Resected Non-small Cell Lung Cancer Research Articles

Whole slide image-based weakly supervised deep learning for predicting major pathological response in non-small cell lung cancer following neoadjuvant chemoimmunotherapy: a multicenter, retrospective, cohort study

ObjectiveDevelop a predictive model utilizing weakly supervised deep learning techniques to accurately forecast major pathological response (MPR) in patients with resectable non-small cell lung cancer (NSCLC) undergoing neoadjuvant chemoimmunotherapy (NICT), by leveraging whole slide images (WSIs).MethodsThis retrospective study examined pre-treatment WSIs from 186 patients with non-small cell lung cancer (NSCLC), using a weakly supervised learning framework. We employed advanced deep learning architectures, including DenseNet121, ResNet50, and Inception V3, to analyze WSIs on both micro (patch) and macro (slide) levels. The training process incorporated innovative data augmentation and normalization techniques to bolster the robustness of the models. We evaluated the performance of these models against traditional clinical predictors and integrated them with a novel pathomics signature, which was developed using multi-instance learning algorithms that facilitate feature aggregation from patch-level probability distributions.ResultsUnivariate and multivariable analyses confirmed histology as a statistically significant prognostic factor for MPR (P-value< 0.05). In patch model evaluations, DenseNet121 led in the validation set with an area under the curve (AUC) of 0.656, surpassing ResNet50 (AUC = 0.626) and Inception V3 (AUC = 0.654), and showed strong generalization in external testing (AUC = 0.611). Further evaluation through visual inspection of patch-level data integration into WSIs revealed XGBoost’s superior class differentiation and generalization, achieving the highest AUCs of 0.998 in training and robust scores of 0.818 in validation and 0.805 in testing. Integrating pathomics features with clinical data into a nomogram yielded AUC of 0.819 in validation and 0.820 in testing, enhancing discriminative accuracy. Gradient-weighted Class Activation Mapping (Grad-CAM) and feature aggregation methods notably boosted the model’s interpretability and feature modeling.ConclusionThe application of weakly supervised deep learning to WSIs offers a powerful tool for predicting MPR in NSCLC patients treated with NICT.

Prognostic significance and response to immune checkpoint inhibitors of RIPK3, MLKL and necroptosis in non-small cell lung cancer

Lung cancer remains the leading cause of cancer death. Treatment with immune checkpoint inhibitor (ICI) alone or combination with chemotherapy served as first-line therapy in non-small cell lung cancer (NSCLC). However, only 20–50% of NSCLC patients respond to ICI. Necroptosis, an inflammatory form of cell death plays an important role in the regulation of tumor immune microenvironment which may affect prognosis and ICI response but its clinical significance in NSCLC patients has remained largely unknown. Therefore, we aimed to analyze the correlation between key necroptotic proteins and necroptosis and clinical outcomes, the status of tumor-infiltrating immune cells, and response to ICI in NSCLC patients. The expression of receptor-interacting protein kinase 3 (RIPK3), mixed lineage kinase domain-like protein (MLKL) and phosphorylated MLKL (pMLKL) were immunolocalized in 125 surgically resected NSCLC patients and 23 NSCLC patients administered with ICI therapy. CD8 + and FOXp3 + T cells and CD163 + M2 macrophages were also immunolocalized. High RIPK3 status was positively correlated with survival of the patients and RIPK3 turned out an independent favorable prognostic factor of the patients. RIPK3 was negatively correlated with CD8 + T cells, while MLKL positively correlated with CD163 + M2 macrophages, suggesting the possible involvement of RIPK3 and MLKL in formulating immunosuppressive microenvironment. In addition, high RIPK3 status tended to be associated with clinical resistance to ICI therapy (P-value = 0.057). Furthermore, NSCLC cells-expressing RIPK3 suppressed T cells response to ICI therapy in vitro. Therefore, RIPK3 and MLKL could induce an immunosuppressive microenvironment, resulting in low response to ICI therapy in NSCLC.

Exploring clinical factors to predict the survival for resectable non-small cell lung cancer patients with neoadjuvant immunotherapy.

To explore clinical factors and build a predictive model for the disease-free and overall survival in non-small cell lung cancer patients receiving neoadjuvant chemotherapy combined with immune checkpoint inhibitors. Inclusion criteria for patients in this multicentre study were: (1) patients were diagnosed with stage I-III non-small cell lung cancer diagnosed by bronchoscopy biopsy or puncture; (2) computed tomography/positron emission tomography-computed tomography was applied before treatment and surgery; (3) neoadjuvant chemotherapy combined with immune checkpoint inhibitors were applied for 2-6 cycles preoperatively; (4) peripheral blood indicators and tumour markers were assessed before treatment and surgery; (5) patients underwent radical lung cancer surgery after neoadjuvant therapy. Cases were divided into high- and low-risk groups according to 78 clinical indicators based on 10-fold LASSO selection. We employed Cox proportional hazards models in predicting disease-free and overall survival. Then, we used time-dependent area under the curve and decision curve analyses to examine the accuracy of the results. Data were collected continuously, and 212 and 85 cases were randomly assigned to training and testing sets, respectively. The area under curve for the prediction of disease-free survival (training-1-year, 0.83; 2-year, 0.81; 3-year, 0.83 vs testing-1-year, 0.65; 2-year, 0.66; 3-year, 0.70), overall survival (training-1-year, 0.86; 2-year, 0.85; 3-year, 0.86 vs testing-1-year, 0.66; 2-year, 0.57; 3-year, 0.70) were determined. The coefficient factors including pathological response, preoperative tumour maximum diameter, preoperative lymph shorter-diameter, preoperative tumour&lymph maximum standardized uptake value, change in tumour standardized uptake value preoperative, and blood related risk factors were favorably associated with prognosis (P < 0.001). Our prediction model integrating data from preoperative positron emission tomography-CT, preoperative blood parameters, and pathological response was able to make high accuracy predictions for disease-free and overall survival in non-small cell lung cancer patients receiving neoadjuvant immunity with chemical therapy.

Identifying patients who benefit more from perioperative immunotherapy combinations for resectable non-small cell lung cancer based on clinical and molecular characteristics: a meta-analysis of randomized clinical trials.

This study aims to identify patient subgroups who benefit more from perioperative immunotherapy combined with chemotherapy (IO-CT) based on clinical and molecular characteristics in resectable non-small cell lung cancer (NSCLC). Randomized controlled trials (RCTs) on perioperative IO-CT were searched. Beneficial differences of IO-CT regimens across different patient subgroups were assessed by pooling trial-specific ratios in event-free survival (EFS), overall survival (OS), pathological complete response (pCR), and major pathological response (MPR). Six studies (n = 3003) involving five IO-CT regimens were included. Compared to CT alone, all IO-CT regimens significantly improved EFS, OS, MPR, and pCR, but increased toxicity. Toripa-chemo showed the best EFS and nivo-chemo showed the best OS. Patients with PD-L1 ≥ 1% had more EFS benefits compared to those with PD-L1 < 1% (HR [hazard ratio]: 1.55, 95% CI 1.17-2.04). Squamous NSCLC patients had significantly more pCR and MPR benefits than non-squamous NSCLC patients (pCR: OR [odds ratio] 0.68, 95% CI 0.49-0.95; MPR: OR 0.61, 95% CI 0.45-0.82). Former smokers had significantly higher pCR benefits than non-smokers (OR: 2.18; 95% CI 1.21-3.92). Additionally, OS benefit was significantly higher in patients < 65years compared to those ≥ 65years (HR ratio: 0.59, 95% CI 0.36-0.95). For MPR, males benefited significantly more from IO-CT compared to females (OR: 1.69, 95% CI 1.18-2.42). Perioperative IO-CT is more effective but more toxic than CT alone in resectable NSCLC. Patients with PD-L1 ≥ 1%, squamous NSCLC, a history of smoking, age < 65years and male gender may experience greater benefits from perioperative IO-CT.

Osimertinib after definitive chemoradiotherapy in unresectable stage III epidermal growth factor receptor-mutated non-small-cell lung cancer: analyses of central nervous system efficacy and distant progression from the phase III LAURA study.

Distant metastases in non-small-cell lung cancer (NSCLC) are a poor prognostic factor that negatively impact quality of life. The central nervous system (CNS) is a common site of distant progression in epidermal growth factor receptor-mutated (EGFRm) NSCLC. Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor recommended for advanced EGFRm NSCLC and as adjuvant treatment for resected EGFRm NSCLC. In LAURA (NCT03521154), osimertinib demonstrated statistically significant improvement in progression-free survival (PFS) versus placebo in unresectable stage III EGFRm NSCLC without progression during/following chemoradiotherapy (CRT). CNS efficacy and time to death or distant metastases (TTDM) analyses are reported here. Patients without progression during/following definitive platinum-based CRT were randomised 2 : 1 to receive osimertinib (80 mg daily) or placebo until progression [by blinded independent central review (BICR)] or discontinuation. The primary endpoint was PFS by BICR. CNS PFS by neuroradiologist BICR and TTDM by BICR were secondary endpoints. Overall, 216 patients were randomised (143 osimertinib, 73 placebo). Median CNS PFS by neuroradiologist BICR was not reached [95% confidence interval (CI) not calculable (NC)-NC] with osimertinib versus 14.9 months (95% CI 7.4 months-NC) with placebo; hazard ratio (HR) for CNS PFS: 0.17 (95% CI 0.09-0.32). CNS PFS analysis by investigator assessment was consistent with BICR assessment. The cumulative incidence of CNS progression at 12 months was 9% (95% CI 5% to 14%) with osimertinib and 36% (95% CI 24% to 47%) with placebo. There was clinically meaningful improvement in TTDM with osimertinib versus placebo; HR for TTDM: 0.21 (95% CI 0.11-0.38). The cumulative incidence of distant metastases at 12 months was 11% (95% CI 6% to 17%) with osimertinib and 37% (95% CI 26% to 48%) with placebo. Osimertinib demonstrated clinically meaningful improvements in CNS PFS and TTDM versus placebo, supporting osimertinib post-CRT as the standard of care in unresectable stage III EGFRm NSCLC.

Neoadjuvant Osimertinib for the Treatment of Stage I-IIIA Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer: A Phase II Multicenter Study.

To assess the safety and efficacy of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib as neoadjuvant therapy in patients with surgically resectable stage I-IIIA EGFR-mutated non-small cell lung cancer (NSCLC). This was a multi-institutional phase II trial of neoadjuvant osimertinib for patients with surgically resectable stage I-IIIA (American Joint Committee on Cancer [AJCC] V7) EGFR-mutated (L858R or exon 19 deletion) NSCLC (ClinicalTrials.gov identifier: NCT03433469). Patients received osimertinib 80 mg orally once daily for up to two 28-day cycles before surgical resection. The primary end point was major pathological response (MPR) rate. Secondary safety and efficacy end points were also assessed. Exploratory end points included pretreatment and post-treatment tumor mutation profiling. A total of 27 patients were enrolled and treated with neoadjuvant osimertinib for a median 56 days before surgical resection. Twenty-four (89%) patients underwent subsequent surgery; three (11%) patients were converted to definitive chemoradiotherapy. The MPR rate was 14.8% (95% CI, 4.2 to 33.7). No pathological complete responses were observed. The ORR was 52%, and the median DFS was 40.9 months. One treatment-related serious adverse event (AE) occurred (3.7%). No patients were unable to undergo surgical resection or had surgery delayed because of an AE. The most common co-occurring tumor genomic alterations were in TP53 (42%) and RBM10 (21%). Treatment with neoadjuvant osimertinib in surgically resectable (stage IA-IIIA, AJCC V7) EGFR-mutated NSCLC did not meet its primary end point for MPR rate. However, neoadjuvant osimertinib did not lead to unanticipated AEs, surgical delays, nor result in a significant unresectability rate.

The efficacy and safety of neoadjuvant immunochemotherapy in resectable stage I-III non-small cell lung cancer: a systematic review and network meta-analysis.

Neoadjuvant immunochemotherapy (NICT) is a new treatment method for resectable non-small-cell lung cancer (NSCLC). Network meta-analysis assessed efficacy, safety, and optimal treatment. We searched for randomized controlled trials (RCTs) comparing NICT with neoadjuvant chemotherapy (NCT) in PubMed, Embase, Web of Science, Cochrane Library, and international conferences. Outcomes were surgical resection rate, pathological complete response(pCR),event-free survival (EFS), and Grade 3-5 treatment-related adverse events (TRAEs). RCTs of 3,387 patients, six treatment combinations, and two modalities were included. Meta-analysis showed that NICT yielded higher pCR and EFS rates than NCT. The toripalimab-chemotherapy combination had the highest surgical resection rate (OR = 1.68, 95% CI: 1.05-2.73), pCR (OR = 38.84, 95% CI: 11.05-268.19) and EFS (HR = 0.40, 95% CI: 0.28-0.58).This regimen worked well for patients with low programmed death-ligand 1 (PD-L1) expression or squamous cell pathology. For high PD-L1 expression and patients with NSCLC, neoadjuvant nivolumab with chemotherapy had the most efficacy. The incidence of treatment-related adverse events increased with longer treatment cycles, with perioperative nivolumab combined with chemotherapy showing the worst safety profile (RR = 1.32, 95% CI: 1.00-1.76), while neoadjuvant nivolumab combined with chemotherapy alone had the best safety profile (RR = 0.91, 95% CI: 0.68-1.21). Indirect comparison showed no survival benefit for neoadjuvant-adjuvant immunotherapy (HR = 0.93, 95% CI: 0.65-1.35). In the indirect comparison between the two immune checkpoint inhibitors(ICIs), although there was no significant difference in EFS (HR = 0.81, 95% CI: 0.61-1.08), PD-1 inhibitors may still be the most effective treatment option. NICT effectively and safely treats resectable NSCLC. The optimal treatment combination is typically toripalimab and chemotherapy. Treatment based on PD-L1 expression and pathological type is recommended.

Perioperative immunotherapy in nonsmall cell lung cancer.

To evaluate and summarize the current clinical efficacy, safety, treatment patterns, and potential biomarkers, to guide future treatment strategies for nonsmall cell lung cancer (NSCLC), improve patient prognosis, and provide a scientific basis for personalized therapy. In recent years, the class of immune checkpoint inhibitors (ICIs), with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors at the helm, has catalyzed groundbreaking advancements within the perioperative treatment milieu for NSCLC. With the positive results of several phase III clinical trials, perioperative immunotherapy has been confirmed to significantly reduce the risk of postoperative recurrence in resectable NSCLC, becoming the new standard for perioperative treatment of stages II to III NSCLC. With the advent of the perioperative immunotherapy era, clinical issues such as the selection of the treatment population, the choice of regimen, the duration of treatment, whether patients with pCR need further adjuvant therapy, and the comprehensive management of patients throughout the perioperative period have attracted widespread attention. The perioperative treatment of NSCLC has fully entered the era of immunotherapy. Multiple clinical studies have confirmed that perioperative immunotherapy can significantly improve the survival benefit of resectable stages II to III NSCLC, establishing a new standard for the perioperative treatment of stages II to III NSCLC.

The Impact of a Multidisciplinary Team Conference on Non-Small Cell Lung Cancer Care: Time Barriers and Long-Term Outcomes.

Background/Objectives: The prolonged time to reach investigation and management decisions in non-small cell lung cancer (NSCLC) patients can negatively impact long-term outcomes. This retrospective cohort study aims to assess the impact of a multidisciplinary team conference (MDT) on NSCLC care quality and outcomes. Methods: This retrospective study included resectable NSCLC patients who underwent pulmonary resection at Chiang Mai University Hospital, Thailand, from 1 January 2009 to 31 December 2021. Patients were divided into two groups: non-MDT and MDT groups, based on the initiation of MDT on 1 March 2018. The study compared overall survival, disease-free survival, and waiting times for investigation and surgery between the two groups. The effect of MDT on these outcomes was analyzed using multivariable analysis with inverse-probability weighting propensity scores. Results: The study included 859 patients, with 583 in the non-MDT group and 276 in the MDT group. MDT groups had a higher proportion of stage I and II NSCLC patients undergoing pulmonary resection (78.6% vs. 59.69%, p < 0.001). In multivariable analysis, patients in the MDT group had a significantly higher likelihood of longer survival compared to the non-MDT group (adjusted HR 0.23, 95% CI 0.09-0.55). Median waiting times for bronchoscopy (3 days vs. 12 days, p = 0.012), pathologic report (7 days vs. 13 days, p < 0.001), and surgery scheduling (18 days vs. 25 days, p = 0.001) were significantly shorter in the MDT group. Conclusions: An MDT has a survival benefit in NSCLC care and improves waiting times for investigation and treatment steps. Further studies are needed to validate these results.

Different DLCO Parameters as Predictors of Postoperative Pulmonary Complications in Mild Chronic Obstructive Pulmonary Disease Patients with Lung Cancer.

Numerous studies have investigated methods of predicting postoperative pulmonary complications (PPCs) in lung cancer surgery, with chronic obstructive pulmonary disease (COPD) and low forced expiratory volume in 1 second (FEV1) being recognized as risk factors. However, predicting complications in COPD patients with preserved FEV1 poses challenges. This study considered various diffusing capacity of the lung for carbon monoxide (DLCO) parameters as predictors of pulmonary complication risks in mild COPD patients undergoing lung resection. From January 2011 to December 2019, 2,798 patients undergoing segmentectomy or lobectomy for non-small cell lung cancer (NSCLC) were evaluated. Focusing on 709 mild COPD patients, excluding no COPD and moderate/severe cases, 3 models incorporating DLCO, predicted postoperative DLCO (ppoDLCO), and DLCO divided by the alveolar volume (DLCO/VA) were created for logistic regression. The Akaike information criterion and Bayes information criterion were analyzed to assess model fit, with lower values considered more consistent with actual data. Significantly higher proportions of men, current smokers, and patients who underwent an open approach were observed in the PPC group. In multivariable regression, male sex, an open approach, DLCO <80%, ppoDLCO <60%, and DLCO/VA <80% significantly influenced PPC occurrence. The model using DLCO/VA had the best fit. Different DLCO parameters can predict PPCs in mild COPD patients after lung resection for NSCLC. The assessment of these factors using a multivariable logistic regression model suggested DLCO/VA as the most valuable predictor.

1235P Pathologic response as a surrogate endpoint for event-free survival in neo-adjuvant immunotherapy trials of resectable non-small cell lung cancer: A subgroup analysis

1235P Pathologic response as a surrogate endpoint for event-free survival in neo-adjuvant immunotherapy trials of resectable non-small cell lung cancer: A subgroup analysis

LBA48 CCTG BR.31: A global, double-blind placebo-controlled, randomized phase III study of adjuvant durvalumab in completely resected non-small cell lung cancer (NSCLC)

LBA48 CCTG BR.31: A global, double-blind placebo-controlled, randomized phase III study of adjuvant durvalumab in completely resected non-small cell lung cancer (NSCLC)

1213P Neoadjuvant tislelizumab (TIS) plus chemotherapy (CT) with adjuvant TIS vs. neoadjuvant placebo (PBO) plus CT with adjuvant PBO in resectable non-small cell lung cancer (NSCLC): patient-reported outcomes (PRO) in the RATIONALE-315 trial

1213P Neoadjuvant tislelizumab (TIS) plus chemotherapy (CT) with adjuvant TIS vs. neoadjuvant placebo (PBO) plus CT with adjuvant PBO in resectable non-small cell lung cancer (NSCLC): patient-reported outcomes (PRO) in the RATIONALE-315 trial

1190P Circulating tumor DNA from the tumor-draining pulmonary vein as a biomarker in resected non-small cell lung cancer

1190P Circulating tumor DNA from the tumor-draining pulmonary vein as a biomarker in resected non-small cell lung cancer

1209MO Neoadjuvant nivolumab and nivolumab+ipilimumab in resectable non-small cell lung cancer: Combined analysis of 5-year outcomes from NEOSTAR and CA209-159

1209MO Neoadjuvant nivolumab and nivolumab+ipilimumab in resectable non-small cell lung cancer: Combined analysis of 5-year outcomes from NEOSTAR and CA209-159

1239TiP NEO-PIONEER: Neoadjuvant hypofractionated radiotherapy plus tislelizumab with anlotinib followed by adjuvant tislelizumab with anlotinib in patients with resectable non-small cell lung cancer (NSCLC): A phase II trial in progress

1239TiP NEO-PIONEER: Neoadjuvant hypofractionated radiotherapy plus tislelizumab with anlotinib followed by adjuvant tislelizumab with anlotinib in patients with resectable non-small cell lung cancer (NSCLC): A phase II trial in progress

1244P Association of tumor-draining lymph node metastatic patterns and neoadjuvant immunochemotherapy effectiveness in resectable non-small cell lung cancer

1244P Association of tumor-draining lymph node metastatic patterns and neoadjuvant immunochemotherapy effectiveness in resectable non-small cell lung cancer

1230P Association between early endpoints and survival outcomes in neoadjuvant treatment of resectable non-small cell lung cancer (NSCLC): A multi-country retrospective study

1230P Association between early endpoints and survival outcomes in neoadjuvant treatment of resectable non-small cell lung cancer (NSCLC): A multi-country retrospective study

1236P ctDNA-Lung-Detect: Profiling of non-shedding ctDNA early stage resected non-small cell lung cancers

1236P ctDNA-Lung-Detect: Profiling of non-shedding ctDNA early stage resected non-small cell lung cancers

1225P Perioperative serplulimab and chemotherapy in patients with resectable squamous non-small cell lung cancer: An open-label, single-arm, phase II trial

1225P Perioperative serplulimab and chemotherapy in patients with resectable squamous non-small cell lung cancer: An open-label, single-arm, phase II trial