Prognosis In Advanced Non-small Cell Lung Cancer Patients Research Articles

Prognostic value of body mass index for first-line chemoimmunotherapy combinations in advanced non-small cell lung cancer in Chinese population

BackgroundFew studies have examined the correlation between body mass index (BMI) and effectiveness of first-line chemoimmunotherapy in patients with advanced non-small cell lung cancer (NSCLC); moreover, the conclusion remains elusive and no such studies have been conducted in the Chinese population. Our study aimed to validate the predictive significance of BMI in Chinese patients with advanced NSCLC receiving first-line chemoimmunotherapy combinations. MethodsData of patients with advanced NSCLC treated with first-line chemoimmunotherapy between June 2018 and February 2022 at three centers were retrieved retrospectively. The association between baseline BMI with progression-free survival (PFS) and overall survival (OS) was evaluated using the Kaplan–Meier method and Cox regression models. BMI was categorized according to the World Health Organization criteria. ResultsOf the included 805 patients, 5.3 % were underweight, 63.4 % had normal weight, 27.8 % were overweight, and 3.5 % were obese. Survival analysis showed that patients in the high BMI group had significantly better PFS (p = 0.012) and OS (p = 0.014) than those in the low BMI group. Further, patients in the overweight subgroup had better PFS (p = 0.036) and OS (p = 0.043) compared to the normal weight population. The results of Cox regression analysis confirmed the correlations between BMI and prognosis of advanced NSCLC patients receiving first-line chemoimmunotherapy combinations. ConclusionsBaseline BMI affected the clinical outcomes of first-line chemoimmunotherapy combinations in patients with advanced NSCLC, and was especially favorable for the overweight subgroup.

CircNOX4 activates an inflammatory fibroblast niche to promote tumor growth and metastasis in NSCLC via FAP/IL-6 axis

BackgroundCancer-associated fibroblasts (CAFs) orchestrate a supportive niche that fuels cancer metastatic development in non-small cell lung cancer (NSCLC). Due to the heterogeneity and plasticity of CAFs, manipulating the activated phenotype of fibroblasts is a promising strategy for cancer therapy. However, the underlying mechanisms of fibroblast activation and phenotype switching that drive metastasis remain elusive.MethodsThe clinical implications of fibroblast activation protein (FAP)-positive CAFs (FAP+CAFs) were evaluated based on tumor specimens from NSCLC patients and bioinformatic analysis of online databases. CAF-specific circular RNAs (circRNAs) were screened by circRNA microarrays of primary human CAFs and matched normal fibroblasts (NFs). Survival analyses were performed to assess the prognostic value of circNOX4 in NSCLC clinical samples. The biological effects of circNOX4 were investigated by gain- and loss-of-function experiments in vitro and in vivo. Fluorescence in situ hybridization, luciferase reporter assays, RNA immunoprecipitation, and miRNA rescue experiments were conducted to elucidate the underlying mechanisms of fibroblast activation. Cytokine antibody array, transwell coculture system, and enzyme-linked immunosorbent assay (ELISA) were performed to investigate the downstream effectors that promote cancer metastasis.ResultsFAP+CAFs were significantly enriched in metastatic cancer samples, and their higher abundance was correlated with the worse overall survival in NSCLC patients. A novel CAF-specific circRNA, circNOX4 (hsa_circ_0023988), evoked the phenotypic transition from NFs into CAFs and promoted the migration and invasion of NSCLC in vitro and in vivo. Clinically, circNOX4 correlated with the poor prognosis of advanced NSCLC patients. Mechanistically, circNOX4 upregulated FAP by sponging miR-329-5p, which led to fibroblast activation. Furthermore, the circNOX4/miR-329-5p/FAP axis activated an inflammatory fibroblast niche by preferentially inducing interleukin-6 (IL-6) and eventually promoting NSCLC progression. Disruption of the intercellular circNOX4/IL-6 axis significantly suppressed tumor growth and metastatic colonization in vivo.ConclusionsOur study reveals a role of the circRNA-induced fibroblast niche in tumor metastasis and highlights that targeting the circNOX4/FAP/IL-6 axis is a promising strategy for the intervention of NSCLC metastasis.

The Association Between Modified Albumin-Bilirubin (mALBI) and Survival in Advanced Non-small Cell Lung Cancer Patients Treated With Immunotherapy.

This study aimed to assess the clinical value of the modified albumin-bilirubin (mALBI) grade in predicting the survival of patients with advanced non-small cell lung cancer (NSCLC) treated with immunotherapy. We conducted a retrospective cohort study of patients with advanced NSCLC who received immune checkpoint inhibitors (ICIs) from January 2020 to May 2022. The primary endpoints were overall survival (OS), treatment response, and the association between different mALBI grades and survival. In these 67 patients, 85.1% (57/67) were male, and the median age was 63 years. The patients with mALBI grades 1 and 2a at baseline had a median OS of 12.83 months (95% CI: 9.4 to 16.27 months), whereas it was 3.2 months (95% CI: NA to 11.59 months) for patients with mALBI grades 2b and 3. The OS for patients with dynamic mALBI grades 1 and 2a was 13.27 months (95% CI: 8.72 to 17.81 months), significantly longer than five months (95% CI: 2.47 to 7.53 months) for dynamic mALBI grades 2b and 3 patients (p<0.01). Conclusion: In conclusion, mALBI grade may be a potential dynamic biomarker for predicting the prognosis in advanced NSCLC patients treated with immunotherapy.

Evaluating the Clinical Characteristics and Prognosis of Advanced Non-Small Cell Lung Cancer with Exon 20 Insertions.

Epidermal growth factor receptor exon 20 insertion (EGFR ex20ins), an uncommon mutation in non-small cell lung cancer (NSCLC), can induce poor patient response to EGFR tyrosine kinase inhibitors (EGFR-TKI). However, the clinical features and prognosis of patients with EGFR ex20ins are not clearly understood. This study investigated the clinical characteristics and prognosis of advanced NSCLC patients with EGFR ex20ins. Advanced NSCLC patients treated at Fujian Cancer Hospital were consecutively recruited from June 1, 2014 to December 20, 2021 and retrospectively examined. EGFR ex20ins was identified by polymerase chain reaction (PCR) or next-generation sequencing (NGS). The clinical characteristics, treatment methods, and patient outcomes were retrieved from the hospital database. The progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier analysis. Fourteen mutation subtypes of EGFR ex20ins were identified in the 24 enrolled patients, with EGFR ex20ins mutation more prevalent in non-smoking women. A763_Y764insFQEA and A767_V769dup (12.5% for both) were the most common mutation subtypes. Notably, no significant differences in PFS and OS were found between the first-line targeted therapy group [PFS: 257 days, 95% confidence interval (CI): 116-397 days; OS: not reached] and chemotherapy-based combination therapy group (PFS: 182 days, 95% CI: 156-207 days; OS: 998 days, 95% CI: 674-1321 days). TP53 mutation was the commonest concomitant mutation (62%), followed by EGFR amplification (25%). Chemotherapy combined with immunotherapy improved the prognosis of patients with high PD-L1 expression. For NSCLC patients with EGFR ex20ins, limited therapeutic benefits can be gleaned from either EGFR-TKIs or chemotherapy-based combination therapy.

Prognostic nomogram based on pre-treatment HALP score for patients with advanced non-small cell lung cancer

BackgroundTo explore the correlation of pre-treatment Hemoglobin-Albumin-Lymphocyte-Platelet (HALP) score with the prognosis of patients with advanced Non-Small Cell Lung Cancer (NSCLC) undergoing first-line conventional platinum-based chemotherapy. MethodsIn this retrospective cohort study, 203 patients with advanced NSCLC were recruited from January 2017 to December 2021. The cut-off value for the HALP score was determined by Receiver Operating Characteristic (ROC) curve analysis. The baseline characteristics and blood parameters were recorded, and the Log-rank test and Kaplan-Meier curves were applied for the survival analysis. In the univariate and multivariate analyses, the Cox regression analysis was carried out. The predictive accuracy and discriminative ability of the nomogram were determined by the Concordance index (C-index) and calibration curve and compared with a single HALP score by ROC curve analysis. ResultsThe optimal cut-off value for the HALP score was 28.02. The lower HALP score was closely associated with poorer Progression-Free Survival (PFS) and Overall Survival (OS). The male gender and other pathological types were associated with shorter OS. Disease progression and low HALP were correlated with shorter OS and PFS. In addition, nomograms were established based on HALP scores, gender, pathology type and efficacy rating, and used to predict OS. The C-index for OS prediction was 0.7036 (95% CI 0.643 to 0.7643), which was significantly higher than the C-index of HALP at 6-, 12-, and 24-months. ConclusionThe HALP score is associated with the prognosis of advanced NSCLC patients receiving conventional platinum-based chemotherapy, and the nomogram established based on the HALP score has a better predictive capability for OS.

Soluble PD-L1 changes in advanced non-small cell lung cancer patients treated with PD-1 inhibitors: an individual patient data meta-analysis.

Currently, first-line immune checkpoint inhibitors (ICIs), including programmed cell death protein-1 (PD-1) inhibitors, are utilized as monotherapy in advanced non-small cell lung cancer (NSCLC) patients with high programmed death ligand-1 (PD-L1) expression (≧50%). Pre-treatment or post-treatment serum soluble PD-L1 (sPD-L1) has been identified as a potential biomarker for assessing ICI efficacy through fixed-point observations. However, existing studies on sPD-L1 changes have produced inconsistent results or have had sample sizes too small to detect clinically meaningful effect sizes. To elucidate the role of sPD-L1, we conducted a collaborative individual patient data meta-analysis of PD-1 inhibitor treatments. We conducted a thorough search of articles in PubMed via Medline, Embase, Scopus, and Cochrane databases from inception to October 20, 2023. Trials were deemed eligible if they contained individual datasets for advanced NSCLC patients, including data on overall survival (OS)/progression-free survival (PFS), as well as pre- and post-treatment sPD-L1 levels after 3-4 cycles of PD-1 inhibitor treatments. Our analysis focused on patients who completed 3-4 cycles of PD-1 inhibitor treatments. The primary outcome measure was OS/PFS, and we assessed changes in sPD-L1 concentration pre- and post-treatment through ELISA analyses. From our search, we identified a potential seven trials, encompassing 256 patients. Among these, two trials with 26 patients met the criteria for inclusion in our primary analyses. Over a median follow-up period of 10 months, pooled univariate analysis revealed that increases in sPD-L1 levels during PD-1 inhibitor treatment were not associated with OS (HR = 1.25; CI: 0.52-3.02)/PFS (HR = 1.42; CI: 0.61-3.30) when compared to cases with sPD-L1 decreases. Subgroup analyses indicated that the impact of sPD-L1 changes on overall mortality/progression-related mortality remained consistent regardless of gender, age, or the type of treatment (nivolumab or pembrolizumab). Our findings suggest that changes in sPD-L1 levels during PD-1 inhibitor treatment do not significantly influence the prognosis of advanced NSCLC patients, regardless of gender, age, or treatment type. Continuous monitoring of sPD-L1 may not offer significant advantages compared to fixed-point observations.

Epidermal Growth Factor Receptor Mutation Status and the Impact on Clinical Outcomes in Patients with Non-Small Cell Lung Cancer.

Epidermal growth factor receptor (EGFR) mutation status differs according to ethnicity, gender, smoking history, and histology types. The present study aimed to evaluate EGFR mutation status in patients with non-small cell lung cancer (NSCLC) and further explore its association with clinical characteristics and prognosis in advanced NSCLC patients (Stage IIIB-IV). 238 NSCLC patients were enrolled in this study from October 2016 through December 2019. Patient characteristics and clinical data including age, gender, smoking history, histology types, tumor stage, survival status, and time were collected via electronic medical record system or telephone. 21 somatic mutations which spanned exons 18-21 of EGFR were detected using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) method, followed by analysis of links to clinical characteristics, progression-free survival (PFS) and overall survival (OS). 103 patients were detected harboring EGFR mutations among the 238 cases tested (43.3%), and exons 19 and 21 were the highest mutation frequencies, with 20.6% and 19.3% respectively. The EGFR mutation rate was much higher in female versus male (57.4% vs 31.5%, p <0.001), in non-smokers compared to smokers (56.8% vs 25.9%, p <0.001), and in those with adenocarcinoma than other histology types (48.3% vs 3.7%, p <0.001). For patients in advanced stage, median PFS was 11 months in patients harboring EGFR mutations, versus 4 months in patients with wild type EGFR (p <0.001); median OS was 24 versus 12 months (p <0.001). Never smoking (p = 0.042) and adenocarcinoma (p = 0.007) were independent favorable factors for EGFR mutations. Our data strengthen the findings of high prevalence of EGFR mutations in Asian patients with NSCLC. Mutations are prevalent in those patients who are female, adenocarcinoma, and have never smoked. Moreover, advanced EGFR mutation-positive patients have better PFS and OS than those with wild type EGFR.

Predictive factors and prognosis of immune checkpoint inhibitor-related pneumonitis in non-small cell lung cancer patients.

To investigate the influencing factors and prognosis of immune checkpoint inhibitor-related pneumonitis (CIP) in advanced non-small cell lung cancer (NSCLC) patients during or after receiving immune checkpoint inhibitors(ICIs). The clinical and laboratory indicator data of 222 advanced NSCLC patients treated with PD-1/PD-L1 inhibitors at the First Affiliated Hospital of Zhengzhou University between December 2017 and November 2021 were collected retrospectively. The patients were divided into a CIP group (n=41) and a non-CIP group (n=181) according to whether they developed CIP or not before the end of follow-up. Logistic regression was used to evaluate risk factors of CIP, and Kaplan‒Meier curves were used to describe the overall survival (OS) of different groups. The log-rank test was used to compare the survival of different groups. There were 41 patients who developed CIP, and the incidence rate of CIP was 18.5%. Univariate and multivariate logistic regression analyses showed that low pretreatment hemoglobin (HB) and albumin (ALB) levels were independent risk factors for CIP. Univariate analysis suggested that history of chest radiotherapy was related to the incidence of CIP. The median OS of the CIP group and non-CIP were 15.63 months and 30.50 months (HR:2.167; 95%CI: 1.355-3.463, P<0.05), respectively. Univariate and multivariate COX analyses suggested that a high neutrophil-to-lymphocyte ratio (NLR) level, a low ALB level and the development of CIP were independent prognostic factors for worse OS of advanced NSCLC patients treated with ICIs. Additionally, the early-onset and high-grade CIP were related to shorter OS in the subgroup. Lower pretreatment HB and ALB levels were independent risk factors for CIP. A high NLR level, a low ALB level and the development of CIP were independent risk factors for the prognosis of advanced NSCLC patients treated with ICIs.

Novel predictors of immune checkpoint inhibitor response and prognosis in advanced non-small-cell lung cancer with bone metastasis.

Immune checkpoint inhibitors (ICIs) can significantly prolong the survival of patients with advanced non-small-cell lung cancer (NSCLC); however, few studies on the therapeutic effects of ICIs on bone metastases were performed. This retrospective study aimed to investigate the therapeutic effects of ICIs and determine predictors of favorable ICI response and prognosis in 55 advanced NSCLC patients with bone metastases who initiated ICI treatment between 2016 and 2019, with a mean follow-up period of 23.2 months. Patients were classified into responders (complete or partial response) and non-responders (stable or progressive disease) according to the MD Anderson Cancer Center (MDA) criteria, and the predictors of therapeutic response were identified using multivariate logistic regression analysis. Furthermore, overall survival from the time of ICI administration to the final follow-up or death was evaluated, and prognostic predictors were identified using Cox proportional hazards regression analysis. ICI response rate was 30.9% (complete in three cases, partial in 14). Median survival time was 9.3 months, with 1-year and 2-year survival rates of 40.6% and 19.3%, respectively. Responders survived significantly longer than non-responders (p = 0.03). Based on the receiver operating characteristic curve, the predictive cutoff value of the pretreatment neutrophil-to-lymphocyte ratio (NLR) was 2.1. Multivariate analysis identified female sex (p = 0.03), use of ICIs as first-line therapy (p < 0.01), and NLR <2.1 (p = 0.03) as significant predictors of therapeutic response, whereas concomitant use of a bone-modifying agent (p < 0.01), Katagiri score ≤6 points (p < 0.01), and NLR <2.1 (p = 0.02) were identified as significant predictors of good prognosis. This study identified some novel predictors for favorable therapeutic response and prognosis in advanced NSCLC patients with bone metastases undergoing ICI treatment. Pretreatment NLR less than 2.1 can be considered the most important predictor.

Abstract 2811: CDK4/6 inhibition plus radiotherapy enhances anti-tumor immunity in non-small cell lung cancer

Abstract Lung cancer is the main cause of cancer-related mortality, of which non-small cell lung cancer (NSCLC) accounts for 85%. Abemaciclib, a selective CDK4/6 inhibitor, enhanced the radiosensitivity of NSCLC in vivo and in vitro and improved the prognosis of advanced NSCLC patients according to a Phase I clinical trial. This study aimed to explore the impact of CDK4/6 inhibition combined with irradiation and immunotherapy on NSCLC. The in vivo xenograft tumor mouse model was used to investigate the synergistic effects of CDK4/6 inhibitor abemaciclib and irradiation together with anti-PD-1 antibodies. The tumor infiltrating lymphocytes (TILs) in tumor microenvironment (TME) were analyzed by flow cytometry. The complete blood count and serum tests were used to determine the safety of this combination therapy. The human phospho-kinase array and dual-luciferase report assay were used to study the regulatory mechanisms of abemaciclib and irradiation combination on PD-L1 transcription in NSCLC cells in vitro. Our results indicated the significantly synergistic effects of abemaciclib, irradiation and anti-PD-1 antibodies on NSCLC growth in vivo, accompanied by increased CD8+ T cell infiltration and decreased regulatory T cells and myeloid-derived suppressor cells (MDSCs), suggesting a strong anti-tumor combination of CDK4/6 inhibition, radiotherapy and immunotherapy. This synergistic effect could be partially impaired by CD8 depletion, and alleviated the anemia and inflammation caused by tumor burden without hepatorenal toxicity. Abemaciclib induced PD-L1 transcription through JNK/c-Jun pathway in vitro, which might elevate PD-L1 expression synergistically with irradiation through TBK1/IRF3 pathway. Our studies suggested that CDK4/6 inhibition plus irradiation enhanced anti-tumor immune responses in NSCLC. Together with immunotherapy, the combination of CDK4/6 inhibitors and radiotherapy could lower the doses of individual treatment, thus alleviating the potential toxicity and side effects of CDK4/6 inhibition and irradiation on normal cells. Citation Format: Zhengrong Huang, Jiang Luo, Mengqin Wang, Hongxin Xie, Yuxin Zeng, Yu Yuan, Wan Xiang, Ziyu Jiang, Conghua Xie, Yan Gong. CDK4/6 inhibition plus radiotherapy enhances anti-tumor immunity in non-small cell lung cancer [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 2811.

Effect of Stereotactic Body Radiation Therapy on Diverse Organ Lesions in Advanced Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors.

The combination of stereotactic body radiation therapy (SBRT) and immune checkpoint inhibitors (ICIs) is actively being explored in advanced non-small-cell lung cancer (NSCLC) patients. However, little is known about the optimal fractionation and radiotherapy target lesions in this scenario. This study investigated the effect of SBRT on diverse organ lesions and radiotherapy dose fractionation regimens on the prognosis of advanced NSCLC patients receiving ICIs. The medical records of advanced NSCLC patients consecutively treated with ICIs and SBRT were retrospectively reviewed at our institution from Dec. 2015 to Sep. 2021. Patients were grouped according to radiation sites. Progression-free survival (PFS) and overall survival (OS) were recorded using the Kaplan-Meier method and compared between different treatment groups using the log-rank (Mantel-Cox) test. A total of 124 advanced NSCLC patients receiving ICIs combined with SBRT were identified in this study. Radiation sites included lung lesions (lung group, n=43), bone metastases (bone group, n=24), and brain metastases (brain group, n=57). Compared with the brain group, the mean PFS (mPFS) in the lung group was significantly prolonged by 13.3 months (8.5 months vs. 21.8 months, HR=0.51, 95%CI: 0.28-0.92, P=0.0195), and that in the bone group prolonged by 9.5 months with a 43% reduction in the risk of disease progression (8.5 months vs. 18.0 months, HR=0.57, 95%CI: 0.29-1.13, P=0.1095). The mPFS in the lung group was prolonged by 3.8 months as compared with that in the bone group. The mean OS (mOS) in the lung and bone groups was longer than that of the brain group, and the risk of death decreased by up to 60% in the lung and bone groups as compared with that of the brain group. When SBRT was concurrently given with ICIs, the mPFS in the lung and brain groups were significantly longer than that of the bone group (29.6 months vs. 16.5 months vs. 12.1 months). When SBRT with 8-12 Gy per fraction was combined with ICIs, the mPFS in the lung group was significantly prolonged as compared with that of the bone and brain groups (25.4 months vs. 15.2 months vs. 12.0 months). Among patients receiving SBRT on lung lesions and brain metastases, the mPFS in the concurrent group was longer than that of the SBRT→ICIs group (29.6 months vs. 11.4 months, P=0.0003 and 12.1 months vs. 8.9 months, P=0.2559). Among patients receiving SBRT with <8 Gy and 8-12 Gy per fraction, the mPFS in the concurrent group was also longer than that of the SBRT→ICIs group (20.1 months vs. 5.3 months, P=0.0033 and 24.0 months vs. 13.4 months, P=0.1311). The disease control rates of the lung, bone, and brain groups were 90.7%, 83.3%, and 70.1%, respectively. The study demonstrated that the addition of SBRT on lung lesions versus bone and brain metastases to ICIs improved the prognosis in advanced NSCLC patients. This improvement was related to the sequence of radiotherapy combined with ICIs and the radiotherapy fractionation regimens. Dose fractionation regimens of 8-12 Gy per fraction and lung lesions as radiotherapy targets might be the appropriate choice for advanced NSCLC patients receiving ICIs combined with SBRT.

Interleukin 8 in plasma is an efficacy marker for advanced non-small cell lung cancer treated with hypofractionated radiotherapy and PD-1 blockade.

Programmed death-1 (PD-1) blockade promotes combination therapy in advanced non-small cell lung cancer (NSCLC), hypofractionated radiotherapy (HFRT) and chemotherapy combined with immunotherapy improves the outcome of prognosis in advanced NSCLC, while effective biomarkers to follow prognostic efficacy are still to be found. We enrolled 44 NSCLC patients with HFRT combined with PD-1 blockade, 13 patients with chemotherapy combined with immunotherapy, additionally collected tissue samples from 8 patients with earlystage NSCLC without therapy, and peripheral whole blood from 16 healthy donors, detected the expression differences of cytokines Interleukin 6 (IL-6), Interleukin 8 (IL-8) and Interleukin 17A (IL-17A) in the peripheral plasma and tissues by flow cytometry, immunofluorescence, and real-time fluorescence quantitative PCR. Cultured peripheral blood mononuclear cell (PBMC) and tumor-infiltrating T cells with recombinant human IL-8 in vitro to observe the changes of immune memory T cell subtypes and apoptosis. Our results show that IL-6, IL-8, and IL-17A are highly expressed in advanced NSCLC, high levels of IL-8 are significantly associated with poor prognosis in advanced NSCLC patients treated with HFRT+PD1 blockade, high circulating IL-8 in NSCLC increased apoptosis of effector memory RA (TemRA; CD45RA+CCR7-) T cell subsets and CD8+ T cell subsets in tissues, resulting in decreased peripheral TemRA and stem cell-like memory T cells (TSCM: CD45RA +CCR7 + CD95 +) in tissue. We suggest that IL-8 can impair immune memory function in NSCLC. It is a useful biomarker to evaluate the efficacy of HFRT+PD1 blockade in advanced NSCLC. Further exploration of easily available plasma biomarkers for personalized treatment of NSCLC is required.

EP16.03-023 KRAS Alterations, Clinicopathological Features and Co-occurring Drivers Associated with Prognosis in Advanced NSCLC Patients

Genetic profiling has proven essential and changed the landmark in non-small cell lung cancer (NSCLC). Next-generation sequencing (NGS) has increased the identification of patients with different genomic alterations, which are novel targets for personalized therapies. Among them, KRAS is the isoform most commonly mutated in NSCLC, with a prevalence that is higher in Western populations compared to Asian (26 vs 11%). However, the information about the frequency, clinical characteristics and prognostic significance of KRAS in patients with NSCLC from Mexico has been limited.

Association of lymphocyte subsets with efficacy and prognosis of immune checkpoint inhibitor therapy in advanced non-small cell lung carcinoma: a retrospective study

BackgroundImmune checkpoint inhibitors (ICIs) have achieved promising effects in patients with non-small cell lung cancer (NSCLC). However, not all patients with NSCLC benefit from immunotherapy. There is an urgent need to explore biomarkers that could predict the survival outcomes and therapeutic efficacy in advanced NSCLC patients treated with immunotherapy. In this study, we aimed to assess the changes in peripheral blood lymphocyte subsets and their association with the therapeutic efficacy and clinical prognosis of advanced NSCLC patients treated with immunotherapy.MethodsA total of 276 patients with advanced NSCLC were enrolled. Peripheral blood lymphocyte subsets including CD4+ T cells, CD8+ T cells, CD4+/CD8+ ratio, NK cells, Tregs and B cells were collected before any treatment, before immunotherapy or chemotherapy, and after 4 cycles of immunotherapy or chemotherapy. T-test was used to analyze the factors influencing lymphocyte subsets and their changes before and after therapy. Logistic regression was used to plot ROC curves and analyze the relationship between lymphocyte subsets and therapeutic efficacy. Log-rank test and Cox regression model were used to evaluate the relationship between lymphocyte subsets and progression-free survival (PFS).ResultsGender, distant metastasis, and EGFR mutation status are known to affect the proportion of peripheral blood lymphocyte subsets in patients with advanced NSCLC. The proportions of CD4+ T cells, CD8+ T cells, Tregs and B cells were found to decrease after chemotherapy as compared to the baseline. The proportion of CD4+ T cells, CD8+ T cells, CD4+/CD8+ ratio, NK cells and Tregs were higher after immunotherapy than after chemotherapy. Compared to the baseline, the effective group showed significant increase in the proportions of CD4+ T cells, CD4+/CD8+ ratio, NK cells and Tregs, and the number of CD8+ T cells was significantly lower in the peripheral blood after 4 cycles of immunotherapy. On the contrary, the ineffective group did not show any significant differences in the above parameters. Baseline CD4+ T cells and NK cells were independent predictors of immunotherapy efficacy and PFS. Baseline Tregs were independent predictor of immunotherapy efficacy.ConclusionImmune checkpoint inhibitors induced changes in the proportion of peripheral blood lymphocyte subsets in patients that responded well to immunotherapy. The levels of the different lymphocyte subsets could serve as valuable predictive biomarkers of efficacy and clinical prognosis for NSCLC patients treated with immunotherapy.

Volumetric Analysis of Intravoxel Incoherent Motion Diffusion-Weighted Imaging for Predicting the Response to Chemotherapy in Patients With Locally Advanced Non-Small Cell Lung Cancer.

We aimed to prospectively investigate intravoxel incoherent motion parameters to predict the response to chemotherapy in locally advanced non-small cell lung cancer (NSCLC) patients. From July 2016 to March 2018, 30 advanced NSCLC patients were enrolled and underwent chest intravoxel incoherent motion-diffusion-weighted imaging at Siemens 3T magnetic resonance imaging before and at the end of the first cycle of chemotherapy. Regions of interest were drawn including the whole tumor volume to derive the apparent diffusion coefficient value, D, D*, and f, respectively. Time-dependent receiver operating characteristic curves were generated to evaluate the cutoff values of continuous variables. A Cox proportional hazards model was used to assess the independent predictors of progression-free survival (PFS) and overall survival (OS). Kaplan-Meier curves and log-rank test were generated. Among the 30 patients, 28 cases (93.3%) died and 2 cases (6.7%) survived till the closeout date. Univariate Cox regression analyses revealed that the significant predictors of PFS and OS were the tumor size reduction rate, the change rates of D and apparent diffusion coefficient values, and the D value before therapy (PFS: P = 0.015, hazard ratio [HR] = 2.841; P < 0.001, HR = 5.840; P = 0.044, HR = 2.457; and P = 0.027, HR = 2.715; OS: P = 0.008, HR = 2.987; P < 0.001, HR = 4.357; P = 0.006, HR = 3.313; and P = 0.013, HR = 2.941, respectively). Multivariate Cox regression analysis suggested that △D% was identified as independent predictors of both PFS and OS (P = 0.003, HR = 9.200 and P = 0.016, HR = 4.617). In addition, the cutoff value of △D% was 21.06% calculated by receiver operating characteristic curve analysis. In the Kaplan-Meier analysis, the PFS and OS were significantly greater in the group of patients with △D% larger than 21.06% (log-rank test, χ2 = 16.453, P < 0.001; χ2 = 13.952, P < 0.001). Intravoxel incoherent motion-diffusion-weighted imaging was preferred for predicting the prognosis of advanced NSCLC patients treated with chemotherapy. A D increase more than 21.06% at 1 month was associated with a lower rate of disease progression and death.

Assessment of sarcopenia as a predictor of poor overall survival for advanced non-small-cell lung cancer patients receiving salvage anti-PD-1 immunotherapy.

BackgroundSarcopenia, which is defined as the loss of skeletal muscle mass, has been identified as a poor prognostic factor for cancer patients. This study sought to elucidate the effects of sarcopenia on the outcomes of advanced non-small cell lung cancer (NSCLC) patients receiving salvage anti-programmed death-1 (PD-1) immunotherapy.MethodsIn total, 105 NSCLC patients receiving second-line anti-PD-1 immunotherapy at the Sun Yat-sen University Cancer Center between January 2015 and December 2017 were enrolled in this study, and detailed patient data were collected. Available lumbar computed tomography images of the patients were analyzed to determine the total skeletal muscle cross-section area. The efficacy of the predictive and prognostic role of sarcopenia in progression-free survival (PFS) and overall survival (OS) was analyzed using the Kaplan-Meier method, and the risk factors were analyzed using Cox analyses.ResultsWe found that patients with sarcopenia receiving salvage anti-PD-1 immunotherapy had significantly worse PFS (2.67 vs. 7.96 months; P<0.001) and OS (9.08 vs. 21.84 months; P<0.001) than their non-sarcopenic counterparts. We also found that sarcopenia was associated with the neutrophil-to-lymphocyte ratio (NLR) (P=0.041), and that the NLR acts as a predictor of OS.ConclusionsSarcopenia was associated with a poor prognosis in advanced NSCLC patients receiving salvage anti-PD-1 immunotherapy. Further research needs to be conducted to identify more biomarkers and the patients most likely to benefit from immunotherapy.

Survival impact of treatment for chronic obstructive pulmonary disease in patients with advanced non-small-cell lung cancer

Chronic obstructive pulmonary disease (COPD) may coexist with lung cancer, but the impact on prognosis is uncertain. Moreover, it is unclear whether pharmacological treatment for COPD improves the patient’s prognosis. We retrospectively investigated patients with advanced non-small-cell lung cancer (NSCLC) who had received chemotherapy at Kyoto University Hospital. Coexisting COPD was diagnosed by spirometry, and the association between pharmacological treatment for COPD and overall survival (OS) was assessed. Of the 550 patients who underwent chemotherapy for advanced NSCLC between 2007 and 2014, 347 patients who underwent spirometry were analyzed. Coexisting COPD was revealed in 103 patients (COPD group). The median OS was shorter in the COPD group than the non-COPD group (10.6 vs. 16.8 months). Thirty-seven patients had received COPD treatment, and they had a significantly longer median OS than those without treatment (16.7 vs. 8.2 months). Multivariate Cox regression analysis confirmed the positive prognostic impact of COPD treatment. Additional validation analysis revealed similar results in patients treated with immune checkpoint inhibitors (ICIs). Coexisting COPD had a significant association with poor prognosis in advanced NSCLC patients if they did not have pharmacological treatment for COPD. Treatment for coexisting COPD has the potential to salvage the prognosis.

Dynamics of Early Serum Tumour Markers and Neutrophil-to-Lymphocyte Ratio Predict Response to PD-1/PD-L1 Inhibitors in Advanced Non-Small-Cell Lung Cancer.

PurposeTo evaluate the dynamics of early serum tumour markers (STMs) and the neutrophil-to-lymphocyte ratio (NLR) to predict clinical efficacy and prognosis of advanced non-small-cell lung cancer (NSCLC) patients who received programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors.Patients and MethodsWe retrospectively reviewed patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors between September 2017 and August 2020. NLR and STMs were routinely measured between immunotherapy initiation and the first radiological evaluation. A combination score based on the leading STM and NLR and their dynamic changes was established. The effects of leading STM change, NLR change, and the combination score on the objective response rate (ORR), durable clinical benefit (DCB), progression-free survival (PFS), and overall survival (OS) were analysed. The accuracy of the combination score was evaluated by receiver operating characteristic (ROC) curve and the area under the curve (AUC).ResultsOverall, 124 patients were included in this retrospective cohort study. The ORR was 22.8%, DCB was 54.5%, and the median OS and PFS were 21.6 and 14.9 months, respectively. Patients with low combination scores had a significantly improved ORR and DCB compared with those with intermediate or high scores (P = 0.002 for ORR, P < 0.0001 for DCB). In a multivariate model, the combination score was an independent indicator of PFS (P < 0.0001) and OS (P < 0.0001). The AUC demonstrated that the combination score (AUC = 0.706) has greater predictive power than either the posttreatment NLR (AUC = 0.668) or the leading STM change (AUC = 0.648) alone.ConclusionAn easy, cost-effective, and novel combination score based on the dynamics of an early STM and the NLR can accurately predict the clinical efficacy of PD-1/PD-L1 inhibitors and prognosis in advanced NSCLC patients.

Chinese Herbal Medicine Combined With First-Generation EGFR-TKIs in Treatment of Advanced Non-Small Cell Lung Cancer With EGFR Sensitizing Mutation: A Systematic Review and Meta-Analysis.

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. First-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) significantly improve prognosis of advanced NSCLC patients harboring EGFR sensitizing mutation. However, acquired resistance to EGFR-TKIs limits the good outcomes. Chinese herbal medicine (CHM) has been used for NSCLC patients receiving EGFR-TKIs for more than 10°years as an adjuvant treatment.Methods: Studies were searched from China BioMedical Literature, Chinese National Knowledge Infrastructure, Cqvip Database, Wanfang Database, MEDLINE (PubMed), EMBASE (Ovid), Google Scholar, and Cochrane Library from inception to March, 2021. Randomized controlled clinical trials (RCT) comparing EGFR-TKIs + CHM (TKIs + CHM) versus EGFR-TKIs with/without placebo (TKIs ± placebo) in participants with advanced NSCLC harboring EGFR sensitizing mutation were included in this study. Two authors screened all references, assessed the risk of bias and extracted data independently. Data were summarized using hazard ratio (HR) and risk ratios (RR), with 95% confidence intervals (CI) for binary outcomes. Meta-analysis was performed using random effects model. Overall quality of evidence was assessed using GRADE.Results: A total of 9 RCTs (1137 participants, 581 in the TKIs + CHM group and 556 in the TKIs ± placebo group) were included in this review. Only first-generation EGFR-TKIs were included. Most trials included used oral CHM preparations to tonify Qi and/or Yin. Treatment lasted from enrollment until disease progression (PD) or intolerable adverse events (AE). Combination of CHM with EGFR-TKIs improved median progression-free survival (mPFS) (HR,0.59; 95% CI, 0.52–0.68; P < 0.00001) and objective response rate (ORR) (RR, 1.23; 95% CI, 1.13–1.34; P < 0.00001) compared with used of EGFR-TKIs ± placebo. CHM reduced AE associated with EGFR-TKIs such as cutaneous toxicity (RR, 0.58; 95% CI, 0.46–0.73; P < 0.00001) and diarrhea (RR, 0.43; 95% CI, 0.30–0.60; P < 0.00001).Conclusion: Combination therapy of CHM and EGFR-TKIs significantly delays acquired resistance while improving ORR to EGFR-TKIs. Furthermore, CHM reduces AE induced by EGFR-TKIs. More international multi-centered, double-blinded, placebo-controlled, well-designed clinical trials are needed in future research.

Prognostic significance of cachexia in advanced non-small cell lung cancer patients treated with pembrolizumab.

Cancer cachexia is a multifactorial syndrome characterized by weight loss leading to immune dysfunction that is commonly observed in patients with advanced non-small cell lung cancer (NSCLC). We examined the impact of cachexia on the prognosis of patients with advanced NSCLC receiving pembrolizumab and evaluated whether the pathogenesis of cancer cachexia affects the clinical outcome. Consecutive patients with advanced NSCLC treated with pembrolizumab were retrospectively enrolled in the study. Serum levels of pro-inflammatory cytokines and appetite-related hormones, which are related to the pathogenesis of cancer cachexia, were analyzed. Cancer cachexia was defined as (1) a body weight loss > 5% over the past 6months, or (2) a body weight loss > 2% in patients with a body mass index < 20kg/m2. A total of 133 patients were enrolled. Patients with cachexia accounted for 35.3%. No significant difference in the objective response rate was seen between the cachexia and non-cachexia group (29.8% vs. 34.9%, P = 0.550), but the median progression-free survival (PFS) and overall survival (OS) periods were significantly shorter in the cachexia group than in the non-cachexia group (PFS: 4.2months vs. 7.1months, P = 0.04, and OS: 10.0months vs. 26.6months, P = 0.03). The serum TNF-alpha, IL-1 alpha, IL-8, IL-10, and leptin levels were significantly associated with the presence of cachexia, but not with the PFS or OS. The presence of cachexia was significantly associated with poor prognosis in advanced NSCLC patients receiving pembrolizumab, not with the response to pembrolizumab.