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Importance: For patients with non-small cell lung cancer whose disease progressed while receiving EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy, particularly third-generation TKIs, optimal treatment options remain limited., Objective: To compare the efficacy of ivonescimab plus chemotherapy with chemotherapy alone for patients with relapsed advanced or metastatic non-small cell lung cancer with the epidermal growth factor receptor (EGFR) variant., Design, Setting, and Participants: Double-blind, placebo-controlled, randomized, phase 3 trial at 55 sites in China enrolled participants from January 2022 to November 2022; a total of 322 eligible patients were enrolled., Interventions: Participants received ivonescimab (n = 161) or placebo (n = 161) plus pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy of ivonescimab plus pemetrexed or placebo plus pemetrexed., Main Outcomes and Measures: The primary end point was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee (IRRC) per Response Evaluation Criteria in Solid Tumors version 1.1. The results of the first planned interim analysis are reported., Results: Among 322 enrolled patients in the ivonescimab and placebo groups, the median age was 59.6 vs 59.4 years and 52.2% vs 50.9% of patients were female. As of March 10, 2023, median follow-up time was 7.89 months. Median progression-free survival was 7.1 (95% CI, 5.9-8.7) months in the ivonescimab group vs 4.8 (95% CI, 4.2-5.6) months for placebo (difference, 2.3 months; hazard ratio [HR], 0.46 [95% CI, 0.34-0.62]; P < .001). The prespecified subgroup analysis showed progression-free survival benefit favoring patients receiving ivonescimab over placebo across almost all subgroups, including patients whose disease progressed while receiving third-generation EGFR-TKI therapy (HR, 0.48 [95% CI 0.35-0.66]) and those with brain metastases (HR, 0.40 [95% CI, 0.22-0.73]). The objective response rate was 50.6% (95% CI, 42.6%-58.6%) with ivonescimab and 35.4% (95% CI, 28.0%-43.3%) with placebo (difference, 15.6% [95% CI, 5.3%-26.0%]; P = .006). The median overall survival data were not mature; at data cutoff, 69 patients (21.4%) had died. Grade 3 or higher treatment-emergent adverse events occurred in 99 patients (61.5%) in the ivonescimab group vs 79 patients (49.1%) in the placebo group, the most common of which were chemotherapy-related. Grade 3 or higher immune-related adverse events occurred in 10 patients (6.2%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Grade 3 or higher vascular endothelial growth factor-related adverse events occurred in 5 patients (3.1%) in the ivonescimab group vs 4 (2.5%) in the placebo group., Conclusions: Ivonescimab plus chemotherapy significantly improved progression-free survival with tolerable safety profile in TKI-treated non-small cell lung cancer., Trial Registration: ClinicalTrials.gov Identifier: NCT05184712.

The role of CD161 + CD127 + CD8 + T cells in non-small cell lung cancer (NSCLC) patients with diabetes remains unexplored. This study determined the prevalence, phenotype, and function of CD8 + T cell subsets in NSCLC with diabetes. We recruited NSCLC patients ( n  = 436) treated with anti-PD-1 immunotherapy as first-line treatment. The progression-free survival (PFS), overall survival (OS), T cells infiltration, and peripheral blood immunological characteristics were analyzed in NSCLC patients with or without diabetes. NSCLC patients with diabetes exhibited shorter PFS and OS ( p  = 0.0069 and p  = 0.012, respectively) and significantly lower CD8 + T cells infiltration. Mass cytometry by time-of-flight (CyTOF) showed a higher percentage of CD161 + CD127 + CD8 + T cells among CD8 + T cells in NSCLC with diabetes before anti-PD-1 treatment ( p  = 0.0071) than that in NSCLC without diabetes and this trend continued after anti-PD-1 treatment ( p  = 0.0393). Flow cytometry and multiple-immunofluorescence confirmed that NSCLC with diabetes had significantly higher CD161 + CD127 + CD8 + T cells to CD8 + T cells ratios than NSCLC patients without diabetes. The RNA-sequencing analysis revealed immune-cytotoxic genes were reduced in the CD161 + CD127 + CD8 + T cell subset compared to CD161 + CD127 - CD8 + T cells in NSCLC with diabetes. CD161 + CD127 + CD8 + T cells exhibited more T cell-exhausted phenotypes in NSCLC with diabetes. NSCLC patients with diabetes with ≥ 6.3% CD161 + CD127 + CD8 + T cells to CD8 + T cells ratios showed worse PFS. These findings indicate that diabetes is a risk factor for NSCLC patients who undergo anti-PD-1 immunotherapy.CD161 + CD127 + CD8 + T cells could be a key indicator of a poor prognosis in NSCLC with diabetes. Our findings would help in advancing anti-PD-1 therapy in NSCLC patients with diabetes., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background: Mucosal-associated invariant T (MAIT) cells have been reported to regulate tumor immunity. However, the immune characteristics of MAIT cells in non-small cell lung cancer (NSCLC) and their correlation with the treatment efficacy of immune checkpoint inhibitors (ICIs) remain unclear., Patients and Methods: In this study, we performed single-cell RNA sequencing (scRNA-seq), flow cytometry, and multiplex immunofluorescence assays to determine the proportion and characteristics of CD8+MAIT cells in patients with metastatic NSCLC who did and did not respond to anti-PD-1 therapy. Survival analyses were employed to determine the effects of MAIT proportion and C-X-C chemokine receptor 6 (CXCR6) expression on the prognosis of patients with advanced NSCLC., Results: The proportion of activated and proliferating CD8+MAIT cells were significantly higher in responders-derived peripheral blood mononuclear cells (PBMCs) and lung tissues before anti-PD-1 therapy, with enhanced expression of cytotoxicity-related genes including CCL4, KLRG1, PRF1, NCR3, NKG7, GZMB, and KLRK1. The responders' peripheral and tumor-infiltrating CD8+MAIT cells showed an upregulated CXCR6 expression. Similarly, CXCR6+CD8+MAIT cells from responders showed higher expression of cytotoxicity-related genes, such as CST7, GNLY, KLRG1, NKG7, and PRF1. Patients with ≥15.1% CD8+MAIT cells to CD8+T cells ratio and ≥35.9% CXCR6+CD8+MAIT cells to CD8+MAIT cells ratio in peripheral blood showed better progression-free survival (PFS) after immunotherapy. The role of CD8+MAIT cells in lung cancer immunotherapy was potentially mediated by classical/non-classical monocytes through the CXCL16-CXCR6 axis., Conclusion: CD8+MAIT cells are a potential predictive biomarker for patients with NSCLC responding to anti-PD-1 therapy. The correlation between CD8+MAIT cells and immunotherapy sensitivity may be ascribed to high CXCR6 expression., (© 2024. The Author(s).)

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.)

Non-small cell lung cancer (NSCLC) ranks as one of the leading causes of cancer-related deaths worldwide. Despite the prominence and effectiveness of kinase-target therapies in NSCLC treatment, these drugs are suitable for and beneficial to a mere ~30% of NSCLC patients. Consequently, the need for novel strategies addressing NSCLC remains pressing. Deubiquitinases (DUBs), a group of diverse enzymes with well-defined catalytic sites that are frequently overactivated in cancers and associated with tumorigenesis and regarded as promising therapeutic targets. Nevertheless, the mechanisms by which DUBs promote NSCLC remain poorly understood. Through a global analysis of the 97 DUBs' contribution to NSCLC survival possibilities using The Cancer Genome Atlas (TCGA) database, we found that high expression of Josephin Domain-containing protein 2 (JOSD2) predicted the poor prognosis of patients. Depletion of JOSD2 significantly impeded NSCLC growth in both cell/patient-derived xenografts in vivo. Mechanically, we found that JOSD2 restricts the kinase activity of LKB1, an important tumor suppressor generally inactivated in NSCLC, by removing K6-linked polyubiquitination, an action vital for maintaining the integrity of the LKB1-STRAD-MO25 complex. Notably, we identified the first small-molecule inhibitor of JOSD2, and observed that its pharmacological inhibition significantly arrested NSCLC proliferation in vitro/in vivo. Our findings highlight the vital role of JOSD2 in hindering LKB1 activity, underscoring the therapeutic potential of targeting JOSD2 in NSCLC, especially in those with inactivated LKB1, and presenting its inhibitors as a promising strategy for NSCLC treatment., (© 2023. The Author(s).)

There are no standard third-line or beyond treatments for patients with driver mutation-positive advanced lung adenocarcinoma (LUAD). Anlotinib was approved as a third-line multitarget drug in China in 2018. Limited data are available regarding the efficacy and safety of anlotinib compared with chemotherapy. To investigate the efficacy and safety of anlotinib compared with traditional chemotherapy in patients with epidermal growth factor receptor (EGFR)-positive advanced LUAD. We conducted a retrospective study of 83 EGFR mutation-positive patients with advanced LUAD between 2011 and 2022. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints, whereas the objective response rate (ORR) and disease control rate (DCR) were the secondary endpoints. Anlotinib-related adverse events (AEs) were recorded to evaluate the safety of anlotinib. 39 patients with LUAD received anlotinib and 44 patients with LUAD received chemotherapy were enrolled in the study. Patients treated with anlotinib exhibited longer PFS (11.2 vs 4.5 months, P  < .01) and OS (18.8 vs 15.8 months, P  < .05) than patients treated with chemotherapy. There were no significant differences in ORR (7.9% vs 20.5%, P  = .129) or DCR (100% vs 93.2%, P  = .120) between the two groups. Anlotinib-related AEs grading 3-4 level were observed in 2 (5.1%) patients, no anlotinib-related death was recorded. Cox regression analyses of PFS and OS showed that brain metastases and age < 30 years at diagnosis had negative effects on clinical outcomes. Anlotinib is effective and safe in patients with EGFR-positive advanced LUAD. Patients without brain metastases had better clinical outcomes., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

A 54-year-old, non-smoking woman was diagnosed as stage ⅣB adenocarcinoma with widespread bone metastasis (cT4N2M1c) in the First Affiliated Hospital, Zhejiang University School of Medicine. Immunohistochemistry result showed the presence of anaplastic lymphoma kinase (ALK) gene rearrangement; next-generation sequencing (NGS) indicated EML4 - ALK fusion ( E6 : A20 ) with concurrent CCDC148 - ALK ( C1 : A20 ) , PKDCC - ALK ( Pintergenic : A20 )and VIT - ALK ( V15 : A20 ) fusions. After 32 weeks of alectinib treatment, the patient complained cough and exertional chest distress but had no sign of infection. Computed tomography (CT) showed bilateral diffuse ground glass opacities, suggesting a diagnosis of alectinib-related interstitial lung disease (ILD). Following corticosteroid treatment and discontinuation of alectinib, clinical presentations and CT scan gradually improved, but the primary lung lesions enlarged during the regular follow-up. The administration of crizotinib was then initiated and the disease was stable for 25 months without recurrence of primary lung lesions and ILD.

Introduction: Neoadjuvant immunochemotherapy is effective in resectable NSCLC. However, its role in unresectable stage IIIB NSCLC patients remains controversial. This study aimed to demonstrate the efficacy and safety of neoadjuvant immunochemotherapy followed by surgical resection to treat initial unresectable stage IIIB NSCLC patients., Methods: This study retrospectively analyzed 59 initial unresectable stage IIIB NSCLC patients who received induction pembrolizumab combined with chemotherapy between June 2019 and April 2022. Clinical characteristics, radiological and pathological responses, and survival outcomes were collected and evaluated., Results: Fifity-nine initial unresectable stage IIIB NSCLC patients were identified and divided into surgery (n = 23) and non-surgery (n = 36) groups with a median follow-up time of 15.0 months. The median PFS/DFS of the surgery group was significantly longer than the non-surgery group (not reached vs. 15.5 months, p = 0.0031). The median overall survival (OS) was not reached in both groups, and the OS rate was 100% (23/23) in the surgery group and 83.3% (30/36) in the non-surgery group. The pathological analysis suggested that 13 of 23 patients (56.5%) achieved major pathological response (MPR) or pathological complete response (pCR), and more squamous cell carcinoma cases were observed in the MPR group compared to the non-MPR group (p = 0.034). All patients in the surgery group had an R0 resection, and no surgical-related mortality was recorded; only three patients (13.0%) experienced any postoperative complications., Conclusion: In this retrospective study, surgical resection after neoadjuvant immunochemotherapy was promising for initial unresectable stage IIIB NSCLC patients, with a high MPR rate and good surgical safety., 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 © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: This study aimed to evaluate the efficacy and safety of cadonilimab (anti PD-1 and CTLA-4 bispecific antibody) in patients with previously treated metastatic non-small-cell lung cancer (NSCLC)., Methods: In this multicenter, open-label, phase Ib/II study, patients with previously treated NSCLC were enrolled in three different cohorts: Cohort A, patients who had failed previous platinum-based doublet chemotherapy and were immunotherapy naïve; Cohort B, patients who had failed previous platinum-based doublet chemotherapy and had primary resistance to immunotherapy (IO); Cohort C, patients who had failed previous platinum-based doublet chemotherapy and had acquired resistance to IO. Eligible patients were given cadonilimab 6 mg/kg intravenously every 2 weeks. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1., Results: A total of 53 patients were enrolled: including 30 patients in cohort A, 7 in cohort B, and 16 in cohort C. ORR was 10% in cohort A, and there were no responder in cohort B and cohort C. Median overall survival was 19.61 (95% CI 11.30-NE) months, 4.93 (95% CI 1.97-NE) months and 13.16 (95% CI 6.18-NE) months in cohort A, B and C, respectively. Grade 3-4 treatment-related adverse events were reported in 6 (11.3 %) patients, including alanine aminotransferase increased (1.9%), rash (1.9%), chest discomfort (1.9%), hypercalcaemia (1.9%), anaemia (1.9%) and infusion related reaction (1.9%)., Conclusion: The study did not meet its primary endpoint. Cadonilimab demonstrated limited efficacy in patients with IO failure, especially in cases of primary resistance. However, cadonilimab might play a role as a second-line immune monotherapy after platinum-based doublet chemotherapy failure and IO naïve, as its efficacy is similar to other immune checkpoint inhibitors after first-line chemotherapy. Cadonilimab was well-tolerated with mild toxicity, making it a potential candidate for the combination strategy. Clinical trial number NCT04172454., Competing Interests: Declaration of Competing Interest Li Zhang has received research support from Hengrui, BeiGene, Xiansheng, Eli Lilly, Novartis, Roche, Hansoh and Bristol-Myers Squibb Pharma and consulting for MSD, Beigene and Xiansheng Pharma. Weifeng Song, Zhongmin Maxwell Wang, Baiyong Li and Yu Xia are employees of Akeso Biopharma, Inc. Other authors declared no conflict of interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Lung cancer is the most common malignancy in the world and the leading cause of cancer death. Human epidermal growth factor receptor 2 (HER2) positive non-small cell lung cancer (NSCLC) refers to the NSCLC caused by mutation, amplification or overexpression of the HER2 gene, resulting in its dysfunction. HER2 is the most active receptor in the HER family and can combine with other members to form dimers, which can activate multiple signaling pathways and regulate cell proliferation, differentiation, migration and apoptosis. In NSCLC, HER2 positivity is usually considered a poor prognostic marker. At present, the diagnosis and treatment of HER2-positive NSCLC are not mature. Immunohistochemistry (IHC), next generation sequencing (NGS) and other technologies are often used to detect the positive status of HER2 mutation, amplification or overexpression. In previous studies, antitumor drugs did not show ideal therapeutic effects in HER2-positive NSCLC. However, in recent years, related researches have shown that antibody-drug conjugates (ADCs) and new tyrosine kinase inhibitors (TKIs) in targeted therapy show good antitumor activity against HER2 positive NSCLC. This article summarized the progress in diagnosis and treatment of HER2-positive NSCLC, so as to provide reference for subsequent researches.
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Immune checkpoint inhibitors (ICIs) have successfully treated a number of different types of cancer, which is of great significance for cancer treatment. With the widespread use of ICIs in clinical practice, the increasing checkpoint inhibitor pneumonia (CIP) will be a challenge to clinicians. To guide the diagnosis and treatment of CIP, we conducted in-depth discussions based on the latest evidence, forming a consensus among Chinese experts on the multidisciplinary management of CIP., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Tissue tumor mutation burden (tTMB) assessed by whole-exome sequencing (WES), which has been regarded as the gold standard method of tTMB measurement, can predict the clinical benefits of immune checkpoint inhibitors (ICIs). Multiple studies have investigated the feasibility of utilizing large panels to evaluate TMB but have obtained conflicting results. Furthermore, whether blood TMB (bTMB) can also be a predictive biomarker in NSCLC has not been determined., Methods: Fifty-six advanced NSCLC patients treated with ICIs were enrolled, including an exploratory cohort (n = 42) and a small independent validation cohort (n = 14). Next-generation sequencing was performed on tumor and plasma samples collected prior to ICI treatment using a panel consisting of 520 cancer-related genes (OncoScreen) to evaluate tTMB/bTMB. WES was also performed on tumor samples to serve as references., Results: A positive correlation between tTMB derived from WES and OncoScreen was observed. OncoScreen-derived tTMB showed a positive correlation with OncoScreen-derived bTMB. Patients with OncoScreen-derived tTMB [Formula: see text] 7 mutations/Mb (p = 0.003) or bTMB [Formula: see text] 11 mutations/Mb (p = 0.0029) had superior progression-free survival (PFS). In the small validation cohort, patients with OncoScreen-derived bTMB [Formula: see text] 11 mutations/Mb exhibited longer PFS (p = 0.192) with a nonsignificant difference. In all 42 patients who had available bTMB and PFS, patients with bTMB [Formula: see text] 11 mutations/Mb had significantly longer PFS (p = 0.011) than those with bTMB [Formula: see text] 11 mutations/Mb., Conclusion: Our study confirmed the feasibility of using large panels to estimate TMB. We also demonstrated that bTMB can serve as a potential biomarker for predicting the efficacy of ICIs in NSCLC., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

EGFR inhibitors have revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC). Mefatinib is a novel, bioavailable, second-generation, irreversible pan-EGFR inhibitor. This phase Ib/II open-label, single-arm, multi-center study investigated the efficacy, safety, biomarker, and resistance mechanisms of mefatinib in the first-line treatment of patients with advanced EGFR-mutant NSCLC. This study included 106 patients with EGFR-mutant stage IIIB-IV NSCLC who received first-line mefatinib at a daily dose of either 60 mg (n = 51) or 80 mg (n = 55). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. The cohort achieved an ORR of 84.9% and DCR of 97.2%. The median PFS was 15.4 months and the median OS was 31.6 months. Brain metastasis was detected in 29% of patients (n = 31) at diagnosis and demonstrated an ORR of 87.1%, PFS of 12.8 months, and OS of 25.2 months. Adverse events primarily involved skin and gastrointestinal toxicities, which were well-tolerated and manageable. Analyses of mutation profiles were performed using targeted sequencing of plasma samples at baseline, first follow-up 6 weeks from starting mefatinib therapy (F1), and at progression. Patients with concurrent TP53 mutations had comparable PFS as wild-type TP53 (14.0 vs 15.4 months; p = 0.315). Furthermore, circulating tumor DNA clearance was associated with longer PFS (p = 0.040) and OS (p = 0.002). EGFR T790M was the predominant molecular mechanism of mefatinib resistance (42.1%, 16/38). First-line mefatinib provides durable PFS and an acceptable toxicity profile in patients with advanced EGFR-mutant NSCLC., (© 2021. The Author(s).)

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.)

Lung cancer is the most common malignancy and is a major public health problem worldwide. Programmed cell death receptor 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors provide a new treatment strategy for non-small cell lung cancer (NSCLC). The existing biomarkers all have advantages and defects in selecting patients who benefit from immunotherapy. The multiplex immunohistochemistry/immunofluorescence (mIHC/IF) provides multiplex staining, allows comprehensive studies of cellular composition, cellular functions and cell-cell interactions. A number of studies have used mIHC/IF to explore specific immune cells in tumor immune microenvironment (TIME) and found that it is helpful for clinical prognosis and efficacy prediction in patients with lung cancer. In the era of immunotherapy for lung cancer, this technique has a bright future in translational research and clinical practice. The research progress of mIHC/IF detection in lung cancer immunotherapy is summarized in this review.
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Background: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are rapidly being developed for treatment of non-small-cell lung cancer (NSCLC) in patients harboring EGFR T790M mutations. This first-in-human phase 1 study evaluated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, tolerability, and pharmacokinetics (PK), and preliminarily determined the antitumor activity of ES-072 in NSCLC patients with EGFR T790M mutations., Patients and Methods: Dose escalation and expansion studies were performed using an accelerated titration method. Oral ES-072 doses (25-450 mg) were administrated once daily for single- and multiple-dose escalation trials. Characteristic PK parameters were assessed in the single-dose escalation phase and in the first cycle of the multiple-dose escalation phase. Tumor responses were assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 to evaluate ES-072 antitumor activity., Results: Nineteen patients were enrolled onto this study, 16 to the dose-escalation phase and 3 to the dose-expansion phase. The most common adverse events were QT interval prolongation (11/19, 57.9%), anemia (5/19, 26.3%), mouth ulceration (4/19, 21.1%), keratosis (4/19, 21.1%), and cough (4/19, 21.1%). Safety and tolerability evaluation of ES-072 showed an maximum tolerated dose of 300 mg, and the RP2D dose was therefore 300 mg once daily. PK analysis showed an ES-072 half-life of 24.5 hours and a T max of approximately 4 hours. The total objective response rate and disease control rate were 46.2% and 76.9%, respectively., Conclusion: ES-072 was safe and well tolerated in NSCLC patients harboring EGFR T790M mutations, and adverse events were controllable and reversible. A RP2D of 300 mg once daily was determined, and preliminary investigations showed promising antitumor activity., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: ROS1 rearrangements are seen in 1-2 % of non-small cell lung cancer (NSCLC) patients. The aim of this study was to determine the effectiveness of crizotinib as first-line treatment in patients with ROS1 rearranged NSCLC., Methods: The data of 56 patients with ROS1-rearranged advanced NSCLC who received first-line crizotinib treatment from 5 hospitals in China were retrospectively reviewed. The clinical characteristics, outcomes of first-line crizotinib therapy and prognostic factors were evaluated. In addition, mechanisms of resistance to crizotinib were analyzed in a cohort of crizotinib-resistant patients., Results: The median age of the cohort was 53.0 years and most patients (91.1 %) had adenocarcinomas. The median progression free survival (mPFS) after first-line crizotinib therapy was 23.0 months, and the median overall survival (mOS) was 60.0 months. In the univariate analysis, mPFS was significantly shorter in female patients compared to males (12.0 months versus 24.0 months; p = 0.015) and in patients with >2 baseline metastatic organ involvement compared to those with ≤2 baseline metastatic organ involvement (4.0 months vs 24.0 months; p < 0.001).In addition, the mOS was significantly shorter in patients with >2 baseline metastatic organ involvement relative to that in patients with ≤2 baseline metastatic organ involvement (6.0 months vs 60.0 months; p < 0.001). Multivariable analysis further showed that >2 baseline metastatic organ involvement was the only independent prognostic factor of PFS (p = 0.008). Four out of 8 patients (50 %) with crizotinib resistance harbored a G2032R mutation in the ROS1 kinase domain., Conclusions: First-line crizotinib treatment is beneficial in Chinese patients with ROS1-rearranged advanced NSCLC. Resistance to crizotinib correlated with the G2032R mutation in the ROS1 kinase domain., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Despite the efficacy of crizotinib in non-small cell lung cancer (NSCLC) with genomic rearrangement between echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK), clinical outcomes are heterogeneous among these patients. In our study, we investigated concurrent molecular factors that could contribute to the heterogeneity of their clinical outcomes to crizotinib therapy., Methods: We retrospectively analyzed the clinical and targeted sequencing data from 32 crizotinib-treated patients with EML4-ALK-rearranged advanced NSCLC., Results: Analysis of the mutation profile revealed the detection of concurrent deleterious mutations in 17 patients (53 %, 17/32). Of which, 5 patients had deleterious copy number variations and 12 patients had deleterious single nucleotide variations. Seven patients did not harbor any concurrent mutations from the genes included in the panel. The remaining 8 patients harbored concurrent mutations which were either non-deleterious or variants of uncertain significance. TP53, detected from 34 % (11/32) of the patients and the most commonly co-occurring mutation in our cohort, was not significantly associated with survival outcomes. Interestingly, significantly shorter progression-free survival (P = 0.032) was observed in patients harboring concurrent deleterious mutations, particularly copy number amplifications (PFS, P = 0.0021; OS, P = 0.034), than those without concurrent deleterious mutations. Harboring more copy number variations, reflected by chromosomal fluctuation coefficient varscore, was associated with shorter progression-free survival (P = 0.02)., Conclusion: Our study revealed that concurrent deleterious mutations, particularly copy number amplifications in oncogenic genes have prognostic implications in patients with EML4-ALK-rearranged NSCLC receiving crizotinib therapy. These observations advance the understanding of the heterogeneity of treatment responses among patients with EML4-ALK-rearranged tumors., Competing Interests: Declaration of Competing Interest Analyn Lizaso, Bing Yu, Jing Lin, and Songan Chen are employees of Burning Rock Biotech., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Ensartinib is a potent new-generation ALK inhibitor with high activity against a broad range of known crizotinib-resistant ALK mutations and CNS metastases. We aimed to assess the efficacy and safety of ensartinib in ALK-positive patients with non-small-cell lung cancer (NSCLC), in whom crizotinib therapy was unsuccessful. The associations between ensartinib efficacy and crizotinib-resistant mutations were also explored., Methods: We did a single-arm, open-label, phase 2 study at 27 centres in China. Patients were aged 18 years or older, had stage IIIb or stage IV ALK-positive NSCLC that had progressed while they were on crizotinib therapy, an Eastern Cooperative Oncology Group performance status of 2 or less, had measurable disease, and had received fewer than three previous treatments. Patients with CNS metastases were included if these metastases were asymptomatic and did not require steroid therapy. All patients received 225 mg ensartinib orally once daily on a continuous dosing schedule. The primary outcome was the proportion of patients with an objective response according to the Response Evaluation Criteria in Solid Tumors (version 1.1), as assessed by an independent review committee in all patients who received at least one dose of ensartinib with no major violations of the inclusion criteria (ie, the full analysis set). Safety was assessed in all enrolled patients who received at least one dose of ensartinib. This trial was registered with ClinicalTrials.gov, NCT03215693., Findings: Between Sept 28, 2017, and April 11, 2018, 160 patients were enrolled and had at least one dose of ensartinib (safety analysis set). Four patients had inclusion violations and were excluded from the efficacy analysis, which thus included 156 patients (full analysis set). 97 (62%) patients in the full analysis set had brain metastases. 76 (52% [95% CI 43-60]) of 147 patients in the full analysis set, with responses that could be assessed by the independent review committee, had an objective response. 28 (70% [53-83]) of 40 patients with measurable brain metastases as assessed by the independent review committee had an intracranial objective response. 145 (91%) of 160 patients had at least one treatment-related adverse event, which were mostly grade 1 or 2. The most common treatment-related adverse events were rash (89 [56%]), increased alanine aminotransferase concentrations (74 [46%]), and increased aspartate aminotransferase concentrations (65 [41%])., Interpretation: Ensartinib has activity and is well tolerated in patients with crizotinib-refractory, ALK-positive NSCLC, including those with brain metastases. The role of ensartinib in patients in whom other second-generation ALK inhibitors have been unsuccessful warrants further studies., Funding: Betta Pharmaceuticals., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

PD-1/PD-L1 inhibitors play an important role in the first-line and second-line treatment of non-small cell lung cancer (NSCLC), indicating a new treatment strategy of NSCLC. Completed clinical trials have shown that effective detection of PD-L1 expression is the key to the use of immunosuppressive agents. However, the gold standard for PD-L1 detection has still lacked. In recent years, immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA) have been continuously innovated, which accounts for good prospect in PD-L1 detection. The research progress of PD-L1 detection methods in NSCLC is summarized in this review.
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Background: To compare the efficacy of crizotinib, pemetrexed and other chemotherapy regimens as a first-line treatment in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) in real world clinical use and to evaluate the +86-571-87,236,876 predictive clinical factors of the efficacy of crizotinib., Methods: The 73 patients with ALK-positive advanced NSCLC were divided into three groups based on the first-line treatment: first-line crizotinib group (1-CRZ group, n = 32); first-line platinum-based pemetrexed treatment group (1-PP group, n = 28), and first-line chemotherapy platinum-based non-pemetrexed group (N1-PP, n = 12). Sixty eight of the 73 patients received crizotinib treatment and followed up in our hospital. Differences in the objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) were compared in the different groups. The clinical factors were evaluated to predict the efficacy of crizotinib by the Kaplan-Meier survival analysis and Cox proportional hazards model., Results: The PFS, ORR, DCR were 16.1 months, 78.1% (25/32) and 100% (32/32) in the 1-CRZ group; were 6.0 months, 17.9% (5/28) and 57.2% (16/28) in the 1-PP group; and were 2.9 months, 15.4% (2/13) and 46.2% (6/13) in the N1-PP group. The PFS of the 1-CRZ group was significantly longer than that of the 1-PP group (P < 0.001) and the N1-PP group (P < 0.001). The ORR and DCR of the 1-CRZ group was significantly greater than that of the 1-PP group and the N1-PP group (all the P < 0.001). Higher Eastern Cooperative Oncology Group (ECOG) performance status score (> = 2) (HR 2.345, 95% CI 1.137-4.834, P = 0.021) and patients received crizotinib after N1-PP chemotherapy (HR 2.345, 95% CI 1.137-4.834, P = 0.021) were two factors associated with shorter PFS after crizotinib treatment., Conclusions: In patients with ALK-positive NSCLC who did not receive previous treatment, crizotinib was superior to standard chemotherapy for the longer PFS and greater ORR and DCR. Higher ECOG score (> = 2) and patients received crizotinib after N1-PP chemotherapy predict poor efficacy of crizotinib.

KRAS is one of the most commonly mutated oncogenes in non-small cell lung cancer (NSCLC). Resistance to MEK inhibitor monotherapy develops through a variety of mechanisms. CDK4 was reported to have a synthetic lethal interaction with KRAS. In this study, we demonstrated the combination effects of the MEK inhibitor selumetinib and the CDK4/6 inhibitor palbociclib in RAS-driven NSCLC. In vitro, cell lines with CDKN2A mutations were insensitive to selumetinib. We used siRNA and pharmacologic inhibition of CDK4 and found that the combination of selumetinib and palbociclib synergistically inhibited RAS-driven NSCLC cases with CDKN2A mutations but not those with wild type CDKN2A. The combination treatment potentiated growth inhibition and increased the population of cells in G1 phase. Selumetinib completely inhibited p-ERK but not p-RB. The addition of palbociclib markedly inhibited p-RB and downregulated survivin expression. In vivo, the combination treatment inhibited the growth of NSCLC xenografts, which correlated with decreased levels of p-RB, downregulated survivin and decreased Ki-67 staining. These data suggest that the combination treatment of palbociclib and selumetinib is effective in preclinical models of RAS-driven NSCLC with CDKN2A mutations., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Pancreatic metastasis from non-small cell lung cancer (NSCLC) is usually asymptomatic or presents with abdominal pain, acute pancreatitis, or jaundice. A lung primary is associated with worse survival compared to pancreatic metastases from other organs. Surgical treatment of solitary metastasis to the pancreas from NSCLC has been reviewed in several studies, one of which had a notable disease-free interval. To our knowledge, there are no prior reports of targeted therapy of pancreatic metastasis of NSCLC followed by a significant response. Herein we report the case of a 31-year-old female with a solitary pancreatic metastasis from ALK-rearranged lung adenocarcinoma despite treatment with chemotherapy and crizotinib; she presented with symptoms of hyperglycemia. Targeted therapy with ceritinib (LDK378) led to symptomatic improvement and a significant radiologic response in the lung and pancreas, but not in the brain.

Defining distinctive histologic characteristics of ROS1-rearranged non-small-cell lung carcinomas (NSCLCs) may help identify cases that merit molecular testing. However, the majority of previous reports have focused on surgical specimens but only limited studies assessed histomorphology of advanced NSCLCs. In order to identify the clinical and histological characteristics of ROS1-rearranged advanced NSCLCs, we examined five hundred sixteen Chinese patients with advanced NSCLCs using ROS1 fluorescence in situ hybridization and real-time polymerase chain reaction and then analyzed for clinical and pathological features. We performed univariate and multivariate analyses to identify predictive factors associated with ROS1 rearrangement. 19 tumors were identified with ROS1 rearrangement (3.7% of adenocarcinomas). 16 ROS1+ and 122 ROS1- samples with available medical records and enough tumor cells were included for histological analysis. Compared with ROS1-negative advanced NSCLCs,ROS1-rearranged advanced NSCLCs were associated with a younger age at presentation. ROS1 rearrangements were not significantly associated with sex, smoking history, drinking history and metastatic sites. The most common histological pattern was solid growth (12/16), followed by acinar (4/16) growth. 66.7% cases with solid growth pattern showed hepatoid cytology (8/12) and 75% cases with acinar growth pattern showed a cribriform structure (3/4). 18.8% cases were found to have abundant extracellular mucus or signet-ring cells (3/16). Only one case with solid growth pattern showed psammomatous calcifications. In conclusion, age, hepatoid cytology and cribriform structure are the independent predictors for ROS1-rearranged advanced NSCLCs, recognizing these may be helpful in finding candidates for genomic alterations, especially when available tissue samples are limited.

Aims: To identify the clinical and histological characteristics of ROS1-rearranged non-small-cell lung carcinomas (NSCLCs) and build a prediction model to prescreen suitable patients for molecular testing., Methods and Results: We identified 27 cases of ROS1-rearranged lung adenocarcinomas in 1165 patients with NSCLCs confirmed by real-time PCR and FISH and performed univariate and multivariate analyses to identify predictive factors associated with ROS1 rearrangement and finally developed prediction model. Detected with ROS1 immunochemistry, 59 cases of 1165 patients had a certain degree of ROS1 expression. Among these cases, 19 cases (68%, 19/28) with 3+ and 8 cases (47%, 8/17) with 2+ staining were ROS1 rearrangement verified by real-time PCR and FISH. In the resected group, the acinar-predominant growth pattern was the most commonly observed (57%, 8/14), while in the biopsy group, solid patterns were the most frequently observed (78%, 7/13). Based on multiple logistic regression analysis, we determined that female sex, cribriform structure and the presence of psammoma body were the three most powerful indicators of ROS1 rearrangement, and we have developed a predictive model for the presence of ROS1 rearrangements in lung adenocarcinomas., Conclusions: Female, cribriform structure and presence of psammoma body were the three most powerful indicator of ROS1 rearrangement status, and predictive formula was helpful in screening ROS1-rearranged NSCLC, especially for ROS1 immunochemistry equivocal cases., Competing Interests: The authors have declared that no competing interests exist.

Aim: To evaluate the clinical value of cell block samples from malignant pleural effusion (MPE) as alternative samples to tumour tissue for anaplastic lymphoma kinase (ALK) detection in patients with advanced non-small-cell lung cancer (NSCLC)., Methods and Results: Fifty-two matched samples were eligible for analysis. ALK status was detected by Ventana immunohistochemistry (IHC) (with the D5F3 clone), reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in-situ hybridization (FISH) in MPE cell block samples, and by FISH in tumour tissue block samples. In total, ALK FISH results were obtained for 52 tumour tissue samples and 41 MPE cell block samples. Eight cases (15.4%) were ALK-positive in tumour tissue samples by FISH, and among matched MPE cell block samples, five were ALK-positive by FISH, seven were ALK-positive by RT-PCR, and eight were ALK-positive by Ventana IHC. The ALK status concordance rates between tumour tissue and MPE cell block samples were 78.9% by FISH, 98.1% by RT-PCR, and 100% by Ventana IHC. In MPE cell block samples, the sensitivity and specificity of Ventana IHC (100% and 100%) and RT-PCR (87.5% and 100%) were higher than those of FISH (62.5% and 100%)., Conclusions: Malignant pleural effusion cell block samples had a diagnostic performance for ALK detection in advanced NSCLC that was comparable to that of tumour tissue samples. MPE cell block samples might be valid alternative samples for ALK detection when tissue is not available. Ventana IHC could be the most suitable method for ALK detection in MPE cell block samples., (© 2014 John Wiley & Sons Ltd.)

EML4-ALK rearrangement is detected in 2% to 7% of lung adenocarcinomas, these tumors are sensitive to crizotinib. The histologic feature of ALK translocated non-small-cell lung cancer (NSCLC) has been studied, presence of signet-ring cells was a powerful histologic indicator of ALK rearrangement, and this characteristic histology was present both in primary sites and metastases. However, the case we discribed here has different histomorphology in primary sites and metastases, but has the same genotype which both present ALK rearrangement, while absent of EGFR mutation, KRAS mutation and ROS1 rearrangement. This histologic heterogeneity may be a supplement of the histologic feature of ALK rearranged tumor. Moreover, genomic analysis can help distinguish clonal tumors from independent primaries.

Objective: To explore the clinicopathological features associated with epidermal growth factor receptor (EGFR) gene mutation in non-small cell lung cancer (NSCLC) patients., Methods: In this series, 677 NSCLC patients at lung disease center during June 2010 through July 2013 were included. The EGFR gene type was determined through pyrosequencing assay. The factors associated with EGFR gene mutation were explored by comparing their clinicopathological features., Results: Among them, 313 (46.2%) patients had mutant EGFR. It happened more frequently in females (60.4% vs 33.3%), non-smoker (54.8% vs 32.4%), stagesIa-IIIa (51.1% vs 38.6%), well-differentiated (81.1% vs 46.1%) and adenocarcinoma (50.7% vs 15.3%) patients than in males, smoker, stages IIIb-IV, poorly differentiated and non-adenocarcinoma counterparts (all P < 0.05). However, the mutation rate was lower in patients with AB blood type (25.0%) than those with other blood types (type A 49.4%, type B 46.0%, type O 50.0%) (all P < 0.05). The patients with mutant EGFR gene had a higher level of serum carcino-embryonic antigen (CEA) than those with wild-type EGFR gene (114.5 vs 41.8 µg/L, P = 0.038)., Conclusions: The female, non-smoker, stagesIa-IIIa, well-differentiated and adenocarcinoma patients of NSCLC have significantly higher incidence of EGFR gene mutation while mutation is rare in those with AB blood type. And pathology, differentiation and blood type are independent factors affecting EGFR mutation.

Objective: To explore the clinicopathological characteristics and imaging features of lung adenocarcinoma with a micropapillary pattern (MPP)., Methods: Eighty cases of pulmonary adenocarcinoma with a micropapillary pattern treated in our hospital from July 2011 to December 2012 were selected to retrospectively analyze their clinicopathological characteristics and imaging features., Results: Among the 80 cases of lung adenocarcinoma with MPP, there were 38 cases of stage I (47.5%), 12 cases of stage II (15.0%), 25 cases of stage III (31.3%) and 5 cases of stage IV (6.2%). There were 14 cases of moderately differentiated (17.5%) and moderately/poorly differentiated (82.5%) tumors. Sixty-three cases had pleural involvement, vascular invasion, involving the bronchial wall, invasion of large vessels, nerve invasion, and lymph node metastasis (at least one of them) (78.8%). Immunohistochemical staining revealed that both positive rates of TTF-1 and CK7 were 100%, and that of pulmonary surfactant apolipoprotein-A (SPA) was 84.0%. Imaging examination revealed hilar or mediastinal lymph node enlargement in 15 cases (18.8%). but the pathology confirmed hilar or mediastinal lymph node metastasis in 36 cases (45.0%). Lung CT imaging showed that the majority of the cases were peripheral type, and only a few of central type, and most cases were solid lesions, with lobulation, spiculation, pleural indentation, and vascular convergence sign, while there were few ground-glass opacity sign and vacuole sign., Conclusions: Lung adenocarcinoma with MPP component often presents with early invasions of pleura, blood vessels, lymphatic vessels, and lymph nodes. Imaging manifestation of this cancer mainly shows as peripheral and solid lesions, often with lobulation, spiculation, pleural indentation, vascular convergence sign, but GGO and vacuole signs are unusual. Overexpression of TTF-1, CK7 and SPA, and elevated CEA level are associated with clinical staging of the disease.

Right detection of anaplastic lymphoma kinase (ALK) gene rearrangement is pivotal to selection of patients with lung adenocarcinoma for ALK-targeted therapy. We explored the potential of combination of immunohistochemistry (IHC) screening and fluorescence in situ hybridization (FISH) as an affordable practice. We analyzed 410 unselected lung adenocarcinomas by ALK IHC (D5F3 clone) and FISH. Some equivocal cases were further analyzed by RT-PCR. The EGFR mutation was detected by pyrosequencing assay. In total 368 cases which got all IHC, FISH, EGFR mutation results were eligible for analysis. Cases were evaluated as IHC score 3+ (n = 26), score 2+ (n = 9), score 1+ (n = 51), and score 0 (n = 282), respectively. 23 of 26 IHC 3+ and 5 of 9 IHC 2+ cases were FISH positive, whereas 3 of 26 IHC 3+, 4 of 9 IHC 2+ and all 333 IHC 1+/0 cases were FISH negative. If considering FISH as the standard, the sensitivity and specificity of ALK IHC 3+/2+ as ALK positive were 100% and 97.9%, respectively. Three IHC 3+ cases reported as FISH "negative" were actually ALK positive confirmed by ALK RT-PCR or re-detected. Based on the final classify, ALK IHC 3+/2+ was 100% sensitive and 98.8% specific. However, FISH was 90.3% sensitive and 100% specific. IHC 2+ was regarded as equivocal and need to be confirmed by FISH or RT-PCR. In the 368 cases, 8.4% cases had ALK positive, 52.2% cases had EGFR mutation, and only one case had a coexisting. Manually semiquantitative ALK IHC (primary antibody D5F3 coupled with secondary DAKO Envision system) used as the initial screening combined with auxiliary FISH confirmation is a reliable, economical approach to identify ALK positive lung adenocarcinoma. The IHC can find some ALK positive cases which would be missed by FISH only.

Purpose: The goal of this study was to assess the safety and tolerability of icotinib hydrochloride (BPI-2009H), a new selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), and to explore its pharmacokinetics (PK) and clinical activity in patients with advanced solid tumors, mainly those with non-small-cell lung cancer (NSCLC) after the failure of the prior platinum-based chemotherapy., Experimental Design: Different doses of oral icotinib were administered once every 8 h (Q8H) for a 28-continuous-day cycle until disease progression and or undue toxicity was observed. PK studies of subjects' blood were performed during cycle one (day 1 through 28). Patients aged ≥18 and ≤70 years with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 and adequate organ functions eligible for the study. Tumor responses were assessed by Response Evaluation Criteria in Solid Tumors (RECIST). K-ras and EGFR mutations in the extracted DNA of fourteen specimens were examined using PCR-based direct sequencing assay., Results: Thirty-six patients were enrolled in the study. PK analysis demonstrated that the mean elimination half-life of icotinib was 6 h, and the T(max) was around 2 h. The steady-state concentration of icotinib administered at a dose of 125 mg once every 8 h (Q8H) was significantly higher than that achieved by a dose of 100mg Q8H. The most frequent treatment-related adverse events (TRAEs) were an acne-like (folliculitis) rash (16/36, 44.4%), diarrhea (8/36, 22.2%) and a decrease in white blood cells (4/36, 11.1%). The maximum-tolerated dose (MTD) was not reached. Among 33 patients with NSCLC, 7 patients exhibited a partial response, 7 showed stable disease at the 24 weeks. Among 14 patients undergoing DNA sequence for K-ras and EGFR mutations, 3 with K-ras mutation presented 2 stable disease (SD) and 1 partial response (PR), 5 with EGFR exon 19 or 21 mutation 2 PR and 3 SD within 4 weeks., Conclusions: Oral icotinib was generally well tolerated, with manageable and reversible adverse events (AEs) and showed positive clinical anti-tumor activities in patients with advanced NSCLC. The recommended dose for phase II/III studies with icotinib is 125 mg or 150 mg Q8H., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)