in multivariable analysis. The effect was consistent across both histologies, and a model combining the CHAI score with clinicopathologic variables was well-calibrated in validation. The biomarker was not associated with stage, age, sex, or histologic subtype, and its adjusted prognostic effect was unchanged after relevant genomic alterations were added to the model. CHAI-positive tumors were, however, enriched for KRAS mutations (21% vs. 11% wild-type, p adjusted = 0.005). Conclusions: An H&E-only CHAI NSCLC biomarker was developed and provided independent prognostic stratification in a held-out NSCLC validation cohort. Such a biomarker has the potential to refine risk stratification in NSCLC. Full article

Background: Patients presenting with concurrent lung and brain lesions pose a unique diagnostic and therapeutic challenge. The role of neurosurgical resection in the management of de novo non-small-cell lung cancer brain metastases (NSCLC-BM) remains poorly defined. Methods: Consecutive patients undergoing resection for NSCLC-BM between February 2018 and October 2025 were retrospectively analyzed. De novo NSCLC-BM was defined as radiographic detection of pulmonary and intracranial lesions concurrently or within 1 month during the initial diagnostic work-up. Clinical characteristics and outcomes were compared between de novo and metachronous brain metastases (BM). Multivariable Cox regression identified factors associated with overall survival (OS). Factors associated with long-term postoperative survival in the de novo subgroup were further explored using Firth logistic regression. Results: Among 248 surgically treated patients, 113 (45.6%) presented with de novo BM. Compared with metachronous BM, de novo patients more frequently presented with symptomatic and multifocal intracranial disease. Among 73 de novo patients with evaluable survival, median postoperative OS was 57.0 months (95% CI, 22.9–not reached). Postoperative OS and intracranial progression-free survival (iPFS) did not differ significantly between the two groups, and de novo presentation was not independently associated with postoperative survival. Driver-positive status and lower intracranial tumor burden were associated with durable postoperative survival in the de novo subgroup. Conclusions: Neurosurgical resection represents a reasonable option for appropriately selected patients with de novo NSCLC-BM. These findings provide real-world evidence to inform multidisciplinary, individualized decision-making in patients presenting with concurrent lung and brain lesions. Full article

Background: The Lung Immune Prognostic Index (LIPI), based on the derived neutrophil-to-lymphocyte ratio and lactate dehydrogenase, may reflect systemic inflammation and tumor-related metabolic burden. This study evaluated the prognostic value of pretreatment LIPI and its relationship with programmed death-ligand 1 (PD-L1) expression in patients with advanced non-small cell lung cancer (NSCLC) receiving nivolumab after first-line therapy. Methods: A total of 158 patients were included in this retrospective, single-center study. Patients were classified into LIPI 0, LIPI 1, or LIPI 2 groups according to their pretreatment LIPI scores. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan–Meier analysis and multivariable Cox regression. The prognostic value of LIPI was also evaluated within PD-L1-negative and PD-L1-positive subgroups, and LIPI × PD-L1 interactions were explored. Harrell’s concordance index was used to examine whether adding LIPI improved model discrimination beyond clinical variables and PD-L1 expression. PD-L1 data were available for 145 patients. Results: Median PFS was 566, 340, and 109 days for the LIPI 0, LIPI 1, and LIPI 2 groups, respectively, while median OS was 841, 760, and 201 days, respectively; the differences were statistically significant for both outcomes (both p < 0.001). The objective response rate (ORR) was 55.6%, 36.5%, and 4.9%, whereas the disease control rate (DCR) was 75.9%, 65.1%, and 14.6% in the LIPI 0, LIPI 1, and LIPI 2 groups, respectively (both p < 0.001). In multivariable analyses, higher LIPI remained independently associated with shorter PFS and OS, with the strongest association observed in the LIPI 2 group. LIPI also differentiated survival outcomes within both PD-L1-negative and PD-L1-positive subgroups, although no significant LIPI × PD-L1 interaction was identified for PFS or OS. The addition of LIPI increased the C-index from 0.583 to 0.698 for PFS (ΔC-index, 0.115; p < 0.001) and from 0.588 to 0.697 for OS (ΔC-index, 0.109; p = 0.003). Conclusions: Pretreatment LIPI was independently associated with PFS and OS in patients with advanced NSCLC receiving nivolumab after first-line therapy. Its association remained after adjustment for available PD-L1 expression data, and its addition improved model discrimination. These findings suggest that LIPI may provide prognostic information complementary to PD-L1 expression and routinely available clinical factors. Full article

Aptamer-functionalized liposomes are a promising strategy to improve the selectivity of anticancer therapies. AT11-L2 is a G-quadruplex (G4)-forming aptamer with high affinity for nucleolin (NCL), which is overexpressed at the surface of non-small cell lung cancer (NSCLC) cells. Here, we developed AT11-L2-functionalized liposomes loaded with doxorubicin (DOX) or BRACO-19 for targeted delivery to NSCLC cells. The effects of both compounds on AT11-L2 stability and the ability of the aptamer to retain G4 folding after liposome conjugation were evaluated. Liposomes were characterized for size, polydispersity, surface charge, stability, encapsulation efficiency, and release profile. Biological activity was assessed in A549 and MRC-5 cells. Liposomes had an average size of approximately 110 nm, with a slight size increase and reduced surface charge after AT11-L2 functionalization. The aptamer retained G4 folding in 100 mM KCl after conjugation. Encapsulation efficiency was approximately 90%. DOX showed substantial release within 72 h, whereas BRACO-19 exhibited a more sustained profile. AT11-L2-DOX liposomes showed preferential effects in A549 cells, while BRACO-19 formulations displayed lower selectivity and cytotoxicity. Additionally, the NCL-dependent internalization of AT11-L2-functionalized liposomes was supported by a protein-blocking assay using an anti-NCL antibody. These results support AT11-L2-functionalized liposomes as a versatile NCL-targeted delivery system for NSCLC. Full article

Lung cancer is the leading cause of cancer-related mortality worldwide, yet the majority of cases are diagnosed at advanced stages when a cure is rarely achievable. Low-dose computed tomography (LDCT) screening in high-risk populations reduces lung cancer mortality by 20–24% in randomised trials, but fewer than 20% of eligible adults in the United States undergo annual screening. We conducted a structured narrative review of PubMed, Embase, and the Cochrane Library for studies published between January 2002 and March 2026, supplemented by review of current clinical guidelines from the USPSTF, NCCN, ACS, CHEST, and ERS. Evidence from the National Lung Screening Trial (NLST) and the NELSON trial establishes the mortality benefit of LDCT screening, though both trials have important methodological limitations that affect generalisability. The NLST predominantly detected non-small cell lung cancer (NSCLC), particularly adenocarcinoma and squamous cell carcinoma, while small cell lung cancer (SCLC) was infrequently screen detected and showed no survival benefit from early detection. Guideline eligibility criteria have progressively broadened, and multivariable risk model-based selection using the PLCOm2012 now demonstrates superiority over categorical smoking thresholds in prospective validation cohorts, with the added benefit of reducing racial and ethnic eligibility disparities. Overdiagnosis estimates have declined substantially with extended follow-up, reaching 7% when observation exceeds five years. Implementation remains critically deficient: patient stigma, provider knowledge gaps, structural barriers, and inadequate electronic health record infrastructure collectively account for screening uptake below 20%. Integrating smoking cessation into screening encounters is evidence-based and cost-effective. Artificial intelligence tools show promising performance in nodule detection and risk prediction, but lack the prospective external validation required for routine clinical deployment. The field has established efficacy; the urgent challenge is now effectiveness at scale. Transitioning to risk model-based eligibility, expanding access to underserved populations, and mandating cessation integration represent the three highest-priority actions. A research agenda addressing never-smoker screening, personalised intervals, and robust AI validation must proceed in parallel. Full article

Background: Precision oncology has significantly transformed the management of non-small cell lung cancer (NSCLC) through the integration of molecular diagnostics, targeted therapies, and biomarker-driven treatment selection. Advances in next-generation sequencing (NGS) and liquid biopsy have improved the identification of actionable molecular alterations and enabled dynamic monitoring of tumor evolution. Objective: To provide a structured narrative review of current evidence regarding actionable molecular biomarkers, diagnostic methodologies, targeted therapies, and future directions in NSCLC precision oncology, with a specific focus on conceptualizing acquired resistance mechanisms. Methods: A structured narrative literature review was conducted by searching PubMed and Google Scholar for English-language studies published between 2015 and 2026. Eligible publications included clinical trials, cohort studies, translational research, reviews, and clinical guidelines addressing molecular profiling, targeted treatments, diagnostic approaches, and resistance mechanisms in NSCLC. Results: A total of 99 foundational studies and clinical documents were analyzed. Key actionable biomarkers included EGFR (Epidermal Growth Factor Receptor), ALK (Anaplastic Lymphoma Kinase), ROS1 (ROS Proto-Oncogene 1, Receptor Tyrosine Kinase), KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog), RET (Rearranged during Transfection), MET (Mesenchymal–Epithelial Transition Factor), HER2 (Human Epidermal Growth Factor Receptor 2) and NTRK (Neurotrophic Tyrosine Receptor Kinase) alterations, along with emerging targets such as NRG1 (Neuregulin 1) fusions. NGS emerged as the cornerstone of comprehensive molecular profiling, while liquid biopsy enabled longitudinal monitoring of tumor dynamics and resistance development. To organize the biological complexity of treatment failure, acquired resistance mechanisms were categorized into a three-tiered conceptual framework: target-centric genetic evolution (Tier 1), cellular plasticity and intratumoral heterogeneity (Tier 2), and non-genetic/microenvironmental adaptation (Tier 3). Targeted therapies significantly improved clinical outcomes compared with conventional chemotherapy; however, acquired resistance remained a major challenge across all tiers. Conclusions: Precision oncology in NSCLC is evolving from a biomarker-focused approach toward a dynamic framework integrating molecular diagnostics, targeted therapies, and continuous resistance monitoring. The proposed three-tiered resistance framework provides a structured basis for understanding treatment failure, guiding molecular reassessment at progression, and informing future adaptive therapeutic strategies to improve long-term patient outcomes. Full article

Background/Objectives: In recent years, neoadjuvant chemoimmunotherapy followed by surgery has improved outcomes in patients with stage II/III non-small cell lung cancer (NSCLC). However, the prognostic impact of residual mediastinal nodal disease after chemoimmunotherapy remains insufficiently defined, particularly with the introduction of the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) 9th edition nodal subclassification. Methods: In this retrospective study, 90 consecutive patients with clinically node-positive (cN1-2) resectable locally advanced NSCLC who underwent neoadjuvant chemoimmunotherapy followed by curative-intent resection were included. Disease-free survival (DFS) was analyzed according to postoperative pathologic nodal status. Nodal status was assessed using the UICC/AJCC 8th edition (ypN0, ypN1, ypN2) and reclassified according to the 9th edition (ypN0, ypN1, ypN2a, ypN2b). Residual postoperative nodal disease was defined as residual pathologic nodal involvement (ypN+) in patients with clinically node-positive (cN+) disease at baseline. Results: The cohort comprised 90 patients (60% male, median age 63 years [interquartile range (IQR) 58–69]). Following neoadjuvant therapy, surgery revealed pathologic nodal clearance in 53 (58.9%) and residual nodal disease in 37 (41.1%) patients (ypN1, n = 16 [17.8%]; ypN2a, n = 15 [16.7%]; and ypN2b, n = 6 [6.7%]). DFS differed significantly by postoperative nodal status (global log-rank p < 0.001), with progressively poorer outcomes with increasing residual nodal burden. Conclusions: Residual nodal disease after neoadjuvant chemoimmunotherapy and surgery is associated with progressively inferior DFS according to its anatomic extent. The UICC/AJCC 9th-edition staging system provides clinically relevant prognostic granularity, supporting further investigation of mediastinal restaging and postoperative treatment strategies. Full article

Background/Objectives: Clinical outcomes with immune checkpoint inhibitors (ICIs), such as nivolumab, vary among patients with metastatic non-small cell lung cancer (NSCLC). The Lung Immune Prognostic Index (LIPI) may help stratify prognosis. This study evaluated the prognostic significance of LIPI in patients receiving second- or third-line nivolumab and developed a nomogram for individualized survival estimation. Methods: This single-center retrospective study included 142 patients with metastatic NSCLC who received second- or third-line nivolumab between February 2022 and December 2024, after progression on platinum-based chemotherapy. LIPI was calculated from baseline values obtained within 14 days before nivolumab initiation, based on a derived neutrophil-to-lymphocyte ratio (dNLR) > 3 and lactate dehydrogenase (LDH) > 225 U/L (institutional upper limit of normal), classifying patients as good-, intermediate-, or poor-risk (0, 1, or 2 factors, respectively). Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan–Meier method; independent prognostic factors were assessed by multivariable Cox regression, and a prognostic nomogram combining ECOG performance status, serum albumin, and LIPI was developed and internally validated. Results: By LIPI, 34.5%, 45.1%, and 20.4% of patients were at good, intermediate, and poor risk, respectively. Objective response and disease control rates were 29.6% and 55.6%. Median OS and PFS were 19.3/8.0/3.1 and 8.6/3.1/2.5 months across good, intermediate, and poor LIPI groups (log-rank p < 0.001). In multivariable analysis, ECOG 2 (hazard ratio [HR], 4.94), albumin per 1 g/dL (HR 0.27), and poor versus good LIPI (HR 3.74) were independently associated with OS. A nomogram combining these three factors showed acceptable discrimination (optimism-corrected Harrell C-statistic 0.742). Conclusions: LIPI was independently associated with prognosis in this cohort. Combining LIPI with ECOG and albumin may aid individualized risk assessment, pending external validation. Full article

Non-small cell lung cancer is one of the leading causes of cancer-related mortality. The effectiveness of treatment is limited by several factors, including significant tumoral heterogeneity, rapid development of drug resistance, high metastatic potential, and a complex tumor microenvironment. In recent years, natural products have emerged as valuable resources for the discovery of novel antitumor strategies against non-small cell lung cancer. These compounds possess diverse chemical properties, target multiple pathways, are abundant in nature, and exhibit relatively low toxicity. The utilization of existing medications with established pharmacokinetic profiles and safety records, combined with shorter development timelines, shows promise for advancing lung cancer treatment research. A growing body of evidence indicates that both naturally occurring compounds and commercially available drugs exert effects that extend beyond traditional cytotoxic mechanisms. These agents influence processes such as ferroptosis, oxidative stress, metabolic reprogramming, autophagy, apoptosis, epithelial–mesenchymal transition (EMT), tumor immune microenvironments, and epigenetic networks, suggesting that their activities can be leveraged for a robust multi-target antitumor strategy. Accordingly, this review summarizes research advances on natural products and repurposed marketed drugs for non-small cell lung cancer; outlines their potential for combination with chemotherapy, targeted therapy, radiotherapy and immunotherapy; and discusses future directions for clinical translation. Full article

Background: Approximately 13% of NSCLC cases have KRAS G12C mutations. As therapeutic strategies targeting KRAS G12C-mutant NSCLC evolve, it is important to understand clinical presentation and current outcomes for these patients. Methods: This retrospective study used data from two US nationwide databases, an electronic health records (EHR) database and a clinico-genomic database (CGDB) of EHR data linked to data from comprehensive genomic profiling tests. Eligible patients had advanced NSCLC, initiated first-line therapy from August 2018 to December 2022, and had KRAS test results. Clinicopathologic characteristics, treatments, real-world progression-free survival (rwPFS), and overall survival (OS) were analyzed. Results: There were 1227 patients with KRAS G12C-mutant NSCLC in the EHR database and 447 in the CGDB. First-line regimen was platinum-based chemotherapy plus pembrolizumab for 46% and pembrolizumab monotherapy for 20%. Less than 40% of patients received second-line therapy. Median (95% CI) OS for KRAS G12C-mutant NSCLC patients in the EHR was 17.0 (15.2–18.9) months. Variables significantly associated with shorter OS included PD-L1 <1%, brain metastases, STK11 co-mutation, and poor performance status. Patients treated with platinum-based chemotherapy plus pembrolizumab had median rwPFS of 5.3 (4.5–7.3) months and OS of 12.8 (11.1–17.3) months in the CGDB; median OS was 15.6 (12.5–18.6) months in the EHR. Patients with PD-L1 ≥ 50% treated with pembrolizumab monotherapy had median rwPFS of 4.6 (3.0–15.6) months and OS of 20.4 (10.3–38.5) months in the CGDB; median OS was 22.1 (18.7–30.7) in the EHR. Conclusions: These data provide a real-world benchmark of outcomes for patients with KRAS G12C-mutant NSCLC receiving the current standard of care and indicate an unmet need for more effective first-line therapies. Full article

Background: Host-related factors such as skeletal muscle and adipose tissue characteristics are increasingly recognized as determinants of outcome in advanced non-small cell lung cancer (aNSCLC). However, the prognostic relevance of integrated body composition phenotypes in patients receiving first-line immunotherapy-based treatment remains unclear. Methods: We retrospectively analyzed patients with aNSCLC treated with first-line immune checkpoint inhibitors (ICI) alone or combined with chemotherapy (ICI–CT) between October 2018 and December 2023 at LMU University Hospital. AI-derived CT biomarkers included skeletal muscle volume index (SMVI), skeletal muscle density (SMD), visceral adipose volume index (VAVI), and subcutaneous adipose volume index (SAVI), normalized for height. Individual body composition parameters were analyzed as standardized continuous variables. For exploratory phenotype analyses, SMVI and VAVI were categorized using cohort-specific sex-stratified median values. An integrated body composition phenotype was defined as “high-muscle/low-visceral-adiposity” (high SMVI/low VAVI) or “low-muscle/high-visceral-adiposity” (low SMVI/high VAVI), with patients not meeting either definition classified as having an intermediate phenotype. Multivariable Cox regression adjusted for age, sex, treatment modality, and metastatic burden evaluated associations with progression-free survival (PFS) and overall survival (OS). Results: Of 116 screened patients, 103 with evaluable baseline CT imaging were included. The cohort predominantly comprised ever-smokers (81.6%) and patients with adenocarcinoma (62.1%). Higher SMD (per one standard deviation increase) was associated with improved overall survival (HR 0.72, 95% CI 0.52–1.00; p = 0.047), and higher VAVI was associated with a higher risk of death (HR 1.29, 95% CI 1.00–1.65; p = 0.048). Neither SMD nor VAVI was significantly associated with PFS, and SMVI and SAVI were not significantly associated with OS or PFS. In the exploratory integrated phenotype analysis, median OS was 29.5 months in the high-muscle/low-visceral-adiposity group, 16.2 months in the intermediate group, and 19.3 months in the low-muscle/high-visceral-adiposity group; however, the overall Kaplan–Meier comparison was not statistically significant (log-rank p = 0.385). Conclusions: AI-derived CT body composition assessment may provide complementary prognostic information in patients with aNSCLC receiving first-line immunotherapy-based treatment. Higher skeletal muscle density was associated with a lower risk of death, whereas higher visceral adiposity was associated with a higher risk of death. The exploratory integrated phenotype analysis did not demonstrate a consistent risk gradient across phenotype categories. These findings require validation in larger prospective cohorts before clinical implementation. Full article