PubMed

(tuberculosis[Title/Abstract]) OR (lung cancer [Title/ Abstract])

Filters applied: from 2025/9/1 - 2025/9/30.

1. CA Cancer J Clin. 2025 Sep-Oct;75(5):387-409. doi: 10.3322/caac.70024. Epub 2025 Jul 17.

Personalized care for patients with EGFR-mutant nonsmall cell lung cancer: Navigating early to advanced disease management.

The discovery of activating mutations in the epidermal growth factor receptor (EGFR) gene has revolutionized the management of lung cancer, enabling the development of targeted tyrosine kinase inhibitors (TKIs). These therapies offer improved survival and reduced side effects compared with conventional treatments. Recent advancements have significantly reshaped the treatment paradigm for EGFR-mutant non-small cell lung cancer. TKIs are now incorporated into the management of early stage and locally advanced disease, and phase 3 trials have explored combination strategies in metastatic settings. Although these intensified approaches improve progression-free survival, they come with increased toxicity and higher costs, underscoring the need for precise patient selection to maximize benefit. Emerging data on biomarkers, such as co-mutations and circulating tumor DNA, show promise for refining treatment decisions. In addition, significant progress in understanding resistance mechanisms to EGFR TKIs has broadened therapeutic options. This review provides a comprehensive overview of the current landscape of EGFR-mutant nonsmall cell lung cancer, highlighting recent breakthroughs and discussing strategies to optimize treatment based on the latest evidence.

PMID: 40673977 [Indexed for MEDLINE]

2. J Clin Oncol. 2025 Sep 10;43(26):2875-2887. doi: 10.1200/JCO-25-00883. Epub 2025 Jun 2.

Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non-Small Cell Lung Cancer.

PURPOSE: Adjuvant osimertinib is the standard of care for patients with resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Neoadjuvant treatment could improve surgical and long-term outcomes.

METHODS: In this randomized, controlled, phase III study, patients with resectable, EGFR-mutated, stage II-IIIB NSCLC were randomly assigned (1:1:1) to receive neoadjuvant osimertinib (80 mg orally once daily for ≥9 weeks) plus platinum-based chemotherapy (once every 3 weeks for three cycles), osimertinib monotherapy (for ≥9 weeks), or placebo plus platinum-based chemotherapy (control), followed by surgical resection. Adjuvant osimertinib was offered to eligible patients after completion of surgery. The primary end point was major pathologic response (MPR) by blinded central pathology review. Event-free survival (EFS) was a secondary end point.

RESULTS: Overall, 358 patients were randomly assigned to receive osimertinib plus chemotherapy (121 patients), osimertinib monotherapy (117 patients), or placebo plus chemotherapy (120 patients). Osimertinib plus chemotherapy (MPR rate 26%) and osimertinib monotherapy (25%) demonstrated statistically significant improvement in the MPR rate versus placebo plus chemotherapy (2%), with corresponding odds ratios of 19.82 (95.002% CI, 4.60 to 85.33; P < .0001) and 19.28 (99.9% CI, 1.71 to 217.39; P < .0001), respectively. With 15% data maturity, the EFS rates at 12 months were 93%, 95%, and 83% with osimertinib plus chemotherapy, osimertinib monotherapy, and placebo plus chemotherapy, respectively. In the neoadjuvant period, grade ≥3 adverse events of any cause occurred in 36%, 13%, and 33% of patients with osimertinib plus chemotherapy, osimertinib monotherapy, and placebo plus chemotherapy, respectively. No new safety concerns were identified.

CONCLUSION: Neoadjuvant osimertinib with or without chemotherapy demonstrated statistically significant improvement in the MPR rate over chemotherapy alone in patients with resectable, EGFR-mutated, stage II-IIIB NSCLC.

PMID: 40454705 [Indexed for MEDLINE]

3. J Thorac Oncol. 2025 Sep;20(9):1289-1301. doi: 10.1016/j.jtho.2025.05.012. Epub 2025 May 16.

Amivantamab in Participants With Advanced NSCLC and MET Exon 14 Skipping Mutations: Final Results From the CHRYSALIS Study.

INTRODUCTION: Amivantamab is an EGFR-MET bispecific antibody with immune cell-directing activity. We assessed the safety and efficacy of amivantamab in participants with advanced NSCLC harboring primary MET exon 14 skipping mutations (METex14).

METHODS: CHRYSALIS enrolled participants with METex14 NSCLC who progressed after or declined standard-of-care therapy. Participants received intravenous amivantamab weekly for 4 weeks and biweekly thereafter. Objective response rate, duration of response (DoR), clinical benefit rate, progression-free survival, overall survival, safety, and circulating tumor DNA were analyzed.

RESULTS: Among 97 participants, 16 were treatment naive, 28 received prior treatment without MET therapies, and 53 received prior MET therapies. Objective response rate was 32% overall, 50% in treatment-naive participants, 46% in participants without prior MET therapies, and 19% in participants with prior MET therapies. In participants without prior MET therapies, amivantamab activity was observed regardless of co-occurring genomic alterations. Clinical benefit rate was 69% overall, 88% in treatment-naive participants, 64% in participants without prior MET therapies, and 66% in participants with prior MET therapies. Median DoR was 11.2 months; 61% (19/31) of the responders had DoR greater than or equal to 6 months. Median progression-free survival was 5.3 months (95% confidence interval, 4.3-7.0); median overall survival was 15.8 months (95 confidence interval, 14.6-not estimable). Most common adverse events were rash (79%) and infusion-related reactions (72%), most being grades 1 to 2 (52%).

CONCLUSIONS: The safety profile was consistent with previous reports of amivantamab in EGFR-mutant NSCLC. Amivantamab demonstrated clinically meaningful and durable antitumor activity in participants with METex14 advanced NSCLC, including those who progressed on prior MET therapies.

PMID: 40383434 [Indexed for MEDLINE]

4. J Thorac Oncol. 2025 Sep;20(9):1268-1278. doi: 10.1016/j.jtho.2025.04.010. Epub 2025 May 2.

Overall Survival in EGFR-Mutant Advanced NSCLC Treated With First-Line Osimertinib: A Cohort Study Integrating Clinical and Biomarker Data in the United States.

INTRODUCTION: Patients with NSCLC harboring EGFR mutations (EGFRm) have high mortality. The third-generation tyrosine kinase inhibitor, osimertinib, is approved for first-line EGFRm NSCLC. We used longitudinal U.S. medical oncology databases to evaluate real-world overall survival (rwOS) and prognostic risk factor groups in advanced EGFRm NSCLC treated with first-line osimertinib.

METHODS: This retrospective, new-user cohort study used electronic records from ConcertAI, Flatiron Clinical-Genomics, and COTA databases. Patients with advanced or metastatic EGFRm NSCLC initiating osimertinib monotherapy in first line between April 1, 2018, and October 30, 2022, were included. Follow-up was until death or October 31, 2023. rwOS was estimated using the Kaplan-Meier method. Risk factors were evaluated using multivariate analysis.

RESULTS: A total of 1323 patients were included with a median follow-up of 20 months. Median age was 70 (range 35-89) years. Median rwOS was 28.6 months (95% confidence interval 26.8-30.9). In high-risk subgroups, median rwOS (mo) was 18.1 in patients with Eastern Cooperative Oncology Group score greater than or equal to 2, 24.3 with brain metastases, 19.3 with liver metastases, and 25.7 with TP53 co-mutation. In total, 95% of patients had at least one high-risk factor. Prevalence of Eastern Cooperative Oncology Group greater than or equal to 2 was 17%, brain metastases 36%, liver metastases 15%, and TP53 co-mutation 63%. Risk of death was significantly higher in patients with high-risk factors (p ≤ 0.011 for all). In total, 58% of patients survived to 2 years, 18% to 5 years, and 33% did not receive second-line therapy.

CONCLUSION: Despite advances in tyrosine kinase inhibitor treatments, long-term survival of patients with advanced EGFRm NSCLC remains poor. Nearly all patients had risk factors for mortality and one-third did not receive second-line therapy.

PMID: 40320171 [Indexed for MEDLINE]

5. J Clin Oncol. 2025 Sep 20;43(27):2986-2997. doi: 10.1200/JCO-25-00056. Epub 2025 Jul 11.

Stereotactic Radiosurgery in Patients With Small Cell Lung Cancer and 1-10 Brain Metastases: A Multi-Institutional, Phase II, Prospective Clinical Trial.

PURPOSE: Stereotactic radiation (SRS/SRT) as opposed to whole-brain radiation (WBRT) represents the standard of care for patients with a limited number of brain metastases given the relatively favorable toxicity profile associated with stereotactic treatment. However, in patients with small cell lung cancer (SCLC), WBRT remains standard because of a lack of prospective data supporting SRS/SRT and concerns related to intracranial progression and neurologic death when WBRT is omitted. We conducted a single-arm, multicenter, phase II trial of SRS/SRT in patients with SCLC and 1-10 brain metastases to assess neurologic death rates relative to historical controls managed with WBRT (ClinicalTrials.gov identifier: NCT03391362).

METHODS: Patients were eligible if they had SCLC or an extrathoracic small cell primary and 1-10 brain metastases. Previous brain-directed radiation including prophylactic cranial irradiation was not permitted. Neurologic death was defined as marked, progressive, radiographic brain progression accompanied by corresponding neurologic symptomatology without systemic disease progression or systemic symptoms of a life-threatening nature. Close imaging-based surveillance of the brain post-SRS/SRT was used.

RESULTS: Between February 2018 and April 2023, 100 patients were enrolled. The median number of brain metastases was 2 (IQR, 1-4; range, 1-10). The median overall survival was 10.2 months; only 22% of patients required salvage WBRT. In total, 20 neurologic deaths were observed, relative to 64 non-neurologic deaths. The neurologic death rate at 1 year was 11.0% (95% CI, 5.8 to 18.1); the historical rate in patients managed with WBRT was 17.5%.

CONCLUSION: Our prospective, multi-institutional study demonstrated low rates of neurologic death when SRS/SRT as opposed to WBRT is used in patients with SCLC and 1-10 brain metastases who are surveilled closely post-treatment, supporting the utility of stereotactic approaches in this population.

PMID: 40644657 [Indexed for MEDLINE]

6. Nat Genet. 2025 Sep;57(9):2226-2237. doi: 10.1038/s41588-025-02307-x. Epub 2025 Sep 10.

DNA methylation cooperates with genomic alterations during non-small cell lung cancer evolution.

Aberrant DNA methylation has been described in nearly all human cancers, yet its interplay with genomic alterations during tumor evolution is poorly understood. To explore this, we performed reduced representation bisulfite sequencing on 217 tumor and matched normal regions from 59 patients with non-small cell lung cancer from the TRACERx study to deconvolve tumor methylation. We developed two metrics for integrative evolutionary analysis with DNA and RNA sequencing data. Intratumoral methylation distance quantifies intratumor DNA methylation heterogeneity. MR/MN classifies genes based on the rate of hypermethylation at regulatory (MR) versus nonregulatory (MN) CpGs to identify driver genes exhibiting recurrent functional hypermethylation. We identified DNA methylation-linked dosage compensation of essential genes co-amplified with neighboring oncogenes. We propose two complementary mechanisms that converge for copy number alteration-affected chromatin to undergo the epigenetic equivalent of an allosteric activity transition. Hypermethylated driver genes under positive selection may open avenues for therapeutic stratification of patients.

PMID: 40931149 [Indexed for MEDLINE]

7. J Thorac Oncol. 2025 Sep;20(9):1328-1335. doi: 10.1016/j.jtho.2025.04.016. Epub 2025 May 8.

Treatment Sequences in BRAF-V600-Mutated NSCLC: First-Line Targeted Therapy Versus First-Line (Chemo-) Immunotherapy.

BACKGROUND: Targeted treatment of patients with metastatic BRAF-V600-mutated NSCLC using BRAF/MEK-inhibitors is effective but limited by acquired resistance. Patients with BRAF-mutant NSCLC may derive long-lasting benefit from immune checkpoint inhibition with programmed death-1/programmed death-ligand 1 (PD-L1) antibodies (immuno-oncology [IO]). Although IO is the preferred first-line therapy in BRAF-mutated melanoma, the optimal treatment sequence in BRAF-mutated NSCLC is not defined.

METHODS: This retrospective study investigated the clinical outcome of patients with metastatic BRAF-V600-mutated NSCLC diagnosed in the German national Network Genomic Medicine Lung Cancer.

RESULTS: We identified 205 patients with BRAF-V600-mutated NSCLC; 175 patients received first-line therapy with dabrafenib/trametinib (DAB/TRM, 65.1%), IO alone (19.4%), or chemotherapy-IO (15.4%). Overall survival (OS) and time-to-treatment failure of first-line therapy was identical for patients receiving first-line DAB/TRM (median OS 28.0 months) or chemo/IO (27.8 months, hazard ratio [HR] 1.1, p = 0.68). Female patients had superior OS (HR 0.65, p = 0.049, confirmed in multivariate model), which was mainly driven by superior OS of female to that of male patients receiving first-line DAB/TRM (OS HR 0.53, p = 0.015). There was no sex difference in survival of patients receiving IO-based first-line treatment (OS HR 1.02). Surprisingly, high PD-L1 status (tumor proportion score ≥50%) was associated with shortened time-to-treatment failure in first-line treatment (HR 1.83, p = 0.002, confirmed in multivariate models adjusting for sex; OS with nonsignificant trend, HR 1.4), regardless of whether the first-line regimen was IO-based or targeted therapy.

CONCLUSIONS: Targeted or IO-based first-line treatment of BRAF-V600-mutated NSCLC has similar survival outcomes. Sex and PD-L1 status may support decision-making at the individual patient level.

PMID: 40345491 [Indexed for MEDLINE]

8. J Thorac Oncol. 2025 Oct;20(10):1441-1458. doi: 10.1016/j.jtho.2025.07.002. Epub 2025 Sep 8.

The International Association for the Study of Lung Cancer Staging Project: The Impact of Smoking Status on Lung Cancer Staging in the Ninth Edition of the TNM Classification.

INTRODUCTION: Cigarette smoking negatively affects lung cancer prognosis. Incorporating smoking history into stage-stratified survival analyses may improve prognostication.

METHODS: Using the International Association for the Study of Lung Cancer ninth edition NSCLC database, we evaluated the association between smoking status at diagnosis and overall survival (OS) using Kaplan-Meier plots and multivariate Cox proportional hazard regression models adjusted for age, region, sex, histologic type, performance status, and TNM stage. Subgroup analyses evaluated within- and between-stage survival according to smoking status. Recursive partitioning analysis evaluated the effect of smoking relative to anatomical staging factors.

RESULTS: Among 48,531 patients, 26%, 41%, and 34% currently, formerly, or never smoked, respectively; 75% had adenocarcinoma and 21%, squamous cell carcinoma. Compared with those who never smoked, those who currently (adjusted hazard ratio [aHR] = 1.39, 95% confidence interval [CI] [1.34-1.46], p < 0.0001) or formerly (aHR = 1.32, 95% CI: 1.27-1.36, p < 0.0001) smoked had worse OS. Current smoking was associated with worse OS (aHR = 1.05, 95% CI: 1.02-1.06] p = 0.005) compared with former smoking. These associations were consistent within each stage. In pair-wise comparisons, those who formerly or currently smoked had similar OS to patients in the next higher stage who never smoked. These associations remained consistent among patients from Asia, patients with adenocarcinoma, and both sexes. In recursive partitioning analysis, among patients with early stage (up to T3N1M0), smoking had greater prognostic impact than N0 versus N1 categories.

CONCLUSIONS: Smoking is an important prognostic factor and may be more impactful on prognosis than anatomical staging. Further exploration of combining smoking status with TNM classification for lung cancer is planned in the tenth edition International Association for the Study of Lung Cancer staging project.

PMID: 40920143 [Indexed for MEDLINE]

9. JAMA Intern Med. 2025 Sep 1;185(9):1102-1108. doi: 10.1001/ jamainternmed. 2025.2875.

Frequent Missed Opportunities for Earlier Diagnosis of Advanced-Stage Colorectal or Lung Cancer.

IMPORTANCE: Missed and delayed cancer diagnoses worsen patient outcomes. Overlooking cancer-related diagnostic signals may result in advanced-stage presentations.

OBJECTIVE: To develop and implement a digital quality measure of the proportion of advanced-stage cancer diagnoses in the US and assess the rate of missed diagnostic opportunities.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study used electronic health records and a cancer registry of patients with cancer diagnosed from 2016 to 2020 at 2 integrated health care systems, Department of Veterans Affairs (VA) health system and Geisinger Health System. Patients with incident colorectal cancer (CRC) or non-small cell lung cancer, with at least 1 primary care visit in the 2 years before cancer diagnosis, were included. A random sample of 100 advanced-stage cases per cancer type and health system was manually reviewed using a 2-year look-back period. Data were analyzed from January 27 to June 9, 2025.

MAIN OUTCOMES AND MEASURES: The primary outcome was a digital quality measure for advanced stage cancer and a descriptive analysis (by health system and cancer type) of the rate of missed opportunities in diagnosis, dates of investigation initiation and completion, and factors associated with missed opportunities.

RESULTS: There were 37 691 patients from the VA health system and 2914 patients from Geisinger with lung cancer, and there were 14 674 patients from the VA health system and 627 patients from Geisinger with CRC. For lung cancer, the advanced stage comprised 45.9% at the VA health system and 58.3% at Geisinger. Advanced CRC stage was 33.2% at the VA health system and 36.2% at Geisinger. Notably, 58.9% (95% CI, 48.6%-68.5%) of patients from the VA health system and 77.8% (95% CI, 68.6%-84.8%)of patients from Geisinger with advanced-stage lung cancer had missed opportunities in diagnosis. For CRC, 66.3% (95% CI, 56.3%-75.0%) of patients at the VA health system and 69.7% (95% CI, 60.0%-77.9%) of patients at Geisinger had missed opportunities. Patients with missed opportunities had notable delays in diagnosis (eg, the median time from diagnostic signal to workup completion ranged from 1 to 20 months). Lack of screening was associated with 6.1% to 16.7% of late-stage cancers across health systems and cancer types. For lung cancer, missed opportunities were associated with problems in patient-clinician encounters and performing and interpreting diagnostic tests. For CRC, missed opportunities were primarily associated with patient-related factors and problems performing and interpreting diagnostic tests.

CONCLUSIONS AND RELEVANCE: This study found high rates of missed diagnostic opportunities among patients with advanced-stage cancer. By using advanced stage as a digital quality measure, health systems, payers, and other stakeholders can better identify care gaps and track initiatives to reduce preventable delays in cancer diagnosis.

PMID: 40690229 [Indexed for MEDLINE]

10. J Thorac Oncol. 2025 Sep;20(9):1257-1267. doi: 10.1016/j.jtho.2025.05.009. Epub 2025 May 14.

Risk-Based Lung Cancer Screening in Clinical Practice.

INTRODUCTION: Current U.S. lung cancer screening guidelines use only age and smoking history; however, individual risk calculators may better stratify risk.

METHODS: In a referred cohort design, we implemented a multisite lung cancer screening program across four states. We screened patients who qualified by either the USPSTF2013 criteria or a PLCOm2012 risk of greater than or equal to 1.34%. Invasive procedures were abstracted retrospectively. We compared the incidence and prevalence of lung cancer among patients who qualified by only USPSTF2013 or PLCOm2012 and along the continuum of prospective lung cancer risk using PLCOm2012.

RESULTS: Of 2471 screened patients, 114 had lung cancer. Furthermore, 84% of all patients and 91% of patients who were diagnosed with having cancer qualified by both criteria. Prevalence of lung cancers were over 7 times higher in the 10% of the cohort with the highest prospective risk than the lowest risk 10%. Incidence of cancers were higher among patients who qualified only by PLCOm2012 (3.6 per 1000 person-years) compared with patients who qualified only by USPSTF2013 (0 per 1000 person-years). Of screen-detected NSCLC, 74% was stage I or II. Three (4.5%) surgical resections were performed for screen-identified nodules which proved to be benign. Overall, 106 patients (4.3%) underwent an invasive intervention due to screening.

CONCLUSIONS: Most patients qualified for lung cancer screening by both UPSTSF2013 and PLCOm2012 criteria. Incidence cancers were higher among patients who qualified by PLCOm2012 but not USPSTF2013 criteria. Prevalence and incidence cancer identification increased with prospective risk. Invasive procedures and resections for benign disease were relatively low.

PMID: 40379047 [Indexed for MEDLINE]

11. Lancet Oncol. 2025 Oct;26(10):1300-1311. doi: 10.1016/S1470-2045(25)00480-2. Epub 2025 Sep 8.

Safety and activity of tarlatamab in combination with a PD-L1 inhibitor as first-line maintenance therapy after chemo-immunotherapy in patients with extensive-stage small-cell lung cancer (DeLLphi-303): a multicentre, non-randomised, phase 1b study.

BACKGROUND: Tarlatamab is a delta-like ligand 3 (DLL3)-directed bispecific T-cell engager immunotherapy that has improved survival in patients with previously treated small-cell lung cancer (SCLC). We evaluated the safety and activity of tarlatamab in combination with atezolizumab or durvalumab as first-line maintenance therapy in patients with extensive-stage (ES)-SCLC.

METHODS: In this multicentre, non-randomised, phase 1b study, patients aged 18 years and older, with Eastern Cooperative Oncology Group performance status of 0-1 and without disease progression after four to six cycles of platinum-etoposide chemotherapy plus a programmed cell death ligand 1 (PD-L1) inhibitor (if available), received tarlatamab 10 mg intravenously once every 2 weeks, after an initial tarlatamab 1 mg dose, with atezolizumab intravenously (1680 mg once every 4 weeks) or durvalumab intravenously (1500 mg once every 4 weeks) as maintenance until disease progression. Patients were enrolled from 30 centres in 13 countries. The primary objective was to evaluate safety and to determine the recommended phase 2 dose or maximum tolerated dose of tarlatamab in combination with a PD-L1 inhibitor through assessment of dose-limiting toxicities, treatment-emergent adverse events, treatment-related adverse events, and changes in vital signs, electrocardiograms, and clinical laboratory tests. All patients who received at least one dose of tarlatamab were included in the analyses. Because overall survival data were immature at the primary analysis, in this Article, we report a non-specified interim analysis to provide an updated examination of overall survival and longer-term safety. This study is registered with ClinicalTrials.gov, NCT05361395; the EU Clinical Trials registry, 2021-005462-17; and EudraCT, 2024-511021-58.

FINDINGS: Between Aug 31, 2022, and Jan 30, 2024, 88 patients received tarlatamab with atezolizumab or durvalumab after standard-of-care first-line chemo-immunotherapy. The median time from start of standard-of-care first-line chemo-immunotherapy to start of tarlatamab maintenance was 3·6 months (IQR 3·2-4·3). The median follow-up from the start of maintenance was 18·4 months (15·2-23·0) and the median exposure to tarlatamab was 35 weeks (8-75). The most common grade 3-4 adverse events were hyponatraemia (nine [10%] of 88 patients), anaemia (seven [8%] of 88 patients), and neutropenia (six [7%] of 88 patients). Serious adverse events occurred in 50 (57%) of 88 patients. The most common serious adverse events were cytokine release syndrome (21 [24%] of 88 patients), pyrexia (six [7%] of 88 patients), immune effector cell-associated neurotoxicity syndrome (four [5%] of 88 patients), and pneumonia (four [5%] of 88 patients). There were no deaths due to treatment-related adverse events. Median overall

survival was 25·3 months (95% CI 20·3-not estimable).

INTERPRETATION: Tarlatamab plus a PD-L1 inhibitor as maintenance after first-line chemo-immunotherapy showed a manageable safety profile with promising anticancer activity, supporting the ongoing phase 3 trial (NCT06211036).

FUNDING: Amgen.

PMID: 40934933 [Indexed for MEDLINE]

12. ACS Nano. 2025 Sep 30;19(38):34097-34109. doi: 10.1021/acsnano.5c10202. Epub 2025 Sep 19.

Efficiently Reversing Immunotherapy Resistance in Lung Cancer by an Inhalable 2D Molybdenum Disulfide T Cell Hyperactivation Platform.

Immunotherapy has revolutionized the treatment of lung cancer, but many patients still experience inadequate responses or develop resistance, emphasizing the urgent need for more effective therapeutic strategies. Here, we present the design of an inhalable flexible 2D molybdenum disulfide (MoS2) T cell hyperactivation platform (2D MoS2-THP) based on anchoring therapeutic proteins onto the surface of metallic molybdenum disulfide. By loading IL2 and anti-PD1 proteins onto a flexible metallic molybdenum disulfide crystalline form, we achieved effective T cell hyperactivation. Our platform leverages the synergistic effects of anti-PD1 and IL2 to remodel exhausted T cells while simultaneously overcoming regulatory T cell (Treg)-mediated immunosuppression, resulting in a superior T cell activation. Additionally, 2D metallic MoS2 not only serves as a carrier for delivering therapeutic proteins but also plays a pivotal functional role by inducing cuproptosis in Tregs through disruption of mitochondrial function and elevation of oxidative stress, thereby clearing a key barrier to effector T cell activation. The inhalation administration route further improves intratumoral accumulation, enhances therapeutic potency, and minimizes systemic immune-related side effects. Overall, this inhalable "three-in-one" immunotherapy platform achieves robust T cell hyperactivation with reduced systemic toxicity, efficiently removing immunosuppressive barriers, and remodeling the tumor immune microenvironment to overcome cancer immunotherapy resistance.

PMID: 40970395 [Indexed for MEDLINE]

13. Signal Transduct Target Ther. 2025 Sep 10;10(1):290. doi: 10.1038/s41392-025-02378-6.

Characterization of the extrinsic and intrinsic signatures and therapeutic vulnerability of small cell lung cancers.

Small-cell lung cancer (SCLC), an aggressive neuroendocrine tumor strongly associated with exposure to tobacco carcinogens, is characterized by early dissemination and dismal prognosis with a five-year overall survival of less than 7%. High-frequency gain-of-function mutations in oncogenes are rarely reported, and intratumor heterogeneity (ITH) remains to be determined in SCLC. Here, via multiomics analyses of 314 SCLCs, we found that the ASCL1+/MKI67+ and ASCL1+/CRIP2+ clusters accounted for 74.38% of the 190,313 SCLC cancer cells from 39 patients, with the ASCL1+SOX1+ stem-like cell cluster across SCLC subtypes. The major histocompatibility complex (MHC) class I molecules were expressed at low levels in six and high levels in five cancer cell clusters and were inversely associated with the KI67 expression level. Abnormal splicing of mRNAs was a feature of SCLC, with focal adhesion kinase (FAK) splicing variants identified in 119 (77.3%) of 154 patients. FAK variants exhibited elevated kinase activity, were associated with the worst prognosis, and were sensitive to FAK inhibitors in patient-derived organoids and xenograft models. Eleven high-frequency mutations were identified in addition to TP53 and RB1, and smoking status and tumor stage did not affect microbiota variance in SCLC. Taken together, our data further revealed the complicated ITH and discovered that FAK splicing variants represent high-frequency gain-of-function alterations in oncogene in SCLC and potential therapeutic targets for this recalcitrant cancer.

PMID: 40925909 [Indexed for MEDLINE]

14. Nat Rev Clin Oncol. 2025 Sep;22(9):640-666. doi: 10.1038/s41571-025-01051-9. Epub 2025 Jul 18.

Evolving roles of MET as a therapeutic target in NSCLC and beyond.

Alterations in the proto-oncogene MET are associated with tumour development, invasion and metastasis across various solid cancers. Therapeutically actionable MET alterations include MET exon 14 skipping (METex14) mutations, MET amplification and/or MET overexpression and MET fusions, which vary in incidence by tumour type. In contrast to rare de novo MET alterations, acquired MET amplification and/or MET overexpression is a relatively common phenomenon that is associated with distinct clinical implications and responses to treatment. METex14 is a distinct oncogenic driver mutation in non-small-cell lung cancer (NSCLC). To date, the MET tyrosine-kinase inhibitors (TKIs) capmatinib, tepotinib and savolitinib have been approved for the treatment of advanced-stage METex14-mutant NSCLC. However, the treatment paradigms for MET-altered solid tumours are rapidly evolving to include diverse MET-targeted agents. Emerging data support the role of MET TKIs, anti-MET antibodies and MET-directed antibody-drug conjugates (ADCs) as monotherapy or in combination with other therapies for NSCLC or other tumour types with MET amplification and/or overexpression. Indeed, in May 2025, the MET-directed ADC telisotuzumab vedotin was approved by the FDA for patients with previously treated advanced-stage nonsquamous NSCLC overexpressing MET (≥50% of tumour cells with 3+ staining on immunohistochemistry). Understanding the unique MET-related adverse events will be crucial when incorporating these agents into daily clinical practice. In this Review, we highlight the rationale for targeting MET alterations across various solid tumour types and provide a summary of the clinical efficacy and toxicity profiles of the approved and emerging MET-targeted TKIs, monoclonal or bispecific antibodies and ADCs.

PMID: 40681868 [Indexed for MEDLINE]

15. Signal Transduct Target Ther. 2025 Sep 29;10(1):317. doi: 10.1038/s41392-025-02408-3.

Consolidative nivolumab versus observation in unresectable stage III non-small cell lung cancer patients following neoadjuvant nivolumab plus chemotherapy and concurrent chemoradiotherapy (CA209-7AL): a randomized clinical trial.

CA209-7AL is a randomized, multicenter, phase 2 trial evaluating the efficacy and safety of consolidative nivolumab (NIVO) versus observation following neoadjuvant NIVO plus chemotherapy and concurrent chemoradiotherapy (CCRT) for unresectable stage III NSCLC. Patients received 2 cycles of neoadjuvant chemo-NIVO therapy (docetaxel + cisplatin + NIVO) and CCRT (total dose 54-64 Gy). Post-CCRT, eligible patients were randomized 1:1 to receive consolidative NIVO (360 mg every 3 weeks for up to 12 months) or observation. The primary endpoint was progression-free survival (PFS) from randomization. Between December 3rd, 2019, and August 18th, 2023, 264 patients were enrolled, and 172 were randomized to NIVO consolidation (n = 86) or observation (n = 86). With a median follow-up of 22·8 months, NIVO consolidation resulted in significantly longer PFS than did observation (median not reached vs. 12.2 months [95% CI 10.2-20.8]; stratified hazard ratio 0·49 [95% CI 0.30-0.79], p = 0.003). NIVO consolidation also demonstrated superior PFS compared with a parallel real-world study, where patients received CCRT followed by consolidative immunotherapy (median PFS: 15.7 months [95% CI 11.9-NA]). Grade 3 or 4 toxicities occurred in 9.3% of patients in the consolidation group versus 4·6% in the observation group, with similar rates of pneumonitis (2.3% each) and proximal bronchial tree toxicity (3.5% vs. 2.3%). Treatment-related death occurred in 1 (1.2%) patient in the consolidation group because of pneumonitis. Patients with a high TMB had a longer PFS with consolidation (NR vs. 15.2 months, p = 0.042). Consolidative NIVO following neoadjuvant NIVO plus chemotherapy and CCRT demonstrated effectiveness and tolerability for patients with unresectable stage III NSCLC (ClinicalTrials.gov NCT04085250).

PMID: 41016926 [Indexed for MEDLINE]

16. Nat Med. 2025 Sep;31(9):3002-3010. doi: 10.1038/s41591-025-03780-x. Epub 2025 Jul 9.

Real-world deployment of a fine-tuned pathology foundation model for lung cancer biomarker detection.

Artificial intelligence models using digital histopathology slides stained with hematoxylin and eosin offer promising, tissue-preserving diagnostic tools for patients with cancer. Despite their advantages, their clinical utility in real-world settings remains unproven. Assessing EGFR mutations in lung adenocarcinoma demands rapid, accurate and cost-effective tests that preserve tissue for genomic sequencing. PCR-based assays provide rapid results but with reduced accuracy compared with next-generation sequencing and require additional tissue. Computational biomarkers leveraging modern foundation models can address these limitations. Here we assembled a large international clinical dataset of digital lung adenocarcinoma slides (N = 8,461) to develop a computational EGFR biomarker. Our model fine-tunes an open-source foundation model, improving task-specific performance with out-of-center generalization and clinical-grade accuracy on primary and metastatic specimens (mean area under the curve: internal 0.847, external 0.870). To evaluate real-world clinical translation, we conducted a prospective silent trial of the biomarker on primary samples, achieving an area under the curve of 0.890. The artificial-intelligence-assisted workflow reduced the number of rapid molecular tests needed by up to 43% while maintaining the current clinical standard performance. Our retrospective and prospective analyses demonstrate the real-world clinical utility of a computational pathology biomarker.

PMID: 40634781 [Indexed for MEDLINE]

17. J Am Chem Soc. 2025 Oct 8;147(40):36657-36668. doi: 10.1021/jacs.5c11862. Epub 2025 Sep 7.

Mode-Specific Coherent Interference of Vibrational Sum-Frequency Generation Imaging: An Approach to Differentiate Lung Tumors through Collagen Interfibrillar Distances.

Chemical imaging holds great promise for chemical, materials, and biological applications. However, its contrast often relies on subtle spectral differences arising from molecular-level changes. Here, we introduce label-free chemical imaging based on bond-specific coherent interference, which is highly sensitive to nanoscopic structural variations in collagen fibers. We demonstrated this idea using vibrational sum-frequency generation (VSFG) microscopy to identify lung tumors by detecting collagen I structural remodeling. Hyperspectral VSFG images reveal dramatic differences in the NH and CHx stretch regions between metastatic and tumor-free lung tissues. Based on these differences, key spectral signatures, such as the intensity ratio of NHS/CH2, Ss and CHS/CH2,Ss modes, were established to reliably distinguish metastatic tumor and tumor-free tissues with high fidelity. Theoretical modeling based on structural knowledge from Electron Microscopy indicates that distinctive interferences between VSFG vibrational modes make the intensity ratio directly related to interfibrillar distances at the 20-50 nm level. These findings suggest that collagen fibrils are more densely packed in tumors, corroborating the enhanced stiffness observed in tumor tissues. This result establishes an interference-based imaging mechanism that enhances chemical contrast and enables nanoscale structural readouts without labels. This method not only preserves sample integrity but also provides a powerful platform for fundamental biophysical studies and holds strong potential for future applications in oncology and pathology.

PMID: 40916209 [Indexed for MEDLINE]

18. Mil Med Res. 2025 Sep 23;12(1):61. doi: 10.1186/s40779-025-00649-5.

Are metformin-based combination approaches beneficial for non-small cell lung cancer: evidence from experimental and clinical studies.

Despite having multiple treatment options, the overall outcomes, including the survival rates of non-small cell lung cancer (NSCLC) patients, remain relatively low, indicating the need to explore new approaches to achieve improved therapeutic responses. To that end, repurposed drugs such as metformin have been evaluated against many cancer types, including NSCLC. Metformin, a widely used oral hypoglycemic drug for type 2 diabetes, exhibits anticancer properties and synergy with several standards of care agents. In this review, we provide a comprehensive overview of the role and anticancer mechanisms of metformin-based combination approaches for the treatment of NSCLC. We logically discussed the experimental evidence from the in vitro and in vivo studies utilizing metformin alone, and then its combination with chemotherapeutic agents, targeted therapy, and immunotherapy. We also present clinical trials that underscore the beneficial and adverse outcomes of metformin use in combination with targeted therapy and chemotherapeutic agents, and emphasize the limitations and challenges for the treatment of diabetic and non-diabetic NSCLC patients. It appears that, regardless of the diverse anticancer mechanisms of this biguanide, the benefits may be confined to a specific patient subgroup, which opens new avenues to be explored for NSCLC treatment.

PMID: 40983975 [Indexed for MEDLINE]

19. Drug Resist Updat. 2025 Sep;82:101266. doi: 10.1016/j.drup.2025.101266. Epub 2025 Jun 9.

Molecular mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer.

Tyrosine kinase inhibitors (TKIs) have revolutionized the management of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Despite the initially favorable outcomes, these patients inevitably acquire resistance to EGFR-TKIs. The molecular mechanism of the acquired resistance is highly complex and heterogeneous, and can be generalized as three categories, including EGFR pathway reactivation (re-engagement of EGFR downstream), EGFR pathway bypass (adoption of a parallel pathway to re-engage the downstream transcriptional oncogenic output of the original EGFR), and EGFR pathway indifference (acquirement of a cellular state alternate to the original EGFR-driven output). This review summarizes the recent progress on the identification and understanding of the acquired resistance mechanisms to EGFR-TKIs in patients with NSCLC. The potential strategies to delay or overcome the acquired resistance are also discussed.

PMID: 40505315 [Indexed for MEDLINE]

20. Drug Resist Updat. 2025 Sep;82:101272. doi: 10.1016/j.drup.2025.101272. Epub 2025 Jun 30.

Metabolic reprogramming of tumor-associated macrophages via adenosine-A(2A)R signaling drives cross-resistance in non-small cell lung cancer.

Immunosuppression within the tumor microenvironment (TME) is frequently associated with chemoresistance. However, the mechanisms by which chemoresistance promotes immune evasion and impairs subsequent immunotherapy remain poorly understood, underscoring the urgent need for novel therapeutic strategies to counteract these effects. In this study, we observed that tumors exhibit cross-resistance to immunotherapy following chemoresistance in a non-small cell lung cancer (NSCLC) mouse model. The aberrant accumulation of tumor-associated macrophages (TAMs) and extracellular adenosine (Ado) were identified as mediators of immunosuppression, fostering cross-resistance to immunotherapy in the context of chemoresistance. Mechanistically, selective activation of the Ado/A2AR signaling pathway induced metabolic reprogramming of TAMs, thereby creating an immunosuppressive niche in cross-resistant NSCLC. Based on these findings, we designed a novel selective A2AR inhibitor DL082 and explored its therapeutic potential for treating cross-resistant NSCLC. The combination of DL082 with an anti-PD-L1 antibody significantly enhanced immune activation and inhibited tumor progression in cross-resistant NSCLC. These findings elucidate the specific mechanisms underlying cross-resistance between chemotherapy and immunotherapy in NSCLC and propose targeting the Ado-TAM axis as a potential strategy for overcoming resistance in NSCLC therapy.

PMID: 40618433 [Indexed for MEDLINE]

21. J Clin Oncol. 2025 Sep 20;43(27):3021-3031. doi: 10.1200/JCO-25-00363. Epub 2025 Jul 24.

Phase I Dose-Escalation Results for the Delta-Like Ligand 3/CD3 IgG-Like T-Cell Engager Obrixtamig (BI 764532) in Patients With Delta-Like Ligand 3+ Small Cell Lung Cancer or Neuroendocrine Carcinomas.

PURPOSE: We report phase I results for obrixtamig (BI 764532), a delta-like ligand 3 (DLL3)/CD3 IgG-like T-cell engager, in patients with previously treated DLL3-positive small cell lung cancer (SCLC), extrapulmonary neuroendocrine carcinomas (epNECs), or large cell neuroendocrine carcinoma of the lung (LCNEC-L).

METHODS: Patients received escalating intravenous obrixtamig doses using four regimens: a fixed dose once every 3 weeks (A); a fixed dose once weekly (B1); a step-up dose once weekly for two weeks and target dose once weekly (B2); and a step-up dose once weekly for 3 weeks, target dose once weekly for 3 weeks, and once every 3 weeks thereafter (B3). The primary objective was maximum tolerated dose (MTD). Secondary objectives included safety, pharmacokinetics, and tumor response (RECIST v1.1).

RESULTS: As of February 21, 2024, 168 patients received obrixtamig, 72% received ≥2 lines of previous anticancer therapy, and 51% received previous anti-PD-1/PD-L1 therapy. Seven dose-limiting toxicities occurred during MTD evaluation (Regimen A, n = 1; Regimen B2, n = 6). MTD was not reached. The most common treatment-related adverse event was cytokine release syndrome (any grade: 57%; grade ≥3: 3%); most cases occurred early and were reversible. Across all doses, regimens, and tumor types, the overall response rate (ORR) was 23% (95% CI, 17.4% to 30.2%), the median duration of response (DoR) was 8.5 months (95% CI, 6.2 to not reached), and the 6-month DoR rate was 70% (95% CI, 53% to 88%). All patients in Regimens B2/B3 received the minimum effective dose (≥90 μg/kg once weekly or once every 3 weeks), achieving an ORR of 28% (95% CI, 20.7% to 35.9%). With Regimens B2/B3, ORRs were 21% (95% CI, 12.9% to 33.1%), 27% (95% CI, 17.4% to 39.6%), and 70% (95% CI, 39.7% to 89.2%) for SCLC, epNECs, and LCNEC-L, respectively.

CONCLUSION: The demonstrated tolerability and efficacy of obrixtamig regimens, administered as step-up followed by target doses of 90-1,080 μg/kg (once weekly or once every 3 weeks), in patients with heavily pretreated DLL3-positive tumors support further exploration in SCLC, epNEC, and LCNEC-L.

PMID: 40706016 [Indexed for MEDLINE]

22. Cancer Res. 2025 Sep 15;85(18):3518-3539. doi: 10.1158/0008-5472.CAN-25-1464.

CRISPR-Drug Combinatorial Screening Identifies Effective Combination Treatments for MTAP-Deleted Cancer.

Cyclin-dependent kinase inhibitor 2A (CDKN2A)/methylthioadenosine phosphorylase (MTAP) codeletion occurs frequently in non-small cell lung cancer and other solid tumors, including glioblastoma and pancreatic ductal adenocarcinoma. Lung cancer remains the leading cause of cancer-related mortality, and fewer than 15% of patients with glioblastoma or pancreatic cancer survive 5 years, underscoring the need for more effective therapies. Protein arginine methyltransferase 5 (PRMT5) is a synthetic-lethal dependency in MTAP-null tumors and an attractive therapeutic target for CDKN2A/MTAP-deleted cancers. A new revolutionary class of inhibitors, referred to as methylthioadenosine (MTA)-cooperative PRMT5 inhibitors (PRMT5i), has shown promising results in ongoing early-phase clinical trials. Nonetheless, effective cancer treatment typically requires therapeutic combinations to improve response rates and defeat emergent resistant clones. Thus, we sought to determine whether perturbation of other pathways could improve the efficacy of MTA-cooperative PRMT5is (MTAC-PRMT5i). Using a paralog and single gene targeting CRISPR library, we screened MTAP-deleted cancers in the presence or absence of MTAC-PRMT5is. Loss of several genes sensitized cells to PRMT5 inhibition, including members of the MAPK pathway. Chemical inhibition of MAPK pathway members using KRAS, MEK, ERK, and RAF inhibitors synergized with PRMT5 inhibition to kill CDKN2A/MTAP-null, RAS-active tumors. Furthermore, MTAC-PRMT5is combined with either KRAS or RAF inhibitors led to complete responses in vivo, emphasizing the potential benefit for patients. Lastly, cell lines resistant to KRAS inhibition were not resistant to MTAC-PRMT5is and vice versa, suggesting noncross-reactive mechanisms of resistance. Overall, this study identifies therapeutic combinations with MTAC-PRMT5is that may offer significant benefits to patients.

SIGNIFICANCE: Combining PRMT5 and MAPK pathway inhibitors leads to complete, durable responses in lung cancer models, providing an effective therapeutic strategy for the 4-5% of cancer patients harboring CDKN2A/MTAP deletion and MAPK alterations. See related article by Drizyte-Miller et al., p. 3540.

PMID: 40694540 [Indexed for MEDLINE]

23. ACS Nano. 2025 Sep 16;19(36):32674-32692. doi: 10.1021/acsnano.5c10375. Epub 2025 Aug 29.

Anti-Triggering Receptor Expressed on Myeloid Cells 2-Conjugated Nanovesicles Loaded Vadimezan Reprogram Tumor-Associated Macrophages to Combat Recurrent Lung Cancer.

Postoperative lung recurrent cancer exhibited characteristics of an immunosuppressive tumor microenvironment (TME) and low immunogenicity, hindering the therapeutic efficacy of monotherapy, which requires a combination of several treatment modules. Strategies that activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and repolarize tumor-associated macrophages (TAMs) toward the antitumoral M1-like phenotype to reverse the TME are rarely reported. The triggering receptor expressed on myeloid cells 2 (TREM2) is a promising therapeutic target, owing to its critical role in enhancing tumor immunogenicity within the TME. This work describes the design of an anti-TREM2-modified FePt-based biomimetic nanovesicle (FP/Vad@CC-aT2) for the delivery of STING agonist Vadimezan (Vad), which increases tumor immunogenicity to sensitize recurrent lung tumors to immunotherapy. FePt not only acted as a photoacoustic/magnetic resonance imaging contrast agent but also enhanced ferroptosis by catalyzing a Fenton reaction with reactive oxygen species production under X-rays. Simultaneously, anti-TREM2 effectively repolarized TAMs into M1-type macrophages, thereby reversing immunosuppressive TME together with a Vad-activated STING pathway, which promoted the maturation of dendritic cells and enhanced the infiltration of cytotoxic T lymphocytes. Therefore, this study highlighted the FP/Vad@CC-aT2-mediated cascade immune response for suppressing lung cancer recurrence that involves ferroptosis potentiation, TAM repolarization, and STING pathway activation.

PMID: 40879116 [Indexed for MEDLINE]

24. J Thorac Oncol. 2025 Oct;20(10):1423-1440. doi: 10.1016/j.jtho.2025.06.025. Epub 2025 Sep 8.

The International Association for the Study of Lung Cancer Staging Project: The Impact of Common Molecular Alterations on Overall Survival in NSCLC in Initial Analyses of the IASLC Ninth Edition Staging Database.

INTRODUCTION: TNM staging systems create prognostic categories by anatomic extent of disease. Whether therapeutically important molecular alterations in NSCLC augment the prognostic information of TNM staging is unclear. To study this, we analyzed molecular data from the ninth edition of the lung cancer staging system.

METHODS: Eligible patients were diagnosed between 2011 and 2019. Analysis was restricted to the following three genes for reliable statistical analyses: EGFR mutations (L858R, exon 19 deletion), ALK fusions, and KRAS mutations (codons 12, 13, or 61). Overall survival (OS) was calculated by the Kaplan-Meier method, and differences in OS were assessed by Cox proportional hazard regression models.

RESULTS: A total of 20,580 patients had tumors with molecular data (EGFR = 16,497, ALK = 11,546, KRAS = 2909 patients). EGFR mutations were found in 5428 (32.9%), ALK fusions in 723 (6.3%), and KRAS mutations in 890 (30.6%) tumors. OS was significantly better across all TNM stages among patients with EGFR-mutated tumors and patients with stage IV ALK fusion-positive tumors, whereas patients with stage I KRAS-mutated tumors had significantly worse OS. Multivariable analyses confirmed the OS associations with EGFR-mutated tumors (stage I hazard ratio [HR] = 0.79, stage II HR = 0.71, stage III HR = 0.67, stage IV HR = 0.49) and stage IV ALK fusion-positive tumors (HR = 0.56).

CONCLUSIONS: Patients with EGFR-mutated tumors had improved OS regardless of stage, whereas an OS benefit was found in stage IV patients with ALK-positive tumors. In the tenth edition, we will evaluate the systematic integration of molecular biomarkers and treatment to refine prognostication for molecular subsets of NSCLC.

PMID: 40920144 [Indexed for MEDLINE]

25. J Thorac Oncol. 2025 Oct;20(10):1517-1530. doi: 10.1016/j.jtho.2025.07.117. Epub 2025 Sep 9.

Enhanced Versus Standard Dermatologic Management With Amivantamab-Lazertinib in EGFR-Mutated Advanced NSCLC: The COCOON Global Randomized Controlled Trial.

INTRODUCTION: Amivantamab plus lazertinib significantly improved progression-free and overall survival versus osimertinib in patients with previously untreated, EGFR-mutant advanced NSCLC. EGFR-targeted therapies are associated with dermatologic adverse events (AEs), which can affect quality of life (QoL). COCOON was conducted to assess prophylactic management and improve treatment experience.

METHODS: In the phase 2 COCOON study (NCT06120140), participants with previously untreated, EGFR-mutant, locally advanced or metastatic NSCLC received intravenous amivantamab plus oral lazertinib and were randomized 1:1 to enhanced dermatologic management (COCOON DM) or standard of care (SoC DM) per local guidelines. COCOON DM included oral doxycycline or minocycline (100 mg twice daily; weeks 1-12), clindamycin 1% (on scalp daily; weeks 13-52), chlorhexidine 4% (on fingernails and toenails daily), and ceramide-based moisturizer (on body and face at least daily). Primary end point was incidence of grade 2 or higher dermatologic AEs of interest (DAEIs) by week 12.

RESULTS: In total, 201 participants were randomized (99 to COCOON DM and 102 to SoC DM). At a median follow-up of 7.1 months, COCOON DM demonstrated significant reduction in the primary end point versus SoC DM (42% versus 75%; OR, 0.24; 95% confidence interval, 0.13-0.45; p < 0.0001). By week 12, the largest benefit with COCOON DM was observed in DAEIs involving the face and body (excludes paronychia; 26% versus 60%; p < 0.0001) and DAEIs involving the scalp (10% versus 26%; p = 0.0049). This benefit was maintained at 6 months, with significant reductions of DAEIs involving face, body, and scalp (excluding paronychia). Patient-reported outcomes favored COCOON DM, indicating reduced impact of dermatologic symptoms on QoL.

CONCLUSION: An uncomplicated, widely available, prophylactic regimen (COCOON DM) reduced the incidence of DAEIs with amivantamab-lazertinib and the impact of symptoms on QoL.

PMID: 40923969 [Indexed for MEDLINE]

26. J Clin Oncol. 2025 Oct 10;43(29):3198-3208. doi: 10.1200/JCO-25-00788. Epub 2025 Sep 9.

Phase II Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non-Small Cell Lung Cancer With Epidermal Growth Factor Receptor Exon 20 Insertion Mutations (WU-KONG1B).

PURPOSE: WU-KONG1B (ClinicalTrials.gov identifier: NCT03974022) is a multinational phase II, dose-randomized study to assess the antitumor efficacy of sunvozertinib in pretreated patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations (exon20ins).

METHODS: Eligible patients with advanced-stage EGFR exon20ins NSCLC were randomly assigned by 1:1 ratio to receive sunvozertinib 200 mg or 300 mg once daily (200 and 300 mg-rand cohorts). After predefined interim analysis, additional patients were enrolled and treated with the 300 mg dose once daily. The primary end point was blinded independent review committee (IRC)-assessed confirmed objective response rate (cORR), and the key secondary end point was duration of response (DoR).

RESULTS: Among 85, 89, and 107 efficacy-evaluable patients in 200 mg-rand, 300 mg-rand, and 300 mg-all (including randomly assigned and nonrandomized patients) cohorts, the cORRs were 45.9% (97.5% CI, 33.6% to 58.5%), 47.2% (97.5% CI, 35.1% to 59.5%), and 45.8% (97.5% CI, 34.8% to 57.0%), respectively, per IRC assessment. The predefined null hypothesis was rejected with statistical significance (P < .0001). Comparing 300 and 200 mg-rand cohorts, higher cORRs were observed in patients with baseline brain metastasis (52.4% v 28.6%) and previous amivantamab treatment (41.7% v 25%), as well as longer DoR (13.8 v 11.1 months). At 200 and 300 mg once daily, the most common treatment-related adverse events with grade ≥3 included diarrhea (2.2% v 18%), blood creatine phosphokinase increased (6.6% v 12.6%), and anemia (4.4% v 6.3%).

CONCLUSION: Sunvozertinib is efficacious at both 200 and 300 mg once daily in treating platinum-pretreated patients with advanced EGFR exon20ins NSCLC. The treatment-related adverse events of sunvozertinib were consistent with an EGFR tyrosine kinase inhibitor, with a more favorable safety profile at 200 mg than 300 mg once daily.

PMID: 40923280 [Indexed for MEDLINE]

27. ACS Nano. 2025 Oct 7;19(39):34708-34723. doi: 10.1021/acsnano.5c09056. Epub 2025 Sep 25.

Exploring the Potentials of Silver Nanoparticles in Overcoming Cisplatin Resistance in Lung Adenocarcinoma: Insights from Proteomic and Xenograft Mice Studies.

Silver nanoparticles (AgNPs) have shown great potential as therapeutic agents due to their ability to cause apoptotic cell death in cancer cells. However, little knowledge is available regarding the underlying action mechanisms of AgNPs toward multidrug-resistant cancer cells. Herein, we employed quantitative proteomics to investigate the cytotoxic mechanisms of AgNPs and their potential anticancer properties on both cisplatin-sensitive (A549 cells) and -resistant (A549/DDP cells) human lung adenocarcinoma using quantitative proteomics and mice xenograft model approaches. We first performed cytotoxicity tests and found that AgNPs exerted similar cytotoxic effects on A549 and A549/DDP cells. At the proteome level, A549 and A549/DDP cells responded to AgNPs distinctively and similarly by causing cell apoptosis via upregulating RNA metabolism, suppressing the VEGF signaling pathway, repressing p53-mediated pathways, promoting cell cycle arrest, etc. Additionally, we found that AgNPs induced ROS generation and disrupted mitochondrial function and respiration in the A549 and A549/DDP cells. Lastly, animal studies using established mice xenograft models administered with AgNPs showed that AgNPs exhibit similar antitumoral effects on both A549 and A549/DDP-bearing mice. Overall, our investigations showed that AgNPs could effectively induce cell death in lung adenocarcinoma regardless of their sensitivities to cisplatin, suggesting that AgNPs could be potentially used in biomedical aspects as anticancer agents in alleviating the problem of acquired drug resistance in chemotherapy.

PMID: 40999704 [Indexed for MEDLINE]

28. Nat Commun. 2025 Sep 17;16(1):8301. doi: 10.1038/s41467-025-63957-3.

Learning the cellular origins across cancers using single-cell chromatin landscapes.

Deciphering the pre-malignant cell of origin (COO) of different cancers is critical for understanding tumor development and improving diagnostic and therapeutic strategies in oncology. Prior work demonstrates that somatic mutations preferentially accumulate in closed chromatin regions of a cancer's COO. Leveraging this information, we combine 3,669 whole genome sequencing patient samples, 559 single-cell chromatin accessibility cellular profiles, and machine learning to predict the COO of 37 cancer subtypes with high robustness and accuracy, confirming both the known anatomical and cellular origins of numerous cancers, often at cell subset resolution. Importantly, our data-driven approach predicts a basal COO for most small cell lung cancers and a neuroendocrine COO for rare atypical cases. Our study also highlights distinct cellular trajectories during cancer development of different histological subtypes and uncovers an intermediate metaplastic state during tumorigenesis for multiple gastrointestinal cancers, which have important implications for cancer prevention, early detection, and treatment stratification.

PMID: 40962882 [Indexed for MEDLINE]

29. Signal Transduct Target Ther. 2025 Sep 12;10(1):299. doi: 10.1038/s41392-025-02382-w.

Coinhibition of the MEK/RTK pathway has high therapeutic efficacy in KRAS-mutant non-small cell lung cancer.

Oncogenic KRAS mutations are frequently detected in NSCLC. It remains a major challenge to target all KRAS mutants. MEK inhibitors are considered candidates for treating KRAS-mutant NSCLC; however, their easy adaptive resistance precludes further application. Here, we found that MEK inhibitor-trametinib treatment results in the feedback activation of multiple receptor tyrosine kinases (RTKs) and that treatment with the pan-RTK inhibitor anlotinib effectively inhibits the progression of KRAS-mutant NSCLC. Furthermore, we evaluated this strategy in a clinical study (NCT04967079) involving 33 advanced non-G12C KRAS-mutant NSCLC patients. The phase Ia containing 13 patients showed that the recommended phase 2 dose (RP2D) is trametinib (2 mg) plus anlotinib (8 mg), the objective response rate (ORR) is 69.2% (95% CI: 38.6-90.9), the median progression-free survival (PFS) is 6.9 months (95% CI: 3.9 to could not be evaluated), disease control rate (DCR) is 92% (95% CI: 64.0-99.8) and the rate of adverse events (AEs) ≥grade 3 is 23%. The phase Ib containing 20 patients demonstrated the high efficacy of this combinational therapy with RP2D, with the ORR at 65% (95% CI: 40.8-84.6), the median PFS is 11.5 months (95% CI: 8.3-15.5), the median overall survival (OS) is 15.5 months (95% CI: 15.5 to could not be evaluated), the DCR at 100% (95% CI: 83.2-100.0), the median duration of overall response (DoR) is 9.3 months (95% CI: 2.5-12.1), and the rate of AEs ≥ grade 3 at 35%. Overall, this study provides a potential combinational therapeutic strategy for KRAS-mutant NSCLC through the cotargeting of MEK and RTKs.

PMID: 40935839 [Indexed for MEDLINE]

30. Nat Commun. 2025 Sep 26;16(1):8499. doi: 10.1038/s41467-025-63414-1.

Comparison of imaging based single-cell resolution spatial transcriptomics profiling platforms using formalin-fixed paraffin-embedded tumor samples.

Update of

    bioRxiv. 2024 Dec 17:2024.12.13.628390. doi: 10.1101/2024.12.13.628390.

    Res Sq. 2025 Jan 17:rs.3.rs-5656204. doi: 10.21203/rs.3.rs-5656204/v1.

Imaging-based spatial transcriptomics (ST) is evolving as a pivotal technology in studying tumor biology and associated microenvironments. However, the strengths of the commercially available ST platforms in studying spatial biology have not been systematically evaluated using rigorously controlled experiments. We use serial 5 μm sections of formalin-fixed, paraffin-embedded surgically resected lung adenocarcinoma and pleural mesothelioma samples in tissue microarrays to compare the performance of the ST platforms (CosMx, MERFISH, and Xenium (uni/multi-modal)) in reference to bulk RNA sequencing, multiplex immunofluorescence, GeoMx, and hematoxylin and eosin staining data. In addition to an objective assessment of automatic cell segmentation and phenotyping, we perform a manual phenotyping evaluation to assess pathologically meaningful comparisons between ST platforms. Here, we show the intricate differences

between the ST platforms, reveal the importance of parameters such as probe design in determining the data quality, and suggest reliable workflows for accurate spatial profiling and molecular discovery.

PMID: 41006245 [Indexed for MEDLINE]

31. BMJ. 2025 Sep 2;390: e082834. doi: 10.1136/bmj-2024-082834.

Cardiovascular adverse events associated with epidermal growth factor receptor tyrosine kinase inhibitors in EGFR-mutated non-small cell lung cancer: systematic review and network meta-analysis.

OBJECTIVE: To evaluate the risk of cardiovascular adverse events associated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with EGFR-mutated non-small cell lung cancer (NSCLC).

DESIGN: Systematic review and network meta-analysis.

DATA SOURCES: PubMed, Embase, Web of Science, Scopus, Cochrane CentralRegister of Controlled Trials, and three clinical trial registries, from inception to 20 November 2024.

STUDY SELECTION: Randomised controlled trials comparing EGFR tyrosine kinase inhibitor monotherapy with placebo or other treatments in patients with EGFR-mutated NSCLC.DATA EXTRACTION AND SYNTHESIS: Pairs of reviewers extracted data and assessed risk of bias. A random effects network meta-analysis using a frequentist

approach compared adverse drug reactions across different treatments. Certainty of evidence was evaluated using the confidence in network meta-analysis approach. Pairwise meta-analyses were done to compare the three generations of EGFR tyrosine kinase inhibitors.

RESULTS: The network meta-analysis comprised 89 randomised controlled trials involving 29 813 participants, mean follow-up 2.18 years. Compared with placebo, both first generation (odds ratio 1.51, 95% confidence interval 1.01 to 2.26; high certainty; pooled incidence 3.2%) and third generation EGFR tyrosine kinase inhibitors (2.18, 1.46 to 3.27; high certainty; 9.5%) were associated with increased risks of cardiac adverse events. Among third generation inhibitors, osimertinib (2.53, 1.53 to 4.19; high certainty; 8.9%) and lazertinib (2.84, 1.17 to 6.91; moderate certainty; 2.7%) were associated with cardiac adverse events. Combined therapies, such as antiangiogenesis with erlotinib or

gefitinib, were associated with vascular adverse events (high certainty), whereas antiangiogenesis with osimertinib was associated with cardiovascular adverse events (moderate to high certainty). Also, the risk of arrhythmias was significantly higher with third generation inhibitors (3.26, 1.83 to 5.81; high certainty; 7.3%), such as osimertinib alone (3.35, 1.75 to 6.40; high certainty; 6.2%) and in combination with antiangiogenesis. Almonertinib was associated with vascular toxicity. In pairwise meta-analysis, third generation inhibitors were associated with higher risks of any grade and grade ≥3 cardiovascular adverse events compared with first generation inhibitors.

CONCLUSIONS: In patients with EGFR-mutated NSCLC, first and third generation EGFR tyrosine kinase inhibitors, as well as combination therapies with antiangiogenesis, were associated with increased risks of cardiovascular adverse events. Risks were significantly higher with third generation compared with first generation inhibitors.

SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023433003.

PMID: 40897431 [Indexed for MEDLINE]

32. Am J Respir Crit Care Med. 2025 Sep;211(9):1644-1651. doi: 10.1164/rccm.202409-1846OC.

Robotic versus Electromagnetic Bronchoscopy for Peripheral Pulmonary Lesions: A Randomized Trial (RELIANT).

Comment in

    Am J Respir Crit Care Med. 2025 Sep;211(9):1541-1542. doi: 10.1164/rccm.202506-1374ED.

Rationale: Robotic-assisted bronchoscopy has emerged as an alternative to electromagnetic navigational bronchoscopy for patients undergoing bronchoscopic biopsy of a peripheral pulmonary lesion. Although both platforms are routinely used in clinical practice, comparative effectiveness data are lacking.

Objectives: We sought to compare the effectiveness of robotic-assisted and electromagnetic navigational bronchoscopy for the evaluation of peripheral pulmonary lesions. Methods: In an investigator-initiated, single-center, cluster-randomized noninferiority trial, we assigned patients undergoing diagnostic bronchoscopy for evaluation of a peripheral pulmonary lesion to either robotic-assisted or electromagnetic navigational bronchoscopy. The cluster randomization unit was the operating room in which patients were scheduled. The primary outcome was the diagnostic yield of the procedure, defined as the proportion of cases yielding lesional tissue. Secondary and safety outcomes included procedure duration and complications. Measurements and Main Results: Among the 411 patients included in the modified intention-to-treat analysis, lesional tissue was obtained in 158 of 203 (77.8%) patients in the robotic-assisted group and 157 of 208 (75.5%) patients in the electromagnetic group; the P value for noninferiority was 0.007. The median duration of bronchoscopy was 37 minutes in the robotic-assisted group and 32 minutes in the electromagnetic group (difference, 5 min; 95% confidence interval = 2.0-7.7). Pneumothorax occurred in 4 patients in the robotic-assisted group and 6 patients in the electromagnetic group. Conclusions: In patients undergoing bronchoscopy for the evaluation of a peripheral pulmonary lesion, the diagnostic yield of robotic-assisted bronchoscopy was not inferior to that of electromagnetic navigation bronchoscopy. Clinical trial registered with www.clinicaltrials.gov (NCT05705544).

PMID: 40460390 [Indexed for MEDLINE]

33. Sci Bull (Beijing). 2025 Sep 15;70(17):2852-2867. doi: 10.1016/j.scib.2025.06.030. Epub 2025 Jun 24.

Liquid biopsy-based multi-cancer early detection: an exploration road from evidence to implementation.

Current cancer screening methods are limited in scope, often detecting only a few cancer types with low positive predictive value and suboptimal patient adherence. In recent years, liquid biopsy-based multi-cancer early detection (MCED) has emerged as a promising approach to revolutionize cancer control. Despite several MCED tests reaching clinical trial phases and seeking regulatory approval, none have yet been approved for clinical use, highlighting uncertainties regarding their efficacy and applicability. This review comprehensively examines the advancements in MCED technologies and offers insights into the selection of cancer types for inclusion in MCED panels. We explore the clinical development pathway for MCED, from biomarker discovery and analytical validation to large-scale randomized controlled trials, emphasizing the importance of selecting appropriate endpoints such as reducing late-stage cancer incidence or cancer-specific mortality. Key challenges, including achieving optimal sensitivity for early-stage cancers, minimizing false positives and negatives, and ensuring equitable access to MCED tests, are also addressed. Finally, we evaluate the added value and health economic benefits of integrating MCED into established healthcare systems through widespread implementation. By providing a thorough analysis of these aspects, this review aims to advance the field of cancer screening and guide future research and development efforts.

PMID: 40670203 [Indexed for MEDLINE]

34. JAMA Oncol. 2025 Sep 1;11(9):990-998. doi: 10.1001/jamaoncol.2025.2010.

Risk Factors for COVID-19-Related Hospitalization and Death in Patients With Cancer: The National Cancer Institute COVID-19 in Cancer Patients Study (NCCAPS).

Comment on

    JAMA Oncol. 2025 Sep 1;11(9):965-967. doi: 10.1001/jamaoncol.2025.1937.

IMPORTANCE: Retrospective case series have identified having cancer and receiving treatment for cancer as risk factors for inferior COVID-19 outcomes.

OBJECTIVE: To determine risk factors for hospitalization and death in patients with cancer with COVID-19 infection.DESIGN, SETTING, AND PARTICIPANTS: The National Cancer Institute COVID-19 in Cancer Patients Study (NCCAPS) is a prospective longitudinal natural history cohort study examining the impact of COVID-19 on patients with cancer. Adults were eligible within 14 days of an initial positive SARS-CoV-2 test result if they were receiving active treatment for cancer or had prior stem cell/bone marrow transplant or CAR T-cell treatment. The statistical analysis took place between September 2024 and April 2025.

MAIN OUTCOMES AND MEASURES: The primary objective of the study was to determine patient factors, therapy types, and cancer types associated with COVID-19 severity, defined as hospitalization for or death from COVID-19 within 30 and 90 days after the first positive SARS-CoV-2 test result. Multivariable regressions were performed for COVID-19-specific hospitalization and mortality (proportional hazard and cause-specific hazard models).

RESULTS: Of 1572 eligible adult patients (median [range] age, 60 [18-93] years; 840 female [53.4%]), 1066 (67.8%) had a solid tumor, with 683 (64.0%) having metastatic disease; breast (252 [23.6%]) and lung cancer (148 [13.9%]) were most common. At enrollment, 1013 patients (64.4%) were unvaccinated for SARS-CoV-2. COVID-19-related mortality at 90 days was 3.0% and did not increase at subsequent time points. The cumulative incidence of COVID-19-specific death in the first 90 days was highest in patients with lymphoma, intermediate in patients with acute leukemia and lung cancer, and lowest in patients with other solid tumors and other hematologic cancers. In multivariable analysis, receipt of chemotherapy (hazard ratio [HR], 1.97; 95% CI, 1.52-2.54) and baseline history of stroke, atrial fibrillation, or pulmonary embolism (HR, 1.78; 95% CI, 1.33-2.38) were associated with a higher risk of hospitalization. Vaccination prior to SARS-CoV-2 infection was associated with a lower risk of hospitalization (HR, 0.52; 95% CI, 0.38-0.70). Over 2 years of follow-up, there were 1739 cancer treatment disruptions, of which 881 (50.7%) were attributed to COVID-19, with most disruptions occurring within the first 30 days.CONCLUSIONS AND RELEVANCE: The results of this prospective cohort study showed that COVID-19 had a significant impact on patients with cancer, including hospitalization, treatment disruptions, and death.

PMID: 40674082 [Indexed for MEDLINE]

35. Pharmacol Rev. 2025 Sep;77(5):100076. doi: 10.1016/j.pharmr.2025.100076. Epub 2025 Jun 25.

Cracking the EGFR code: Cancer biology, resistance mechanisms, and future therapeutic frontiers.

Epidermal growth factor receptor (EGFR) plays a crucial role in tumorigenesis across multiple cancer types. EGFR mutations, overexpression, amplifications, dysregulated signaling, and impaired receptor downregulation drive cancer progression, particularly in non-small cell lung cancer, glioblastoma, colorectal cancer, gastric cancer, and head and neck cancers. Over the past decades, EGFR-targeted therapies, including tyrosine kinase inhibitors and monoclonal antibodies, have significantly improved patient outcomes. However, drug resistance inevitably arises through on-target mutations, activation of bypass signaling pathways, and disruptions in receptor trafficking and degradation. To overcome resistance, novel therapeutic strategies such as new generation of tyrosine kinase inhibitors, antibody-drug conjugates, and targeted protein degradation approaches like proteolysis-targeting chimeras are being actively explored. Additionally, combination therapies targeting parallel or compensatory pathways are being explored in mitigating drug resistance. Advances in genomic profiling and liquid biopsy technologies further enable personalized treatment strategies tailored to individual genetic backgrounds. In this review, we provide an overview of EGFR signaling and examine the landscape of EGFR mutations and currently available targeted therapies, while highlighting key resistance mechanisms. Furthermore, emerging strategies designed to overcome resistance are discussed, offering insights into future directions for EGFR-targeted cancer treatment. SIGNIFICANCE STATEMENT: Epidermal growth factor receptor (EGFR) is a key driver of tumorigenesis across multiple cancers, with overexpression, mutations, and amplifications promoting disease progression and therapeutic resistance. Despite the success of EGFR-targeted therapies, resistance remains a significant barrier to sustainable efficacy. This review provides an overview of EGFR biology and therapy, resistance mechanisms, and emerging new therapeutic strategies. A deeper understanding of these aspects is crucial for overcoming resistance and guiding the development of more effective and personalized cancer treatments.

PMID: 40675056 [Indexed for MEDLINE]

36. Mil Med Res. 2025 Sep 3;12(1):56. doi: 10.1186/s40779-025-00645-9.

Global patterns and trends in cancer-related premature death and their impact on life expectancy across 185 countries: a population-based analysis.

BACKGROUND: The level of premature deaths (deaths among those aged 30-69 years) caused by cancer is an important indicator of evaluating the level of cancer prevention and control. However, the current burden and temporal trends in cancer-related premature deaths, and their impact on life expectancy at the global, regional, and national levels are not clear.

METHODS: Cancer mortality data for 185 countries were obtained from the GLOBOCAN 2022 database. High-quality cancer mortality data and national population statistics for 47 countries were extracted from the United Nations and national cancer registry databases, covering the period 2003-2022. Countries were classified based on the human development index (HDI). The death probability, the year of life lost (YLL), and the potential gain in life expectancy (PGLE) attributable to premature deaths from site-specific and all-cancers combined were calculated.

RESULTS: Globally, the probability of premature cancer deaths was 6.49% (95% UI 6.49-6.50). The YLLs caused by cancer-related premature death were 163.86 million (95% UI 163.70-164.03), constituting 65.58% of the total cancer-related YLLs. The PGLEs were 1.16 years (95% UI 1.16-1.16). The premature death probability increased with higher HDI levels in men, but decreased in women. Cancer-related premature deaths as a proportion of total cancer deaths varied from 18.31% (95% UI 18.20-18.43) in Japan to 84.44% (95% UI 76.10-91.16) in São Tomé and Príncipe. Lung cancer was the leading cause of cancer-related premature deaths in men, and breast cancer ranked first in women. By eradicating premature deaths attributable to lung, liver, colorectal, and stomach cancer in men, and to breast, cervical, and lung cancer in women, 0.55 years (95% UI 0.55-0.55) and 0.49 years (95% UI 0.49-0.49) of PGLEs could be achieved, accounting for 48.67% and 42.24% of the total PGLEs, respectively. Cancer-related premature deaths decreased significantly in 38 countries during 2003-2022 (P < 0.05). The probability of premature cancer-related deaths decreased by more than 15.50% from 2015 to 2022 in 16 countries.

CONCLUSIONS: Cancer-related premature deaths declined in many countries, with 16 of them having achieved the expected reduction by 2022. The current burden of cancer-related premature deaths is profound but varies around the world. Eliminating premature deaths from major cancer types could substantially increase life expectancy, underscoring the importance of prevention and treatment efforts for these cancers.

PMID: 40903768 [Indexed for MEDLINE]

37. Adv Mater. 2025 Sep 8:e08137. doi: 10.1002/adma.202508137. Online ahead of print.

A Readily Synthesized All-In-One Nanowire Hydrogel: Toward Inhibiting Tumor Recurrence and Postoperative Infection.

Surgical resection remains the frontline intervention for cancer; however, postoperative tumor recurrence and wound infection remain critical unmet challenge in surgical oncology. Herein, an all-in-one nanowired hydrogel (V-Hydrogel) is developed through a facile one-step assembly employing enzyme-mimetic V2O5 nanowires and bactericidal crosslinker THPS. The V-Hydrogel reserves the glutathione peroxidase-, peroxidase-, catalase-, and oxidase-mimetic enzymatic activities derived from vanadium oxide nanowires, thereby exhibiting efficient tumor-specific catalytic therapy. Simultaneously, the introduction of bactericide THPS endows the potent antibacterial capabilities of V-Hydrogel against surgical site infections. This hydrogel exhibits dynamic mechanical adaptability to the tumor microenvironment (f), ensuring conformal coverage of irregular resection cavities for precise therapy. Additionally, the V-Hydrogel can reprogram the immunosuppressive TME via polarizing macrophages into antitumor M1 phenotypes and recruiting cytotoxic T cells, thereby establishing systemic antitumor immunity. This multifunctional vanadium-integrated hydrogel platform, designed based on the pathological characteristics of postoperative tumors, addresses key limitations in conventional postoperative therapies, offering a strategy for postoperative adjuvant tumor therapy.

PMID: 40919848

38. J Thorac Oncol. 2025 Sep 8:S1556-0864(25)01039-1. doi: 10.1016/ j.jtho. 2025. 09. 001. Online ahead of print.

Trajectories of Synchronous Subsolid Nodules in Patients With Resected Subsolid Lung Adenocarcinoma: A Multicenter Cohort Study.

INTRODUCTION: Multifocal subsolid nodules (SSNs), representing a spectrum of multifocal lung adenocarcinomas (LUADs), are increasingly detected with widespread lung cancer screening and advanced thoracic imaging. When synchronous SSNs coexist with a surgically confirmed subsolid LUAD, their trajectories remain poorly understood, contributing to uncertainty regarding optimal management strategies. This study aimed to evaluate the clinical course and impact of synchronous SSNs in such patients and to identify features associated with their progression.

METHODS: The clinical course of synchronous SSNs in individuals who underwent surgical resection for subsolid LUAD between January 2009 and December 2019 at four referral centers in South Korea, with follow-up to June 2024, was analyzed. Longitudinal outcomes, including growth patterns and subsequent lung cancer diagnosis, were evaluated using comprehensive nodule-level assessments. Multivariable Cox regression models were used to identify risk factors associated with SSN trajectories and patient-level mortality outcomes.

RESULTS: Overall, 1791 synchronous SSNs in 409 patients with surgically resected subsolid LUAD as the index lesion were included. During the initial surgery for the 409 index LUADs, 380 synchronous SSNs were resected concurrently, whereas 1002 SSNs were followed up in a mean duration of 80.6 months. Among the 1002 SSNs, 16.9% exhibited growth and 7.9% were subsequently diagnosed as lung cancer-all of which were stage 0 to I adenocarcinomas. Factors associated with SSN growth and lung cancer diagnosis included part-solid type, larger nodule size, the presence of bubble lucency, and pleural retraction. Notably, the number of synchronous SSNs was not associated with an increased risk of growth. At the individual patient level, neither the absolute number nor the mere growth of synchronous SSNs significantly affected lung cancer-related mortality or overall survival.

CONCLUSIONS: Synchronous SSNs in patients with subsolid LUAD exhibited growth in 16.9% of cases, with varying trajectories and clinical impact. Identified risk factors were primarily related to the characteristics of each SSN. Our findings highlight the need for nodule-based, individualized management strategies, along with a more clinically relevant growth threshold to guide balanced intervention decisions.

PMID: 40930418