Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors targeting the PD-1/PD-L1 and CTLA-4 axes have fundamentally transformed its treatment landscape. This narrative review traces the evolution of NSCLC immunotherapy, from advanced-stage monotherapy and chemoimmunotherapy to its critical expansion into early-stage disease, highlighting the paradigm shift brought by neoadjuvant, adjuvant, and perioperative strategies. We examine essential clinical challenges, including optimal treatment duration, management of brain metastases, immune-related adverse events, and mechanisms of primary and acquired resistance, with a focus on genomic alterations like KRAS co-mutations with STK11 and KEAP1. Furthermore, we critically evaluate the evolving biomarker landscape, moving beyond PD-L1 to encompass circulating tumour DNA, microbiome composition, and multiparametric approaches like T-cell receptor clonality. Finally, we provide an in-depth exploration of next-generation strategies, including bispecific antibodies, novel checkpoint targets, mRNA vaccines, antibody-drug conjugates, and advanced cellular therapies. While significant progress has been made, refining biomarker-driven selection and optimizing combination sequencing remain paramount. This thorough synthesis highlights promising future directions to overcome these hurdles and improve long-term survival in NSCLC.

Supplementary Table 1. Clinical Information of Tissues from Early-Stage LUAD Patients

Neoadjuvant immunotherapy improves pathologic response in resectable non-small-cell lung cancer (NSCLC), but routine haematoxylin-eosin (H&E) evaluation may underestimate residual mediastinal nodal disease. We included 261 patients with ypN0-1M0 NSCLC after neoadjuvant immunotherapy (2019–2023) and analysed 2182 H&E-negative mediastinal lymph nodes using anti-cytokeratin immunohistochemistry to detect occult micrometastasis (LN-OM), defined as cytokeratin-positive tumour cells or clusters ≤2 mm. LN-OM was identified in 29 patients (11.1%), with significantly higher prevalence in cN2 disease (P=0.010). LN-OM positivity was associated with significantly worse overall survival (OS) and disease-free survival (DFS) (both P<0.01). Multivariable analysis confirmed LN-OM as an independent risk factor for poorer OS (HR=3.04; P=0.013) and DFS (HR=3.56; P<0.001). Stratified analyses showed that LN-OM predicted poor outcomes in the cN2 subgroup (OS: HR=3.02, P=0.038; DFS: HR=4.08, P<0.001) but not in cN0–N1 subgroup. Among patients achieving pathologic complete response (pCR), LN-OM was associated with significantly shorter DFS (HR=10.39; P=0.001) and a trend toward worse OS (HR=6.00; P=0.054). In conclusion, cytokeratin-detected mediastinal LN-OM persists after neoadjuvant immunochemotherapy and may serve as a tissue-based marker of occult residual nodal disease, complementing conventional ypN staging and pathologic response for postoperative risk stratification. Prospective validation is needed before clinical application.

OBJECTIVES:Neoadjuvant immunotherapy is the standard of care for resectable non-small cell lung cancer (NSCLC); however, the impact of adjuvant immunotherapy (adj-IO) remains to be elucidated. In this study, we aimed to explore the impact of adj-IO on survival of patients who underwent neoadjuvant immunotherapy for stage II-IIIB NSCLC. MATERIALS AND METHODS:We retrospectively collected data of patients who received neoadjuvant immunotherapy followed by complete resection for stage II-IIIB NSCLC from January 2019 to August 2023 in Guangdong Provincial People's Hospital (China). The non-adj-IO group was matched 1:1 with the adj-IO group via propensity score matching (PSM). Disease-free survival (DFS) and overall survival (OS) were analyzed using Kaplan-Meier analysis and compared using the log-rank test. The impact of adj-IO on survival was assessed via Cox regression analysis. RESULTS:This study included 267 patients. After PSM, the final cohort comprised 102 patients per group (median [range] age: 60 [25-82] years; 168 male). Patients who received adj-IO had a similar DFS (hazard ratio [HR]: 1.11, 95% confidence interval [CI]: 0.65-1.88, P = 0.705) and OS (HR: 0.47, 95% CI: 0.21-1.06, P = 0.070) to those without adj-IO. In subgroup analyses, adj-IO did not improve DFS or OS in terms of pathological response, the programmed death-ligand 1 (PD-L1) expression level (PD-L1 = 0% vs. others), or the histological subgroup (adenocarcinoma vs. others). Adj-IO was not an independent prognostic factor for DFS (P = 0.427) or OS (P = 0.210). CONCLUSION:Adj-IO may have no impact on survival in patients who undergo complete resection after neoadjuvant immunotherapy and may be omitted in perioperative immunotherapy.

8509 Background: Neoadjuvant target therapy has improved objective response rate (ORR) or major pathological response (MPR) of stage IIA-IIIB non-small cell lung cancer (NSCLC) with EGFR mutation. EGFR-TKI-induced evolution indicated a hot-tumor status in residual disease. However, the role of immunotherapy in this phrase remained unclear. Here, we present the results of a phase II, open-label study investigating the efficacy and safety of sequential almonertinib and chemo-immunotherapy (IO) in potentially resectable stage IIA-IIIB EGFR-mutant NSCLC patients. (NCT06300424). Methods: Untreated patients with II-IIIB NSCLC were enrolled in this study. Patients received almonertinib for 6 weeks, followed by 3 cycles of adebrelimab and chemotherapy before surgery. Primary end point was MPR, Secondary end points included pathological complete response (PCR), ORR, event-free survival (EFS), overall survival (OS) and safety. Results: A total of 32 patients were enrolled from Apr 2024 to Aug 2025. EGFR mutation subtype was 19del in 16 (50.0%) patients, L858R in 11 (34.4%) patients, others in 5 (15.6%) patients. All the patients completed neoadjuvant almonertinib, 30 (93.8%) patients completed 3 circles of chemo-IO and underwent surgery, R0 was achieved in 29 (96.7%) patients. ORR was 46.9% (15/32) and 59.4% (19/32) after target therapy and chemo-IO, respectively. MPR was documented in 13 (40.6%) patients, including PCR in 5 (15.6%) patients. In patients underwent resection, MRP and PCR rate were 66.7% and 33.3% in patients with PD-L1≥1%, compared with 21.4% and 0% in PD-L1 ＜1% subgroup, respectively, N downstage was confirmed in 44.8% (13/29) patients. After a median follow-up of 13.5 months (interquartile range [IQR], 7.5–16.1 months), 31 (96.9%) patients were alive. Median EFS and OS were not reached. One-year EFS and OS rate was 89.5% and 95.2%, respectively. Grade ≥ 3 AEs occurred in 28 (87.5%) patients during neoadjuvant therapy. Conclusions: This study met its primary endpoint, indicating almonertinib followed by chemo-IO was a feasible neoadjuvant treatment in patients with resectable stage IIA-IIIB EGFR-mutant NSCLC, especially in patients with PD-L1 expression. The study was partially supported by Jiangsu Hengrui Pharmaceuticals and Hansoh Pharmaceutical Group Co. Ltd. Clinical trial information: NCT06300424 . Primary and secondary outcomes. Outcomes ITT (N=32) Resection (N=29) Major pathological response rate 40.6% (13/32) 44.8% (13/29) PD-L1＜1% 18.8% (3/16) 21.4% (3/14) PD-L1≥1% 62.5% (10/16) 66.7% (10/15) Complete pathological response rate 15.6% (5/32) 17.2% (5/29) PD-L1＜1% 0.0% (0/16) 0.0% (0/14) PD-L1≥1% 31.3% (5/16) 33.3% (5/15) After receiving neoadjuvant TKI ORR 46.9% (15/32) 44.8% (13/29) DCR 93.8% (30/32) 96.6% (28/29) After receiving neoadjuvant TKI+IO ORR 59.4% (19/32) 58.6% (17/29) DCR 100.0% (32/32) 100.0% (29/29) TKI: Tyrosine kinase inhibitor; IO: Immunotherapy.

Supplementary Figure 1 to 7, and Supplementary Materials and Methods

Background: Chest tube placement after pulmonary resection has been conventionally recommended, yet the associated patient discomfort can hinder postoperative recovery. In previous work, we demonstrated that catheter drainage is a safe alternative to conventional chest tube following wedge resection and provides superior pain relief. This study aims to evaluate whether a complete tubeless strategy offers further advantages compared to catheter drainage. Methods: We conducted a retrospective cohort study and enrolled patients who underwent video-assisted thoracoscopic surgery (VATS) pulmonary wedge resection at our institution between September 2020 and November 2024. Participants were categorized into a catheter drainage group or a tubeless group based on the absence of postoperative thoracic drainage. Propensity score matching (PSM) was applied in a 1:1 ratio to balance baseline characteristics. Univariate analysis was then used to compare operative outcomes and perioperative complications between the matched groups. Results: Of the 460 initially eligible patients, 133 matched pairs were generated after PSM. The tubeless group demonstrated a significantly shorter operative duration (57.00 vs. 80.00 min, P<0.001) and lower postoperative pain scores [Numerical Rating Scale (NRS): 0.00 vs. 2.00, P<0.001] than the catheter group. No significant differences were observed in the incidence of postoperative complications, rates of reintubation, or length of postoperative hospital stay. Conclusions: Omitting thoracic drainage entirely is a feasible and advantageous approach for a highly selected subset of patients undergoing pulmonary wedge resection. In this selected cohort, the tubeless strategy is associated with diminished postoperative pain and enhanced patient satisfaction, without increasing perioperative risks. The observed reduction in operative time is likely confounded by patient selection factors and should not be interpreted as a direct benefit of the technique. These findings support its consideration in patients intraoperatively assessed as low-risk; however, the observed benefits should be interpreted in the context of the stringent selection criteria applied, which may limit generalizability.

Determining tumor progression status is critical for early-stage lung adenocarcinoma (esLUAD) diagnosis and treatment, yet histopathology-based grading often overlooks heterogeneity within grades. We propose RadioTrace, a deep contrastive learning framework integrating radiomic and pathological information to learn a radiomic trajectory for quantifying esLUAD progression. Across four multi-institutional cohorts, RadioTrace well predicted tumor phenotypes including spread through air spaces (STAS) and lymph node metastasis (LNM). Survival analyses demonstrated it as an independent prognostic factor (log-rank test p < 0.004 across all cohorts). Within the same pathological grade, it revealed significant survival heterogeneity (p < 0.02 across all cohorts), underscoring the limitations of current grading criteria. Genomic and transcriptomic analyses confirmed associations with progression-related molecular features. Longitudinal analysis of patients with multiple CT follow-ups further showed consistency with continuous progression. These findings demonstrate that RadioTrace enables quantitative, interpretable assessment of esLUAD progression, providing insights beyond histopathology and assisting clinical decision-making.

Early-stage lung adenocarcinoma generally has a favorable prognosis. However, more than 30% of early-stage lung adenocarcinoma cases relapse within 5 years of initial treatment, even after complete removal of the primary tumor. Identification of the factors contributing to early-stage lung adenocarcinoma metastasis is needed to develop effective prevention and treatment strategies. In this study, we found upregulation of xylosyltransferase 1 (XYLT1), a glycosyltransferase that initiates the biosynthesis of sulfated glycosaminoglycan (sGAG) chains, in metastatic recurrent lesions of early-stage lung adenocarcinoma, which correlated with poor prognosis. In vitro and in vivo experiments showed that XYLT1 promoted lung adenocarcinoma cell survival and metastasis by activating the NF-κB pathway. Mechanistically, XYLT1 interacted with IκBα and facilitated the biosynthesis of sGAG-conjugated IκBα, which enhanced the interaction between IκBα and IKKs to promote the proteasomal degradation of IκBα. These results illustrate that proteoglycan modification-mediated activation of NF-κB signaling is a driver of early-stage lung adenocarcinoma metastasis, providing a possibility for the detection and intervention of early lung adenocarcinoma metastasis. Significance: XYLT1 promotes metastatic recurrence of early-stage lung adenocarcinoma by facilitating sulfated glycosaminoglycan conjugation and proteasomal degradation of IκBα to activate NF-κB, providing potential biomarker and treatment strategies for lung cancer metastasis.

INTRODUCTION:Neoadjuvant immunochemotherapy has improved pathologic complete response (pCR) rates and event-free survival in resectable NSCLC, yet its efficacy in SMARCA4-altered NSCLC, a subset associated with poor prognosis, remains unclear. METHODS:We retrospectively analyzed clinical characteristic and next-generation sequencing of 29 patients with SMARCA4-altered NSCLC who received neoadjuvant immunochemotherapy from Guangdong Provincial People's Hospital. The Cancer Genome Atlas of lung adenocarcinoma was classified through SMARCA4 condition by whole exome sequencing and further analyzed the difference between the two groups. In the altered group, BostonGene molecular functional portraits were used for tumor immune microenvironment classification. RESULTS:In general, 29 NSCLC patients with SMARCA4 alterations received neoadjuvant immunochemotherapy, the objective response rate was 70.4%, and the pCR rate was 51.7%. The pCR rate significantly differed among pathologic subgroups (squamous cell carcinoma [SCC] versus adenocarcinoma, 83.3% versus 28.6%, p = 0.045). After a median follow-up of 17 months, seven patients relapsed and one died from non-cancer causes. In adenocarcinoma subgroup, SMARCA4 alterations were associated with early progression (42.8%) with a median event-free survival of 13 months, although some patients achieved durable survival. All patients harboring co-occurring KRAS with KEAP1/STK11 mutations relapsed. The Cancer Genome Atlas data revealed that patients with SMARCA4-altered lung adenocarcinoma had worse survival (34.8 versus 50.9 mo, p = 0.033), down-regulation in innate immunity, and enrichment of mTOR/MYC signaling. Immune classification revealed both immune-desert and immune-enriched subtypes within the altered cohort. The lacking immune cell infiltration group had significantly shorter overall survival compared with the immune-enriched subtypes (28.8 versus 49.9 mo, p = 0.043). CONCLUSIONS:In conclusion, SMARCA4-altered NSCLC is heterogeneous. SCC demonstrates remarkable sensitivity with immunochemotherapy, but non-SCC, especially with KRAS+KEAP1/STK11 co-mutations, represents a distinct, immune-cold, high-risk subtype.

Background Robot-assisted thoracic surgery (RATS) was advantageous in complex procedures. Neoadjuvant therapy leads to intra-operative difficulty in non-small cell lung cancer (NSCLC). The aim of this study was to compare RATS and video-assisted thoracic surgery (VATS) in neoadjuvant setting. Methods This retrospective study included stage II-IIIB(N2) NSCLC patients who underwent surgery after receiving neoadjuvant therapy. Patients were grouped by RATS or VATS. The primary outcomes are R0 resection rate, operation time and estimated blood loss. The secondary outcome is the rate of conversion to thoracotomy. Demographic data, clinical data and pathological data were collected for analysis. Propensity score matching (PSM) was applied to balance bias. Results Between July 2021 and June 2024, 118 patients received RATS and 317 patients received VATS were included. Before PSM, RATS was associated with a significantly shorter operative time (194 min vs. 223 min, p < 0.001) and a lower conversion rate to thoracotomy (8.47 % vs. 18.6 %, p = 0.015). However, no significant differences were observed in the R0 resection rate (p = 0.306) or mean estimated blood loss (p = 0.371). After PSM, RATS still demonstrated advantages in operation time (194 min vs 223 min, p = 0.001), reducing conversion caused by fibrosis or difficult exposure (p = 0.005), and number of N2 lymph nodes (p = 0.02). Single and multiple regressions both suggested RATS was associated with shorter operation time and lower conversion rate. Conclusions Our study suggested that RATS is a superior approach compared with VATS in neoadjuvant context, with advantages in shortening operation time, reducing conversion rate, and lymph node dissection.

Background::Despite increased response and long-term benefit of anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC) harboring ALK-fusion, the role of induction ALK-TKIs in locally advanced NSCLC remained poorly investigated. This study aimed to demonstrate the short-term and long-term efficacy of ALK-targeted induction therapy in stage III lung cancer. Methods::We consecutively collected data of patients from Guangdong Lung Cancer Institute since 2016, and those who were pathologically confirmed stages IIIA-IIIB NSCLC treated with induction ALK-TKIs initially were eligible for subsequent analysis. Patients’ clinicopathological features as well as therapeutic management were fully reviewed. Analysis of longitudinal single-cell RNA sequencing from patients treated with alectinib were performed. Fisher’s exact test was used to compare two categorical variable and Kaplan-Meier was applied for survival curve with estimation for median and 95% confidence interval (CI) value if available.Results::Forty stage III NSCLC patients treated with either alectinib or crizotinib were enrolled. Among those who had surgery, all patients had R0 resection without postoperative radiotherapy. Only two patients suffered grade 2 postoperative complications in terms of Clavien-Dindo score. Induction alectinib showed numerically superior pathological response compared with crizotinib with both major pathological response (MPR) (11/17, 64.7% vs. 6/13, 46.2%, P = 0.46) and complete pathological response (pCR) (6/17, 35% vs. 2/13, 15%, P = 0.41). Patients who received induction alectinib had significantly longer PFS (not reached [NR] vs. 17.9 months, P <0.001) and numerically improved overall survival (NR vs. NR, P = 0.092) compared with crizotinib. Brain metastasis remained the most common recurrent pattern after induction ALK-TKIs. Longitudinal single-cell RNA sequencing revealed increased tumor stemness and induced a more suppressive immune microenvironment in the residual tumor while highly inflamed microenvironment along with low infiltrating regulatory T cell and exhausted T cell was observed in resected specimens which achieved pCR. Conclusion::Induction ALK-TKIs provided a clinically efficient and well-tolerated therapeutic strategy in locally advanced ALK-positive NSCLC.

8025 Background: Previously, we reported the clinical findings of stage-one enrollment from a phase II trial of neoadjuvant immunochemotherapy (IO) in untreated patients with resectable non-small cell lung cancer (NSCLC) (CTONG1804, NCT04015778). Recently, two-stage enrollment has been completed. This trial provided an opportunity to investigate the correlation of pathological response and early immune microenvironment during neoadjuvant IO. Methods: We conducted single-cell RNA sequencing (scRNA-seq) on fresh tumor tissue of 21 patients at pre- and post-IO treatment. Multi-omics sequencing was also used in this exploratory study, that included bulk RNA sequencing and tumor-informed MRD sequencing. Results: The pathological complete response (pCR) rate was 42.9% (9/21). Unexpectedly, a total of 143 cancer cells with genome alterations were identified in six (6/9=66.7%) patients with pCR. Only one pCR patient presented MRD positive within one month after surgery, who had the highest number of cancer cells. These residual cancer cells exhibited reduced proliferative capacity and diminished stem cell-like features but retained epithelial-mesenchymal transition (EMT) markers, suggesting metastatic potential and drug resistance. Elevated antigen presentation pathways, particularly involving CD74-MHC class II, were observed in pCR cancer cells, alongside a significant reduction in tumor neoantigen burden. When comparing the immune cells of different pathological response, we found that conventional dendritic cell type 2 (cDC2) emerged as a critical antigen-presenting cell subtype in pCR patients, enhancing T-cell activation and promoting immune response. Reduced CD4-Treg3 populations correlated with improved treatment outcomes, while CD8-MAIT cells exhibited functional plasticity, transitioning from tumor-promoting to tumor-rejecting phenotypes post-therapy. Conclusions: Our study highlights the persistence of residual cancer cells even in pCR patients and identifies key immune cell subsets, such as cDC2 and CD8-MAIT cells, that play pivotal roles in modulating anti-tumor response. These findings provide valuable insights into the mechanisms of immune activation and suppression in NSCLC and suggest potential biomarkers and therapeutic targets for optimizing neoadjuvant immunochemotherapy. Clinical trial information: NCT04015778 .

OBJECTIVES:In recent years, with the advancement of sublobar resection, a safe, painless method for locating peripheral pulmonary nodules was needed. Previously, an alternative method of arterial watershed localization was introduced to remedy the shortcomings of preoperative computed tomography (CT)-guided localization or other methods for locating pulmonary nodules, but its technical limitations were discovered during clinical applications. Therefore, we developed a technique to localize non-subpleural nodules using basin analysis of the target vein and validated its feasibility and safety. METHODS:We performed a retrospective analysis of surgical cases of pulmonary nodules smaller than 2 cm in our centre. The vein watershed locational method (V-WALM) was compared with CT-guided percutaneous puncture localization wedge dissection in terms of success rate, the mean duration of the operation, mean volume of intraoperative bleeding and median postoperative stay, mean postoperative drainage and mean drainage tube indwelling time. RESULTS:V-WALM and CT-guided localization were used for localized resection of pulmonary nodules in 50 patients. The localization success rates were 94.0% for V-WALM and 90.0% for CT-guided localization, respectively, with no statistical difference noted. In addition, no statistical difference in patient population distribution between the 2 groups was noted. The operating time was 95.5 ± 26.4 min for V-WALM and 94.3 ± 37.5 min for CT-guided localization, with no statistical difference. Neither were there statistical differences in intraoperative bleeding, postoperative drainage and drainage tube indwelling time. The lymph node sampling rate of V-WALM was 48.0%, which was much higher than the 24% noted in the CT-guided localization group. CONCLUSIONS:The results of this study demonstrate that V-WALM is a safe and feasible intraoperative localization method for peripheral lung nodules. It provides a high-precision, fast and minimally invasive approach to intraoperative localization.

ImportanceUninterrupted targeted therapy until disease progression or intolerable toxic effects is currently the routine therapy for advanced non−small cell lung cancer (NSCLC) involving driver gene variations. However, drug resistance is inevitable.ObjectiveTo assess the clinical feasibility of adaptive de-escalation tyrosine kinase inhibitor (TKI) treatment guided by circulating tumor DNA (ctDNA) for achieving complete remission after local consolidative therapy (LCT) in patients with advanced NSCLC.Design, Setting, and ParticipantsThis prospective nonrandomized controlled trial was conducted at a single center from June 3, 2020, to July 19, 2022, and included 60 patients with advanced NSCLC with driver variations without radiologically detectable disease after TKI and LCT. The median (range) follow-up time was 19.2 (3.8-29.7) months. Data analysis was conducted from December 15, 2022, to May 10, 2023.InterventionCessation of TKI treatment and follow-up every 3 months. Treatment was restarted in patients with progressive disease (defined by the Response Evaluation Criteria in Solid Tumors 1.1 criteria), detectable ctDNA, or elevated carcinoembryonic antigen (CEA) levels, whichever manifested first, and treatment ceased if all indicators were negative during follow-up surveillance.Main Outcomes and MeasuresProgression-free survival (PFS). Secondary end points were objective response rate, time to next treatment, and overall survival.ResultsAmong the total study sample of 60 participants (median [range] age, 55 [21-75] years; 33 [55%] were female), the median PFS was 18.4 (95% CI, 12.6-24.2) months and the median (range) total treatment break duration was 9.1 (1.5-28.1) months. Fourteen patients (group A) remained in TKI cessation with a median (range) treatment break duration of 20.3 (6.8-28.1) months; 31 patients (group B) received retreatment owing to detectable ctDNA and/or CEA and had a median PFS of 20.2 (95% CI, 12.9-27.4) months with a median (range) total treatment break duration of 8.8 (1.5-20.6) months; and 15 patients (group C) who underwent retreatment with TKIs due to progressive disease had a median PFS of 5.5 (95% CI, 1.5-7.2) months. For all participants, the TKI retreatment response rate was 96%, the median time to next treatment was 29.3 (95% CI, 25.3-35.2) months, and the data for overall survival were immature.Conclusions and RelevanceThe findings of this nonrandomized controlled trial suggest that this adaptive de-escalation TKI strategy for patients with NSCLC is feasible in those with no lesions after LCT and a negative ctDNA test result. This might provide a de-escalation treatment strategy guided by ctDNA for the subset of patients with advanced NSCLC.Trial RegistrationClinicalTrials.gov Identifier: NCT03046316

To elucidate the impact of [18F]FDG positron emission tomography/computed tomography (PET/CT) vs. CT workup on staging and prognostic evaluation of clinical stage (c) I-II NSCLC. We retrospectively identified 659 cI-II NSCLC who underwent CT (267 patients) or preoperative CT followed by PET/CT (392 patients), followed by curative-intended complete resection in our hospital from January 2008 to December 2013. Differences were assessed between preoperative and postoperative stage. Five-year disease-free survival (DFS) and overall survival (OS) rates were calculated using the Kaplan–Meier approach and compared with log-rank test. Impact of preoperative PET/CT on survival was assessed by Cox regression analysis. The study included 659 patients [mean age, 59.5 years ± 10.8 (standard deviation); 379 men]. The PET/CT group was superior over CT group in DFS [12.6 vs. 6.9 years, HR 0.67 (95

Supplementary Data from Longitudinal Undetectable Molecular Residual Disease Defines Potentially Cured Population in Localized Non–Small Cell Lung Cancer

This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive (N) and nivolumab–chemotherapy (N/C) combinations based on PD-L1 expression. Eligible patients exhibited resectable clinical stage IIA–IIIB (AJCC 8th edition) NSCLC without EGFR / ALK alterations. Patients received either mono-nivolumab (N) or nivolumab + nab-paclitaxel+ carboplatin (N/C) for three cycles based on PD-L1 expression. The primary endpoint was the major pathological response (MPR). Key secondary endpoints included the pathologic complete response (pCR), objective response rate (ORR), and event-free survival (EFS). Baseline PD-L1 expression and perioperative circulating tumor DNA (ctDNA) status were correlated with pCR and EFS. Fifty-two patients were enrolled, with 46 undergoing surgeries. The MPR was 50.0% (26/52), with 25.0% (13/52) achieving pCR, and 16.7% and 66.7% for patients with PD-L1 ≥ 50% in N and N/C groups, respectively. Thirteen (25.0%) patients experienced grade 3 or higher immune-related adverse events during neoadjuvant treatment. Patients with post-neoadjuvant ctDNA negativity was more likely to have pCR (39.1%) compared with those remained positive (6.7%, odds ratio = 6.14, 95% CI 0.84-Inf, p = 0.077). With a median follow-up of 25.1 months, the 18-month EFS rate was 64.8% (95% CI 51.9–81.0%). For patients with ctDNA– vs. ctDNA + , the 18m-EFS rate was 93.8% vs 47.3% (HR, 0.15; 95% CI 0.04, 0.94; p = 0.005). Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression ≥ 50%. ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits, which requires further confirmation in a prospective clinical trial (NCT04015778).

AbstractObjectiveIn recent years, the lung cancer incidence has grown and the population is younger. We intend to find out the true detection rate of pulmonary nodules and the incidence of lung cancer in the population and search for the risk factors.MethodHospital employees ≥40 years old who underwent low‐dose computed tomography (CT) lung cancer screening from January 2019 to March 2022 were selected to record CT‐imaging characteristics, pathology, staging, and questionnaires to investigate past history, smoking history, diet, mental health, etc. PM2.5 and radiation intake in radiation‐related occupation received monitoring in hospital.ResultThe detection rate of suspicious pulmonary nodules was 9.1% (233/2552), and the incidence rate of lung cancer (including adenocarcinoma in situ) was 4.0% (103/2552). Morbidity among doctors, nurses, technicians, administers, and logistics was no difference (p = 0.184), but higher in women than in men (4.7% vs 2.4% p = 0.002). The invasiveness increased with age and CT density of nodules (p = 0.018). The relationship between lung cancer morbidity and PM2.5 was not clear (p = 0.543); and no lung cancer has been found in employees related ionizing radiation.ConclusionThe high screening rate has brought about a high incidence of lung cancer. At present, the risk factor analysis of lung cancer based on small samples cannot find the direct cause. Most of the ground glass opacity (GGO)s detected by LDCT screening are indolent, but there are also rapidly progressive lung cancer. A predictive model to identify active and indolent GGO is necessary.

Background Estimating the growth of pulmonary sub-solid nodules (SSNs) is crucial to the successful management of them during follow-up periods. The purpose of this study is to (1) investigate the measurement sensitivity of diameter, volume, and mass of SSNs for identifying growth and (2) seek to establish a deep learning-based model to predict the growth of SSNs. Methods A total of 2,523 patients underwent at least 2-year examination records retrospectively collected with sub-solid nodules. A total of 2,358 patients with 3,120 SSNs from the NLST dataset were randomly divided into training and validation sets. Patients from the Yibicom Health Management Center and Guangdong Provincial People’s Hospital were collected as an external test set (165 patients with 213 SSN). Trained models based on LUNA16 and Lndb19 datasets were employed to automatically obtain the diameter, volume, and mass of SSNs. Then, the increase rate in measurements between cancer and non-cancer groups was studied to evaluate the most appropriate way to identify growth-associated lung cancer. Further, according to the selected measurement, all SSNs were classified into two groups: growth and non-growth. Based on the data, the deep learning-based model (SiamModel) and radiomics model were developed and verified. Results The double time of diameter, volume, and mass were 711 vs. 963 days (P = 0.20), 552 vs. 621 days (P = 0.04) and 488 vs. 623 days (P< 0.001) in the cancer and non-cancer groups, respectively. Our proposed SiamModel performed better than the radiomics model in both the NLST validation set and external test set, with an AUC of 0.858 (95% CI 0.786–0.921) and 0.760 (95% CI 0.646–0.857) in the validation set and 0.862 (95% CI 0.789–0.927) and 0.681 (95% CI 0.506–0.841) in the external test set, respectively. Furthermore, our SiamModel could use the data from first-time CT to predict the growth of SSNs, with an AUC of 0.855 (95% CI 0.793–0.908) in the NLST validation set and 0.821 (95% CI 0.725–0.904) in the external test set. Conclusion Mass increase rate can reflect more sensitively the growth of SSNs associated with lung cancer than diameter and volume increase rates. A deep learning-based model has a great potential to predict the growth of SSNs.