Management Of NSCLC Research Articles

EP.17A.02 Diagnostic and Treatment Gaps in NSCLC Management Compared to NCCN Recommendations: An Audit Analysis of 214 Cases

EP.17A.02 Diagnostic and Treatment Gaps in NSCLC Management Compared to NCCN Recommendations: An Audit Analysis of 214 Cases

VELOCITY-Lung substudy-03: A phase 2 study of neoadjuvant domvanalimab (dom)+zimberelimab (zim)+chemotherapy (chemo) or zim+chemo followed by adjuvant dom+zim or zim in patients with resectable stage II-III non-small cell lung cancer (NSCLC).

TPS8121 Background: Management of resectable NSCLC involves surgery with perioperative systemic therapy. Immune checkpoint inhibitors (CPIs) and targeted therapies are now used in the perioperative setting, leading to improved survival outcomes. The combination of dom (anti–T-cell immunoglobulin and ITIM domain [TIGIT]) and zim (anti–programmed death protein 1 [PD-1]) has shown promising antitumor activity with a manageable safety profile in metastatic NSCLC and may provide an opportunity to improve clinical outcomes in the perioperative setting in early-stage, resectable NSCLC. Substudy-03 of the VELOCITY-Lung platform study is evaluating novel perioperative treatment combinations in patients with newly diagnosed, resectable, stage II-III NSCLC. Methods: VELOCITY-Lung (NCT05633667) is an open-label, multicenter, phase 2 platform study with 3 ongoing substudies targeting the different NSCLC patient populations. Key eligibility criteria for Substudy-03 include age ≥ 18 years, histologically/cytologically confirmed stage II, IIIA, IIIB (T[3-4]N2) (per AJCC 8th ed.) squamous or nonsquamous NSCLC considered resectable with curative intent, no prior systemic or CPI therapy or radiotherapy, ECOG PS 0-1, any PD-1 ligand (PD-L1) status, and no actionable EGFR or ALK genomic alterations in patients with nonsquamous NSCLC. Randomization in Substudy-03 will be stratified by disease stage (II vs III) and baseline PD-L1 expression status (≥ 50% vs < 50%). Current treatment groups in the neoadjuvant phase of the preliminary stage are: (A) dom+zim+platinum (Pt)-based chemo or (B) zim+Pt-based chemo for a maximum of 3 cycles; this will be followed by definitive surgery within 6 weeks of completing neoadjuvant treatment. Adjuvant treatment will include: (A) dom+zim or (B) zim and will begin within 12 weeks of surgery. Patients will continue to receive adjuvant treatment until disease recurrence, death, or unacceptable toxicity or to a maximum of 14 cycles. Dosing will be as follows: zim 360 mg intravenously (IV) once every 3 weeks (Q3W) and dom 1200 mg IV once Q3W (up to 3 cycles in the neoadjuvant phase and up to 14 cycles in the adjuvant phase). Pt-based chemo will be based on patient tumor histology (squamous vs nonsquamous). The primary endpoint is pathological complete response rate, defined as the percentage of patients with no residual invasive cancer in resected lung specimens and lymph nodes, assessed by local pathology review. Secondary endpoints include major pathological response rate (percentage of patients with ≤ 10% residual tumor in lung and lymph nodes at surgery), event-free survival, overall survival, and safety. Approximately 31 patients will be enrolled into each treatment group of the preliminary phase. The study is currently recruiting. Clinical trial information: NCT05633667 .

The significance of inflammatory markers in prognosticating the effectiveness and safety of immunotherapy in conjunction with chemotherapy during the primary intervention of advanced non-small cell lung carcinoma

ObjectiveThe aim of this study is to scrutinize the prognostic significance of inflammatory biomarkers concerning the effectiveness and safety of combining PD-1 inhibition with chemotherapy in the management of advanced NSCLC. MethodsWe conducted a retrospective analysis involving 206 NSCLC patients who received treatment at Qingdao Municipal Hospital. The study encompassed the acquisition of baseline clinical attributes and hematological parameters of these patients. The optimal threshold values for PLT and NLR were ascertained based on pre-treatment evaluations, with a particular focus on their association with PFS. Variables linked to PFS were subject to scrutiny through Kaplan-Meier analysis and logistic regression. The Receiver Operating Characteristic (ROC) curve served as the means to determine the ideal cut-off values for categorizing levels of inflammatory markers into high and low classifications. We employed Chi-square tests to evaluate the relationship between elevated and reduced baseline levels of inflammatory markers and irAE. ResultsKaplan-Meier analysis disclosed that patients in the low baseline PLT group and the low NLR group exhibited a substantially more favorable prognosis in contrast to their counterparts in the high baseline PLT and high NLR groups. Multivariate analysis indicated that diminished baseline PLT and NLR levels before treatment independently foretell extended PFS. Chi-square analysis underscored a substantial correlation between baseline WBC, NEUT, LYMPH, MONO, and NLR levels and irAE. ConclusionSubdued baseline PLT and NLR levels may serve as indicators of a more auspicious prognosis in patients contending with advanced NSCLC undergoing the combination of PD-1 inhibition and chemotherapy. Elevated baseline levels of inflammatory markers antedating PD-1 therapy in advanced NSCLC may be intimately interrelated with the occurrence of irAE.

Does FDG PET-Based Radiomics Have an Added Value for Prediction of Overall Survival in Non-Small Cell Lung Cancer?

Objectives: Radiomics and machine learning are innovative approaches to improve the clinical management of NSCLC. However, there is less information about the additive value of FDG PET-based radiomics compared with clinical and imaging variables. Methods: This retrospective study included 320 NSCLC patients who underwent PET/CT with FDG at initial staging. VOIs were placed on primary tumors only. We included a total of 94 variables, including 87 textural features extracted from PET studies, SUVmax, MTV, TLG, TNM stage, histology, age, and gender. We used the least absolute shrinkage and selection operator (LASSO) regression to select variables with the highest predictive value. Although several radiomics variables are available, the added value of these predictors compared with clinical and imaging variables is still under evaluation. Three hundred and twenty NSCLC patients were included in this retrospective study and underwent 18F-FDG PET/CT at initial staging. In this study, we evaluated 94 variables, including 87 textural features, SUVmax, MTV, TLG, TNM stage, histology, age, and gender. Image-based predictors were extracted from a volume of interest (VOI) positioned on the primary tumor. The least absolute shrinkage and selection operator (LASSO) Cox regression was used to reduce the number of variables and select only those with the highest predictive value. The predictive model implemented with the variables selected using the LASSO analysis was compared with a reference model using only a tumor stage and SUVmax. Results: NGTDM coarseness, SUVmax, and TNM stage survived the LASSO analysis and were used for the radiomic model. The AUCs obtained from the reference and radiomic models were 80.82 (95%CI, 69.01-92.63) and 81.02 (95%CI, 69.07-92.97), respectively (p = 0.98). The median OS in the reference model was 17.0 months in high-risk patients (95%CI, 11-21) and 113 months in low-risk patients (HR 7.47, p < 0.001). In the radiomic model, the median OS was 16.5 months (95%CI, 11-20) and 113 months in high- and low-risk groups, respectively (HR 9.64, p < 0.001). Conclusions: Our results indicate that a radiomic model composed using the tumor stage, SUVmax, and a selected radiomic feature (NGTDM_Coarseness) predicts survival in NSCLC patients similarly to a reference model composed only by the tumor stage and SUVmax. Replication of these preliminary results is necessary.

Brief Report on Global Clinician Practices in the First-Line Management of Metastatic Non-Small Cell Lung Cancer

IntroductionIn the dynamic landscape of metastatic NSCLC (mNSCLC) management, marked by several frontline options and the integration of next generation sequencing (NGS) for informed decision-making, barriers persist despite advancements. This includes challenges in clinical trial recruitment. To gain global insights into clinicians’ practices, we conducted a survey on their testing and management approaches for patients with mNSCLC. MethodsThe survey, conducted from July 12 to August 20, 2023, utilized multiple-choice questions and qualitative research questions, employing the Likert Scale for comprehensive insights. ResultsA total of 127 individuals responded, with 72% affiliated with academic health systems, and 55% practicing in the USA. Regarding testing practices, 93% consistently ordered NGS for non-squamous histology, while 54% did so for squamous cell histology. Concurrent tissue and liquid biopsies were routinely ordered by 28%, while 39% reported ordering both testing platforms concurrently for select cases only. Respondents cited logistical barriers, such as insufficient tissue and lack of infrastructure, as the most common hindrance to molecular testing (76%), followed by reimbursement challenges (56%) and concerns about delayed turnaround time (50%). While most respondents were confident in interpreting NGS results, 22% lacked confidence. Concerning treatment decisions, 72% preferred awaiting molecular testing results before initiating systemic therapy. Less than 50% routinely referred patients for clinical trials in the frontline setting for mNSCLC. For patients with disease expressing high PD-L1 levels, most oncologists preferred pembrolizumab monotherapy. For disease with low PD-L1 expression, a platinum doublet chemotherapy regimen combined with pembrolizumab was favored. In disease cases with negative PD-L1 expression, a platinum doublet chemotherapy regimen with pembrolizumab was preferred. Key factors influencing oncologists' preferred immune checkpoint inhibitor (ICI) included experience with one ICI over another, preferred status per national guidelines, availability of trial data with a significant follow-up period, and consideration of drug cost. ConclusionAlthough this study demonstrates an improved awareness and adoption of ordering NGS for the management of mNSCLC, it underscores the persistence of various barriers that must be addressed to improve upon the quality of care for patients diagnosed with mNSCLC.

Identification of exosome protein panels as predictive biomarkers for non-small cell lung cancer

BackgroundNon-small cell lung cancer (NSCLC) remains a leading cause of cancer-related deaths worldwide, primarily due to its propensity for metastasis. Patients diagnosed with localized primary cancer have higher survival rates than those with metastasis. Thus, it is imperative to discover biomarkers for the early detection of NSCLC and the timely prediction of tumor metastasis to improve patient outcomes.MethodsHere, we utilized an integrated approach to isolate and characterize plasma exosomes from NSCLC patients as well as healthy individuals. We then conducted proteomics analysis and parallel reaction monitoring to identify and validate the top-ranked proteins of plasma exosomes.ResultsOur study revealed that the proteome in exosomes from NSCLC patients with metastasis was distinctly different from that from healthy individuals. The former had larger diameters and lower concentrations of exosomes than the latter. Furthermore, among the 1220 identified exosomal proteins, we identified two distinct panels of biomarkers. The first panel of biomarkers (FGB, FGG, and VWF) showed potential for early NSCLC diagnosis and demonstrated a direct correlation with the survival duration of NSCLC patients. The second panel of biomarkers (CFHR5, C9, and MBL2) emerged as potential biomarkers for assessing NSCLC metastasis, of which CFHR5 alone was significantly associated with the overall survival of NSCLC patients.ConclusionsThese findings underscore the potential of plasma exosomal biomarkers for early NSCLC diagnosis and metastasis prediction. Notably, CFHR5 stands out as a promising prognostic indicator for NSCLC patients. The clinical utility of exosomal biomarkers offers the potential to enhance the management of NSCLC.

The International Association for the Study of Lung Cancer Staging Project for Lung Cancer: Proposals for the Revision of the N Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Lung Cancer

IntroductionThe accurate assessment of nodal (N) status is crucial to the management and prognostication of nonmetastatic NSCLC. We sought to determine whether the current N descriptors should be maintained or revised for the upcoming ninth edition of the international TNM lung cancer staging system. MethodsData were assembled by the International Association for the Study of Lung Cancer on patients with NSCLC, detailing both clinical and pathologic N status, with information about anatomical location and individual station-level identification. Survival was calculated by the Kaplan-Meier method and prognostic groups were assessed by a Cox regression analysis. ResultsData for clinical N and pathologic N status were available in 45,032 and 35,009 patients, respectively. The current N0 to N3 descriptors for both clinical N and pathologic N categories reflect prognostically distinct groups. Furthermore, single-station N2 involvement (N2a) exhibited a better prognosis than multistation N2 involvement (N2b) in both clinical and pathologic classifications, and the differences between all neighboring nodal subcategories were highly significant. The prognostic differences between N2a and N2b were robust and consistent across resection status, histologic type, T category, and geographic region. ConclusionsThe current N descriptors should be maintained, with the addition of new subdescriptors to N2 for single-station involvement (N2a) and multiple-station involvement (N2b).

Efficacy of Robotic Bronchoscopy for Molecular Marker Analysis in Primary Lung Cancer

BackgroundMolecular testing has become a more frequent necessity in NSCLC management. Using next-generation sequencing, multiple targets for therapy can be identified with small amounts of nuclear material. The authors evaluated the performance of robotic-assisted bronchoscopy in acquiring tissue that meets pre-analytic criteria for PD-L1 immunohistochemistry and/or next-generation sequencing. Materials and MethodsPatients with a diagnosis of primary lung cancer identified through robotic bronchoscopy were retrospectively reviewed. Pathology reports were assessed for results of molecular testing and detection of programmed death-ligand 1 (PD-L1). An independent pathologist evaluated each specimen type (smears, cell block, tissue biopsy, and/or touch prep) to determine whether each tissue type would meet pre-analytic criteria for attempting next-generation sequencing and/or PD-L1 immunohistochemistry. ResultsSeventy-eight patients with primary lung were reviewed. By independent pathologic assessment of cytological smears, cell block, biopsy, and/or touch preparations, 72% of samples were found to be adequate for molecular and PD-L1 testing. Preanalytic adequacy (%) for next-generation sequencing (NGS) and PD-L1 staining was determined based on specimen type: cytological smear 48.6% for NGS; cell block 14.3% for NGS and 32.9% for PD-L1; biopsy 29.2% for NGS and 62.5% for PD-L1; and touch prep 61.4% for NGS. ConclusionRobotic-assisted bronchoscopy yielded samples that met preanalytic criteria for molecular testing in 72% of cases. These results support the use of robotic-assisted bronchoscopy for both the diagnosis and molecular testing of early-stage lung cancer.

Dynamic ctDNA to inform the precise management of resected NSCLC: LUNGCA-2 study.

8528 Background: Circulating tumor DNA (ctDNA) has been reported to be valuable for minimal residual disease (MRD) detection, but there is a lack of studies comprehensively assessing whether dynamic ctDNA monitoring can inform whole-course precise postoperative cancer management. In the present study (LUNGCA-2), we analyzed data obtained from longitudinal ctDNA monitoring of stage I-III NSCLC patients in the LUNGCA cohort, and sought to assess the use of dynamic ctDNA monitoring for precise whole-course postoperative management of NSCLC patients. Methods: All eligible NSCLC patients underwent curative-intent surgery and subsequently received adjuvant therapies when indicated by clinical practice guidelines for NSCLC. The clinical follow-up was scheduled to be every 3-6 months mainly involving CT and/or MRI. Fresh frozen or paraffin-embedded tissues of primary tumors were collected intraoperatively for baseline somatic mutation profiling. Blood samples were collected before surgery, at 3 days and 1 month after surgery, and then every 3-6 months at clinical visits up to 3 years postoperatively. 233 patients with a total of 2123 plasma samples were ultimately included in the longitudinal ctDNA analysis in the current study. NGS assays were performed with a custom-designed panel that covered 769 cancer-related genes via the MinerVA platform (Genecast Biotechnology Co., Ltd). Results: Among the cohort, 166 patients harboring targetable mutations in the primary tumor tissue, 15 were preadjuvant ctDNA positive, and among them, only 25% patients treated with adjuvant TKI therapy experienced relapse during follow-up, and patients received ACT or no adjuvant therapy had a relapse rate of 100%. TKI treatment tended to improve RFS compared with no treatment (HR 0.1, P = 0.025), but ACT failed to improve RFS (HR 1.1, P = 0.834). Among all 82 patients receiving adjuvant therapy, the pre- and post-adjuvant therapy postoperative ctDNA status with a negative-negative or positive-negative pattern had similar and favorable RFS ( P = 0.545) but that patients with a positive-positive or negative-positive pattern had significantly inferior RFS than those with a negative-negative pattern (both P &lt; 0.001). For recurrence monitoring, posttreatment ctDNA MRD status had a positive predictive value of 100% and a negative predictive value of 91.8%, and the sensitivity of MRD detection was affected by the organ of relapse. Among positive ctDNA MRD patients, faster increase of ctDNA concentration correlated with more imminent clinical relapse. The median lead time from ctDNA detection to radiological relapse was 273 days. Moreover, ctDNA negativity after relapse was associated with favorable survival. Conclusions: These findings highlight the clinical significance of ctDNA dynamics for the precise whole-course postsurgical management of NSCLC patients.

LncRNA ENST00000434223 exerts regulatory effects on NSCLC cells via Wnt/β-catenin signaling pathway

Purpose: To identify the role and underlying mechanism of lncRNA ENST00000434223 (lncRNA ENST) in the occurrence of NSCLC. &#x0D; Methods: Quantitative real time-polymerase chain reaction (qRT-PCR) was used to evaluate relative lncRNA ENST, β-catenin, Wnt1, and cyclin D1 expression levels in NSCLC tissues, cells, and sera. Proliferation of NSCLC cells was assessed using CCK-8 assay, while Transwell assay was utilized in evaluating changes in cell invasion/migration. Changes in Wnt1, cyclin D1, and β-catenin expressions were determined using qRT-PCR, while alterations in their protein expressions were determined by western blot (WB). In vivo experiments were conducted in nude mice to investigate the effects of lncRNA ENST on tumor growth. &#x0D; Results: lncRNA ENST expression was low in sera, cells, and tissues of NSCLC (p &lt;0.05). Tumor metastasis and size, lymphatic metastasis, and clinical stage were correlated with lncRNA ENST expression (p &lt; 0.05). It was found that ENST could be applied as independent prognostic factor in NSCLC patients. Upregulated expression of lncRNA ENST restrained cell migration, proliferation, and invasion (p &lt; 0.05). Compared with t NC group, lncRNA ENST expression decreased expressions of Wnt1, cyclin D1, and β-catenin in SPC-A1 cells and A549 cells (p &lt; 0.05). &#x0D; Conclusion: lncRNA ENST inhibits the proliferation and apoptosis of NSCLC cells via Wnt/β-catenin pathway. Thus, it is a possible biomarker for NSCLC, and provides a novel insight into the clinical management of NSCLC.

Circulating Tumour DNA (ctDNA) as a Predictor of Clinical Outcome in Non-Small Cell Lung Cancer Undergoing Targeted Therapies: A Systematic Review and Meta-Analysis.

Liquid biopsy (LB) analysis using (ctDNA)/cell-free DNA (cfDNA) is an emerging alternative to tissue profiling in (NSCLC). LB is used to guide treatment decisions, detect resistance mechanisms, and predicts responses, and, therefore, outcomes. This systematic review and meta-analysis evaluated the impact of LB quantification on clinical outcomes in molecularly altered advanced NSCLC undergoing targeted therapies. We searched Embase, MEDLINE, PubMed, and Cochrane Database, between 1 January 2020 and 31 August 2022. The primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS), objective response rate (ORR), sensitivity, and specificity. Age stratification was performed based on the mean age of the individual study population. The quality of studies was assessed using the Newcastle-Ottawa Scale (NOS). A total of 27 studies (3419 patients) were included in the analysis. Association of baseline ctDNA with PFS was reported in 11 studies (1359 patients), while that of dynamic changes with PFS was reported in 16 studies (1659 patients). Baseline ctDNA-negative patients had a trend towards improved PFS (pooled hazard ratio [pHR] = 1.35; 95%CI: 0.83-1.87; p < 0.001; I2 = 96%) than ctDNA-positive patients. Early reduction/clearance of ctDNA levels after treatment was related to improved PFS (pHR = 2.71; 95%CI: 1.85-3.65; I2 = 89.4%) compared to those with no reduction/persistence in ctDNA levels. The sensitivity analysis based on study quality (NOS) demonstrated improved PFS only for good [pHR = 1.95; 95%CI: 1.52-2.38] and fair [pHR = 1.99; 95%CI: 1.09-2.89] quality studies, but not for poor quality studies. There was, however, a high level of heterogeneity (I2 = 89.4%) along with significant publication bias in our analysis. This large systematic review, despite heterogeneity, found that baseline negative ctDNA levels and early reduction in ctDNA following treatment could be strong prognostic markers for PFS and OS in patients undergoing targeted therapies for advanced NSCLC. Future randomised clinical trials should incorporate serial ctDNA monitoring to further establish the clinical utility in advanced NSCLC management.

Abstract 4832: Copy number amplification of OXPHOS genes drives tumor hypoxia in NSCLC

Abstract Non-small cell lung cancer (NSCLC) is a highly aggressive disease with a dismal prognosis associated with high rates of treatment resistance and disease recurrence. High-dose stereotactic body radiation therapy (SBRT) is the standard of care for locally advanced non-resectable NSCLC. However, as discovered more than six decades ago, tumor hypoxia is a significant barrier to effective radiation therapy. In the last decade, immunotherapy targeting immune checkpoints such as programmed cell death 1 (PD-1) has been introduced as first-line NSCLC treatment, yet long-term disease control occurs in less than 25% of patients. Therefore, understanding the mechanisms of the treatment resistance is essential to address the need for novel synergistic therapies to sensitize refractory NSCLC tumors to anti-cancer treatment. Tumor hypoxia has been associated with treatment resistance for decades, yet its role in the clinical management of NSCLC remains largely unexplored. The basis of tumor hypoxia has traditionally been attributed to the oxygen supply deficit as malformed tumor vasculature fails to meet the high demand of the rapidly proliferating tumor mass. However, our preliminary analysis of NSCLC patient datasets in the Cancer Genome Atlas (TCGA) revealed a significant correlation between high-level expression of nuclear genes encoding mitochondrial subunits essential for oxidative phosphorylation (OXPHOS) and the expression of validated hypoxia-regulated genes (Buffa hypoxia score). The oxygen-consumption expression signature was implemented in software that enables the calculation of numerous tumor microenvironment expression signatures, called tmesig. Furthermore, we have observed a direct positive correlation between the hypoxia expression signatures levels in NSCLC patient samples and the copy number amplification (CNA) of essential OXPHOS genes. Because mitochondrial function consumes up to 90% of available cellular oxygen, its activity may indirectly regulate oxygen availability in the tumor microenvironment by rapidly consuming oxygen upon its delivery to the tumor. Mechanistically, this leads to the hypothesis that OXPHOS gene amplification drives mitochondrial function, which may, in turn, promote tumor hypoxia and treatment resistance in NSCLC. Citation Format: Martin Benej, Katarina Benejova, McKenzie Kreamer, Jinghai Wu, Syed Ashraf, Caroline Wheeler, Rebecca Hoyd, Daniel Spakowicz, Nicholas C. Denko. Copy number amplification of OXPHOS genes drives tumor hypoxia in NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4832.

Frailty Index is Associated with Treatment Decisions for Stage I Non-Small Cell Lung Cancer at a High-Burden Safety-Net Hospital

BackgroundLobectomy remains the cornerstone of care for stage I NSCLC while sublobar resection and stereotactic body radiation therapy (SBRT) are reserved for patients with smaller tumors and/or poor operative risk. Herein, we investigate the effect of patient frailty on treatment modality for stage I NSCLC at a safety-net hospital. Patients and MethodsA retrospective chart review was performed of stage I NSCLC patients between 2006 and 2015. Demographics, patient characteristics, and treatment rates were compared to a National Cancer Database cohort of stage 1 NSCLC patients. Patient frailty was assessed using the MSK-FI. ResultsIn our cohort of 304 patients, significantly fewer patient were treated via lobectomy compared to national rates (P < .001). Advanced age (P = .02), lower FEV1 (P < .001) and DLCO (P < .001), not socioeconomic factors, were associated with higher utilization of non-lobectomy (sublobar resection or SBRT). Patients with lower MSK-FI were more likely to receive any surgical treatment (P = .01) and lobectomy (P = .03). Lower MSK-FI was an independent predictor for use of lobectomy over other modalities (OR 0.75, P = .04). MSK-FI (OR 0.64, P = .02), and FEV1 (OR 1.03, P < .001) were independently associated with use of SBRT over any surgery. ConclusionOur safety-net hospital performed fewer lobectomies and lung resections compared to national rates. Patient frailty and clinical factors were associated with use of SBRT or sublobar resection suggesting that the increased illness burden of a safety-net population may drive the lower use of lobectomy. The MSK-FI may help physicians stratify patient risk to guide stage I NSCLC management.

A novel DNA damage repair-related signature for predicting prognositc and treatment response in non-small lung cancer.

DNAdamage repair (DDR) is essential for maintaining genome integrity and modulating cancer risk, progression, and therapeutic response. DDR defects are common among non-small lung cancer (NSCLC), resulting in new challenge and promise for NSCLC treatment. Thus, a thorough understanding of the molecular characteristics of DDR in NSCLC is helpful for NSCLC treatment and management. Here, we systematically analyzed the relationship between DDR alterations and NSCLC prognosis, and successfully established and validated a six-DDR gene prognostic model via LASSO Cox regression analysis based on the expression of prognostic related DDR genes, CDC25C, NEIL3, H2AFX, NBN, XRCC5, RAD1. According to this model, NSCLC patients were classified into high-risk subtype and low-risk subtype, each of which has significant differences between the two subtypes in clinical features, molecular features, immune cell components, gene mutations, DDR pathway activation status and clinical outcomes. The high-risk patients was characterized with worse prognosis, lower proportion and number of DDR mutations, unique immune profile and responsive to immunetherapy. And the low-risk patients tend to have superior survival, while being less responsive to immunotherapy and more sensitive to treatment with DNA-damaging chemotherapy drugs. Overall, this molecular classification based on DDR expression profile enables hierarchical management of patients and personalized clinical treatment, and provides potential therapeutic targets for NSCLC.

OA14.05 Intraoperative Molecular Imaging Guided Resection of CEACAM5+ Lung Tumors: First In-Human SGM-101 Lung Cancer Surgical Trial

Surgical management of NSCLC has multiple challenges including localization of sub-centimeter nodules, assessment of margin adequacy, and detection of occult lesions. Intraoperative molecular imaging (IMI) has emerged as a potential solution that addresses these surgical dilemmas. The purpose of our study (NCT04315467) was to evaluate the suitability of SGM-101, a CEACAM5 antibody targeted NIR fluorochrome, for molecular imaging guided lung cancer resections, as the glycoprotein is expressed in >80% of adenocarcinomas.

EP05.01-022 Evaluation of the Management of Stage III NSCLC at Mohamed IV Center for Cancer Treatment Casablanca

Stage III in the NSCLC should be separated into stages IIIA, IIIB and IIIC according to the 8th edition of the TNM classification. Subgroup N2 remains the most controversial. In our study, we evaluated the management of NSCLC in our oncology center.

Drug discovery of PD-L1 inhibitor Atezolizumab

Immunotherapy, especially immune checkpoint inhibitors have made a tremendous breakthrough in NSCLC management. Over last decades, ICIs targeting the PD-1, PD-L1 and CTLA-4 have exhibited promising antitumor efficacy and durable response including NSCLC patients with advanced or refractory, metastatic disease. We will provide an overview of mechanism of cancer development and how current available ICIs can be employed to improve patients’ outcome. This review also summarized the discovery process of atezolizumab which led to final FDA approval for its indication. Our major focus is on the significant survival benefit achieved by atezolizumab and taking into consideration of its advantages and disadvantages when we applied it into clinical setting. We hope to help patients and clinicians to better understand the mechanisms, clinical progress and future research direction of NSCLC atezolizumab in decision making.

Retrospective Analysis of Real-World Management of EGFR-Mutated Advanced NSCLC, After First-Line EGFR-TKI Treatment: US Treatment Patterns, Attrition, and Survival Data.

Background and ObjectivesEpidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard-of-care first-line (1L) treatment for EGFR mutation-positive advanced/metastatic non-small cell lung cancer. In 2015, osimertinib, a third-generation EGFR-TKI, received US accelerated approval for second-line (2L) EGFR T790M-positive non-small cell lung cancer treatment. The objective of this US study was to characterize treatment patterns, attrition, and survival in EGFR mutation-positive non-small cell lung cancer, after 1L first-/second-generation EGFR-TKI treatment.MethodsWe retrospectively analyzed 1029 patients diagnosed with stage IIIB/IV non-small cell lung cancer from 1 January, 2011 to 31 December, 2018 using the US electronic medical record CancerLinQ Discovery® database. Demographic/disease characteristics, EGFR mutations, treatments, and death dates were collected.ResultsFrom 1 January, 2011 to 31 December, 2014 (< 2015 cohort), 519 patients received 1L EGFR-TKIs and 510 between 1 January, 2015 and 31 December, 2018 (≥ 2015 cohort). Median follow-up from advanced diagnosis was 19.8 months (interquartile range: 9.9–33.4 months). Twenty-eight percent of patients (288/1029) died without receiving 2L, and 52% (539/1029) initiated 2L with 35% (186/539) receiving osimertinib; in the < 2015 and ≥ 2015 cohorts, the same proportion initiated 2L (52%; 272/519 vs 267/510, respectively). Median overall survival from advanced diagnosis for patients initially diagnosed with stage I–IIIA disease was 43.3 months (95% confidence interval 30.9–73.7), vs 26.4 months (95% confidence interval 24.4–28.1) for stage IIIB–IV; all-cause mortality hazard ratio: 1.56 (95% confidence interval 1.2–2.0; p = 0.001).ConclusionsWe identified disease stage, performance status, and central nervous system metastasis as survival predictors, highlighting the importance of optimal 1L treatment selection. Over a quarter of patients died before initiating 2L; half progressed after 1L and received 2L, of whom a third received 2L osimertinib.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40801-022-00302-w.

Management of stage IIIA NSCLC: the role of radiotherapy—a narrative review

Management of stage IIIA NSCLC: the role of radiotherapy—a narrative review

Real-World Management and Outcomes of Crizotinib-Treated ROS1-Rearranged NSCLC: A Retrospective Canadian Cohort.

The use, safety and effectiveness of crizotinib as part of the management of ROS1-rearranged NSCLC patients in a real-world Canadian clinical cohort was the focus of this retrospective review. Twenty-one ROS1-rearranged patients with advanced/metastatic disease receiving crizotinib between 2014–2020 were identified; crizotinib demonstrated tolerability and effectiveness in this population where outcomes were similar to those described in other crizotinib-treated real-world cohorts, but lower than those of the PROFILE 1001 clinical trial population. Systemic anti-cancer therapy prior to crizotinib initiation occurred in half of the study cohort, with platin-pemetrexed and immune checkpoint inhibitors being most common. Platin-pemetrexed showed good effectiveness in this cohort, but despite high prevalence of upregulated PD-L1 expression, immune checkpoint inhibitors showed poor effectiveness in his cohort. Among all systemic therapies received, crizotinib showed the most effective disease control, although longer intervals between diagnosis and crizotinib initiation were more common among those showing a lack of clinical response to crizotinib, and patients with brain metastases at the time of crizotinib initiation also showed increased diagnosis to crizotinib initiation intervals and decreased clinical response to crizotinib. This study reveals crizotinib has clinical benefit, but timely identification of ROS1-rearrangements and initiation targeted therapies appears important to maximize outcome in this population.