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Small-cell lung cancer (SCLC) transformation accounts for 3-14% of resistance in EGFR-TKI relapsed lung adenocarcinomas (LUADs), with unknown molecular mechanisms and optimal treatment strategies. We performed transcriptomic analyses (including bulk and spatial transcriptomics) and multiplex immunofluorescence on pre-treated samples from LUADs without transformation after EGFR-TKI treatment (LUAD-NT), primary SCLCs (SCLC-P) and LUADs with transformation after EGFR-TKI treatment (before transformation: LUAD-BT; after transformation: SCLC-AT). Our study found that LUAD-BT exhibited potential transcriptomic characteristics for transformation compared with LUAD-NT. We identified several pathways that shifted during transformation, and the transformation might be promoted by epigenetic alterations (such as HDAC10, HDAC1, DNMT3A) within the tumor cells instead of within the tumor microenvironment. For druggable pathways, transformed-SCLC were proved to be less dependent on EGF signaling but more relied on FGF signaling, while VEGF-VEGFR pathway remained active, indicating potential treatments after transformation. We also found transformed-SCLC showed an immuno-exhausted status which was associated with the duration of EGFR-TKI before transformation. Besides, SCLC-AT exhibited distinct molecular subtypes from SCLC-P. Moreover, we constructed an ideal 4-marker model based on transcriptomic and IHC data to predict SCLC transformation, which obtained a sensitivity of 100% and 87.5%, a specificity of 95.7% and 100% in the training and test cohorts, respectively. We provided insights into the molecular mechanisms of SCLC transformation and the differences between SCLC-AT and SCLC-P, which might shed light on prevention strategies and subsequent therapeutic strategies for SCLC transformation in the future., (© 2024. The Author(s).)

Background: SUZ12 is one of the core members of the polycomb repressive complex 2 (PRC2), but its expression and role in lung adenocarcinoma (LUAD) are unclear. We aimed to explore the expression, prognosis, biological functions and roles of SUZ12 in LUAD., Methods: The expression of SUZ12 was detected by immunohistochemical staining, qRT-PCR, and western blotting in LUAD tissues and cells. The biological functions and molecular mechanisms of SUZ12 were characterized by a range of in vitro and in vivo experiments., Results: SUZ12 was overexpressed in LUAD tissues, and high SUZ12 expression was correlated with worse clinicopathological features and a poorer prognosis. Knockdown of SUZ12 significantly inhibited cell growth, colony formation, invasion, and migration, and induced apoptosis and G1/S phase arrest, while overexpression of SUZ12 had the opposite effects. Knockdown of SUZ12 decreased the tumorigenic capacity of A549 cells in vivo. The expression of key signaling molecules related to the cell cycle, apoptosis, migration, and immunity were altered by the knockdown or overexpression of SUZ12. SUZ12 can directly bind to the Bax promoter region, EZH2 and H3K27me3 levels dependents on SUZ12. The expression levels of SUZ12 and Bax were negatively correlated in LUAD tissues., Conclusions: SUZ12 is a new oncogene related to the poor prognosis of LUAD. SUZ12 regulates LUAD progression by regulating the expression of related signaling molecules, and as a part of the PRC2 complex, it may bind to the Bax promoter to silence Bax expression., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Treatment options for second-generation (2 nd -gen) ALK tyrosine kinase inhibitor (TKI)-resistant patients are limited. We evaluated the safety, pharmacokinetics, and efficacy of ficonalkib (SY-3505), a third-generation (3 rd -gen) ALK TKI, in patients with advanced ALK-positive non-small cell lung cancer., Methods: This first-in-human, phase 1/2 study (Chinese Clinical Trial Registry identifier: ChiCTR1900025619; ClinicalTrials.gov identifier: NCT05257512) had two parts. Phase 1 included a dose-escalation phase (25-800 mg quaque die [QD]) and a dose-expansion phase (500 mg QD or 600 mg QD). Phase 2 enrolled patients treated at recommended phase 2 dose. Primary end points were safety in phase 1 and objective response rate (ORR) in phase 2., Results: Between April 21, 2020, and August 31, 2023, a total of 127 patients with advanced ALK-positive non-small cell lung cancer were enrolled, with 62 in phase 1. Ficonalkib was well absorbed and tolerated, with one dose-limited toxicity event occurring at 800 mg QD. Treatment-related adverse events occurred in 85.5% of patients, with 19.4% experienced greater than or equal to grade 3 events. The ORR was 38.3% (23 of 60, 95% confidence interval [CI]: 26.1%-51.8%) in phase 1, and 600 mg QD was established as recommended phase 2 dose. In phase 2, a total of 65 patients received ficonalkib at 600 mg QD. In total, 88 patients received ficonalkib at 600 mg QD in phase 1/2, and all had received prior 2 nd -gen ALK TKI treatment. Furthermore, 90.9% of the patients experienced treatment-related adverse events and 14.8% experienced greater than or equal to grade 3 events. The ORR in efficacy-assessable patients who received ficonalkib at 600 mg QD was 47.5% (38 of 80, 95% CI: 36.2%-59.0%), with an intracranial ORR of 37.5% (12 of 32, 95% CI: 21.1%-56.3%) in these patients with measurable brain lesions at baseline., Conclusions: Ficonalkib (SY-3505) was well tolerated, with favorable safety profiles and promising efficacy in patients resistant to prior 2 nd -gen ALK TKI., Competing Interests: Disclosure Dr. Yuankai Shi reports receiving grants from the National Science and Technology Major Project for Key New Drug Development. Mr. Limin Yang and Dr. Yinghui Sun report having employment from Shouyao Holdings (Beijing) Co., Ltd., Beijing, the People’s Republic of China. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Befotertinib (D-0316) is a novel, selective oral third-generation epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor. This phase 3 trial compared the efficacy and safety of befotertinib with icotinib as a first-line treatment for patients with EGFR mutation-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC)., Methods: This study was a multicentre, open-label, randomised, controlled phase 3 study at 39 hospitals in China. Eligible patients were 18 years of age or older, had histologically confirmed locally advanced or metastatic stage IIIB, IIIC, or IV unresectable NSCLC, and had confirmed exon 19 deletions or exon 21 Leu858Arg mutation. Patients were randomly assigned (1:1) via an interactive web response system to receive either oral befotertinib (75-100 mg once daily) or oral icotinib (125 mg three times per day) in 21-day cycles until disease progression or withdrawal criteria were met. Randomisation was stratified by type of EGFR mutation, CNS metastasis status, and gender, and participants, investigators, and data analysts were not masked to treatment allocation. The primary endpoint was independent review committee (IRC)-assessed progression-free survival in the full analysis set, which comprised all randomly assigned patients. All patients who received at least one dose of the study drug were included in safety analyses. This study was registered with ClinicalTrials.gov, NCT04206072, and the overall survival follow-up is still in progress., Findings: Between Dec 24, 2019, and Dec 18, 2020, 568 patients were screened, of whom 362 were randomly assigned to the befotertinib (n=182) or icotinib (n=180) group; all 362 patients were included in the full analysis set. Median follow-up was 20·7 months (IQR 10·2-23·5) in the befotertinib group and 19·4 months (10·3-23·5) in the icotinib group. Median IRC-assessed progression-free survival was 22·1 months (95% CI 17·9-not estimable) in the befotertinib group and 13·8 months (12·4-15·2) in the icotinib group (hazard ratio 0·49 [95% CI 0·36-0·68], p<0·0001). Grade 3 or higher treatment-related adverse events occurred in 55 (30%) of 182 patients in the befotertinib group and in 14 (8%) of 180 patients in the icotinib group. Treatment-related serious adverse events were reported in 37 (20%) patients in the befotertinib group and in five (3%) patients in the icotinib group. Two (1%) patients in the befotertinib group and one (1%) patient in the icotinib group died due to treatment-related adverse events., Interpretation: Befotertinib demonstrated superior efficacy compared with icotinib in first-line treatment for patients with EGFR mutation-positive NSCLC. Although serious adverse events were more common in the befotertinib than the icotinib arm, the safety profile of befotertinib was manageable overall., Funding: Betta Pharmaceuticals (China)., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests SL received research support from AstraZeneca, Hutchison, BMS, Heng Rui, Beigene and Roche, Hansoh, and Lilly Suzhou Pharmaceutical; received speaker fees from AstraZeneca, Roche, Hansoh, and Heng Rui Therapeutics; and served as an advisor and consultant of AstraZeneca, Pfizer, Boehringer Ingelheim, Hutchison MediPharma, Zai Lab, GenomiCare, Yuhan Corporation, Menarini, InventisBio, and Roche. LD, YW, XY, and PW are employees of Betta Pharmaceuticals, which provided funding for this study. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: This study sought to assess the efficacy and safety of immunotherapy combined with single-agent chemotherapy as a second- or later-line setting for metastatic non-small cell lung cancer (NSCLC) and to provide clinical evidence for this treatment regimen. The predictive value of extracellular vesicle (EV) membrane proteins was explored in patients who underwent this treatment., Methods: Clinical data from patients diagnosed with metastatic NSCLC who received immunotherapy plus single-agent chemotherapy as a second- or later-line setting were retrospectively collected between March 2019 and January 2022. A total of 30 patients met the inclusion criteria, and all were pathologically confirmed to have NSCLC. Short-term efficacy, progression-free survival (PFS), EV markers for response prediction, and adverse events were assessed., Results: Efficacy data were available for all 30 patients and included a partial response in 5 patients, stable disease in 18 patients, and disease progression in 7 patients. The objective response rate was 16.7%, the disease control rate was 76.7%, and the median PFS was 3.2 months. Univariate analysis showed that PFS was not associated with sex, age, smoking status, treatment lines, prior use of immunotherapy, or prior use of antiangiogenic drugs. The EV membrane proteins MET proto-oncogene, receptor tyrosine kinase (c-MET), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor receptor 2 (VEGFR2) at baseline were associated with poor prognosis and correlated with the efficacy of immunotherapy plus chemotherapy. According to the receiver operating characteristics and Kaplan-Meier curve analyses, patients with high c-MET, EGFR, and VEGFR2 expression at baseline had significantly shorter PFS than those with low expression. In addition, VEGFR2 expression was increased after combined immunotherapy in responders, which was decreased in non-responders. The most common grade 2 or higher adverse events were neutropenia, gastrointestinal reactions, and thyroid dysfunction, all of which were tolerated., Conclusions: Immunotherapy plus single-agent chemotherapy as a second- or later-line treatment is safe, effective, and tolerable for metastatic NSCLC. EV markers can be used as predictive markers of efficacy in patients with metastatic NSCLC treated with immunotherapy plus chemotherapy to help monitor treatment efficacy and guide treatment decisions., Competing Interests: Author MF was employed by the company EVbio Technology Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Li, Wang, Hu, Jiang, Li, Yang, Fan, Shi, Lv and Liu.)

Current management of small cell lung cancer (SCLC) remains challenging. Effective biomarkers are needed to subdivide patients presenting distinct treatment response and clinical outcomes. An understanding of heterogeneous phenotypes of aneuploid CD31 - circulating tumor cells (CTCs) and CD31 + circulating tumor endothelial cells (CTECs) may provide novel insights in the clinical management of SCLC. In the present translational and prospective study, increased cancer metastasis-related cell proliferation and motility, accompanied with up-regulated mesenchymal marker vimentin but down-regulated epithelial marker E-cadherin, were observed in both lentivirus infected SCLC and NSCLC cells overexpressing the stemness marker CD44v6. Aneuploid CTCs and CTECs expressing CD44v6 were longitudinally detected by SE-iFISH in 120 SCLC patients. Positive detection of baseline CD44v6 + CTCs and CD44v6 + CTECs was significantly associated with enhanced hepatic metastasis. Karyotype analysis revealed that chromosome 8 (Chr8) in CD44v6 + CTCs shifted from trisomy 8 towards multiploidy in post-therapeutic patients compared to pre-treatment subjects. Furthermore, the burden of baseline CD44v6 + CTCs (t 0 ) or amid the therapy (t 1-2 ), the ratio of baseline CD31 + CTEC/CD31 - CTC (t 0 ), and CTC-WBC clusters (t 0 ) were correlated with treatment response and distant metastases, particularly brain metastasis, in subjects with limited disease (LD-SCLC) but not in those with extensive disease (ED-SCLC). Multivariate survival analysis validated that longitudinally detected CD44v6 + /CD31 - CTCs was an independent prognostic factor for inferior survival in SCLC patients. Our study provides evidence for the first time that comprehensive analyses of CTCs, CTECs, and their respective CD44v6 + subtypes enable clinical stratification and improve prognostic prediction of SCLC, particularly for potentially curable LD-SCLC., Competing Interests: Declaration of competing interest Dr. Peter P. Lin is the president at Cytelligen. None of the authors has Cytelligen's stock. No additional COI to be declared., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The aim of the study was to explore the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with non-small cell lung cancer (NSCLC)., Methods: Studies that enrolled NSCLC patients treated with two lines of ICIs were included using four databases. The initial line (1L-) and subsequent lines (2L-) of ICIs were defined as 1L-ICI and 2L-ICI, respectively., Results: A total of 17 studies involving 2100 patients were included. The pooled objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and median overall survival (mOS) for 2L-ICIs were 10%, 50%, 3.0 months, and 13.1 months, respectively. The 2L-ICI discontinuation rates caused by toxicities ranged from 0% to 23.5%. Original data were extracted from six studies, covering 89 patients. Patients in whom 1L-ICIs were discontinued following clinical decision (the mPFS of 2L-ICIs was not reach) achieved a more prolonged mPFS of 2L-ICIs than those due to toxicity (5.2 months) and progressive disease (2.1 months) (p < 0.0001). Patients' 1L-PFS for more than 2-years had preferable 2L-ORR (35.0% vs. 9.8%, p = 0.03), 2L-DCR (85.0% vs. 49.0%, p = 0.007), and 2L-mPFS (12.4 vs. 3.0 months, p < 0.0001) than those less than 1-year. Patients administered the same drugs achieved a significantly prolonged mPFS compared with the remaining patients (5.4 vs. 2.3 months, p = 0.0004), and those who did not accept antitumor treatments during the intervals of two lines of ICIs achieved a prolonged mPFS compared to those patients who did accept treatments (7.6 vs. 1.9 months, p < 0.0001)., Conclusions: ICI rechallenge is a useful therapeutic strategy for NSCLC patients, especially suitable for those who achieve long-term tumor remission for more than 2-years under 1L-ICIs., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Furmonertinib (AST2818) is a brain penetrant pan-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both EGFR sensitizing mutations and T790M mutation. We report the pooled central nervous system (CNS) efficacy data of furmonertinib in patients with EGFR T790M mutated non-small cell lung cancer (NSCLC) from two phase 2 studies., Methods: This was a pooled, post-hoc analysis of two phase 2 studies (NCT03127449 [phase 2a study of furmonertinib], NCT03452592 [phase 2b study of furmonertinib]). In the phase 2a study, patients received furmonertinib 40 mg, 80 mg, 160 mg, or 240 mg orally once daily. In the phase 2b study, all patients received furmonertinib 80 mg orally once daily. CNS efficacy of furmonertinib was analyzed in patients with baseline CNS lesions by an independent review center per Response Evaluation Criteria in Solid Tumors version 1.1., Results: A total of 132 patients with baseline CNS metastases were included in this analysis. In 52 patients with measurable CNS lesions, CNS objective response rates were zero (0/1), 65% (22/34), 85% (11/13), and 25% (1/4), and CNS disease control rates were zero (0/1), 97% (33/34), 100% (13/13), and 100% (4/4) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively. In patients with measurable or non-measurable CNS lesions, median CNS progression-free survival was 2.8 months (95% confidence interval [CI] 1.4-8.3), 11.6 months (95% CI 8.3-13.8), 19.3 months (95% CI 5.5-not available [NA]), and not reached (95% CI 2.8 months-NA) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively., Conclusions: Furmonertinib showed promising CNS efficacy in doses of 80 mg orally once daily or higher in patients with EGFR T790M mutated NSCLC., Trial Registration: Both studies were registered on ClinicalTrial.gov. The phase 2a study was registered with NCT03127449 on April 25, 2017; The phase 2b study was registered with NCT03452592 on March 2, 2018., (© 2023. The Author(s).)

Background: As a potential target receptor tyrosine kinase, mesenchymal-epithelial transition factor (MET) exhibits high aberrant expression across various tumors. This study aimed to evaluated the safety, tolerability, efficacy and pharmacokinetics (PK) of BPI-9016M, a novel tyrosine kinase inhibitor (TKI) targeting c-MET, in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC)., Methods/design: In this two-part multicenter phase Ib study, eligible patients with locally advanced or metastatic NSCLC harboring c-MET overexpression or MET exon 14 skipping mutation were enrolled into Part A (tested positive for c-MET overexpression [immunohistochemical staining score ≥ 2+]; 300 mg quaque die [QD], 450 mg QD and 600 mg QD cohorts) or Part B (tested positive for MET exon 14 skipping mutation; 400 mg bis in die [BID] cohort), respectively. The primary endpoints were safety, objective response rate (ORR) and disease control rate (DCR), the second endpoints were PK parameters, progression-free survival (PFS) and overall survival (OS)., Results: Between March 15, 2017 and September 18, 2021, 38 patients were enrolled (Part A, n = 34; Part B, n = 4). Of 38 patients, 32 (84.2%) patients completed the treatment protocol. As of the data cut-off date on January 27, 2022, all patients reported at least one treatment-emergent adverse event (TEAE). Ninety-two point one percent (35/38) of patients experienced treatment-related adverse events (TRAEs), and grade ≥ 3 TRAEs were observed in 11 (28.9%) patients. The most common TRAEs were elevated alanine aminotransferase (ALT, 14/38, 36.8%) and elevated aspartate aminotransferase (AST, 11/38, 28.9%). Only one (2.6%) patient had treatment-related serious adverse event (SAE) in 600 mg QD cohort due to thrombocytopenia. PK analysis showed BPI-9016M and its main metabolites (M1 and M2-2) reached steady state after seven days of continuous administration. At the dose of 300 mg QD and 450 mg QD, the exposure of BPI-9016M increased with increasing dose. Exposure of BPI-9016M was similar at 450 mg QD and 600 mg QD, which may exhibit a saturation trend. In all patients, ORR and DCR were 2.6% (1/38, 95% confidence interval [CI] 0.1-13.8%) and 42.1% (16/38, 95% CI 26.3-59.2%), respectively. Only one partial response (PR) patient was observed at a dose of 600 mg QD in Part A. In Part B, DCR was 75.0% (3/4, 95% CI 19.4-99.4%). The median PFS and OS in all 38 patients were 1.9 months (95% CI 1.9-3.7) and 10.3 months (95% CI 7.3-not evaluable [NE]), respectively., Conclusion: BPI-9016M showed manageable safety profile in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic NSCLC, but showed limited efficacy., Trial Registration: Clinicaltrials.gov NCT02929290 (11/10/2016)., (© 2023. The Author(s).)

Objective: To retrospectively analyze the efficacy and safety of osimertinib combined with anlotinib in the treatment of advanced non-small-cell lung cancer (NSCLC) after drug resistance, and to explore the related factors affecting the efficacy., Methods: The clinical data of 34 patients with advanced NSCLC who received osimertinib combined with anlotinib as three or more lines of treatment in the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from June 2019 to March 2022 were collected, and the therapeutic efficacy and safety were analyzed., Results: A total of 34 advanced NSCLC patients met the inclusion criteria. The objective response rate was 20.6%, the disease response rate was 88.2%, the median overall survival was 19.0 months, and the median progression-free survival was 6.0 months. The common adverse events were mainly grade 1-2, and only three cases (11.1%) of adverse events were grade 3, including hypertension, proteinuria, and vomiting. No grade 4 or above adverse events were observed. Multivariate Cox regression analysis showed that the Eastern Cooperative Oncology Group Performance Status score and bone metastasis were independent prognostic factors for osimertinib combined with anlotinib as three or more lines of treatment in advanced NSCLC., Conclusions: Osimertinib combined with anlotinib as three or more lines of treatment in advanced NSCLC was effective and adverse events were tolerable., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Introduction: The treatment response to neoadjuvant immunochemotherapy varies among patients with potentially resectable non-small cell lung cancers (NSCLC) and may have severe immune-related adverse effects. We are currently unable to accurately predict therapeutic response. We aimed to develop a radiomics-based nomogram to predict a major pathological response (MPR) of potentially resectable NSCLC to neoadjuvant immunochemotherapy using pretreatment computed tomography (CT) images and clinical characteristics., Methods: A total of 89 eligible participants were included and randomly divided into training (N=64) and validation (N=25) sets. Radiomic features were extracted from tumor volumes of interest in pretreatment CT images. Following data dimension reduction, feature selection, and radiomic signature building, a radiomics-clinical combined nomogram was developed using logistic regression analysis., Results: The radiomics-clinical combined model achieved excellent discriminative performance, with AUCs of 0.84 (95% CI, 0.74-0.93) and 0.81(95% CI, 0.63-0.98) and accuracies of 80% and 80% in the training and validation sets, respectively. Decision curves analysis (DCA) indicated that the radiomics-clinical combined nomogram was clinically valuable., Discussion: The constructed nomogram was able to predict MPR to neoadjuvant immunochemotherapy with a high degree of accuracy and robustness, suggesting that it is a convenient tool for assisting with the individualized management of patients with potentially resectable NSCLC., Competing Interests: Author HL was employed by the company GE Healthcare. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Zhao, Xie, Lin, Hu, Li, Shang, Wang, Jiang, Ding, Peng, Xu, Hu, Huang, Gao, Liu, Liu and Ma.)

Background: To report the efficacy and safety data of immunotherapy plus angiogenic inhibitors treatment in lung adenocarcinoma patients., Methods: Eligible patients with pathological or cytological confirmed locally advanced or metastatic lung adenocarcinoma and treated with immune checkpoint inhibitors (ICI) plus angiogenic inhibitors were enrolled. The primary endpoints were progressive free survival (PFS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety., Results: A total of 46 consecutive enrolled patients received ICI plus angiogenic inhibitor, and the median follow-up was 9.6 months (range 1.5-32.5). The ORR and DCR were 8.7% (n = 4) and 50% (n = 23), respectively. Median PFS and OS were 2.9 months (95% CI 2.1-3.7) and 12.3 months (95% CI 7.6-17.0), respectively. Patients at stage IVB had an inferior PFS than stage IIIC or IVA (2.8 months vs 4.4 months, P = 0.003). The median PFS of patients who were treated with ICI plus bevacizumab was shorter than ICI plus anlotinib or apatinib (1.2 months vs 3.3 months, P = 0.005). The occurrence of hypertension during the combination treatment has been related to a tendency for prolonged PFS (5.5 months vs 2.6 months; P = 0.05). The overall incidence of treatment-related adverse events (TRAE) was 89.1% (n = 41), and grade 3-4 TRAE was occupied 21.4% (n = 10)., Conclusion: This study objectively demonstrated that the treatment of ICI and antiangiogenic agents in lung adenocarcinoma could be a promising alternative therapeutic regimen, and the toxic effects were manageable. Subgroup analysis revealed that small molecular angiogenic inhibitors plus ICI and low tumor burden during treatment were better prognostic factors., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Resistance to epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (TKIs) is a pervasive barrier in TKIs therapy for EGFR/ALK-positive non-small cell lung cancer (NSCLC) patients. Immune checkpoint inhibitor (ICI) monotherapy has exhibited an encouraging anti-tumor activity in high-selected EGFR/ALK-positive NSCLC patients with acquired resistance to TKI therapy. However, the effect of ICI plus chemotherapy therapy on those with brain metastases in this subset of patients is still unknown., Methods: From April 2019 to August 2021, EGFR-mutated or ALK-rearranged NSCLC patients who progressed after previous EGFR/ALK-TKIs with brain metastases and received ICI plus chemotherapy ± bevacizumab at Cancer Hospital of the Chinese Academy of Medical Sciences (CAMS) were included. We retrospectively analyzed the efficacy, toxicity and progression site after ICI treatment., Results: A total of 19 patients were included in the study, including 16 (84.4%) patients with EGFR mutations, 2 (10.5%) with ALK translocations and 1 (5.3%) with RET rearrangement. All of the patients progressed after previous TKI therapy and had brain metastatic lesions when received ICI combination therapy. The overall response rate (ORR) and disease control rate (DCR) were 15.8 and 57.9%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 4.7 months (95% confidence interval CI 0.43-8.96) and 19.2 months (95% CI 15.08-23.29), respectively. The intracranial ORR was 10.5% and extracranial ORR was 15.8%, and the intracranial and extracranial DCR were 68.4 and 63.2%, respectively. The most common progression pattern was extracranial failure, and primary lesions enlargement rather than new sites metastases accounted for the vast majority of progressions. The most common grade 3-4 adverse event (AE) was leukopenia (31.6%), followed by neutropenia (26.3%), thrombocytopenia (10.5%) and rash (5.3%) successively. No grade 5 AE and discontinuation of ICI therapy for severe AEs were observed., Conclusions: ICI combined with chemotherapy ± bevacizumab might be effective and safe for EGFR/ALK-positive NSCLC patients who progressed after previous TKI therapy, and synergistic anti-tumor activity for brain metastases was also observed., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Real-world application of osimertinib with antiangiogenic agents in non-small cell lung cancer (NSCLC) is common, but the efficacy data are rarely reported., Methods: To obtain an objective efficacy report of different real-world treatment models of osimertinib and antiangiogenic agents., Results: A total of 54 patients with NSCLC were enrolled into the study. Twelve (22.2%) who received a combination of antiangiogenic agents, when there was a trend of osimertinib resistance but did not reach imageology progressive disease (PD), were assigned to Group A, with a median overall survival (OS) and progression-free survival (PFS) of 48.0 (95% CI, not reached) and 21.0 (95% CI: 16.7-25.3) months, respectively. Thirty (55.6%) who received a combination of antiangiogenic agents when there was imageology PD during treatment with osimertinib were assigned to Group B, with a median OS and PFS of 31.8 (95% CI: 26.6-37.1) and 9.2 (95% CI: 5.9-12.6) months, respectively. Twelve (22.2%) who received a combination of antiangiogenic agents at the initial treatment with osimertinib were assigned to Group C, with a median OS and PFS of 28.5 (95% CI: 15.2-41.8) and 15.3 (95% CI: 7.9-22.7) months, respectively. Patients in Group A achieved a significant prolonged median PFS (p < 0.001) compared with Groups B and C. Absence of epidermal growth factor receptor (EGFR) T790M mutations (p = 0.043; hazard ratio [HR] = 2.124, 95% CI: 1.023-4.413) and no previous antiangiogenic agent application (p = 0.012; HR = 0.362, 95% CI: 0.163-0.863) were the independent prognostic factors of OS., Conclusion: The well-timed action to combine antiangiogenic agents was when there was a trend of osimertinib resistance. The absence of EGFR T790M mutations and previous use of antiangiogenic agents were poor prognostic factors., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Although targeted agents have been gradually applied in the treatment of HER2-mutated non-small cell lung cancer (NSCLC) in recent years, patients' therapeutic demands are far from being met. PATHER2 was the first phase 2 trial to explore the efficacy and safety of the HER2-targeted tyrosine kinase inhibitor (TKI) pyrotinib plus the antiangiogenic agent apatinib in previously treated HER2-altered metastatic NSCLC patients., Methods: HER2-mutated or HER2-amplified metastatic NSCLC patients who had failed at least first-line chemotherapy or HER2-targeted TKIs received oral pyrotinib 400 mg plus apatinib 250 mg once daily until disease progression, intolerable toxicity, or death. The primary endpoint was the investigator-assessed objective response rate (ORR)., Results: Between March 2019 and December 2020, 33 patients were enrolled; 13 (39.4%) presented brain metastases, and 16 (48.5%) had received at least two lines of prior chemotherapy or HER2-targeted TKIs. As of September 20, 2021, the median follow-up duration was 11.3 (range, 3.5-26.0) months. The investigator-assessed ORR was 51.5% (17/33; 95% CI, 33.5 to 69.2%), and the disease control rate was 93.9% (31/33; 95% CI, 79.8 to 99.3%). The median duration of response, progression-free survival, and overall survival were 6.0 (95% CI, 4.4 to 8.6) months, 6.9 (95% CI, 5.8 to 8.5) months, and 14.8 (95% CI, 10.4 to 23.8) months, respectively. The most frequent grade ≥ 3 treatment-related adverse events included diarrhea (3.0%) and hypertension (9.1%). No treatment-related deaths were reported., Conclusions: Pyrotinib plus apatinib demonstrated promising antitumor activity and a manageable safety profile in HER2-mutated or HER2-amplified metastatic NSCLC patients., Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR1900021684 ., (© 2022. The Author(s).)

Purpose: To investigate the feasibility of biomarkers based on dynamic circulating tumor DNA (ctDNA) to classify small cell lung cancer (SCLC) into different subtypes., Materials and Methods: Tumor and longitudinal plasma ctDNA samples were analyzed by next-generation sequencing of 1,021 genes. PyClone was used to infer the molecular tumor burden index (mTBI). Pre-treatment tumor tissues [T1] and serial plasma samples were collected (pre-treatment [B1], after two [B2], six [B3] cycles of chemotherapy and at progression [B4])., Results: Overall concordance between T1 and B1 sequencing (n=30) was 66.5%, and 89.5% in the gene of RB1. A classification method was designed according to the changes of RB1 mutation, named as subtype Ⅰ (both positive at B1 and B2), subtype Ⅱ (positive at B1 but negative at B2), and subtype Ⅲ (both negative at B1 and B2). The median progressive-free survival for subtype Ⅰ patients (4.5 months [95%CI: 2.6-5.8]) was inferior to subtype Ⅱ (not reached, p<0.0001) and subtype Ⅲ (10.8 months [95%CI: 6.0-14.4], p=0.002). The median overall survival for subtype Ⅰ patients (16.3 months [95%CI: 5.3-22.9]) was inferior to subtype Ⅱ (not reached, p=0.01) and subtype Ⅲ (not reached, p=0.02). Patients with a mTBI dropped to zero at B2 had longer median overall survival (not reached vs. 19.5 months, p=0.01). The changes of mTBI from B4 to B1 were sensitive to predict new metastases, with a sensitivity of 100% and a specificity of 85.7%., Conclusion: Monitoring ctDNA based RB1 mutation and mTBI provided a feasible tool to predict the prognosis of SCLC.

Background: Antibodies targeting programmed cell death-1(PD1) and its ligand (PDL1) have revolutionized cancer therapy. However, little is known about the preexisted anti-PD1/PDL1 autoantibodies (AAbs) distribution in multiple cancer types, nor is their potential biomarker role for anti-PD1 therapy., Method: Plasma anti-PD1/PDL1 AAb IgG and subclasses (IgG1-4) were detected by enzyme-linked immune sorbent assay (ELISA) in 190 cancer patients, covering 10 cancer types (lung, breast, esophageal, colorectal, liver, prostatic, cervical, ovarian, gastric cancers and lymphoma), the comprehensive correlation of AAbs with multiple clinical parameters was analyzed. We further tested these AAbs in 76 non-small cell lung cancer (NSCLC) samples receiving anti-PD1 therapy, the association of AAbs level with survival was analyzed and validated in an independent cohort (n = 32)., Results: Anti-PD1/PDL1 AAb IgG were globally detected in 10 types of cancer patients. IgG1 and IgG2 were the major subtypes for anti-PD1/PDL1 AAbs. Correlation analysis revealed a distinct landscape between various cancer types. The random forest model indicated that IgG4 subtype was mostly associated with cancer. In discovery cohort of 76 NSCLC patients, high anti-PD1 IgG4 was associated with a reduced overall survival (OS, p = 0.019), not progression-free survival (PFS, p = 0.088). The negative association of anti-PD1 IgG4 with OS was validated in 32 NSCLC patients (p = 0.032)., Conclusion: This study reports for the first time the distribution of preexisted anti-PD1/PDL1 AAb IgG and subclasses across 10 cancer types. Moreover, the anti-PD1 AAb IgG4 subclass was identified to associate with OS, which may serve as a potential biomarker for anti-PD1 therapeutic survival benefit in NSCLC patients., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: There are no approved epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for EGFR-mutated non-small cell lung cancer (NSCLC) without EGFR T790M mutation after progression on first- or second-generation EGFR-TKIs., Methods: We conducted this phase I, open-label, multicenter, dose-escalation/dose-expansion study to evaluate the safety, tolerability, antitumor activity, and pharmacokinetics of FCN-411, a TKI targeting EGFR, HER2, and HER4, in patients with EGFR-mutated advanced NSCLC whose disease had progressed during treatment of EGFR-TKIs. Adult patients with stage IIIB-IV NSCLC harboring EGFR mutations (exon 18/19/20/21) who had progressed on prior EGFR-TKIs were enrolled. In the dose-escalation phase, patients received 4 mg, 8 mg, 12 mg, and 16 mg FCN-411 once daily until the maximum tolerated dose (MTD). In the dose-expansion phase, patients received FCN-411 at the recommended phase II dose (RP2D) continuously in 21-day cycles. The primary endpoints were safety, tolerability, MTD, and RP2D., Results: From July 23, 2018 to September 29, 2020, 77 patients were enrolled, including 30 with EGFR T790M mutation in tumor tissues. The cut-off date was February 1, 2021. No dose-limiting toxicities were observed. The most common grade ≥ 3 treatment-emergent adverse events among all patients were diarrhea (8; 10.4%) and dermatitis acneiform (7; 9.1%). Ten of 67 evaluable patients achieved confirmed partial response, with an objective response rate (ORR) of 14.9% (95% confidence interval [CI], 8.3-24.0); the ORR was 33.3%, 14.0%, 0, and 25.0% at 4 mg, 8 mg, 12 mg, and 16 mg, respectively. Besides, the ORR in patients without and with EGFR T790M mutation was 20.5% and 7.4%, respectively. Moreover, 39 patients achieved stable disease across all doses, and the disease control rate was 73.1% (95% CI, 60.9-83.2). Median progression-free survival was 4.1 (95% CI, 2.9-5.3) months. Median duration of response and overall survival have not been reached., Conclusions: FCN-411 was well tolerated and demonstrated preliminary antitumor activity in patients with EGFR-mutated NSCLC after progression on EGFR-TKIs, especially in those without EGFR T790M mutation. The RP2D was defined as 8 mg once daily. Future studies are warranted., Trial Registration: ClinicalTrials.gov, NCT03420079., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Hyaluronan (HA) is one of the essential elements of the extracellular matrix (ECM), involved in the onset of metastasis in various tumors. The interaction and binding of the ligand-receptor HA/cluster of differentiation-44 (CD44) regulate the physical and biochemical properties of the ECM, which correlates with an increased propensity toward metastasis and poor survival outcome. Our study aimed to explore HA for predicting metastasis and survival rate in patients with small-cell lung cancer (SCLC)., Materials and Methods: This prospective cohort study recruited 72 patients with SCLC. Plasma HA and CD44 levels were assayed by enzyme-linked immunosorbent assay (ELISA) for 72 cases before initial systematic treatment (baseline samples), and plasma HA was detected via after-2-cycle-chemotherapy (A-2-C-CT) in 48 samples. Logistic regression analysis and the Cox proportional risk model were used to determine the independent predictors of distant metastasis and survival rate of patients., Results: Baseline plasma HA was notably associated with bone metastasis (BM) [OR (95% CI = 1.015 (1.006-1.024), p = 0.001]. Multivariate logistic regression analysis showed that baseline plasma HA was chosen as an independent predictor of BM. Either baseline HA or CD44 or both were associated with BM. Dynamic alteration of HA was notably associated with A-2-C-CT clinical efficacy. Multivariate Cox regression analysis in forward likelihood ratio showed that A-2-C-CT HA was an independent predictor of progression-free survival (PFS) and overall survival (OS)., Conclusions: HA appears to be used as an independent predictive factor for BM, and the dynamic detection of HA can predict prognosis in SCLC patients. The mechanism of the HA/CD44 axis in BM of SCLC deserves further exploration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Zhang, Hu, Zhang, Liu, Wang, Guo, Zhang, Li and Li.)

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have improved the prognosis of mutant lung cancer; however, the clinical application value of TKIs for nonclassical EGFR mutation is unclear, especially for patients with rare uncommon mutations., Methods: A retrospective study based on electronic medical records was conducted to collect data on the effectiveness of afatinib in patients with stage IIIB/IV lung adenocarcinoma (LUAD) bearing uncommon mutations between January 2017 and January 2021., Results: Forty-two patients with uncommon mutations treated with afatinib were enrolled. The objective response rate (ORR) was 50.0% (10 of 20 patients). The median time to treatment failure (TTF) was 11.7 months (95% confidence interval = 8.5-18.3 months). Of the 42 patients, the median TTF was 15.0, 11.7, and 16.6 months in patients with Gly719Xaa (G719X), Ser768Ile (S768I), and Leu861Gln (L861Q) mutations, respectively. In patients with the rare uncommon mutation, the median TTF was 10.0 months, and the ORR was 50.0%. Afatinib demonstrated clinical activity across a set type of specific rare uncommon mutations, including EGFR L747P, A767&#95;V769dup, and L833V/H835L, with a case having a TTF of more than 1 year. Molecular profiling reports of 16 afatinib-resistant biopsy samples were available, and the secondary T790M mutation was detected in one patient with L833V/H835L mutation and one harboring S768I/L858R mutation., Conclusions: Our findings suggested that afatinib is effective in patients with uncommon mutations. Mechanisms of afatinib resistance vary and need further investigation., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Transformation to small cell lung cancer (SCLC) is a resistance mechanism of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (LADC) patients treated with EGFR tyrosine kinase inhibitors (TKIs). Here, we describe the clinical characteristics and prognosis of these patients and explore the treatment modes after transformation., Methods: EGFR-mutant LADC patients with SCLC transformation were retrospectively included in the study. Demographic and clinical data were collected. Survival outcomes and corresponding influential factors were analyzed., Results: Twenty-nine patients were included in the study. The median progression-free survival (PFS) of patients who received first-line EGFR-TKIs was 13.1 months. The median time to SCLC transformation was 27.5 months. After transformation, the objective response rates of patients who received first-line chemotherapy with or without EGFR-TKIs were 43.8% and 37.5%, respectively. The median PFS of patients reveiving chemotherapy with EGFR-TKIs was significantly longer than that of patients receiving chemotherapy without EGFR-TKIs (5.2 vs. 3.0 months; HR, 0.19; 95% CI: 0.05-0.72; p = 0.014). However, there was no significant difference in median overall survival (OS) between patients who received chemotherapy with or without EGFR-TKIs (14.8 vs. 13.0 months; p = 0.474). In the multivariate Cox proportional hazards regression analysis, both anti-angiogenic treatment (HR, 0.04; 95% CI: 0.01-0.29; p = 0.001) and local radiotherapy (HR, 0.28; 95% CI: 0.08-0.97; p = 0.044) were significantly associated with better patient OS after transformation., Conclusions: Compared with chemotherapy alone, the combination of chemotherapy and EGFR-TKIs as first-line treatment after SCLC transformation can benefit patients in PFS but not in OS. However, anti-angiogenic therapies and local radiotherapy can significantly prolong OS after transformation., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Previous studies have demonstrated that PD-1 inhibitors are effective in the treatment of advanced or metastatic non-small cell lung cancer (NSCLC). However, whether the combination of PD-1 inhibitors and antiangiogenic agents benefit advanced NSCLC patients as subsequent therapy remains unknown. In this study, we retrospectively reviewed the efficacy and safety profile of this combination strategy as subsequent therapy for NSCLC patients in a real-world setting., Methods: A total of 30 patients with advanced NSCLC, who progressed after at least two cycles of platinum-based chemotherapy or targeted therapy and subsequently received combination therapy with a PD-1 inhibitor and antiangiogenic agent, were included in this study. The safety profile and efficacy were also investigated., Results: At the time of a median follow-up period of 10.7 months, 28 patients had experienced progression of disease and 16 patients had died. The median progression-free survial (mPFS) was 5.0 months (95% confidence interval [CI]: 3.179-6.821), and the median overall survival (mOS) was 14.3 months (95% CI: 8.912-19.659). The objective response rate (ORR) and the disease control rate (DCR) were 10.3% and 72.4%, respectively (0 complete remission, three partial responses and 18 stable disease in 29 patients with measurable lesions). Patients with PD-L1 expression of at least 1% of tumor cells (n = 5) had relatively longer mPFS compared to those with PD-L1-negative tumors (n = 14), (11.6 months vs. 3.7 months). Treatment was suspended in two patients due to grade 3 immune-related pneumonia and pancreatitis, respectively. No novel adverse events (AEs) or grade 4 AEs were observed., Conclusions: A combination of PD-1 inhibitors and antiangiogenic targeting agents may be beneficial for patients with advanced or metastatic NSCLC as subsequent treatment, especially for patients with PD-L1 protein expression positive, and treatment is well tolerated., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Furmonertinib (AST2818) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both sensitising EGFR and EGFR Thr790Met (T790M) mutations. This study aimed to assess the efficacy and safety of furmonertinib in patients with EGFR T790M mutated advanced non-small-cell lung cancer (NSCLC)., Methods: This study was a single-arm, open-label, phase 2b study at 46 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC with centrally confirmed EGFR T790M mutations in tumour tissue who progressed after first or second generation EGFR TKIs or with primary EGFR T790M mutations received furmonertinib 80 mg orally once daily. The primary endpoint was objective response rate. Efficacy was assessed by blinded independent central review as per the Response Evaluation Criteria in Solid Tumors (version 1.1) in all patients who had measurable disease at baseline and received at least one dose of furmonertinib. Safety was assessed as per the Common Terminology Criteria for Adverse Events (version 4.03) in all patients who received at least one dose of furmonertinib with at least one safety assessment during follow-up. This study is registered with ClinicalTrials.gov (NCT03452592) and is ongoing for survival follow-up., Findings: From Jun 4, 2018, to Dec 8, 2018, 220 patients received furmonertinib treatment. All 220 patients were included in the efficacy and safety analyses. At the data cutoff point of Jan 29, 2020, 71 (32%) patients remained on treatment. The median duration of follow-up was 9·6 months (range 0·7-19·4). The objective response rate was 74% (163 of 220 [95% CI 68-80]). Grade 3 or higher adverse events occurred in 58 (26%) patients and treatment-related grade 3 or higher adverse events occurred in 25 (11%) patients. The most common all-cause grade 3 or higher adverse events were increased γ-glutamyltransferase (five; 2%), increased aspartate aminotransferase, increased alanine aminotransferase, hyponatraemia, hypertension, pulmonary infection, hypermagnesaemia, and pericardial effusion (three each; 1%). Treatment-related diarrhoea was reported in ten (5%) patients and rashes were reported in 16 (7%) patients, all grade 1-2. Serious adverse events were reported in 52 (24%) patients, of which 12 (5%) were possibly treatment-related as evaluated by the investigator., Interpretation: Furmonertinib has promising efficacy and an acceptable safety profile for the treatment of patients with EGFR T790M mutated NSCLC. Furmonertinib is expected to become a new treatment option after first or second generation EGFR TKIs in the Chinese population., Funding: Shanghai Allist Pharmaceutical Technology, Ministry of Science and Technology of the People's Republic of China, and Chinese Academy of Medical Sciences., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests YJ and CG are employees and shareholders of Shanghai Allist Pharmaceutical Technology. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: While prospective clinical studies on immunotherapy in epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC) with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) are ongoing, this study aimed to investigate the outcomes of immunotherapy combinations in such a population in a real-world setting., Methods: The clinical data of pretreated EGFR-mutated NSCLC patients who acquired EGFR-TKI resistance and received immunotherapy were retrospectively analyzed in this study. Progression-free survival (PFS) was assessed using the Kaplan-Meier log-rank test, and univariate and multivariate analysis were performed., Results: A total of 31 patients were analyzed in this study. A total of 25 (80.6%) patients received combination immunotherapy. In the univariate analysis, patients who received combination immunotherapy seemingly acquired longer PFS than those who received monotherapy, although there was no significant difference (3.42 months vs. 1.61; P = 0.078; hazard ratio (HR) 0.43, 95% CI: 0.16-1.13). Patients who received antiangiogenic drugs prior to immunotherapy acquired better PFS (3.42 months vs. 1.58; P = 0.027; HR 0.37, 95% CI: 0.15-0.93), while patients with liver metastasis had inferior PFS (2.04 months vs. 3.42; P = 0.031; HR 2.83, 95% CI: 1.05-7.60). Furthermore, multivariate analysis confirmed that the above three factors had independent prognostic value., Conclusions: The study revealed that immunotherapy combinations are better choices than single-agent regimens in previously treated and EGFR-mutant NSCLC patients with progressive disease. In addition, antiangiogenic drugs administered before immunotherapy might be a favorable prognostic factor, while liver metastasis was associated with a short PFS in this setting. In future, more robust and prospective clinical trial results are expected to guide clinical practice., Key Points: Significant study findings Immunotherapy-based combination therapies are better choices than single-agent regimens in heavily treated EGFR-mutant NSCLC patients. What this study adds Patients without liver metastasis and with prior antiangiogenic drugs obtained more benefit from immunotherapy in this setting., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Bevacizumab is the first antiangiogenetic monoclonal antibody, combined with platinum-based double agent chemotherapy, which has been reported to improve the objective response rate (ORR) and progression-free survival (PFS) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC), and to improve overall survival (OS) in patients when combined with carboplatin and paclitaxel. However, serious adverse effects have been reported to be associated with bevacizumab therapy. In this multicenter prospective cohort study of advanced lung adenocarcinoma patients with stable disease after two cycles of platinum-based double agent chemotherapy, we will compare the ORR between the group who continued with their original chemotherapy regimen and the group in which bevacizumab was added to the original regimen. It is expected that there will be an ORR improvement of 20% in patients in the bevacizumab group plus chemotherapy, compared with those in the original chemotherapy group. This study has been registered as Clinical Trial NCT03240549., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Purpose: Osimertinib, a third-generation epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI), has demonstrated substantial clinical benefit in patients with non-small-cell lung cancer (NSCLC) who were resistant to early-generation EGFR-TKIs and had acquired a T790M mutation. The aim of our study was to identify the mechanisms underlying resistance to osimertinib and to correlate them with clinical outcomes., Methods: We retrospectively analyzed patients with advanced NSCLC who received osimertinib for T790M-mutated acquired resistance to prior EGFR-TKIs between March 1, 2017 and December 31, 2018. Patients with paired molecular data of pre-osimertinib and after resistance development, which were not confirmed with small-cell lung cancer (SCLC) transformation, were included in the molecular analysis set., Results: Of 49 patients evaluated in the molecular analysis set, 24 patients maintained T790M mutation, while 25 patients exhibited T790M-loss. Molecular modifications were identified in 27 of 49 patients including EGFR acquired mutations (C797S, C796S, G796S, V802I, V834L, E758D and G724S), non-EGFR-dependent mutations (PIK3CA, ALK, BRAF, KRAS and TP53), EGFR amplification and MET amplification. At data cutoff, median progression-free survival (PFS) was 9.3 months in the T790M-retain group compared with 7.8 months in T790M-loss patients (P = 0.053). Median PFS was significantly longer in patients with EGFR-dependent resistance mechanism (13.5 months) than in those with alternative pathway activation (8.2 months; P = 0.012)., Conclusions: The study revealed heterogeneous mechanisms of resistance to osimertinib in advanced NSCLC patients and their association with clinical outcomes. Patients who maintained T790M mutation or with EGFR-dependent resistance mechanism had longer clinical outcome benefits.

Purpose: Our primary purpose is to explore safety and efficacy of high-dose icotinib in comparison with routine-dose icotinib in patients with non-small cell lung cancer (NSCLC) harboring 21-L858R mutation., Patients and Methods: Patients with treatment-naïve, EGFR-mutant (21-L858R or exon 19 deletion at 2:1) NSCLC were enrolled. Patients with 21-L858R mutation were randomized to receive routine-dose icotinib (125 mg, thrice daily; L858R-RD) or high-dose icotinib (250 mg, thrice daily; L858R-HD), whereas patients with exon 19 deletion received only routine-dose icotinib (19-Del-RD) until progression, death, or unacceptable toxicity. The primary endpoint was median progression-free survival (mPFS), assessed by an independent review committee., Results: From May 2015 to November 2017, 253 patients (86 in L858R-RD; 90 in L858R-HD; and 77 in 19-Del-RD) were enrolled. The mPFS in L858R-HD group was similar to that in 19-Del-RD group (12.9 months and 12.5 months, respectively) and was significantly longer than that in L858R-RD group [12.9 months vs. 9.2 months, hazard ratio (HR): 0.75; 95% confidence interval (CI), 0.53-1.05]. A longer but statistically nonsignificant mPFS was observed between 19-Del-RD and L858R-RD groups (12.5 months vs. 9.2 months, HR: 0.80; 95% CI, 0.57-1.13). A higher objective response rate (ORR) was observed in L858R-HD group compared with L858R-RD group (73% vs. 48%), also between 19-Del-RD and L858R-RD groups (75% vs. 48%). Similar incidences of grade 3/4 toxicities were observed among the three treatment groups., Conclusions: High-dose icotinib improved mPFS and ORR in patients with NSCLC harboring 21-L858R mutation with acceptable tolerability, which could be a new therapeutic option for this patient population., (©2020 American Association for Cancer Research.)

Introduction: Alflutinib (AST2818) is a newly developed third-generation EGFR tyrosine kinase inhibitor selective for EGFR-sensitizing and T790M-resistant mutations. We assessed the safety, efficacy, and pharmacokinetics of alflutinib in patients with advanced NSCLC with confirmed EGFR T790M mutation, whose status progressed after the first- or second-generation EGFR tyrosine kinase inhibitor therapy., Methods: In the dose-escalation (NCT02973763) and dose-expansion (NCT03127449) studies, patients received alflutinib orally until disease progression, unacceptable toxicity, or subject withdrawal. The primary end points were safety, tolerability, and pharmacokinetics for the dose-escalation study and the objective response rate (assessed by an independent radiological review committee) for the dose-expansion study., Results: Between November 30, 2016, and July 24, 2018, a total of 130 patients (14 in dose escalation, 116 in dose expansion) received alflutinib treatment (20 mg, 40 mg, 80 mg, 160 mg, or 240 mg once daily). On October 30, 2018, 79 patients (61%) remained on the treatment. No dose-limiting toxicities were observed in the dose-escalation study. In the dose-expansion study (40-240 mg), the overall objective response rate was 76.7% (89 of 116), and it was 70.6% in patients with central nervous system metastases (12 of 17). A total of 79% of all patients had possibly treatment-related adverse events (AEs) (103 of 130); 8% had treatment-related grade 3 or higher AEs (11 of 130). Serious AEs were reported in 15% of patients (20 of 130), and two serious AEs were related to treatment. No clear dose-response (antitumor activity and AEs) relationships were observed. Exposures to alflutinib and its active metabolite (AST5902) were comparable at steady state., Conclusions: Alflutinib was clinically effective with an acceptable toxicity profile in patients with advanced NSCLC (including those with central nervous system metastases) with EGFR T790M mutation. Further investigation is ongoing., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Because of rapid disease progression and lack of optimal treatment strategies beyond the second-line, the prognosis of patients with extensive-stage (ES) small cell lung cancer (SCLC) still remains depressing. Alternative treatment strategies are required to improve their prognosis. In this prospective clinical study, we aimed to evaluate the feasibility of single-agent apatinib, a vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, as a treatment option for patients with ES-SCLC after failure of at least two prior chemotherapy regimens., Materials and Methods: Twenty-two patients with ES-SCLC treated with 500 mg single-agent apatinib as subsequent-line regimen in our institution from November 2016 to August 2018 were enrolled in the study. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs)., Results: Clinical outcomes included partial response in 3 patients (13.6%), stable disease in 18 patients (81.8%), and disease progression in 1 patient (4.5%), with an ORR of 13.6% and DCR of 95.5%. The median PFS and OS were 5.4 and 10.0 months, respectively. Apatinib demonstrated a manageable toxicity profile, with grade I-III secondary hypertension and proteinuria as the most common AEs. No grade IV and V AEs were observed among the patients. Multivariate analysis revealed secondary hypertension as an independent predictor of OS (p = .047); however, the association became insignificant after Q correction (p = .455)., Conclusions: Apatinib was safe and effective in the management of patients with ES-SCLC and can be considered as a treatment option after failure of at least two prior chemotherapy regimens. ClinicalTrials.gov identifier. NCT02995187 IMPLICATIONS FOR PRACTICE: This study indicated the acceptable toxicity profile and promising efficacy of apatinib in the management of patients with extensive-stage small cell lung cancer after failure from at least two prior chemotherapy regimens. Secondary hypertension can be a potential prognostic factor for apatinib treatment., (© 2020 The Authors. The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Introduction: Blood-based tumor mutational burden (bTMB) has been studied to identify patients with NSCLC who would benefit from anti-programmed cell death protein 1 (anti-PD-1) or anti-programmed death ligand 1 (anti-PD-L1) therapies. However, it failed to predict overall survival (OS) benefits, which warrants further exploration., Methods: Three independent cohorts of patients with NSCLC treated with immunotherapy were used in this study. A new bTMB algorithm was first developed in the two independent cohorts (POPLAR, N = 211, and OAK, N = 462) and further validated in the third National Cancer Center (NCC) cohort (N = 64)., Results: bTMB-H (bTMB ≥ cutoff point) was not associated with favorable OS after immunotherapy regardless of the cutoff points in either the POPLAR and OAK or the NCC cohorts (p > 0.05) owing to its correlation with the amount of circulating tumor DNA, which was associated with poor OS. In the POPLAR and OAK cohorts, with allele frequency (AF) adjustment, a high AF bTMB (HAF-bTMB, mutation counts with an AF > 5%) was strongly correlated with the amount of circulating tumor DNA (Pearson r = 0.65), whereas a low AF bTMB (LAF-bTMB, mutation counts with an AF ≤ 5%) was not (Pearson r = 0.09). LAF-bTMB-H was associated with favorable OS (hazard ratio [HR] = 0.70, 95% confidence interval [CI]: 0.52-0.95, p = 0.02), progression-free survival (PFS; HR = 0.62, 95% CI: 0.47-0.80, p < 0.001), and objective response rate (ORR) (p < 0.001) after immunotherapy but not chemotherapy, with a cutoff point of 12 trained in the POPLAR cohort and validated in the OAK cohort. The LAF-bTMB algorithm was further validated in the NCC cohort in which LAF-bTMB-H was associated with OS (HR = 0.20, 95% CI: 0.05-0.84, p = 0.02), PFS (HR = 0.30, 95% CI: 0.13-0.70, p = 0.003), and ORR (p = 0.001)., Conclusions: We developed and validated a new LAF-bTMB algorithm as a feasible predictor of OS, PFS, and ORR after anti-PD-(L)1 therapies in patients with NSCLC, which needs to be prospectively validated., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: BPI-9016M is a novel small-molecule inhibitor that simultaneously targets both c-Met and AXL tyrosine kinases. This phase I study aimed to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of BPI-9016M in Chinese patients with advanced non-small cell lung cancer (NSCLC)., Methods: Over the dose range of 100 mg to 800 mg, eligible patients were administered with a single dose of 9016M tablet and received 7 days of pharmacokinetics evaluation, followed by continuous dose administration (QD dosing, 28 days). Standard "3 + 3" dose escalations were performed., Results: Twenty NSCLC patients were treated. All patients experienced at least one adverse event (AE), of which treatment-related adverse events (TRAEs) were reported in 17 (85.0%) patients. The most common TRAEs were alanine transaminase (ALT) elevation (60%), bilirubin increased (40%), dysgeusia (40%), constipation (30%), hypertension (25%), and palmar-plantar erythrodysesthesia syndrome (15%). The TRAEs of grade 3 or higher during treatment were hypertension (15%), pulmonary embolism (5%), and laryngeal pain (5%). No dose-limiting toxicity (DLT) was observed, and the MTD was not reached. The median time to C max ranged from 2.0 to 3.5 h, and the plasma concentration of BPI-9016M declined rapidly after T max fitting a single-compartment model. The mean AUC 0-72 h of M1 and M2-2, main metabolites of BPI-9016M, were 4.8-6.6 folds and 4.1-9.8 folds higher than that of BPI-9016M, respectively. Exposure to BPI-9016M, M1, and M2-2 reached moderate saturation at 600 mg. Among 19 evaluable patients, 1 had a partial response and 10 patients had stable disease., Conclusion: BPI-9016M showed favorable safety and pharmacokinetic profiles, and no DLT was observed at doses up to 800 mg once daily. The promising antitumor activity in Chinese NSCLC patients supports further development of this tyrosine kinase inhibitor., Trial Registration: Clinical Trial ID: NCT02478866, registered May 21, 2015.

Aim: Most epidermal growth factor receptor (EGFR) gene mutations affecting exon 19 (inframe deletions; 19 Del) and 21 (L858R), while the rest (referred as uncommon EGFR mutation) have not been fully described due to their rarity. Here we present a retrospective study that investigated clinical characteristics and outcome of patients with different EGFR mutations., Methods: We retrospectively analyzed the EGFR mutation pattern and its association with clinical-pathological characteristics from 100 cases of nonsmall-cell lung cancer (NSCLC) harboring EGFR mutations, and compiled the genotype response data for NSCLC patients with common and uncommon EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs). Patients with advanced EGFR-mutated NSCLC were enrolled and treated with icotinib (oral administration, 125 mg, thrice per day)., Results: Among 100 patients, 85 and 15 had common and uncommon mutations, respectively. Four patients had a single mutation in 18 or 20 exon, and 11 had a complex mutation with del-19 or L858R. There was no significant association between the presence of different mutation type and the type of any clinical and pathological characteristics. Prolonged but not significant progression-free survival (PFS) was noted in patients with common EGFR mutations (18.07 [14.00-26.23] vs 12.9 [8.43-23.27], P = 0.056). Patients without brain metastases had increased PFS to icotinib than those with brain metastases (18.07 [95% confidence interval, CI 14.77-27.03] vs 13.17 [95% CI 8.63-22.63], P = 0.038)., Conclusion: Uncommon EGFR mutations comprised 15% of all mutated patients, in which most were complex mutations. Compared with common EGFR mutation, uncommon EGFR mutations were associated with a modest sensitivity to EGFR TKIs. Our findings will be helpful to make clinical decision and select the appropriate therapy for EGFR-mutated NSCLC patients., (© 2018 John Wiley & Sons Australia, Ltd.)

Background: Patients with small cell lung cancer (SCLC) younger than 40 years are limited in number. Our research aimed to assess the characteristics, diagnosis and outcomes of this patient population., Methods: Records of patients under the age of 40 with SCLC at the Chinese Academy of Medical Sciences between January 2006 and December 2015 were reviewed and evaluated., Results: One hundred and three patients (67.0% limited stage, 33.0% extensive stage) were included, along with 54 (52.4%) never-smokers. The median diagnostic interval and the median survival time (MST) were 51.0 days and 24.0 months, respectively. A total of 41 (39.8%) patients claimed to have undergone antibiotic treatment before diagnosis, with a median duration of 2 weeks. In univariate analysis, survival was better for the limited stage group than the extensive stage group (MST, 28.0 vs. 13.0 months, P < 0.0001). Also, patients who received concurrent radiochemotherapy had better survival than those who received chemotherapy alone (MST, 29.0 vs. 18.0 months, P = 0.001). Patients with antibiotic treatment before SCLC diagnosis have worse prognosis than those without (MST, 21.0 vs. 27.0 months, P = 0.008). Moreover, a timely diagnosis (≤1 month) exerted a positive impact on the overall survival in limited stage patients (48.0 vs. 26.0 months, P = 0.047) and on progression-free survival in extensive stage patients (6.0 vs. 3.0 months, P = 0.030). Multivariate analysis suggested that disease stage, history of antibiotic treatment before SCLC diagnosis and performance status independently correlated with survival., Conclusion: Our study identified distinct characteristics and prognostic factors of SCLC patients under 40 years. More timely care may improve patient prognosis., (© 2018 John Wiley & Sons Ltd.)

Background: Bevacizumab (Bev) plus platinum-based chemotherapy is a standard first-line treatment option for advanced non-squamous non-small cell lung cancer (NS-NSCLC). We evaluated the efficacy and safety of continuing Bev in Chinese patients with advanced NS-NSCLC progression after first-line treatment containing Bev in a real-world setting., Methods: The data of 118 patients with advanced NS-NSCLC who received Bev between July 2009 and July 2017 were retrospectively collected. The patients were divided into groups: 15 in Bev first-line, 82 in Bev ≥ second-line, and 21 in Bev cross-lines. The primary endpoint was overall survival; secondary objectives were progression-free survival, objective response rate, disease control rate, and safety., Results: The overall survival was 21.8, 32.5, and 18.9 months (P = 0.092) in the overall population and 39.3, 25.8, and 15.0 months (P = 0.347) in the wild-type population in the Bev first-line, Bev ≥ second-line, and Bev cross-lines groups, respectively. There were no significant differences in progression-free survival of second-line treatment between the groups in the overall population: 2.6, 3.7, and 3.2 months in the Bev first-line, Bev ≥ second-line, and Bev cross-lines groups, respectively (P = 0.796). No statistically significant improvement in objective response or disease control rates in the Bev cross-lines group was observed. No unexpected or severe adverse events were recorded., Conclusion: We found no benefit in continuing Bev treatment beyond progression after first-line treatment containing Bev for patients with advanced NS-NSCLC. Further research of validated predictive biomarkers of response to treatment after long-term antiangiogenic therapy is required., (© 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: EGFR-tyrosine kinase inhibitors (TKIs) combined with TS-1 might overcome EGFR-TKI resistance, which has been indicated by several preclinical studies. We investigated the synergistic efficacy and safety of the combination therapy of EGFR-TKIs and TS-1 in non-small cell lung cancer (NSCLC) patients with acquired resistance to previous EGFR-TKI therapy., Methods: This was a phase II, single-arm and single-center prospective study. Stage IIIB-IV NSCLC patients with acquired resistance to prior EGFR-TKI treatment were enrolled. All patients were administered combination therapy of TS-1 and continuing EGFR-TKIs in this study. The primary endpoints were progression-free survival (PFS), while overall survival (OS), disease control rate (DCR), and safety were secondary endpoints., Results: A total of 42 patients with acquired resistance to EGFR-TKIs were eligible for this study. The median PFS for all patients was five months (95% confidence interval [CI] 3.6-5.4). The OS and DCR were 31.9 (95% CI 17.8-46.0) months and 69.0% (29/42), respectively. No grade 4 toxicity or grade 3 hematologic toxicity was observed in this study. One patient (2%) experienced grade 3 elevated total serum bilirubin., Conclusion: The combination treatment of TS-1 and EGFR-TKIs was effective and well tolerated by patients who had experienced prior EGFR-TKI treatment failure. Our results need to be validated by larger prospective clinical trials., (© 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: This study was conducted to evaluate the value of gemcitabine combined with cisplatin as adjuvant chemotherapy for radical resection of non-small cell lung cancer., Methods: Data of 100 patients who had undergone radical resection of non-small cell lung cancer and were treated with cisplatin/gemcitabine as adjuvant chemotherapy between June 2007 and December 2010 at the Chinese Academy of Medical Sciences were reviewed., Results: The median age was 59 years (range 36-73); 82% of the patients were male. Forty-two percent had adenocarcinoma and 55% had squamous cell carcinoma. Most patients had pathologic IIB (29%) and IIIA (44%) stage disease. Eighty-five percent of patients completed four cycles of chemotherapy, with 76% completing the planned full dose. The main reason for a reduced gemcitabine dose in 13 patients was grade 3/4 neutropenia or thrombocytopenia. The median dose and dose intensity were 8377.1 mg/m 2 and 708 mg/(m 2 /week) for gemcitabine and 293.38 mg/m 2 and 25.24 mg/(m 2 /week) for cisplatin, respectively. During follow-up the median disease-free survival was 33.8 months (95% confidence interval [CI] 15.938-51.676). Patients with squamous cell carcinoma (hazard ratio [HR] 0.404, 95% CI 0.241-0.676; P = 0.001) and pathologic stage I (HR 4.379, 95% CI 1.721-11.142; P = 0.002) achieved better disease-free survival. The survival rates at one, two, and five years were 94%, 77%, and 55%, while the survival rates without recurrence were 64%, 53%, and 39%, respectively., Conclusion: As an adjuvant chemotherapy regimen, gemcitabine with cisplatin is well tolerated. Patients with squamous cell carcinomas or pathologic stage I achieve better results., (© 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Squamous cell carcinoma (SCC) is a common pathological type of non-small cell lung cancer, and advanced lung SCC is incurable. Chemotherapy combined with anti-angiogenesis agents can prolong the patients' survival time. The aim of the study was to analyze the efficacy and safety of recombinant human endostatin (Endostar) in treating advanced lung SCC., Methods: We retrospectively analyzed the short-term efficacy and toxicity of recombinant human endostatin combined with traditional chemotherapy regimens in treating 15 advanced lung squamous cell carcinoma patients in Department of Medical Oncology retrospectively, Cancer Hospital, Chinese Academy of Medical Sciences from November 2011 to May 2015. Treatment-related survival was also analyzed., Results: Among the evaluble 14 patients, the best overall response was partial response in 5 patients (35.7%), stable disease in 7 patients (50.0%), and progressive disease in 2 patients (14.3%). The objective response rate (ORR) was 35.7%, and disease control rate (DCR) was 85.7%. The median progression-free survival (PFS) was 9.3 months. The main grade 3 toxicity was neutropenia (2/15, 13.3%) and vomitting (1/15, 6.7%)., Conclusions: Chemotherapy combined with recombinant human endostatin enabled good objective response in advanced SCC patients and had well security.

Background: Small cell lung cancer (SCLC) is a rapidly growing tumor with characteristic of neuroendocrine cellular function. Neuron specific enolase (NSE), pro-gastrin-releasing peptide (ProGRP) and lactic dehydrogenase (LDH) are valuable in diagnosis and treatment of SCLC. By analyzing the variation of NSE, ProGRP and LDH before and after treatment, the aim of this study is to investigate the efficacy of tumor markers in diagnostic staging, therapeutic evaluation and prediction of disease relapsing., Methods: Patients with SCLC who receiving the first line chemotherapy in Cancer Hospital, Chinese Academy of Medical Sciences were enrolled and retrospectively analyzed. Clinical characteristic (includes NSE, ProGRP and LDH level before and after 2 cycles chemotherapy), efficacy evaluation, progression-free survival (PFS) were analyzed., Results: Before treatment, Serum NSE, ProGRP and LDH in patients with extensive disease (ED) were significantly higher than those with limited disease (LD)(all P<0.005); NSE level increased obviously accompanied by increase of lymph nodes stage in LD group (P=0.010); Patients with weight reduction when diagnosis had higher NSE and LDH than those without loss of weight (P=0.032, P=0.014). After 2 cycles chemotherapy, decrease of NSE and ProGRP in effective group was higher than which in stable and ineffective groups (P=0.015, P=0.002). The relapse risk was lower in patients who accepted >4 cycles chemotherapy and with obvious decrease of ProGRP than those who accepted ≤4 cycles chemotherapy and with less obvious decrease of ProGRP in LD group; ED patients with no more than 2 distant metastasis, normal LDH level before treatment and obvious decrease of ProGRP after chemotherapy had lower short term relapse risk. In addition, the types of relapse (sensitive relapse, drug resistance relapse and refractory relapse) were negatively correlated with decrease of ProGRP (P=0.044). By multivariate analysis, numbers of chemotherapy cycle was independent prognostic factor for PFS in LD SCLC; numbers of distant metastasis and decrease of ProGRP were independent prognostic factors for PFS in ED SCLC., Conclusions: Increase level of serum tumor markers is related to tumor burden. Decrease level of ProGRP after treatment may prognose efficacy and relapse risk.

Poor prognosis of advanced non-small-cell lung cancer (NSCLC) patients and the promising therapeutic effect of platinum urge the oncologists to evaluate the role of platinum doublet as second-line chemotherapy and establish the definition of platinum sensitivity in NSCLC. We retrospectively analyzed 364 advanced NSCLC patients who received platinum-doublet regimens as second-line chemotherapy after platinum-based first-line treatment. Patients were divided into four groups by their time-to-progression (TTP) after first-line chemotherapy: 0-3, 4-6, 7-12, and >12-month group, respectively. Treatment efficacy of patients' overall survival (OS), progression-free survival (PFS), and response rate (RR), as well as treatment-related toxicity, were compared among the four groups. A prognosis score system and a nomogram were established by Cox proportional hazard model, and validated by concordance index (c-index). Median OS was 14.0, 16.0, 20.0, 25.0 months for patients in the 0-3, 4-6, 7-12, >12-month group, respectively. Age ≤60 years (P = 0.002), female (P = 0.019), and TTP>12 months (P = 0.003) were independent prognostic factors. Prognostic score was calculated by adding 1 point each for any of the above three indicators, with a c-index of 0.590 (95% confidential interval [CI], 0.552-0.627). Median OS were equal to 25.0, 16.0, and 11.0 months for best (2-3 points), intermediate (1 point) and worst (0 point) category, respectively (P < 0.0001). A nomogram that integrated patient's age, gender, and TTP for OS has a c-index of 0.623 (95% CI, 0.603-0.643). Female, younger than 60 years, and TTP greater than 12 months may indicate prolonged survival after platinum-doublet second-line chemotherapy in advanced NSCLCpatients., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The aim of this study was to evaluate the efficacy and safety of the combination of docetaxel (TXT) plus tamoxifen (TAM) in advanced non-small-cell lung cancer (NSCLC) patients who had received platinum-based first-line chemotherapy. A total of 120 advanced NSCLC patients pretreated with platinum-based chemotherapy were randomized into two treatment groups (the TXT and TXT+TAM groups) in a 1 : 1 ratio. Reversal of P-glycoprotein (P-gp) expression, tumor response, progression-free survival, overall survival, and safety were evaluated on an intention-to-treat basis. The median number of cycles of allocated chemotherapy was four in each treatment group (range: 2-6 cycles). The overall response rate and disease control rate in the TXT+TAM group were significantly higher than those in the TXT group (36.7 vs. 15.0% for overall response rate, P=0.007; 85.0 vs. 68.3% for disease control rate, P=0.031). The combination of TXT and TAM could effectively reverse P-gp expression in tumor tissues and provide a significant survival benefit for advanced NSCLC patients compared with TXT alone (11.6 vs. 9.1 months, P=0.030). In addition, in the TXT+TAM group, patients achieving P-gp reversal had a significantly greater median progression-free survival and overall survival than nonreversal patients. Furthermore, the combined therapy showed a safety profile comparable to that of TXT. The combination of TXT and TAM may be an effective and safe treatment option for advanced NSCLC patients who have already developed P-gp-mediated multidrug resistance.

Background: Cetuximab is a monoclonal antibody directed against epidermal growth factor receptor. Emerging evidence showed improved efficacy with the addition of cetuximab to chemotherapy in advanced non-small cell lung cancer (NSCLC), but the data in oriental population are limited. The aim of this study is to investigate the efficacy of cetuximab in combination with chemotherapy in Chinese patients with advanced NSCLC., Methods: NSCLC patients receiving cetuximab in combination with chemotherapy in Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College were enrolled and retrospectively analyzed. Clinical characteristic, efficacy, outcome and toxicity data were analyzed., Results: A total of 40 patients were enrolled into this study in which 29 were male, 36 with adenocarcinoma. In the 23 patients who had received palliative chemotherapy previously (with a median of 2 prior chemotherapy regimens), the median progression-free survival (PFS) after the last prior chemotherapy regimen was 2.3 months. For the overall population, 13 (32.5%) patients achieved partial response after cetuximab in combination with chemotherapy. Response rate were 52.9% (9/17) and 17.4% (4/23) in chemotherapy-naive patients and chemotherapy-treated patients, respectively (P=0.018). The median PFS was 4.8 months for the overall population. In chemotherapy-naive patients and chemotherapy-treated patients, the median PFS was 8.4 months and 4.1 months, respectively (P=0.062). The estimated median overall survival was 17.1 months. Toxicities were generally manageable and no treatment-related deaths occurred., Conclusions: Cetuximab in addition to chemotherapy appears to be associated with promising efficacy and acceptable toxicity profile in Chinese patients with advanced NSCLC. Further validation is needed.

Background: Gemcitabine and pemetrexed have been used as maintenance therapy. However, few systematic reviews and meta-analyses have assessed their effects in the newest studies. This systematic review and meta-analysis were conducted to assess the role of gemcitabine and pemetrexed in the maintenance treatment of non-small-cell lung carcinoma (NSCLC)., Methods: We performed a literature search using PubMed, EMBASE and Cochrane library databases from their inceptions to September 16, 2015. We also searched the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and National Comprehensive Cancer Network (NCCN) databases from 2008 to 2015. Two authors independently extracted the data. The Cochrane Collaboration's risk of bias graph was used to assess the risk of bias. The GRADE system was used to assess the grading of evidence, and a meta-analysis was conducted using Stata 11.0 software., Results: Eleven randomized controlled trial (RCT) studies were collected. Ten studies were included in the meta-analysis and divided into the following 4 groups: gemcitabine vs. best supportive care (BSC)/observation, pemetrexed vs. BSC/placebo, pemetrexed + bevacizumab vs. bevacizumab and pemetrexed vs. bevacizumab. Gemcitabine exhibited significantly improved progression-free survival (PFS) compared with BSC (hazard ratio (HR) = 0.62, p = 0.000). Pemetrexed exhibited significantly improved PFS (HR = 0.54, p = 0.000) and OS (HR = 0.75, p = 0.000) compared with BSC. Pemetrexed + bevacizumab almost exhibited significantly improved PFS (HR = 0.71, p = 0.051) compared with bevacizumab. Pemetrexed exhibited no improvement in PFS or overall survival (OS) compared with bevacizumab. Regarding the grade, the GRADE system indicated that the gemcitabine group was "MODERATE", the pemetrexed group was "HIGH", and both the pemetrexed + bevacizumab vs. bevacizumab groups and pemetrexed vs. B groups were "LOW"., Conclusions: Gemcitabine or pemetrexed compared with BSC/observation/placebo significantly improved PFS or OS. Whether pemetrexed + bevacizumab compared with bevacizumab alone significantly improves PFS requires further investigation.

Background: The phase 3 ICOGEN trial established the non-inferiority of icotinib to gefitinib in terms of progression-free survival (PFS) in non-small cell lung cancer (NSCLC) patients, and this led to the approval of icotinib for NSCLC by the China Food and Drug Administration. A phase 4 study was conducted to assess the safety and efficacy of icotinib in a broad range of patients with advanced NSCLC across China., Methods: This study retrospectively analyzed data from unresectable, recurrent, and/or advanced NSCLC patients who received oral icotinib 125 mg three times per day. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR) and disease control rate (DCR), which were investigated overall and in subgroups such as patients with an EGFR mutation and elderly patients., Results: Between August, 2011 and August, 2012, a total of 6087 advanced NSCLC patients were registered in this study, of which 5549 were evaluable for safety and tumor response. The median age was 63 years (range 21-95 years), and 1571 (28.3%) patients were over the age of 70. The majority of patients were non-smokers, and had adenocarcinoma and stage IV disease. The overall incidence of adverse drug reactions (ADRs) of any grade was 31.5%. The most common ADRs included rash (17.4%) and diarrhea (8.5%), and three patients experienced interstitial lung disease (ILD). The ORR and DCR were 30.0% and 80.6%, respectively, for the overall population, and 33.4% and 81.2%, 30.3% and 80.3%, and 30.4% and 89.3%, for first-line, second-line, and third-line or multiple line subsets, respectively. In 665 EGFR-mutated patients who were evaluable for tumor response, the ORR and DCR were 49.2% (327/665) and 92.3% (614/665), respectively., Conclusions: The data from over 6000 patients was consistent with the results of the ICOGEN study. Icotinib demonstrated a favorable toxicity profile and efficacy in the routine clinical setting., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background and Objective: Lung cancer in young patients (less or equal to 45 years) is relatively rare. We explored the efficacy and survival of Gefitinib for young patients with unknown epidermal growth factor receptor (EGFR) gene mutation of advanced lung adenocarcinoma., Methods: The clinical data of 55 young patients with unknown EGFR gene mutation in advanced lung adenocarcinoma referred to the Cancer Hospital & Institute, Chinese Academy of Medical Sciences from Jan 2006 through Dec 2010 were analyzed retrospectively., Results: Of 55 young patients enrolled, the median age was 41 years. The objective response rate and disease control rate were 43.6% and 90.9%, respectively.. The median progression-free survival (PFS) was 9.0 months. Among the factors analyzed, brain metastasis had significant effect on PFS (P=0.017). The median overall survival (OS) was 24.0 months. The independent prognostic factors to significantly improve OS included non-smoking history (P=0.028) and receiving other anti-cancer treatment after Gefitinib therapy (P<0.001)., Conclusions: The median PFS and OS of the young patients with Unknown EGFR gene mutation in advanced lung adenocarcinoma were similar with general population.

Background: The use of biomarkers for selecting non-small cell lung cancer (NSCLC) patients for treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is essential. The aim of this study was to explore whether biomarkers detected in plasma were predictive for response to EGFR-TKIs and survival time of NSCLC patients., Methods: Tumor tissues and paired blood were collected from 134 advanced NSCLC patients treated with EGFR-TKIs. EGFR mutations in both types of specimens, and expression of transforming growth factor-alpha and beta one (TGF-α and TGF-β1) were assessed in NSCLC patients. Concentrations of circulating free DNA were detected in plasma from both NSCLC patients and healthy subjects. The clinical significance of EGFR mutations, levels of cytokines, and circulating free DNA was assessed in advanced NSCLC patients., Results: EGFR mutations were detected in 68 tumor samples and 17 plasma samples of 134 NSCLC patients. The concentrations of circulating free DNA were higher in NSCLC patients than in healthy subjects. Patients with high TGF-β1 level showed shorter overall survival and worse response to EGFR-TKIs than patients with low TGF-β1 level., Conclusions: Plasma levels of TGF-β1 may be a marker for predicting response to EGFR-TKIs and survival time in NSCLC patients., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background and Objective: Subsequent chemotherapy were needed in patients with advanced pulmonary adenocarcinoma experiencing disease progression after epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. The study is to explore factors potentially influencing efficacy of subsequent chemotherapy., Methods: One hundred and ninety-one patients with advanced lung adenocarcinoma, who were resistant from EGFR-TKIs and then received subsequent chemotherapy, were identified. Data of patient's characteristics, responses to chemotherapy and survival time were analyzed retrospectively., Results: The overall response rate of the pemetrexed-based chemotherapy (9.3%) was higher than non-pemetrexed-based regimen (1.1%), P=0.011. Furthermore, the response in the second-line was more obvisous [objective response rate (ORR) 14.3% vs 3.7%, P=0.041]. The patients who achieved response of partial response (PR) showed longer progression-free survival (PFS) than those who achieved non-PR (PFS 10.1 months and 2.3 months, P=0.012). The patients treated with platinum-based chemotherapy had longer PFS and OS than those with non-platinum-based chemotherapy, therefore platinum-based regimen was independent prognosis factors for PFS and OS (PFS: RR=0.634, 95%CI: 0.466-0.832, P=0.004; OS: RR=0.666, 95%CI: 0.460-0.960, P=0.030), especially the pateients who were aquired EGFR-TKIs resistance and who got drmatic progression from EGFR-TKIs treatment might got more benefits from platinum-based chemotherapy. However there was no significant difference in ORR, PFS or OS between patients with TKIs primary resistance and acquired resistance, or between dramtic progression and gradual/local progression., Conclusion: The patients with advanced lung adenocarcinoma might get benefits from pemetrexed-based or platinum-based chemotherapy after they were EGFR-TKIs resistace.

Background and Objective: Due to the various inter-individual differences in the biological characteristics of tumor cells, as well as issues on the efficacy, adverse reactions, and defects of existing drugs, we compared the clinical efficacy and toxicity of pemetrexed and gemcitabine combined with cisplatin for the treatment of previously untreated advanced non-small cell lung cancer (NSCLC)., Methods: 251 patients were randomly divided into pemetrexed combined with cisplatin group (PP group) with 127 cases and gemcitabine combined with cisplatin group (GP group) with 124 cases. PP group received pemetrexed 500 mg/m² iv infusion d1 and cisplatin 75 mg/m² iv infusion d1, whereas GP group received gemcitabine 1,000 mg/m² iv infusion d1,8 and cisplatin 75 mg/m² iv infusion d1. The treatment cycle was once every three weeks. In addition, folic acid, vitamin B12, and dexamethasone were administered in both groups., Results: The total clinical effective rates in PP group and GP group were 25.20% and 17.74%, respectively. The total efficiencies of non-squamous cell carcinoma were 27.62% and 16.00%. The tumor progression duration in these two groups was 6.5 and 5.6 months, respectively. The median survival time in the two groups was 16.9 and 17.0 months, respectively, with 59.62% and 65.87% survival rates of 1 year and 27.28% and 27.93% survival rates of 2 years, respectively. The total efficacy of non-squamous cell carcinoma in the PP group was significantly higher than that in GP group. The results were statistically significant. However, there were no significant differences in total response rates, tumor progression duration, and median survival rates of 1 and 2 years. The rate of adverse reactions, including white blood cell reduction, lower platelet count, lower hemoglobin, and hair loss in the PP group was significantly lower than that in the GP group. The results were statistically significant., Conclusion: The clinical efficacy of pemetrexed and gemcitabine combined with cisplatin for the treatment of previously untreated advanced NSCLC was roughly the same, but the adverse reactions decreased significantly in the PP group compared with those in the GP group. Therefore, pemetrexed combined with cisplatin can be used as a safe and effective drug for clinical first-line treatment for previously untreated NSCLC.

Background: It has been proven that metastasis-associated in colon cancer 1 (MACC1) is a new gene that is related to the invasion and metastasis of tumors. MACC1 also regulates c-met expression. The aim of this study is to explore the expressions of MACC1 and hepatocyte growth factor receptor (c-met), and its relationship with invasion, metastasis, and prognosis of non-small cell lung cancer (NSCLC)., Methods: MACC1 and c-met expressions were detected in 103 cases of NSCLC and 40 cases of neighboring normal lung cancer tissue using immunohistochemistry., Results: MACC1 and c-met expressions were significantly higher in lung cancer tissues than that in neighboring normal tissue (P<0.001). MACC1 and c-met expressions were associated with poor differentiation, advanced T stages, lymph node metastasis, and advanced TNM stages (P<0.05) of NSCLC, but not with sex, age, smoking, and histological classification (P>0.05). In addition, a positive correlation between MACC1 and c-met expressions was observed (r=0.403, P<0.001). The result from the Kaplan-Meier survival analysis showed that the five-year survival rate in patients with positive MACC1 and c-met expressions was remarkanly lower than that in patients with negative expressions (P<0.05). The result from the Cox regression analysis showed that MACC1 expression was an independent prognostic factor for NSCLC (P=0.026)., Conclusions: MACC1 and c-met have an important function in the differentiation, invasion, and metastasis of NSCLC. MACC1 and c-met have poor prognosis in patients with NSCLC. Moreover, MACC1 expression is an independent prognostic factor for NSCLC.