Advanced Stage Non-small Cell Lung Research Articles

Impact of Race on Outcomes of Advanced Stage Non-Small Cell Lung Cancer Patients Receiving Immunotherapy.

The impact of race in advanced stage non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) is conflicting. Our study sought to examine racial disparities in time to treatment initiation (TTI), overall survival (OS), and progression-free survival (PFS) using a population that was almost equally black and white. This was a retrospective cohort study of stage IV NSCLC patients > 18 years receiving immunotherapy at our center between 2014 and 2021. Kaplan-Meier curves and the multivariate Cox proportional hazards model determined the predictors of OS and PFS. Analyses were undertaken using IBM PSAW (SPSS v.28). Out of 194 patients who met the inclusion criteria, 42.3% were black (n = 82). In the multivariate analysis, there was no difference in PFS (HR: 0.96; 95% CI: 0.66,1.40; p = 0.846) or OS (HR: 0.99; 95% CI: 0.66, 1.48; p = 0.966). No difference in treatment selection was observed between white and black patients (p = 0.363), nor was there a difference observed in median time to overall treatment initiation (p = 0.201). No difference was observed in OS and PFS in black and white patients. Black patients' reception of timelier immunotherapy was an unanticipated finding. Future studies are necessary to better understand how race impacts patient outcomes.

Abstract 1125: Neoantigen immunogenicity landscapes and evolution of tumor ecosystems during immunotherapy with nivolumab

Abstract Immune checkpoint blockade (ICB) therapy is a cornerstone of oncologic treatment for patients with advanced stage non-small cell lung cancer (NSCLC) and other malignancies. Neoantigen immunoediting drives ICB efficacy, yet how tumor evolution and neoantigen immunogenicity shape treatment response remains poorly understood. To address these questions, we conducted a prospective clinical trial of NSCLC patients treated with nivolumab. We assessed genomic alterations in tumors from 58 patients and performed large-scale immune epitope analyses, before and during treatment (CheckMate153, CA209-153). Tumors were analyzed by whole-exome and transcriptome sequencing. In responding patients, loss of mutation and neoantigen burden early during therapy was associated with clinical benefit. We evaluated the immunogenicity of 1,453 candidate neoantigens and identified 502 neopeptides that bound to MHC I and 196 neopeptides that were immunogenic and recognized by T cells in the setting of nivolumab treatment. These T cell reactive neoantigens were differentially present in clonal populations that underwent distinctive evolutionary trajectories across responders and nonresponders. Mapping these neoantigens to tumor clonal dynamics and clinical response revealed strong selection against immunogenic mutations compared to non-immunogenic mutations. We used this large collection of neoantigens to build ImmunoSEEK, a machine learning-based neoantigen prediction model and validated it using an orthogonal set of neoantigens. Changes in the genomic and neoantigen immunogenicity landscapes were accompanied by temporal changes in the tumor microenvironment. Nivolumab-induced microenvironmental evolution in NSCLC shared some similarities with that in melanoma, yet critical differences in immunologic programs were apparent from comparative network analysis between tumor types. This study provides unprecedented molecular portraits of the genomic and neoantigen landscapes underlying nivolumab’s mechanism of action. Citation Format: Tyler Joseph Alban, Nadeem Riaz, Prerana Parthasarathy, Vlad Makarov, Slav Kendall, Seong-Keun Yoo, Rachna Shah, Nils Weinhold, Raghvendra Srivastava, Xiaoxiao Ma, Chirag Krishna, Edward Garon, Wallace Akerley, Ben Creelan, Nivedita Aanuren, Diego Chowell, William Geese, Naiyer Rizvi, Timothy Chan. Neoantigen immunogenicity landscapes and evolution of tumor ecosystems during immunotherapy with nivolumab [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 1125.

Endobronchial ultrasound-guided transbronchial needle injection of cisplatin results in dynamic changes in the tumor immune microenvironment

RationaleDirect intratumoral delivery of cisplatin via endobronchial ultrasound guided-transbronchial needle injections (EBUS-TBNI) is a novel approach for salvage treatment of advanced stage non-small cell lung cancer (NSCLC). The goal of this study was to evaluate changes in the tumor immune microenvironment during the course of EBUS-TBNI cisplatin therapy. MethodsUnder an IRB approved protocol, patients with recurrence after radiation therapy who were not receiving other cytotoxic therapy, were prospectively enrolled, and underwent weekly treatments with EBUS-TBNI with additional biopsies obtained for research. Needle aspiration was performed prior to cisplatin delivery at each procedure. Samples were evaluated by flow cytometry for the presence of immune cell types. ResultsThree of the six patients responded to the therapy based on RECIST criteria. Compared to the pre-treatment baseline, intratumoral neutrophils increased in 5 of the 6 patients (p = 0.041), with an average increase of 27.1%, but was not associated with response. A lower pre-treatment CD8+/CD4+ ratio at baseline was associated with response (P = 0.01). Responders demonstrated a lower final proportion of PD-1+ CD8+ T cells compared to non-responders (8.6% vs. 62.3%, respectively, P<0.001. Lower doses of intratumoral cisplatin were associated with subsequent increases in CD8+ T cells within the tumor microenvironment (P = 0.008). ConclusionsEBUS-TBNI cisplatin resulted in significant alterations in the tumor immune microenvironment. Further studies are needed to determine if the changes seen here generalize to larger cohorts.

Abstract B127: Impact of race on the outcomes of advanced stage non-small cell lung cancer in an equal access setting

Abstract Introduction: Immunotherapy has improved outcomes in patients with advanced stage lung cancer. However, the studies which led to approval of these therapies did not include a substantial number of Black patients. Studies focusing on racial disparities in advanced stage non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) report conflicting data. In an equal access setting, some studies have demonstrated improved outcomes in Black patients. Very few studies have high or equal representation of Black patients, and these studies lack detail on access to care, such as time to treatment initiation (TTI) in this target population. To our knowledge, this study is one of few with almost equal representation of Black and White patients. Methods: This was an IRB approved retrospective study of stage IV NSCLC patients &amp;gt; 18 years who received immunotherapy-based systemic therapy at Vidant Medical Center between 2014 and 2021. Analyses were done utilizing IBM PSAW (SPSS Version 28). Associations between race and other demographic characteristics were examined using chi-square tests. Kaplan-Meier curves were generated to determine overall survival (OS) and progression-free survival (PFS) stratified by race. Multivariate Cox proportional hazards model was applied to determine predictors of OS and PFS. A p-value &amp;lt; 0.05 was deemed statistically significant. Results: Of 194 patients who met the eligibility criteria, 42.3% were Black (n=82). On Kaplan-Meier analysis, there was no difference in median PFS (6.30 versus 7.90 months; log-rank p=0.977) and OS (9.50 versus 11.77 months; log-rank p=0.457) between White and Black patients respectively. On multivariate analysis, there was no difference in PFS (HR: 0.98; 95% CI: 0.68,1.43; p=0.928) or OS (HR: 1.01; 95% CI: 0.67,1.51; p=0.969) when controlling for race, sex, age at diagnosis, pack years, marital status, insurance type, histology, and Charlson Comorbidity Index (CCI). The most frequently administered ICIs were pembrolizumab (74.7%), nivolumab (13.4%), atezolizumab (8.8%), nivolumab plus ipilimumab (1.5%), and durvalumab (1.5%). There was no difference in treatment selection between Black and White patients (p=0.184; chi-square). Median time to initial overall cancer treatment initiation (28.00 days versus 22.00 days; p=0.159) did not differ, but there was a significant difference in median time to immunotherapy initiation (34.00 versus 27.00 days; p=0.042) between White and Black patients respectively. Conclusion: Although race was expected to permeate patient outcomes, OS and PFS did not differ between Black and White patients. The significantly shorter time to immunotherapy treatment for Black patients is an unexpected finding. In our study we highlighted that equitable access reduces disparities, bridges gaps in care, and improves patient outcomes, regardless of race. Further studies with equitable representation of diverse racial groups are warranted to better understand how race impacts cancer outcomes. Citation Format: Melisa Pasli, Radhamani Kannaiyan, Praveen Namireddy, Mahvish Muzaffar. Impact of race on the outcomes of advanced stage non-small cell lung cancer in an equal access setting [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B127.

Role of 18F-FDG PET/CT and sarcopenia in untreated non-small cell lung cancer with advanced stage.

Sarcopenia is essential in managing advanced stage (III-IV) non-small cell lung cancer (NSCLC) but is laborious to diagnose using currently available method. This study aimed to establish a simple approach to predict sarcopenia using 18F-FDG PET/CT parameters and clinical characteristics and determine their roles in prognostication in advanced stage NSCLC. Untreated 202 NSCLC patients with stage III-IV were retrospectively reviewed. Sarcopenia was defined using the skeletal muscle index (SMI) measured at the third lumbar vertebra (L3). 18F-FDG PET/CT metabolic parameters of maximum standard uptake value, metabolic tumor volume, and total lesion glycolysis of the primary tumor (SUVmax_T, MTV_T, and TLG_T) and of whole-body lesions (MTV_WB and TLG_WB) were measured. Besides, SUVmax of the psoas major muscle (SUVmax_Muscle) was measured at the L3 level. The diagnostic endpoint was the probability of sarcopenia, and the survival endpoints included progression-free survival (PFS) and overall survival (OS). Among the enrolled 202 patients, 82 (40.6%) were diagnosed with sarcopenia. Higher age, male, lower BMI, and lower SUVmax_Muscle were correlated with a higher incidence of sarcopenia (P < 0.05), while age, sex, BMI, and SUVmax_Muscle were independently predictive of sarcopenia, and thus were utilized to construct a nomogram model. Multivariate Cox regression analysis revealed that sarcopenia score derived from the nomogram model, sarcopenia, stage, and TLG_WB were independently predictive of both PFS and OS. The incidence of sarcopenia increased with declining SUVmax_Muscle in advanced stage NSCLC. Our model using age, sex, BMI, and SUVmax_Muscle might be substituted for the complicated measurement of SMI. After adjustment by stage and TLG_WB, both sarcopenia score and sarcopenia were found to be independently predictive of PFS and OS.

31P The IOpener study: Tyrosine kinase activity profiling to predict response to immune checkpoint inhibitors in patients with advanced stage non-small cell lung cancer

Treatment with immune checkpoint inhibitors (ICIs) is successful, but only in a subset of patients with advanced stage non-small cell lung cancer (NSCLC). Blood-based kinase profiling of peripheral blood mononuclear cells (PBMCs) has previously shown its predictive value for response to ICI treatment in a discovery cohort (Hurkmans et al., JITC 2020). The aim of the current prospective study was to perform a blind validation of the predictive value of kinase activity profiles in PBMCs for ICI response in patients with NSCLC in a standardized setting.

Elevated Levels of Circulating Hsp70 and an Increased Prevalence of CD94+/CD69+ NK Cells Is Predictive for Advanced Stage Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is the second most frequently diagnosed tumor worldwide. Despite the clinical progress which has been achieved by multimodal therapies, including radiochemotherapy, and immune checkpoint inhibitor blockade, the overall survival of patients with advanced-stage NSCLC remains poor, with less than 16 months. It is well established that many aggressive tumor entities, including NSCLC, overexpress the major stress-inducible heat shock protein 70 (Hsp70) in the cytosol, present it on the plasma membrane in a tumor-specific manner, and release Hsp70 into circulation. Although high Hsp70 levels are associated with tumor aggressiveness and therapy resistance, membrane-bound Hsp70 can serve as a tumor-specific antigen for Hsp70-primed natural killer (NK) cells, expressing the C-type lectin receptor CD94, which is part of the activator receptor complex CD94/NKG2C. Therefore, we investigated circulating Hsp70 levels and changes in the composition of peripheral blood lymphocyte subsets as potential biomarkers for the advanced Union for International Cancer Control (UICC) stages in NSCLC. As expected, circulating Hsp70 levels were significantly higher in NSCLC patients compared to the healthy controls, as well as in patients with advanced UICC stages compared to those in UICC stage I. Smoking status did not influence the circulating Hsp70 levels significantly. Concomitantly, the proportions of CD4+ T helper cells were lower compared to the healthy controls and stage I tumor patients, whereas that of CD8+ cytotoxic T cells was progressively higher. The prevalence of CD3-/CD56+, CD3-/NKp30, CD3-/NKp46+, and CD3-/NKG2D+ NK cells was higher in stage IV/IIIB of the disease than in stage IIIA but were not statistically different from that in healthy individuals. However, the proportion of NK cells expressing CD94 and the activation/exhaustion marker CD69 significantly increased in higher tumor stages compared with stage I and the healthy controls. We speculate that although elevated circulating Hsp70 levels might promote the prevalence of CD94+ NK cells in patients with advanced-stage NSCLC, the cytolytic activity of these NK cells also failed to control tumor growth due to insufficient support by pro-inflammatory cytokines from CD4+ T helper cells. This hypothesis is supported by a comparative multiplex cytokine analysis of the blood in lung cancer patients with a low proportion of CD4+ T cells, a high proportion of NK cells, and high Hsp70 levels versus patients with a high proportion of CD4+ T cells exhibiting lower IL-2, IL-4, IL-6, IFN-γ, granzyme B levels.

Modeling strategies to analyse longitudinal biomarker data: An illustration on predicting immunotherapy non-response in non-small cell lung cancer

Serum tumor markers acquired through a blood draw are known to reflect tumor activity. Their non-invasive nature allows for more frequent testing compared to traditional imaging methods used for response evaluations. Our study aims to compare nine prediction methods to accurately, and with a low false positive rate, predict progressive disease despite treatment (i.e. non-response) using longitudinal tumor biomarker data. Bi-weekly measurements of CYFRA, CA-125, CEA, NSE, and SCC were available from a cohort of 412 advanced stage non-small cell lung cancer (NSCLC) patients treated up to two years with immune checkpoint inhibitors. Serum tumor marker measurements from the first six weeks after treatment initiation were used to predict treatment response at 6 months. Nine models with varying complexity were evaluated in this study, showing how longitudinal biomarker data can be used to predict non-response to immunotherapy in NSCLC patients.

Clinical Laboratory Results as Prognosis Marker in Advanced Stage Non-small Cell Lung Cancer (NSCLC) in Indonesia.

Background: Lung cancer is the most common cause of cancer-related death among men in the world. Given the very high mortality caused by lung cancer, a biological marker to determine a more sensitive therapy among non-small cell lung cancer (NSCLC) patients is needed. This study aims to demonstrate that the clinical laboratory result can be a prognosis marker in NSCLC patients in Indonesia.Methods: This study was a retrospective cohort study. The sample was obtained from the patient's serum and the examined routine blood test (hemoglobin, leukocyte, platelets), hemostasis (fibrinogen and D-dimers), blood chemistry test (aspartate transaminase [AST], alanine transaminase [ALT], albumin, urea, creatinine, and blood glucose), electrolyte (sodium, potassium, chloride, and calcium) and tumor markers (carcinoembryonic antigen [CEA] and Cyfra 21-1). Data were analyzed and interpreted using SPSS (IBM Corp., Armonk, NY, USA). Analysis of the data was done to find the survival rate of sociodemographic variables, clinicopathologic variables, and clinic laboratory variables.Results: The study findings showed statistically significant results that were poor prognosis for these following conditions: performance status (PS) 3-4 median survival (MS):26 days, p=<0.001; TNM stage IVb MS:58 days, p=0.001; high leukocyte MS:69 days, p=0.018; low platelet MS:50 days, p=0.013; high D-dimer MS:69 days, p=0.020; low albumin MS:56 days, p=0.001; high sodium MS:15 days, low sodium MS:50 days, p=<0.001; high chloride MS:15 days, low chloride MS:27 days, p=<0.001.Conclusion: In the advanced stage NSCLC, these findings indicate poorer prognoses; PS 3-4, IVb clinical stage, leukocytosis, thrombocytopenia, hyper-coagulopathy, hypoalbuminemia, hyper-hyponatremia, and hyper-hypochloremia. Further studies regarding the correlation between clinical laboratory and survival rate are needed.

EP08.02-090 Sotorasib Drug-Drug Interactions: Essential Guidance Requested by Physicians Worldwide

The life expectancy of advanced stage non-small cell lung cancer patients has increased significantly over the last years due to the introduction of immunotherapy and multiple targeted therapies. One of the most recent important developments is the registration of the KRAS p.G12C targeting agent sotorasib (LUMAKRAS/LUMYKRAS®). The KRAS p.G12C driver mutation is one the most prevalent driver mutations in NSCLC, occurring in 13% of lung adenocarcinomas. Sotorasib causes relevant drug-drug interactions (DDIs), both as a perpetrator (P-gp inhibitor, CYP3A4 inducer) and as a victim (CYP3A4 and P-gp substrate) which may lead to (cancer) treatment inefficacy or serious side effects.

950O Ipilimumab plus nivolumab and chemoradiotherapy followed by surgery in patients with resectable and borderline resectable lung cancer: The INCREASE trial

Neoadjuvant chemoradiotherapy (CRT) and surgery is a treatment option for patients with locally advanced stage non-small cell lung cancer (NSCLC) with limited mediastinal lymph node metastases. Pathological complete response (pCR) correlates with improved survival but is achieved in only approximately 30% of patients after CRT. Neo-adjuvant ipilimumab plus nivolumab (IPI-NIVO) can modulate the tumor microenvironment and may increase pathological responses. In a phase II study (INCREASE, EudraCT-Nr: 2019–003454-83), we studied the addition of IPI-NIVO to CRT.

P2.02-01 Value of Albumin-to-Globulin Ratio for Survival Prediction in Advanced Stage Non-Small Cell Lung Cancer Treated with Chemotherapy

According to previous data, pretreatment albumin-to-globulin ratio (AGR) was a simplified biomarker that was an independent prognostic factor in lung cancer, but there are no data on the use of AGR as a prognostic factor in metastatic non-small cell lung cancer (NSCLC) treated with chemotherapy. The aim of this study was to determine whether AGR can be used as a prognostic factor under these conditions.

Evaluation of the Molecular Landscape in PD-L1 Positive Metastatic NSCLC: Data from Campania, Italy.

Background: Immune-checkpoint inhibitors (ICIs) have increased and improved the treatment options for patients with non-oncogene-addicted advanced stage non-small cell lung cancer (NSCLC). However, the role of ICIs in oncogene-addicted advanced stage NSCLC patients is still debated. In this study, in an attempt to fill in the informational gap on the effect of ICIs on other driver mutations, we set out to provide a molecular landscape of clinically relevant oncogenic drivers in programmed death-ligand 1 (PD-L1) positive NSCLC patients. Methods: We retrospectively reviewed data on 167 advanced stage NSCLC PD-L1 positive patients (≥1%) who were referred to our clinic for molecular evaluation of five driver oncogenes, namely, EGFR, KRAS, BRAF, ALK and ROS1. Results: Interestingly, n = 93 (55.7%) patients showed at least one genomic alteration within the tested genes. Furthermore, analyzing a subset of patients with PD-L1 tumor proportion score (TPS) ≥ 50% and concomitant gene alterations (n = 8), we found that n = 3 (37.5%) of these patients feature clinical benefit with ICIs administration, despite the presence of a concomitant KRAS gene alteration. Conclusions: In this study, we provide a molecular landscape of clinically relevant biomarkers in NSCLC PD-L1 positive patients, along with data evidencing the clinical benefit of ICIs in patient NSCLC PD-L1 positive alterations.

State-of-the-art combination treatment strategies for advanced stage non-small cell lung cancer.

Non–small cell lung cancer (NSCLC) is the most abundant type of epithelial lung cancer being diagnosed after 40% of invasions of excrescence in pulmonary tissues. According to WHO, 30% of NSCLC patients can be cured if diagnosed and treated early. Mutations play an important role in advanced stage NSCLC treatment, which includes critical proteins necessary for cellular growth and replication. Restricting such mutations may improve survival in lung cancer patients. Newer technologies include endoscopic bronchial ultrasonography and esophageal ultrasonography. Currently, policymaking or decision-making for treatment regimens merely depends on the genomic alterations and mutations. DNA sequencing, methylation, protein, and fragmented DNA analysis do NSCLC screening. Achievement of these goals requires consideration of available therapeutics in current anticancer approaches for improving quality of life and treatment outcomes for NSCLC patient. The specific goals of this review are to discuss first-line and second-line therapies for advanced-stage NSCLC and molecularly targeted therapy including thoughtful discussion on precise role of treatment strategies in specific tumors. Also, concerned diagnostics, new clinical trial designs, and pursuing appropriate combinations of radiotherapy and/or chemotherapy with biological therapy for exceptional cases considering resistance mechanisms and palliative care will be discussed.

The relationship between clinicopathological parameters and PD-L1 expression level in advanced stage non-small cell lung cancer.

Clinicopathological parameters related to programmed death ligand 1 (PD-L1) expression levels have been investigated in several studies. However, the results of these studies are conflicting and vary in different populations. This study aimed to investigate the relation of clinicopathological parameters with PD-L1 expression level in advanced stage non-small cell lung cancer patients. The patients diagnosed with non-small cell lung cancer were enrolled, retrospectively. The data of clinicopathological parameters was collected. Clinicopathological parameters in relation to PD-L1 expression levels (0%, 1-50%, and >50%) were analyzed as univariable and multivariable. In total, 384 patients were enrolled. PD-L1 expression in tumor cells was between 1-50%, and >50% in 41.4%, and 23.4% of patients, respectively. There was no PD-L1 expression in 35.2% of the patients. In univariable analysis, we found that the parameters associated with PD-L1 expression levels revealed that metastatic site number, the subtype of cancer, diagnostic material type, platelet number, and LDH level were statistically significant. Adenocarcinoma frequency was higher in tumors that had PD-L1 expression >50% than in tumors that did not express PD-L1 and the difference was statistically significant (p= 0.04, coefficient= 0.3, 95% CI 0.09-0.94). Cytology as diagnostic material was significant in PD-L1 level 1-50% comparing to >50% (p= 0.02, coefficient= 2.2, 95% CI= 1.08-4.46). According to the results of our study, many of the clinicopathological parameters are not related to the PD-L1 level. The histological subtype and diagnostic material may affect the level of PD-L1 expression.

Risk Factors Predicting Chemotherapy-induced Severe Neutropenia and Outcome in Advanced Stage Non-small Cell Lung Cancer: Data from the Limited Resource in Thailand

Introduction: Chemotherapy-induced severe neutropenia requires dose reduction, delay in treatment, or discontinuation, and induces neutropenic complications resulting in poor outcomes and increased healthcare costs. This study aims to identify the risk factors for chemotherapy-induced severe neutropenia and outcome in advanced-stage NSCLC. Method: From July 2014-January 2019, advanced-stage NSCLC who received chemotherapy were retrospectively analyzed. Demographic and risk factors data were collected from the electronic medical record system. Univariate and multivariate logistic regression analyses were performed to identify risk factors for severe neutropenia. Survival curves were estimated using the Kaplan–Meier method. Results: Among 259 patients, 37 (14.28%) and 3 patients (1.2%) developed severe neutropenia and febrile neutropenia respectively. In multivariate analysis, restriction of protein diet (OR 9.54; 95%CI 2.44-37.24; P=0.001), concomitant use herbal medicine (OR 8.66; 95% CI 1.04-72.07; P=0.045), high BMI (OR3.1; 95% CI 1.07-8.99; P=0.04), renal disease (OR 3.9; 95% CI 1.7-8.91; P=0.001), number of cycle chemotherapy &gt; 4 (OR 3.97; 95% CI 1.11-14.18; P=0.03) were significant predictors of Chemotherapy-induced severe neutropenia. No difference in response rate, progression-free survival and overall survival among groups (RR 18.9% vs 26.7%; median PFS; 9.6 vs 8.2 months, P=0.32 and median OS 13.8 vs 16.7 months, P=0.79 in severe and non-severe neutropenia respectively).Conclusions: The present study indicates that protein-restricted diet, concomitant use of herbal medicine, BMI ≥ 25 kg/m2, renal disease, and more than 4 cycles of chemotherapy are significant risk factors for chemotherapy-induced severe neutropenia. Therefore, patients with these risk factors should be more carefully monitored.

Radioresistance of Non-Small Cell Lung Cancers and Therapeutic Perspectives.

Simple SummaryThe poor survival of unresectable locally advanced stage non-small cell lung cancer is due to the resistance to chemoradiotherapy and local/distant relapses. However, with the advent of new drugs, it has become possible to improve the prognosis of patients with stage III NSCLC harboring certain genetic mutations. Herein, we review new therapeutic strategies to overcome this radioresistance with drugs targeting cancer stem cells/specific mutations or new radiotherapy modalities.Survival in unresectable locally advanced stage non-small cell lung cancer (NSCLC) patients remains poor despite chemoradiotherapy. Recently, adjuvant immunotherapy improved survival for these patients but we are still far from curing most of the patients with only a 57% survival remaining at 3 years. This poor survival is due to the resistance to chemoradiotherapy, local relapses, and distant relapses. Several biological mechanisms have been found to be involved in the chemoradioresistance such as cancer stem cells, cancer mutation status, or the immune system. New drugs to overcome this radioresistance in NSCLCs have been investigated such as radiosensitizer treatments or immunotherapies. Different modalities of radiotherapy have also been investigated to improve efficacity such as dose escalation or proton irradiations. In this review, we focused on biological mechanisms such as the cancer stem cells, the cancer mutations, the antitumor immune response in the first part, then we explored some strategies to overcome this radioresistance in stage III NSCLCs with new drugs or radiotherapy modalities.

Digital quantification of lymphocytic infiltration on routine H&amp;E images and immunotherapy response in non–small cell lung cancer.

9066 Background: Current biomarker(s) for immuno-oncology (IO) therapy response prediction in lung cancer are limited. Additional predictive biomarkers are useful to help refine patient selection and guide precision therapy. Methods: Biopsy and surgical specimens stained with hematoxylin-eosin (H&amp;E) were subjected to whole-slide scanning for 446 advanced stage non-small cell lung cancer (NSCLC) treated with single agent immune check point inhibitors (ICI). A machine learning model was trained on H&amp;E images for classification of tumor infiltrating lymphocytes (TILs), tumor cells, and stromal cells in specific tissue types. Results: TIL levels were found to be highly variable, with a range of 12 to 4270 cells/mm2, and median of 319 (Q1 = 159, Q3 = 681). TIL levels were assessed on tissue samples from multiple organs which had shown primary or metastatic NSCLC, and were similar across all specimen sites except the liver, for which median TIL levels were significantly lower, at 90 cells/mm2. There was no correlation between tumor mutational burden (TMB) and TIL levels, while high TIL levels were correlated with high PD-L1 (≥ 50%) expression. Patients who experienced a partial/complete response to ICI therapy had a trend to higher median TILs compared to those who had progressive/stable disease (350 versus 310 cells/mm2, P = 0.09). In a multivariable analysis after controlling for covariates (incl. sex, age, cigarette smoking, ECOG, PD-L1, TMB &amp; treatment line), a higher TIL level (≥ 250 cells/mm2) was an independent predictor of IO response for both progression-free survival (PFS; HRadj 0.70; 95% CI, 0.55 - 0.89; P = 0.003) and overall survival (HRadj 0.73; 95% CI, 0.56 - 0.95; P = 0.02). In a ROC analysis considering single biomarkers, PD-L1 had the highest AUC (0.68, P &lt; 0.001), while TIL (AUC = 0.53, P = 0.08) and TMB (AUC = 0.55, P = 0.05) had similar AUC values for classifying responders from non-responders based on objective response rate. Using weighted linear regression approach to combine the biomarkers, paired PD-L1/TMB had the greatest AUC (0.70, P &lt; 0.001) compared to PD-L1 single assay. In the PD-L1 negative (&lt; 1%, N = 50) subgroup, TIL levels had superior predictive performance for classification of IO responders (AUC = 0.77, P = 0.02) compared to TMB (AUC = 0.57, P = 0.3), such that patients with a high TIL level (≥ 250 cells/mm2) had an improved PFS (median PFS: 2.7 vs 2.2 months; HR = 0.48; 95% CI, 0.26 - 0.87; P = 0.02). Conclusions: Digital TIL quantification with use of machine learning is feasible. TIL levels appear to be a robust and independent biomarker of likelihood of response to IO treatment in NSCLC, especially in the PD-L1 negative subgroup. The findings of this study are under validation in additional lung cancer cohorts.

Serum protein level as a predictor of therapeutic response and adverse effects associated with afatinib use.

BackgroundAfatinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor with significant serum protein binding. Total protein level was found to be associated with plasma afatinib level. The trough serum concentration was shown to be associated with development of adverse effects. This study aims to explore the association between serum protein levels and clinical responses and adverse effects in advanced stage non-small cell lung cancer (NSCLC) treated with afatinib.MethodsThis was a retrospective cohort study of Chinese patients with metastatic NSCLC harboring EGFR mutations who received first or second line afatinib treatment. The association of serum protein and album levels, as well as their ratio, and the development of adverse effects was investigated.ResultsAmong 217 patients included, 91 were on afatinib as first line treatment and 126 as second line treatment. Higher serum protein levels, albumin levels and albumin to globulin ratio, were found to be associated with clinical response to afatinib among patients on first or second line setting. Among patients on first line afatinib with Eastern Cooperative Oncology Group Performance State (ECOG PS) at 1 or above, those with lower serum protein levels at baseline had higher risks of developing grade 2 or above gastrointestinal adverse effects. Among patients on second line afatinib and with ECOG PS at 1 or above, patients with lower serum protein levels at baseline had higher risks of developing grade 3 or above cutaneous adverse effects. Lower serum albumin to globulin ratio at baseline was associated with increased risks of grade 3 or above gastrointestinal adverse effects among patients with ECOG PS at 1 or above and no prior systemic chemotherapy.ConclusionsSerum protein, albumin level and serum albumin to globulin ratio may predict the response to afatinib and occurrence of adverse effects with afatinib treatment.

A narrative review of predictive immuno-histo/cyto chemistry in lung cancer: focus on gene fusions and PD-L1 expression

Background and Objective: Personalized medicine has significant modified the way advanced stage non-small cell lung cancer (NSCLC) patients have been managed. In fact, the development of different target drugs has significantly improved the clinical outcomes of these patients. In this scenario, gene rearrangements play a crucial role. Gene fusions, including those involving anaplastic lymphoma receptor tyrosine kinase (ALK), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), rearranged during transfection (RET) and neurotrophic receptor tyrosine kinase (NTRK) genes, occur very rarely in advanced stage NSCLC patients. Remarkably, these genomic alterations represent an important target for treatment decision algorithm in these patients. In addition, programmed death-ligand 1 (PD-L1) protein expression evaluation is crucial for immune-checkpoint inhibitors (ICIs) administration.