IIIA Non-small Cell Lung Cancer Patients Research Articles

Predicting therapeutic response to neoadjuvant immunotherapy based on an integration model in resectable stage IIIA (N2) non-small cell lung cancer

ObjectiveAccurately predicting response during neoadjuvant chemoimmunotherapy for resectable non-small cell lung cancer (NSCLC) remains clinically challenging. In this study, we investigate the effectiveness of blood-based tumor mutational burden (bTMB) and a deep learning (DL) model in predicting major pathologic response (MPR) and survival from a phase II trial. MethodsBlood samples were prospectively collected from 45 stage IIIA (N2) NSCLC patients undergoing neoadjuvant chemoimmunotherapy. An integrated model, combining the CT-based DL score, bTMB, and clinical factors, was developed to predict tumor response to neoadjuvant chemoimmunotherapy. ResultsAt baseline, bTMB were detected in 77.8% (35 of 45) of patients. Baseline bTMB ≥11 Muts/Mb was associated with significantly higher MPR rates (77.8% vs. 38.5%, p = 0.042), and longer disease-free survival (DFS, p = 0.043), but not overall survival (p = 0.131), compared to bTMB < 11 Muts/Mb in 35 patients with bTMB available. The developed DL model achieved an area under the curve (AUC) of 0.703 in all patients. Importantly, the predictive performance of the integrated model improved to an AUC of 0.820 when combining the DL score with bTMB and clinical factors. Baseline circulating tumor DNA (ctDNA) status was not associated with pathological response and survival. Compared to ctDNA residual, ctDNA clearance before surgery was associated with significantly higher MPR rates (88.2% vs. 11.1%, p < 0.001) and improved DFS (p = 0.010). ConclusionsThe integrated model shows promise as a predictor of tumor response to neoadjuvant chemoimmunotherapy. Serial ctDNA dynamics provide a reliable tool for monitoring tumor response.

Rates of surgery and adjuvant chemotherapy use in patients with stage IB to IIIA non-small cell lung cancer: A provincial population-based study.

134 Background: The current standard of treatment for early-stage (IB to IIIA) non-small cell lung cancer (NSCLC) include surgery and adjuvant chemotherapy. The objective of this study is to identify rates of adherence to guideline recommended surgery and adjuvant chemotherapy treatment for early-stage NSCLC for patients living in Ontario, the most populous province of Canada. Methods: A retrospective population-based study using linked administrative data through ICES was completed that included all adult patients with a diagnosis of stage IB to IIIA NSCLC made from 2010 to 2020 in Ontario. Rates of surgery and chemotherapy completion were calculated using available OHIP (Ontario Health Insurance Plan) billing codes. Logistic multivariate regressions were completed to assess for any predictors for completion of surgery and chemotherapy. Results: A total of 24,237 eligible patients were included. By cancer staging, there were 6,495 (26.8%) stage IB, 7,156 (29.5%) stage II, and 10,586 (43.7%) stage IIIA NSCLC patients. Within 180 days of diagnosis, surgery was completed for 9,929 (41.0%) of patients, by cancer staging were 4090/6495 (63.0%), 3719/7156 (52.0%), and 2120/10586 (20.0%) for IB, II, and IIIA respectively. The median time from diagnosis to surgery was 49 days (IQR 23-77 days). Amongst patients who completed surgery, 3344/9929 (33.7%) underwent at least 1 cycle of adjuvant chemotherapy within 180 days. Having advanced age (p&lt;0.001), high Charlson comorbidity score (p&lt;0.001), and low income (p&lt;0.001) are predictors for poor uptake for both chemotherapy and surgery. Being male also reduces the likelihood of undergoing surgery (p&lt;0.001). Conclusions: In our population-based study, less than half of the patients with early-stage (IB-IIIA) NSCLC underwent surgical resection and chemotherapy. These low treatment rates are concerning and may be contributing to suboptimal outcomes. Our findings indicate that elderly individuals with multiple comorbidities and those with low incomes are at the highest risk of not receiving appropriate chemotherapy and surgery. Our data highlight the need for quality improvement strategies aimed at identifying and enhancing treatment uptake within this patient population.

Clinical significance of DNA damage response mutations in stage I and stage IIIa NSCLC.

DNA damage response (DDR) pathways are essential to sustain genomic stability and play a critical role in cancer development and progression. Here, we investigated the profile of DDR gene mutations in early-stage non-small cell lung cancer (NSCLC) and their prognostic values. We first examined 74 DDR genes involved in seven DDR pathways and then focused on six specific genes: ATM, BRCA1, BRCA2, CHEK1, BARD1, and BRIP1. A total of 179 stage I and IIIa NSCLC patients who received curative resection in Peking Union Medical College Hospital and their corresponding samples were collected for DNA sequencing, immunohistochemistry and survival analysis. A total of 167 eligible patients were finally analyzed. Mutation frequencies were 82% and 26.3% for the selected 74 genes and six genes, respectively. Mismatch repair (MMR) and nucleotide excision repair (NER) alterations were observed more frequently in lung squamous cell carcinoma (LUSC) and smokers were more likely to develop the selected six DDR gene mutations than those who never smoked. Deleterious mutations in the six genes were independent prognostic indicators of significantly longer disease-free survival and overall survival. No association was found between DDR gene status and PD-L1 expression, CD8 positive lymphocyte and tumor-associated macrophage infiltration in tumor area. However, numbers of mutations were significantly increased among patients with DDR alterations. Deleterious mutations of these six genes were common in resected NSCLC and could serve as prognostic biomarkers.

Sociodemographic factors affecting survival in stage IIIA NSCLC treated with surgery-based treatment or definitive chemoradiation with immunotherapy consolidation: An NCDB analysis.

e18555 Background: Stage IIIA non-small cell lung cancer (NSCLC) is a heterogeneous disease treated by surgery-based approach or definitive chemoradiation (CRT) and immunotherapy (ICI) consolidation. Studies have shown that black patients in general are diagnosed at advanced stages, are less likely to receive ICI, and have lower overall survival (OS) compared to whites. Importantly, ICI was shown to impart similar or even better OS among advanced-stage black NSCLC patients, compared to whites. Geographical location and socioeconomic status have also been shown to affect outcomes. There are no studies on sociodemographic factors affecting survival in stage IIIA NSCLC in the ICI era. Methods: We used National Cancer Database (NCDB) to identify 23,110 patients with clinical stage IIIA NSCLC treated with either surgery-based approach or definitive CRT followed by ICI during 2017-2019, and surgery-based treatment or CRT during 2014-2016. We analyzed age, race, sex, insurance type, income, geographic location, Charlson Comorbidity Index (CCI) and education. Kaplan-Meier (KM) plots were used to examine survival curves and descriptive analysis was performed to examine the characteristics of sociodemographic variables by the two treatment modalities. Cox regression analysis was used to identify factors associated with OS. Results: ICI maintenance improved the OS of all stage IIIA NSCLC patients after CRT during 2017-2019 compared to CRT only in 2014-2016. On multivariate analysis of surgical and CRT-ICI cohorts, blacks had slightly better OS compared to whites (HR, 95%CI, p-value) (0.89, 0.84-0.95, &lt; 0.001) but lower than other races including Asians (0.77, 0.69-0.87, &lt; 0.001). While there was no OS difference in the surgical arm (0.94, 0.83-1.07, p = 0.356) between black and white patients, better survival was seen in blacks in the CRT-ICI arm (0.88, 0.82-0.94, &lt; 0.001). No significant interaction between race and CRT-ICI was identified which indicates the benefit of CRT-ICI is independent of the race effect. Other factors associated with lower OS were older age with age &gt; 75 HR 1.00, ages 19-39 (0.47, 0.35-0.64) ages 40-64 (0.71, 0.67-0.75), ages 65-74 (0.79, 0.76-0.83), median quartile income &lt; $40,227 (1.07, 1.01-1.14), non-metro location (1.12, 1.07-1.17), non-academic facility (1.09, 1.05-1.14), and male sex (1.24, 1.20-1.29). Insurance status had no effect on OS. Conclusions: Our study indicates that there is no survival difference between white and black patients treated with surgery, but blacks had better survival when treated with CRT-ICI. Racial disparity in NSCLC survival depends on stage and access to care. Treatment modality, income, metro location, and access to an academic center are more significant predictors of survival than race. Interestingly, health insurance had no impact on OS.

The Validation of Predictive Risk Scoring Model of Radiation Pneumonitis (RP) in Lung Cancer Patients

<h3>Purpose/Objective(s)</h3> In our previous research, pulmonary emphysema (PE) was reported as a risk factor of radiation pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC). Subclinical interstitial lung disease (SILD) was associated with severe RP in small cell lung cancer patients. A predictive risk scoring model of RP was developed in stage IIIA or Stage IIIB NSCLC patients receiving radical radiotherapy. The risk score has not been validated using an independent dataset. The aim of this study was to validate the predictive risk score which established in our previous study and evaluate the predictive value of the model. <h3>Materials/Methods</h3> From January 2019 to October 2021,129 lung cancer patients were recruited in study which included in validation group. Those patients were received thoracic radiotherapy with ≥50Gy total radiotherapy dose. The risk scoring model in our previous research as follow: PRS=5 (if subclinical ILD grade≥1) + 3 (if age >68 years) + 3 (if PE grade >1). According to the risk score, the cases in validation group were scored, predictive value of this model were evaluated by receiver operator characteristic curve (ROC) using statistical software. The decision curve analysis was constructed using Stata 17.0 software. <h3>Results</h3> In 129 eligible patients, 13(10.08%, 13/129) developed grade 1 RP, 15(11.62%, 15/129) developed grade 2 RP, grade 3 and grade 4 RP were not observed. 23 (16.60%, 23/129) had PE grade >1. Risk scores of all patients were calculated according to the risk score, 37 had 3 points which incidence of RP ≥2 grade was 13.50%, 2 had 5 points which incidence of RP ≥2 grade was 100.0%, 3 had 6 points which incidence of RP ≥2 grade was 33.33%. ROC curve was plotted according to the risk score of all patients, the area of ROC curve (AUC) was 0.695 (95%CI: 0.541-0.849, P < 0.05). The decision curve indicated that the net benefit of the model was higher in the high-risk threshold of 0.2-0.3. <h3>Conclusion</h3> The previous predictive risk scoring model indicated good discrimination and clinical application value, which can be used in clinical treatment.

Real-life long-term outcomes of upfront surgery in patients with resectable stage I-IIIA non-small cell lung cancer.

BackgroundTreatment of early-stage non-small cell lung cancer (NSCLC) is rapidly evolving. When introducing novelties, real-life data on effectiveness of currently used treatment strategies are needed. The present study evaluated outcomes of stage I–IIIA NSCLC patients treated with upfront radical surgery in everyday clinical practice, between 2010–2017.Patients and methodsData of 539 consecutive patients were retrieved from a prospective hospital-based registry. All diagnostic, treatment and follow-up procedures were performed at the same thoracic oncology centre according to the valid guidelines. The primary outcome was overall survival (OS) analysed by clinical(c) and pathological(p) TNM (tumour, node, metastases) stage. The impact of clinicopathological characteristics on OS was evaluated using univariable (UVA) and multivariable regression analysis (MVA).ResultsWith a median follow-up of 53.9 months, median OS and 5-year OS rate in the overall population were 90.4 months and 64.4%. Five-year OS rates by pTNM stage I, II and IIIA were 70.2%, 60.21%, and 49.9%, respectively. Both cTNM and pTNM stages were associated with OS; but only pTNM retained its independent prognostic value (p = 0.003) in MVA. Agreement between cTNM and pTNM was 69.0%. Next to pTNM, age (p = 0.001) and gender (p = 0.004) retained their independent prognostic value for OS.ConclusionsThe study showed favourable outcomes of resectable stage I–IIIA NSCLC treated with upfront surgery in real-life. Relatively low agreement between cTNM and pTNM stages and independent prognostic value of only pTNM, observed in real-life data, suggest that surgery remains the most accurate provider of the anatomical stage of disease and important upfront therapy.

Single-cell profiling of immune cells after neoadjuvant pembrolizumab and chemotherapy in IIIA non-small cell lung cancer (NSCLC)

The combination of immune checkpoint inhibitors (ICIs) with chemotherapy (chemoimmunotherapy) in the neoadjuvant setting have achieved favorable clinical benefits in non-small cell lung cancer (NSCLC), but the mechanism of clinical responses remain unclear. We provide a rich resource of 186,477 individual immune cells from 48 samples of four treatment-naive and eight neoadjuvant chemoimmunotherapy treated IIIA NSCLC patients (responders versus non-responders) by single-cell RNA-seq and TCR-seq. We observed the synergistic increase of B cells and CD4+ T cells were associated with a positive therapeutic response of neoadjuvant chemoimmunotherapy. B cell IgG subclasses IgG1 and IgG3 played a critical role in anti-tumor immune response in tumor lesions, and this process was driven by increased IL-21 secreted by infiltrated T follicular helper (Tfh) cells after neoadjuvant chemoimmunotherapy. Furthermore, we uncovered several critical events for positive clinical outcomes, including the diminished activated TNFRSF4+ regulatory T cells (Tregs), increased LAMP3+ dendritic cells (DCs), and the expansion of intratumoral CD4+ T clones and peripheral C3-Cytotoxic CD8+ T clones. A validation cohort of 26 treatment-naive and 30 neoadjuvant chemoimmunotherapy treated IIIA/ IIIB NSCLC patients verified these findings. In total, our comprehensive study of the single-cell profile of immune cells provides insights into mechanisms underlying anti-PD-1-based therapies and identified potential predictive factors and therapeutic targets for improving the efficiency of neoadjuvant chemoimmunotherapy in NSCLC.

Combining variant detection and fragment length analysis improves detection of minimal residual disease in postsurgery circulating tumour DNA of stage II-IIIA NSCLC patients.

Stage II–IIIA nonsmall cell lung cancer (NSCLC) patients receive adjuvant chemotherapy after surgery as standard‐of‐care treatment, even though only approximately 5.8% of patients will benefit. Identifying patients with minimal residual disease (MRD) after surgery using tissue‐informed testing of postoperative plasma circulating cell‐free tumour DNA (ctDNA) may allow adjuvant therapy to be withheld from patients without MRD. However, the detection of MRD in the postoperative setting is challenging, and more sensitive methods are urgently needed. We developed a method that combines variant calling and a novel ctDNA fragment length analysis using hybrid capture sequencing data. Among 36 stage II–IIIA NSCLC patients, this method distinguished patients with and without recurrence of disease in a 20 times repeated 10‐fold cross validation with 75% accuracy (P = 0.0029). In contrast, using only variant calling or only fragment length analysis, no signification distinction between patients was shown (P = 0.24 and P = 0.074 respectively). In addition, a variant‐level fragmentation score was developed that was able to classify variants detected in plasma cfDNA into tumour‐derived or white‐blood‐cell‐derived variants with 84% accuracy. The findings in this study may help drive the integration of various types of information from the same data, eventually leading to cheaper and more sensitive techniques to be used in this challenging clinical setting.

Single-cell profiling of immune cells associated with response to neoadjuvant chemoimmunotherapy in IIIA non-small cell lung cancer (NSCLC).

e20584 Background: The combination of immune checkpoint inhibitors (ICIs) with chemotherapy (chemoimmunotherapy) in the neoadjuvant setting have achieved favorable clinical benefits in non-small cell lung cancer (NSCLC), but the underlying molecular mechanism has not been fully elucidated. Methods: To identify factors associated with the clinical outcome, single-cell RNA/TCR sequencing was performed using 10x Genomics on CD45+ immune cells isolated from tumor and multiple immune-relevant tissues and peripheral blood of four treatment-naïve and eight neoadjuvant chemoimmunotherapy treated IIIA NSCLC patients (responders versus non-responders). Bioinformatics analysis was used to screen immune cell factors associated with therapy response in single-cell sequencing profiles, and results were verified at protein level by flow cytometry, multiplex fluorescent immunohistochemistry (mIHC) and ELISA. Results: A total of 186,477 immune cells from 48 samples were acquired after quality-control filtering. The synergistic increase of B cells and CD4+ T cells are associated with positive therapeutic response of neoadjuvant chemoimmunotherapy. B cell class switching to IgG1 and IgG3 plays a critical role in anti-tumor immune response in tumor lesion, and this process is driven by increased IL-21 protein secreted by infiltrated T follicular helper (Tfh) cells after neoadjuvant chemoimmunotherapy. Several critical events lead to the positive clinical outcome during neoadjuvant chemoimmunotherapy, including the diminished activated TNFRSF4+ regulatory T cells (Tregs), increased LAMP3+ dendritic cells (DCs), high pretreatment peripheral blood T-cell diversity, and the expansion of intratumoral CD4+ T clones and peripheral CD8+ T clones. A validation cohort of 26 treatment-naïve and 30 neoadjuvant chemoimmunotherapy treated IIIA NSCLC patients verified these findings. Conclusions: Single-cell profiling of the immune response to neoadjuvant chemoimmunotherapy uncovered several critical factors of anti-tumor immune response and provided insight of potential novel predictive factors and therapeutic targets for improving the efficacy of treatment in NSCLC.

A validated nomogram integrating baseline peripheral T-lymphocyte subsets and NK cells for predicting survival in stage I-IIIA non-small cell lung cancer after resection.

BackgroundAccurately predicting the risk of recurrence in stage I–IIIA non-small cell lung cancer (NSCLC) after resection is critical in the treatment process. This study aimed to establish a novel nomogram to identify patients with a risk of disease progression in stage I–IIIA lung cancer based on clinical characteristics, peripheral T-lymphocyte subsets, and CD16+56 natural killer (NK) cells.MethodsA total of 306 NSCLC patients from Shanghai Municipal Hospital of Traditional Chinese Medicine between 2010 and 2020 who met the inclusion and exclusion criteria between January 2011 and December 2020 were retrospectively reviewed. Patients were randomly assigned to the training cohort (206 patients) and the validation cohort (100 patients). A nomogram model was developed based on the results of multivariate Cox regression in the training cohort. The optimal cut-off values were determined by X-tile software. The bootstrap method was used to validate the nomogram. Receiver operating characteristics curves (ROC) and the area under the ROC curve (AUC) were used to compare prognostic factors. The concordance index (C-index) was calculated to determine the accuracy of the nomogram in predicting disease-free survival (DFS).ResultsGender, drinking history, TNM stage, and CD4+T/CD8+T were independent factors for DFS and were integrated into the model, while CD16+56 NK cells were not proven to be significant independent factors for DFS. The calibration curves for probability of 3- and 5-year DFS showed excellent agreement between predicted and actual survival. The C-index for the nomogram to predict DFS was 0.839 in the training cohort. The nomogram showed an excellent predictive performance in the training cohort (3-/5-year AUC: 0.860/0.847) and in the validation cohort (3-/5-year AUC: 0.726/0.748).ConclusionsWe developed a prognostic model which provided individual prediction of DFS for stage I–IIIA NSCLC patients after resection. This practical prognostic tool may help oncologists in clinical treatment planning.

Molecular Markers for Long-term Survival in Stage IIIA (N2) NSCLC Patients.

Survival rates among non-small cell lung cancer (NSCLC) stage IIIA (N2) patients are generally low and depend on the treatment. We aimed to identify predictive markers for long term survival in responders and non-responders to chemotherapy, analyzing tumour and non-tumour samples by microarray (n=35) and whole exome sequencing (WES, n=25). WES data showed correlation of overall survival of all patients with rs9905892 in the SLFN12L gene. High frequency of mutations (4/6, 66.7%) was identified in members of SWI/SNF complex in responder patients and in patients that were alive after seven years. Microarray data for immune components showed that VISTA (VSIR) was down-regulated in tumoral tissue. Our research suggests that mutations in SWI/SNF complex associate with long term survival after multimodal treatment, while down-regulation of VISTA might indicate its immunomodulatory role in NSCLC stage III (N2) patients.

Importance of tumour volume and histology in trimodality treatment of patients with Stage IIIA non-small cell lung cancer-results from a retrospective analysis.

OBJECTIVESChemoradiotherapy (CRT) has been the backbone of guideline-recommended treatment for Stage IIIA non-small cell lung cancer (NSCLC). However, in selected operable patients with a resectable tumour, good results have been achieved with trimodality treatment (TT). The objective of this bi-institutional analysis of outcomes in patients treated for Stage IIIA NSCLC was to identify particular factors supporting the role of surgery after CRT.METHODSIn a 2-centre retrospective cohort study, patients with Stage III NSCLC (seventh edition TNM) were identified and those patients with Stage IIIA who were treated with CRT or TT between January 2007 and December 2013 were selected. Patient characteristics as well as tumour parameters were evaluated in relation to outcome and whether or not these variables were predictive for the influence of treatment (TT or CRT) on outcome [overall survival (OS) or progression-free survival (PFS)]. Estimation of treatment effect on PFS and OS was performed using propensity-weighted cox regression analysis based on inverse probability weighting.RESULTSFrom a database of 725 Stage III NSCLC patients, 257 Stage IIIA NSCLC patients, treated with curative intent, were analysed; 186 (72%) with cIIIA-N2 and 71 (28%) with cT3N1/cT4N0 disease. One hundred and ninety-six (76.3%) patients were treated by CRT alone (high-dose radiation with daily low-dose cisplatin) and 61 (23.7%) by TT. The unweighted data showed that TT resulted in better PFS and OS. After weighting for factors predictive of treatment assignment, patients with a large gross tumour volume (>120 cc) had better PFS when treated with TT, and patients with an adenocarcinoma treated with TT had better OS, regardless of tumour volume.CONCLUSIONSPatients with Stage IIIA NSCLC and large tumour volume, as well as patients with adenocarcinoma, who were selected for TT, had favourable outcome compared to patients receiving CRT. This information can be used to assist multidisciplinary team decision-making and for stratifying patients in studies comparing TT and definitive CRT.

Neoadjuvant camrelizumab, nab-paclitaxel, and carboplatin in patients with stage IB-IIIA non-small cell lung cancer (NANE-LC): a study protocol of prospective, single-arm, multicenter, phase II study.

BackgroundPrevious studies have shown that neoadjuvant immune checkpoint inhibitors (ICIs) combined with chemotherapy in patients with stage IB–IIIA non-small cell lung cancer (NSCLC) significantly improved the major pathological response (MPR) and the pathological complete response (pCR) rates. However, high-level evidence-based medical data confirming this effect are still lacking. In addition, there is an urgent need to develop an appropriate strategy to predict the benefit for patients receiving ICIs. In this study, we describe an ongoing study on the effect of neoadjuvant therapy with camrelizumab, nab-paclitaxel, and carboplatin on stage IB–IIIA NSCLC patients. The aim of this study is to establish a multiomics artificial intelligence system for predicting neoadjuvant therapy efficacy and assisting decision-making.MethodsThis prospective, single-arm, multicenter, phase II trial will enroll a total of 40 patients who will undergo surgery after three cycles of neoadjuvant therapy with camrelizumab, nab-paclitaxel, and carboplatin. The MPR rate is the primary endpoint, while the rates of pCR, complete resection, objective response, disease-free survival (DFS), adverse events (AEs), and quality of life (QOL) are secondary endpoints. Exploratory endpoints will serve to establish a multiomics artificial intelligence system for neoadjuvant therapy effect prediction and decision-making assistance based on radiomics, metabolism, genetic, and clinic-pathological characteristics and to explore the mechanisms of drug resistance.DiscussionThe efficacy of ICIs is influenced by many factors, including patient’s driver genes and smoking status. Thus, further subgroup analysis is needed. This study will indicate if our new multiomics artificial intelligence system constitutes a valid strategy for neoadjuvant therapy effect prediction and decision-making assistance in the context of neoadjuvant camrelizumab, nab-paclitaxel, and carboplatin treatment for patients with stage IB–IIIA NSCLC.Trial RegistrationThis trial has been registered at ClinicalTrials.gov (identification number: NCT04541251).

Abstract 2606: A nCounter-Based mRNA signature in plasma associates with localized non-small cell lung cancer

Abstract Background: 80% of non-small cell lung cancer (NSCLC) cases are diagnosed at stages IIIB-IV and have a dismal prognosis with a median life expectancy that does not exceed 2 years. In contrast, patients diagnosed at early and locally advanced stages (I-IIIA) can undergo surgery and have the potential to be totally cured. Imaging technologies often detect lung nodules of unknown significance that pose a diagnostic challenge; some patients with benign nodules are submitted to unnecessary surgical interventions while others with small tumors are just kept in observation, risking a significant delay for treatment. A diagnostic test that could differentiate between benign and malignant masses would be of great help in this setting. Methods: Circulating-free RNA (cfRNA) was isolated from the plasma of healthy individuals (N=21), early(I-II) stage (N=22) and stage IIIA (N=12) NSCLC patients, using an automatic extraction method(Qiasymphony, Qiagen). Purified cfRNA was quantified using Qubit, retrotranscribed and pre-amplified (14cycles) using the Low RNA Input Amplification kit (NanoString Technologies). Gene expression analysis was performed on the nCounter platform using the PanCancer IO360TM (NanoString Technologies), which can detect 770 transcripts related to tumor biology, micro-environment and the immune system. Results: Gene expression analysis revealed differential patterns for some cf-mRNAs from localized stage NSCLC patients versus healthy controls. A bioinformatics recursive feature elimination algorithm selected a 16-gene mRNA signature that was able to distinguish between localized NSCLC and control samples with an area under the ROC curve of 0.91 to 0.95. Furthermore, the signature scores derived from the algorithm were significantly different between the two cohorts. Conclusions: We have found an 16-gene signature that can differentiate between cfRNA of localized stages NSCLC patients and control individuals. Our results warrant validation studies in larger cohorts. Citation Format: Ana Giménez Capitán, Jillian Bracht, Nicolas Potie, María González-Cao, Santiago Viteri, Alejandro Martínez-Bueno, Carlos Cabrera-Gálvez, Pablo Rubinstein, Clara Mayo-de-las-Casas, Joselyn Valarezo, Chung-Ying Huang, Carlos Pedraz, Richard Boykind, Sarah Warren, Rafael Rosell, Miguel Ángel Molina-Vilaa, Andrés Aguilar-Hernández. A nCounter-Based mRNA signature in plasma associates with localized non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2606.

Blood biomarkers associated to complete pathological response on NSCLC patients treated with neoadjuvant chemoimmunotherapy included in NADIM clinical trial.

BackgroundImmunotherapy is being tested in early‐stage non‐small cell lung cancer (NSCLC), and achieving higher rates of complete pathological responses (CPR) as compared to standard of care. Early identification of CPR patients has vital clinical implications. In this study, we focused on basal peripheral immune cells and their treatment‐related changes to find biomarkers associated to CPR.MethodsBlood from 29 stage IIIA NSCLC patients participating in the NADIM trial (NCT03081689) was collected at diagnosis and post neoadjuvant treatment. More than 400 parameters of peripheral blood mononuclear cells (PBMCs) phenotype and plasma soluble factors were analyzed.ResultsNeoadjuvant chemoimmunotherapy altered more than 150 immune parameters. At diagnosis, 11 biomarkers associated to CPR were described, with an area under the ROC curve >0.70 and p‐value <.05. CPR patients had significantly higher levels of CD4+PD‐1+ cells, NKG2D, and CD56 expression on T CD56 cells, intensity of CD25 expression on CD4+CD25hi+ cells and CD69 expression on intermediate monocytes; but lower levels of CD3+CD56–CTLA‐4+ cells, CD14++CD16+CTLA‐4+ cells, CTLA‐4 expression on T CD56 cells and lower levels of b‐NGF, NT‐3, and VEGF‐D in plasma compared to non‐CPR. Post treatment, CPR patients had significantly higher levels of CD19 expression on B cells, BCMA, 4‐1BB, MCSF, and PARC and lower levels of MPIF‐1 and Flt‐3L in plasma compared to non‐CPR.ConclusionsPatients achieving CPR seem to have a distinctive peripheral blood immune status at diagnosis, even showing different immune response to treatment. These results reinforce the different biology behind CPR and non‐CPR responses.

Modeling the cost-effectiveness of adjuvant osimertinib in resected EGFR-mutant non-small cell lung cancer patients.

8527 Background: Adjuvant Osimertinib (Osi) was recently approved for resected EGFR-mutant non-small cell lung cancer (NSCLC) based on disease free survival (DFS) benefits from the ADAURA trial. Prior studies of adjuvant EGFR inhibitors yielding DFS benefits have lacked an overall survival (OS) benefit, leading to debate over early clinical implementation given the associated drug costs. This study aims to evaluate the cost-effectiveness (CE) of Osi in this setting. Methods: We constructed Markov models using post-resection health state transitions with digitized DFS data from the ADAURA trial to compare cost and quality-adjusted life years (QALYs) of the use of 3 years of adjuvant Osi versus placebo in the ADAURA patient population of stage IB to IIIA NSCLC patients over a 10-year time horizon. All patients entering the progressive disease (PD) state were assigned for re-treatment with Osi. Cost and utility values were derived from Medicare reimbursement data and literature (Table). A CE threshold of 3 times the GDP per capita was used. Deterministic sensitivity analyses were performed to assess the impact of a range of OS benefit, as the impact of adjuvant Osi on OS has not yet been reported. Results: The incremental cost-effectiveness ratio (ICER) for adjuvant Osi was $317,119.90 per QALY gained. Initial costs of Osi are higher in the first 3 years, but become lower than the placebo group in year 4 onward, with similar costs after year 7. Costs due to PD are higher in the placebo group through the first 6.5 years. Average pre-PD, post-PD, and total costs were $2,388, $379,047, and $502,937, respectively in the placebo group, compared to $505,775, $255,638, and $800,697, respectively in the Osi group. QALYs were higher in the Osi arm throughout. Sensitivity analysis using incremental OS gains reaches the CE threshold of $195,000 between 25-30% OS benefit of Osi over placebo. A 50% discount to the Osi annual cost yielded an ICER of $115,419. Conclusions: 3 years of adjuvant Osi is more cost-effective than placebo if one is willing to pay $317,119 more per QALY gained, with most costs accruing in the first 3 years as drug cost. This strategy became cost-effective with an OS benefit between 25-30% over placebo. Discount to Osi annual costs improves the ICER significantly. True cost-effectiveness of adjuvant Osi will require further study due to immaturity of ADAURA OS data and model limitations.[Table: see text]

Influence of bilateral mediastinal lymph node dissection on survival in non-small cell lung cancer patients – Randomized study

ObjectivesThis study aimed to analyze the effect of bilateral mediastinal lymphadenectomy (BML) on survival of non-small cell lung cancer (NSCLC) patients. The hypothesis was: BML offers survival benefit as compared with SLND. MethodsA randomized clinical trial including stage I–IIIA NSCLC patients was performed. All patients underwent anatomical lung resection. BML was performed during the same operation via additional cervical incision (BML group). In the control group, standard lymphadenectomy (systematic lymph node dissection, SLND) was performed. ResultsIn total, 102 patients were randomized. No significant difference was found in the type of lung resection, blood loss, chest tube output, air leak, pain, and complications (p = 0.188–0.959). In the BML group, the operative time was longer (318 vs 223 min, p < 0.001) with higher number of removed N2 nodes (24 vs 14, p < 0.001). The 5-year survival rate was 72 % in the BML group vs 53 % in the SLND group (OR 2.33, 95 % CI 0.95–5.69, p = 0.062). Separate comparisons for different lobar locations of the tumor have shown no significant difference in survival for the right lung tumors and left upper lobe tumors. For the left lower lobe tumors, survival time was longer in the BML group (p = 0.021), and the 5-year survival rate was 90.9 % vs 37.5 %, (OR 16.66, 95 % CI 1.36–204.04, p = 0.0277). ConclusionsIn patients with NSCLC located in the left lower lobe, bilateral lymph node dissection may be associated with better survival. The invasiveness of BML is comparable to that of SLND.

The safety and efficacy of neoadjuvant programmed death 1 inhibitor therapy with surgical resection in stage IIIA non-small cell lung cancer.

BackgroundLung cancer ranks as the most prevalent solid cancer in the world. The non-small-cell lung cancer (NSCLC) histological subtype accounts for the largest proportion of lung cancers. Even though neoadjuvant therapy has shown encouraging efficacy for resectable NSCLC, there is a lack of clinical data on the treatment of stage IIIA NSCLC patients. Therefore, we carried out an evaluation of the safety and efficacy of programmed cell death 1 (PD-1) inhibitor as an addition to neoadjuvant chemotherapy.MethodsThis prospective study involved 72 treatment-naive adult subjects with stage IIIA NSCLC between September 2019 and July 2020. Two circles PD-1 inhibitor with chemotherapy (Albumin paclitaxel 100 mg/m2 d1,8 + Carboplatin AUC 5 d1) were administered intravenously every 3 weeks. The patients were operated on between 3 and 5 weeks following the second cycle. Feasibility and safety served as the primary endpoints for this study. The rates of pathologic complete response, complete resection, response rate, and operative and postoperative complications among the patients were also analyzed.ResultsSeventy-two patients with untreated stage IIIA NSCLC were enrolled. The postoperative pathological specimens of 21 (29.1%) and 47 (65.2%) patients suggested pathologic complete response and partial remission, respectively. Neoadjuvant PD-1 inhibitor with chemotherapy had an acceptable side effect profile, and none of the subjects withdrew from the study preoperatively due to disease progression or toxicity. According to Response Evaluation Criteria in Solid Tumors (RESIST), responses evaluated by CT scan before surgery, 21 and 47 patients achieved complete response (CR) and partial response (PR), respectively, and a single patient was evaluated as stable disease (SD). There were no postoperative deaths.ConclusionsThe outcomes of PD-1 inhibitor with chemotherapy as a novel treatment for stage IIIA NSCLC in the neoadjuvant setting are satisfactory with respect to the high R0 resection rate and low toxicity profile. Prospective comparative and longer follow-up trials are needed to confirm the long-term outcomes of this novel treatment and to reach definitive conclusions.

Clinical impact of the tumor immune microenvironment in completely resected stage IIIA(N2) non-small cell lung cancer based on an immunoscore approach.

Background:Completely resected stage IIIA(N2) non-small cell lung cancer (NSCLC) comprises a heterogeneous population according to discrepancies in survival prognosis. Accumulating evidence suggests that tumor-infiltrating lymphocytes (TILs) are clinically significant, despite a lack of consensus regarding the immunoscore (IS) in NSCLC. Here, we determined the prognostic value of the immune microenvironment as an IS in a uniform cohort of patients with completely resected stage IIIA(N2) NSCLC.Methods:Consecutive patients with pathologically confirmed stage IIIA(N2) NSCLC and who underwent complete resection (2005–2012) were retrospectively reviewed. Tissue microarrays (TMAs) were constructed from surgical paraffin-embedded primary lung tumor specimen. For each case, two representative regions from the tumor center (CT) and two from the invasive margin (IM) containing the highest density of lymphocytes were selected. Densities of CD3+, CD45RO+, and CD8+ lymphocytes were assessed using immunohistochemistry (IHC) by specialized pathologists according to predefined scoring scales. Patients were classified according to IS definition based on TIL type, density, and distribution, and relationships between IS and prognosis were evaluated.Results:Patients (N = 288) with complete IHC-based TMA spots were included. Univariate analyses showed that CD3+ T cell density was associated with neither overall survival (OS) nor distant metastasis-free survival (DMFS), whereas CD45RO+ T cell density in the IM was a significant prognostic factor for DMFS (p = 0.02) and was predictive of OS (p = 0.05). Combined CD45RO+ and CD8+ cell infiltration in tumor regions (CT and IM) significantly improved IS prognostic impact. Multivariate analyses revealed IS as an independent prognostic predictor for both DMFS (p = 0.001) and OS (p = 0.002).Conclusion:The proposed IS might provide valuable prognostic information, including prediction of DMFS and OS in stage IIIA(N2) NSCLC patients. Larger patient cohorts are needed to validate this IS classification, which might assist with accurate risk stratification and treatment decisions.

Variation Between Multidisciplinary Tumor Boards in Clinical Staging and Treatment Recommendations for Patients With Locally Advanced Non-small Cell Lung Cancer

BackgroundAccurate diagnosis and staging are crucial to ensure uniform allocation to the optimal treatment methods for non-small cell lung cancer (NSCLC) patients, but may differ among multidisciplinary tumor boards (MDTs). Discordance between clinical and pathologic TNM stage is particularly important for patients with locally advanced NSCLC (stage IIIA) because it may influence their chance of allocation to curative-intent treatment. We therefore aimed to study agreement on staging and treatment to gain insight into MDT decision-making.Research QuestionWhat is the level of agreement on clinical staging and treatment recommendations among MDTs in stage IIIA NSCLC patients?Study Design and MethodsEleven MDTs each evaluated the same 10 pathologic stage IIIA NSCLC patients in their weekly meeting (n = 110). Patients were selected purposively for their challenging nature. All MDTs received exactly the same clinical information and images per patient. We tested agreement in cT stage, cN stage, cM stage (TNM 8th edition), and treatment proposal among MDTs using Randolph’s free-marginal multirater kappa.ResultsConsiderable variation among the MDTs was seen in T staging (κ, 0.55 [95% CI, 0.34-0.75]), N staging (κ, 0.59 [95% CI, 0.35-0.83]), overall TNM staging (κ, 0.53 [95% CI, 0.35-0.72]), and treatment recommendations (κ, 0.44 [95% CI, 0.32-0.56]). Most variation in T stage was seen in patients with suspicion of invasion of surrounding structures, which influenced such treatment recommendations as induction therapy and type. For N stage, distinction between N1 and N2 disease was an important source of discordance among MDTs. Variation occurred between 2 patients even regarding M stage. A wide range of additional diagnostics was proposed by the MDTs.InterpretationThis study demonstrated high variation in staging and treatment of patients with stage IIIA NSCLC among MDTs in different hospitals. Although some variation may be unavoidable in these challenging patients, we should strive for more uniformity.