Advanced Stage Non-small Cell Lung Research Articles

Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as mortality predictor of advanced stage non-small cell lung cancer (NSCLC) with COVID-19 in Indonesia.

This study aimed to compare the mortality rate between advanced-stage non-small cell lung cancer patients (NSCLC) with and without COVID-19. This study also explores the possible laboratory characteristics used for prognostication in patients with NSCLC and COVID-19. Additionally, this study evaluated potential differences in laboratory values between the case and control groups. This is a single-center retrospective cohort study conducted in Dharmais National Cancer Hospital, Indonesia, enrolling patients with NSCLC undergoing chemotherapy or targeted therapy between May 2020 and January 2021. All patients with NSCLC and COVID-19 in these periods were enrolled into the case group. The control group was age-matched NSCLC patients without COVID-19 that was derived from the NSCLC cohort through randomization. There were 342 patients with NSCLC between May 2020 and January 2021. Twenty-seven (7.9%) of the patients were infected by COVID-19. To facilitate comparison, thirty-five age-matched controls with NSCLC were selected from the cohort. The mortality rate in patients with COVID-19 was 46.2%. Eleven patients (40.7%) had severe COVID-19, of which none survived. NLR >8.35 has a sensitivity of 83.3%, specificity of 92.9%, LR+ of 12, and LR- of 0.18. The AUC was 0.946 (95% CI 0.867-1.000), p<0.001. PLR >29.14 has a sensitivity of 75.0%, specificity of 71.4%, LR+ 2.62, LR- 0.35, and AUC 0.851 (95% CI 0.706-0.996), p=0.002. Both NLR and PLR were associated with shorter time-to-mortality in the unadjusted and adjusted model CONCLUSIONS: NLR and PLR are independent predictors of mortality in COVID-19 patients with NSCLC.

Efficacy of Combination Docetaxel and Nintedanib in Advanced Non-Small Cell Lung Cancer in Thailand: A Multicenter Study.

IntroductionThe mainstay systemic treatment for non-oncogenic addictive advanced stage non-small cell lung cancer is chemotherapy. Anti-angiogenic agents are additive compounds that enhance disease control and lead to improvement of overall survival benefit. Recently PD-(L)1 blockage, a checkpoint inhibitor, has been adopted as another line of treatment. A sequential strategy to enhance the efficacy of combination docetaxel and nintedanib after immunotherapy, correlated with genomic mutation, has been explored.MethodA retrospective cohort study of 56 patients from 8 centers in Thailand who received combination docetaxel and nintedanib via the Thai nintedanib Named Patient Use program was conducted. Demographic characteristics, treatment details, and treatment responses were retrieved from medical records.ResultsThe majority of patients were male (62.5%) with adenocarcinoma subtype (88%). Thirty-five percent had sensitizing EGFR mutation. Combination docetaxel and nintedanib was given as second to fourth line of treatment. Median PFS of docetaxel/nintedanib was 5.6 months [95% CI 4.8-6.9]. Median OS of the entire cohort was 22.5 months [95% CI 20.2-31.1]. Among them, only four patients received this combination after immunotherapy which limited the validity of efficacy analysis. Median PFS of those four patients was 7.9 months [range 5.2-9.1] which was slightly higher than the remaining cohort (median PFS 4.5 months, 95% CI: 4.0-6.0, p-value 0.09). Among the adenocarcinoma subtype, a relapse-time of platinum-doublet chemotherapy of more than 6 months was solely indicated as a benefit of combination docetaxel/nintedanib treatment compared to the relapse-time of platinum-doublet chemotherapy of less than 6 months by multivariate HR of PFS 0.32 [95% CI: 0.14-0.68, p-value 0.003].ConclusionCombination docetaxel and nintedanib provided more benefit in relapse-time of platinum-doublet chemotherapy of more than 6 months in advanced stage adenocarcinoma lung cancer. Neither EGFR nor ALK alteration influenced the outcome of treatment.

Molecular Biomarker and Programmed Death-Ligand 1 Expression Testing in Patients With Advanced Stage Non-small Cell Lung Cancer Across North Carolina Community Hospitals

Precision medicine in advanced non-small cell lung cancer (NSCLC) requires molecular biomarker testing in patients with nonsquamous and select patients with squamous histologies, and programmed death-ligand 1 (PD-L1) testing in both. What are rates of molecular and PD-L1 biomarker testing in patients with advanced NSCLC in community practices, and do rates vary by sociodemographic factors? What is the prevalence of molecular biomarker mutations and PD-L1 expression levels? From 389 stage IV NSCLC pathology reports obtained through the University of North Carolina Lineberger Comprehensive Cancer Center's Rapid Case Ascertainment Program from 38 community hospitals across North Carolina, we abstracted demographics, histology, molecular biomarker testing and results, and PD-L1 testing and expression. We geocoded patient and hospital addresses to determine travel time, distance to care, and census block level contextual variables. We compared molecular biomarker and PD-L1 testing rates, the prevalence of molecular biomarkers, and PD-L1 expression levels by race and sex, using χ2 tests. We determined predictors of testing, using multivariable logistic regression and report adjusted ORs and 95%CI. Among patients with nonsquamous NSCLC, 64.4%were tested for molecular biomarkers, and among all NSCLC patients 53.2%were tested for PD-L1 expression. Differences in biomarker testing rates by sociodemographic factors were not statistically significant in univariate or adjusted analyses. Adjusted analyses showed that patients living in areas with higher household internet access were more likely to undergo PD-L1 testing (adjusted OR= 1.66, 95%CI, 1.02-2.71). Sociodemographic differences in molecular biomarker prevalence and PD-L1 expression levels were not statistically significant, except for human epidermal growth factor receptor 2 (HER2) mutations, which occurred in 16.7%of males vs0%in females, P= .05. Biomarker testing remains underused in NSCLC. Future work should include larger populations and evaluate hospital-specific testing protocols to identify and address barriers to guideline-recommended testing.

Prognostic Value of Metabolic Tumor Parameters in Pretreatment 18F-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography Scan in Advanced Non-Small Cell Lung Cancer.

Objective:This retrospective study aimed to investigate whether metabolic parameters of primary tumour i.e. maximum standardized uptake value (SUVmax), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) predict overall survival (OS) in patients with advanced stage non-small cell lung cancer (NSCLC).Materials and Methods:SUVmax, MTV and TLG of the primary tumors were measured in staging 18F-Fluorodeoxyglucose Positron emission tomography- Computed tomography (18F-FDG PET/CT) scan of 97 NSCLC patients by gradient based tumour segmentation method. Prognostic ability was assessed for overall survival (OS) of the patients.Result:The median follow-up period of the study was 15.84 months (range 1.3 to 47.97 months).The estimated median OS was 11.29 months (range 1.37 to 38.63 months). Total of 40 (41.24%) patients had progressive disease and 21 (21.65%) patients died during the follow up period. Receiver Operating Characteristic (ROC) analysis showed that the area under the curve (AUC) for MTV was significant (area = 0.652 ± 0.065; 95% CI = 0.548 – 0.746; P = 0.020). Kaplan-Meier survival curves showed that the OS differences between the groups of patients who were dichotomized by the median value of MTV (38.76 ml, P = 0.0150) and TLG (301.69 ml, P = 0.0046) were significant. MTV (hazard ratio = 4.524; 95% CI = 1.244 – 16.451; P = 0.022) was found to be an independent prognostic factor for OS in multivariate analysis.Conclusion:MTV of the primary tumor is a potential prognostic parameter for OS in our population of advanced NSCLC patients independent of other risk factors.

The role for chemotherapy in 80 years and older patients with metastatic non-small cell lung cancer: A National cancer database analysis

BackgroundThere are limited data on the role for chemotherapy in patients > 80 years old with advanced stage non-small cell lung carcinoma (NSCLC). We used the National Cancer Database (NCDB) to evaluate treatment patterns and outcomes for patients ≥80 years old with advanced NSCLC. MethodsWe identified patients diagnosed with metastatic NSCLC between 2004 and 2014. We divided them into two groups: < 80 years old (n = 218,365) and ≥ 80 years old (n = 33,352). Patient characteristics including median age at diagnosis, gender, ethnicity, histology, chemotherapy status, tumor grade, treatment center, insurance status, income, education, and Charlson-Deyo co-morbidity index were collected. Continuous variables were compared using t-test and categorical variables were compared using chi-square or Fisher's exact test. Multivariable (MV) and propensity matched analyses were performed to analyze the impact of chemotherapy on overall survival. ResultsWe identified 33,352 patients > 80 years old diagnosed with advanced NSCLC. Only 29 % received chemotherapy, those who received chemotherapy had improved median overall survival of 8 months compared to 2 months in patients not receiving chemotherapy; adjusted hazards ratio (HR) 0.46; confidence interval (CI) 0.45−0.47; p < .001. MV analysis showed benefit of chemotherapy in all age subgroups (80–84 years, 85–89 years and 90+ years; p < .0001) and it was confirmed by propensity matched analysis. Patients receiving multiagent chemotherapy had improved 1-year survival of 35.5 % compared to 32.8 % with single agent chemotherapy (adjusted HR 0.92; CI 0.88−0.96; p < .001). Despite benefit from chemotherapy, the proportion of patients age ≥ 80 years receiving chemotherapy did not change over time. ConclusionsChemotherapy improved overall survival in ≥80 years old patients with advanced stage NSCLC. Despite improved survival and an increase in the proportion of ≥80 years old patients diagnosed with advanced NSCLC, less than one-third receive chemotherapy.

Nab-Paclitaxel Plus Durvalumab in Patients With Previously Treated Advanced Stage Non-small Cell Lung Cancer (ABOUND.2L+).

Background: The standard therapy for advanced stage non-small cell lung cancer (NSCLC) with no actionable gene alterations is a platinum-based chemotherapy doublet and immune checkpoint blocker (ICB), either concurrently or sequentially, followed by docetaxel at the time of tumor progression. However, more effective treatments are needed. We evaluated the nab-paclitaxel and durvalumab combination in patients with previously treated advanced stage NSCLC.Methods: Patients with advanced stage NSCLC previously treated with one line of platinum-based doublet with or without an ICB and no activating EGFR mutations or ALK translocations received nab-paclitaxel 100 mg/m2 (days 1 and 8) plus durvalumab 1,125 mg (day 15) every 21 days. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and safety.Results: Between February 2016 and December 2016, 79 patients were enrolled. The median age was 63 years. Most patients were males (68.4%), had non-squamous histology (69.6%), and had no prior ICB treatment (88.6%). The median PFS was 4.5 months; median OS was 10.1 months. A post hoc analysis of survival by prior ICB treatment revealed a median PFS and OS of 4.4 and 9.9 months, respectively, in ICB-naive patients and 6.9 months and not estimable, respectively, in patients previously treated with ICB. The most common treatment-emergent adverse events were asthenia (46.2%) and diarrhea (34.6%); four treatment-related deaths (5.1%) occurred.Conclusions: The nab-paclitaxel and durvalumab combination is feasible and demonstrated antitumor activity without new safety signals. Additional studies using taxanes and ICB in patients with previously treated NSCLC are warranted.Clinical Trial Registration: ClinicalTrials.gov registration (NCT02250326).EudraCT number: 2014-001105-41

Molecular profiling of advanced non-small cell lung cancer in the era of immunotherapy approach: a multicenter Italian observational prospective study of biomarker screening in daily clinical practice

AimsHeterogeneous implementation of molecular tests in current diagnostic algorithm at a European and international level is emerging as a major issue for efficient lung cancer molecular profiling.MethodsFrom May 2017 until...

Detecting Resistance to Therapeutic ALK Inhibitors in Tumor Tissue and Liquid Biopsy Markers: An Update to a Clinical Routine Practice.

The survival of most patients with advanced stage non-small cell lung cancer is prolonged by several months when they are treated with first- and next-generation inhibitors targeting ALK rearrangements, but resistance inevitably emerges. Some of the mechanisms of resistance are sensitive to novel ALK inhibitors but after an initial tumor response, more or less long-term resistance sets in. Therefore, to adapt treatment it is necessary to repeat biological sampling over time to look for different mechanisms of resistance. To this aim it is essential to obtain liquid and/or tissue biopsies to detect therapeutic targets, in particular for the analysis of different genomic alterations. This review discusses the mechanisms of resistance to therapeutics targeting genomic alterations in ALK as well as the advantages and the limitations of liquid biopsies for their identification.

Detection of programmed cell death-ligand 1 using 22C3 antibody in patients with unresectable stage III non-small cell lung cancer receiving chemoradiotherapy.

The expression of programmed cell death-ligand 1 (PD-L1) is a biomarker for administering immune check point inhibitors in patients with advanced stage non-small cell lung cancer. Although the consolidation therapy of durvalumab after definitive chemoradiotherapy has become the new standard of care for patients with unresectable stage III non-small cell lung cancer, the prevalence and prognostic role of PD-L1 expression in this population remain unclear. We retrospectively reviewed data from patients with unresectable stage III non-small cell lung cancer who received definitive chemoradiotherapy at our institution between 2012 and 2017. Levels of PD-L1 were assessed using 22C3 antibody, and associations of progression-free and overall survival rates with PD-L1 statuses at a tumor proportion score cutoff of 1% were analyzed. Among the 104 patients enrolled, PD-L1 statuses were as follows: tumor proportion score < 1%, 73 (70.2%); 1-49%, 21 (20.2%); and ≥ 50%, 10 (9.6%). The number of patients with stage III non-small cell lung cancer with pretreatment PD-L1 tumor proportion score ≥ 1% was less than the number with advanced stage disease. There was no association between patient characteristics and PD-L1 status, and no significant differences were observed in progression-free and overall survival rates relative to PD-L1 status. Expression of PD-L1 in patients with stage III non-small cell cancer before chemoradiotherapy should be assessed because of the low prevalence of tumors with tumor proportion scores ≥ 1%. Further studies are needed to clarify whether durvalumab improves survival after definitive chemoradiotherapy, irrespective of tumor PD-L1 expression.

The Impact of Priming Effect of Immune Checkpoint Inhibitor Therapy for Advanced Stage Non-Small Cell Lung Cancer: A Meta-Epidemiological Study

The Impact of Priming Effect of Immune Checkpoint Inhibitor Therapy for Advanced Stage Non-Small Cell Lung Cancer: A Meta-Epidemiological Study

Tumor mutational burden on cytological samples: A pilot study.

Immune-checkpoint inhibitors (ICIs) represent an important treatment option for patients who have advanced stage non-small cell lung cancer (NSCLC). Currently, evaluation of the expression level of programmed death-ligand 1 (PD-L1) has proven highly successful as a positive predictive biomarker for ICIs. In addition to PD-L1, other promising predictive biomarkers are emerging, including high tumor mutational burden (TMB-H). However, measuring TMB-H remains challenging for several reasons, among which is the difficulty in obtaining adequate tissue material from NSCLC patients. There are no data in the current literature regarding the possibility of adopting cell blocks (CBs) for TMB evaluation; therefore, our goal was to evaluate the feasibility of analyzing TMB on CBs. For evaluation of differences in run metric parameters, 8 pairs of histological and CB samples from patients with NSCLC were analyzed using the Oncomine Tumor Mutational Load Assay on Ion Torrent S5 GS next-generation sequencing (NGS) platform. Most CBs (6/8, 75.0%) were successfully analyzed by adopting the broad NGS panel approach. CBs provided results similar to those obtained on histological matched specimens in terms of median total reads (7207048.80 vs 7558817.80), median mapped reads (7075753.83 vs 7513822.00), median read lengths (115.50 vs. 113.00), median percentage of reads on-target (97.49% vs. 98.45%), median average reads per amplicon (454.67 vs 476.14), and median uniformity of amplicon coverage (83.52% vs 84.13%). In this pilot study, we demonstrated the technical feasibility of assessing TMB on CBs.

Chemotherapy in the Last 30 Days and 14 Days of Life in African Americans With Lung Cancer.

African Americans with lung cancer are diagnosed at later stages and have high mortality rates. Chemotherapy is considered aggressive treatment near the end of life and prevents enrollment in hospice. This study explored chemotherapy in the last 30 and 14 days of life among African Americans with lung cancer. A retrospective chart review was used to gather sociodemographic and treatment data on persons newly diagnosed with lung cancer between January 1, 2016 and June 30, 2017. African Americans with a documented date of death were included. The mean age (N=74) was 64.0 years, 58.1% were rural dwellers, and 59.5% had Medicare. Most had advanced stage non-small cell lung cancer (Stage IIIB, 18.8%; Stage IV, 46.4%). In this study, 17.6% received chemotherapy in the last 14 days of life and 27.0% received chemotherapy in the last 30 days of life. No significant associations between age, sex, residence (rural vs urban) and receipt of chemotherapy in the last 14 or 30 days of life were found. A significant association was found between type of insurance and chemotherapy in the last 14 or 30 days of life: Medicare was associated with chemotherapy in both last 14 days of life χ2(1) = 4.448, p = .035 and last 30 days of life χ2(1) = 4.773, p = .029. A binomial logistic regression using demographic factors, including insurance, was not significant. Our results indicate a need for improvement in the number of individuals who receive chemotherapy in the final month of life.

Real world experience on maintenance chemotherapy with gemcitabine in second line setting for advanced non-small cell lung carcinoma

Maintenance chemotherapy was studied in first line setting for advanced stage non-small cell lung carcinoma (NSCLC). There has not been any data on the role of continuation maintenance chemotherapy in second line setting. A retrospective cohort study that included 226 patients with advanced stage NSCLC that received second line gemcitabine ± platinum was conducted. Patients who had continuation maintenance gemcitabine were compared with those who went on drug holiday. The primary endpoint was progression-free survival (PFS), counted from the end of induction therapy. The median PFS was significantly longer for patients who continued with maintenance gemcitabine when compared with those on drug holiday (5.6 vs 1.7 months, HR 0.392, p-value < 0.001). The overall survival was also significantly longer (21.4 vs 15.8 months, HR 0.508, p-value 0.047). There was no increase in incidence of adverse events for patients who underwent maintenance gemcitabine. Continuation maintenance therapy with gemcitabine in second line setting is a potentially feasible and safe option for patients with advanced NSCLC.

Les CBNPC de stades avancés hors addiction oncogénique : les traitements systémiques de deuxième ligne: Advanced stage NSCLC excluding oncogenic addiction: Second-line systemic treatments

AbstractThe emergence of immunotherapy as the cornerstone of first line therapy in advanced stage non-small cell lung cancer, without oncogenic driver, has led to change the treatment algorithm of second line, which was previously and mainly based on anti-PD(L)-1 given as a single agent. Second-line treatment is currently based on chemotherapy, with a platinum-based doublet for patients treated in first line by pembrolizumab alone, and standard second-line chemotherapy options for patients treated by chemotherapy-immunotherapy combinations, i.e. docétaxel regardless of histology or pemetrexed for non-squamous cell carcinoma when not used in first line. Addition of an antiangiogenic agent to docétaxel only achieved a modest improvement of overall survival but neither nintedanib, nor docétaxel is available in France. The future of second line treatment would require a better knowledge and understanding of resistance mechanisms to anti-PD(L)-1, and randomized phase III clinical trials, in order to optimize therapeutic options, including or not a rechallenge to an immunotherapy, targeting to restore anti-tumour immune response.© 2020 SPLF. Published by Elsevier Masson SAS. All rights reserved.

KNOWLEDGE AND PRACTICE PATTERNS AMONG PULMONOLOGISTS FOR MOLECULAR BIOMARKER TESTING IN ADVANCED NON-SMALL CELL LUNG CANCER

SESSION TITLE: Lung Cancer Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Over the last decade, targeted agents for advanced stage non-small cell lung cancer (NSCLC) offer improved outcomes and survival for eligible patients. These therapies require testing for molecular biomarkers to assess eligibility and recent evidence suggests that testing is underutilized. Pulmonologists often perform endobronchial ultrasound (EBUS) to evaluate these patients and should be aware of indications for testing and obtain enough tissue for molecular biomarker analysis. In collaboration with The National Lung Cancer Roundtable of the American Cancer Society and CHEST, a survey of pulmonologists was performed to better understand barriers to testing. METHODS: The survey was developed by a group which included pulmonologists, thoracic surgeons, a radiologist, radiation oncologists, and an epidemiologist. Questions focused on respondent’s clinical volume, tissue sampling methods for patients with advanced stage NSCLC, responsible party for ordering molecular testing, and knowledge of available molecular biomarkers and approved targeted therapies. 7,238 pulmonologists in the CHEST analytic database were randomly sampled to receive the survey. RESULTS: 453 pulmonologists responded. Pulmonologists in academics center report seeing higher volumes of patients with advanced NSCLC per week than those in the community, 36% and 14% respectively. 87% report performing or referring for EBUS and about half (48%) perform EBUS themselves. 39 (14%) who perform EBUS obtain only 0-2 passes for molecular analysis, while 88 (31%) perform more than 5 passes. Responsible party for test ordering widely varied and 48% indicate having an institutional policy for testing. Presence of an institutional policy was associated with increased guideline awareness and higher rates of conducting molecular analysis. Rates of testing were high for EGFR and ALK, 99% and 95%, and lower for PD-L1, BRAF and ROS1, 77%, 44% and 48% respectively. Interventional pulmonologists and those in academic settings report higher rates of testing for biomarkers. For example, interventionalists test for BRAF and ROS1 nearly twice as often compared to generalists and those in an academic setting test 10-15% more often than those working in community settings (p<0.05). CONCLUSIONS: Our study suggests there is significant variation among pulmonologists in their practice acquiring tissue and awareness of and testing for molecular biomarkers in advanced NSCLC. This study suggests that pulmonologists should focus on knowledge for sending biomarkers and on obtaining adequate tissue for testing. Additionally, institutional policies correlate with higher rates of testing and may improve knowledge of available biomarkers for testing and treatment. CLINICAL IMPLICATIONS: Identifying and reducing barriers to molecular testing for patients with advanced stage NSCLC can improve access to treatment and outcomes in this population. DISCLOSURES: No relevant relationships by Upal Basu Roy, source=Web Response stockholder relationship with Merck Please note: $20001 - $100000 Added 03/09/2020 by Adam Fox, source=Web Response, value=Ownership interest stockholder relationship with MMM Please note: $20001 - $100000 Added 03/09/2020 by Adam Fox, source=Web Response, value=Ownership interest Consultant relationship with Biodesix Please note: $20001 - $100000 Added 05/31/2020 by James Jett, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with AstraZeneca Please note: $1-$1000 Added 06/26/2020 by Jennifer King, source=Web Response, value=to GO2 Foundation Speaker/Speaker's Bureau relationship with Foundation Medicine Please note: $1-$1000 Added 06/26/2020 by Jennifer King, source=Web Response, value=to GO2 Foundation Speaker/Speaker's Bureau relationship with ThermoFisher Please note: $1-$1000 Added 06/26/2020 by Jennifer King, source=Web Response, value=to GO2 Foundation Speaker/Speaker's Bureau relationship with Merck Please note: $1001 - $5000 Added 06/26/2020 by Jennifer King, source=Web Response, value=to GO2 Foundation Advisory Committee Member relationship with GRAIL Please note: $1-$1000 Added 06/26/2020 by Jennifer King, source=Web Response, value=Consulting fee No relevant relationships by Gerard Silvestri, source=Web Response No relevant relationships by Robert Smith, source=Web Response

Abstract 5806: Hypoxia-related radiomics predict checkpoint blockade immunotherapy response of non-small cell lung cancer patients

Abstract Checkpoint blockade immunotherapy exhibits durable responses in a subset of advanced stage non-small cell lung cancer (NSCLC) patients. However, not all patients respond and markers that predict response to immunotherapy are still an unmet clinical need. In this study, pre-treatment quantitative image-based biomarkers (radiomics) were utilized to predict survival risk among NSCLC patients treated with immunotherapy. Study cohorts were compromised of NSCLC patients that were treated with single or double agent immunotherapy and were divided into three independent groups from two different hospitals for Training (N = 180), test (N = 90) and validation (N = 62). Overall survival (OS) and progression-free survival (PFS) were used as endpoints. The most prognostic radiomic features and clinical covariates were used as inputs to a Classification and Regression Tree (CART) machine learning algorithm to stratify patients into survival risk-groups utilizing the training cohort. The risk groups identified were then tested and validated in the test and validation cohorts. Additionally, four independent non-immunotherapy treated NSCLC cohorts (total N = 446) were utilized to further investigate the prognostic value of the derived radiomics signature. The biological underpinnings of the most informative radiomics were assessed using gene expression data from a radiogenomics dataset and an immunohistochemistry (IHC) data.The final parsimonious model was able to stratify patients into four risk groups (from low-risk to very-high-risk) and the models were successfully tested and validated in independent cohorts. Specifically, the very-high-risk group was found to be associated with extremely poor OS outcomes (0% 3-year OS; hazard ratio [HR] = 5.35, 95% confidence interval [CI]: 2.14 - 13.36) compared to the low-risk group (38.9% 3-year OS; HR = 1.00). When PFS was assessed, similar outcomes were observed (0% vs. 29.8% 3-year PFS). A radiomic feature that quantifies the heterogeneity of tumor structural phenotype (GLCM inverse difference) was highly associated with OS in all three immunotherapy treated cohorts. Utilizing gene expression data, GLCM inverse difference was found to be positively associated with expression of carbonic anhydrase-9 (CA-IX), a surrogate for tumor hypoxia. This was validated by IHC, and further analysis showed that it was also associated with OS in the four other independent non-immunotherapy treated NSCLC cohorts.In this study, we utilized non-invasive image-based features and standard-of-care clinical covariates to identify novel risk groups that can predict OS and PFS among NSCLC patients treated with IO. These models have important translational associations as a potential risk score that could be used to assist decision making by identifying potentially vulnerable patients in the setting of immunotherapy. Citation Format: Ilke Tunali, Yan Tan, Jhanelle E. Gray, Evangelia Katsoulakis, Steven A. Eschrich, James Saller, Theresa Boyle, Jin Qi, Albert Guvenis, Robert J. Gillies, Matthew B. Schabath. Hypoxia-related radiomics predict checkpoint blockade immunotherapy response of non-small cell lung cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5806.

Clinical significance of tumor mutation burden and DNA damage repair in advanced stage non-small cell lung cancer patients.

This study aimed to investigate the impact of tumor mutational burden (TMB) and DNA damage repair (DDR) gene alteration on overall survival (OS) in advanced non-small cell lung cancer (NSCLC) patients. A DNA library of cancer cells from 67 NSCLC patients in stages III-IV was constructed for next-generation sequencing (NGS). Geneseeq422 probes were used for hybridization enrichment. The target-enriched library was sequenced on HiSeqNGS platforms, and we analyzed the relevant signaling pathways. Then, we correlated the OS of the patients with TMB and DDR mutations. Many significant alterations were found, including in the EGFR, p53, KRAS, RB1, ERBB2, NF1, DNMT3A, ALK, MYC, PIK3CA, ROS1, BRAF, ARID1A, PTEN, CDKN2A, and FGF19 genes. We also identified many mutations in the genes relevant to the DDR pathway. Interestingly, we found that the TMB of patients with DDR gene mutations was dramatically higher than that in the DDR wild-type (WT). Univariable analysis showed that DNMT3A, RB1, DDR pathway-related gene mutations, and TMB were critical factors for the effects on OS. Multivariable analysis confirmed that DNMT3A and mutations in the DDR pathway-related genes were important for predicting OS. Multiple mutations in the genes of the DDR pathway caused higher TMB levels, which resulted in longer OS. By contrast, OS was significantly longer in patients with non-DNMT3A mutations than in those with DNMT3A variants. DNMT3A alteration in NSCLC patients led to poor outcomes.

KRAS mutations testing in non-small cell lung cancer: the role of Liquid biopsy in the basal setting.

In advanced stage non-small cell lung cancer (NSCLC) patients, Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) testing may soon acquire a predictive significance to select patients for AMG510 treatment. Since tissue samples are not always available, liquid biopsy may represent a viable option for KRAS testing. Here, we review the last three years clinical practice performed on 194 plasma based liquid biopsies by next generation sequencing (NGS) SiRe® panel. In particular, 36 (18.6%) KRAS mutated cases were identified, with an overall median allelic frequency of 5.0% (ranging between 0.2% and 46.8%). No concomitant mutations were observed in the other NSCLC clinical relevant genes included in the SiRe® panel, such as epidermal growth factor receptor (EGFR) and v-Raf murine sarcoma viral oncogene homolog B (BRAF). Exon 2 p.G12C was the most common detected mutation (13/36, 36.1%). In conclusion, our data update and confirm that SiRe® NGS panel represents a robust analytical tool to assess KRAS mutational status on circulating tumor DNA. Further investigation is required to design more cost-effective diagnostic algorithms to harmonize clinical relevant biomarker testing on tissue and blood in advanced stage NSCLC clinical practice.

Comprehensive assessment of PD-L1 immunohistochemistry on paired tissue and cytology specimens from non-small cell lung cancer

ObjectivesPD-L1 staining assessed by immunohistochemistry (IHC) is a predictive biomarker used to select advanced stage non-small cell lung carcinoma (NSCLC) patients who are likely to respond to PD-1/PD-L1 inhibitors. Cytology specimens represent a significant percentage of the diagnostic samples and additional data are required to show that they provide reliable PD-L1 results when compared to tissue specimens. We aimed to compare PD-L1 staining obtained from patient-matched tissue and cytology specimens. We also want to assess the feasibility of PD-L1 testing on cell blocks with two assays by evaluating the intra- and inter-observer agreement and the level of difficulty for determining the percentage of stained tumor cells (TPS). Materials and methodsForty-six patients with NSCLC were selected. Each patient provided a surgical specimen and a cytology sample (cell block) and/or a biopsy at diagnosis. PD-L1 staining using Agilent PD-L1 IHC 28-8 pharmDx and VENTANA PD-L1 (SP263) assays was evaluated by four pathologists using the TPS. Sixty slides were rescored to document intra-observer agreement. Pathologists were asked to score the level of difficulty for evaluating PD-L1 TPS for each slide. Fleiss’s and Cohen’s kappas (k) were used to assess the agreement between paired specimens as well as intra- and inter-observer agreement. ResultsThe concordance in PD-L1 TPS between cell blocks and surgical specimens (k varying from 0.56 to 0.82) or biopsies (k from 0.43 to 0.81) was moderate to substantial, depending on the cut-off. On cell blocks, inter-observer agreement was substantial (k from 0.74 to 0.82) and intra-observer agreement was almost perfect (k from 0.85 to 0.93). The perceived difficulty of PD-L1 evaluation of cell blocks was not different from surgical specimens but more difficult than biopsy samples. ConclusionPD-L1 TPS was concordant between cell blocks and tissue specimens, mainly at 10, 25 and 50 % cut-offs. PD-L1 evaluation on cell blocks was feasible and reproducible between different observers and assays.

Ablation Therapy for Advanced Stage Non-Small Cell Lung Cancer: A National Cancer Database Study

PurposeTo compare overall survival (OS) of ablation with no treatment for patients with advanced stage non-small cell lung cancer. MethodsPatients with clinical stage IIIB (T1–4N3M0, T4N2M0) and stage IV (T1–4N0–3M1) non-small cell lung cancer, in accordance with the American Joint Committee on Cancer, 7th edition, who did not receive treatment or who received ablation as their sole primary treatment besides chemotherapy from 2004 to 2014, were identified from the National Cancer Data Base. OS was estimated using the Kaplan-Meier method and evaluated by log-rank test, univariate and multivariate Cox proportional hazard regression, and propensity score-matched analysis. Relative survival analyses comparing age- and sex-matched United States populations were performed. ResultsA total of 140,819 patients were included. The 1-, 2-, 3- and 5-year survival rates relative to age- and sex-matched United States population were 28%, 18%, 12%, and 10%, respectively, for ablation (n = 249); and 30%, 15%, 9%, and 5%, respectively for no treatment (n = 140,570). Propensity score matching resulted in 249 patients in the ablation group versus 498 patients in the no-treatment group. After matching, ablation was associated with longer OS than that in the no-treatment group (median, 5.9 vs 4.7 months, respectively; hazard ratio, 0.844; 95% confidence interval, 0.719–0.990; P = .037). These results persisted in patients with an initial tumor size of ≤3 cm. ConclusionsPreliminary results suggest ablation may be associated with longer OS in patients with late-stage non-small cell lung cancer than survival in those who received no treatment.