To explore whether adjuvant immunotherapy can improve postoperative prognosis for non-small cell lung cancer (NSCLC) patients harboring oncogenic driver alterations beyond EGFR and ALK, a population with unclear benefit. Main inclusion criteria included resected NSCLC, stage IB-IIIB, and oncogenic driver alterations of KRAS mutation, ROS1 fusion, RET fusion, HER2 mutation, NTRK fusion, BRAF V600E mutation, and MET exon 14 skipping mutation. The positive PD-L1 cut-off was 1

8607 Background: Brain metastases (BM) are common in patients with EGFR -mutated ( EGFR m) non-small cell lung cancer (NSCLC) and are associated with poor prognosis. Furmonertinib is a pan- EGFR tyrosine kinase inhibitor (TKI) characterized by high central nervous system penetration and a wide therapeutic window. This study evaluated the efficacy and safety of high-dose furmonertinib (160 mg once daily) in previously EGFR-TKI-treated patients with EGFR m NSCLC and BM. Methods: iFORCE was a prospective, single-arm study conducted at a single center. Eligible patients had EGFR exon 19 deletion or L858R-mutant NSCLC with at least one measurable intracranial lesion (≥5 mm) and had received ≥1 prior EGFR-TKI therapy. Patients received furmonertinib 160 mg orally once daily. The primary endpoints were intracranial progression-free survival (iPFS). Results: Twenty-three patients were enrolled, with a median follow-up time of 19.7 months (95% confidence interval [CI], 14.5-25.3 months). Median iPFS was 14.6 months (95% CI, 4.2-not reached), with 12- and 24-month iPFS rates of 53.8% and 30.8%, respectively. The intracranial objective response rate (iORR) was 34.8% (95% CI, 16.4-57.3), and the intracranial disease control rate (iDCR) was 91.3% (95% CI, 72.0-98.9). Median systemic progression-free survival (PFS) was 10.7 months (95% CI, 3.9-not reached). Treatment-related adverse events occurred in 13 (56.5%) of patients and were predominantly grade 1; one patient (4.3%) experienced a grade 3 stomatitis. No treatment discontinuations or treatment-related deaths were observed. Conclusions: High-dose furmonertinib demonstrated encouraging intracranial efficacy with a manageable safety profile in previously EGFR-TKI-treated patients with EGFR m NSCLC and BM, supporting further investigation in randomized studies. Clinical trial information: NCT05465343 .

BACKGROUND:Although emerging agents have broadened the therapeutic landscape for non-small cell lung cancer (NSCLC) harboring HER2 alterations, effective and accessible first-line therapy remains limited. METHODS:In this single-arm, phase II trial, treatment-naïve patients with stage IIIB-IV NSCLC harboring de novo HER2 mutations or amplification were given oral pyrotinib (400 mg) in combination with apatinib (250 mg) once daily until disease progression, intolerable toxicity, or death. The primary endpoint was overall response rate (ORR). Secondary endpoints consisted of disease control rate (DCR), progression-free survival (PFS), and safety. RESULTS:Between November 2021 and March 2024, 22 eligible patients were enrolled. The ORR was 72.7 % (95 % CI, 49.8-89.3), and the DCR reached 95.5 % (95 % CI, 77.2-99.9). With a median follow-up of 37.0 months (95 % CI, 36.1-37.9), the median PFS was 10.7 months (95 % CI, 6.6-14.8). Both patients harboring HER2 amplification achieved PFS exceeding 10 months, while the patient harboring HER2 exon 19 L755P mutation achieved a PFS exceeding 24 months. Grade 3-4 treatment-related adverse events occurred in 27.3 % of subjects, with diarrhea being the most prevalent (18.2 %). In the propensity score-matched analysis, pyrotinib plus apatinib prolonged PFS compared with chemotherapy-based regimens (robust standard error HR 0.53, 95 % CI: 0.34-0.81, P = 0.003). Circulating tumor DNA analysis demonstrated decreased HER2 variant allele frequency in 93.3 % of patients with paired baseline and post-C1 samples. CONCLUSION:Pyrotinib combined with apatinib demonstrated promising first-line activity, rapid responses, and manageable toxicity in advanced HER2-altered NSCLC, supporting its potential as an accessible chemotherapy-sparing therapy, particularly in resource-constrained settings.

Background:Current evidence on the efficacy and safety of lorlatinib as first-line or subsequent-line therapy for patients with anaplastic lymphoma kinase (ALK)-positive (ALK +) non-small cell lung cancer (NSCLC) in real-world clinical settings remains insufficient. We aim to further evaluate the efficacy and safety of lorlatinib through a real-world cohort study and investigate potential mechanisms of resistance. Methods:This study is a single-center cohort study in China. We retrospectively and prospectively collected data on patients with advanced or metastatic ALK + NSCLC who initiated lorlatinib treatment at National Cancer Center from December 1, 2020. Patients were categorized into two groups based on lorlatinib treatment sequence: first-line cohort and subsequent-line cohort. Demographic characteristics, efficacy, and safety outcomes were comprehensively documented. Survival curves were generated using the Kaplan-Meier method, and group comparisons were performed with the log-rank test. Continuous variables were analyzed using Student's t-tests. The endpoints of this study included measures of both treatment efficacy and safety. Results:As of July 18, 2025, a total of 36 patients were enrolled in the lorlatinib first-line treatment cohort, and 43 patients were enrolled in the lorlatinib subsequent-line treatment cohort for analysis. For the first-line treatment cohort, the median follow-up time was 12.7 months and the median progression-free survival (PFS) had not yet been reached; the objective response rate (ORR) was 82.9%, and the disease control rate (DCR) was 100%. For the subsequent-line treatment cohort, the median follow-up time was 19.9 months and the median PFS was 16.8 months; the ORR was 40.5%, and the DCR was 92.9%. Among all patient groups included in this study, the adverse events associated with lorlatinib treatment predominantly comprised hypercholesterolemia, hypertriglyceridemia, edema, cognitive impairment/mood disorders, elevated transaminases, weight gain, and peripheral neuropathy. No cases of interstitial lung disease were observed. The overall safety profile of lorlatinib is manageable. Analysis of next-generation sequencing (NGS) test results from patients with lorlatinib resistance demonstrated that ALK compound mutations, novel ALK fusions, and MET gene amplification may be potential mechanisms contributing to lorlatinib resistance. Conclusions:Lorlatinib has shown remarkable efficacy in both first-line and subsequent-line treatment settings for patients with locally advanced or metastatic ALK + NSCLC. Effective management of lorlatinib-related adverse events, through close monitoring and timely intervention, is essential to enhance patient tolerance. Lorlatinib has progressively transformed the therapeutic landscape for patients with ALK + NSCLC.

Distant metastasis, characterized by organotropism, is a major cause of mortality in lung adenocarcinoma (LUAD). In this study, digital spatial profiling (DSP), multiplex immunofluorescence (mIF), and clinical data from 52 LUAD patients were integrated to develop organ-specific metastasis risk models, and the molecular mechanisms underlying metastatic organotropism were investigated. Random forest models based on primary tumor spatial transcriptomics accurately predicted metastasis to the brain (AUC = 0.974), liver (AUC = 0.975), adrenal gland (AUC = 0.929), and bone (AUC = 0.907). Key compartment-specific gene expression signatures associated with organotropic metastasis were identified, including those expressed in tumors (e.g., FKBP1A for the brain and MOCOS for the liver), immune cells (e.g., ADAMTSL2 for the liver), and stromal cells (e.g., CKAP2 for the brain). Pathway analyses revealed distinct biological processes associated with organotropism, such as enriched cell death pathways in brain metastasis and extracellular matrix (ECM) remodeling in liver metastasis. Postmetastasis survival models highlight stromal gene expression (e.g., PKM for OS and VCAM1 for PFS) and immunosuppressive microenvironments (e.g., M2 macrophage infiltration) as critical prognostic factors. The high-precision prediction models and key molecular signatures identified in this study enhance our understanding of "seed-soil" interaction dynamics and offer promising biomarkers and therapeutic targets for future clinical use.

BACKGROUND:Chemoimmunotherapy is the first-line standard for advanced lung adenocarcinoma (LUAD) without driver mutations, but predictive biomarkers are still limited. TP53 is the most frequently mutated gene in LUAD, and its mutation subtypes affect treatment efficacy differently. METHODS:This is a retrospective observational study. We retrospectively analyzed 133 patients with advanced LUAD who received first-line chemoimmunotherapy in our hospital. TP53 mutations were classified using a multidimensional approach. Key subtypes were identified through elastic-net and multivariate Cox regression analyses in clinical cohorts. The underlying mechanisms were further explored by transcriptomic and pathway analyses, including gene set variation analysis (GSVA) and immune cell deconvolution, using TCGA data. RESULTS:An elastic-net Cox model within the TP53-mutant cohort identified three key features: TP53 variant allele frequency (VAF), CpG site mutation status, and dominant-negative effects (DNE)-loss-of-function (LOF) classification. Subsequent multivariate Cox regression in the full cohort confirmed that TP53 mutations at CpG sites were an independent favorable prognostic factor. Patients harboring CpG site mutations had significantly longer median progression-free survival (PFS) for first-line chemoimmunotherapy than both non-CpG-mutant and wild-type patients. Exploratory transcriptomic analyses revealed that CpG-mutant tumors were associated with an immune-activated tumor microenvironment (TME) characterized by enhanced T-Cell receptor (TCR) signaling, antigen presentation, IFN-γ signaling, and CD8+ T-cell infiltration, whereas non-CpG-mutant tumors exhibited a glycolytic metabolic profile and potentially reduced immune activity. CONCLUSIONS:In conclusion, this study demonstrates that TP53 mutations at CpG sites define a distinct subgroup of patients with advanced LUAD who derive significantly greater PFS benefit from first-line chemoimmunotherapy.

The efficacy of immune checkpoint inhibitor plus chemotherapy (ICI-chemo) following third-generation EGFR-TKI resistance in EGFR-mutant lung adenocarcinoma (LUAD) is variable and lacks reliable predictive biomarkers. This study investigated associations between treatment-naïve primary tumor transcriptomic profiles, tumor immune microenvironment (TIME) characteristics, and subsequent ICI-chemo efficacy. This retrospective study enrolled 12 advanced LUAD patients who received ICI-chemo after progressing on third-generation EGFR-TKIs. Patients were stratified into Better (N = 7) and Worse (N = 5) efficacy groups using 6-month progression-free survival (PFS) as cutoff. Treatment-naïve tumor specimens were analyzed using Digital Spatial Profiling (DSP) whole transcriptome sequencing and multiplex immunofluorescence (mIF) to assess compartment-specific gene expression, pathway enrichment, and infiltration of 19 immune cell types. LASSO-Cox regression was performed to identify key prognostic genes. SFTPC expression was significantly elevated across all compartments in the Worse efficacy group. Enrichment analysis revealed that the efficacy of ICI-chemo in EGFR-mutant patients arises from a combination of proliferative tumor cells and an activated TIME. A total of eight key prognostic genes were identified: DNM1L_Immune, ADPGK_Immune, SLC12A4_Stroma, PLA2G6_Immune, FKBP1A_Immune, CHST15_Tumor, TRMT5_Immune, TAX1BP1_Immune. Complex correlations were observed between these key genes and the expression of immune checkpoints. mIF revealed significantly higher infiltration of cancer-associated fibroblast subtype I (CAFI) in the Worse group, while the Better efficacy group exhibited a more activated antitumor TIME. Baseline upregulation of SFTPC, enrichment of CAFI, and specific immune checkpoint expression patterns are associated with poor response to ICI-chemo following EGFR-TKI resistance in EGFR-mutant LUAD. The eight spatially resolved genes identified may serve as potential predictive biomarkers for patient stratification. These findings underscore the functional interdependence between tumor-intrinsic properties and TIME characteristics in determining immunotherapy outcomes, and provide biologically plausible candidates warranting independent validation in larger cohorts.

Solute carrier family 6 member 8 (SLC6A8) is a Na+- and Cl--dependent creatine transporter that mediates the transmembrane uptake of creatine, thereby sustaining intracellular creatine pools and cellular energy homeostasis. Dysregulated expression and function of SLC6A8 have been linked to creatine transporter deficiency (CTD), multiple malignancies, diabetes, obesity, and heart failure, underscoring its promising potential as a therapeutic target. Conventional creatine supplementation yields limited therapeutic benefit in the majority of CTD patients. Nevertheless, emerging strategies including gene therapy, small-molecule correctors, and lipophilic prodrug approaches have demonstrated preliminary efficacy in preclinical models of CTD. SLC6A8 is aberrantly expressed across numerous cancer types, and its inhibitor RGX-202 (also termed ompenaclid, chemically identified as β-GPA) exerts broad antitumor activity in preclinical models of colorectal cancer and hepatocellular carcinoma. This review summarizes recent advances delineating the involvement of SLC6A8 in neurological disorders, cancer, and other pathological conditions, with a particular emphasis on its translational potential as a therapeutic target. Clarifying the research status of SLC6A8 in various systemic diseases enables subsequent researchers to comprehensively understand its biological functions and clinical translational value from a more systematic perspective.

Psoriasis is an inflammatory skin disease, which is distinguished by parakeratosis and hyperkeratosis. Abnormal keratinocyte activity is crucial to its onset and development. Recent evidence reveals the significance of metabolic reprogramming in keratinocytes during psoriasis progress, demonstrating its strong association with the control of immune and inflammatory responses in the cutaneous microenvironment. This review systematically outlines metabolic abnormalities in keratinocytes, emphasizing key metabolic targets in glucose, lipid, and amino acid metabolism that mediate psoriasis progression and discusses the application prospects of metabolic targets in clinical practice. The objective is to provide a rationale for developing novel psoriasis therapies based on the metabolic regulation of keratinocytes.

High-grade lung neuroendocrine carcinomas (Lu-NECs) are clinically refractory malignancies with poor prognosis and limited therapeutic advances. The biological and molecular features underlying the histological heterogeneity of Lu-NECs are not fully understood. In this study, we present a multi-omics integration of whole-exome sequencing and deep proteomic profiling in 93 Chinese Lu-NECs to establish the first comprehensive proteogenomic atlas of this disease spectrum. Our analyses revealed a high degree of mutational concordance among the subtypes at the genomic level; however, distinct proteomic profiles enabled a clear differentiation of histological subtypes, unveiling subtype-specific molecular and biological features related to tumor metabolism, immunity, and proliferation. Furthermore, RB1 mutations confer divergent prognostic effects through subtype-specific cis- and trans-proteomic regulation. In addition, we identified potential protein biomarkers for histological subtype classification and risk stratification, which were validated by immunohistochemistry in an independent cohort. This study provides a valuable proteogenomic resource and insight into Lu-NEC heterogeneity.

ABSTRACTBackgroundThe clinical implications of different EML4‐ALK fusion variants remain poorly elucidated in the era of second‐generation ALK inhibitors.MethodsThis was a retrospective cohort study, wherein patients diagnosed with locally advanced or metastatic non‐small cell lung cancer harboring EML4‐ALK fusion were stratified into two cohorts based on their first‐line treatment: Cohort 1 received alectinib, while Cohort 2 received crizotinib. Statistical analysis was employed to investigate the impact of different EML4‐ALK variants and TP53 status on the efficacy of first‐line ALK‐TKIs.ResultsFinally, 49 patients were enrolled in cohort 1 and 53 patients in cohort 2. In cohort 1, patients with long EML4‐ALK fusion variants exhibited prolonged PFS (NR vs. 34.0 m, p = 0.004, HR = 0.30, 95% CI: 0.12–0.74) and an elevated 5‐year OS rate (93.3% vs. 68.4%, p = 0.020, HR = 0.12, 95% CI: 0.02–0.62) compared to those with short variants. The median PFS was not reached in TP53‐wt group and 47.0 m in TP53‐mut group (p = 0.087, HR = 0.44, 95% CI: 0.17–1.17). The TP53‐wt group exhibited a superior 5‐year OS rate (100% vs. 77.8%, p = 0.030) compared to TP53‐mut group. In cohort 2, the median PFS was 14.0 m in long variant group and 12.9 m in short variant group (p = 0.094, HR = 0.65, 95% CI: 0.37–1.13); the median OS was not reached in long variant group and 69.2 m in short variant group (p = 0.254, HR:0.62, 95% CI: 0.27–1.42). However, the efficacy of first‐line crizotinib did not appear to be influenced by the TP53 status.ConclusionsEML4‐ALK short variants and TP53 mutations are both adverse factors for first‐line alectinib efficacy, but they have little effect on first‐line crizotinib.

ABSTRACT Background ROS1 gene rearrangement is an important target for NSCLC treatment. There is not yet sufficient real‐world data on ROS1 diagnostic methods, treatment selection, and clinical outcomes in the Chinese population. Methods A single‐center retrospective collection of patients with a diagnosis of ROS1‐positive advanced NSCLC from July 2011 to November 2021 was performed to document the method of ROS1 testing, treatment options, efficacy, and resistance to ROS1 inhibitors in these patients. Results The method of ROS1 testing and initial treatment selection were significantly correlated with time. ROS1 testing shifted from FISH (67% pre‐2019) to NGS (96.3% post‐2019; p < 0.001). First‐line ROS1‐TKI use increased from 60.0% to 92.0% (p = 0.041). The vast majority of patients (90.0%) chose crizotinib as the initial ROS1 inhibitor, with objective response rates (for patients with target lesions) and median progression‐free survival of 82.8% (95% CI: 68.1%–97.9%) and 18.7 months (95% CI: 8.9–28.4 months), respectively. CNS was the most common site of progression for crizotinib (60%, 13/26, including 11 intracranial progressions alone). Compared to patients who received a chemotherapy‐based regimen (n = 8) as first‐line therapy, patients who received ROS1‐TKI (n = 32) as first‐line therapy had significantly longer median PFS (18.3 months vs. 3.7 months, p < 0.001). For ROS1 inhibitor‐resistant patients, 48.3% of patients underwent rebiopsy throughout the course of their disease, with G2032R being the most common secondary ROS1 mutation (7/8). Conclusion With the innovation of diagnostic and therapeutic methods and the expansion of the scope of the health insurance coverage, more and more patients are benefiting from new technologies and targeted drugs. Although crizotinib has brought excellent therapeutic data for ROS1‐positive patients, better brain protection strategies should be explored for ROS1‐positive patients in the future. In addition, the low rate of rebiopsy in real‐world ROS1‐positive patients should also be emphasized in clinical practice.

Background:Compared with chemotherapy alone, the addition of atezolizumab to the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC) improves the overall survival (OS), but the benefit remains limited. This study aims at investigating the factors influencing prognosis and to assess the effect of the number of induction chemotherapy cycles on treatment efficacy. Methods:We retrospectively analyzed the data of patients with ES-SCLC treated in five centers between March 2020 and September 2022. All 45 patients received first-line treatment with etoposide plus platinum combined with atezolizumab. The primary endpoints were progression-free survival (PFS) and OS in the total population and subpopulations based on the number of induction chemotherapy cycles. Least absolute shrinkage and selection operator (LASSO) regression were applied to identify the prognostic variables, and the effect of varying the number of induction chemotherapy cycles on the treatment efficacy was evaluated. Results:A total of 45 patients were enrolled in the study. The median PFS for the first-line treatment was 7 months, and the median OS was 17.6 months. The following 10 variables were analyzed using LASSO regression: gender, age, liver metastasis, bone metastasis, brain metastasis, number of first-line induction chemotherapy cycles, first-line immunotherapy maintenance, receipt of cross-line immunotherapy, chest radiotherapy, and brain radiotherapy. The analysis revealed that receiving ≥6 cycles of induction chemotherapy was the most important variable affecting prognosis and the only one significant [concordance index: 0.658; hazard ratio: 0.32 (95% confidence interval: 0.17-0.63)]. Patients who received ≥6 cycles of induction chemotherapy (n=25) had a longer median PFS (8 vs. 5 months) and median OS (18.5 vs. 13.1 months) than those who received <6 cycles (n=20). Subgroup analyses indicated consistent survival benefits of ≥6 induction chemotherapy cycles across key subgroups, including males, patients aged ≤65 years, and those with or without brain metastasis (all P value <0.05). Conclusions:Receiving ≥6 cycles of induction chemotherapy significantly prolonged the median PFS and median OS of patients, highlighting its crucial factor influencing the efficacy of first-line atezolizumab combined with chemotherapy in patients with ES-SCLC.

ABSTRACT Background Optimal treatment for driver gene‐negative non‐small cell lung cancer (NSCLC) with brain metastases (BM) remains unclear, particularly regarding immune checkpoint inhibitor (ICI)‐based combinations and local BM therapy. Predictive biomarkers for intracranial efficacy are also undefined. Methods This retrospective study analyzed driver gene‐negative NSCLC patients with BM treated with first‐line ICI‐based systemic therapy (ICI plus chemotherapy [ICI + CT] or ICI + CT plus bevacizumab [ICI + CT + Bev]) from June 2019 to June 2024. The intracranial progression‐free survival (icPFS), progression‐free survival (PFS), and overall survival (OS) were compared between treatment groups and by BM local therapy. The PD‐L1 tumor proportion score (TPS) expression was evaluated for correlation with intracranial efficacy. Results A total of 36 patients were enrolled in the study. The intracranial objective response rate (icORR) was 70.6% (ICI + CT) versus 78.6% (ICI + CT + Bev) (p = 0.689), with no significant differences in icPFS, PFS, or OS between the two different first‐line systemic regimens (all p > 0.05). Local BM therapy (n = 18) did not improve icPFS and OS (all p > 0.05). Extracranial PD‐L1 (TPS ≥ 50%, n = 13) correlated with superior icPFS, PFS, and OS (all p < 0.05) versus PD‐L1 TPS < 50%. Multivariate analysis confirmed PD‐L1 ≥ 50% as an independent prognostic factor (HR = 0.155; 95% CI, 0.025–0.939; p = 0.042). Conclusions Adding bevacizumab to first‐line ICI‐chemotherapy did not enhance survival outcomes. Local treatment for BM did not provide additional survival advantages when combined with first‐line ICI‐based systemic therapy. Extracranial PD‐L1 TPS ≥ 50% predicted improved intracranial efficacy.

As a common dermatosis, atopic dermatitis (AD) is primarily driven by type 2 inflammation. Sappanone A (SA), derived from the traditional medicinal plant Caesalpinia sappan L., has demonstrated a broad range of anti-inflammatory activities in various diseases. However, the pharmacological mechanisms underlying its efficacy remain unelucidated in AD. The objective of our research was to investigate the therapeutic efficacy and molecular mechanisms of SA in treating AD. In vitro, the anti-inflammatory effects of SA were evaluated in IL-4/IL-13/TNF-α stimulated HaCaT cells. In vivo, mice were treated with SA following the induction of AD-like symptoms with MC903 and assessed for inflammatory parameters. Furthermore, transcriptomics and network pharmacology were utilized to elucidate the therapeutic mechanisms of SA in AD. SA significantly suppressed the generation of type 2 inflammatory cytokines in HaCaT cells stimulated by IL-4/IL-13/TNF-α and alleviated MC903-induced AD-like symptoms in C57BL/6J mice. The integration of transcriptomics and network pharmacology displayed that SA regulated the type 2 inflammatory response in AD through the IL-21R-mediated JAK1/STAT3 signaling pathway. SA exerted a strong anti-inflammatory role in treating AD by inhibiting the activation of the JAK1/STAT3 signaling pathway mediated by IL-21R. This research not only supports the potential of SA as a novel agent for treating AD, but also offers methods for studying compounds derived from natural herbs in AD therapy.

The clinical effectiveness of vemurafenib that targets BRAF V600E mutation in patients with melanoma had been recognized. However, the drug resistance severely hampers the clinical application of vemurafenib. We combined metabolomics and transcriptomics analysis and found that phospholipase D2 (PLD2), a key enzyme in choline metabolism, was significantly highly expressed in vemurafenib-resistant melanoma cells, and knockdown of PLD2 significantly increased the drug sensitivity of vemurafenib in melanoma resistant cells. Furtherly, we found that the transcription factor forkhead box protein A1 (FOXA1) positively regulated the expression of PLD2 and promoted the resistance of vemurafenib. Importantly, the knockdown of PLD2 significantly enhanced the DNA breaks induced by vemurafenib treatment, which prompted that PLD2-mediated protection from vemurafenib was responsible for the drug resistance of vemurafenib. In addition, we furtherly found that the combination of PLD2 inhibitor CAY10594 or PLD1/PLD2 dual inhibitors FIPI and vemurafenib exerted synergistic antiproliferative effects in melanoma sensitive cells. The implementation of our study systematically clarified the molecular mechanism by which the FOXA1/PLD2 functional axis mediated vemurafenib resistance via protection from DNA breaks likely subsequent to apoptosis induction in melanoma, and proposed that targeted inhibition of PLD2 synergistically enhances the efficacy of vemurafenib or reverses its resistance, which provided us new insight for the clinical precision medicine of vemurafenib in melanoma.

BACKGROUND:Dacomitinib, a second-generation, irreversible tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), showed statistically significant progression-free survival improvement over gefitinib in patients with treatment-naive EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) in the phase 3 ARCHER 1050 study (NCT01774721). We report results from the final analysis of ARIA (NCT04609319), a noninterventional study of dacomitinib's real-world utilization and associated clinical outcomes in Asian patients with EGFR mutation-positive advanced NSCLC. METHODS:This longitudinal, multicenter cohort study collected prospective and retrospective data from patients with EGFR mutation-positive locally advanced or metastatic NSCLC who were treated with first-line dacomitinib. Study objectives were to describe clinical and disease characteristics, therapeutic patterns of dacomitinib use, and clinical outcomes. RESULTS:299 patients located in China (n = 261), India (n = 24), and Malaysia (n = 14) were enrolled and included in the analysis. Starting dose was 30 mg once daily in 159 (53.2 %) patients, 45 mg once daily in 138 (46.2 %), and other doses in 2 (0.7 %). As of May 28, 2024, 95 patients (31.8 %) had dose reductions, 47 (15.7 %) had dose increases, 41 (13.7 %) had dose interruptions, and 223 (74.6 %) had permanently discontinued dacomitinib. Median duration of treatment was 17.2 months (IQR, 19.2). Median time to treatment failure was 17.0 months (95 % CI, 14.5-19.8). Median progression-free survival was 20.1 months (95 % CI, 17.4-22.4). 148 (49.5 %) patients had treatment-related adverse events; most common were rash (n = 93 [31.1 %]), diarrhea (n = 81 [27.1 %]), and paronychia (n = 57 [19.1 %]). CONCLUSIONS:To our knowledge, ARIA is the largest real-world study of dacomitinib's efficacy and safety. Final analysis of this study showed substantial clinical efficacy of dacomitinib and revealed treatment patterns, such as starting dose, in the real world. Safety data were consistent with dacomitinib's known safety profile. These results support first-line dacomitinib use in Asian patients with EGFR mutation-positive advanced NSCLC. CLINICALTRIALS:gov NCT04609319.

Background:The PORT-C trial was the first published phase III randomized clinical trial (RCT) to evaluate the role of postoperative radiotherapy (PORT) using intensity-modulated radiation therapy (IMRT)/three-dimensional conformal radiation therapy (3D-CRT) in patients with resected pIIIA-N2 non-small-cell lung cancer (NSCLC). We aimed to assess the long-term outcomes of this RCT. Methods:Patients with pIIIA-N2 NSCLC treated with complete resection followed by four cycles of platinum-based chemotherapy between January 1, 2009 and December 31, 2017 were randomly assigned in a 1:1 ratio to PORT or observation. Radiotherapy was delivered using a 6 MV-X ray linear accelerator via 3D-CRT or IMRT, with 2 Gy per fraction up to 50 Gy over 5 weeks. The primary endpoint was disease-free survival (DFS), analyzed using modified intent-to-treat (mITT). Secondary endpoints included overall survival (OS), locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and toxic effects. DFS, OS, LRFS, and DMFS rates were estimated using Kaplan-Meier method, compared using log-rank test, and modeled using Cox proportional hazards method. The patterns of first failures were analyzed using competing risk analyses. This trial is registered with ClinicalTrials.gov, NCT00880971. Findings:Overall, 394 patients were randomly allocated to the PORT (n = 184) or observation (n = 180) arms. The median follow-up time was 87.9 months (interquartile range [IQR] 72.2-113.8). In the mITT analyses, DFS showed no significant difference between the PORT and observation arms (hazards ratio [HR], 0.90; 95% CI, 0.70-1.12; p = 0.39). The 5-year DFS rates in the PORT and observation arms were 36% (95% confidence interval [CI], 28.9%-43.1%) and 31.5% (95% CI, 24.6%-38.4%), respectively; the 5-year OS rates were 64.7% (95% CI, 57.6%-71.8%) and 70.4% (95% CI, 63.5%-77.3%), respectively (p = 0.20). In the per-protocol analyses, 140 and 170 patients were included in the PORT and observation arms, respectively. PORT did not significantly improve DFS (HR, 0.80; 95% CI, 0.61-1.05; p = 0.11) or OS (HR, 1.09; 95% CI, 0.77-1.53; p = 0.63). Most patients died of cancer. However, more deaths due to cardiopulmonary disease were observed in the PORT arm than in the observation arm (6/184, 3.3% vs. 2/180, 1.1%). The first failure of locoregional recurrence (LR)-only was significantly lower in the PORT arm than in the observation arm (10.9%, 95% CI, 6.8%-15.9% vs. 18.9%, 95% CI, 14.0%-26.2%, p = 0.031). Only 1 patient (0.5%) in the PORT arm had grade 3 radiation pneumonitis. No radiotherapy-related grade 4 or 5 AEs were observed. Interpretation:The long-term results of the PORT-C trial indicated no DFS benefit from receiving PORT for patients with pIIIA-N2 NSCLC after complete resection and adjuvant chemotherapy. Funding:National Key R&D Program of China, National Natural Science Foundation of China, Capital's Funds for Health Improvement and Research, Beijing Hope Run Special Fund of Cancer Foundation of China, and Beijing Xisike Clinical Oncology Research Foundation.

BackgroundRecent studies indicate that microorganisms significantly influence lung cancer pathogenesis. This research explores the variations in microbiota and metabolites in the lower respiratory tract between lung cancer patients and individuals with benign pulmonary lesions to identify potential diagnostic biomarkers.MethodsTwo hundred eight patients undergoing bronchoscopy at Tianjin Cancer Institute & Hospital and Tianjin Chest Hospital from October 2022 to October 2023 were screened. Ninety-five bronchoalveolar lavage fluid (BALF) was collected for metagenomic sequencing and untargeted metabolomic analysis. Comparisons of microbial diversity, taxonomic composition, and metabolite profiles were conducted between groups with lung cancer and benign lung conditions.ResultsThe cohort comprised 70 patients with lung cancer and 25 with benign lung lesions. Patients with lung cancer showed significantly reduced β-diversity (p = 0.005). Predominant microbes in lung cancer cases included Streptococcus, Haemophilus influenzae, and Veillonella parvula. A microbial-based diagnostic model differentiated lung cancer from benign lesions with an AUC of 0.931 (95%CI: 0.916–0.946). Metabolites increased in lung cancer were Citric acid, N-Acetylneuraminic acid, Oxoglutaric acid, and Neopterin, whereas L-Tryptophan, Uridine, 3-Hydroxybutyric acid decreased. The KEGG pathways suggest a significant link between microbial presence and both tumorigenesis and progression.ConclusionSpecific microbial patterns in the lower respiratory tract of lung cancer patients could assist in the auxiliary diagnosis of the disease. The notably altered microorganisms and metabolites in the BALF from lung cancer patients, as opposed to those with benign conditions, correlate with cancer initiation and advancement.