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e21145 Background: Although PD-1/L1 inhibitors have shown efficacy in advanced/metastatic sqNSCLC, many patients do not respond to this treatment. More effective combination therapies are needed. The efficacy and safety of IBI110 in combination with sintilimab as first-line therapy for advanced sqNSCLC was evaluated in a phase Ib study. Here, we report the initial results. Methods: Eligible patients with previously untreated, unresectable, locally advanced or metastatic NSCLC were enrolled in cohort D. Patients received IBI110 200mg IV Q3W and sintilimab 200mg IV Q3W until disease progression, unacceptable toxicity or death, in combination with chemo regimen (paclitaxel 175 mg/m2 plus carboplatin) IV Q3W for 4 cycles. The primary objective was to evaluate the safety, tolerability and efficacy of the combination therapy. Results: Totally, 20 patients were enrolled (median age: 63 [range: 52-74]; male: n = 19; ECOG 1: n = 16). As of data cutoff date, Jan 20, 2022, median follow up was 3.3 months (range: 2.6-7.0). The median exposure of combination therapy was 15.1 weeks (range: 6-52). The objective response rate was 80% (16/20, 9 patients with ≥2 efficacy assessments were confirmed PR and 7 needed further confirmation). The median progression-free survival and overall survival were not reached. The most common treatment-related adverse events (TRAEs) included white blood cell count decreased (50%), alopecia (50%), anaemia (45%), asthenia (40%), neutrophil count decreased (35%), rash (35%), and hyperglycaemia (30%); most common TRAEs ≥ grade 3 were neutrophil count decreased (30%), and white blood cell count decreased (20%). Immune-related AEs occurred in 11 patients (55%) and most were grade 1-2. The biomarker analysis including LAG-3 and PD-L1 expression in tumor specimen was ongoing. Conclusions: IBI110 in combination with sintilimab in first-line advanced sqNSCLC showed promising anti-tumor activity with acceptable safety. The study is still ongoing. Clinical trial information: NCT04085185.

BACKGROUND This multicenter, retrospective study explored the value of oncogene driver subtype, programmed death-1 ligand (PD-L1) status, and smoking status for predicting which patients with oncogene-driven non-small cell lung cancer (NSCLC) would benefit from treatment with programmed death-1 (PD-1)/PD-L1 inhibitors. METHODS The clinical features, PD-L1 tumor proportion scores, and PD-1/PD-L1 inhibitor (PDi) outcomes (objective response rate and progression-free survival) of patients who had advanced NSCLC with Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutations or common, actionable oncogenic drivers were captured. RESULTS In total, 189 oncogene-positive patients were analyzed. Of these, 104 received a PDi, and 108 had undergone prior PD-L1 testing. The frequency of PD-L1 positivity (≥1%) was higher in patients who had KRAS mutations (P = .031), smokers (P = .006), and non-Asian patients (P = .002). Multivariable analysis indicated that smoking status (P < .001) was the only factor associated significantly with KRAS mutation. The objective response rate to PDi treatment was 16.9% (11 of 65 patients) among smokers (17.3% in the KRAS-mutant and 15.4% in the non-KRAS-mutant smoker subgroups), which was significantly higher than the 0% rate (0 of 26 patients; P = .019) among never-smokers. In subgroup analyses, progression-free survival was influenced by KRAS mutation status (median, 4.57 vs 1.63 months; P = .004), smoking status (4.07 vs 1.73 months; P = .004), PD-L1 positivity (3.8 vs 1.2 months; P = .040), and non-Asian race (3.0 vs 1.97 months; P = .046). In multivariable analysis, only smoking status (P = .008) remained a significant predictor when a PD-L1 level ≥1% was used. However, both smoking status (P = .001) and PD-L1 status (P = .028) were independent predictors when a PD-L1 level ≥50% was used. CONCLUSIONS Among associated clinical features among patients who have NSCLC with oncogenic drivers, smoking status potentially was the most important, easily available predictor of single PDi efficacy.

Objective Patients with advanced non-small-cell lung cancer (NSCLC) with an adenocarcinoma component are recommended to undergo epidermal growth factor receptor (EGFR) mutation testing when being considered for EGFR targeted therapy. We conducted an exploratory analysis to inform the clinical utility of EGFR mutation testing in blood cell-free DNA using the cobas® EGFR Mutation Test v2. Materials and methods Two EGFR mutation tests, a tissue-based assay (cobas® v1) and a tissue- and blood-based assay (cobas® v2) were used to analyze matched biopsy and blood samples (897 paired samples) from three Asian studies of first-line erlotinib with similar intent-to-treat populations. ENSURE was a phase III comparison of erlotinib and gemcitabine/platinum, FASTACT-2 was a phase III study of gemcitabine/platinum plus erlotinib or placebo, and ASPIRATION was a single-arm phase II study of erlotinib. Agreement statistics were evaluated, based on sensitivity and specificity between the two assays in subgroups of patients with increasing tumor burden. Results Patients with discordant EGFR (tissue+/plasma-) mutation status achieved longer progression-free and overall survival than those with concordant (tissue+/plasma+) mutation status. Tumor burden was significantly greater in patients with concordant versus discordant mutations. Pooled analyses of data from the three studies showed a sensitivity of 72.1% (95% confidence interval [CI] 67.8–76.1) and a specificity of 97.9% (95% CI 96.0–99.0) for blood-based testing; sensitivity was greatest in patients with larger baseline tumors. Conclusions Blood-based EGFR mutation testing demonstrated high specificity and good sensitivity, and offers a convenient and easily accessible diagnostic method to complement tissue-based tests. Patients with a discordant mutation status in plasma and tissue, had improved survival outcomes compared with those with a concordant mutation status, which may be due to their lower tumor burden. These data help to inform the clinical utility of this blood-based assay for the detection of EGFR mutations.

Background Novel adjuvant strategies are needed to optimise outcomes after complete surgical resection in patients with early-stage non-small-cell lung cancer (NSCLC). We aimed to evaluate adjuvant atezolizumab versus best supportive care after adjuvant platinum-based chemotherapy in these patients. Methods IMpower010 was a randomised, multicentre, open-label, phase 3 study done at 227 sites in 22 countries and regions. Eligible patients were 18 years or older with completely resected stage IB (tumours ≥4 cm) to IIIA NSCLC per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system (7th edition). Patients were randomly assigned (1:1) by a permuted-block method (block size of four) to receive adjuvant atezolizumab (1200 mg every 21 days; for 16 cycles or 1 year) or best supportive care (observation and regular scans for disease recurrence) after adjuvant platinum-based chemotherapy (one to four cycles). The primary endpoint, investigator-assessed disease-free survival, was tested hierarchically first in the stage II-IIIA population subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells (SP263), then all patients in the stage II-IIIA population, and finally the intention-to-treat (ITT) population (stage IB-IIIA). Safety was evaluated in all patients who were randomly assigned and received atezolizumab or best supportive care. IMpower010 is registered with ClinicalTrials.gov, NCT02486718 (active, not recruiting). Findings Between Oct 7, 2015, and Sept 19, 2018, 1280 patients were enrolled after complete resection. 1269 received adjuvant chemotherapy, of whom 1005 patients were eligible for randomisation to atezolizumab (n=507) or best supportive care (n=498); 495 in each group received treatment. After a median follow-up of 32·2 months (IQR 27·4-38·3) in the stage II-IIIA population, atezolizumab treatment improved disease-free survival compared with best supportive care in patients in the stage II-IIIA population whose tumours expressed PD-L1 on 1% or more of tumour cells (HR 0·66; 95% CI 0·50-0·88; p=0·0039) and in all patients in the stage II-IIIA population (0·79; 0·64-0·96; p=0·020). In the ITT population, HR for disease-free survival was 0·81 (0·67-0·99; p=0·040). Atezolizumab-related grade 3 and 4 adverse events occurred in 53 (11%) of 495 patients and grade 5 events in four patients (1%). Interpretation IMpower010 showed a disease-free survival benefit with atezolizumab versus best supportive care after adjuvant chemotherapy in patients with resected stage II-IIIA NSCLC, with pronounced benefit in the subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells, and no new safety signals. Atezolizumab after adjuvant chemotherapy offers a promising treatment option for patients with resected early-stage NSCLC. Funding F Hoffmann-La Roche and Genentech.

Lung cancer is a highly heterogeneous disease. Cancer cells and cells within the tumor microenvironment together determine disease progression, as well as response to or escape from treatment. To map the cell type-specific transcriptome landscape of cancer cells and their tumor microenvironment in advanced non-small cell lung cancer (NSCLC), we analyze 42 tissue biopsy samples from stage III/IV NSCLC patients by single cell RNA sequencing and present the large scale, single cell resolution profiles of advanced NSCLCs. In addition to cell types described in previous single cell studies of early stage lung cancer, we are able to identify rare cell types in tumors such as follicular dendritic cells and T helper 17 cells. Tumors from different patients display large heterogeneity in cellular composition, chromosomal structure, developmental trajectory, intercellular signaling network and phenotype dominance. Our study also reveals a correlation of tumor heterogeneity with tumor associated neutrophils, which might help to shed light on their function in NSCLC., Comprehensive profiles of tumour and microenvironment are critical to understand heterogeneity in non-small cell lung cancer (NSCLC). Here, the authors profile 42 late-stage NSCLC patients with single-cell RNA-seq, revealing immune landscapes that are associated with cancer subtype or heterogeneity.

Hao Wang,1,2 Shanhao Chen,1 Die Meng,1,2 Chunyan Wu,3 Junjie Zhu,4 Minlin Jiang,1,2 Jing Ning,1,2 Shengyu Wu,1,2 Lijia Wu,5 Jingjie Li,5 Bin Chen,1 Sha Zhao,1 Wei Li,1 Jia Yu,1,2 Qiyu Fang,1,2 Jun Zhu,1,2 Wencheng Zhao,1,2 Yayi He,1 Caicun Zhou1 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Shanghai, 200433, People’s Republic of China; 2Medical School, Tongji University, Shanghai, 200433, People’s Republic of China; 3Pathology Department, Shanghai Pulmonary Hospital, Shanghai, 200433, People’s Republic of China; 4Surgery Department, Shanghai Pulmonary Hospital, Shanghai, 200433, People’s Republic of China; 5Genecast Biotechnology Co., Ltd, Wuxi City, Jiangsu, 214104, People’s Republic of ChinaCorrespondence: Yayi He; Caicun ZhouDepartment of Medical Oncology, Shanghai Pulmonary Hospital, No. 507 Zhengmin Road, Shanghai, People’s Republic of ChinaTel +86 13818828623; Tel +86 13818828623Email 2250601@qq.com; caicunzhoudr@126.comIntroduction: Nowadays, immune checkpoint blockades (ICBs) have been extensively applied in non-small cell lung cancer (NSCLC) treatment. However, the outcome of anti-program death-1/program death ligand-1 (anti-PD-1/PD-L1) therapy is not satisfying in EGFR-mutant lung adenocarcinoma (LUAD) patients and its exact mechanisms have not been fully understood. Since tumor mutation burden (TMB) and tumor immune phenotype had been thought as potential predictors for efficacy of ICBs, we further studied the TMB and immune phenotype in LUAD patients to explore potential mechanisms for poor efficacy of ICBs in EGFR positive mutated patients and to find possible factors that could impact the tumor immune phenotype which might uncover some new therapeutic strategies or combination therapies.Methods: We enrolled 223 LUAD patients who underwent surgery in our hospital. We evaluated TMB through targeted panel sequencing. The tumor immune phenotype, which could be divided into non-inflamed, intermediate and inflamed, was determined through immunohistochemistry using formalin-fixed paraffin-embedded samples. Enumeration data were analyzed by Chi-square test or Fisher exact test and shown as number (proportion). Logistic regression model was employed for univariate and multivariate analysis of the association between TMB levels and clinical characteristics.Results: The median TMB level was 4.0445 mutations/Mb. Multivariate analysis showed the TMB level was significantly associated with age (P=0.026), gender (P=0.041) and EGFR mutation status (P=0.015), and in EGFR-mutant patients we found a lower proportion of patients with mutated KRAS and BRCA2. Furthermore, we found patients with or without metastatic lesions would have different immune phenotype (P=0.007). And the mutational frequencies of ALK, CDKN2A, MAP2K1, IDH2 and PTEN were significantly different among three immune phenotypes.Conclusion: Low TMB level could be the reason for the poor efficacy of ICBs in patients having EGFR mutation. And mutational frequencies of KRAS and BRCA2 were lower in EGFR-mutant patients. Furthermore, ALK, CDKN2A, MAP2K1, IDH2 and PTEN might involve in the formation of immune phenotypes.Keywords: lung adenocarcinoma, EGFR mutation, tumor mutation burden, immune phenotype, immune checkpoint blockade

BackgroundImmunotherapies may prolong the survival of patients with small-cell lung cancer (SCLC) to some extent. The role of forkhead box protein P3 (FOXP3) in tumor microenvironment (TME) remains controversial. We aimed to examine FOXP3-related expression characteristics and prognostic values and to develop a clinically relevant predictive system for SCLC.MethodsWe enrolled 102 patients with histologically confirmed SCLC at stages I–III. Through immunohistochemistry, we determined the expression pattern of FOXP3 and its association with other immune biomarkers. By machine learning and statistical analysis, we constructed effective immune risk score models. Furthermore, we examined FOXP3-related enrichment pathways and TME traits in distinct cohorts.ResultsIn SCLC, FOXP3 level was significantly associated with status of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), CD4, CD8, and CD3 (p=0.002, p=0.001, p=0.002, p=0.030, and pCD28, basic excision repair genes MUTYH, POLD1, POLD2, and oxidative phosphorylation related gene cytochrome c oxidase subunit 8A with FOXP3 expression were revealed. Moreover, we found low-immune risk score group had statistically higher activated CD4+ memory T cells (p=0.014) and plasma cells (p=0.049) than the high-risk group. The heterogeneity of tumor-infiltrating immune cells might represent a promising feature for risk prediction in SCLC.ConclusionFOXP3 interacts closely with immune biomarkers on tumor-infiltrating cells in TME. This study highlighted the crucial prognostic value and promising clinical applications of FOXP3 in SCLC.

BACKGROUND: Acute complications, such as venous thromboembolism (VTE), are common in patients with advanced severe lung cancers. However, current VTE risk scores cannot adequately identify high-risk patients with non-small cell lung cancer (NSCLC). The study proposed to elucidated the incidence of thromboembolism (TE) in patients with different oncogenic aberrations and the impact of these aberrations on the efficacy of targeted therapy in patients with NSCLC. METHODS: A systemic review was conducted in Web of Science, PubMed, Embase and the Cochrane Library to evaluate the incidence of TE in different molecular subtypes of NSCLC. Data from patients diagnosed of advanced NSCLC who harboring anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) rearrangements since 2016 to 2019 were also retrospectively collected. A meta-analysis with random-effects model, sensitivity analysis and publication bias were performed. The principal summary measure was incidence of thrombotic events in NSCLC patients. And the efficacy of tyrosine kinase inhibitor (TKI) therapy was compared between the two subgroups. RESULTS: A total of 5,767 cases from 20 studies were included in the analysis of the incidence of thrombosis in patients with different oncogenic alterations. The pooled analysis showed a higher risk of thrombosis in ROS1-fusion types (41%, 95% CI: 35–47%) and ALK-fusion types (30%, 95% CI: 24–37%) than in EGFR-mutation (12%, 95% CI: 8–17%), KRAS-mutation (25%, 95% CI: 13–50%), and wild-type (14%, 95% CI: 10–20%) cases. A high prevalence of thrombosis (ALK: 24.4%; ROS1: 32.6%) was observed in the Shanghai Pulmonary Hospital (SPH) cohort of 224 patients with ALK or ROS1 fusion. Furthermore, patients with embolism had significantly shorter progression-free survival (PFS) after TKI therapy than those without embolism, both in the ALK+ cohort (5.6 vs. 12.9 months, P

BackgroundDespite disappointing outcomes from immuno-monotherapy, studies reported that NSCLC patients with EGFR mutation may possibly benefit from combined immunotherapy. Whether the response to prior EGFR-TKI has association with the outcomes of subsequent immunotherapy remains unclear.Patients and MethodsAdvanced NSCLC patients with resistance to EGFR-TKIs and received ICI treatment from January 2016 to June 2019 were retrospectively analyzed. Single cell sequencing and flow cytometry were conducted to explore the difference of cell components in tumor microenvironments (TME). A 1:3 matched case–control study was conducted to compare the clinical effects of combined immunotherapy with standard chemotherapy as second-line treatment.ResultsFifty-eight patients treated with anti-PD-1/PD-L1 based immunotherapy behind EGFR-TKI treatment were enrolled. Correlation analysis showed TKI-PFS had a significantly negative association with corresponding IO-PFS (r = −0.35, p = 0.006). TKI-PFS cutoff 10 months had the most significant predictive function for posterior immunotherapy and was validated to be an independent predictor by uni- and multivariate analyses. Kaplan–Meier analysis showed that patients with TKI-PFS less than 10 months had significantly prolonged IO-PFS and higher ORR than those with long (median PFS, 15.1 vs 3.8 months; HR, 0.26, p = 0.0002; ORR, 31.8 versus 10%, p = 0.04). Single cell RNA-seq revealed that the cell components were varied among patients after treatment with EGFR-TKI. Patients with short TKI-PFS demonstrated a relatively higher proportion of CD8 effector cells and lower ratio of M2 like macrophage to M1 like macrophages, which was validated by flow cytometry. Case–control study demonstrated that combined immunotherapy achieved significantly longer PFS (HR, 0.51, 95% CI: 0.31–0.85, p = 0.02), longer OS (HR, 0.48, 95% CI: 0.26–0.89, p = 0.05) and higher ORR (33.3 vs 10.0%, p = 0.02) than traditional chemotherapy for patients with short TKI-PFS.ConclusionPatients with short TKI-PFS conferred better response to immunotherapy than those with long. The status of TME were different among those two populations. Combined ICI treatment could promisingly be a better choice than classical chemotherapy in second-line setting for patients with short TKI-PFS and no T790M mutation. Underlying mechanisms need to be further explored.

BACKGROUND: To investigate the significance of metastatic sites and their numbers to the efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancer (NSCLC). METHODS: A total of 232 patients who received ICI monotherapy or ICI-based combination therapy were retrospectively identified from January 2016 to February 2019. Six metastatic sites (brain, liver, bone, adrenal gland, contralateral lung, pleura) were included to analyze their significance to ICI efficacy. To explore the association between liver metastasis (LM) and tumor T cell infiltration, 46 patients with available tumor specimens were tested for PD-L1 expression, CD8+ tumor infiltrating lymphocytes (TILs) density. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier curves. RESULTS: More metastatic organs involved were associated with significantly worse PFS (0–1 organ: 5.7 months, 2–3 organs: 3.5 months, ≥4 organs: 2.7 months, P

With the increasing clinical potential of tumor immunotherapy, more and more clinical trials are undergoing with immune checkpoint inhibitors (ICIs). Immune checkpoints (ICs) have been identified as crucial regulators of the immune response and have improved ICIs-inhibitor therapeutic strategies. The most important ICs in lung cancer include programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), lymphocyte activation gene-3 (LAG-3), major histocompatibility complex class II (MHC II), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), and Galectin-9 (GAL-9), OX-40, OX40L. However, the expression and prognostic value of these ICs are still controversial. Among them, high expression of PD-L1 on tumor cells (>50%) predicts a better therapeutic effect of anti-PD-1 monoclonal antibody compared to patients with low PD-L1 expression. However, only 20-30% of non-small cell lung cancer (NSCLC) patients seem to get benefit from immunotherapy. In order to improve the immunotherapy outcomes, more and more attention is paid to combination immunotherapy. Analyzing the co-expression of ICs can give us a more comprehensive basis for combination immunotherapy. This review article summarized our comprehensive expression of ICs based on our previous research, and analyzed their correlation with prognosis in NSCLC patients. We also provided suggestions for potentially personalized combination immunotherapy in NSCLC.

Xiaofei Yu,1,* Zhengwei Dong,2,* Wanying Wang,1 Shiqi Mao,1 Yingying Pan,1 Yiwei Liu,1 Shuo Yang,1 Bin Chen,1 Chunyan Wang,1 Xuefei Li,3 Chao Zhao,3 Keyi Jia,1 Chuchu Shao,1 Chunyan Wu,2 Shengxiang Ren,1 Caicun Zhou1 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China; 2Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China; 3Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shengxiang RenDepartment of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of ChinaTel +86-21-65115006Fax +86-21-65111298Email harry_ren@126.comChunyan WuDepartment of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507, Zheng Min Road, Shanghai, 200433, People’s Republic of ChinaFax +86-21-65111298Email wuchunyan581@163.comPurpose: High-grade patterns (micropapillary/solid/complex gland) are associated with a higher recurrence rate and shorter disease-free survival. Thus far, it remains unclear whether the efficacy of first-line anticancer therapy is different from that of the other adenocarcinoma subgroups for patients with high-grade patterns. The study aimed to investigate the association between an adenocarcinoma with high-grade patterns with the outcomes of first-line treatment in patients with lung cancer.Patients and Methods: Patients with a high-grade pattern adenocarcinoma (more than 20% of micropapillary/solid components/complex glandular patterns) were retrospectively analyzed between June 2015 and June 2017. Patients’ clinical characteristics and treatment outcomes were compared with those of the remaining control adenocarcinoma subgroups.Results: In total, 239 patients with adenocarcinoma, including 115 (48.1%) high-grade patterns and 124 (51.9%) control groups, were enrolled. Patients’ clinical characteristics such as age, sex, smoking status, and stage were similar between the two groups. Among them, 108 patients received first-line chemotherapy, and 131 received epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs). In the chemotherapy group, adenocarcinoma of high-grade patterns had a significantly lower objective response rate (ORR; 15.6% vs 36.4%, P=0.045), shorter progression-free survival (PFS; median 4.1 vs 5.4 months, P=0.007) and overall survival (OS, median 19.6 vs 23.8 months, P=0.048) compared with the control group. As for these treated with EGFR-TKIs, a similar ORR (70.7% vs 72.1%, P=0.703), PFS (median 11.3 vs 13.9 months, P=0.065) and OS (median 34.1 vs 29.6%, p=0.575) were observed between these two groups.Conclusion: An adenocarcinoma with high-grade patterns is associated with inferior outcomes to first-line chemotherapy in relapsed lung cancer. Patients who received chemotherapy had a significantly shorter PFS and OS and lower ORR than control subjects, while there was no difference in the EGFR-TKI cohort. This study is the first to report the distribution of adenocarcinoma with high-grade patterns.Keywords: adenocarcinoma, micropapillary, solid, chemotherapy, EGFR-TKIs

Intertumor heterogeneity is common in various cancers and has been widely accepted as the primary cause of the diversity and variation of the effect of the same treatment on patients with the same type of tumor. Percutaneous microwave coagulation therapy (PMCT) is a minimally invasive and effective approach for destroying tumors by microwave beam under image guidance, which has been applied in lung cancer. However, no previous study has investigated the capability of PMCT solving intertumor heterogeneity. Here, we performed a component analysis of four lung cancer patients’ tumor microenvironment (TME) via single-cell RNA sequencing (scRNA-seq) and treated all four cases with PMCT. One patient’s TME could be classified into a hot tumor, mainly proinflammatory cytokines, and T cell infiltration. The other three patients’ TMEs were cold tumors, where immunosuppressive cells occupied a large proportion, including tumor-associated macrophages and cancer cells. Despite a high level of heterogeneity among their tumor microenvironment compositions, disease type and stage, and basic physical conditions, all four patients presented a stable disease (SD) without any cancer cell detected in the TME of cancer tissues after PMCT. In conclusion, this report uniquely contributed to the knowledge of the PMCT adaptation to tumor heterogeneity. Therefore, PMCT is promising to demonstrate a stable and robust antitumor efficacy in unresectable lung cancers with various TMEs.

Pulmonary sarcomatoid carcinoma (PSC) is an uncommon subtype of lung cancer, and immune checkpoint blockade promises in clinical benefit. However, virtually nothing is known about the expression of common immune checkpoints in PSC. Here, we performed immunohistochemistry (IHC) to detect nine immune-related proteins in 97 PSC patients. Based on the univariable Cox regression, random forests were used to establish risk models for OS and DFS. Moreover, we used the GSEA, CIBERSORT, and ImmuCellAI to analyze the enriched pathways and microenvironment. Univariable analysis revealed that CD4 (P = 0.008), programmed cell death protein 1 (PD-1; P = 0.003), galectin-9 (Gal-9) on tumor cells (TCs; P = 0.021) were independent for DFS, while CD4 (P = 0.020), PD-1 (P = 0.004), Gal-9 (P = 0.033), and HLA on TILs (P = 0.031) were significant for OS. Meanwhile, the expression level of CD8 played a marginable role in DFS (P = 0.061), limited by the number of patients. The combination of Gal-9 on TC with CD4 and PD-1 on TILs demonstrated the most accurate prediction for DFS (AUC: 0.636-0.791, F1-score: 0.635–0.799), and a dramatic improvement to TNM-stage (P < 0.001 for F1-score of 1-y, 3-y, and 5-yDFS). A similar finding was also observed in the predictive ability of CD4 for OS (AUC: 0.602-0.678, F1-score: 0.635–0.679). CD4 was negatively associated with the infiltration of neutrophils (P = 0.015). PDCD1 (coding gene of PD-1) was positively correlated to the number of exhausted T cells (Texs; P = 0.020) and induced regulatory T cells (iTregs; P = 0.021), and LGALS9 (coding gene of Gal-9) was positively related to the level of dendritic cells (DCs; P = 0.021). Further, a higher combinational level of CD4, PDCD1 on TILs, and LAGLS9 on TCs were proved to be infiltrated with more M1-type macrophages (P < 0.05). We confirmed the expression status of nine immune-related proteins and established a TNM-Immune system for OS and DFS in PSC to assist clinical risk-stratification.

Recent clinical trials of lung adenocarcinoma with immune checkpoint inhibitors revealed that lung adenocarcinoma patients with EGFR mutations have a poor response to immunotherapy. However, the mechanisms have not been addressed. We performed immunohistochemistry analyses of resected lung adenocarcinoma tissues with and without EGFR mutations to investigate and compare the characteristics of the tumor microenvironment (TME). We retrospectively enrolled a total of 323 lung adenocarcinoma patients (164 had EGFR mutations), and their corresponding tissue samples were analyzed by the EGFR mutation test and immunohistochemistry. We selected the markers of the immune checkpoint molecule (PD1, PD-L1, and LAG-3) and immune cell (CD3, CD4, CD8, and Foxp3) as markers of the tumor microenvironment. Our results revealed that patients had a distinct tumor microenvironment between EGFR-mutant and wild-type lung adenocarcinomas; the expression of CD3, CD4, PD-L1, and Foxp3 in EGFR-mutant tumors was significantly higher than that in wild-type tumors, while the expression of LAG3 and PD-1 showed a positive correlation with EGFR-wild-type tumors. In survival analysis, EGFR-wild-type patients had longer disease-free survival (DFS) than EGFR-mutant patients ( P = 0.0065 ). Our research demonstrates significant differences in tumor microenvironment composition between EGFR-mutant and wild-type patients. Our findings provide novel evidence that contributes to understanding the mechanism underlying the poor efficacy of immune checkpoint inhibitors.

Although immune checkpoint inhibitors (ICIs) that target programmed cell death protein-1/programmed cell death ligand-1 axis have significantly shifted the treatment paradigm in advanced NSCLC, clinical benefits of these agents are limited in patients with EGFR-mutated NSCLC. Several predictive biomarkers (e.g., programmed cell death ligand-1 expression, tumor mutation burden), which have been validated in EGFR-wild type NSCLC, however, are not efficacious in EGFR-mutated tumors, suggesting the unique characteristics of tumor microenvironment of EGFR-mutated NSCLC. Here, we first summarized the clinical evidence on the efficacy of ICIs in patients with EGFR-mutated NSCLC. Then, the cancer immunogram features of EGFR-mutated NSCLC was depicted to visualize the state of cancer-immune system interactions, including tumor foreignness, tumor sensitivity to immune effectors, metabolism, general immune status, immune cell infiltration, cytokines, and soluble molecules. We further discussed the potential subpopulations with EGFR mutations that could benefit from ICI treatment. Lastly, we put forward future strategies to adequately maximize the efficacy of ICI treatment in patients with EGFR-mutated NSCLC in the upcoming era of combination immunotherapies.

Introduction Immune checkpoint inhibitor (ICI) monotherapy has limited efficacy in patients with non-small cell lung cancer (NSCLC) and brain metastases (BMs). With the wide use of ICI-based combinations, the efficacy of different ICI combination strategies in patients with NSCLC and BMs needs to be further elucidated. Methods We retrospectively reviewed 526 patients with non-small cell lung cancer (NSCLC) treated with ICIs from January 2016 to December 2019 in the Shanghai Pulmonary Hospital. Patients with BMs treated with ICIs were further divided into two groups: those with BM prior to the ICI treatment (pBM group), and those with BM after the treatment (aBM group). We assessed intracranial progression-free survival (IPFS), systemic progression-free survival (SPFS), overall survival (OS), intracranial objective response rate (IORR), and intracranial disease control rate (IDCR). Results We found 77 patients out of 526 with BMs; 69 presented the BMs prior to the ICI treatments and 8 showed BMs after the ICI treatments. In the pBM group, the median IPFS and SPFS were 7.39 months and 5.39 months, respectively. Combination therapy significantly improved both the IPFS (p=0.007) and the SPFS (p=0.007) when compared with monotherapy. Further analysis demonstrated that ICIs combined with chemotherapy significantly improved both the IPFS (p=0.009) and the SPFS (p=0.006) when compared with monotherapy. While ICIs combined with anti-angiogenic therapy improved the SPFS (p=0.005) but not the IPFS (p=0.139). The median OS was 27.43 months for patients in the pBM group. Further analyses suggested that combination treatment also improved the OS when compared with monotherapy (p=0.003). Subgroup analysis results showed that ICIs combined with chemotherapy led to better OS than ICIs monotherapy (p=0.006). Radiotherapy had no significant impact on survival (IPFS p=0.272, OS p=0.142) in the patients of the pBM group. Conclusion ICIs combined with chemotherapy demonstrated survival benefits over ICI monotherapy in patients with NSCLCs and BMs.

Background To investigate the impact of ALK variants on the features of brain metastases (BM), the outcome of chemotherapy and targeted therapy using crizotinib, as well as the progression pattern in patients with ALK fusion. Methods Patients with ALK fusion were retrospectively collected from January 2013 to July 2017 in Shanghai Pulmonary Hospital. ALK rearrangements were identified via ARMS-PCR. ALK variants were identified via Sanger Sequencing. Results A total of 135 patients and 41 with brain metastasis were identified. Radiological features showed that the patients with ALK variant 1 had a larger BM size compared with patients with ALK non-variant 1 (median tumor size: 16.89 vs. 11.01 mm, P=0.031). Similar time to treatment failure (TTF) was observed in patients with ALK variant 1 and non-variant 1 who received first-line crizotinib (median TTF: 15.7 vs. 13.8 months, HR =0.75, P=0.34). Patients with ALK variant 1 who had baseline BM had significantly shorter TTF than non-variant 1 with baseline BM when treated with first-line crizotinib (median TTF: 9.1 vs. 14.9 months, HR =2.68, P=0.037). In patients treated with chemotherapy, ALK variant 1 was associated with inferior TTF (median TTF: 5.6 vs. 8.1 months, HR =1.66, P=0.039). Progression pattern was similar between ALK variant 1 and non-variant 1. Conclusions Patients with ALK variant 1 and baseline BM had inferior TTF on first-line crizotinib treatment and presented with more aggressive radiological features. Patients with ALK non-variant 1 had better clinical outcome on first-line chemotherapy.

Immune checkpoint inhibitors (ICI) monotherapy was standard of care in second-line treatment of patients with advance non-small cell lung cancer (NSCLC). This study aims to investigate the efficacy of ICI plus chemotherapy in patients with previously treated advanced NSCLC. An investigator-initiated trial (IIT) aiming to evaluate the efficacy and safety of ICI in combination with chemotherapy as second line and beyond for patients with advanced NSCLC was undergone at Shanghai Pulmonary Hospital (ChiCTR1900026203). Patients who received ICI monotherapy as second or later line setting during the same period were also collected as a comparator. From April 2018 to June 2019, 31 patients were included into this IIT study, simultaneously 51 patients treated with ICI monotherapy were selected as a comparator. ICI plus chemotherapy showed a significantly higher ORR (35.5% vs. 15.7%, p=0.039), prolonged PFS (median: 5.6 vs. 2.5 months, p = 0.013) and OS (median: NE vs. 12.6 months, p = 0.038) compared with ICI alone. In the subgroup of negative PD-L1 expression (9 patients in combination group and 12 patients in monotherapy group), ICI plus chemotherapy also had a favorable ORR (44.4% vs. 8.3%, p = 0.119), longer PFS (median: 6.5 vs 3.0 months, p < 0.05) and OS (median: NE vs. 8.2 months, p = 0.117). Meanwhile, the addition of chemotherapy did not increase immune-related adverse events. ICI plus chemotherapy showed superior ORR, PFS and OS than ICI alone patients with previous treated advanced NSCLC. These findings warrant further investigation.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are recommended first-line treatments in EGFR-mutated (EGFRm) non-small-cell lung cancer (NSCLC). However, acquired resistance (e.g. MET amplification) is frequently observed. Savolitinib (volitinib, HMPL-504, AZD6094) is an oral, potent, and highly selective MET-TKI. In this phase Ib, open-label, multicenter study, we enrolled Chinese patients with EGFRm advanced NSCLC, whose disease progressed following prior EGFR-TKI treatment. In the safety run-in, patients received savolitinib 600 or 800 mg plus gefitinib 250 mg orally once daily, and dose-limiting toxicities were recorded. In the expansion phase, patients with MET amplification received savolitinib plus gefitinib. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity. Thirteen patients were enrolled in the safety phase (median age 52 years, 46% female) and 51 enrolled in the expansion phase (median age 61 years, 67% female). No dose-limiting toxicities were reported in either dose group during the safety run-in. Adverse events of grade ≥ 3 in the safety run-in and expansion phases (n = 57) were reported in 21 (37%) patients. The most frequently reported adverse events (all grades) were: vomiting (n = 26, 46%), nausea (n = 23, 40%), increased aspartate aminotransferase (n = 22, 39%). Of four deaths, none were treatment-related. The objective response rates in EGFR T790M-negative, −positive, and -unknown patients were 52% (12/23), 9% (2/23), and 40% (2/5), respectively. Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and demonstrated promising antitumor activity in EGFRm, MET-amplified advanced NSCLC patients who had disease progression on EGFR-TKIs. NCT02374645, Date of registration: March 2nd 2015.

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.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).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 and90 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.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.

Programmed cell death ligand 1 (PD-L1) expressed on tumor tissues is a vital molecule for immune suppression and its impact on the response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has been reported. The significance of soluble PD-L1 (sPD-L1) for lung cancer patients remains unknown. This study investigated whether sPD-L1 could predict the response of EGFR-mutated non-small cell lung cancer (NSCLC) to EGFR-targeted therapy. We retrospectively evaluated patients who received first-line treatment with EGFR-TKIs for advanced NSCLC with EGFR mutations. Pre-treatment plasma concentrations of PD-L1 and on-treatment (1 month after treatment initiation) plasma concentrations of PD-L1 were measured using the R-plex Human PD-L1 assay. The association between the sPD-L1 level and the clinical outcome was analyzed. Among 66 patients who were eligible for the study, patients with high pre-treatment or on-treatment sPD-L1 levels had decreased objective response rate (ORR) compared with that of patients with low sPD-L1 levels (39.4 vs. 66.7%, p = 0.026 for pre-treatment sPD-L1 level, and 43.5 vs. 73.9%, p = 0.025 for on-treatment sPD-L1 level). A high baseline sPD-L1 level was associated with a shortened progression-free survival (PFS) rate (9.9 vs. 16.1 months, p = 0.005). Both univariate and multivariate analyses showed that a high baseline sPD-L1 level was an independent factor associated with the PFS (hazard ratio [HR] 2.56, p = 0.011). Our study revealed that the sPD-L1 level was strongly related to the outcome of EGFR-TKIs in NSCLC patients harboring EGFR mutations.

Targeted therapies against non-small-cell lung cancer (NSCLC) harboringPatients with stage IIIB or IVBetween October 20, 2016, and December 10, 2018, 60 patients received pyrotinib monotherapy. At baseline, 58 (96.7%) were stage IV, and 25 (41.7%) received at least 2 lines of prior chemotherapy. As of data cutoff on June 20, 2019, IRC-assessed objective response rate was 30.0% (95% CI, 18.8% to 43.2%). All subgroups of patients with differentPyrotinib showed promising antitumor activity and an acceptable safety profile in chemotherapy-treated patients with

We performed a meta-analysis to comprehensively investigate the efficacy and safety of immune-checkpoint inhibitors (ICIs) plus chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). The primary outcome was overall survival (OS). The secondary outcomes included progression-free survival (PFS), objective response rate (ORR) and ≥grade 3 adverse events (AEs). A total of six studies involving 2905 patients were identified, including 469 patients receiving program death ligand 1 (PD-L1) inhibitor plus chemotherapy, 308 receiving PD-1 inhibitors plus chemotherapy, 563 receiving CTLA-4 inhibitors plus chemotherapy, 268 receiving PD-L1/CTLA-4 inhibitors plus chemotherapy, and 1297 receiving chemotherapy alone. 10.8% (283/2615) patients had baseline brain metastases (BMs). Notably, ICIs plus chemotherapy was associated with significantly improved OS (HR, 0.82; 95% CI, 0.75 to 0.89). Subgroup analyses revealed that PD-1 inhibitors (HR, 0.77; 95% CI, 0.64 to 0.92) and PD-L1 inhibitors (HR, 0.73; 95% CI, 0.63 to 0.85) plus chemotherapy yielded a statistically significant improvement in OS while CTLA-4 inhibitors did not (HR, 0.92; 95% CI, 0.81 to 1.06). In patients with baseline BMs, ICIs plus chemotherapy showed no survival benefits over chemotherapy alone (HR, 1.23; 95% CI, 0.92 to 1.64). ICIs plus chemotherapy also significantly prolonged PFS (HR, 0.81; 95% CI, 0.75 to 0.87) while the pooled ORRs were comparable between ICIs plus chemotherapy and chemotherapy alone (RR, 1.04; 95% CI, 0.99 to 1.10). Patients treated with CTLA-4 inhibitors (relative risk (RR), 1.12; 95% CI, 0.99 to 1.28) experienced more≥grade 3 AEs than those treated with PD-1/PD-L1 inhibitors (RR, 1.03; 95% CI, 0.96 to 1.11). The addition of PD-1/PD-L1 inhibitors to chemotherapy resulted in significant improvements in both PFS and OS for patients with treatment-naïve ES-SCLC, not at the cost of increased AEs.

Immunotherapy has changed the pattern of treatment in cancer. The interaction between programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibits the activation of T cells, and PD-1/PD-L1 inhibitors can increase the immune response to cancer cells by inducing the immune cells, which has become an important clinical method to treat cancer. However, the alteration in the activation of T cells might lead to misidentification between the body's own cells and tumor cells and induce immune-related adverse events (IRAEs), such as pneumonitis, liver dysfunction, rash, colitis, nephritis, and endocrinopathies. And the IRAEs might lead to serious consequences. Studies have reported that PD-1/PD-L1 inhibitor-related hepatotoxicity is one of these adverse events. Most of the studies reported that hepatitis resulting from PD-1 inhibitor was manifested as elevated liver enzymes and bilirubin. Quite a few patients experienced lower degree of hepatotoxicity treated with checkpoint inhibitors, which indicated that it was necessary to focus on immunotherapy-related liver dysfunction. Here, we report a case of immunotherapy-related liver dysfunction with hypoproteinemia as the first manifestation under the treatment of PD-1 inhibitors combined with chemotherapy. This case suggests that hypoproteinemia was one of the manifestations of immunotherapy-related liver dysfunction, which helps us better understand the immunotherapy-related disease.

BACKGROUND: There is a lack of well-established biomarkers to predict the efficacy of pemetrexed-based chemotherapy. In this prospective phase II study, we investigated the correlation of folate receptor (FR)-positive circulating tumor cell (CTC) level with the clinical outcomes of patients with advanced non-squamous non-small cell lung cancer (nsNSCLC) when treated with pemetrexed-based chemotherapy. METHODS: A total of 98 nsNSCLC patients were enrolled. Peripheral blood was collected from each patient prior to initiation of treatment. FR-positive CTCs were enriched by immunomagnetic leukocyte depletion and quantified using ligand-targeted polymerase chain reaction (LT-PCR) method. RESULTS: Patients with relatively low CTC level (11–16 FU/3 mL, n=32) showed a significantly shorter progression-free survival (PFS) and overall survival (OS) compared with those in the “high CTC level group” (>16 FU/3mL, n=28; median PFS, 133 versus 320 days, P

Great advances in immune checkpoint blockade have resulted in a paradigm shift in patients with lung cancer. Immune-checkpoint inhibitor (ICI) treatment, either as monotherapy or combination therapy, has been established as the standard of care for patients with locally advanced/metastatic non-small cell lung cancer without EGFR/ALK alterations or extensive-stage small cell lung cancer. An increasing number of clinical trials are also ongoing to further investigate the role of ICIs in patients with early-stage lung cancer as neoadjuvant or adjuvant therapy. Although PD-L1 expression and tumor mutational burden have been widely studied for patient selection, both of these biomarkers are imperfect. Due to the complex cancer-immune interactions among tumor cells, the tumor microenvironment and host immunity, collaborative efforts are needed to establish a multidimensional immunogram to integrate complementary predictive biomarkers for personalized immunotherapy. Furthermore, as a result of the wide use of ICIs, managing acquired resistance to ICI treatment remains an inevitable challenge. A deeper understanding of the underlying biological mechanisms of acquired resistance to ICIs is helpful to overcome these obstacles. In this review, we describe the cutting-edge progress made in patients with lung cancer, the optimal duration of ICI treatment, ICIs in some special populations, the unique response patterns during ICI treatment, the emerging predictive biomarkers, and our understanding of primary and acquired resistance mechanisms to ICI treatment.

Background Personalized cancer vaccines based on tumor-derived neoantigens have shown strong and long-lasting antitumor effect in patients with some solid tumors. However, whether neoantigens identified from primary lesions could represent their metastatic lesions, and consequently the effect of vaccine therapy remained unknown. Methods To investigate whether neoantigens identified from primary tumors are similar to their matched metastases in lung cancer, we identified 79 samples from 24 cases. All of samples were collected before any systemic therapy. Major criteria for neoantigen identification included: derived from tumor-specific mutations, fold change >10 comparing to germline expression level, high predicted human leukocyte antigen (HLA) binding affinity and peptide of 9-11 amino acids in length. Results We found a wide range of tumor neoantigen burden in both primaries and metastases. The counts, overall distribution pattern and predicted HLA binding affinity of neoantigens were similar between primaries and metastases. However, only 20% of shared neoantigens (presented in both primaries and metastases) was observed, which were mainly derived from single nucleotide variants (SNVs) and fusions. A variety of corresponding HLA alleles were observed and 50.0% of cases were HLA-C*06:02. Finally, we observed the neoantigen intrametastases homogeneity in patients with sole brain metastases. Conclusions Neoantigen landscape in terms of the number, type and predicted HLA binding affinity was similar between primaries and metastases, but the percentage of shared neoantigens is only modest, suggesting vaccine development based solely on primary tumor neoantigen may not offer optimal therapeutic outcome, and shared neoantigen needs to be seriously considered.

Small cell lung cancer (SCLC), an aggressive disease characterized by rapid progression, early relapse and widespread metastasis, accounts for about 13-15% of lung cancer cases. Despite its initial sensitivity to chemotherapy and radiotherapy, SCLC commonly develops resistance to these treatments and, as such, has high recurrence rates. In recent years, immunotherapy has shown promising antitumor activity and the approach to tumor treatment has been changed, in particular, by programmed death receptor-1/ligand 1 (PD-1/L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) checkpoint inhibitors. SCLC has high immunogenicity, a high mutation burden, and other favorable immune factors, meaning immune checkpoint inhibitors (ICIs) could become a breakthrough in the treatment of SCLC. In our case report, we found that ICIs resulted in partial response (PR), and in our review, we focused on clinical trials of immunotherapy, especially in relation to ICIs in SCLC.

Nowadays, immune checkpoint inhibitor therapy has been used in more and more cancer patients. These agents were associated with immune-related adverse effects, and autoimmune diabetes mellitus is one of them. And it is not common but can be potentially fatal. Anti PD-1 monoclonal antibody is a humanized IgG4 antibody against PD-1, which has been applied in advanced non-small cell lung cancer (NSCLC) treatment. In this paper, we reported the case of autoimmune diabetes mellitus induced by anti PD-1 monoclonal antibody in NSCLC treatment. Here is a 73-year-old male patient with no diabetes history who had anti PD-1 monoclonal antibody 200 mg every 3 weeks for NSCLC treatment. After 10 cycles of the therapy, his blood glucose level elevated and he suffered diabetic ketoacidosis (DKA). And his C-peptide was significantly decreased with negative relative auto-antibodies. Combined with his medical history and the laboratory examination, anti PD-1 monoclonal antibody induced autoimmune diabetes mellitus was diagnosed. After recovering from DKA and controlling his blood glucose, his anti PD-1 therapy was continued and he still got some benefit. This report suggested that glycemic monitoring is imperative during this anti PD-1 monoclonal antibody treatment. Moreover, after controlling the blood glucose level, continuing the immune therapy could still be benefit and safe for the patient.

Introduction The optimal treatment for EGFR-mutant lung adenocarcinoma (LUAD) remains challenging because of intratumor heterogeneity. We aimed to explore a refined stratification model based on the integrated analysis of circulating tumor DNA (ctDNA) tracking. Methods ctDNA was prospectively collected at baseline and at every 8 weeks in patients with advanced treatment-naive EGFR-mutant LUAD under gefitinib treatment enrolled in a phase 2 trial and analyzed using next-generation sequencing of a 168-gene panel. Results Three subgroups categorized by baseline comutations—EGFR-sensitizing mutations (59, 32.8%), EGFR-sensitizing mutations with tumor suppressor mutations (97, 53.9%), and EGFR-sensitizing mutations with other driver mutations (24, 13.3%)—exhibited distinct progression-free survival (13.2 [11.3–15.2] versus 9.3 [7.6–10.5] versus 4.0 [2.4–9.3] months) and overall survival (32.0 [29.2–41.5] versus 21.7 [19.3–27.0] versus 15.5 [10.5–33.7] months, respectively), providing evidence for initial stratification. A total of 63.7% of the patients achieved week 8 ctDNA clearance, with significant difference noted among the three subgroups (74.5% versus 64.0% versus 29.4%, respectively, p = 0.004, Fisher’s exact test). Patients without week 8 ctDNA clearance had worse progression-free survival (clearance versus nonclearance 11.2 [9.9–13.2] versus 7.4 [5.6–9.6] months, p = 0.016, Cox regression], especially in the second subgroup [5.8 (5.6–11.5) months], suggesting the necessity of adaptive stratification during treatment. During follow-up, 56.0% and 20.8% of the patients eventually harbored p.T790M and non-p.T790M mutations, respectively, with a significant difference in non-p.T790M mutations among the three subgroups (7.5% versus 15.7% versus 80.0%, respectively, p Conclusions The patients with baseline comutations and ctDNA nonclearance at first visit might require combined therapy because of the limited survival benefit of EGFR tyrosine kinase inhibitor monotherapy. We proposed a refined stratification mode for the whole-course management of EGFR-mutant LUAD.

Summary 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/m2) 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.

Natural killer cells (NK cells) play a crucial role in tumor immunity. The function of the NK cells is regulated by various receptors expressed on the surface. Among them, the killer immunoglobulin-like receptor (KIR) is one of the most important. The ligand of KIR is major histocompatibility complex class-I (MHC class-I), which is also called human leukocyte antigen class-I (HLA class-I). The combination of HLA class-I and inhibitory KIRs could inhibit NK cells and induce autoimmune tolerance. Inhibitory KIRs were highly expressed on malignant tumor patients, which were related to poor prognosis. KIR/HLA class-I pathway affected the clinical outcomes of cancer through several mechanisms, and inhibitory KIRs could be an ideal target of immunotherapy strategy.

Introduction Immune therapy has shown good results in small-cell lung cancer (SCLC), but the impact of immune microenvironment of the disease is unclear. In this work, we detected expression of programmed death 1 (PD-1), PD-ligand 1 (PD-L1), and other immune biomarkers of cancer. We also analyzed the correlations between these markers and survival in SCLC. Patients and Methods Protein expression of PD-1, PD-L1, PD-L2, CD3, CD4, CD8, and FOXP3 was analyzed in surgical tissues from 102 SCLC patients by immunohistochemistry. Results Positive expression of PD-1 on tumor-infiltrating lymphocytes (TILs) was found in 40.2% of patients; 37.3% of patients showed positive expression of PD-L1 on TILs; and 3.9% showed positive expression of PD-L1 on tumor cells. PD-L2 protein was not expressed on tumor cells or TILs. Survival analysis showed that positive expression of PD-L1 on TILs was correlated with longer relapse-free survival (RFS) (p=0.004). Positive expression of PD-1 combined with a high ratio of lymphocytes (CD3, p=0.004; CD4, p=0.011; CD8, p=0.009; FOXP3, p=0.009) was associated with significantly better RFS than negative expression of PD-1 combined with a lower ratio of lymphocytes. Positive expression of PD-L1 combined with a high ratio of lymphocytes (CD3, p

Background Immune checkpoint inhibitor (ICI) monotherapy targeting PD-1/PD-L1 has been a prominent option for the patients with advanced non-small cell lung cancer (NSCLC), which is now commonly used in second- or later-line settings after the failure of conventional chemotherapy. Chemotherapy can modulate tumor immunity in drug-dependent manner, suggesting pre-ICI chemotherapeutic regimens might influence the efficacy of immunotherapy. Therefore, it is of interest to investigate the associations between the types of pre-ICI chemotherapy and the outcomes of patients receiving ICIs treatment. Methods The data from NSCLC patients who received anti-PD-1/PD-L1 ICI monotherapy after the failure of first-line chemotherapy were retrospectively reviewed. Clinical outcomes of the patients following ICIs monotherapy were compared according to different pre-ICI chemotherapeutic regimens. Results Eighty-nine cases receiving ICI monotherapy immediately after the failure of first-line chemotherapy were included into final analysis. The patients in Gem group had the longest PFS (median: 6.50 m) following ICIs treatment (P=0.031), compared to Pem group and Tax group (median: 3.49 and 3.30 m, respectively). Pre-ICI chemotherapy with Gem retained independently associated with favorable PFS (P=0.014, HR 0.52; 95% CI, 0.31-0.88) in multivariate analysis after adjusting for other covariates. The patients in Gem group also achieved better objective response rate (ORR) (P=0.046) and disease control rate (DCR) (P=0.005) following ICIs treatment compared to those in Pem/Tax group. The differences in depth of response to ICIs between Gem and Pem/Tax groups were also compared. Of the 48 patients who achieved controlled disease and had ≥1 measurable target lesion during ICIs treatment, no greater tumor shrinkage was observed in Gem group (P=0.374), however, Gem group trended to have shorter TTM (P=0.074). Conclusions Prior-line chemotherapy regimens might influence outcomes of the following ICIs monotherapy. Patients received pre-ICI gemcitabine-containing chemotherapy are significantly correlated with longer PFS and better response to ICIs treatment.

BACKGROUND: Immunotherapy has shown promising effect for non-small cell lung cancer (NSCLC) patients. Yet the biomarkers for predicting immunotherapy efficiency are still lacking. METHODS: We tested 139 surgical resected NSCLC primary tumor samples from Medical University of Gdansk, Poland, for T cell immunoglobulin and mucin-domain containing-3 (TIM-3) level by immunohistochemistry (IHC), analyzed the expression of TIM-3 protein on NSCLC tumor cells and tumor infiltrating lymphocytes (TILs). RESULTS: TIM-3 on TILs was correlated with programmed cell death protein-1 (PD-1) on TILs (correlation coefficient =0.346, P

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are recommended first-line treatments in EGFR- mutated non-small-cell lung cancer (NSCLC). However, acquired resistance (e.g. MET amplification) is common. Savolitinib (volitinib, HMPL-504, AZD6094) is an oral, potent, and highly selective MET-TKI. Methods: In this phase 1b, open-label, multicentre study, we enrolled Chinese patients with EGFR-mutated, advanced NSCLC, whose disease progressed during or after treatment with prior EGFR-TKIs. In the safety run-in, patients received savolitinib 600 or 800 mg plus gefitinib 250 mg orally, once-daily and dose-limiting toxicities were recorded. In the expansion phase, patients with MET amplification received savolitinib plus gefitinib. The primary endpoints were safety and tolerability. Secondary endpoints included antitumour activity and pharmacokinetics. Findings: No dose-limiting toxicities were reported in either dose group during the safety run-in (n=13). Savolitinib 600 mg plus gefitinib 250 mg once daily was selected as the recommended phase 2 dose and evaluated in the expansion phase (n=51). The objective response rates in EGFR T790M-negative, -positive and -unknown patients were 52% (12/23), 9% (2/23), and 40% (2/5), respectively. Thirty-five patients (69%) were evaluable for longitudinal circulating tumour DNA analysis. Pharmacokinetic parameters for savolitinib plus gefitinib were consistent with previous monotherapy studies, showing no evidence of drug-drug interactions. Adverse events of grade 3 or more in the safety run-in and expansion phases (n=57) were reported in 21 (37%) patients. The most common adverse events (all grades) were: vomiting (n=26, 46%), nausea (n=23, 40%), increased aspartate aminotransferase (n=22, 39%). There were four deaths, none treatment-related. Interpretation: Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and demonstrated promising antitumour activity in EGFR-mutated, MET- amplified advanced NSCLC patients who had progressed on EGFR-TKIs. Trial Registration: NCT02374645. Funding Statement: The study was funded by AstraZeneca, Cambridge, UK, the manufacturer of savolitinib and gefitinib. Hutchison MediPharma authorised AstraZeneca to conduct this study. Declaration of Interests: MF, RH, GFA, CE, SM, RBV and AM are AstraZeneca employees and shareholders. RH also owns shares in Foundation medicine, and has a patent pending for Foundation Medicine. MF is also a patent holder for AstraZeneca. Y-LW has received personal fees from AstraZeneca, Roche, Boehringer Ingeiheim, Pfizer, Bristol-Myers Squibb, Merck Sharp & Dohme, and Sanofi; and grants from AstraZeneca, Roche, and Boehringer Ingelheim. J-JY, JF, Y-QS, J-HC, G-YC, J-XH, WL, X-QL, NY, CZ, J-AH and LY declare no conflicts of interest. Ethics Approval Statement: The study was approved by Institutional Review Boards/Independent Ethics Committees at each study centre, and by the Human Genetics Resources Administration of China. The trial was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines, the provisions of the Declaration of Helsinki, applicable regulatory requirements, and the AstraZeneca policy on Bioethics and Human Biological Samples. All patients provided written informed consent before study procedures.

Background: The correlation matrix in COVID-19 clinical characteristics especially immunological features of peripheral blood is blank And the dynamic changes

Background: It remains unknown what is the optimal front-line choice for advanced non-small-cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) fusion. Methods: We conducted a systematic review and network meta-analysis of randomized phase III clinical trials comparing two or more treatments as the front-line setting for patients with advanced ALK-positive NSCLC. Results: Nine phase III randomized clinical trials with 2367 patients were included. As to efficacy, lorlatinib had the most favorable progression-free survival [PFS; surface under the cumulative ranking curve (SUCRA) = 98.4%] in the first-line setting, with noticeable outcome benefits versus chemotherapy [hazard ratio (HR): 0.12; 95% confidence interval (CI): 0.08–0.19], crizotinib (HR: 0.28; 95% CI: 0.19–0.41), ceritinib (HR: 0.22; 95% CI: 0.13–0.37), and brigatinib (HR: 0.58; 95% CI: 0.35–0.96), as well as beneficial trends when compared with alectinib (HR: 0.66; 95% CI: 0.41–1.04) and ensartinib (HR: 0.62; 95% CI: 0.36–1.08). Meanwhile, alectinib showed the optimal overall survival (OS; SUCRA = 91.2%), with significant improvements over chemotherapy (HR: 0.47; 95% CI: 0.30–0.72) and crizotinib (HR: 0.58; 95% CI: 0.41–0.82). Similarly, brigatinib also displayed prolonged OS compared with crizotinib after adjustment for crossover by the marginal structural model (HR: 0.54; 95% CI: 0.31–0.92). In terms of safety, alectinib had the fewest grade 3–5 adverse events (SUCRA = 98.9%), with marked advantages versus crizotinib [odds ratio (OR): 0.67; 95% CI: 0.46–0.97], ceritinib (OR: 0.21; 95% CI: 0.10–0.43), brigatinib (OR: 0.37; 95% CI: 0.20–0.69), ensartinib (OR: 0.48; 95% CI: 0.27–0.89), and lorlatinib (OR: 0.30; 95% CI: 0.16–0.54). Conclusions: Lorlatinib may have advantageous PFS compared with other agents but a greater risk of severe toxicity. Second-generation inhibitors, including alectinib, brigatinib, and ensartinib, provide major efficacy with less toxicity and remain appropriate regimens in the front-line setting.

Purpose We report CNS efficacy of osimertinib versus standard epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKIs) in patients with untreated EGFR-mutated advanced non–small-cell lung cancer from the phase III FLAURA study. Patients and Methods Patients (N = 556) were randomly assigned to osimertinib or standard EGFR-TKIs (gefitinib or erlotinib); brain scans were not mandated unless clinically indicated. Patients with asymptomatic or stable CNS metastases were included. In patients with symptomatic CNS metastases, neurologic status was required to be stable for ≥ 2 weeks after completion of definitive therapy and corticosteroids. A preplanned subgroup analysis with CNS progression-free survival as primary objective was conducted in patients with measurable and/or nonmeasurable CNS lesions on baseline brain scan by blinded independent central neuroradiologic review. The CNS evaluable-for-response set included patients with ≥ one measurable CNS lesion. Results Of 200 patients with available brain scans at baseline, 128 (osimertinib, n = 61; standard EGFR-TKIs, n = 67) had measurable and/or nonmeasurable CNS lesions, including 41 patients (osimertinib, n = 22; standard EGFR-TKIs, n = 19) with ≥ one measurable CNS lesion. Median CNS progression-free survival in patients with measurable and/or nonmeasurable CNS lesions was not reached with osimertinib (95% CI, 16.5 months to not calculable) and 13.9 months (95% CI, 8.3 months to not calculable) with standard EGFR-TKIs (hazard ratio, 0.48; 95% CI, 0.26 to 0.86; P = .014 [nominally statistically significant]). CNS objective response rates were 91% and 68% in patients with ≥ one measurable CNS lesion (odds ratio, 4.6; 95% CI, 0.9 to 34.9; P = .066) and 66% and 43% in patients with measurable and/or nonmeasurable CNS lesions (odds ratio, 2.5; 95% CI, 1.2 to 5.2; P = .011) treated with osimertinib and standard EGFR-TKIs, respectively. Probability of experiencing a CNS progression event was consistently lower with osimertinib versus standard EGFR-TKIs. Conclusion Osimertinib has CNS efficacy in patients with untreated EGFR-mutated non–small-cell lung cancer. These results suggest a reduced risk of CNS progression with osimertinib versus standard EGFR-TKIs.

Introduction Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death in China. Four epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors – afatinib, erlotinib, icotinib, and gefitinib – are available for first-line treatment of NSCLC in China; however, there are few data to guide treatment choice. The Phase III LUX-Lung 6 trial compared afatinib with platinum-based chemotherapy for first-line treatment of patients from Southeast Asia with EGFR mutation-positive advanced NSCLC. This post hoc analysis assessed the findings from LUX-Lung 6 in Chinese patients. Clinical trial registration ClinicalTrials.gov: NCT01121393. Materials and methods Previously untreated patients with EGFR mutation-positive stage IIIB/IV lung adenocarcinoma were randomized 2:1 to receive afatinib or ≤6 cycles of gemcitabine/ cisplatin. The key outcomes were progression-free survival (PFS; primary), objective response rate, disease control rate, overall survival (OS), duration of response and disease control, patient-reported outcomes, and safety. Three hundred and twenty-seven patients from mainland China were treated (89.8% of overall LUX-Lung 6 population; afatinib 217, gemcitabine/cisplatin 110). Results PFS was significantly longer with afatinib than gemcitabine/cisplatin (median 11.0 versus 5.6 months; hazard ratio [HR], 0.30 [95% CI, 0.21, 0.43]; P,0.0001). Overall, there was no significant difference in OS between treatment arms; however, in a subgroup analysis, afatinib significantly improved OS versus gemcitabine/cisplatin in patients with an EGFR Del19 mutation (median 31.6 versus 16.3 months; HR, 0.61 [95% CI, 0.41, 0.91]; P=0.0146). Afatinib was well tolerated, with most treatment-related adverse events (TRAEs) being of grade 1 or 2 severity. The most common grade 3/4 TRAEs with afatinib were rash/acne (15.9%/0.5%), stomatitis (6.1%/0%), and diarrhea (5.6%/0%). TRAEs leading to permanent discontinuation were reported in 12 patients (5.6%) receiving afatinib and 43 (41.7%) receiving gemcitabine/cisplatin. Afatinib significantly improved PFS compared with standard first-line chemotherapy in Chinese patients with EGFR mutation-positive NSCLC and demonstrated a manageable safety profile. Conclusion The findings support the rationale for using afatinib as a first-line treatment option for this patient population., Video abstract

Background The global Phase III LUX-Lung 8 trial (ClinicalTrials.gov: NCT01523587) identified significant improvements in progression-free survival (PFS), overall survival (OS), and patient-reported outcomes (PROs) with second-line afatinib vs erlotinib in patients with advanced squamous cell carcinoma (SCC) of the lung. Materials and methods We conducted a post hoc analysis of data for patients in LUX-Lung 8 from mainland China (n=67). Compared with erlotinib, afatinib reduced the risk of disease progression or death (PFS) in the Chinese subgroup by 30% (HR=0.70; 95% CI: 0.38–1.27). Results The risk of death was reduced by 31% (HR=0.69; 95% CI: 0.39–1.21). The proportion of Chinese patients with improvements in PROs also favored afatinib vs erlotinib (global health status/quality of life [QoL], 52.8% vs 29.6%, P=0.072; dyspnea, 47% vs 26%, P=0.091; “dyspnea walked”, 44% vs 15%, P=0.017; QoL rate, 53% vs 26%, P=0.037). Discussion While this analysis was not powered to demonstrate differences compared to the overall trial population (OTP), and there were some differences in baseline characteristics (eg, the proportion of patients aged ≥65 years old), the benefits of afatinib treatment in Chinese patients with SCC of the lung appeared to be at least comparable to that observed in LUX-Lung 8. As with the OTP, the most common adverse events (AEs) with afatinib in the Chinese subgroup were diarrhea and rash/acne, and the incidence and type of the most frequently occurring AEs were similar. Conclusion The results suggest that afatinib represents a feasible treatment option for Chinese patients with advanced SCC of the lung following progression on platinum-based chemotherapy., Video abstract

Herpes Virus Entry Mediator (HVEM) is an important immune checkpoint in cancer recognition. HVEM expressed on tumor cell membranes activates immune cell signaling pathways leading to either inhibition of activity (B- and T-lymphocyte attenuator, BTLA) or activation of immune activity (LIGHT). The aim of this study is to investigate the prevalence of HVEM expression and its association with PDL1 expression in NSCLC.A TMA of 527 resected NSCLC samples and 56 NSCLC cell lines were evaluated for HVEM and PD-L1 expression. The IHC assay for HVEM was optimized on the Dako Link48 autostainer using a polyclonal antibody from RD Systems(AF356). PD-L1 IHC was performed on the Dako Link48 autostainer using the PD-L1 28-8 pharmDx kit. Scoring HVEM employed the H-score system while for PD-L1 the tumor proportion score (TPS) was used.HVEM expression in the NSCLC resected samples and cell lines revealed a positive H-score more than 1 was 18.6% (77/415) and 48.2% (27/56) respectively. HVEM expression was significantly higher in patients with lymph node N2 metastasis (25.5% vs 7.9% vs 17.5%, p = 0.046) when comparing with N1 or no lymph node metastasis, and was marginally significantly higher in patients with stage III/IV disease (24.5% vs 16.4%, p = 0.059). Subgroup analysis showed that HVEM (median 45 vs 36 months, p = 0.706) and PD-L1 expression (median 45 vs 48 months, p = 0.178) status was not predictive of overall survival. HVEM was found to have a significant negative correlation with PD-L1 expression (r=-0.274, p 0.001) in patients with NSCLC and also a weak negative correlation in NSCLC cell lines (r=-0.162, p = 0.352).HVEM was found to be overexpressed in NSCLC patients of N2 lymph node metastasis or later stage and has a negative co-relationship with PD-L1 expression. HVEM was not prognostic for NSCLC patients.

Objectives Apatinib exhibits broad-spectrum antitumor activities by selectively inhibiting vascular endothelial growth factor receptor-2. This study evaluated the efficacy and safety of apatinib in patients with advanced non-squamous non–small-cell lung cancer who were heavily pretreated or not suitable to receive standard second-line chemotherapy. Patients and Methods This was an open-label, single-arm phase II clinical trial ( ClinicalTrials.gov NCT02515435 ). Patients received 500 or 750 mg apatinib daily until progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was the objective response rate. The secondary endpoints included disease control rate, progression-free survival, overall survival, and side effects. Apatinib administration was allowed beyond disease progression. Results Between March 2015 and August 2016, 40 patients were enrolled. Among them, 6 (15.0%), 16 (40.0%), and 18 (45.0%) received apatinib as the second-, third-, and fourth-line or beyond treatment, respectively. The mean dosage of apatinib was 477.0 ± 85.3 mg/day. Thirty-eight patients were available for response evaluation; the objective response rate and disease control rate were 13.2% and 63.2%, respectively. The median progression-free survival was 3.06 months (95% confidence interval [CI], 2.20-4.14 months). The median overall survival was 7.69 months (95% CI, 5.36 months to not estimable). The most common treatment-related adverse events were hand-foot-skin reaction (30.0%), proteinuria (27.5%), oral mucositis (22.5%), fatigue (20.0%), and hypertension (17.5%). Nine patients received apatinib after progression, and the median duration of apatinib therapy beyond progression was 5.13 months (95% CI, 4.27-7.82 months). Conclusion Apatinib shows promising efficacy and manageable toxicity in patients with advanced non-squamous non–small-cell lung cancer. Apatinib therapy beyond progression could provide further benefits in specific subpopulations.

Patients with malignant tumor treated with immunotherapy have received significant clinical benefits over the years. Immune checkpoint blocking agents, such as anti-cytotoxic T-lymphocyte-associated protein-4 (anti-CTLA-4) and anti-programmed cell death protein-1 (anti-PD-1) monoclonal antibodies, have produced impressive clinical results in different types of cancer. T-cell immunoglobulin and mucin domain-3 (TIM-3), another immune checkpoint, could inhibit cancer immunity. Recent studies have highlighted that TIM-3 has an important role to play in T-cell exhaustion and correlates with the outcome of anti-PD-1 therapy. Targeting TIM-3 might be a promising approach for cancer immunotherapy. Here, we review the role of TIM-3 in cancer and clinical trials with TIM-3 inhibitors.