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Objective: The present study endeavors to furnish an exhaustive review of the research advancements on solid tumors harboring RET rearrangement within the Chinese context, particularly emphasizing the examination of real-world therapeutic strategies and clinical outcomes observed in individuals diagnosed with advanced non-small cell lung cancer (NSCLC). The review delves into a critical assessment of the therapeutic efficacy of targeted RET inhibitors, while also scrutinizing the diverse array of treatment modalities employed in the Chinese patient population., Methods: The study conducted a comprehensive review of the advancements made by Chinese scholars in the realm of RET driver genes. It delved into the analysis of the incidence of RET rearrangements in solid tumors, alongside an examination of the varied treatment paradigms and their current status within China. Utilizing the RECIST 1.1 criteria, the study evaluated the therapeutic efficacy achieved in RET-positive NSCLC patients undergoing diverse treatment modalities. Furthermore, treatment-related adverse events (TRAEs) were meticulously graded following the Common Terminology Criteria for Adverse Events (CTCAE)., Results: A retrospective, multi-center, real-world analysis was conducted, encompassing 64 patients diagnosed with pathologically confirmed RET rearrangement advanced non-small cell lung cancer (NSCLC) between December 2015 and November 2023. Notably, KIF5B-RET emerged as the most prevalent RET fusion partner, accounting for 59.4% of cases. Therapeutic interventions among these patients included specific targeted inhibitors such as Pralsetinib (48.4%), chemotherapy (34.3%), multi-target inhibitors (15.6%), and one case (1.6%) involving immunotherapy combined with anti-angiogenic therapy. In terms of progression-free survival (PFS), Pralsetinib monotherapy demonstrated a median PFS of 16.03 months, outperforming chemotherapy (2.87 months; p < 0.0001), chemotherapy combined with anti-angiogenic therapy (6.90 months; p = 0.048), and multi-target inhibitors (2.50 months; p < 0.0001). Furthermore, the one-year and two-year overall survival (OS) rates for Pralsetinib monotherapy were 64.3% and 46.4%, respectively. Regarding safety, 71.0% of patients receiving Pralsetinib experienced at least one adverse event, with 45.2% classified as grade 3-4 in severity. Notably, no fatalities were attributed to adverse events. Common adverse events included hemoglobin reduction (35.5%) and neutropenia (32.3%), indicative of an overall favorable safety profile for Pralsetinib in this patient population., Conclusion: This study encapsulates the research endeavors and treatment advancements of RET rearrangement solid tumors within the Chinese healthcare landscape, specifically highlighting the diverse real-world therapeutic approaches and their effectiveness in managing advanced RET rearrangement NSCLC among Chinese patients. Notably, targeted RET inhibitors like Pralsetinib have emerged as potent therapeutic agents, exhibiting remarkable efficacy and a manageable safety profile in this patient cohort. These findings underscore the potential of Pralsetinib and similar targeted therapies as novel treatment options for individuals with RET fusion-positive NSCLC., (© 2024. The Author(s).)

Background and Aims: Manual navigation (MN), drawing a bronchoscopic road map simply by looking at the consecutive computed tomography (CT), is feasible and economical. However, scant data about the use of MN in radial endobronchial ultrasound (r-EBUS) bronchoscopy have been documented till now. We aimed to evaluate the diagnostic performance of r-EBUS bronchoscopy guided by MN for diagnosing peripheral pulmonary lesions (PPLs) and to determine clinical factors affecting the diagnostic yield., Methods: We performed a retrospective, cohort study of consecutive patients with PPLs who underwent r-EBUS bronchoscopic biopsy via guidance of MN from May 2020 to June 2021 in our Respiratory Endoscopic Division. The overall diagnostic yield of MN-guided r-EBUS, the factors affecting the yield, and the diagnostic performance for malignancy were evaluated., Results: A total of 102 patients (103 lesions) were evaluated. The overall diagnostic yield of MN-guided r-EBUS was 82.0%, and it ranged from 79.6% to 82.5%, assuming the undermined cases were all positive cases (79.6%) or negatives (82.5%). The sensitivity of MN-guided r-EBUS for malignancy was 71.4%, ranging from 68.2% to 71.4%, the specificity was 100%, the positive predictive value was 100%, and the negative predictive value was 67.3%, ranging from 63.8% to 69.0%. The multivariate logistic regression showed that "bronchus sign on CT" was the only predictor of the overall diagnostic yield (odds ratio = 11.5, 95% confidence interval: 1.9-70.9, P = 0.009)., Conclusions: MN-guided r-EBUS is feasible in diagnosing PPLs, especially for lesions with bronchus sign on CT., (© 2024 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Background: Stenosis and obliteration of the pulmonary vein can be developed by multiple diseases and might cause hemoptysis. Traditional therapy including surgical procedure and conservative treatments might be inappropriate choices to manage massive hemoptysis., Case Presentation: A 64-year-old man, diagnosed with advanced stage IVA lung squamous cell carcinoma, presented with dyspnea and recurrent, massive hemoptysis. An initial contrast-enhanced computed tomography revealed a giant tumor in the left lung hilus and occlusion of the left superior pulmonary vein. Despite immediate selective bronchial artery embolization and simultaneous embolization of an anomalous branch of the internal thoracic artery, the massive hemoptysis continued. Subsequently, embolization of the left superior pulmonary artery was performed, achieving functional pulmonary lobectomy, which successfully treated the hemoptysis without relapse during a six-month follow-up. The patient continues to undergo cancer therapy and remains stable., Conclusions: This case successfully managed massive hemoptysis associated with lung cancer invasion into the pulmonary vein through functional pulmonary lobectomy via embolization of the corresponding pulmonary artery., (© 2024. The Author(s).)

Non-small-cell lung carcinoma (NSCLC) is a type of pernicious tumor, which owns high morbidity and mortality. TRIM34 has a stimulative role in cell apoptosis and a suppressive role in inflammation. However, no studies were focused on the regulatory impacts of TRIM34 in NSCLC. This study aimed to examine the underlying regulatory effects of TRIM34 in NSCLC. TRIM34 exhibited lower expression in NSCLC. TRIM34 facilitated mitochondrial damage and apoptosis in NSCLC. TRIM34 induced the increased activity of mTORC1 and accelerated glycolysis in NSCLC. Enhanced mitochondrial damage induced by TRIM34 overexpression was reversed after rapamycin (mTORC1 inhibitor) treatment in NSCLC. The strengthened cell apoptosis stimulated by TRIM34 overexpression was rescued after rapamycin treatment. TRIM34 activated mTORC1 to suppress NSCLC progression in vivo. TRIM34 suppressed NSCLC via inducing mTORC1-dependent glucose utilization and promoting cellular death. The results suggest that TRIM34 can be a useful therapeutic biomarker for NSCLC patients., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib-refractory, anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study., Methods: In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by Kaplan‒Meier methods with two-sided 95% confidence intervals (CIs). Next-generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management., Results: At the data cut-off date (August 31, 2022), with a median follow-up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3-53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline ALK or tumor protein 53 (TP53) mutation. In addition, patients with concurrent TP53 mutations had shorter OS than those without concurrent TP53 mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated ALK mutation abundance at 6 weeks., Conclusion: Ensartinib led to a favorable OS in patients with advanced, crizotinib-resistant, and ALK-positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification., (© 2024 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat‐sen University Cancer Center.)

This study aimed to screen differentially expressed genes (DEGs) involved in the influence of antiangiogenic therapy on myeloid-derived suppressor cell (MDSC) infiltration and investigate their mechanisms of action. Data on DEGs after the action of antiangiogenic drugs in a pan-cancer context were obtained from the Gene Expression Omnibus (GEO) database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the clusterProfiler package in R software. Single-sample gene set enrichment analysis was performed using the gene set variation analysis package to evaluate the levels of immune cells and the activity of immune-related pathways. The relationships of DEGs with the infiltration levels of MDSCs and specific immune cell subpopulations were investigated via gene module analysis. The top 10 key genes were subsequently obtained from PPI network analysis using the cytoHubba plugin of the Cytoscape platform. When the DEGs of the four datasets were intersected, a DEG in the intersection of three datasets and 12 DEGs in the intersection of two datasets were upregulated, and 28 DEGs in the intersection of two datasets were downregulated. GO and KEGG pathway enrichment analyses revealed that the DEGs were associated with multiple important signaling pathways closely related to tumor onset and development, including cell differentiation, cell proliferation, the cell cycle, and immune responses. Most downregulated genes in lung adenocarcinoma (LUAD) were positively correlated with MDSC expression. Only MGP was negatively correlated; the correlation between CACNG6 and MDSC expression was statistically insignificant. In lung squamous cell carcinoma (LUSC), the relationships of PMEPA1, PCDH7, NEURL1B, and CACNG6 with MDSC expression were statistically insignificant; MGP was negatively correlated with MDSC expression. The top 10 key genes with the highest degree scores obtained using the cytoHubba plugin of Cytoscape were AURKB, RRM2, BUB1, NUSAP1, PRC1, TOP2A, NCAPH, CENPA, KIF2C, and CCNA2. Most of these genes were upregulated in LUAD and associated with immune cell infiltration and prognosis in tumors. An analysis of the relationships between DEGs and infiltration by other specific immune cells revealed the presence of consistent patterns in the downregulated genes, which exhibited positive correlations with the levels of Th2 cells, γδ T cells, and CD56dim NK cells, and negative correlations with other infiltrating immune cells. Antiangiogenic therapy may regulate MDSC infiltration through multiple important signaling pathways closely associated with tumor onset and development, such as cell differentiation, cell proliferation, the cell cycle, and immune responses. Antiangiogenic drugs may exert effects by affecting various types of infiltrating cells associated with immune suppression., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: The use of immune checkpoint inhibitors, particularly PD-1 inhibitors, has revolutionized the treatment of advanced tumors and shown significant improvements in patient survival rates. However, which PD-1 inhibitor is more effective and safer for a specific indication remains unclear. To address this problem, our study aimed to evaluate the effectiveness and safety of different PD-1 inhibitors in combination with chemotherapy as first-line therapy for individuals with advanced non-small-cell lung cancer (NSCLC) without driver genes in the real world., Materials and Methods: We conducted a retrospective study of individuals diagnosed with aNSCLC who received immune checkpoint inhibitors (ICIs) with modified PD-1 inhibitors, including Sintilimab, Toripalimab, Tislelizumab, Camrelizumab, or Pembrolizumab as first-line treatment between March 5th, 2016 and October 20th, 2022. We assessed demographic and clinical information and analyzed clinical response, survival outcomes, and safety profiles. The primary endpoint was overall survival (OS), and the secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety., Results: As of the date cut-off on October 20th, 2022, the median follow-up time was 20.62 months. A total of 204 patients were enrolled in the study, including 56 (27.5%) patients receiving modified PD-1 inhibitors (Sintilimab, Toripalimab, Tislelizumab, or Camrelizumab) in combination with chemotherapy and 148 (72.5%) patients receiving Pembrolizumab in combination with chemotherapy. In the overall cohort, the median overall survival (OS) was 26.9 months (95%CI, 22.3-31.6), the median progression-free survival (PFS) was 8.4 months (95%CI, 6.9-9.8), and the objective response rate (ORR) and disease control rate (DCR) were 47.6% (95%CI, 29.9-43.6) and 84.3% (95%CI, 78.4-88.9). The mOS of modified PD-1 inhibitors group and Pembrolizumab group were 30.7 (95%CI, 17.3-44.4) months and 26.8 (95%CI, 22.2-31.4) months. The mPFS of two groups were 8.3(95%CI, 6.9-9.6) months and 8.8 (95%CI, 6.9-10.7) months, respectively. There was no statistical difference between the two groups in terms of OS or PFS. The ORR for the two groups was 48.2% (95%CI, 34.8-61.8) and 47.3% (95%CI, 39.1-5.6), respectively. However, due to the limited sample size, the difference was not statistically significant. On the other hand, the DCR tended to be higher in the Pembrolizumab group (86.5%; 95%CI, 79.7-91.4) compared to the modified PD-1 inhibitors group (78.6%; 95%CI, 65.2-87.9), and this difference was statistically significant (p = 0.006). In terms of safety, both groups exhibited favorable clinical safety profiles. The only two types of potentially immune-related adverse events reported were pneumonitis and reactive cutaneous capillary endothelial proliferation (RCCEP)., Conclusions: The modified PD-1 inhibitors showed comparable survival outcomes and manageable safety profiles in NSCLC compared to Pembrolizumab. Moreover, these inhibitors exhibited improved accessibility and economic outcomes compared to Pembrolizumab. While there were similarities in drug-related and immunotherapy-related adverse reactions between the modified PD-1 inhibitors and Pembrolizumab, there were some slight differences. Further prospective and retrospective studies would be necessary to validate these findings beyond the scope of the CTONG1901 study., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Immune checkpoint inhibitor (ICI) rechallenge in non-small cell lung cancer (NSCLC) is a promising therapeutic strategy. The situation for ICI rechallenge can be divided into three categories: adverse events (AEs); resistance to ICIs, and rechallenge becomes compulsive because of tumor relapse while the patients had completed a 2 year course of immunotherapy. However, these categories are still controversial and should be explored further. Through voting at the 6th Straits Summit Forum on Lung Cancer, in this study we summarize the consensus of 147 experts in ICI rechallenges. A total of 97.74% experts agreed to rechallenge; 48.87% experts rechallenge with the original drug, and the others rechallenge with a different drug; 40.3% agreed to rechallenge directly after progression; 88.06% experts agreed to ICI rechallenge with a combination regimen; and factors such as previous performance status score, PD-1 expression, and age should also be considered. Understanding the the clinical studies in ICI rechallenge could bring us one step closer to understanding the consensus. In patients with advanced NSCLC who have suffered recurrent or distant metastasis after immunotherapy, the option of rechallenge with ICIs is a promising treatment option., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background: Immunotherapy targeting PD-1/PD-L1 has revolutionized the treatment of extensive-stage small cell lung cancer (ES-SCLC). However, clinical trials suggest differential efficacy of anti-PD-1 agents and anti-PD-L1 agents in first-line treatment of ES-SCLC. This retrospective multicenter study aimed to compare the efficacy and safety of anti-PD-1 agents versus anti-PD-L1 agents in first-line treatment of ES-SCLC in real-world practice., Methods: Patients with pathologically or cytologically confirmed ES-SCLC treated with platinum plus etoposide combined with anti-PD-1 or PD-L1 agents as first-line treatment in different centers of PLA General Hospital between January 2017 and October 2021 were included for this study. Survival outcomes and safety were compared between patients receiving anti-PD-1 and PD-L1 agents., Results: Of the total 154 included patients, 68 received anti-PD-1 agents plus chemotherapy (PD-1 group), and 86 received anti-PD-L1 agents plus chemotherapy (PD-L1 group). Progression-free survival (PFS) and overall survival (OS) in the entire cohort were 7.6 months (95% confidence interval [CI]: 6.5-8.2 months) and 17.4 months (95% CI: 15.3-19.3 months), respectively. Median PFS and OS were comparable between the PD-1 group and PD-L1 group (PFS: 7.6 months vs. 8.3 months, HR = 1.13, 95% CI: 0.79-1.62, p = 0.415; OS: 26.9 months vs. 25.6 months, HR = 0.96, 95% CI: 0.63-1.47, p = 0.859. The objective response rate and disease control rate were comparable between the two groups: 79.4% vs. 79.1% and 92.6% vs. 94.2%, respectively. The 6-month, 12-month, and 18-month PFS and OS rates were slightly higher in the PD-L1 group than in the PD-1 group, while the 24-month PFS rate was slightly higher in the PD-1 group than in the PD-L1 group. Stratified analysis showed that locoregional thoracic radiotherapy and normal lactate dehydrogenase level were independent predictors of better OS in ES-SCLC patients treated with first-line chemotherapy plus ICI. Adverse events were not significantly different between the two groups., Conclusions: Anti-PD-1 agents and anti-PD-L1 agents combined with chemotherapy as first-line treatment for ES-SCLC are comparably effective and well tolerated., (© 2024. The Author(s).)

Objective: Lung cancer patients mostly had different degrees of impaired pulmonary function, and these damage also significantly affect quality of life. The concept of pulmonary rehabilitation applicable to patients with chronic respiratory diseases is also applicable to patients with lung cancer. The current application of pulmonary rehabilitation for lung cancer is inconsistent, and reliable guidelines are lacking. The purpose of this study was to investigate the effect of pulmonary rehabilitation exercise based on wearable device pedometer on lung cancer patients with impaired pulmonary function, and to find a suitable pulmonary rehabilitation program for patients with lung cancer., Methods: In this retrospective study, 100 lung cancer patients with impaired pulmonary function were included. Among them, 51 patients received pulmonary rehabilitation exercise based on a wearable device pedometer (Experiemental group), while 49 received routine nursing mode (Control group). The respiratory function, quality of life, and sports endurance of the two groups were observed., Results: The incidence of postoperative atelectasis, pulmonary infection, hypoxemia, postoperative oxygen therapy time, chest tube indwelling time, and postoperative hospital stay in the experimental group were significantly lower than those in the control group (P < .05); The FEV1, FVC and FVE1% of the experimental group were significantly higher than those of the control group after intervention (all P < .05)., Conclusion: Pulmonary rehabilitation exercise based on a wearable device pedometer can effectively improve the respiratory function and exercise endurance of lung cancer patients with impaired pulmonary function and can improve the quality of life and reduce the length of hospital stay.

Purpose: PD-1 blockade plus chemotherapy has become the new standard of care in patients with untreated advanced non-small cell lung cancer (NSCLC), whereas predictive biomarkers remain undetermined., Experimental Design: We integrated clinical, genomic, and survival data of 427 NSCLC patients treated with first-line PD-1 blockade plus chemotherapy or chemotherapy from two phase III trials (CameL and CameL-sq) and investigated the predictive and prognostic value of HLA class I evolutionary divergence (HED)., Results: High HED could predict significantly improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in those who received PD-1 blockade plus chemotherapy [in the CameL trial, ORR: 81.8% vs. 53.2%; P = 0.032; PFS: hazard ratio (HR), 0.47; P = 0.012; OS: HR, 0.40; P = 0.014; in the CameL-sq trial, ORR: 89.2% vs. 62.3%; P = 0.007; PFS: HR, 0.49; P = 0.005; OS: HR, 0.38; P = 0.002], but not chemotherapy. In multivariate analysis adjusted for PD-L1 expression and tumor mutation burden, high HED was independently associated with markedly better ORR, PFS, and OS in both trials. Moreover, the joint utility of HED and PD-L1 expression showed better performance than either alone in predicting treatment benefit from PD-1 blockade plus chemotherapy. Single-cell RNA sequencing of 58,977 cells collected from 11 patients revealed that tumors with high HED had improved antigen presentation and T cell-mediated antitumor immunity, indicating an inflamed tumor microenvironment phenotype., Conclusions: These findings suggest that high HED could portend survival benefit in advanced NSCLC treated with first-line PD-1 blockade plus chemotherapy. See related commentary by Dimou, p. 4706., (©2023 American Association for Cancer Research.)

Background: Traditional electromagnetic navigation bronchoscopy (ENB) is a real-time image-guided system and used with thick bronchoscopes for the diagnosis of peripheral pulmonary nodules (PPNs). A novel ENB that could be used with thin bronchoscopes was developed. This study aimed to evaluate the diagnostic yield and the experience of using this ENB system in a real clinical scenario., Methods: This multicentre study enrolled consecutive patients with PPNs adopting ENB from March 2019 to August 2021. ENB was performed with different bronchoscopes, ancillary techniques and sampling instruments according to the characteristics of the nodule and the judgement of the operator. The primary endpoint was the diagnostic yield. The secondary endpoints included the diagnostic yield of subgroups, procedural details and complication rate., Results: In total, 479 patients with 479 nodules were enrolled in this study. The median lesion size was 20.9 (IQR, 15.9-25.9) mm. The overall diagnostic yield was 74.9% (359/479). A thin bronchoscope was used in 96.2% (461/479) nodules. ENB in combination with radial endobronchial ultrasound (rEBUS), a guide sheath (GS) and a thin bronchoscope was the most widely used guided method, producing a diagnostic yield of 74.1% (254/343). The median total procedural time was 1325.0 (IQR, 1014.0-1676.0) s. No severe complications occurred., Conclusion: This novel ENB system can be used in combination with different bronchoscopes, ancillary techniques and sampling instruments with a high diagnostic yield and safety profile for the diagnosis of PPNs, of which the combination of thin bronchoscope, rEBUS and GS was the most common method in clinical practice., Trial Registration Number: NCT03716284., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immune checkpoint inhibitors (PD-1/PD-L1 and CTLA-4 blockade) have revolutionized the treatment landscape in non-small cell lung cancer (NSCLC). Secondary resistance to immunotherapy (IO), which poses a substantial challenge in clinical settings, occurs in several initial responders. Currently, new treatment approaches have been extensively evaluated in investigational studies for these patients to tackle this difficult problem; however, the lack of consistency in clinical definition, uniform criteria for enrollment in clinical trials, and interpretation of results remain significant hurdles to progress. Thus, our expert panel comprehensively synthesized data from current studies to propose a practical clinical definition of secondary resistance to immunotherapy in NSCLC in metastatic and neoadjuvant settings. In addition to patients who received IO alone (including IO-IO combinations), we also generated a definition for patients treated with chemotherapy plus IO. This consensus aimed to provide guidance for clinical trial design and facilitate future discussions with investigators. It should be noted that additional updates in this consensus are required when new data is available., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Objective: Oncogenic alternation in RET is one of the important targets of non-small cell lung cancer (NSCLC). Pralsetinib has shown great efficacy in RET fusion-positive NSCLC, but a series of adverse reactions will inevitably occur in the meantime. We aimed to explore the clinical characteristics of patients with pneumonia and recognition it in early stage, so patients could longer benefit from pralsetinib., Methods: This is a multicenter, retrospective study. RET fusion-positive advanced NSCLC patients who developed pneumonia during pralsetinib treatment from January 2020 to December 2022 were included. Clinical data, time to onset of pneumonia, methods of pneumonia diagnosis, treatment with pneumonia, prognosis of pneumonia, and the effect of pneumonia on the efficacy of pralsetinib., Results: A total of 8 patients with pneumonia were included in the study, most of which were non-smoking female patients and the main fusion gene was KIF5B (87.5%), which was consistent with the general characteristics of RET fusion population. The median occurrence time of pralsetinib-associated pneumonia was 2.15 (range 1.1-6.63) months. All patients were infected by opportunistic pathogens, and the most common pathogen was human herpesviruses and pneumospora yerbii. Fever was always the first symptom, and timely anti-infective treatment including antibiotics, antiviral drugs, and antifungal drugs was effective. Until February 28, 2023, the median follow-up time was 18.7 months, the mean PFS of patients was 17.4 months, and the median PFS was not reached. Fortunately, patients who restarted pralsetinib after infection control continued to benefit., Conclusions: Opportunistic infection may be a unique adverse effect of pralsetinib. During the treatment of pralsetinib, we should be vigilant about the occurrence of pneumonia and achieve early recognition and timely treatment., (© 2023. The Author(s).)

Background: The gut mycobiome of patients with lung adenocarcinoma (LUAD) remains unexplored. This study aimed to characterize the gut mycobiome in patients with LUAD and evaluate the potential of gut fungi as non-invasive biomarkers for early diagnosis., Methods: In total, 299 fecal samples from Beijing, Suzhou, and Hainan were collected prospectively. Using internal transcribed spacer 2 sequencing, we profiled the gut mycobiome. Five supervised machine learning algorithms were trained on fungal signatures to build an optimized prediction model for LUAD in a discovery cohort comprising 105 patients with LUAD and 61 healthy controls (HCs) from Beijing. Validation cohorts from Beijing, Suzhou, and Hainan comprising 44, 17, and 15 patients with LUAD and 26, 19, and 12 HCs, respectively, were used to evaluate efficacy., Results: Fungal biodiversity and richness increased in patients with LUAD. At the phylum level, the abundance of Ascomycota decreased, while that of Basidiomycota increased in patients with LUAD. Candida and Saccharomyces were the dominant genera, with a reduction in Candida and an increase in Saccharomyces, Aspergillus, and Apiotrichum in patients with LUAD. Nineteen operational taxonomic unit markers were selected, and excellent performance in predicting LUAD was achieved (area under the curve (AUC) = 0.9350) using a random forest model with outcomes superior to those of four other algorithms. The AUCs of the Beijing, Suzhou, and Hainan validation cohorts were 0.9538, 0.9628, and 0.8833, respectively., Conclusions: For the first time, the gut fungal profiles of patients with LUAD were shown to represent potential non-invasive biomarkers for early-stage diagnosis., (© 2023. The Author(s).)

By exploring the effects of an antiangiogenic small molecule drug named anlotinib on the levels of myeloid-derived suppressor cells (MDSCs) in a mouse xenograft model of lung cancer, the role of anti-angiogenesis in remodeling the immune microenvironment was discussed. In addition, the impact of anlotinib on the normalization of the immune microenvironment and time window was examined, providing a theoretical basis for the optimization of clinical strategies applying anlotinib combined with PD-1 inhibitors. On the basis of the LLC mouse xenograft model, MDSCs and MDSCs + immune microenvironment were examined in tissues, respectively, according to different samples. The former observation included the control (group A) and anlotinib monotherapy (group B) groups; the latter also included the control (group C) and anlotinib monotherapy (group D) groups. The levels of MDSCs in peripheral blood at different time points were analyzed by flow cytometry, and the levels of MDSCs in tissue samples at different time points were evaluated by immunofluorescence and immunohistochemistry. The volumes of subcutaneous xenografts were significantly smaller in the anlotinib treatment group compared with the control group ( P  < 0.005). Flow cytometry showed that compared with the control group, the intratumoral percentages of total MDSCs ( P  < 0.01) and mononuclear-MDSCs ( P  < 0.05) were significantly decreased on days 3 and 17 after anlotinib treatment in peripheral blood samples; however, there was no significant difference in granulocytic-MDSCs changes between the experimental and control groups. Immunofluorescence showed that the levels of MDSCs in both the experimental and control groups reached the lowest points 10 days after drug administration, and were significantly lower in the experimental group than in the control group ( P  < 0.05). Anlotinib reduces the levels of MDSCs in the mouse xenograft model of lung cancer, with the characteristics of time window. This study provides a basis for further exploring strategies for anti-angiogenic treatment combined with immunotherapy in lung cancer based on time-window dosing., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Checkpoint inhibitor pneumonitis (CIP) is the most common fatal immune-related adverse event; however, its pathophysiology remains largely unknown. Comprehensively dissecting the key cellular players and molecular pathways associated with CIP pathobiology is critical for precision diagnosis and develop novel therapy strategy of CIP. Herein, we performed a comprehensive single-cell transcriptome analysis to dissect the complexity of the immunological response in the bronchoalveolar lavage fluid (BALF) microenvironment. CIP was characterized by a dramatic accumulation of CXCL13+ T cells and hyperinflammatory CXCL9+ monocytes. T-cell receptor (TCR) analysis revealed that CXCL13+ T cells exhibited hyperexpanded- TCR clonotypes, and pseudotime analysis revealed a potential differentiation trajectory from naïve to cytotoxic effector status. Monocyte trajectories showed that LAMP3+ DCs derived from CXCL9+ monocytes possessed the potential to migrate from tumors to the BALF, whereas the differentiation trajectory to anti-inflammatory macrophages was blocked. Intercellular crosstalk analysis revealed the signaling pathways such as CXCL9/10/11-CXCR3, FASLG-FAS, and IFNGR1/2-IFNG were activated in CIP+ samples. We also proposed a novel immune signature with high diagnostic power to distinguish CIP+ from CIP- samples (AUC = 0.755). Our data highlighted key cellular players, signatures, and interactions involved in CIP pathogenesis., (© 2023. The Author(s).)

With the development of medical technology, tumor vaccines as a novel precise immunotherapy approach have gradually received attention in clinical applications. Against the backdrop of the global corona virus disease 2019 (COVID-19) outbreak, vaccine technology has further advanced. Depending on the types of antigens, tumor vaccines can be divided into whole-cell vaccines, peptide vaccines, messenger ribonucleic acid (mRNA) vaccines, recombinant virus vaccines, etc. Although some tumor vaccines have been marketed and achieved certain therapeutic effects, the results of tumor vaccines in clinical trials have been unsatisfactory in the past period. With the maturation of next-generation sequencing (NGS) technology and the continuous development of bioinformatics, dynamic monitoring of the entire process of tumor subpopulation development has become a reality, which has laid a solid foundation for personalized, neoantigen-centered therapeutic tumor vaccines. This article reviews the recent developments of tumor vaccines of different types, starts with lung cancer and summarizes the achievements of tumor vaccines in clinical applications, and provides an outlook for the future development of antigen-centered tumor vaccines.
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Objective: This study aimed to reveal the insomnia burden and relevant influencing factors among informal caregivers (ICs) of hospitalized patients with lung cancer., Methods: A cross-sectional study on ICs of hospitalized patients with lung cancer was conducted from December 31, 2020 to December 31, 2021. ICs' burden was assessed using the Caregiver Reaction Assessment (CRA), Hospital Anxiety and Depression Scale (HADS), and Insomnia Severity Index (ISI). Linear and logistic regression models were used to identify the influencing factors., Results: Among 289 ICs of hospitalized patients with lung cancer, 83 (28.72%), 53 (18.34%), and 14 (4.84%) ICs experienced mild, moderate, and severe insomnia, respectively. The scores concerning self-esteem, lack of family support, financial problems, disturbed schedule, and health problems were 4.32 ± 0.53, 2.24 ± 0.79, 2.84 ± 1.14, 3.63 ± 0.77, and 2.44 ± 0.95, respectively. ICs with higher Activities of Daily Living Scale (ADLS) scores were associated with a lower risk of insomnia, with an odd ratio ( OR ) and 95% confidence interval ( CI ) of 0.940 (0.898-0.983). Among the ICs, female gender ( OR = 2.597), alcohol consumption ( OR = 3.745), underlying medical conditions ( OR = 11.765), long-term caregiving experience ( OR = 37.037), and higher monthly expenses ( OR = 5.714) were associated with a high risk of insomnia., Conclusion: Of the hospitalized patients with lung cancer, 51.9% experienced insomnia. Patients' ADL, ICs gender, alcohol consumption, underlying medical conditions, caregiving duration, and monthly expenses were influencing factors. Therefore, prompt screening and early intervention for ICs of patients with lung cancer is necessary., (Copyright © 2023 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

This study aimed to investigate the roles of METTL3, a regulator of m6A, in NSCLC. RT-qPCR was applied to determine mRNA of m6A-associated genes and SFRP2, and western blot were used for ZEB1 and MMP9 protein expression. Total m6A level was measured using methylated RNA immunoprecipitation (MeRIP) assay, and RIP was used to access m6A level of SFRP2. Cellular behaviors were detected using CCK-8 and tranwell assays. Xenograft assays were conducted to further verify the roles of METTL3 and SFRP2 in NSCLC. The expression level of METTL3 was higher in NSCLC than normal controls. However, downregulation of METTL3 restrained the proliferation, migration and invasion of NSCLC cells. Enhanced expression of METTL3 caused the inverse consequences. Moreover, SFRP2 was found to be negatively regulated by METTL3. Intriguingly, the anti-tumor functions of METTL3 knockdown in the phenotype of NSCLC cells and xenograft mice were overturned by inhibition of SFRP2. Silencing METTL3 resulted in the enhanced stability of SFRP2. Finally, downregulation of SFRP2 induced by METTL3 activated the Wnt/β-catenin signaling pathway in NSCLC. METTL3 acted as an oncogene in the pathogenesis of NSCLC via suppressing SFRP2 to activate Wnt/β-catenin signaling pathway, indicating that METTL3 might be a promising predictor in NSCLC., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Anaplastic lymphoma kinases (ALK) tyrosine kinase inhibitors (TKIs) are effective and safe targeted therapies used in advanced ALK-positive non-small cell lung cancers (NSCLC). However, ALK-TKIs associated cardiovascular toxicities in patients with ALK-positive NSCLCremain incompletely characterized. We conducted the first meta-analysis to investigate this., Research Design and Methods: To determine the cardiovascular toxicities associated with these agents, we carried out a meta-analysis comparing ALK-TKIs with chemotherapy and a meta-analysis comparing crizotinib with other ALK-TKIs. Statistical analysis was conducted to calculate the RRs and 95% confidence intervals (CIs) by using either random effects or fixed-effect models according to the heterogeneity of the included studies., Results: A total of 11 studies (2855 patients) were included. ALK-TKIs ranked to have more severe cardiovascular toxicities than chemotherapy (RR 5.03, 95% CI 1.97-12.84, P = 0.0007) . Compared with other ALK-TKIs, increased risks of cardiac disorders and VTEs associated with crizotinib were found (cardiac disorders RR 1.75, 95% CI 1.07-2.86, P = 0.03; risk of VTEs RR 3.97, 95% CI 1.69-9.31, P = 0.002; respectively)., Conclusion: ALK-TKIs were associated with higher risks of cardiovascular toxicities. Special attention should be given to the risks of cardiac disorders and VTEs related to crizotinib therapy.

EGFR exon 20 insertion (20ins)-positive non-small-cell lung cancer (NSCLC) is an uncommon disease with limited therapeutic options and dismal prognosis. Here we report the activity, tolerability, potential mechanisms of response and resistance for dual targeting EGFR 20ins with JMT101 (anti-EGFR monoclonal antibody) plus osimertinib from preclinical models and an open label, multi-center phase 1b trial (NCT04448379). Primary endpoint of the trial is tolerability. Secondary endpoints include objective response rate, duration of response, disease control rate, progression free survival, overall survival, the pharmacokinetic profile of JMT101, occurrence of anti-drug antibodies and correlation between biomarkers and clinical outcomes. A total of 121 patients are enrolled to receive JMT101 plus osimertinib 160 mg. The most common adverse events are rash (76.9%) and diarrhea (63.6%). The confirmed objective response rate is 36.4%. Median progression-free survival is 8.2 months. Median duration of response is unreached. Subgroup analyses were performed by clinicopathological features and prior treatments. In patients with platinum-refractory diseases (n = 53), confirmed objective response rate is 34.0%, median progression-free survival is 9.2 months and median duration of response is 13.3 months. Responses are observed in distinct 20ins variants and intracranial lesions. Intracranial disease control rate is 87.5%. Confirmed intracranial objective response rate is 25%., (© 2023. The Author(s).)

Introduction: In CameL phase 3 study (ClinicalTrials.gov: NCT03134872), addition of camrelizumab to first-line chemotherapy significantly improved the progression-free survival in patients with stages IIIB to IV nonsquamous NSCLC. Here, we present outcomes after a minimum follow-up of 43.9 months since last patient randomization., Methods: Eligible patients were randomized 1:1 to 4 to 6 cycles of camrelizumab plus carboplatin and pemetrexed or chemotherapy alone every 3 weeks, followed by maintenance camrelizumab plus pemetrexed or pemetrexed only (n = 205 and 207, respectively). Total camrelizumab exposure was up to 2 years., Results: As of January 31, 2022, camrelizumab plus chemotherapy exhibited substantially improved overall survival over chemotherapy alone (median, 27.1 versus 19.8 mo; hazard ratio = 0.72 [95% confidence interval: 0.57-0.92]). In the chemotherapy-alone group, 95 patients (45.9%) crossed over to camrelizumab monotherapy. After adjustment for crossover, the survival benefit with camrelizumab plus chemotherapy was more pronounced (adjusted hazard ratio = 0.55 [95% confidence interval: 0.42-0.71]). In camrelizumab plus chemotherapy group, 33 patients completed 2 years of camrelizumab. Objective response rate was 97.0%, with ongoing responses in 17 of the 32 responses (53.1%), and 93.9% (31 of 33) of the patients were alive at data cutoff. Safety profiles were consistent with the previous report, and no obvious evidence of cumulative toxicity was found with long exposure to camrelizumab., Conclusions: Camrelizumab plus carboplatin and pemetrexed provides long-term survival benefit over chemotherapy, with manageable toxicity and remarkable and durable response in patients receiving 2 years of camrelizumab, further supporting camrelizumab combination as first-line treatment for advanced nonsquamous NSCLC., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Antibody-drug conjugates (ADC) using DNA topoisomerase I inhibitor DXd/SN-38 have transformed cancer treatment, yet more effective ADCs are needed for overcoming resistance. We have designed an ADC class using a novel self-immolative T moiety for traceless conjugation and release of exatecan, a more potent topoisomerase I inhibitor with less sensitivity to multidrug resistance (MDR). Characterized by enhanced therapeutic indices, higher stability, and improved intratumoral pharmacodynamic response, antibody-T moiety-exatecan conjugates targeting HER2, HER3, and TROP2 overcome the intrinsic or treatment resistance of equivalent DXd/SN-38 ADCs in low-target-expression, large, and MDR+ tumors. T moiety-exatecan ADCs display durable antitumor activity in patient-derived xenograft and organoid models representative of unmet clinical needs, including EGFR ex19del/T790M/C797S triple-mutation lung cancer and BRAF/KRAS-TP53 double-mutant colon cancer, and show synergy with PARP/ATR inhibitor and anti-PD-1 treatment. High tolerability of the T moiety-exatecan ADC class in nonhuman primates supports its potential to expand the responding patient population and tumor types beyond current ADCs., Significance: ADCs combining a novel self-immolative moiety and topoisomerase I inhibitor exatecan as payload show deep and durable response in low-target-expressing and MDR+ tumors resistant to DXd/SN-38 ADCs without increasing toxicity. This new class of ADCs has the potential to benefit an additional patient population beyond current options. See related commentary by Gupta et al., p. 817. This article is highlighted in the In This Issue feature, p. 799., (©2023 American Association for Cancer Research.)

Background: Primary mediastinal germ cell tumor (PMGCT) is a rare but occasionally highly invasive mediastinal tumor. At present, there are few related disease special survival (DSS) studies on PMGCT, rare large data analysis, and uncommon DSS prognostic models. This study was to investigate the prognostic factors of DSS of the PMGCT patients, and build a simple and effective nomogram to predict the DSS prognosis in patients with PMGCT., Methods: Retrospective clinicopathological data of 325 patients with PMGCT from 1975 to 2019 were extracted from Surveillance, Epidemiology, and End Results (SEER) database. The Kaplan-Meier method along with the Log-rank test were utilized to estimate the DSS. Cox proportional hazard regression model was used to screen the independent risk factors affecting prognosis, from which an individualized nomogram was constructed to predict 3-yr, 5-yr and 8-yr DSS of patients with PMGCT. The prediction accuracy of the model is evaluated by receiver operating characteristic (ROC) curve, correction curve and decision curve analysis (DCA) curve., Results: The 3-yr, 5-yr and 8-yr survival rates of PMGCT were 84.6%, 83.6% and 83.3%, respectively. Univariate analysis showed that histology, surgery, age, tumor size, metastasis and stage could affect the prognosis of PMGCT. Multivariate analysis showed that histology, surgery, age and tumor size were independent risk factors for the prognosis of PMGCT patients, and the nomogram was constructed using these independent risk factors. The area under the curve (AUC) of ROC curve was 0.824. The results of the correction curves of 3-yr, 5-yr and 8-yr survival time and DCA, indicated that there was a good consistency between the predicted results of the nomogram evaluation and the real results., Conclusions: Patients with histological classification of seminoma in PMGCT have a better prognosis than patients with non-seminoma. The prognosis of patients with over the age of 40 yr, tumor size ≥15 cm and without surgical treatment was even worse. The nomogram model can accurately and intuitively predict the DSS of patients with PMGCT.

In the era of precision medicine, with the deepening of the research on malignant tumor driving genes, clinical oncology has fully entered the era of targeted therapy. For non-small-cell lung cancer (NSCLC), the development of targeted drugs targeting driver genes, such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), has successfully opened up a new model of targeted therapy. At present, proto-oncogene rearranged during transfection (RET) fusion gene is an important novel oncogenic driving target, and specific receptor tyrosine kinase inhibitors (TKIs) targeting RET fusion have been approved. This article will review the latest research about the molecular characteristics, pathogenesis, detection, and clinical treatment strategies of RET rearrangements especially in China.

Introduction: The Pathology Committee of the International Association for the Study of Lung Cancer (IASLC) proposed a new histological grading system based on the combination of predominant and high-grade patterns in 2020., Materials and Methods: Pathological sections from 631 patients with stage I-III invasive lung adenocarcinoma were reviewed. We then determined the histological grade according to the new grading system and confirmed the pathological features that included the filigree micropapillary and discohesive growth pattern. Applying of the novel IASLC grading system in prognosis stratification was verified and the clinical significance of the pathological characteristics was explored., Results: Cox multivariable analysis revealed that in the stage I-III invasive lung adenocarcinoma, the IASLC grading system was significantly associated with disease-free survival (DFS) [hazard ratio (HR) = 1.419; 95 % confidence interval (CI): 1.040-1.937; P = 0.027] and overall survival (OS) (HR = 1.899; 95 % CI: 1.168-3.087; P = 0.010). In patients with IASLC Grades 1 and 2, the simultaneous presence of filigree micropapillary and discohesive growth pattern was significantly correlated with DFS (HR = 1.899; 95 % CI:1.168-3.087; P = 0.010). However, the filigree micropapillary and discohesive growth pattern did not affect the OS (HR = 2.786; P = 0.317). The competitive risk model revealed that in the stage I cohort, the simultaneous presence of filigree micropapillary and discohesive growth pattern was a risk factor for recurrence and metastasis [sub- distribution HR (SHR) = 1.987; 95 %CI: 1.122-3.518; P = 0.019]., Conclusion: Our study verified that the new prognostic stratification system was an effective stratification tool. Filigree micropapillary and discohesive growth pattern may also be risk factors for DFS, postoperative recurrence and metastasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Although programmed cell death 1 (PD-1) blockade plus chemotherapy can significantly prolong the progression-free survival (PFS) and overall survival (OS) in first-line settings in patients with driver-negative advanced non-small-cell lung cancer (NSCLC), the predictive biomarkers remain undetermined. Here, we investigated the predictive value of tumor immune microenvironmental marker expression to characterize the response features to PD-1 blockade plus chemotherapy., Methods: Tumor tissue samples at baseline were prospectively collected from 144 locally advanced or metastatic NSCLC patients without driver gene alterations who received camrelizumab plus chemotherapy or chemotherapy alone. Tumor immune microenvironmental markers, including PD-1 ligand (PD-L1), CD8, CD68, CD4 and forkhead box P3, were assessed using multiplex immunofluorescence (mIF) assays. Kaplan-Meier curves were used to determine treatment outcome differences according to their expression status. Mutational profiles were compared between tumors with distinct expression levels of these markers and their combinations., Results: Responders had significantly higher CD8/PD-L1 (P = 0.015) or CD68/PD-L1 co-expression levels (P = 0.021) than non-responders in the camrelizumab plus chemotherapy group, while no difference was observed in the chemotherapy group. Patients with high CD8/PD-L1 or CD68/PD-L1 co-expression level was associated with significantly longer PFS (P = 0.002, P = 0.024; respectively) and OS (P = 0.006, P = 0.026; respectively) than those with low co-expression in camrelizumab plus chemotherapy group. When comparing survival in the camrelizumab plus chemotherapy with chemotherapy by CD8/PD-L1 co-expression stratification, significantly better PFS (P = 0.003) and OS (P = 0.032) were observed in high co-expression subgroups. The predictive value of CD8/PD-L1 and CD68/PD-L1 co-expression remained statistically significant for PFS and OS when adjusting clinicopathological features. Although the prevalence of TP53 or KRAS mutations was similar between patients with and without CD8/PD-L1 or CD68/PD-L1 co-expression, the positive groups had a significantly higher proportion of TP53/KRAS co-mutations than the negative groups (both 13.0% vs. 0.0%, P = 0.023). Notably, enriched PI3K (P = 0.012) and cell cycle pathway (P = 0.021) were found in the CD8/PD-L1 co-expression group., Conclusion: Tumor immune microenvironmental marker expression, especially CD8/PD-L1 or CD68/PD-L1 co-expression, was associated with the efficacy of PD-1 blockade plus chemotherapy as first-line treatment in patients with advanced NSCLC., (© 2022 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Background: Treatment options for Chinese patients with locally advanced or metastatic squamous-cell non-small-cell lung cancer (sqNSCLC) after failure of first-line chemotherapy are limited. This study (ORIENT-3) aimed to evaluate the efficacy and safety of sintilimab versus docetaxel as second-line treatment in patients with locally advanced or metastatic sqNSCLC., Methods: ORIENT-3 was an open-label, multicenter, randomized controlled phase 3 trial that recruited patients with stage IIIB/IIIC/IV sqNSCLC after failure with first-line platinum-based chemotherapy. Patients were randomized in a 1:1 ratio to receive either 200 mg of sintilimab or 75 mg/m 2 of docetaxel intravenously every 3 weeks, stratified by the Eastern Cooperative Oncology Group performance status. The primary endpoint was overall survival (OS) in the full analysis set (FAS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety., Results: Between August 25, 2017, and November 7, 2018, 290 patients were randomized. For FAS, 10 patients from the docetaxel arm were excluded. The median OS was 11.79 (n = 145; 95% confidence interval [CI], 10.28-15.57) months with sintilimab versus 8.25 (n = 135; 95% CI, 6.47-9.82) months with docetaxel (hazard ratio [HR]: 0.74; 95% CI, 0.56-0.96; P = 0.025). Sintilimab treatment significantly prolonged PFS (median 4.30 vs. 2.79 months; HR: 0.52; 95% CI, 0.39-0.68; P < 0.001) and showed higher ORR (25.50% vs. 2.20%, P < 0.001) and DCR (65.50% vs. 37.80%, P < 0.001) than the docetaxel arm. The median DoR was 12.45 (95% CI, 4.86-25.33) months in the sintilimab arm and 4.14 (95% CI, 1.41-7.23) months in the docetaxel arm (P = 0.045). Treatment-related adverse events of grade ≥ 3 were reported in 26 (18.1%) patients in the sintilimab arm and 47 (36.2%) patients in the docetaxel arm. Exploratory biomarker analysis showed potential predictive values of expression levels of two transcription factors, including OVOL2 (HR: 0.35; P < 0.001) and CTCF (HR: 3.50; P < 0.001)，for sintilimab treatment., Conclusions: Compared with docetaxel, sintilimab significantly improved the OS, PFS, and ORR of Chinese patients with previously treated locally advanced or metastatic sqNSCLC., (© 2022 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Background: The efficacy of immune checkpoint inhibitors (ICIs) in pretreated EGFR -mutated non-small cell lung cancer (NSCLC) patients is controversial. We conducted this multicenter retrospective study to examine the efficacy of ICIs in a real world setting., Patients and Methods: We collected 116 consecutive NSCLC patients with sensitive EGFR mutations who received ICIs alone or in combination after failure to respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs), and 99 patients were included for final analysis. The impacts of ICIs on the patients' objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were assessed. The relationships between outcomes and clinical characteristics were analyzed., Results: The ORR in patients with target lesions was 31.25% (95% CI: 22.18-41.52), and the DCR in all patients was 65.66% (95% CI: 55.44-74.91). The overall median PFS was 5.0 months (95% CI: 3.0-6.6), and the median OS was 15.9 months (95% CI: 10.8-23.8). The outcomes were better in patients receiving combination therapy with ECOG scores of 0-1 and no more than 2 lines of prior therapy, with a median PFS of 7.4 months (95% CI: 3.0-13.3) and a median OS of 29.0 months (95% CI: 11.7-NE). Primary EGFR mutation type and treatment mode were found to have a notable impact on clinical outcomes. Both median PFS and OS in patients with EGFR L858R mutation were significantly shorter than those in patients with EGFR exon 19 deletion (19del) (PFS: 2.5 versus 6.7 months, HR: 1.80, log-rank P =0.011; OS: 9.8 versus 26.9 months, HR: 2.48, log-rank P =0.002). Patients receiving combination therapy had notably longer median PFS and OS than those receiving monotherapy (PFS: 5.2 versus 3.0 months, HR: 0.54, log-rank P =0.020; OS: 19.0 versus 7.4 months, HR: 0.46, log-rank P =0.009)., Conclusions: Our study suggests that ICI-based combination therapy is a potential strategy for EGFR -mutated NSCLC patients after EGFR-TKI failure. The efficacy may differ according to EGFR subtypes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hu, Huang, Wang, Li, Yang, Fu, Du, Zhao, Li, Ma and Hu.)

Background: Pain is a fearful yet common symptom among lung cancer patients. This multicenter, cross-sectional study was conducted to examine the current status of pain prevalence and management in lung cancer patients in northern China., Methods: A total of 18 hospitals across northern China were selected. Patients with primary lung cancer who visited the outpatient clinic or were admitted in the wards on a preplanned day were invited to complete a questionnaire. Meanwhile, physicians who had experience of treating primary lung cancer patients were also surveyed., Results: A total of 533 patients and 197 physicians provided valid responses to the survey, of which 45.4% (242/533) of patients reported pain during the course of disease and 24.2% (129/533) of patients had experienced pain within the past 24 h. The mean average pain intensity by the brief pain inventory was 3.47 ± 1.55. The binary logistic regression analysis showed female gender and stage IV disease were significantly associated with the presence of pain. A total of 74.4% (96/129) of patients reporting pain within 24 h were taking analgesics. The most common reason for patients not using analgesics was that the pain was tolerable (48.2%), while the most common barriers to prescribing opioids as reported by physicians were fear of adverse reactions (43.7%) and fear of addiction (43.1%)., Conclusion: Despite recognition of the importance of pain control by most physicians and an improvement in cancer pain management, inadequate treatment of cancer pain still exists in lung cancer patients in northern China. High-quality pain education for both patients and physicians is needed in the future., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Chemotherapy in combination with immune checkpoint inhibitor (ICI) or bevacizumab has demonstrated a superior effect for non-squamous non-small cell lung cancer (NS-NSCLC). There are still few randomized controlled trials (RCTs) investigating the differences between ICI plus chemotherapy (ICI-chemotherapy) and bevacizumab plus chemotherapy (Bev-chemotherapy) in first-line treatment of NS-NSCLC. We identified RCTs in databases and conference abstracts presented at international conferences by Sep 1, 2021. Bayesian network meta-analysis was performed using randomized effect consistency model to estimate hazard ratio (HR) and odds ratio (OR). The outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade ≥ 3 treatment-related adverse events (TRAEs). Fifteen RCTs (17 articles) of 6561 advanced NS-NSCLC patients receiving ICI-chemotherapy, Bev-chemotherapy, or chemotherapy at first-line were eligible for analysis. NMA results showed that first-line ICI-chemotherapy prolonged OS (HR 0.79, 0.66-0.94) in patients with advanced NS-NSCLC compared with Bev-chemotherapy, while no differences were in PFS, ORR, and grade ≥ 3 TRAEs (p > 0.05). Ranking plots suggested that ICI-chemotherapy had the most probability to offer the best OS (probability 0.993), PFS (probability 0.658), and ORR (probability 0.565), and Bev-chemotherapy had the most risks of grade ≥ 3 TRAEs (probability 0.833). Therefore, our findings showed that first-line ICI-chemotherapy was associated with better OS than Bev-chemotherapy in patients with advanced NS-NSCLC, and more clinical trials are warranted to confirm these results., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Osimertinib is the standard first-line treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation. Resistance to osimertinib remains a clinical challenge. However, the optimal therapy for these patients is still controversial. In this study, we aimed to assess the efficacy and safety of immunotherapy plus chemotherapy (IO+C) compared with chemotherapy (C) in NSCLC patients after progression on osimertinib., Methods: Advanced NSCLC patients after progression on osimertinib were retrospectively reviewed. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were evaluated between the patients treated with IO+C and C., Results: A total of 40 patients were included in the study. There were 20 patients each in the IO+C group or C group. The ORR was significantly higher in patients in the IO+C group (45% vs. 25%, p < 0.01). The median PFS was 6.4 months for patients in the IO+C group compared to 2.8 months for patients in C group (HR: 0.41, 95% confidence interval [CI]: 0.20-0.82, p < 0.01). The median OS was significantly longer in the IO+C group than the C group (OS: 12.8 vs. 10.5 months, HR: 0.39, 95% CI: 0.19-0.80, p < 0.01). In subgroup analysis, patients of both sexes, age ≤ 65, bone or adrenal metastasis, exon19 del mutation, and third-line treatment obtained more OS benefits from immunotherapy. The safety profile of both groups was comparable., Conclusions: Our study provides the clinical evidence of favoring immunotherapy plus chemotherapy in NSCLC patients after progression on osimertinib., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

WX-0593 (Iruplinalkib) is a novel, highly selective oral ALK and ROS1 tyrosine kinase inhibitor (TKI). In this study, the safety, antitumor activity, and pharmacokinetics of WX-0593 were evaluated in advanced non-small cell lung cancer (NSCLC) patients with ALK or ROS1 rearrangement. In the dose-escalation phase and dose-expansion phase, patients were treated with WX-0593 until disease progression, unacceptable toxicity, or subject withdrawal. In the dose-escalation phase, the primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety assessed by investigators. In the dose-expansion phase, the primary endpoint was objective response rate (ORR) assessed by investigators. Between September 25, 2017 and October 15, 2018, a total of 153 patients received WX-0593 treatment. Two dose-limiting toxicities (DLTs) including one grade 3 QT interval prolonged and one grade 2 chronic heart failure were reported at the dose of 300 mg in one patient. MTD was not reached. Overall, 140 of the 152 (92%) patients experienced treatment-related adverse events (TRAEs) and 35 of the 152 (23%) patients had TRAEs ≥grade 3. The overall ORR was 59.3% (32 of 54) for the dose-escalation phase and 56.6% (56 of 99) for the dose-expansion phase. For patients who were ALK-rearranged and ALK TKI naive, the ORR were 81.0% (17 of 21) in the dose-escalation phase and 76.3% (29 of 38) in the dose-expansion phase, and for patients who previously received crizotinib as the only ALK TKI, the ORR were 38.1% (8 of 21) and 45.7% (21 of 46) for the two phases, respectively. For patients who were ROS1-rearranged, the ORR were 30.0% (3 of 10) in the dose-escalation phase and 44.4% (4 of 9) in the dose-expansion phase. WX-0593 showed favorable safety and promising antitumor activity in advanced NSCLC patients with ALK or ROS1 rearrangement., (© 2022. The Author(s).)

Mutation of BRCA2, a breast cancer susceptibility gene, is associated with the development of breast and ovarian cancer. Olaparib is an oral poly-adenosine diphosphate-ribose polymerase (PARP) inhibitor, which has been proven to treat BRCA-mutated tumors effectively, especially breast and ovarian cancer. Here, we report a case of a germline BRCA2-mutated metastatic lung adenocarcinoma, non-small-cell lung cancer, responded well to olaparib. A 41-year-old man with no history of smoking was diagnosed with advanced lung adenocarcinoma. The patient was treated with bevacizumab, pemetrexed disodium, and cis-platinum in the first-line therapy of 6 months, followed by bevacizumab, Abraxane, and sintilimab treatments for another 6 months. As disease progression was confirmed and the presence of germline BRCA2 mutation, the combinational treatment of olaparib/anlotinib was applied to achieve partial response 1 month later, and the progression-free survival was extended for another 5 months. This study shows metastatic lung adenocarcinoma with BRCA2 mutation could also respond well to PARP inhibitor, broadening the spectrum of BRCA-mutated cancers suitable for olaparib therapy. With acquired resistance to chemotherapy, bevacizumab, and immunotherapy, the patient still gained significant benefits from the targeted therapy., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Anti-PD-1 treatment has shown unprecedented clinical success in the treatment of non-small-cell lung cancer (NSCLC), but the underlying mechanisms remain incompletely understood. Here, we performed temporal single-cell RNA and paired T-cell receptor sequencing on 47 tumor biopsies from 36 patients with NSCLC following PD-1-based therapies. We observed increased levels of precursor exhausted T (Texp) cells in responsive tumors after treatment, characterized by low expression of coinhibitory molecules and high expression of GZMK. By contrast, nonresponsive tumors failed to accumulate Texp cells. Our data suggested that Texp cells were unlikely to be derived from the reinvigoration of terminally exhausted cells; instead, they were accumulated by (1) local expansion and (2) replenishment by peripheral T cells with both new and pre-existing clonotypes, a phenomenon we named clonal revival. Our study provides insights into mechanisms underlying PD-1-based therapies, implicating clonal revival and expansion of Texp cells as steps to improve NSCLC treatment., (© 2021. The Author(s).)

Background: Afatinib has been shown as a suitable option for the treatment of epidermal growth factor receptor mutation-positive (EGFRm+) non-small-cell lung cancer (NSCLC) in randomized controlled trials. However, patients treated in real-world clinical practice, including elderly patients, and those with brain metastases or poor Eastern Cooperative Oncology Group (ECOG) performance statuses, are often excluded from these studies., Objective: To report the final results, with a particular focus on patients enrolled in China, from a prospective phase IIIb, "near real-world" study of afatinib in tyrosine kinase inhibitor (TKI)-naïve Asian patients with EGFRm+ NSCLC., Patients and Methods: NCT01953913 was conducted at 34 centers across Asia. Entry criteria were broad to reflect real-world settings. Patients received afatinib 40 mg/day until tumor progression, lack of clinical benefit, or poor tolerability. Assessments included safety, time to symptomatic progression (TTSP), and progression-free survival (PFS)., Results: 541 patients were treated, of whom 412 were enrolled in China. Dose reductions were implemented in 28.7% of patients overall, and 17.7% of patients from China. Safety findings were consistent with phase III studies of afatinib. Median TTSP in all patients was 14.0 months (95% CI 12.9-15.9), and median PFS was 12.1 months (95% CI 11.0-13.6). Median TTSP (13.8 months, 95% CI 12.7-16.1) and PFS (11.4 months, 95% CI 10.9-13.7) were similar in patients from China to the overall population. Among patients from China who had dose reductions, TTSP was numerically longer than in those who did not (16.4 vs. 13.8 months; P = 0.0703), while PFS was significantly longer (13.9 vs. 11.1 months; P = 0.0275). Among patients from China with brain metastases, TTSP was numerically shorter than in those without (11.0 vs. 14.4 months; P = 0.0869), whereas PFS was significantly shorter (9.2 vs. 12.9 months; P = 0.0075)., Conclusions: Safety data for afatinib when used in a "near real-world" setting in patients with EGFRm+ NSCLC was consistent with the known safety profile of afatinib. Supporting efficacy data of afatinib were provided in all patients, and in those enrolled in China. Tolerability-guided afatinib dose reduction allowed patients to remain on treatment and continue to experience clinical benefit., Trial Registration Number and Date of Registration: NCT01953913 (1 October 2013)., (© 2021. The Author(s).)

Small cell lung cancer (SCLC) is a highly malignant tumor which is eventually refractory to any treatment. Intratumoral heterogeneity (ITH) may contribute to treatment failure. However, the extent of ITH in SCLC is still largely unknown. Here, we subject 120 tumor samples from 40 stage I-III SCLC patients to multi-regional whole-exome sequencing. The most common mutant genes are TP53 (88%) and RB1 (72%). We observe a medium level of mutational heterogeneity (0.30, range 0.0~0.98) and tumor mutational burden (TMB, 10.2 mutations/Mb, range 1.1~51.7). Our SCLC samples also exhibit somatic copy number variation (CNV) across all patients, with an average CNV ITH of 0.49 (range 0.02~0.99). In terms of mutation distribution, ITH, TMB, mutation clusters, and gene signatures, patients with combined SCLC behave roughly the same way as patients with pure SCLC. This condition also exists in smoking patients and patients with EGFR mutations. A higher TMB per cluster is associated with better disease-free survival while single-nucleotide variant ITH is linked to worse overall survival, and therefore these features may be used as prognostic biomarkers for SCLC. Together, these findings demonstrate the intratumoral genetic heterogeneity of surgically resected SCLC and provide insights into resistance to treatment., (© 2021. The Author(s).)

Abstract: There has been no effective biomarker for small cell lung cancer (SCLC) patients with first-line immune checkpoint inhibitors (ICIs) treatment. The predictive value of neuron-specific enolase (NSE) in this cohort remains unclear.The medical records of 254 consecutive SCLC patients receiving programmed cell death receptor-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors were compiled from January 2015 to October 2020 in Chinese PLA General Hospital. Survival analysis was performed to explore the prognostic role of NSE at baseline and 3 weeks post treatment.One hundred two advanced SCLC patients treated with first-line PD-1/PD-L1 inhibitors were enrolled in this study. Normal baseline NSE levels were correlated with significantly prolonged progression-free survival (PFS, median: 8.7 vs 4.7 months, P = .006) and overall survival (OS, median: 23.8 vs 15.2 months, P = .014) compared with elevated baseline NSE levels, so as for normal NSE levels at 3 weeks with prolonged PFS (median PFS: 8.4 vs 4.5 months, P = .0002) and OS (median OS: 23.3 vs 7.4 months, P < .0001). Intriguingly, elevated NSE levels at 3 weeks were associated with shorter PFS (median PFS: 4.5 vs 5.8 months, P = .04) and OS (median OS: 5.5 vs 14.7 months, P < .0001) compared with normal NSE levels in the elevated baseline NSE subgroup. Most subgroup analyses stratified by clinical characteristics confirmed the prognostic value of baseline NSE level.Elevated NSE levels at baseline and 3 weeks were associated with worse prognosis in advanced SCLC patients receiving first-line ICIs treatment. NSE level might be applied as a useful prognostic tool for SCLC patients with immunotherapy., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Microparticles (MPs) are extracellular vesicles that are associated with cancer development and progression. Advanced non-small cell lung cancer (NSCLC) still shows disease progression after multiple lines of treatment. Therefore, the objective of this study was to explore the correlation between circulating MPs and disease progression in advanced NSCLC, and to find a new method for concise and rapid determination of disease progression., Methods: Patients with advanced NSCLC admitted to hospital between October 2019 and October 2020 were included and divided into objective remission (OR) and progressive disease (PD) groups. The morphology of MPs was observed using transmission electron microscopy. The circulating total MPs, neutrophil MPs (NMPs), and platelet MPs (PMPs) before and after treatment were detected by flow cytometry, and a predictive model for disease progression in advanced NSCLC was developed., Results: Eighty-six patients were included; 60 in the OR group and 26 in the PD group. There was no significant difference in total MPs, NMPs, or PMPs at baseline between the two groups. After treatment, total MPs, NMPs, and PMPs were significantly higher in the PD than those in the OR group. Multivariate regression analysis showed that post-treatment NMPs≥160 events/μL(OR,3.748;95%CI,1.147-12.253,p = 0.029), PMPs≥80 events/μL(OR,10.968;95%CI,2.973-40.462,p < 0.0001) and neutrophil/lymphocyte ratio (NLR) ≥3.3 (OR,4.929;95%CI,1.483-16.375,p = 0.009) were independently associated with progression of advanced NSCLC. Post-treatment NMPs and PMPs combined with NLR were used to build a predictive model for progression of advanced NSCLC. The area under the curve was 0.825 (95%CI,0.715-0.934, p < 0.0001), optimal cut-off value was 16, sensitivity was 80.8%, and specificity was 88.3%., Conclusion: NMPs and PMPs are associated with progression of advanced NSCLC. The predictive model for progression of advanced NSCLC, established combining NMPs, PMPs, and NLR, can screen out 80.8% of patients with PD. This is helpful for real-time accurate, concise and rapid assessment of disease progression and timely adjustment of drug therapy., Trial Registration: Chinese Clinical Trial Registry, ChiCTR1800020223 . Registered 20 December 2018, http://www.chictr.org.cn/index.aspx ., (© 2021. The Author(s).)

Background: Anlotinib significantly extended progression-free survival (PFS) and overall survival (OS) in small-cell lung cancer (SCLC) as third or later line treatment., Methods: In this study, we retrospectively analyzed the efficacy and safety of anlotinib in the clinical practice and aimed to identify risk factors for predicting the clinical benefit of anlotinib in SCLC patients. 29 SCLC patients treated with anlotinib monotherapy or combination therapy as second or later line treatment were included. PFS, OS, objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were analyzed., Results: In whole patients, the median PFS was 2.1 months (95% confidence interval (CI): 1.1-3.2 months); The ORR and DCR were 10.3% and 48.3%, respectively; The median OS was 7.2 months (95%CI: 3.2-11.2 months). Cox regression analysis demonstrated that response to first-line treatment was the independent risk factor for PFS. The ORR (20.0% vs. 0%) and DCR (53.3% vs. 42.9%) were promoted in patients treated with anlotinib combination therapy comparing to anlotinib monotherapy. The most common AEs were hoarseness, fatigue, decreased appetite, oral mucositis, and anemia. No treatment-related AEs graded 3 or more., Conclusion: Anlotinib is an effective option for SCLC patients with tolerable toxicity as second or later line treatment. Patients sensitive to first-line treatment had longer PFS when treated with anlotinib. Anloitnib combined with other therapy increased the efficacy without adding toxicity., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: By implementing dynamic circulating tumor DNA (ctDNA) analysis, we explored the impact of TP53 mutations on tumor evolution and resistance mechanisms to ensartinib in patients with ALK-positive NSCLC., Methods: In a multicenter phase 2 trial, patients with ALK-positive NSCLC who progressed on crizotinib were treated with ensartinib. Blood samples for ctDNA analysis were collected at baseline, cycle 3 day 1, and progression disease (PD) and analyzed with a 212-gene panel., Results: A total of 440 samples were collected from 168 patients. Baseline TP53 mutations (20.2%) significantly correlated with inferior progression-free survival (4.2 mo versus 11.7 mo, p < 0.0001). Patients with TP53 mutations had higher mutation load than those without TP53 mutations at baseline (13.79 ± 3.72 versus 4.67 ± 0.39, p < 0.001). Although there was no significant difference in mutation load between these groups at cycle 3 day 1 (5.89 ± 2.25 versus 3.72 ± 0.62, p = 0.425), patients with mutated TP53 developed more mutations at PD (7.07 ± 1.25 versus 3.20 ± 0.33, p = 0.003). Frequency and abundance of secondary ALK mutations G1269A, G1202R, and E1210K increased markedly at PD than baseline. In patients without secondary ALK mutations, we identified ALK-independent resistance mechanisms including bypass signaling activation, downstream effector protein reactivation, epithelial-mesenchymal transformation, and epigenetic dysregulation., Conclusions: Our study highlighted the advantage of ctDNA analysis for monitoring tumor evolution. TP53 mutations promoted genetic evolution and accelerated occurrence of resistance. We also unveiled ALK-dependent resistance mechanisms, mainly by G1269A, G1202R, and E1210K mutations, and ALK-independent resistance mechanisms to ensartinib., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer. The systemic antitumor therapy of advanced NSCLC has undergone renovations of chemotherapy, targeted therapy and immunotherapy, which results in greatly improved survival for patients with advanced NSCLC. Immune checkpoint inhibitors (ICIs), especially targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), has changed the treatment paradigm of NSCLC. ICIs have become the standard treatment for advanced NSCLC without epidermal growth factor receptor(EGFR) mutation or anaplastic lymphomakinase(ALK) translocation in the first- or second-line setting, and for locally advanced NSCLC following concurrent radiotherapy and chemotherapy. ICIs are also promising in adjuvant/neoadjuvant therapy. More and more ICIs have been approved domestically for the treatment of NSCLC. Led by the NSCLC expert committee of Chinese Society of Clinical Oncology (CSCO), this consensus was developed and updated based on thoroughly reviewing domestic and foreign literatures, clinical trial data, systematic reviews, experts' discussion and the consensus(2019 version). This consensus will aid domestic clinicians in the treatment of NSCLC with ICIs.
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Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII) have been identified as predictors of treatment response in a variety of cancers. We conducted a retrospective analysis to investigate the usefulness of NLR, PLR and SII at baseline and at 6 weeks post-treatment as predictors of response to anti-PD-1/PD-L1 antibody treatment in small cell lung cancer (SCLC). Data of 41 SCLC patients receiving immunotherapy as second- or later-line treatment were analyzed. The overall median progression-free survival (PFS) was 5.1 months (95% CI 3.2-6.2). The median PFS was significantly longer in patients with NLR < 5 than in patients with NLR ≥ 5 at 6 weeks post treatment (HR = 0.29, 95%CI 0.09-0.96, P = 0.04). However, median PFS was comparable between patients with NLR < 5 and patients with NLR ≥ 5 at baseline (HR = 0.75, 95% CI 0.24-2.26, P = 0.56). The median PFS was similar between patients with PLR < 169 and those with PLR ≥ 169 at baseline (HR = 0.67, 95% CI 0.25-1.80, P = 0.43) and at 6 weeks post treatment (HR = 0.69, 95% CI 0.25-1.86, P = 0.46). No statistically different PFS was found between patients with SII < 730 and those with SII ≥ 730 at baseline (HR = 0.70, 95% CI 0.26-1.89, P = 0.48) and at 6 weeks post treatment (HR = 0.38, 95% CI 0.013-1.09, P = 0.07). In conclusion, NLR at 6 weeks after start of treatment appears to be a biomarker of response in the early phase in SCLC patients treated with anti-PD-1/PD-L1 antibodies as second- or later-line treatment.

Background: Immunotherapy combined with chemotherapy has been shown to be efficacious as treatment for advanced non-squamous non-small-cell lung cancer (NSCLC) without targetable genetic aberrations; however, there is scarce evidence of the effectiveness of the combinations in the Asian population. We evaluated camrelizumab plus chemotherapy against non-squamous NSCLC in China., Methods: We did a randomised, open-label, multicentre, phase 3 trial (CameL) in 52 hospitals in China for patients with non-squamous NSCLC without EGFR and ALK alteration. Eligible patients were aged 18-70 years and had no previous systemic chemotherapy, Eastern Cooperative Oncology Group performance status of 0 or 1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (version 1.1). Patients were randomly assigned (1:1) to receive 4-6 cycles of carboplatin (area under curve 5 mg/mL per min) plus pemetrexed (500 mg/m 2 ) with or without camrelizumab (200 mg) every 3 weeks, followed by maintenance therapy with camrelizumab plus pemetrexed or pemetrexed alone. Medication was administered intravenously on day 1 of each 3-week treatment cycle. Randomisation was done using a centralised interactive web-response system with the block size randomly generated as four or six and stratified by sex and smoking history. The two primary endpoints were progression-free survival per blinded independent central review, in all patients and in patients who were PD-L1 positive. Primary analysis was done in the full analysis set that included all randomly assigned patients who received at least one dose of the study treatment. Herein, due to the primary endpoint being met at the interim analysis, we reported the findings of prespecified interim analysis, which only included confirmatory statistical testing for progression-free survival in all patients. Safety was assessed in the as-treated population. This study is registered with ClinicalTrials.gov, NCT03134872 (follow-up is ongoing)., Findings: Between May 12, 2017, and June 6, 2018, of the 419 patients who were randomly assigned, seven did not receive assigned treatment and 412 received either camrelizumab plus chemotherapy (n=205) or chemotherapy alone (n=207). At interim analysis, median follow-up duration was 11·9 months (IQR 9·0-14·9). Progression-free survival in this interim analysis was significantly prolonged with camrelizumab plus chemotherapy than with chemotherapy alone (median 11·3 months [95% CI 9·6-15·4] vs 8·3 months [6·0-9·7]; hazard ratio 0·60 [0·45-0·79]; one-sided p=0·0001). Most common grade 3 or worse treatment-related adverse events were decreased neutrophil count (78 [38%] patients in the camrelizumab plus chemotherapy group vs 63 [30%] patients in the chemotherapy alone group), decreased white blood cell count (40 [20%] vs 30 [14%]), anaemia (38 [19%] vs 23 [11%]), and decreased platelet count (34 [17%] vs 24 [12%]). Serious treatment-related adverse events occurred in 74 (36%) patients in the camrelizumab plus chemotherapy group and 27 (13%) patients in the chemotherapy alone group., Interpretation: The primary endpoint was met at the interim analysis, showing a statistically significant and clinically meaningful improvement in progression-free survival with camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in all patients, supporting camrelizumab plus carboplatin and pemetrexed as a first-line treatment option for Chinese patients with advanced non-squamous NSCLC without EGFR and ALK alterations. The trial is being continued to collect long-term outcomes in all patients and carry out confirmatory statistical testing for progression-free survival in the PD-L1-positive population., Funding: Jiangsu Hengrui Medicine., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Anti-programmed cell death protein 1 or its ligand (anti-PD-1/L1) monotherapy has become the standard second-line treatment in advanced lung adenocarcinoma. However, the strategy treatment of anti-PD-1/L1 plus anti-angiogenesis therapy has not been evaluated. We conducted this retrospective study to assess the efficacy and safety of anti-PD-1/L1 plus anti-angiogenesis therapy in patients with advanced lung adenocarcinoma in the second-line or later setting., Methods: Patients with advanced lung adenocarcinoma who received anti-PD-1/L1 plus anti-angiogenesis therapy or anti-PD-1/L1 monotherapy in the second-line or later treatment from March 2015 to May 2019 in PLA General Hospital were retrospectively analyzed. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were assessed. Multivariate analyses of PFS and OS were performed with Cox proportional hazard regression models., Results: Seventy-four patients were included in our study. Twenty-five patients were treated with anti-PD-1/L1 plus anti-angiogenesis therapy, and forty-nine patients were treated with anti-PD-1/L1 monotherapy. The disease control rate (DCR) was higher in the anti-PD-1/L1 plus anti-angiogenesis group than in the anti-PD-1/L1 monotherapy group (92.0% vs. 46.9%, P = 0.0004). The median progression-free survival (PFS) was 5.1 months vs. 2.0 months (HR 0.551 [95% confidence interval 0.337-0.902], P = 0.002) and median overall survival (OS) was 14.3 months vs. 8.4 months (HR 0.549 [95% CI 0.305-0.990], P = 0.046), respectively. Multivariate Cox proportional hazard regression models showed that anti-PD-1/L1 plus anti-angiogenesis group had prolonged PFS (HR 0.541 [95% CI 0.298-0.981], P = 0.033). The incidences of grade 3/4 adverse events were 12% (3/25) in anti-PD-1/L1 plus anti-angiogenesis group and 6% (3/49) in anti-PD-1/L1 monotherapy group., Conclusion: Compared with anti-PD-1/L1 monotherapy, anti-PD-1/L1 plus anti-angiogenesis therapy could significantly improve the clinical response and bring longer PFS and OS in patients with advanced lung adenocarcinoma who had failed first-line or later treatment. Further prospective studies are needed to validate our findings.

Objective: To evaluate the efficacy of rapid on-site cytological evaluation (ROSE) in determining specimen adequacy and diagnostic accuracy in the interventional diagnosis of lung lesions., Methods: This retrospective study included 127 consecutive cases of lung lesions, which were sampled by bronchoscopy or transthoracic fine needle aspiration, and diagnosed on ROSE followed by histopathology. ROSE was performed by a trained pulmonologist and the diagnosis of ROSE was compared with the final diagnosis., Results: The sensitivity of ROSE in determining adequacy of specimens was 97.5% and specificity in determining inadequacy was 85.7%. The diagnostic efficacy of ROSE for assessing malignancy (sensitivity of 94.5% and specificity of 100%) and non-malignancy (sensitivity of 97.8% and specificity of 100%) was excellent. The sensitivity of ROSE for diagnosing small cell carcinoma (100%) was highest, followed by adenocarcinoma (89.2%) and squamous cell carcinoma (75.0%). Performance of ROSE by a trained pulmonologist also determined tuberculosis with a high diagnostic sensitivity (83.3%) and specificity (100%)., Conclusions: A trained pulmonologist can reliably carry out ROSE to ensure the adequacy of the sample, distinguish between malignancy and non-malignancy, and make a preliminary diagnosis in a large number of cases.

Introduction: Treatment options in the second-line extensive-stage SCLC (ED-SCLC) setting are limited. The PASSION study (ClinicalTrials.gov identifier: NCT03417895) was a phase 2 study of camrelizumab plus apatinib in ED-SCLC after platinum-based chemotherapy., Methods: In stage I of the study, patients were randomized (1:1:1) to receive camrelizumab 200 mg every 2 weeks plus apatinib 375 mg once daily (QD), 5 days on and 2 days off, or 7 days on and 7 days off (six patients each cohort). On the basis of tolerability during the first 28-day cycle and efficacy data at stage I, one cohort was chosen to expand to 45 patients at stage II. The primary end point was objective response rate (ORR)., Results: From April 20, 2018 to March 12, 2019, a total of 59 patients were enrolled, with 47 patients in the QD cohort. In the QD cohort, confirmed ORR reached 34.0% (95% confidence interval: 20.9‒49.3), the median progression-free survival was 3.6 months, and the median overall survival was 8.4 months. Chemotherapy-sensitive and chemotherapy-resistant patients (defined as patients with disease relapse at ≥90 and <90 d after platinum-based chemotherapy, respectively) had comparable confirmed ORR (37.5% versus 32.3%), median progression-free survival (3.6 versus 2.7 mo), and median overall survival (9.6 versus 8.0 mo). Treatment-related adverse events of grade 3 or higher were reported in 43 of 59 patients (72.9%). Five patients (8.5%) discontinued because of treatment-related adverse events., Conclusions: Camrelizumab plus apatinib exhibited potential antitumor activity in patients with both chemotherapy-sensitive and chemotherapy-resistant ED-SCLC who had failed platinum-based chemotherapy with an acceptable toxicity profile. This phase 2 data warrant further clinical studies of camrelizumab plus apatinib in SCLC., (Copyright © 2020. Published by Elsevier Inc.)

Cisplatin resistance of non-small-cell lung cancer (NSCLC) needs to be well elucidated. RING finger protein (RNF38) has been proposed as a biomarker of NSCLC poor prognosis. However, its role in drug resistance in NSCLC is poorly understood. RNF38 expression was detected in normal lung epithelial cell and four NSCLC cell lines. RNF38 was stably overexpressed in A549 and H460 cells or silenced in H1975 and cisplatin-resistant A549 cells (A549-CDDP resistant) using lentiviral vectors. RNF38 expression levels were determined using quantitative real-time polymerase chain reaction and western blotting analysis. Cell viability in response to different concentrations of cisplatin was evaluated by Cell Counting Kit-8 assay. RNF38 expression levels were markedly elevated in NSCLC cells and cells harboring high RNF38 were less sensitive to cisplatin. Overexpression of RNF38 reduced, while RNF38 silencing increased the drug sensitivity of cisplatin in NSCLC cells. Cisplatin-resistant cells expressed high RNF38 level. RNF38 silencing promoted cell apoptosis and enhanced the drug sensitivity of cisplatin in cisplatin-resistant NSCLC cells. These findings indicate that RNF38 might induce cisplatin resistance of NSCLC cells via promoting cell apoptosis and RNF38 could be a novel target for rectify cisplatin resistance in NSCLC cases., (© 2020 International Federation for Cell Biology.)