Progress in Detection of EGFR Exon 20 Insertion Mutation and Targeted Therapies in Non-small Cell Lung Cancer / 中国肺癌杂志

Epidermal growth factor receptor exon 20 insertion (EGFR ex20ins) is one of the earliest driver gene activation mutations in non-small cell lung cancer (NSCLC). However, due to the unique structure of protein variation caused by this mutation, most patients with EGFR ex20ins mutation (except A763_Y764insFQEA) have poor response to the launched first/second/third generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). With the successive approval of new specific targeted drugs for EGFR ex20ins in Food and Drug Administration (FDA) and other national regulatory agencies, the development and clinical research of targeted drugs for EGFR ex20ins in China have also developed rapidly and Mobocertinib has been approved recently in China. It is worth noting that EGFR ex20ins is a variant type with strong molecular heterogeneity. How to detect it comprehensively and accurately in clinical practice, so as to enable more patients to benefit from targeted therapy, is a very important and urgent problem to be solved. This review introduces the molecular typing of EGFR ex20ins, then discusses the importance of EGFR ex20ins detection and the differences of various detection methods, and summarizes the research and development of new drugs progress of EGFR ex20ins, in order to optimize the diagnosis and treatment path of EGFR ex20ins patients by selecting accurate, rapid and appropriate detection methods, so as to improve the clinical benefits of the patients.
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Current progression of bevacizumab in advanced non-small cell lung cancer / 中华肿瘤杂志

Non-small cell lung cancer (NSCLC) is one of the malignant diseases with high morbidity, high mortality and poor prognosis in China and worldwide, and the progression of which is significantly related to abnormal angiogenesis. Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), inhibits angiogenesis during tumor progression. It has been widely demonstrated to improve the survival of NSCLC patients. Therefore, bevacizumab is approved and recommended as the first-line treatment of advanced NSCLC by a number of countries and regions. In this paper, various large-scale clinical trials are analyzed to highlight the current clinical applications of bevacizumab in advanced NSCLC, especially patients with EGFR mutations. In addition, this review focuses on the efficacy, safety and predict factors of bevacizumab as anti-angiogenic therapy, in order to screen the patients who can acquire the maximal benefit.

Next-generation ALK-TKI in NSCLC patients / 中国医师杂志

Objective The aim of the study is to investigate the therapeutic efficacy of next-generation anaplastic lynphoma kinase-tyrosine kinase inhibitor (ALK-TKI) in advanced non-small cell lung cancer (NSCLC).Methods The clinical data and outcomes of 22 patients with advanced non-small cell lung cancer who received the next generation of ALK-TKI from 2014 to 2017 in our hospital were retrospectively analyzed.Results 22 patients were included for survival analysis with 15 males and 7 females.The median age was 48 and all of them were adenocarcinoma patients.There were 12,2,7 and 1 patients received ceritinib,alectinib,brigatinib and lorlatinib,respectively.A total of 14 patients could be evaluated,including complete response (CR) in 2 cases,partial response (PR) in 3 cases,stable disease (SD) in 6 cases,progressive disease (PD) in 3 cases.The ORR and DCR were 35.7％ and 78.6％,respectively.The median progression free survival (PFS) of the 22 NSCLC patients was 8.7 months.Progression pattern can be analyzed in 17 patients.Among them,10 patients underwent primary progression (lung),occurring at the leading frequency (accounting for 58.8％) and followed by central nerve system (CNS) progression (accounting for 29.4％).Conclusions Next-generation ALK-TKI provide a reasonable choice for crizotinib-resistant patients.Primary progression (lung) is the leading cause for treatment failure.Multi-disciplinary integration may provide a potential choice for prolonging administration of next-generation ALK-TKI.

Potential Antitumor Activity of SIM-89 in Non-Small Cell Lung Cancer Cells

PURPOSE: c-Met and its ligand, hepatocyte growth factor (HGF), play a critical role in oncogenesis and metastatic progression. The aim of this study was to identify inhibited enzymogram and to test the antitumor activity of SIM-89 (a c-Met receptor tyrosine kinase inhibitor) in non-small cell lung cancer. MATERIALS AND METHODS: Z′-LYTE kinase assay was employed to screen the kinase enzymogram, and mechanism of action (MOA) analysis was used to identify the inhibited kinases. Cell proliferation was then analyzed by CCK8 assay, and cell migration was determined by transwell assay. The gene expression and the phosphorylation of c-Met were examined by realtime-PCR and western blotting, respectively. Finally, the secretion of HGF was detected by ELISA assay. RESULTS: c-Met, activated protein kinase (AMPK), and tyrosine kinase A (TRKA) were inhibited by SIM-89 with the IC₅₀ values of 297 nmol/L, 1.31 µmol/L, and 150.2 nmol/L, respectively. SIM-89 exerted adenosine triphosphate (ATP) competitive inhibition on c-Met. Moreover, the expressions of STAT1, JAK1, and c-Met in H460 cells were decreased by SIM-89 treatment, and c-Met phosphorylation was suppressed in A549, H441, H1299, and B16F10 cells by the treatment. In addition, SIM-89 treatment significantly decreased the level of HGF, which accounted for the activation of c-Met receptor tyrosine kinase. Finally, we showed cell proliferation inhibition and cell migration suppression in H460 and H1299 cells after SIM-89 treatment. CONCLUSION: In conclusion, SIM-89 inhibits tumor cell proliferation, migration and HGF autocrine, suggesting it's potential antitumor activity.

Randomized controlled trial of chemotherapy plus geiftinib as ifrst-line treatment for patients with advancedEGFR mutation-positive lung adenocarcinoma / 中国癌症杂志

Background and purpose:For patients with advanced lung adenocarcinoma harboring an activating EGFR gene mutation, the current standard of care is EGFR-TKI alone. This study aimed to compare efficacy and safety of gefitinib plus chemotherapy with gefitinib or chemotherapy alone for treating advanced lung adenocarcinoma with an activatingEGFR gene mutation.Methods:This study included 61 patients with lung adenocarcinoma harboring an acti-vatingEGFR gene mutation (19 exons deletion and exon 21 L858R mutations) whose ECOG performance status was 0 or 1. Patients were randomly divided into 3 groups. Group A (n=20) were given carboplatin/pemetrexed of a 4-week cycle, six cycles at most, plus gefitinib (pemetrexed 500 mg/m2, d1; carboplatin AUC 5, d1; gefitinib 250 mg/d, d 5-21), and then re-ceived pemetrexed of a 4-week cycle plus gefitinib as maintenance therapy; Group B (n=20) were given carboplatin/peme-trexed of a 4-week cycle, six cycles at most (pemetrexed 500 mg/m2, d1; carboplatin AUC 5, d1), then received pemetrexed as maintenance therapy; Group C (n=21) were given gefitinib (gefitinib 250 mg/d). Patients continued to receive therapy until disease progression or unacceptable toxicity or death. The primary end point was middle PFS and 12 months PFS rate. The secondary end points included objective response rate and adverse events.Results:Groups A and C both lost 1 case during follow-up. Median PFS for patients was 20.1 months (95%CI:18.0-22.2) in group A, 5.5 months (95%CI:3.9-7.2) in group B, and 9.8 months (95%CI:6.8-12.8) in group C. PFS rates of 12 months for groups A, B and C were 78.9%, 15.0% and 40.0%, respectively. The overall objective response rates for groups A, B and C were 84.2%, 35.0% and 65.0%, respectively. Serious adverse events were reported by 36.8% for group A, 30.0% for group B, and 5.0% for group C. The most common grade 3/4 adverse events were neutropenia (3 cases in group A, 4 cases in group B), fatigue (2 cases in group A, 2 cases in group B) and liver function impairment (2 cases in group A, 1 case in group C).Conclusion:Among patients withEGFR mutant lung adenocarcinoma, combination of chemotherapy with gefitinib as first-line treatment demonstrates an improvement in PFS. Long-term survival results will be further followed up.

Clinical observation of efficacy and safety of pemetrexed plus platinum as the first-line chemotherapy with advanced non-squamous non-small cell lung cancer / 中国癌症杂志

Background and purpose:The effective rate of ifrst-line chemotherapy for advanced lung cancer is 30%-40%. The purpose of this study was to evaluate the efifcacy and adverse effects of pemetrexed combined with carboplatin or cisplatin in the treatment of patients with advanced non-squamous non-small cell lung cancer (NSCLC). Methods:One hundrend and twenty-one patients with advanced non-squamous NSCLC were enrolled in this study and all of these patients had been conifrmed with pathology or cytology. Among the 121 cases, 60 cases were male and 61 were female, the median age was 59 years, adnenocarcinoma in 113 patients and large cell carcinoma in 8 patients. Combination regimen: patients received pemetrexed 500 mg/m2 on day 1 and carboplatin 300 mg/m2 or cisplatin 70 mg/m2 on day 1 by intravenous infusion, administrated every 3 weeks for 2 to 6 cycles. All patients who received 2 or more cycles could be evaluated. Disease control rate (DCR) was the primary end point; secondary end points included progression-free survival (PFS), 1-year survival rate and safety.Results:There was 1 case with complete response (CR), 44 cases achieved partial response (PR), 50 had stable disease (SD) and 26 cases had progressive disease (PD) in the overall cases. ORR and DCR were 37.2% (45/121) and 78.5% (95/121), respectively. The median PFS time was 5.2 months and 1-year survival rate was 59.0%. In pemetrexed combined with carboplatin group, the ORR and DCRwere 38.3% (23/60) and 78.3% (47/60), respectively; The median PFS was 5.1 months (95%CI: 3.8-6.4 month) and 1-year survival rate was 55.2%. The patients treated with pemetrexed plus cisplatin, the ORR and DCR were 36.1% (22/61) and 78.7% (48/61), respectively. Median PFS was 6.2 months (95%CI: 4.3-8.1 month) and 1-year survival rate was 62.5%. There were no statistical differences between carboplatin/pemetrexed and cisplatin/pemetrexed for both ORR, DCR, PFS and 1-year survival rate (P>0.05). The major adverse effects were leukopenia, neutropenia, fatigue and gastrointestinal reaction.Conclusion:Pemetrexed plus platinum chemotherapy could be considered as the ifrst-line treatment option for advanced non-squamous NSCLC patients. Pemetrexed combined with carboplatin/ cisplatin regimen has efifcacy with mild toxicity and better tolerability.

A primary study of immunotherapy with carcinoembryonic antigen peptide-pulsed, autologous human cultured dendritic cells in patients with advanced non-small cell lung cancer / 中国肺癌杂志

<p><b>BACKGROUND</b>Dendritic cell (DC)-based immunotherapy is a new approach and effective for some malignant tumors. The aim of this study is to observe the efficacy and toxicity of immunotherapy with carcinoembryonic antigen (CEA) peptide-pulsed DCs in patients with refractory advanced lung cancer.</p><p><b>METHODS</b>Lung cancer patients with high CEA expression were enrolled into this project. Autologous DCs were generated from patients' plastic-adherent peripheral blood mononuclear cells and loaded with CEA 5 days later. Cytokine-induced killer cells (CIK) were cultured from non-adherent peripheral blood mononuclear cells. DCs and CIK were transfused to patients. Responses and toxicities were observed.</p><p><b>RESULTS</b>A total of 22 patients with lung cancer received DCs immunotherapy. DCs doses were 2.5×10⁶-9.6×10⁷ (5.03×10⁶). CIK doses were 3.4×10⁸-46×10⁸. CD3, CD8, NK and IFN-γ levels obviously increased after treatment (P < 0.05). The 1-year survival rate was 68.2% (15/22). Main toxicities were fever and rash.</p><p><b>CONCLUSIONS</b>DCs-based immunotherapy is feasible and safe to patients with lung cancer.</p>

Comparative study on gemcitabine plus cisplatin and vinorelbine plus ifosfamide plus cisplatin combined chemotherapy in the treatment of advanced non-small cell lung cancer / 中国肺癌杂志

<p><b>BACKGROUND</b>To compare the effect and toxicity between gemcitabine and cisplatin (GP) with vinorelbine, ifosfamide and cisplatin (NIP) combined chemotherapy in the treatment of patients with advanced non-small cell lung cancer (NSCLC).</p><p><b>METHODS</b>Eighty patients received either gemcitabine 1 000 mg/m² on days 1, 8, or 15 plus cisplatin 70-80 mg/m² on day 1, or vinorelbine 25 mg/m² on days 1, 8, ifosfamide 1.2 g/m² on days 1-4 plus cisplatin 70-80 mg/m² on day 1, every 28 days as a cycle.</p><p><b>RESULTS</b>The objective response rate was 40.0% in GP goup, compared with 52.5% in NIP group (P > 0.05). Median survival time of GP and NIP groups was 13.68 and 15.34 months respectively, and 1-year survival rates were 54.29% and 59.46% respectively (P > 0.05). Leukopenia at grade III+IV was significantly lower in GP arm (27.5%) than that in NIP arm (55.0%) (P < 0.05). Non-hematological toxicities were less frequent in GP group than those in NIP group (P < 0.05).</p><p><b>CONCLUSIONS</b>Although the response rate tends to be higher in three-drug than in two-drug combined chemotherapy, but no significant difference is observed. Three-drug combinations often result in more toxicities. Two-drug combination GP may be the standard protocol for chemotherapy of advanced NSCLC. Three-drug combination NIP should be given to young patients with good performance status.</p>