bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of uncommon and insensitive mutation on EGFR-TKI in treatment of non-small cell lung cancer.
Authors: Zhang Hui , Jiang Da , Wei Suju , Cui Yanzhi , Li Ying , Tian Caijuan , Dong Qian , Xu Zanmei 
Published: May 2020

e21652 Background: EGFR-TKI application is directed by the situation of mutations of epidermal growth factor receptor, in addition, the mutations of ALK, ROS-1,C-met, BRAF, Her-2, RET,NTRK1, PI3K, MEKI have potential effects on guiding treatment. This study aimed to investigate the uncommon and insensitive mutations and their effect on prognosis in non-small cell lung cancer (NSCLC) patients treated with EGFR-TKI. Methods: 21 NSCLC patients treated with EGFR-TKIs were enrolled, 9 with Gefitinib, 5 with Osimertinib and 7 with Icotinib. All patients were detected with targeted NGS 1000 gene panel. Afterwards, the EGFR sensitive mutation, uncommon mutation and mutations accompanied EGFR T790M were analyzed. Furthermore, the correlations of gene mutation with metastasis, OS and PFS were analyzed. SPSS 21.0 was used for statistical analysis, t test for continuous variables and χ2 test for classified variables. Results: In all the patients, EGFR p.[T790M] and p.[L858R] mutations were detected in 4.76% and 23.81% of the patients, respectively. In the 5 patients treated with Osimertinib, one had EGFR p.[T790M] mutation and curative effects was stable disease (SD). The mutations accompanied EGFR T790M included SMARCA4 p.[K1390Q] (2.23%), DNMT3A p.[F755S] (2.17%), MTOR p.[Y1450*] (2.15%), TPMT p.[L182R] (1.84%), etc. For the other four patients treated with Osimertinib, two of them were partial response (PR) and two were SD, accompanied with mutations such as EGFR p.[L858R] (55.00%), ARID1A p.[P16del] (2.83%), TP53 p.[R248W] (21.73%) and AR p.[Q60L] (4.24%). In addition, among all the mutations, 18 uncommon mutations were detected, in which ATM (23.26%), AR (23.26%) and MTOR (37.21%) were markedly associated with OS. Besides, the mutation frequency of 67 genes, such as ABCG2, AURKA, EPHA3 and ATR were correlated with OS. The mutation frequency of FGFR1 was significantly different between the patients with and without metastasis. The mutations of 22 genes, for instance ABCG2 p.[P21L], FAT1 p.[L398F], GNAS p.[F226V] and KMT2C p.[N2842Ilefs], were correlated with PFS during the treatment. Conclusions: EGFR-TKI has similar curative effects in EGFR p.[T790M] negative patients. Gene mutations, including uncommon mutations and EGFR insensitive mutations, can significantly affect the prognosis in NSCLC patients treated with EGFR-TKIs.
ARC-4 study: Efficacy and safety of AB928 plus carboplatin, pemetrexed and a PD-1 antibody in participants with metastatic non-small cell lung cancer (mNSCLC).
Authors: Spira Alexander I. , Conkling Paul R. , Johnson Melissa Lynne , Gardner Olivia , Gilbert Houston N. , Scharville Michael , Yin Fangfang , Krishnan Kartik , Paoloni Melissa Constance , Chaudhry Arvind 
Published: May 2020

e21659 Background: Adenosine, derived from ATP released by dying cancer cells in response to chemotherapy, binds to and activates the A2a and A2b receptors on immune cells, resulting in an ineffective anti-tumor immune response. Adenosine receptor blockade may therefore enhance the efficacy of chemotherapy when co-administered with a checkpoint inhibitor. AB928, the first clinical-stage small molecule dual A2aR/ A2bR antagonist, is highly potent and was well tolerated in dose escalation studies as a single agent or in combination with chemo/immunotherapy. Methods: ARC-4 (NCT03846310) is a Phase 1/1b, open-label study in participants (pts) with metastatic, locally advanced, or recurrent non-squamous NSCLC with no alternative or curative therapy option. Pts whose tumor has a genetic alteration for which targeted therapy exists must be chemo/immunotherapy naïve. Pts must have ECOG PS 0-1 and at least one measurable lesion. Two escalating doses of AB928 (75 or 150 mg) administered orally daily were given with standard doses of carboplatin, pemetrexed and pembrolizumab. Results: As of 27Dec19, 7 pts have received AB928 in Ph 1: 75 mg (n = 3), 150 mg (n = 4). Number of prior therapies range from 0 to 6 (median = 3). Most treatment emergent AEs (TEAEs) were Grade 1 or 2, with no Grade 5 events. The most common AEs were anemia, nausea and AST elevation. One pt experienced an SAE (Gr4 thrombocytopenia) that was at least possibly related to AB928. One pt discontinued before assessment due to adverse event (muscle weakness). Of the 6 patients with post-baseline disease assessments, all demonstrated decrease size of target lesion. Three patients (43%) achieved a confirmed partial response: one treatment naïve patient, one patient with EGFRmut disease that had previously progressed on treatment with erlotinib and osimertinib, and one patient who had progressed on therapy with ipilimumab and nivolumab. One additional pt had a > 30% decrease in target lesions and findings consistent with new lesions but opted to continue study treatment. Conclusions: Addition of AB928 to carboplatin, pemetrexed and pembrolizumab did not significantly add to the established safety profile of the standard agents. Combination treatment was associated with disease control in all evaluable pts, including responses in those with PD after TKI and immunotherapy. Expansion is on-going in pts with EGFRmut NSCLC that has failed treatment with TKI. Additional updates on the safety, clinical activity, and correlative biomarker results will be presented. Clinical trial information: 03846310.
Safety of nivolumab/pembrolizumab in hepatitis B surface antigen-positive non-small cell lung cancer (NSCLC) patients.
Authors: Xu Chongrui , Tu Hai-Yan , Sun Yue-Li , Li Yang-Si , Xu Bing-Fei , Wang Bin-Chao , Chen Hua-Jun , Wang Zhen , Zhou Qing , Yang Jin-Ji , Wu Yi-Long 
Published: May 2020

e21670 Background: Chronic hepatitis B virus infection patients are noted about 7% in Chinese population who are excluded from the clinical trials of the nivolumab or pembrolizumab in non-small cell lung cancer (NSCLC). However, in clinical practice these patients received checkpoint inhibitors as well. Limited evidence exist on the safety of the checkpoint inhibitors in hepatitis B surface antigen positive NSCLC patients. Methods: From January 1, 2018 to September 30, 2019, clinical information of advanced non-small cell lung cancer patients who received nivolumab or pembrolizumab ± chemotherapy as routine clinical practice in Guangdong Lung Cancer Institute were collected according to a standardized procedure. Gender, histology, treatment regimens, experimental test, respose rate, and adverse events were recorded. Status of hepatitis B surface antigen (HBsAg) were tested for every patient before the treatment and data of the positive patients were accessed for this research. Adverse events were assessed according to Common Terminology Criteria for Adverse Events v5.0. Results: Among 232 eligible patients, HBsAg were found positive in 17 patients(7.3%). Clinical characteristics were list in the table. The median age was 55.2 years (range 39-72) and transaminase and bilirubin of all the patients were normal before treatment. The median treatment cycle was 7 (95%CI 4.6-10.3) and the median time to discontinuation was 4.4 months (95%CI 2.8-7.1). 8 patients received anti-virus therapy including entecavir and adefovir during the treatment. Grade 1 transaminase or bilirubin elevation were noted in 6 patients during the treatment. Grade 3 transaminase and grade 4 bilirubin elevation were found in 1 patient without evidence of viral reactivation. Conclusions: Nivolumab or pembrolizumab are safety treatment options for HBsAg positive NSCLC patients. [Table: see text]
A phase I clinical trial to assess the safety, pharmacokinetics, and antitumor activity of glumetinib (SCC244) in patients with advanced non-small cell lung cancers (NSCLCs).
Authors: Chen Hua-Jun , Yang Jin-Ji , Yang Xuening , Zhou Qing , Sun Minghui , Li Yue , Xiang Ziyong , Wu Yilong 
Published: May 2020

e21702 Background: Aberrant activation of the MET pathway is associated poor prognosis and poor response to standard therapies in cancer patients. Glumetinib (SCC224) is an oral potent and highly selective MET inhibitor. This is an open label, dose-escalation, phase I clinical study to determine the safety, pharmacokinetics and anti-tumor activity in patients with advanced NSCLC regardless of MET status. Methods: Patients with advanced NSCLC failed standard treatments received glumetinib orally according to one of four dose escalation regimens on a 28-day cycle: 100 mg, 200 mg, 300mg and 400 mg once daily, in a Pharmacologically Guided Dose Escalation (PGDE) design (a variation of the standard 3+3 design). The primary endpoints are the incidence of dose limit toxicity (DLT), maximally tolerated dose (MTD), biologically effective dose (BED). The secondary endpoints are treatment-emergent adverse events (TEAE), safety and tolerability, anti-tumor efficacy, pharmacokinetics, and its metabolites. Results: As of Feb 7, 2020, a total of eighteen eligible (18) patients were enrolled into this study: 3 at 100 mg, 3 at 200 mg, 6 at 300 mg and 6 at 400 mg. Only one patient among 6 evaluable patients at 400mg cohort reported one DLT of grade 3 vomiting. Treatment-related adverse events mostly were grade 1 or 2 nausea, vomiting, elevated alkaline phosphatase, elevated conjugated bilirubin, edema, headache, asthenia and decreased appetite. Non-DLT treatment related G3/4 adverse events were peripheral edema (n = 1, 5.5%), hypothyroidism (n = 1, 5.5%). Absorption was rapid after dosing and the median time to reach maximum plasma drug concentration ( Tmax) was 2.0‐6.0 hours. The mean value of half-life(t1/2) in each dose group ranged from 20.43h to 35.36 h. In response to glumetinib, one patient with MET overexpression at 200mg dose level had a best of response of partial response and completed 44 weeks glumetinib treatment, 4 patients (3 with MET amplification) had a best of response of stable disease. Conclusions: Glumetinib was well tolerated at doses up to 400 mg once daily and demonstrated clinical activity in advanced NSCLC with MET alterations. Glumetinib is used in ongoing clinical trials to further explore safety and efficacy in NSCLC. Clinical trial information: NCT03466268.
A phase I study to evaluate safety, tolerability, pharmacokinetics, and preliminary antitumor activity of TQ-B3101.
Authors: Fang Yong , Pan Hongming , Lu Shun , Hu Hong , Lu Qin 
Published: May 2020

e21705 Background: TQ-B3101 is a novel compound, which deacetylated metabolite targets to receptor tyrosine kinases including ALK, ROS1 and MET. Preclinical studies showed TQ-B3101 had a better Inhibition activity and duration compared with equimolar crizotinib. Methods: Patients (pts) with advanced solid tumor failed to standard therapy were enrolled into dose escalation and expansion cohorts. TQ-B3101 was orally administered at doses of 100~300mg QD or 200~350mg BID in a 28-day cycle, then received the same dose until disease progression or intolerable toxicity. Dose escalation was based on dose-limiting toxicities (DLTs) in the first cycle and used “3+3” design to get the maximal tolerated dose (MTD) or recommended phase II dose (RP2D). Other objectives included safety and pharmacokinetics (PK) for all pts, and objective response rate (ORR) for ALK+, ROS1+ and MET amplification pts. Results: As of 20 Dec 2019, 30 pts (median age 51.3, males: 16, females: 14, ALK+: 19, ROS1+: 6, MET amplification: 2, lung cancer: 27, asymptomatic brain metastasis: 8, ECOG PS 1: 30) were enrolled into 7 dose escalation cohorts and 2 dose expansion cohorts (350mg BID/ 300mg BID). One DLT (grade 3 ALT increased) occurred at 350 mg BID. The MTD has not been reached. The most common grade 3 adverse events were neutrophils count decreased (20%), ALT increased (6.67%), leucocyte counts decreased (3.33%) and QT internal prolongation (3.33%). Grade 3 adverse events rate were 40% in 350mg BID cohort and 16.67% in 300mg BID cohort. PK analyses indicated TQ-B3101 metabolized into its deacetylated product rapidly, and exposure (Cmax and AUC) of which generally increased in a dose-proportional manner. Tumor response was evaluated in 24 pts with ALK+/ROS1+/MET amplification. ORR were 62.5% (15/24) in all cohorts, and 87.5% (7/8) in 350mg BID cohort. In 8 pts with brain metastases at baseline, ORR was 62.5% (5/8) . In 22 pts without brain metastases at baseline, the incidence of brain metastasis was 4.55% (1/22). 1 patient with MET amplification is evaluable and the tumor response is PR. Conclusions: TQ-B3101 was well tolerated and showed preliminary antitumor activity in ALK+, ROS1+ and MET amplification pts. Recommended phase II dose (RP2D) might be 300mg BID according longtime safety data. Further anti-tumor research in pts with ROS1+ is under going as multicenter clinical study in China. (NCT03972189). Clinical trial information: NCT03019276.
Molecular profiling of lung adenocarcinoma using pleural effusion specimens.
Authors: Zhang Wei , Zhang Bei , Zhou Yifan , Zhao Xiaochen , Bai Yuezong 
Published: May 2020

e21709 Background: Molecular profiling of lung adenocarcinoma is essential for therapeutic decision-making and prognosis predicting. Pleural effusion may provide an opportunity for molecular profiling and thereby possibly provide information enabling targeted therapy. In this study, we performed next generation sequencing (NGS) in pleural effusion samples in order to study molecular profiling of lung adenocarcinoma using pleural effusion specimens. Methods: 45 Chinese lung adenocarcinoma patients with pleural effusion specimens were included. The pleural effusion samples were centrifugated, then cell pellets were collected and prepared into cell blocks. Genetic mutations were assessed using a validated targeted next generation sequencing assay. Immunohistochemistry (IHC) of PD-L1 was performed with 22C3 kit. Results: In 45 pleural effusion samples collected, 43 (95.5%) patients had at least one mutation classed as pathogenic or likely pathogenic. There were 245 somatic mutation and 160 germline mutations were detected, with an average of 8.0 mutations per patient. Of the 45 specimens with somatic mutations, seventeen (37.8%) of harbored EGFR mutations. The most frequent mutations were the deletion mutation in exon19 (15/17, 40.9%), the point mutation (L858R) in exon 21 (13/17, 76.5%), and resistance mutation (T790M) in exon 20(4/17,23.5%). Aside from the EGFR mutation, 1 case exhibited KRAS mutation (G12C), 1 case harbored ERBB2 mutation(Y772_A775dup),1 case harbored TP53 mutation, and 2 cases exhibited fusion (EML4-ALK, KIF5B-RET). 2 cases exhibited CD274 copy number gain, 2 cases exhibited CDK4 copy number gains, and one case carried CDK6 copy number gain, one case carried CKD6 copy number loss. The top frequent germline mutation genes were APC (5/45), ALK (4/45), ARID1A (4/45) and BARD1 (4/45). Regarding biomarkers for immunotherapy, three sample showed TMB-H (6.7%), and one sample showed MSI-H (2.2%). Of 29 samples underwent PDL1 IHC test, 21 samples (72.4%) show positive PDL1 expression, in concordance with previous reported rates. Conclusions: These results suggest that pleural effusions are important specimens for oncogene mutation analysis and enable targeted therapy for patients with lung adenocarcinoma.
Evaluation of the fully automated Idylla EGFR Mutation Assay in Chinese patients with lung adenocarcinoma.
Authors: Qiu Tian , Junling Li , Zheng Bo , Ying Jianming 
Published: May 2020

e21716 Background: Epidermal growth factor receptor ( EGFR) mutation testing is nowadays an essential part of lung adenocarcinoma diagnosis. Its rapid detection is of utmost significance in order to ensure that patients receive timely and appropriate treatment. However, the current techniques for EGFR examination in China, ARMS-PCR and NGS, often take 3~7 days to deliver the final results. In contrast, the fully automated Idylla EGFR assay could detect 51 EGFR mutations directly from formalin-fixed, paraffin-embedded (FFPE) samples within 2.5 hours with < 2 minutes of hands-on time. The test has proven both accurate and robust among Caucasian lung adenocarcinoma patients but has never been clinically validated in Chinese patients. Methods: FFPE samples were retrospectively collected from 94 lung adenocarcinoma patients followed by EGFR testing using the Idylla system. Seventy-eight samples were also previously assessed with ARMS-PCR, 9 with NGS and 7 with both. In case of discordance, repeat testing was performed on the same tissue block with a third method. The sensitivity and specificity of the Idylla EGFR assay were evaluated against ARMS-PCR or NGS. Mutations beyond the scope of detection by the Idylla EGFR assay were not included in the analyses. Results: Of the 94 tumors enrolled, 77 were stage I-II. The Idylla system was consistent with ARMS-PCR or NGS for the EGFR mutational profiles of 92 tumors: 80 positive and 12 negative. Among the 2 cases of discrepancy, one was wild-type using Idylla but were found to harbor G719X/S768I using ARMS-PCR (and confirmed by NGS), while the other one carried L858R according to Idylla, as confirmed by ARMS-PCR, but was discovered to have an additional mutation L861Q using NGS. The Idylla EGFR test had a sensitivity of 97.6%, a specificity of 100% and an overall concordance of 97.9%. Conclusions: The Idylla system provides a rapid, accurate and user-friendly solution to EGFR characterization, especially in time-sensitive scenarios where special expertise and staff training could be a challenge.
Immune checkpoint inhibitors’ (ICI) efficacy according to PD-L1 expression for advanced or metastatic NSCLC: Systematic review and meta-analysis.
Authors: Maciel Glauber , Carlos Paula , Murad Junior Munir , Araújo Vânia Eloísa , Guerra Augusto , Acúrcio Francisco Assis 
Published: May 2020

e21723 Background: Blocking PD-1 pathway has become a milestone in treating many tumors, including non-small cell lung cancer (NSCLC) for first and second line therapies. Although their benefits for some patients, these drugs are not full available in developing countries due to high treatment cost. In this study, we assessed the efficacy of five PD-1 or PD-L1 blockers (nivolumab, pembrolizumab, atezolizumab, durvalumab and avelumab), associated or not to chemotherapy, according to PD-L1 expression. Methods: We performed a systematic review and meta-analysis of randomized clinical trials in the databases MEDLINE/Pubmed, EMBASE, COCHRANE Library and LILACS up to November 2018. We selected trials comparing ICI alone, or associated with ICI or chemotherapy, versus chemotherapy or placebo. Primary outcome was overall survival (OS) and secondary outcome was progression free survival (PFS). Risk of bias of included trials was assessed by Cochrane’s recommended tool and data meta-analysis was performed by Review Manager V5.3 software. Results: We assessed OS and PFS of 12 trials in our meta-analysis. The methodological quality was considered moderate according to Cochrane’s tool. The pooled hazard ratio were 0.70 (95% CI 0.63, 0.78; p < 0.01; I² = 58%) for OS and 0.75 (95% CI 0.64, 0.89; p < 0.01; I² = 88%) for PFS. Subgroup analysis for PD-L1 < 1%, ≥ 1% and ≥ 50% showed OS of 0.78 (95% CI 0.64, 0.95; p = 0.09; I² = 46%), 0.69 (95% CI 0.59, 0.81; p < 0.01; I² = 79%) and 0.57 (95% CI 0.48, 0.68; p = 0.10; I² = 40%), respectively. Data for PFS were 0.85 (95% CI 0.71, 1.03; p = 0.21; I² = 31%), 0.77 (95% CI 0.64, 0.92; p < 0.01; I² = 83%) and 0.53 (95% CI 0.46, 0.62; p = 0.14; I² = 36%), respectively. Conclusions: Our data suggest a dose-response relationship between PD-L1 level and survival outcomes. It was not possible to conduct our meta-analysis by median OS and median PFS difference once these data were not available for every trial we selected. Considering the high price of immune therapy and budget limitations in developing countries’ health system, our findings could optimize health technology assessment agencies recommendations for treating NSCLC with high expression of PD-L1.
Activin as a biomarker for platinum resistance in non-small cell lung cancer.
Authors: Lim Jennifer Wen Ying , Murphy Alexander David , O'Toole Sandra , Nagrial Adnan , Karikios Deme John , Daneshvar Dariush , Murphy Angela , McCloy Rachael , Watkins Neil , Chin Venessa T. 
Published: May 2020

e21737 Background: Lung cancer is the leading cause of cancer death in Australia with 13,000 new cases per year. Although targeted therapy and immunotherapy have drastically changed the treatment landscape, the majority of patients will receive platinum-based chemotherapy for which the response rate is approximately 30% (Reck et al, 2016). An immunohistochemistry-based, predictive biomarker would be beneficial for patients and help avoid toxicity for patients unlikely to respond. Marini et al (2018) identified 3 biomarkers associated with in-vitro platinum resistance – activin A, growth differentiation factor-11 and transforming growth factor-b – which were investigated in a real-world retrospective cohort to determine their relation to objective radiological response and overall survival. Methods: We identified 101 patients with advanced non-small cell lung cancer who received platinum chemotherapy at 2 cancer centres between 2014-2015. Archival formalin-fixed paraffin embedded tissue samples were stained with activin A. Slides were manually scored by 2 independent clinicians using the multiplicative quickscore method (Detre et al, 1995). Kaplan Meier analysis for overall survival, a Cox-proportional hazards model for confounding variables and a chi-square analysis was performed to analyse the relationship between high immunohistochemistry scores (greater or less than 6) and radiological response. Results: We performed statistical analysis around the median cytoplasmic score (6). The overall median survival was 15.3 months. No significant difference in survival was detected between the two populations (p value = 0.97). The immunohistochemistry score was also not associated with rates of partial response (p value = 0.98) or progressive disease (p value 0.22). Conclusions: Despite an association with lower progression-free survival in a retrospective cohort in a previous study, high expression of activin does not appear to be a useful biomarker for platinum response in the setting of non-small cell lung cancer. Further research into associated antibodies including GDF-11 and TGF-b is in progress.