A retrospective study of first-line therapy and subsequent pyrotinib treatment in advanced lung adenocarcinoma with HER2 mutations.

OBJECTIVES: HER2 is an infrequently mutated driver gene in non-small cell lung cancer (NSCLC). At present, there has been no comprehensive large-scale clinical study to establish the optimal first-line treatment strategy for advanced lung adenocarcinoma (LUAD) with HER2-Mutant. Besides that, the effectiveness and safety of pyrotinib, a pan-HER inhibitor, in the context of NSCLC are still undergoing investigation. MATERIALS AND METHODS: In this study, we conducted a retrospective data collection of HER2-Mutated advanced LUAD who received first-line treatment and pyrotinib between May 2014 and June 2023. Patients treated with chemotherapy, chemotherapy + immune checkpoint inhibitors (ICIs), chemotherapy + bevacizumab and pyrotinib in first-line treatment. Furthermore, we collected data on the efficacy and safety of pyrotinib in these patients after disease progression. The main endpoint of the study was progression-free survival (PFS). RESULTS: In the final analysis, 89 patients were included in the first-line cohort and 30 patients were included in the pyrotinib cohort. In the first-line treatment cohort, chemotherapy + ICIs, chemotherapy + bevacizumab, and pyrotinib exhibited notable survival benefits compared to chemotherapy (median PFS: 9.87 vs. 7.77 vs. 7.10 vs. 5.40 months, p-value < 0.05). Furthermore, patients with a first-line treatment PFS of less than 6 months may potentially benefit from subsequent treatment with pyrotinib (median PFS: 7.467 vs. 3.000, p-value = 0.0490). CONCLUSIONS: In the first-line treatment of HER2-Mutant LUAD, regimens involving combinations like chemotherapy + ICIs, chemotherapy + bevacizumab, and pyrotinib may confer enhanced survival advantages compared to chemotherapy. Nevertheless, no significant distinctions were observed among these three treatment strategies, underscoring the imperative to identify biomarkers for the discerning selection of suitable therapeutic modalities. Moreover, patients with suboptimal response to first-line treatment may potentially derive more benefit from pyrotinib.

DNMT3A-mediated DNA methylation and transcription inhibition of FZD5 suppresses lung carcinogenesis.

Background: Based on the bioinformatics prediction, this study investigates the correlation between aberrant transcription factor Frizzled 5 (FZD5) expression and the establishment of non-small cell lung cancer (NSCLC). Methods: A mouse model with regard to primary NSCLC was encouraged by intraperitoneal injection of urethane. Lentivirus-based FZD5 silencing was then administrated to examine its role in tumorigenesis in the mouse lung. Silencing of FZD5 was induced in two NSCLC cell lines to examine its function in the malignant behavior pertaining to cells in vitro. Quantitative methylation-specific PCR was employed to assess the DNA methylation level within the NSCLC cells. DNA methyltransferases (DNMTs) that administer FZD5 were assessed by chromatin immunoprecipitation assay. Consequently, overexpression of DNMT3A was introduced in mice and NSCLC cells to verify its regulation on FZD and its biological roles in NSCLC development. Results: In NSCLC, FZD5 expression is elevated, and its knockdown reduced tumor incidence rate in the urethane-challenged mice. The FZD5 silencing also inhibited proliferation, migration, as well as invasion with regard to Calu-3 and NCI-H1299 cells in vitro. The aberrant upregulation with regard to FZD5 in NSCLC was due to at least partly by reduced promoter methylation level. DNMT3A, which bound to FZD5 promoter to suppress its transcription, was poorly expressed in NSCLC. Artificial upregulation of DNMT3A suppressed urethane-induced lung carcinogenesis in mice and suppressed the malignant phenotype pertaining to NSCLC cells in vitro. Conclusion: This research demonstrates that the lack of DNA methylation level-induced activation of FZD5 is correlated with NSCLC's onset and progression.

PMS2 amplification contributes brain metastasis from lung cancer.

BACKGROUND: Lung adenocarcinoma metastasizing to the brain results in a notable increase in patient mortality. The high incidence and its impact on survival presents a critical unmet need to develop an improved understanding of its mechanisms. METHODS: To identify genes that drive brain metastasis of tumor cells, we collected cerebrospinal fluid samples and paired plasma samples from 114 lung adenocarcinoma patients with brain metastasis and performed 168 panel-targeted gene sequencing. We examined the biological behavior of PMS2 (PMS1 Homolog 2)-amplified lung cancer cell lines through wound healing assays and migration assays. In vivo imaging techniques are used to detect fluorescent signals that colonize the mouse brain. RNA sequencing was used to compare differentially expressed genes between PMS2 amplification and wild-type lung cancer cell lines. RESULTS: We discovered that PMS2 amplification was a plausible candidate driver of brain metastasis. Via in vivo and in vitro assays, we validated that PMS2 amplified PC-9 and LLC lung cancer cells had strong migration and invasion capabilities. The functional pathway of PMS2 amplification of lung cancer cells is mainly enriched in thiamine, butanoate, glutathione metabolism. CONCLUSION: Tumor cells elevated expression of PMS2 possess the capacity to augment the metastatic potential of lung cancer and establish colonies within the brain through metabolism pathways.

Identification of nomogram associated with durable clinical benefit gene for advanced non-small cell lung cancer with sensitivity to responsive to immunotherapy.

Background: Immunotherapy has become the standard treatment for advanced non-small cell lung cancer (NSCLC). However, a subset of the most advanced NSCLC patients fails to respond adequately to Immune checkpoint inhibitors (ICIs). Developing new nomograms and integrating prognostic factors are crucial for improving the clinical predictability of NSCLC patients undergoing ICIs. Methods: Clinical information and genomic data of NSCLC patients undergoing ICIs were retrieved from cBioPortal. Gene alterations associated with durable clinical benefit (DCB) were compared to those linked to no durable benefit (NDB). The Kaplan-Meier plot method was employed for survival analysis, and a novel nomogram was formulated by selecting pertinent clinical variables. Results: For the NSCLC patients receiving immunotherapy, three subgroups were identified based on the treatment regimen, including anti-PD-1 monotherapy, anti-PD-1 combination with anti-CTLA-4, and first-line treatment. The mutation status of TP53, PGR, PTPRT, RELN, MUC19, LRP1B, and FAT3 was found to be associated with progression-free survival (PFS). Using the clinicopathological parameters and genomic data of the patients, we developed three novel nomograms to predict the prognosis of ICI treatment in different subgroups. Conclusion: Our study revealed that PGR, PTPRD, RELN, MUC19, LRP1B, and FAT3 mutation could serve as predictive biomarkers. Our systematic nomograms demonstrate significant potential in predicting the prognosis for NSCLC patients with sensitivity to different ICI treatment strategies.

Full spectrum flow cytometry-powered comprehensive analysis of PBMC as biomarkers for immunotherapy in NSCLC with EGFR-TKI resistance.

BACKGROUND: Clinical studies suggest that immune checkpoint inhibitor (ICI) monotherapy has limited benefits in non-small cell lung cancer (NSCLC) patients after epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) failure. However, data about efficacy of ICI plus chemotherapy remain controversial, probably attributed to the heterogeneity among such population, and robust efficacy biomarkers are urgent to explore. METHODS: A total of 60 eligible patients who received ICI plus chemotherapy after EGFR-TKI treatment failure were enrolled, 24 of whom peripheral blood mononuclear cell (PBMC) samples were collected at baseline and after 2 cycles of treatment. We have designed a 23-color-antibody panel to detect PBMC by full spectrum flow cytometry. RESULTS: For EGFR-TKI resistant NSCLC patients: 1) ICI plus chemotherapy achieved an objective response rate (ORR) of 21.7% and a median progression-free survival (PFS) of 6.4 months. 2) clinical characteristics associated with worse efficacy included liver metastasis and platelet-to-lymphocyte ratio (PLR) > 200. 3) the proportion of immune cell subset associated with better efficacy was higher baseline effective CD4+T cells (E4). 4) the baseline expression of immune checkpoint proteins (ICPs) on cell subsets associated with better efficacy included: higher expression of CD25 on dendritic cells (DC) and central memory CD8+T cells (CM8), and higher expression of Lymphocyte activation gene 3 (LAG-3) on effective memory CD8+T cells (EM8). 5) the expression of ICPs after 2 cycles of treatment associated with better efficacy included: higher expression of CD25 on CD8+T/EM8 /natural killer (NK) cells. 6) the dynamic changes of ICPs expression associated with worse efficacy included: significantly decrease of T cell immunoglobulin and ITIM domain (TIGIT) expression on regular T cells (Tregs) and decrease of V-domain immunoglobulin suppressor of T cell activation (VISTA) expression on Th1. 7) a prediction model for the efficacy of ICI plus chemotherapy was successfully constructed with a sensitivity of 62.5%, specificity of 100%, and area under curve (AUC) = 0.817. CONCLUSIONS: Some EGFR-TKI-resistant NSCLC patients could indeed benefit from ICI plus chemotherapy, but most patients are primary resistant to immunotherapy. Comprehensive analysis of peripheral immune cells using full spectrum flow cytometry showed that compared to the proportion of cell subsets, the expression type and level of ICPs on immune cells, especially CD25, were significantly correlated with the efficacy of immunotherapy.

Total reward satisfaction profiles and work performance: A person-centered approach.

It has recently become an incentive management challenge for organizations to implement a total reward system. Existing variable-centered studies have neglected to explore the incentive effect of a total reward system from the perspective of individual differences. Our study aimed to initially investigate the profiles of total reward satisfaction (TRS) and the impact of these profiles on work performance. Using a person-centered approach, two studies were conducted using retail industry employees in China as samples. Study 1 identified the TRS profiles of 429 samples using latent profile analysis. Study 2 replicated Study 1's configuration of profiles and examined the relationship of these profiles with demographic variables and work performance using 885 samples. Our results were as follows: (1) there were four quantitatively and qualitatively distinct profiles (subpopulations) of TRS, namely, dissatisfied (DS), development and career opportunities satisfied-dominant (DOS-dominant), work-life balance satisfied-dominant (WLS-dominant), and compensation satisfied-dominant (CS-dominant); (2) demographic variables involving gender, age, education, and position level affected the likelihood of membership in each TRS profile; and (3) the four profiles predicted different levels of work performance, or more specifically, different levels of task and contextual performance. The task and contextual performance of the four subpopulations listed from best to worst were WLS-dominant, DOS-dominant, CS-dominant, and DS. For practical management, organizations should customize a classified total reward system according to employee subpopulations to improve work performance.

Pulmonary adverse events associated with hypertension in non-small cell lung cancer patients receiving PD-1/PD-L1 inhibitors.

Introduction: Non-small cell lung cancer patients have gained therapeutic benefits from immune checkpoint inhibitors, although immune-related adverse events (irAEs) could be inevitable. Whether irAEs are associated with chronic diseases is still unclear, our study aims to clarify the distinct adverse events in NSCLC patients with concomitant hypertension. Methods: Adverse event cases were searched and collected in the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database from January 2015 to December 2021. We performed disproportionality analysis to detect safety signals by calculating reporting odds ratios (ROR) and corresponding 95% confidence intervals (95% CIs), information component (IC), and the lower bound of the information component 95% credibility interval (IC025). Results: Among 17,163 NSCLC patients under treatment with single-agent anti-programmed death-1/programmed death ligand-1 (PD-1/PD-L1) inhibitor (nivolumab, pembrolizumab, cemiplimab, durvalumab, atezolizumab, and avelumab), 497 patients had hypertension while 16,666 patients had no hypertension. 4,283 pulmonary AEs were reported, including 166 patients with hypertension and 4,117 patients without hypertension. Compared with patients without hypertension, patients with hypertension were positively associated with increased reporting of interstitial lung disease (ROR = 3.62, 95%CI 2.68-4.89, IC = 1.54, IC025 = 0.57) among patients receiving anti-PD-1 treatment. The median duration of onset from the time of initiation of anti-PD-1 administration was 28 days (IQR, 12.00-84.25). Conclusion: Our pharmacovigilance analysis showed the profile of pulmonary toxicities in NSCLC patients with hypertension caused by anti-PD-1/PD-L1 inhibitors. Interstitial lung disease was the statistically significant reporting adverse event in patients with hypertension receiving anti-PD-1 treatment.

Predicting checkpoint inhibitors pneumonitis in non-small cell lung cancer using a dynamic online hypertension nomogram.

OBJECTIVES: Checkpoint inhibitors pneumonitis (CIP) is one of the most lethal adverse events in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs). Currently, there is no recognized and effective predictive model to predict CIP in NSCLC. MATERIALS AND METHODS: This study retrospectively analyzed 460 NSCLC patients who were first treated with ICIs. Patients were divided into three cohorts based on the occurrence of CIP: any grade CIP cohort, grade ≥ 2 CIP cohort and grade ≥ 3 CIP cohort. RESULTS: A dynamic hypertension nomogram was constructed with elements including hypertension, interstitial lung disease (ILD), emphysema at baseline, and higher baseline platelet/lymphocyte ratio (PLR). The C indices of the training cohort and the internal and external validation cohort in any grade CIP cohort were 0.872, 0.833 and 0.840, respectively. The constructed hypertension nomogram was applied to grade ≥ 2 cohort and grade ≥ 3 cohort, and their C indices were 0.844 and 0.866, respectively. Compared with the non-hypertension nomogram, the hypertension nomogram presented better predictive power. CONCLUSIONS: After validated by internal and external validation cohorts, the dynamic online hypertension has the potential to become a convenient, intuitive, and personalized clinical tool for assessing the risk of CIP in NSCLC patients.

Low baseline plasma PCSK9 level is associated with good clinical outcomes of immune checkpoint inhibitors in advanced non-small cell lung cancer.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a crucial protein involved in the metabolism of low-density lipoprotein cholesterol. However, the role of plasma PCSK9 in predicting the efficacy of ICIs in advanced non-small cell lung cancer (NSCLC) remains to be clarified. METHODS: We retrospectively reviewed the medical records of NSCLC patients who presented at Shanghai Pulmonary Hospital between April 2019 and June 2020. ELISA was conducted to detect the concentration of PCSK9. Clinical efficacy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). RESULTS: A total of 55 patients were enrolled in the study. The median progression-free survival (PFS) following treatment with ICIs in all patients was 9.9 months. The optimal threshold of baseline plasma PCSK9 was 232.2 ng/ml. Patients with low baseline plasma PCSK9 had a longer PFS (NR vs. 7.37 months, p = 0.017, HR = 0.207, 95% CI: 0.086-0.498) and a better response (ORR 71.4% vs. 43.9%, p = 0.075, DCR 100% vs. 80.5%, p = 0.098) to ICIs. Younger patients (≤66 years) with a lower PCSK9 had a significantly longer PFS and higher treatment response than those with a high baseline level of PCSK9 (NR vs. 5.83 months, p = 0.021, HR = 0.134, 95% CI: 0.044-0.409; ORR 66.7% vs. 30.0%, p = 0.106, DCR 100% vs. 75%, p = 0.153). The situation was similar in patients who received first-line therapy (NR vs. 8.97 months, p = 0.022, HR = 0.138, 95% CI: 0.047-0.400; ORR 63.6% vs. 46.4%, p = 0.480, DCR 100% vs. 89.3%, p = 0.545). Multivariate analysis showed that low PCSK9 concentration was independently associated with PFS (p = 0.032, HR = 0.201). CONCLUSIONS: Low baseline plasma PCSK9 level may predict good outcomes in patients with advanced NSCLC treated with ICIs.

Treatment of small cell lung cancer: recent advances.

PURPOSE OF REVIEW: In this article, we aimed to summarize the recent progress being made in treatment of small cell lung cancer (SCLC). RECENT FINDINGS: SCLC is characterized by strong invasiveness, easy recurrence and early metastasis. In recent years, the emergence of immune checkpoint inhibitors (ICIs) therapy has broken the deadlock in the treatment field of SCLC. Combination strategies, such as the addition of ICIs to chemotherapy and radiotherapy, are actively underway. Some of these strategies have yielded significant survival benefits and tolerable adverse events, whereas several of them have failed with no significant improvement. In addition, the new classification of SCLC based on genomic analysis has deepened the understanding of SCLC and suggested new therapeutic directions. Similarly, the discovery of some new therapeutic targets, such as DDL3, CDK7 and PARP, also brings new hope for improving the survival of patients with SCLC. SUMMARY: In this article, we will review the recent advances of therapeutic regimen for patients with SCLC. Following the revolutionary success of adding ICIs to chemotherapy, more varieties of combination strategies have been explored in recent trials. In addition, therapeutic drug research and efficacy evaluation against for new targets are under investigation. Altogether, progress on genomic analysis, investigation of biological pathways and treatment regimen combination are providing renewed hope for patients with SCLC.

Treatment efficacy of HER2-mutant lung adenocarcinoma by immune checkpoint inhibitors: a multicenter retrospective study.

BACKGROUND: Despite the remarkable clinical advance of immune checkpoint inhibitors (ICIs) in the treatment of lung cancer, there are limited studies focused on evaluating efficacy of ICIs for patients with human epidermal growth factor receptor 2 (HER2)-mutant lung adenocarcinoma. METHODS: We conducted a multicenter retrospective study of patients with HER2-mutant lung adenocarcinoma who received ICIs therapy at Shanghai Pulmonary Hospital, Shanghai Chest Hospital and the First Affiliated Hospital of Wenzhou Medical University between 2016 and 2021. Response was defined with reference to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS: Among the 26 patients enrolled in our study, the overall objective response rate (ORR) was 38.5%, disease control rate (DCR) was 84.6% and median progression-free survival (PFS) was 7.4 months. Majority of patients were treated with immunochemotherapy combination regimens (16/26, 61.5%), with a median PFS of 8.4 months. Among the 9 patients receiving ICIs-based therapy as first-line treatment, 5 patients had partial response (PR) and 4 patients had stable disease (SD), with a median PFS of 9.1 months. Of the entire cohort, 5 patients who received ICIs before epidermal growth factor receptor (EGFR)/HER2-targeting drugs achieved a median PFS of 8.4 months. CONCLUSION: Our retrospective study provides clinical evidence that front line of ICIs-based therapy is also worth considering for the treatment to improve survival outcomes of patients with HER2-mutant lung adenocarcinoma.

Peripheral Blood Autoantibodies Against to Tumor-Associated Antigen Predict Clinical Outcome to Immune Checkpoint Inhibitor-Based Treatment in Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Peripheral blood biomarkers to immunotherapy have attracted more and more attentions owing to noninvasive nature. This study was designed to identify a panel of tumor associated autoantibodies (TAAbs) in plasma to predict the clinical outcome of ICIs-based treatment in advanced NSCLC patients and correlation between TAAbs and checkpoint inhibitor pneumonitis (CIP) would also be investigated. MATERIALS AND METHODS: Baseline plasma was collected from patients with advanced NSCLC before receiving ICIs-based treatment. ELISA was used to detect concentration of autoantibodies. Clinical efficacy was evaluated according to RECIST v1.1. RESULTS: We have identified a panel of five-TAAbs to predict responses of ICIs-based treatment in a discovery cohort (n = 37), and confirmed its predictive value in a validation cohort (n = 129). In the validation cohort, the positivity of this 5-TAAbs panel was significantly associated with better response (ORR: 44.4% vs. 13.6%, P < 0.001) and longer PFS (7.6 vs. 3.3m, P < 0.001). This significant association was remained in subgroup of patients treated with combination therapy (ORR: 43.8% vs. 13.7%, P = 0.004,PFS: 6.7 vs. 3.7m, P = 0 .017). Furthermore, this 5-TAAs panel worked better in patients who received subsequent-line treatment (ORR: 42.4% vs. 7.7%, P = 0.001, PFS: 6.2 vs. 3.0m, P = 0.004) than those received first-line treatment (ORR: 46.7% vs. 35.7%, P = 0.345, PFS: NR vs. 10.48m, P = 0.146). In addition, the CIP incidence in patients with 5-TAAbs positive was significantly higher comparing to negative patients (20.4% vs. 5.9%, P = 0.015). CONCLUSION: Our 5-TAAbs panel is a potential predictive biomarker for responses and toxicities to ICIs-based treatment in patients with advanced NSCLC.

Epidermal growth factor receptor tyrosine kinase inhibitor remodels tumor microenvironment by upregulating LAG-3 in advanced non-small-cell lung cancer.

INTRODUCTION: Previous clinical investigations have demonstrated that patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation have moderate responses to programmed cell death-1 and it's ligand-1 (PD-1/PD-L1) inhibitors, while some patients who failed EGFR-tyrosine kinase inhibitor (TKI) therapy could benefit from immunotherapy. As a result, we have explored alterations in the tumor immune microenvironment (TIME) before and after EGFR-TKI treatment to detect the chances and proper timing of immunotherapy among patients. METHODS: We identified 16 paired tissue samples pre- and post-EGFR-TKI treatment. Sections 4 µm thick were utilized to evaluate CD8, PD-L1, PD-1, LAG-3, and TIM-3 expressions by multiplexed fluorescent immunohistochemical staining. Five to ten representative original multispectral images of each sample were employed in the analysis. RESULTS: Patients with positive CD8 + T-cell infiltration accounted for 37.5 % at baseline. Positive expression of PD-L1, PD1, LAG-3, and TIM-3 cells were observed in seven (43.8 %), four (25 %), one (6.25 %) and five (31.25 %) of the patients, respectively. PD-1 expression and infiltration of CD8+PD-1+-exhausted T cells increased significantly in patients with EGFR L858R mutation compared to patients with EGFR 19DEL. Patients who acquired T790 M after TKI treatment had less infiltrations of CD8+PD-1+ T cells and CD8+TIM-3+ T cells in the TIME at baseline. Positive expression of checkpoint proteins-including PD-1, TIM-3, and LAG-3-significantly correlated with shorter progression-free survival. LAG-3 was significantly upregulated after TKI treatment (p = 0.003), while other checkpoint proteins remained stationary. CONCLUSION: The present study is the first work to report LAG-3 upregulation after EGFR-TKI failure in advanced NSCLC, which proposed novel insights for rational use of LAG-3 inhibitors in advanced NSCLC patients with EGFR mutation.

Favorable clinical outcomes of checkpoint inhibitor-based combinations after progression with immunotherapy in advanced non-small cell lung cancer.

Aim: Immune checkpoint inhibitors (ICIs) have dramatically changed the treatment paradigm in patients with non-small-cell lung cancer (NSCLC). However, progression patterns with immunotherapy are currently unclear and therapeutic options beyond resistance remain challenging. Methods: We reviewed advanced NSCLC patients between January 2016 and December 2019 who were treated with anti-PD-1/PD-L1 inhibitors in our center and identified those who developed disease progression. Later-line treatment strategies were collected and objective response rate, progression-free survival (PFS), and overall survival (OS) were assessed. Results: Of the 118 patients, 46 (39.0%) showed oligoprogression and 72 (61.0%) showed systemic progression. No difference in progression patterns was observed between monotherapy and combination therapy. Systemic progression was strongly associated with never-smokers (51.4% vs. 21.7%, P = 0.001) and ECOG PS = 2 (13.9% vs. 2.2%, P = 0.048) at baseline. The distribution of progression sites was roughly similar between oligoprogression and systemic progression, and the most commonly affected anatomic site was lung (66.9%), followed by bone (12.7%) and lymph nodes (11.0%). For patients beyond first disease progression, checkpoint inhibitor-based combinations could lead to a significantly longer PFS2 compared with ICIs monotherapy (9.63 months vs. 4.23 months, P = 0.004, HR = 0.394, 95%CI: 0.174-0.893) and other therapy (9.63 months vs. 4.07 months, P = 0.046, HR = 0.565, 95%CI: 0.326-0.980). Median OS of the ICIs combination group was not reached but was significantly longer than other therapy group (NR vs. 14.37 months, P = 0.010, HR = 0.332, 95%CI: 0.167-0.661). Conclusion: Systemic progression occurs more frequently among NSCLC patients receiving ICIs. Checkpoint inhibitor-based combinations show favorable outcomes as subsequent treatment strategies after the failure of previous ICIs treatment.

Association of baseline peripheral-blood eosinophil count with immune checkpoint inhibitor-related pneumonitis and clinical outcomes in patients with non-small cell lung cancer receiving immune checkpoint inhibitors.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) have revolutionized the oncologic treatment landscape, but have been accompanied by immune-related adverse events (irAEs). ICI-related pneumonitis (ICI-pneumonitis) is a potentially fatal irAE. However, the risk factors associated with ICI-pneumonitis remain unclear. There is an urgent need to identify risk factors for ICI-pneumonitis using reliable and accessible parameters. Here, we aimed to identify baseline peripheral-blood biomarkers correlated with ICI-pneumonitis and clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC) who were treated with ICIs. MATERIALS AND METHODS: We conducted a retrospective analysis of eligible patients with advanced NSCLC who were treated with ICIs at our center. Receiver operating characteristic (ROC) curve was used to determine the optimal cutoff value for analyzing risk of ICI-pneumonitis. Multivariate logistic analysis was performed to identify risk factors of ICI-pneumonitis. Clinical characteristics and treatment outcomes were collected and compared according to the optimal cutoff value. RESULTS: A total of 300 patients were included, in which 54 patients (18 %) experienced ICI-pneumonitis. Patients with ICI-pneumonitis had a high level of baseline peripheral-blood absolute eosinophil count (AEC) than those without ICI-pneumonitis (P = 0.013). The optimal threshold of baseline peripheral-blood AEC to predict ICI-pneumonitis was 0.125 × 109 cells/L. The incidence of ICI-pneumonitis was higher in the high-AEC group (AEC ≥ 0.125 × 109 cells/L; 27.7 %) than in the low-AEC group (AEC < 0.125 × 109 cells/L; 9.8 %, P < 0.001). Moreover, patients with high AEC (compared with those with low AEC) had a higher objective response rate (ORR) (40.9 % versus 28.8 %, P = 0.029) and longer median progression-free survival (PFS) (8.93 months versus 5.87 months, P = 0.038). CONCLUSIONS: Among patients treated with ICIs, a baseline feature of high AEC (≥0.125 × 109 cells/L) was associated with an increasing risk of ICI-pneumonitis, and with a better clinical outcome.

Non-alcoholic fatty liver disease is associated with immune checkpoint inhibitor-based treatment response in patients with non-small cell lung cancer with liver metastases.

BACKGROUND: Recent studies have suggested obesity could contribute to improved outcomes of immune checkpoint inhibitor (ICI)-based treatment. Non-alcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease, is also obesity-related, but its association with the efficacy of ICI-based treatment has not yet been reported. METHODS: We retrospectively reviewed the medical records of advanced non-small cell lung cancer (NSCLC) patients treated at Shanghai Pulmonary Hospital between June 2015 and June 2019. NAFLD was confirmed by ultrasound examination of the abdomen. The efficacy of ICI-based treatment was evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). Univariate analysis to compare progression-free survival (PFS) was conducted using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards model. RESULTS: A total of 223 patients with advanced NSCLC who received ICI-based treatment were included in the study, of whom 26.9% (n=60) were confirmed to have NAFLD. Patients with NAFLD were more inclined to to have non-squamous carcinoma and higher body mass index (BMI) compared with those without NAFLD. The median PFS of the entire cohort of patients was 6.6 months. Nno significant difference was found in response [objective response rate (ORR) 43.3% vs. 35.6%, P=0.289, disease control rate (DCR) 83.3% vs. 75.5%, P=0.211], nor in PFS (7.0 vs. 6.6 months, P=0.769) between the patients with (n=60) and without NAFLD (n=163). Surprisingly, in the subgroup of patients with liver metastases (LMs), there were dramatically significant differences in ORR (71.4% vs. 9.1%, P=0.013), DCR (85.7% vs. 18.2%, P=0.013), and median PFS [5.1 vs. 2.1 months, P=0.014, hazard ratio (HR): 0.244] between patients with (n=7) and without (n=11) NAFLD. Multivariate analysis revealed NAFLD to have a significant impact on PFS (P=0.017) in patients with LMs. In addition, the DCR of LMs was significantly higher in patients with NAFLD compared to those who did not have NAFLD (DCR: 42.9% vs. 0.0%, P=0.038). CONCLUSIONS: In conclusion, NAFLD holds no clinical benefit for advanced NSCLC patients who undergo ICI-based treatment, but it is associated with improved outcomes in patients with LMs.

Re-biopsy and liquid biopsy for patients with non-small cell lung cancer after EGFR-tyrosine kinase inhibitor failure.

BACKGROUND: Re-biopsy is important for exploring resistance mechanisms, especially for non-small cell lung cancer (NSCLC) patients who develop resistance to EGFR-tyrosine kinase inhibitors (TKIs). Liquid biopsy using circulating tumor DNA has come into use for this purpose. This retrospective study investigated the status of re-biopsy and liquid biopsy in NSCLC patients with EGFR mutations and evaluated their effect on clinical strategies and prognosis. METHODS: Five hundred fifty-five NSCLC patients with resistance to EGFR-TKIs were included and divided into three groups: re-biopsy, liquid biopsy, and no re-biopsy. Amplification refractory mutation system (ARMS) PCR or super ARMS PCR was used to detect EGFR mutations. RESULTS: Three hundred eight (55.5%) patients underwent re-biopsy; 45.5% (140/308) were positive for T790M. The most common re-biopsy procedure was computed tomography-guided percutaneous core needle biopsy (60.1%), followed by effusion drainage (29.5%) and superficial lymph node biopsy (6.5%). One hundred eighteen (21.3%) patients underwent liquid biopsy; the T790M detection rate was 41.5% (49/118.) Of the 308 patients who underwent re-biopsy, 69 were examined for EGFR mutations with plasma. The concordance rate of T790M detection between tissue and plasma was 66.7%. A statistical difference in further treatment after EGFR-TKI failure was observed among all groups (P = 0.014). Patients in the biopsy groups were more likely to receive third-generation EGFR-TKIs. Multivariate analysis showed that re-biopsy had a significant impact on overall survival (P < 0.001). CONCLUSION: Re-biopsy plays a pivotal role in the management of patients with NSCLC and resistance to EGFR-TKIs. Liquid biopsy may be an alternative if difficulties performing re-biopsy exist.