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PURPOSE The CHOICE-01 study investigated the efficacy and safety of toripalimab in combination with chemotherapy as a first-line treatment for advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients (N = 465) with treatment-naive, advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) once every 3 weeks in combination with chemotherapy for 4-6 cycles, followed by the maintenance of toripalimab or placebo once every 3 weeks plus standard care. Stratification factors included programmed death ligand-1 expression status, histology, and smoking status. The primary end point was progression-free survival (PFS) by investigator per RECIST v1.1. Secondary end points included overall survival and safety. RESULTS At the final PFS analysis, PFS was significantly longer in the toripalimab arm than in the placebo arm (median PFS, 8.4 v 5.6 months, hazard ratio = 0.49; 95% CI, 0.39 to 0.61; two-sided P < .0001). At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm (median OS not reached v 17.1 months, hazard ratio = 0.69; 95% CI, 0.53 to 0.92; two-sided P = .0099). The incidence of grade ≥ 3 adverse events was similar between the two arms. Treatment effects were similar regardless of programmed death ligand-1 status. Genomic analysis using whole-exome sequencing from 394 available tumor samples revealed that patients with high tumor mutational burden were associated with significantly better PFS in the toripalimab arm (median PFS 13.1 v 5.5 months, interaction P = .026). Notably, patients with mutations in the focal adhesion-PI3K-Akt signaling pathway achieved significantly better PFS and OS in the toripalimab arm (interaction P values ≤ .001). CONCLUSION Toripalimab plus chemotherapy significantly improves PFS and OS in patients with treatment-naive advanced NSCLC while having a manageable safety profile. Subgroup analysis showed the OS benefit was mainly driven by the nonsquamous subpopulation.

PURPOSE Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor approved in China. This double-blind phase III trial evaluated the efficacy and safety of aumolertinib compared with gefitinib as a first-line treatment for locally advanced or metastatic EGFR-mutated non–small-cell lung cancer (NSCLC; ClinicalTrials.gov identifier: NCT03849768 ). METHODS Patients at 53 sites in China were randomly assigned 1:1 to receive either aumolertinib (110 mg) or gefitinib (250 mg) once daily. The primary end point was progression-free survival (PFS) per investigator assessment. RESULTS A total of 429 patients who were naïve to treatment for locally advanced or metastatic NSCLC were enrolled. PFS was significantly longer with aumolertinib compared with gefitinib (hazard ratio, 0.46; 95% CI, 0.36 to 0.60; P < .0001). The median PFS with aumolertinib was 19.3 months (95% CI, 17.8 to 20.8) versus 9.9 months with gefitinib (95% CI, 8.3 to 12.6). Objective response rate and disease control rate were similar in the aumolertinib and gefitinib groups (objective response rate, 73.8% and 72.1%, respectively; disease control rate, 93.0% and 96.7%, respectively). The median duration of response was 18.1 months (95% CI, 15.2 to not applicable) with aumolertinib versus 8.3 months (95% CI, 6.9 to 11.1) with gefitinib. Adverse events of grade ≥ 3 severity (any cause) were observed in 36.4% and 35.8% of patients in the aumolertinib and gefitinib groups, respectively. Rash and diarrhea (any grade) were observed in 23.4% and 16.4% of patients who received aumolertinib compared with 41.4% and 35.8% of those who received gefitinib, respectively. CONCLUSION Aumolertinib is a well-tolerated third-generation epidermal growth factor receptor tyrosine kinase inhibitor that could serve as a treatment option for EGFR-mutant NSCLC in the first-line setting.

Background QL1706 (PSB205) is a single bifunctional MabPair (a novel technical platform) product consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1), with a shorter elimination half-life (t1/2) for CTLA-4. We report results from a phase I/Ib study of QL1706 in patients with advanced solid tumors who failed standard therapies. Methods In the phase I study, QL1706 was administered intravenously once every 3 weeks at one of five doses ranging from 0.3 to 10 mg/kg, and the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of QL1706 were investigated. In the phase Ib study, QL1706 was administered at the RP2D intravenously every 3 weeks, and the preliminary efficacies in non-small cell lung cancer (NSCLC), nasopharyngeal carcinoma (NPC), cervical cancer (CC), and other solid tumors were evaluated. Results Between March 2020 and July 2021, 518 patients with advanced solid tumors were enrolled (phase I, n = 99; phase Ib, n = 419). For all patients, the three most common treatment-related adverse events (TRAEs) were rash (19.7%), hypothyroidism (13.5%), and pruritus (13.3%). The TRAEs and immune-related adverse events (irAEs) of grade ≥ 3 occurred in 16.0% and 8.1% of patients, respectively. In phase I, 2 of 6 patients in the 10mg/kg group experienced dose-limiting toxicities (DLTs) (grade 3 thrombocytopenia and grade 4 immune-mediated nephritis), so the maximum tolerated dose (MTD) was reached at 10 mg/kg. The RP2D was determined to be 5 mg/kg based on comprehensive analysis of tolerability, PK/PD, and efficacy. For all patients who received QL1706 at the RP2D, the objective response rate (ORR) and median duration of response were 16.9% (79/468) and 11.7 months (8.3—not reached [NR]), respectively; and the ORRs were 14.0% (17/121) in NSCLC, 24.5% (27/110) in NPC, 27.3% (15/55) in CC, 7.4% (2/27) in colorectal cancer, 23.1% (6/26) in small cell lung cancer. For immunotherapy-naive patients, QL1706 exhibited promising antitumor activities, especially in NSCLC, NPC, and CC, with ORRs of 24.2%, 38.7%, and 28.3%, respectively. Conclusions QL1706 was well tolerated and demonstrated promising antitumor activity in solid tumors, especially in NSCLC, NPC, and CC patients. It is currently being evaluated in randomized phase II (NCT05576272, NCT05179317) and phase III (NCT05446883, NCT05487391) trials. Trial Registration ClinicalTrials.gov Identifier: NCT04296994 and NCT05171790.

IntroductionThe efficacy of postoperative radiotherapy (PORT) is still unclear in non-small cell lung cancer (NSCLC) patients with pIIIA-N2 disease. Estrogen receptor (ER) was proven significantly associated with poor clinical outcome of male lung squamous cell cancer (LUSC) after R0 resection in our previous study.MethodsA total of 124 male pIIIA-N2 LUSC patients who completed four cycles of adjuvant chemotherapy and PORT after complete resection were eligible for enrollment in this study from October 2016 to December 2021. ER expression was evaluated using immunohistochemistry assay.ResultsThe median follow-up was 29.7 months. Among 124 patients, 46 (37.1%) were ER positive (stained tumor cells≥1%), and the rest 78 (62.9%) were ER negative. Eleven clinical factors considered in this study were well balanced between ER+ and ER- groups. ER expression significantly predicted a poor prognosis in disease-free survival (DFS, HR=2.507; 95% CI: 1.629-3.857; log-rank p=1.60×10-5). The 3-year DFS rates were 37.8% with ER- vs. 5.7% with ER+, with median DFS 25.9 vs. 12.6 months, respectively. The significant prognostic advantage in ER- patients was also observed in overall survival (OS), local recurrence free survival (LRFS), and distant metastasis free survival (DMFS). The 3-year OS rates were 59.7% with ER- vs. 48.2% with ER+ (HR, 1.859; 95% CI: 1.132-3.053; log-rank p=0.013), the 3-year LRFS rates were 44.1% vs. 15.3% (HR=2.616; 95% CI: 1.685-4.061; log-rank p=8.80×10-6), and the 3-year DMFS rates were 45.3% vs. 31.8% (HR=1.628; 95% CI: 1.019-2.601; log-rank p=0.039). Cox regression analyses indicated that ER status was the only significant factor for DFS (p=2.940×10-5), OS (p=0.014), LRFS (p=1.825×10-5) and DMFS (p=0.041) among other 11 clinical factors.ConclusionsPORT might be more beneficial for ER negative LUSCs in male, and the examination of ER status might be helpful in identifying patients suitable for PORT.

Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation EGFR tyrosine kinase inhibitor (TKI) with revealed activity against EGFR-sensitizing mutations and EGFR T790M mutation.Patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy were enrolled in this registrational phase 2 trial of aumolertinib at 110 mg orally once daily (NCT02981108). The primary end point was objective response rate (ORR) by independent central review.A total of 244 patients with EGFR T790M-positive NSCLC were enrolled. The ORR by independent central review was 68.9% (95% confidence interval [CI]: 62.6-74.6). The disease control rate was 93.4% (95% CI: 89.6-96.2). The median duration of response was 15.1 months (95% CI: 12.5-16.6). The median progression-free survival was 12.4 months (95% CI: 9.7-15.0). Among 23 patients with assessable central nervous system (CNS) metastases, the CNS-ORR and CNS-disease control rate were 60.9% (95% CI: 38.5-80.3) and 91.3% (95% CI: 72.0-98.9), respectively. The median CNS-duration of response was 12.5 months (95% CI: 5.6-not reached). Treatment-related adverse events of more than or equal to grade 3 occurred in 16.4% of the patients, with the most common being increased blood creatine phosphokinase level (7%) and increased alanine aminotransferase level (1.2%). The relative dose density of aumolertinib was 99.2% in this study.Aumolertinib is an effective and well-tolerated third-generation EGFR TKI for patients with EGFR T790M-positive advanced NSCLC after disease progression on first- and second-generation EGFR TKI therapy. On the basis of these findings, aumolertinib was approved in the People's Republic of China for patients positive for EGFR T790M NSCLC.

Shukui Qin,1 Rui-Hua Xu,2 Lin Shen,3 Jianming Xu,4 Yuxian Bai,5 Lei Yang,6 Yanhong Deng,7 Zhen-dong Chen,8 Haijun Zhong,9 Hongming Pan,10 Weijian Guo,11 Yongqian Shu,12 Ying Yuan,13 Jianfeng Zhou,14 Nong Xu,15 Tianshu Liu,16 Dong Ma,17 Changping Wu,18 Ying Cheng,19 Donghui Chen,20 Wei Li,21 Sanyuan Sun,22 Zhuang Yu,23 Peiguo Cao,24 Haihui Chen,25 Jiejun Wang,26 Shubin Wang,27 Hongbing Wang,28 Ning Wang,29 Bin Zhang,29 Qiang Zhang,29 Weiguo Su,30 Xiaojun Guo,30 Jin Li31 1Cancer Center, Jinling Hospital, Nanjing, People’s Republic of China; 2Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, People’s Republic of China; 3Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 4Department of Medical Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 5Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China; 6Department of Medical Oncology, Nantong Cancer Hospital, Nantong, People’s Republic of China; 7Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 8Department of Medical Oncology, The Second Hospital of Anhui Medical University, Hefei, People’s Republic of China; 9Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, People’s Republic of China; 10Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 11Department of Medical Oncology, Shanghai Medical College, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 12Department of Medical Oncology, Jiangsu Provincial Hospital, Nanjing, People’s Republic of China; 13Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 14Department of Medical Oncology, Peking Union Medical College Hospital, Beijing, People’s Republic of China; 15Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, People’s Republic of China; 16Department of Medical Oncology, Fudan University Zhongshan Hospital, Shanghai Medical College, Shanghai, People’s Republic of China; 17Department of Medical Oncology, Guangdong Provincial People’s Hospital, Guangzhou, People’s Republic of China; 18Department of Medical Oncology, The First People’s Hospital of Changzhou, Changzhou, People’s Republic of China; 19Department of Medical Oncology, Jilin Province Cancer Hospital, Changchun, People’s Republic of China; 20Department of Medical Oncology, Shanghai Jiaotong University Affiliated First People’s Hospital, Shanghai, People’s Republic of China; 21Department of Medical Oncology, The First Hospital of Jilin University, Changchun, People’s Republic of China; 22Department of Medical Oncology, Xuzhou Central Hospital, Xuzhou, People’s Republic of China; 23Department of Medical Oncology, The Affiliated Hospital of Medical College Qingdao University, Qingdao, People’s Republic of China; 24Department of Medical Oncology, The Third Xiangya Hospital of Central South University, Changsha, People’s Republic of China; 25Department of Medical Oncology, Liuzhou Worker’s Hospital, Liuzhou, People’s Republic of China; 26Department of Medical Oncology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, People’s Republic of China; 27Department of Medical Oncology, Peking University Shenzhen Hospital, Beijing University, Shenzhen, People’s Republic of China; 28Department of Medical Oncology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou Medical College, Xuzhou, People’s Republic of China; 29Eli Lilly and Company, Shanghai, People’s Republic of China; 30Hutchison MediPharma Limited, Shanghai, People’s Republic of China; 31Department of Medical Oncology, Tongji University Shanghai East Hospital, Shanghai, People’s Republic of ChinaCorrespondence: Jin LiDepartment of Medical Oncology, Tongji University Shanghai East Hospital, Shanghai, People’s Republic of ChinaTel +8613761222111Email lijin@csco.org.cnObjective: The aim of the present subgroup analysis of the FRESCO trial is to determine the efficacy and hepatotoxicity of fruquintinib in Chinese patients with metastatic CRC with liver metastasis (CRLM) who were receiving third-line or posterior-line therapy.Methods: Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan–Meier method. Hazard ratio (HR) was estimated through Cox proportional hazards model. Hepatotoxicity was coded using the standardized MedDRA queries of hepatic failure, fibrosis, cirrhosis, and other liver injury-related conditions and graded using the Common Terminology Criteria Adverse Events grades. The efficacy of fruquintinib in patients with CRLM was evaluated in various subgroups.Results: A total of 287 (69.0%) patients with metastatic CRC had liver metastasis (LM, fruquintinib: 185 and placebo: 102). Median OS in patients with CRLM was significantly prolonged with fruquintinib compared with placebo (8.61 months vs 5.98 months; HR=0.59, 95% CI, 0.45– 0.77, P< 0.001). In patients with CRLM, the incremental median PFS for patients in the fruquintinib-treated group was significantly higher than in the placebo group (median PFS: 3.71 vs.1.84 months; HR=0.22, 95% CI: 0.17– 0.30; P< 0.001). Compared with placebo, significant improvements in OS were observed with fruquintinib in LM patients regardless of lung metastasis, prior target therapy, and K-RAS status. In patients with CRLM, treatment-emergent hepatotoxicities of any grade occurred in 7 (3.8%) patients in the fruquintinib group vs 2 (2.0%) in the placebo group.Conclusion: Fruquintinib demonstrated a statistically significant increase in OS and PFS as compared with placebo in Chinese patients with CRLM. The hepatotoxicity of fruquintinib was less reported, and comparable with placebo in patients with CRLM.ClinicalTrials.gov Identifier: NCT02314819.Keywords: colorectal cancer, FRESCO trial, fruquintinib, liver metastasis

To explore a better treatment strategy for patients with advanced non‐small cell lung cancer harboring sensitive epidermal growth factor receptor mutations, a total of 271 patients were retrospectively analyzed. The patients were divided into two groups: the combination group (58 cases), which received concurrent icotinib, pemetrexed, and platinum treatment, and the sequential group (213 cases), which received the sequential pemetrexed and platinum therapy, followed by icotinib treatment. The primary end points were progression‐free survival (PFS) and PFS on the subsequent line of therapy (PFS2). PFS in the combination group was significantly higher compared with that in the sequential group (16.89 months vs. 9.90 months; p

By implementing dynamic circulating tumor DNA (ctDNA) analysis, we explored the impact of TP53 mutations on tumor evolution and resistance mechanisms to ensartinib in patients with ALK-positive NSCLC.In a multicenter phase 2 trial, patients with ALK-positive NSCLC who progressed on crizotinib were treated with ensartinib. Blood samples for ctDNA analysis were collected at baseline, cycle 3 day 1, and progression disease (PD) and analyzed with a 212-gene panel.A total of 440 samples were collected from 168 patients. Baseline TP53 mutations (20.2%) significantly correlated with inferior progression-free survival (4.2 mo versus 11.7 mo, p0.0001). Patients with TP53 mutations had higher mutation load than those without TP53 mutations at baseline (13.79 ± 3.72 versus 4.67 ± 0.39, p0.001). Although there was no significant difference in mutation load between these groups at cycle 3 day 1 (5.89 ± 2.25 versus 3.72 ± 0.62, p = 0.425), patients with mutated TP53 developed more mutations at PD (7.07 ± 1.25 versus 3.20 ± 0.33, p = 0.003). Frequency and abundance of secondary ALK mutations G1269A, G1202R, and E1210K increased markedly at PD than baseline. In patients without secondary ALK mutations, we identified ALK-independent resistance mechanisms including bypass signaling activation, downstream effector protein reactivation, epithelial-mesenchymal transformation, and epigenetic dysregulation.Our study highlighted the advantage of ctDNA analysis for monitoring tumor evolution. TP53 mutations promoted genetic evolution and accelerated occurrence of resistance. We also unveiled ALK-dependent resistance mechanisms, mainly by G1269A, G1202R, and E1210K mutations, and ALK-independent resistance mechanisms to ensartinib.

Background: FRESCO study demonstrated efficacy and safety of fruquintinib in metastatic colorectal cancer patients. Impact of prior targeted therapy (PTT) on efficacy and safety of fruquintinib was evaluated. Materials & methods: In this subgroup analysis of FRESCO trial, patients were divided into PTT and non-PTT subgroups, and efficacy and safety of fruquintinib were assessed, respectively. Results: In non-PTT subgroup, fruquintinib significantly prolonged overall survival (OS) and progression-free survival (PFS) of patients compared with placebo. In PTT subgroup, the median OS and PFS of patients in fruquintinib arm was significantly higher than those in placebo. Treatment-emergent adverse events (TEAEs) rates were similar in both subgroups. Conclusion: Fruquintinib demonstrated clinically meaningful improvement in OS, PFS, objective response rate, and disease control rate with manageable TEAEs in both subgroups. Clinical trial registration: NCT02314819 ( ClinicalTrials.gov )

Befotertinib (D-0316) is a novel, third-generation EGFR tyrosine kinase inhibitor (TKI). This study evaluated befotertinib in patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy.This was a single-arm, open-label, phase 2 study at 49 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC harboring EGFR T790M mutations with disease progression after prior first- or second-generation EGFR TKI therapy received oral befotertinib of 50 mg (cohort A) or 75 to 100 mg (cohort B) once daily. The primary end point was objective response rate (ORR) assessed by an independent review committee in intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT03861156.A total of 176 patients and 290 patients were included in cohorts A (50 mg) and B (75-100 mg), respectively. At data cutoff (August 15, 2021), independent review committee-assessed ORR was 67.6% (95% confidence interval [CI]: 61.9%-72.9%) in cohort B. The investigator-assessed ORR was 54.0% (95% CI: 46.3%-61.5%) in cohort A and 65.9% (95% CI: 60.1%-71.3%) in cohort B. The median investigator-assessed progression-free survival was 11.0 (95% CI: 9.6-12.5) months in cohort A and 12.5 (95% CI: 11.1-13.8) months in cohort B. The median independent review committee-assessed progression-free survival in cohort B was 16.6 (95% CI: 15.0-not evaluable [NE]) months. The intracranial ORR was 26.7% (95% CI: 7.8%-55.1%) in cohort A by investigator assessment, while 57.1% (95% CI: 34.0%-78.2%) and 55.9% (95% CI: 37.9%-72.8%) in cohort B by investigator and independent review committee assessment, respectively. The median investigator-assessed intracranial progression-free survival was 16.5 (95% CI: 8.6-NE) months in cohort A, while the median intracranial progression-free survival was not evaluable in cohort B due to immature data regardless of investigator or independent review committee assessment. and NE (95% CI: 13.8-NE) in cohort B. The overall survival was immature. Grade 3 or higher treatment-related adverse events and treatment-related serious adverse events occurred in 20.5% and 11.4% of patients in cohort A and in 29.3% and 10.0% of patients in cohort B, respectively.Befotertinib of 75 to 100 mg has satisfying efficacy and manageable toxicity in patients with locally advanced or metastatic NSCLC harboring T790M mutation with resistance to first- or second-generation EGFR TKIs. A phase 3 randomized trial is underway (NCT04206072).

798 Background: Claudin18.2 (CLDN18.2) is specifically expressed in the tight junction of gastric epithelial cells, and has been identified as a promising target in gastric and pancreatic cancer as well as several other malignancies. MIL93 is a humanized afucosylated IgG1 monoclonal antibody targeting CLDN18.2 with enhanced ADCC function, which demonstrated superior activity compared with zolbetuximab in vitro and in vivo, respectively. We conducted a multicenter, dose escalation and expansion phase 1 study of MIL93 for advanced solid tumors. Methods: We enrolled pts aged 18 years or older with advanced solid tumors whose disease had progressed after standard systemic treatments in the monotherapy part of this study. Pts were required to have measurable lesion as per RECIST v1.1; ECOG PS score of 0-1 and adequate organ functions. In the dose escalation phase, 6 dose levels (0.3mg/kg, 1mg/kg, 3mg/kg, 10mg/kg, 20mg/kg and 30mg/kg, Q3W) of MIL93 were conducted for assessment. Accelerated titration was adopted for the first 2 dose levels, and the 3+3 design was used afterwards. In the dose expansion phase, pts with CLDN18.2-positive cancers received the selected RP2D. The primary objectives were the safety and tolerability, dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) of MIL93. Secondary objectives included pharmacokinetics, immunogenicity and preliminary efficacy. Results: At the data cut-off date (August 9, 2022), 30 pts were enrolled from 6 centers in China. MIL93 was well-tolerated for the dosages tested (0.3mg/kg through 30mg/kg Q3W). DLT was observed in one pt during the 3-week window at 30mg/kg. However, none of the three additional patients at 30mg/kg had DLT, and MTD has not been reached. In further expansion study 9 additional pts were enrolled into the expansion phase at the 20 mg/kg Q3W dose and 3 pts were enrolled into the dose escalation at the 10mg/kg Q2W. The most common TEAE occurring in ≥20% of pts were nausea (60%), hypoalbuminemia (46.7%), vomiting (43.3%), anemia (36.7%), hyponatremia (33.3%), hypocalcemia (23.3%), decreased appetite (23.3%), asthenia (23.3%), aspartate aminotransferase increased (20.0%). Serious adverse events (SAEs) were observed in 9 (30%) pts, and MIL93-related SAEs occurred in 6 (20%) pts including hypoalbuminemia/hypoproteinemia, malnutrition, anorexia and vomiting. No treatment related Grade 4 or 5 event was reported. Among the 25 pts who had at least one post-treatment radiological evaluation, 2 gastric cancer pts who progressed on multiple lines of therapies achieved partial response (PR). The disease control rate (DCR) reached 44%. Conclusions: MIL93 had a manageable and tolerable safety profile in patients with advanced solid tumors and preliminary anti-tumor activity in 2 heavily pretreated gastric cancer pts. Combination of MIL93 and standard treatment in selected tumor types is currently underway. Clinical trial information: NCT04671875 .

The relentless debate on postoperative adjuvant radiotherapy in gastric adenocarcinoma (GA) has been lasting for decades. In this study, a new biomarker, named promoter methylation burden of DNA repair genes (RPMB), was established to identify the subgroup of patients who might benefit from adjuvant radiotherapy. Methylation profiles of 397 GA tumor samples were downloaded from The Cancer Genome Atlas (TCGA). RPMB for a patient was defined as the ratio of methylated DNA repair genes to the number of all DNA repair genes. Subgroup analyses in term of overall survival (OS) and disease-free survival (DFS) indicated that most of the subgroups favored the high-RMPB group. Kaplan-Meier analysis showed that overall the patients with high RPMB after R0 resection had a significantly better clinical outcome regarding DFS (hazard ratio [HR] = 0.013, p = 0.042). Additionally, high-RPMB patients, who underwent adjuvant radiotherapy with both ≥T2 tumor and positive lymph nodes, showed superior DFS in comparison with the low-RPMB group (HR = 5.35 × 10−10, n = 26, p = 0.010). RPMB might be considered as a promising biomarker for decision-making with regard to postoperative adjuvant radiotherapy for GA patients., Graphical Abstract, To identify the subgroup of gastric adenocarcinoma (GA) patients who can benefit from postoperative adjuvant radiotherapy, An et al. proposed a new biomarker, named promotor methylation burden of DNA repair genes (RPMB), closely associated with patient prognosis, hopefully to provide guidance for treating GA patients after radical resection.

Supplemental Digital Content is available in the text., Objective: We aim to develop and validate an effective nomogram prognostic model for patients with typical lung carcinoid tumors using a large patient cohort from the Surveillance, Epidemiology, and End Results (SEER) database. Materials and Methods: Data from patients with typical lung carcinoid tumors between 2010 and 2015 were selected from the SEER database for retrospective analysis. Univariate and multivariate Cox analysis was performed to clarify independent prognostic factors. Next, a nomogram was formulated to predict the probability of 3- and 5-year overall survival (OS). Concordance indexes (c-index), receiver operating characteristic analysis and calibration curves were used to evaluate the model. Results: The selected patients were randomly divided into a training and a validation cohort. A nomogram was established based on the training cohort. Cox analysis results indicated that age, sex, T stage, N stage, surgery, and bone metastasis were independent variables for OS. All these factors, except surgery, were included in the nomogram model for predicting 3- and 5-year OS. The internally and externally validated c-indexes were 0.787 and 0.817, respectively. For the 3-year survival prediction, receiver operating characteristic analysis showed that the areas under the curve in the training and validation cohorts were 0.824 and 0.795, respectively. For the 5-year survival prediction, the area under the curve in the training and validation cohorts were 0.812 and 0.787, respectively. The calibration plots for probability of survival were in good agreement. Conclusion: The nomogram brings us closer to personalized medicine and the maximization of predictive accuracy in the prediction of OS in patients with typical lung carcinoid tumors.

Although the prognostic value of the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and lymphocyte/white blood cell ratio (LWR) has been described in advanced non-small cell lung cancer (NSCLC), the association between complete blood cell parameters prior to disease treatment and NSCLC have yet to be identified. The aim of the present study was to assess the complete blood cell parameters prior to disease treatment in patients with advanced NSCLC. A total of 268 patients with advanced NSCLC were enrolled in this study. Clinical and laboratory data of the patients were acquired through medical records. Receiver operating characteristic curve analysis was used to determine the optimal cut-off values of the neutrophil/white blood cell ratio (NWR), NLR, platelet/white blood cell ratio (PWR), PLR, monocyte/white blood cell ratio (MWR), monocyte/lymphocyte ratio (MLR) and LWR. Kaplan-Meier univariate and multivariate Cox regression analyses were used to evaluate the effect of complete blood parameters on progression-free survival (PFS) and overall survival (OS). The optimal cut-off values were identified as 0.67 for NWR, 2.85 for NLR, 37.23 for PWR, 166.56 for PLR, 0.074 for MWR, 0.31 for MLR and 0.24 for LWR. Univariate analysis revealed that sex (P=0.038), histological type (P

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

Accumulating evidence has revealed that the dysregulation of circular RNAs (circRNAs) plays crucial roles in the occurrence and progression of cancers. However, the aberrant expression profile and dysfunction of circRNAs in non-small cell lung cancer (NSCLC) have not been fully explored. Herein, we discovered that a circRNA, hsa_circ_0001666 (circ0001666), was highly expressed in NSCLC tissues and cell lines, and it was positively correlated with NSCLC tumor pathological grade and lymph node metastasis. Moreover, Kaplan-Meier survival analysis implied that NSCLC patients with high circ0001666 expression were negatively correlated with favorable survival. Functionally, circ0001666 could promote migration and invasion of NSCLC cells

Background Clinical options for lung squamous carcinoma (LUSC) are still quite limited. Carcinogenesis is an exceedingly complicated process involving multi-level dysregulations. Therefore, only looking into one layer of genomic dysregulation is far from sufficient. Methods We identified differentially expressed genes with consistent upstream genetic or epigenetic dysregulations in LUSC. Random walk was adopted to identify genes significantly affected by upstream abnormalities. Expression differentiation and survival analysis were conducted for these significant genes, respectively. Prognostic power of selected gene was also tested in 102 male LUSC samples through immunohistochemistry assay. Results Twelve genes were successfully retrieved from biological network, including ERα (ESRS1), EGFR, AR, ATXN1, MAPK3, PRKACA, PRKCA, SMAD4, TP53, TRAF2, UBQLN4 and YWHAG, which were closely related to sex hormone signaling pathway. Survival analysis in public datasets indicated ERα was significantly associated with a poor overall survival (OS) in male LUSC. The result of our immunohistochemistry assay also demonstrated this correlation using R0 resected tumors (n = 102, HR: 2.152, 95% CI: 1.089–4.255, p = 0.024). Although disease-free survival (DFS) difference was non-significant (n = 102, p = 0.12), the tendency of distinction was straight-forward. Cox analysis indicated ERα was the only independent prognostic factor for male patients’ OS after R0 resection (HR = 2.152, p = 0.037). Conclusion ERα was significantly related to a poor prognosis in LUSC, especially for male patients after radical surgery, confirmed by our immunohistochemistry data.

To study the clinical significance of serum epidermal growth factor receptor (EGFR) gene mutation and serum tumor markers in the prediction of tyrosine kinase inhibitor (TKI) efficacy in patients with lung adenocarcinoma. Ninety patients with pathologically diagnosed lung adenocarcinoma were enrolled. Further, 51 out of 90 patients received the EGFR-TKI therapy, oral gefitinib. The correlations among serum EGFR gene mutations in exons 18–21, serum tumor markers such as carcinoembryonic antigen (CEA), carbohydrate antigen 24-2 (CA24-2), carbohydrate antigen 125, carbohydrate antigen 15-3 as well as carbohydrate antigen 19-9 (CA19-9) levels, and EGFR-TKI efficacy were determined. There was a high consistency of EGFR gene mutation rate between serum and tissue samples. The serum EGFR gene mutation rate in female patients or non-smokers was significantly higher than that in male patients or smokers, respectively. Serum CA19-9, CA24-2, and CEA levels were significantly correlated with serum EGFR mutation. After receiving gefitinib, the progression-free survivals (PFSs) of patients with high serum CEA level, high serum CA19-9 level, or serum EGFR gene mutation were significantly higher than those of normal patients, respectively. The PFSs were significantly prolonged in patients with EGFR gene mutation and high serum CEA level or patients with EGFR gene mutation and high serum CA19-9 level compared with those in patients with one abnormal biomarker and normal patients. Combined detection of EGFR gene mutations as well as CA19-9 and CEA levels in peripheral blood can predict the efficacy of EGFR-TKI in the treatment of patients with lung adenocarcinoma.

9096 Background: We previously reported (Lu, ASCO 2021, abstract # 9013) that treatment with aumolertinib (Au), a 3rd generation EGFR TKI, led to robust improvement in progression free survival (PFS) (median PFS 19.3 to 9.9 months, HR = 0.46, p < 0.0001) when compared to gefitinib (G) with a predictable and encouraging safety profile. This benefit was maintained across all prespecified stratification factors including the subset of ̃ 27% of patients (pts) with CNS metastases (HR = 0.38). Here we undertook this analysis to more fully characterize the activity and benefit of Au as compared to G in this clinically important subset of EGFR mutant NSCLC pts. Methods: Pts with previously untreated metastatic or locally advanced NSCLC with EGFR sensitizing mutations were enrolled and randomly assigned in a 1:1 ratio to receive either Au (110 mg QD) or G (250 mg QD). Predefined stratification factors were EGFR-mutated status (Ex19del vs L858R) and CNS metastases (yes vs no). Patients with stable, asymptomatic CNS metastases were eligible for enrollment. All pts had baseline brain imaging by magnetic resonance imaging or computed tomography. The primary endpoint was PFS assessed by investigator per RECIST v1.1 in full analysis set (systemic analysis). Independent CNS efficacy was performed both in pts with baseline CNS metastases (CNS full analysis set, cFAS) and in pts with baseline CNS target lesions (CNS evaluable-for-response set, cEFS) by blinded independent central neuroradiology review (BICR) per RECIST v1.1. Results: Of 429 pts, 106 pts (Au, n = 51; G, n = 55) were found to have CNS metastases (cFAS) and 61 pts (Au, n = 29; G, n = 32) had CNS target lesions as defined by RECIST 1.1 (cEFS) at baseline by BICR. At the cutoff date (Aug 6, 2021), based on cEFS, CNS PFS events were observed in 11 pts (38%) treated with Au versus 20 pts (63%) who were randomized to receive G. Treatment with Au significantly prolonged CNS median PFS compared with G (29.0 vs 8.3 months; HR = 0.300; 95% CI, 0.137-0.657; P = 0.0015). Estimated CNS PFS rate at 12 and 18 months were 71% and 62% in Au arm compared with 23% and 0% in G arm. The confirmed CNS ORR were 82.8% and 75.0% in pts treated with Au and G, respectively (odds ratio = 1.600; 95% CI, 0.457-5.597; P = 0.4621). Au also achieved longer CNS median PFS over G in cFAS (29.0 vs 8.3 months; HR = 0.323; 95% CI, 0.181-0.576; P < 0.0001). No new safety findings were observed. Conclusions: Au demonstrated superior clinical efficacy against CNS metastases over G as first-line therapy in EGFR-mutated advanced NSCLC, and the safety profile was consistent with that reported previously. Additional randomized studies of Au in pts with CNS metastases are ongoing (NCT04870190). Clinical trial information: NCT03849768.

Somatic KEAP1-NRF2 pathway alterations are frequently detected in both lung adenocarcinomas and squamous cell carcinomas. However, the biological characteristics and molecular subtypes of KEAP1/NRF2-mutant lung cancer remain largely undefined. Here, we performed a stepwise, integrative analytic and experimental interrogation of primary tumors and cancer cell lines harboring KEAP1 or NFE2L2 (encoding NRF2) gene mutations. First, we discovered that KEAP1/NRF2-mutant lung cancer presented APOBEC-mediated mutational signatures, impaired tumor angiogenesis, elevated hypoxic stress and deficient immune-cell infiltrates. Second, gene expression-based subtyping revealed three molecular subsets of KEAP1/NRF2-mutant lung adenocarcinomas and two molecular subsets of KEAP1/NRF2-mutant lung squamous cell carcinomas, each associated with distinguishing genetic, differentiation, immunological and clinicopathological properties. Third, single-sample prediction allowed for de novo identification of KEAP1/NRF2-active tumors within KEAP1/NRF2-wild-type samples. Our data demonstrate that KEAP1/NRF2-mutant lung cancer is a microenvironmentally distinct, biologically heterogeneous, and clinically underestimated disease. These new pathological and molecular insights may accelerate the development of efficacious therapeutic strategies against human malignancies featured by KEAP1-NRF2 pathway activation.

Purpose: The induced death signals following oncogene inhibition underlie clinical efficacy of molecular targeted therapies against human cancer, and defects of intact cell apoptosis machinery often lead to therapeutic failure. Despite potential importance, other forms of regulated cell death triggered by pharmacologic intervention have not been systematically characterized. Experimental Design: Pyroptotic cell death was assessed by immunoblot analysis, phase-contrast imaging, scanning electron microscopy, and flow cytometry. Tumor tissues of patients with lung cancer were analyzed using IHC. Functional impact of pyroptosis on drug response was investigated in cell lines and xenograft models. Results: We showed that diverse small-molecule inhibitors specifically targeting KRAS-, EGFR-, or ALK-driven lung cancer uniformly elicited robust pyroptotic cell death, in addition to simultaneously invoking cellular apoptosis. Upon drug treatment, the mitochondrial intrinsic apoptotic pathway was engaged and the mobilized caspase-3 protease cleaved and activated gasdermin E (GSDME, encoded by DFNA5), which permeabilized cytoplasmic membrane and executed cell-lytic pyroptosis. GSDME displayed ubiquitous expression in various lung cancer cell lines and clinical specimens, including KRAS-mutant, EGFR-altered, and ALK-rearranged adenocarcinomas. As a result, cooccurrence and interplay of apoptosis and pyroptosis were widespread in lung cancer cells, succumbing to genotype-matched regimens. We further demonstrated that pyroptotic cell death partially contributed to the drug response in a subset of cancer models. Conclusions: These results pinpoint GSDME-dependent pyroptosis as a previously unrecognized mechanism of action for molecular targeted agents to eradicate oncogene-addicted neoplastic cells, which may have important implications for the clinical development and optimal application of anticancer therapeutics.

Related studies have reported that cystatin C (Cys C), uric acid (UA) and lactate dehydrogenase (LDH) affect tumor growth and invasion; however, the correlation between them and the prognosis of patients with small-cell lung cancer (SCLC) remains unclear. The present study aimed to investigate the effects of serum Cys C, UA and LDH concentrations on the prognosis of patients with SCLC prior to initial treatment, in order to identify potential targets for determining the clinical outcome of patients with SCLC. A total of 205 patients with SCLC were enrolled in the present study, and the clinical and laboratory data were obtained from the medical records. The receiver operating characteristic curve was used to determine the optimal cut-off values of Cys C, UA and LDH, while the Kaplan-Meier method was used for survival analysis. The Cox proportional hazard model was used for univariate and multivariate analyses to identify independent prognostic factors. The optimal cut-off values for Cys C, UA and LDH were 0.775 mg/l, 296.45 µmol/l and 198.5 U/l, respectively. The survival curves demonstrated that progression-free survival (PFS) and overall survival (OS) time were shorter in patients with high levels of Cys C, UA and LDH prior to chemotherapy. Univariate and multivariate analyses indicated that LDH concentration prior to chemotherapy may be an independent prognostic factor for both PFS and OS in patients with SCLC, while Cys C concentration may be an independent prognostic factor for PFS in patients with SCLC. The concentrations of Cys C, UA and LDH prior to chemotherapy were associated with prognosis of patients with SCLC. PFS and OS time were shorter, and the prognosis was poor in patients with elevated serum levels of Cys C, UA and LDH. Taken together, the results of the present study suggest that high concentrations of LDH and Cys C prior to chemotherapy may indicate rapid disease progression, thus it is important to focus on the progression and recurrence of the disease. High LDH concentration may also indicate a shorter survival time.

Sintilimab, an anti-programmed death 1 antibody, plus pemetrexed and platinum had revealed promising efficacy for nonsquamous NSCLC in a phase 1b study. We conducted a randomized, double-blind, phase 3 study to compare the efficacy and safety of sintilimab with placebo, both in combination with such chemotherapy (ClinicalTrials.gov: NCT03607539).A total of 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC without sensitizing EGFR or anaplastic lymphoma kinase genomic aberration were randomized (2:1 ratio) to receive either sintilimab 200 mg or placebo plus pemetrexed and platinum once every 3 weeks for four cycles, followed by sintilimab or placebo plus pemetrexed therapy. Crossover or treatment beyond disease progression was allowed. The primary end point was progression-free survival (PFS) as judged by an independent radiographic review committee.As of November 15, 2019, the median follow-up was 8.9 months. The median PFS was significantly longer in the sintilimab-combination group than that in the placebo-combination group (8.9 versus 5.0 mo; hazard ratio, 0.482, 95% confidence interval [CI]: 0.362-0.643; p0.00001). The confirmed objective response rate was 51.9% (95% CI: 45.7%-58.0%) in the sintilimab-combination group and 29.8% (95% CI: 22.1%-38.4%) in placebo-combination group. The incidence of grade 3 or higher adverse events was 61.7% in sintilimab-combination group and 58.8% in placebo-combination group.In Chinese patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC, the addition of sintilimab to chemotherapy with pemetrexed and platinum resulted in considerably longer PFS than with chemotherapy alone with manageable safety profiles.

B cell malignancies are classified as different types such as B cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL) and B cell non-Hodgkin lymphoma (NHL) based on cell surface expression of various clusters of differentiation molecules. CD19 is a B cell lineage-specific antigen which is expressed on malignant B cells in patients with B-ALL, CLL and NHL. Adoptive transfer of T cells that are genetically modified to express a CD19-specific chimeric antigen receptor (CAR) represents a promising clinical strategy for patients with B cell malignancies. CD19-CAR T cell therapy has achieved high response rates and durable remissions on B cell malignancies. However, the efficacy of CAR-T therapy is still inefficient and the critical factors for better efficacy remain unclear. In this review, we summarized the critical factors for better efficacy of CD19 CAR-T cells in B-lineage malignancies including B-ALL, B-CLL and lymphoma. T cell persistence, lymphodepletion regimen, CD3/CD28 beads treatment and no IL-2 administration to T cells were positively associated with better responses. The method of enhancing the persistence of CAR-T cells need to be further optimized in order to improve the clinical efficacy in the treatment of B cell malignancies. In order to improve the therapeutic effect of CAR-T therapy, new therapeutic strategies should be developed to make factors which influence efficacy the more beneficial.

It has been reported that microRNA-142 (miR-142) is a tumor suppressor gene. The present study primarily investigated whether the overexpression of miR-142 was able to inhibit the proliferation, apoptosis and expression of apoptosis-associated proteins in osteosarcoma (OS) cells. Different concentrations of miR-142 were transfected into the OS MG-63 cell line using Lipofectamine 2000. The cell lines were divided into three groups: Normal group (non-transfected group), miR-142 transfected group, and negative group, which were transfected with random miR-142 fragment. The proliferation of cells was detected by MTT assay. The expression of miR-142 was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). DAPI staining was performed to investigate the influence of miR-142 on the morphology of MG-63c ells. The apoptotic cell percentages were determined by flow cytometry with Annexin V-fluorescein isothiocyanate/propidium iodide double staining. Expression of tumor suppressors, phosphatase and tensin homolog (PTEN) and Retinoblastoma-associated protein (Rb), and apoptosis-associated proteins were evaluated by western blotting. RT-qPCR indicated a higher expression of miR-142 in the transfected group (miR-142 was transfected into the MG-63 cell line) compared with that in the normal (non-transfected group) and negative control groups. The proliferation of miR-142 transfected cells was significantly lower compared with that in the normal and negative groups. Furthermore, an increased apoptosis rate accompanied by a statistically significant upregulation of PTEN, Rb phosphorylation, cleaved caspase-3 and cytochrome c protein levels were detected in the transfected group, indicating an internal apoptosis pathway was involved in this process. Furthermore, no significant changes were identified between the normal and negative groups (P>0.05). The present study demonstrated that miR-142 overexpression by liposomal transfection resulted in an inhibitory effect on MG-63 cell proliferation. The underlying mechanisms may relate to the upregulation of tumor suppressor and activation of caspase signaling pathway, which may provide a novel horizon in short nucleotide drugs on the management of OS.

D-0316 in patients with advanced T790M-positive EGFR-mutant non-small cell lung cancer who progressed on prior EGFR-TKI therapy: results from a phase II study (NCT03861156) Background: Despite initial response to EGFR-TKI, most patients (pts) develop resistance with the EGFR T790M mutation detectable in ~50% of patients treated with first-/second-generation EGFR-TKIs. D-0316 is a third-generation EGFR-TKI that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in pts with non-small cell lung cancer (NSCLC). We report the results of a registered, single-arm, phase II study of D-0316 in NSCLC pts with EGFR T790M who progressed on previous treatment with first-line EGFR-TKIs. Methods: In this phase II, open-label, single-arm study, eligible pts were those who had confirmed locally advanced or metastatic NSCLC, and had disease progression after first-line EGFR-TKI and with T790M mutation. Pts were initially orally given D-0316 50 mg. However, considering the benefits and risks of the pts, the dose was modified to 100 mg once daily with a 21-day lead-in at 75 mg once daily. The primary endpoint was objective response rate (ORR) based on independent review committee (IRC) according to RECIST 1.1.Results: As of October 31, 2019, 176 pts were enrolled in the 50 mg phase, in which 90 pts had partial response, achieving an ORR of 51.1% (95%CI: 43.5-58.7). Despite the immature PFS, disease progression or death occurred in 60 pts (34.1%) and the median PFS was 8.4 months (95% CI: 8.0-NE). Between September 12, 2019 and July 29, 2020, 689 pts were screened and 290 pts (median age 62.5) were enrolled in China and received 100mg D-0316 with a 21-day lead-in at 75 mg. At data cutoff (October 18, 2020), the median duration of follow-up was 5.5 months. 188 of the 290 pts achieved confirmed partial responses by IRC. The ORR was 64.8% (95% CI: 59.0-70.3) and the disease control rate (DCR) was 95.2% (95% CI: 92.0-97.3). The ORR was consistent across in most subgroups. Among 34 pts with brain metastases at baseline, 18 pts achieved confirmed partial responses and the intracranial ORR was 52.9% (95% CI: 35.1-70.2). The PFS, DoR, and OS were premature. The most common treatment-related adverse events were thrombocytopenia (57.2%), headache (27.6%), leukopenia (23.4%), anemia (22.1%) and rash (20.7%). The most common grade 3 or higher treatment-related adverse events were thrombocytopenia (11.7%). One death was due to treatment-related adverse events (interstitial lung disease). Six interstitial lung diseases (2.1%) were observed during study treatment. Conclusion: D-0316 has showed strong anti-tumor activities and tolerable toxicity in pts with EGFR T790M-positive NSCLC who have progressed after EGFR-TKI treatment. Citation Format: Shun Lu, Yiping Zhang, Guojun Zhang, Jianying Zhou, Shundong Cang, Ying Cheng, Gang Wu, Peiguo Cao, Dongqing Lv, Xiangming Jin, Hong Jian, Chengshui Chen, Guanming Jiang, Panwen Tian, Kai Wang, Hui Zhao, Gongyan Chen, Qun Chen, Cuimin Ding, Junquan Yang, Renhua Guo, Guoping Sun, Bin Wang, Liyan Jiang, Wu Zhuang, Zhe Liu, Jian Fang, Yunpeng Liu, Jian Zhang, Jun Chen, Yueyin Pan, Qitao Yu, Min Zhao, Jiuwei Cui, Dianming Li, Tienan Yi, Zhuang Yu, Yan Yang, Yan Zhang, Xiuyi Zhi, Yunchao Huang, Rong Wu, Liangan Chen, Aimin Zang, Lejie Cao, Qingshan Li, Xiaoling Li, Yong Song, Donglin Wang, Shucai Zhang. D-0316 in patients with advanced T790M-positive EGFR-mutant non-small cell lung cancer who progressed on prior EGFR-TKI therapy: results from a phase II study (NCT03861156) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT170.

9013 Background: Au is a novel, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) with favorable pharmacologic properties that selectively inhibits both EGFR sensitizing and resistance mutations. Au has been approved in China for treatment of patients (pts) with EGFR mutant NSCLC with EGFR T790M upon progression of disease on previous EGFR TKIs (Proc. AACR 2020, Abstract CT190). This Phase III trial assessed the efficacy and safety of Au versus G as initial treatment of patients with advanced NSCLC with EGFRm. Methods: Pts with previously untreated metastatic or locally advanced NSCLC and EGFR exon 19 deletion or L858R were randomly assigned in a 1:1 ratio to receive either Au (110 mg once daily) or G (250 mg once daily). The primary endpoint was progression-free survival (PFS) by RECIST v1.1 per investigator assessment. At 262 PFS events, the study had 90% power to detect a PFS HR = 0.67. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR) and safety. Results: Between Nov 30, 2018 and Sept 6, 2019, 429 patients across 53 sites in China were enrolled and randomized. Pt. characteristics were well-balanced. At the planned final event-driven PFS analysis, Au significantly prolonged PFS (median 19.3 vs 9.9 months, HR 0.46, p-value

Background In recent years, systemic chemotherapy and molecular targeted therapy have become standard first-line treatments for locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC). The objective of this survey was to investigate first-line anticancer treatment patterns and gene aberration test status of patients with advanced nonsquamous NSCLC in China. Methods Patients included in this study had unresectable Stage IIIB/IV nonsquamous NSCLC and were admitted during August 2015 to March 2016 into one of 12 tertiary hospitals throughout China for first-line anticancer treatment. Patient data (demographics, NSCLC histologic type, Eastern Cooperative Oncology Group [ECOG] Performance Status [PS], gene aberration test and results [if performed], and first-line anticancer treatment regimen) were extracted from medical charts and entered into Medical Record Abstraction Forms (MERAFs), which were collated for analysis. Results Overall, 1041 MERAFs were collected and data from 932 MERAFs were included for analysis. Patients with unresectable Stage IIIB/IV nonsquamous NSCLC had a median age of 59 years, 56.4% were male, 58.2% were never smokers, 95.0% had adenocarcinoma, and 92.9% had an ECOG PS ≤1. A total of 665 (71.4%) patients had gene aberration tests; 46.5% (309/665) had epidermal growth factor receptor (EGFR) gene mutations, 11.5% (48/416) had anaplastic lymphoma kinase (ALK) gene fusions, and 0.8% (1/128) had a c-ros oncogene 1 gene fusion. The most common first-line treatment regimen for unresectable Stage IIIB/IV nonsquamous NSCLC was chemotherapy (72.5%, 676/932), followed by tyrosine kinase inhibitors (TKIs; 26.1%, 243/932), and TKIs plus chemotherapy (1.4%, 13/932). Most chemotherapy regimens were platinum-doublet regimens (93.5%, 631/676) and pemetrexed was the most common nonplatinum chemotherapy-backbone agent (70.2%, 443/631) in platinum-doublet regimens. Most EGFR mutation-positive patients (66.3%, 205/309) were treated with EGFR-TKIs. Conclusions Findings from our survey of 12 tertiary hospitals throughout China showed an increased rate of gene aberration testing, compared with those rates reported in previous surveys, for patients with advanced nonsquamous NSCLC. In addition, pemetrexed/platinum-doublet chemotherapy was the predominant first-line chemotherapy regimen for this population. Most patients were treated based on their gene aberration test status and results. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3451-x) contains supplementary material, which is available to authorized users.

Hypoxia occurs in a wide range of solid tumors, and is strongly associated with radio-resistance of malignant tumors. The aim of the present study was to investigate the effect of endostatin combined with ionizing radiation (IR) on hypoxic conditions. A total of 24 mice bearing SKOV3 ovarian carcinoma were divided into three groups. Following injection with pEgr-1-endostatin plasmid for 12 h, the mice in the endostatin-IR-treated group were exposed to 300 cGy/min X-ray for 48 h, and the IR-treated group was exposed to the same condition. Then, the expression of endostatin, hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) was detected by reverse transcription-polymerase chain reaction, ELISA, immunohistochemistry and western blotting. In addition, the tumor microvessel density (MVD) was examined by immunohistochemistry analysis of cluster of differentiation 31-positive cells. The results revealed that pEgr-1-endostatin was successfully induced by IR. The level of endostatin messenger RNA in the endostatin-IR-treated group was significantly higher than that in the control and IR-treated groups (F=380.078, P

// Hong-Bo Yang 1 , Meng Xing 1 , Lei-Na Ma 1 , Ling-Xin Feng 1 , Zhuang Yu 1 1 Oncology Department, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China Correspondence to: Zhuang Yu, email: yuzhuang2002@163.com Keywords: NLR, PLR, OS, clinicopathologic parameters, lung cancers Received: April 06, 2016 Accepted: August 10, 2016 Published: October 08, 2016 ABSTRACT Setting: For now, hematological markers of inflammatory response have emerged as prognostic factors for patients with cancer. Many articles have confirm that neutrophil to lymphocyte ratio(NLR) and platelet–lymphocyte ratio (PLR) are relate with poor prognosis in various types of tumors. Objective: To investigate the association between NLR/PLR and progression free survival (PFS), overall survival (OS) and clinicopathologic parameters in lung cancer patients. Design: We performed relevant searches in PubMed database, Google Scholar, Springer Link. We included retrospective cohort studies that reported hazard ratios with 95% confidence intervals for the NLR or PLR and PFS or OS. Results: Both high NLR ( P < 0.00001) and high PLR ( P = 0.01) were significantly predictive of poorer OS. It also demonstrated that elevated NLR predicted poorer PFS ( P = 0.0002). High NLR was significantly associated with deeper Invasive of tumor, ( P = 0.006) extensive lymph nodetastasis(N2–3) ( P = 0.01), poor differentiation ( P = 0.0002) and vascular invasion( P = 0.002).There was no evidence of publication bias. Subgroup analysis indicated that little evidence of heterogeneity. However, PLR has no prognostic significance for SCLC. Conclusions: We provides further evidence in support of elevated NLR and PLR were predictors of poor OS and PFS in patients with lung cancer. Given this, NLR and PLR may be markers to report treatment outcomes.

Until recently, few cases of three or more malignant tumors in one patient have been reported. Owing to the high incidence rate of these tumors, the improvement in cancer diagnosis and treatment, and the extension of patient survival time, the incidence of reported multiple primary malignant neoplasms has gradually increased. The present study reported the case of a 57-year-old man with non-small cell lung cancer combined with B-Raf proto-oncogene serine/threonine kinase V600E mutation, gastrointestinal stromal tumors and lumbar vertebral malignant mucinous sarcoma. The pathogenesis, diagnosis and treatment of these three malignancies are discussed and previous studies are also reviewed. The aim of the study was to analyze the genetic mutations associated with multiple primary malignant tumors and to discuss whether those mutations with unknown functional significance could be used as therapeutic indicators. This case report will serve as a reference for future treatment of such patients.

In recent years, the incidence of lung cancer has been increasing, and lung cancer has become the leading cause of cancer-related death. Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. Platinum-containing chemotherapy is the first-line treatment for advanced patients. For patients with epidermal growth factor receptor ( EGFR ) mutation, EGFR-tyrosine kinase inhibitor (EGFR-TKI) is the best treatment choice. In studies, these patients have initially shown excellent response to EGFR-TKI treatment. However, the median progression-free survival (PFS) of NSCLC patients treated with EGFR-TKI is only 10–12 months, so the problem of drug resistance in treatment needs to be urgently solved. Clinical studies have shown that metformin and EGFR-TKI have synergistic effects in the treatment of NSCLC patients. Additionally, patients who are diagnosed with type 2 diabetes mellitus, with EGFR mutation have shown synergistic effects. This combination therapy can lead to longer PFS and overall survival (OS). This article reviews the synergistic effect of metformin and EGFR-TKI in the treatment of NSCLC.

Background: Golgi protein 73 (GP73) is a potential serum marker for the diagnosis of hepatocellular carcinoma (HCC). However, the diagnostic value of GP73 for HCC remains controversy, and little is known about the relationship between serum GP73 concentration and clinical characteristics of HCC. This study was designed to analyze the clinical values of GP73 in diagnosing HCC and the relationship between GP73 level and clinical characteristics in HCC patients. Materials and Methods: In this study, a total of 443 serum samples including 180 patients with HCC, 61 patients with liver cirrhosis (LC), 99 chronic hepatitis patients, and 103 healthy individuals were enrolled from November 2011 to April 2013. Enzyme-linked immunosorbent assay and chemiluminescent immunoassay were used to detect the serum level of GP73 and other biomarkers. Results: GP73 level in HCC group was significantly higher than LC group, chronic hepatitis B group, and healthy control group. In HCC group, GP73 level significantly increased in patients with lymphatic metastasis; moreover, GP73 level in Child–Pugh Class B and C groups was statistically significantly higher than that in Child–Pugh Class A group (P < 0.05). The area under the receiver operating characteristic (AUROC) curve of GP73 and alpha-fetoprotein (AFP) was 0.840 and 0.718, respectively, when diagnosing HCC. Moreover, the AUROC curve by use of the combination of GP73 and AFP was 0.903. The differences among these three aspects were statistically significant (P < 0.05). Conclusion: GP73 was better than AFP for the diagnosis of HCC, and the expression of serum GP73 is related with the clinical characteristics of HCC patients.

Colorectal cancer is a complex multistage process following the adenoma-carcinoma sequence. Additional research on the basis of molecular dysregulations, particularly in the precancerous stage, may provide insight into the realization of potential biomarkers and therapeutic targets for the disease. In the present study, the expression profile of human multistage colorectal mucosa tissues, including healthy, adenoma and adenocarcinoma samples, was downloaded. Genes that were consistently differentially expressed in precancerous tissues and cancer samples were collected. Based on a merged biological network, the biggest connected component composed of these identified genes and their one-step neighbors were retrieved to conduct random walk with restart algorithm, in order to identify genes significantly affected during carcinogenesis. Therefore, 35 genes significantly affected by carcinogenic dysregulation were successfully identified. Survival and Cox analysis indicated that the expression of these genes was an independent prognostic factor confirmed by six cohorts. In summary, based on the transcription profile of multi-stage carcinogenesis and bioinformatics analysis, 35 genes significantly associated with patient survival were successfully identified, which may serve as promising therapeutic targets for the disease.

Background The A‐kinase anchor proteins (AKAP) are a growing family of scaffolding proteins involved in the occurrence, proliferation, and metastasis of tumors by controlling intracellular signals. In this study, the expression and significance of AKAP4 were analyzed in patients with lung adenocarcinoma and adjacent non‐cancerous tissues. Methods Using reverse transcriptase‐polymerase chain reaction and Western blot, AKAP4 messenger ribonucleic acid (mRNA) and protein expression levels were measured in 108 cases of lung adenocarcinoma and adjacent non‐cancerous tissues. Results AKAP4 mRNA and protein were expressed in lung adenocarcinoma tissues, but not in adjacent non‐cancerous tissues. The expression of AKAP4 mRNA and protein was closely associated with lymphatic metastasis (P < 0.05), but had no relationship with stage, differentiation degree, gender, age or smoking (P > 0.05). AKAP4 expression had an adverse effect on the overall survival rate (P < 0.05). Conclusion The expression of AKAP4 was high in lung adenocarcinoma tissue, which may be closely related to the lymphatic metastasis of lung adenocarcinoma. AKAP4 may be a novel lung adenocarcinoma molecule marker and a predictor of poor prognosis.

Introduction: In the previous phase II clinical trial (NCT03215693), ensartinib, a next generation (NG) ALK TKI, showed comparable efficacy to other NG ALK TKIs in the post-crizotinib setting. In the preplanned biomarker analysis, we investigated the efficacy and the resistance mechanisms of ensartinib via longitudinal ctDNA analysis. Methods: Pts with stage IIIB/IV ALK+ NSCLC, and had progressive disease (PD) after crizotinib were eligible. Plasma samples from this trial were prospectively collected for ctDNA analysis at baseline (BL), cycle 3 day 1 (C3D1) and the end of treatment (EOT). Plasma DNA was analyzed using a 212-gene sequencing panel. ctDNA amount was defined as the sum of variant allele fraction (VAF) of ALK fusions and mutations. Cox model was applied for multivariate analysis. Results: Between 9/2017 and 7/2019, 182 pts were enrolled in the trial. In total, 178 were included in the full analysis set (FAS), with a median PFS (mPFS) of 9.8 months (95% CI, 7.5 to 11.7 months). 169 pts were evaluable by independent review committee (IRC), with an ORR of 57.7% (95% CI, 50.2% to 65.3%). A total of 431 ctDNA samples were analyzed, including 168 at BL, 165 at C3D1, and 106 at EOT (8 overlappings between C3D1 and EOT). 168 (99.4%) pts had evaluable ctDNA at BL. The median ctDNA amount was 0.00704. The higher ctDNA amount was associated with liver metastases, bone metastases, and TP53 mutations. Tumor burden, as measured by the sum of the target lesions' longest diameters, also positively correlated with ctDNA amount (Pearson correlation 0.261; p < 0.001). Multivariable Cox regression revealed that high level of ctDNA amount and TP53 mutations at BL was significantly associated with poor PFS independently (p =0.020 and p < 0.001) (Table). 106 (62.7%) pts had evaluable ctDNA at both BL and EOT. Compared to baseline, the frequency of certain ALK mutations significantly increased at EOT, such as G1269A (7.5% vs 21.7%), G1202R (3.8% vs 17.0%) and E1210K (0% vs 10.4%). TP53 statusctDNA amountTP53 Wildtype TP53 Mutations Low amountHigh amount(n = 34)(n = 134)(n = 46)(n = 47)mPFS, months (95% CI) 11.7 (9.8, 14.0) 4.2 (3.0, 5.6)9.3 (5.6, 11.7) 4.2 (2.8, 5.5)HR (95% CI); p value2.50 (1.65, 3.79) ; p < 0.0012.34 (1.52, 3.61) ; p < 0.001 Consistent with the change in frequency, the abundance of G1269A, G1202R, and E1210K also trended to increase at EOT, while the abundance of C1156Y and I1171X had a downward trend in most pts. Conclusions: Consistent with previous reports, ensartinib showed high clinical efficacy. Longitudinal ctDNA analysis could be a powerful tool in predicting treatment outcomes and revealing resistant mechanisms of ensartinib. We observed G1269A, G1202R and E1210K as the major resistant mutations to ensartinib. Additional analyses are ongoing and results will be updated and reported in the meeting. Citation Format: Yunpeng Yang, Jie Huang, Tao Wang, Jianya Zhou, Jing Zheng, Jifeng Feng, Wu Zhuang, Jianhua Chen, Jun Zhao, Wei Zhong, Yanqiu Zhao, Yiping Zhang, Yong Song, Yi Hu, Zhuang Yu, Youling Gong, Yuan Chen, Feng Ye, Shucai Zhang, Lejie Cao, Yun Fan, Gang Wu, Yubiao Guo, Chengzhi Zhou, Kewei Ma, Jian Fang, Weineng Feng, Yunpeng Liu, Zhendong Zheng, Gaofeng Li, Ning Wu, Wei Song, Xiaoqing Liu, Shijun Zhao, Lieming Ding, Li Mao, Giovanni Selvaggi, Larry Zhu, Shanshan Xiao, Li Zhang. Longitudinal circulating tumor DNA (ctDNA) analysis predicts response and reveals the resistance mechanisms of ensartinib in ALK+ NSCLC patients (pts) progressed on crizotinib: Updated analysis of a phase II clinical trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2997.

Background: Almonertinib (HS-10296) is an oral, potent, high selective third generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) for sensitizing mutations and EGFR T790M mutation. The preliminary clinical data of almonertinib reported in WCLC showed favorable efficacy and safety in target populations. Here, we presented the latest efficacy data, including the subgroup analysis of central nervous system (CNS) response. Methods: Patients aged at least 18 years with centrally confirmed EGFR T790M mutation, locally advanced or metastatic non-small cell lung cancer (NSCLC) progressing on prior EGFR-TKI treatment, received almonertinib 110 mg orally once daily until disease progression. Patients with asymptomatic, stable brain metastases not requiring steroids were enrolled. The primary endpoint was objective response rate (ORR) by independent central review (ICR) using RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), depth of response (DepOR), overall survival (OS) and safety. Response endpoints were assessed in full analysis set (NCT02981108). Results: From May 2018 to October 2018, 244 patients entered study in 36 sites in mainland China (189 patients) and Taiwan (55 patients). Of 88 patients with CNS metastases on baseline brain scans, 23 had at least one intracranial measurable target lesion. At cutoff date (Aug 1, 2019), the median duration of follow-up for progression-free survival was 11.8 months. 168 of 244 patients achieved confirmed partial responses. The ORR was 68.9% (95% CI: 62.6, 74.6). The DCR was 93.4% (95% CI: 89.6, 96.2). The mPFS (48.0% maturity) and mDOR were 12.3 (95% CI: 9.6, 13.8) and 12.4 (95% CI: 11.3, NA) months, respectively. The confirmed CNS ORR and DCR were 60.9% (95% CI: 38.5, 80.3) and 91.3% (95% CI: 72.0, 98.9), respectively. The CNS mPFS (47.8% maturity) was 10.8 (95% CI: 5.5, 12.6) months. The safety profile was consistent with the previous report. The most common grade 3 and 4 adverse reactions were increased blood creatine phosphokinase (17 [7.0%]) and pulmonary embolism (6 [2.5%]). There was no interstitial lung disease reported. Conclusions: Almonertinib demonstrated progression-free survival benefit in EGFR T790M positive NSCLC patients who had progressed after previous EGFR-TKI treatment, especially showed clinically meaningful efficacy against CNS metastases, and the safety profile was consistent with that reported previously. A randomized, controlled, double-blinded, phase III study is ongoing comparing almonertinib with gefinitib in first-line treatment of advanced NSCLC patients. Citation Format: Shun Lu, Qiming Wang, Guojun Zhang, Xiaorong Dong, Cheng-Ta Yang, Yong Song, Gee-Chen Chang, You Lu, Hongming Pan, Chao-Hua Chiu, Zhehai Wang, Jifeng Feng, Jianying Zhou, Xingxiang Xu, Renhua Guo, Jianhua Chen, Haihua Yang, Yuan Chen, Zhuang Yu, Her-Shyong Shiah, Chin-Chou Wang, Nong Yang, Jian Fang, Ping Wang, Kai Wang, Yanping Hu, Jianxing He, Ziping Wang, Jianhua Shi, Shaoshui Chen, Qiong Wu, Changan Sun, Chuan Li, Hongying Wei, Ying Cheng, Wu-Chou Su, Te-Chun Hsia, Jiuwei Cui, Yuping Sun, James Chih-Hsin Yang. A multicenter, open-label, single-arm, phase II study: The third generation EGFR tyrosine kinase inhibitor almonertinib for pretreated EGFR T790M-positive locally advanced or metastatic non-small cell lung cancer (APOLLO) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT190.

e13590 Background: Immunotherapy is becoming one of the promising treatments for cancer administration, and several studies indicated a better outcome was received in patients with high tumor mutation burden (TMB). The distribution of TMB is still unknown and this study aimed to analysis the association between TMB and age especially in East Asian populations. Methods: In our study, TMB value was measured as the numbers of synonymous, nonsynonymous mutations and InDels by next generation sequencing with 539 genes panel in tumor tissue. TMB-H was defined as highest mutation load quintile (top 20%) in each cancer type. The association between TMB and age in 874 patients was investigated including 174 patients with liver cancer, 32 patients with bile duct cancer, 54 patients with gastric cancer, 119 patients with colorectal cancer, 27 patients with pancreatic cancer, 32 patients with melanoma, 25 patients with glioma and 411 patients with lung cancer cases, respectively. Spearman rank correlation analysis, Mann-Whitney U-test and Fisher’s exact test were used for statistical analysis. Results: A significant correlation between TMB and ages was observed in patients with solid tumors (r = 0.204, p = 1.263×10−9). The median age of included patients was 60 years-old. Based on nonparametric test, the value of TMB in patients with liver cancer ( p = 2.310×10−4), gastric cancer ( p = 0.029) and lung cancer ( p = 0.001) aged ≥ 60 years-old was significantly higher than the corresponding patients aged < 60 years-old. No significant differences of TMB values were found between patients < 60 and ≥ 60 years-old in bile duct cancer ( p = 0.419), colorectal cancer ( p = 0.075), pancreatic cancer ( p = 1), melanoma ( p = 0.952) and glioma ( p = 0.720). The TMB-H ratio in patients with liver ( p = 0.049) and gastric ( p = 0.015) cancer aged < 60 years old was significantly lower than patients aged ≥ 60 years-old. Conclusions: Our study indicated the TMB value and TMB-H ratio were relatively higher with ages ≥ 60 years old in specific tumors, which might provide useful information to guide precisely the the application of PD-1 or PD-L1 inhibitors. As a retrospective study with a relatively small population, the conclusions of this study needed to be verified with a larger sample.

Objectives This study investigated factors associated with (i) the likelihood of receiving a gene aberration test and (ii) the choice of treatment between chemotherapy and targeted therapy in patients with non-small cell lung cancer (NSCLC) in China. Materials and methods This cross-sectional study analyzed data previously extracted from the medical charts of patients with unresectable Stage IIIB/IV nonsquamous NSCLC discharged from one of 12 tertiary hospitals in China between August 2015 and March 2016. Logistic regressions were applied to investigate factors associated with receiving a gene aberration test and the treatment decision. Results Data from 932 patients were analyzed. Patients were less likely to have a gene aberration test if they had a histologic subtype other than adenocarcinoma or a hospital waiting time for test results of >5 days. Patients were more likely to receive tyrosine kinase inhibitor (TKI) treatment than chemotherapy if they had a positive result for epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase gene aberration testing. EGFR positive patients were more likely to receive TKI treatment than chemotherapy if they did not have insurance for TKI or pemetrexed treatment, and more likely to receive chemotherapy than TKI treatment if they had a waiting time for test results of >5 days. EGFR wild-type/unknown patients receiving chemotherapy were more likely to receive pemetrexed if they attended a hospital in a developed area or had insurance for pemetrexed. Conclusion In this real-world setting in China, the choice of first-line treatment for advanced NSCLC was appropriately guided by gene aberration testing for most patients. However, gene aberration testing and the treatment decision were influenced by practical factors such as hospital location, the waiting time for test results, and insurance coverage, which should be addressed to ensure optimal patient care.

Background Traditional diagnostic technology with tumor biomarkers is inefficient, expensive and requires a large number of serum samples. The purpose of this study was to construct human lung cancer protein chips with new lung cancer biomarkers screened by the T7-phage display library, and improve the early diagnosis rate of lung cancer. Methods A T7-phage cDNA display library was constructed of fresh samples from 30 lung cancer patients. With biopanning and high-throughput screening, we gained the immunogenic phage clones from the cDNA library. The insert of selected phage was blasted at GeneBank for alignment to find the exact or the most similar known genes. Protein chips were then constructed and used to assay their expression level in lung cancer serum from 217 cases of lung cancer groups:80 cases of benign lung disease and 220 healthy controls. Results After four rounds of Biopanning and two rounds of enzyme-linked immunosorbent assay, 12 phage monoclonal samples were selected from 2880 phage monoclonal samples. After blasting at GeneBank, six similar genes were used to construct diagnostic protein chips. The protein chips were then used to assay expression level in lung cancer serum. The expression level of six genes in lung cancer groups was significantly higher than those in the other two groups (P < 0.05). Conclusions In this study, we successfully constructed diagnostic protein chips with biomarkers selected from the lung cancer T7-phage cDNA library, which can be used for the early screening of lung cancer patients.

The aim of the present study was to investigate the role of miR-124 in lung cancer and identify the potential predictive value of miR-124 in postoperative non-small cell lung cancer (NSCLC) patients. We detected miR-124 expression in A549, NCL-H460 and normal lung epithelial BEAS-2E cells and showed a significantly lower expression level of miR-124 in NSCLC cells than in BEAS-2E cells. Upregulation of miR-124 expression levels in both A549 and NCL-H460 cells by transfection with miR-124 mimics suppressed cell proliferation and induced apoptosis. Further investigation revealed that miR-124 bound directly to the 3' UTR region of STAT3, thereby inhibiting STAT3 expression. In addition, miR-124 levels detected in NSCLC tissues were lower than those in adjacent normal lung tissues, while the opposite was observed for STAT3. In NSCLC, the expression levels of miR-124 and STAT3 correlated significantly with the tumor node metastases (TNM) stage, differentiation grade and lymph node metastasis, while the levels of these molecules did not differ significantly by gender, age, location, smoking index, pleural invasion or pathological type. The expression level of miR-124 was significantly associated with disease-free survival (DFS) in both positive and negative lymph node groups. Furthermore, patients with low miR-124 or high STAT3 expression generally received a worse prognosis in terms of both overall survival (OS) and DFS. In conclusion, our findings suggest that miR-124 functions as a tumor suppressor by targeting STAT3, and that miR-124 may potentially serve as a useful biomarker for the prognosis of NSCLC patients.

In diagnosis of lung cancer, rapid distinction between small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) tumors is very important. Serum markers, including lactate dehydrogenase (LDH), C-reactive protein (CRP), carcino-embryonic antigen (CEA), neurone specific enolase (NSE) and Cyfra21-1, are reported to reflect lung cancer characteristics. In this study classification of lung tumors was made based on biomarkers (measured in 120 NSCLC and 60 SCLC patients) by setting up optimal biomarker joint models with a powerful computerized tool - gene expression programming (GEP). GEP is a learning algorithm that combines the advantages of genetic programming (GP) and genetic algorithms (GA). It specifically focuses on relationships between variables in sets of data and then builds models to explain these relationships, and has been successfully used in formula finding and function mining. As a basis for defining a GEP environment for SCLC and NSCLC prediction, three explicit predictive models were constructed. CEA and NSE are frequently- used lung cancer markers in clinical trials, CRP, LDH and Cyfra21-1 have significant meaning in lung cancer, basis on CEA and NSE we set up three GEP models-GEP 1(CEA, NSE, Cyfra21-1), GEP2 (CEA, NSE, LDH), GEP3 (CEA, NSE, CRP). The best classification result of GEP gained when CEA, NSE and Cyfra21-1 were combined: 128 of 135 subjects in the training set and 40 of 45 subjects in the test set were classified correctly, the accuracy rate is 94.8% in training set; on collection of samples for testing, the accuracy rate is 88.9%. With GEP2, the accuracy was significantly decreased by 1.5% and 6.6% in training set and test set, in GEP3 was 0.82% and 4.45% respectively. Serum Cyfra21-1 is a useful and sensitive serum biomarker in discriminating between NSCLC and SCLC. GEP modeling is a promising and excellent tool in diagnosis of lung cancer.

Background Dulanermin is a recombinant soluble human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that activates apoptotic pathways by binding to proapoptotic death receptor (DR) 4 and DR5. The purpose of this study was to evaluate the efficacy and safety of dulanermin combined with vinorelbine and cisplatin (NP) as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Experimental design Patients were randomly assigned to receive NP chemotherapy (vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 30 mg/m2 on days 2 to 4) for up to six cycles plus dulanermin (75 μg/kg on days 1 to 14) or placebo every three weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was progression-free survival (PFS), and the secondary end points included objective response rate (ORR), overall survival (OS), and safety evaluation. Results Between October 2009 and June 2012, 452 untreated patients with stage IIIB to IV NSCLC were randomly assigned to receive dulanermin plus NP (n = 342) and placebo plus NP (n = 110). Median PFS was 6.4 months in the dulanermin arm versus 3.5 months in the placebo arm (hazard ratio (HR), 0.4034; 95% CI, 0.3181 to 0.5117, p

The long-term prognosis for patients with gastric cancer (GC) following radical resection remains poor. It is important to identify prognostic markers to predict survival. In the present retrospective study, the association between the metastatic lymph node ratio (rN) and the Lauren classification on predicting overall survival (OS) was investigated. Furthermore, a subgroup analysis was performed on the Lauren classification, using rN score as an independent prognostic marker. In total, 261 pathologically confirmed patients with GC were retrospectively reviewed. Kaplan-Meier curves and Cox's proportional hazards modeling were applied to analyze the OS of patients, and were utilized in the subgroup analysis. Receiver operating characteristic (ROC) curves were used to compare the accuracy of prognosis between the rN score and lymph node staging (N stage). The χ2 test was used to analyze the association between the rN score and Lauren classification. Univariate survival and multivariate analysis demonstrated that the rN score and Lauren classification were significant prognostic markers for patients with GC. The ROC analysis confirmed that the rN score was more effective than N staging for OS prediction. Subgroup analysis indicated that rN was more accurate at predicting OS time in patients with diffuse type GC. The rN score and the Lauren classification were independent prognostic factors for the OS of patients with GC following radical resection, and the rN score was more accurate than the N stage for predicting the prognosis. Overall, the rN may be suitable as an independent predictor for OS in patients with diffuse type GC.

Background: This meta-analysis was performed to investigate the relationship between methylation of the P14 and O6-methylguanine-DNA methyltransferase (MGMT) genes and the risk of hepatocellular carcinoma (HCC). Materials and Methods: We searched PubMed, EMBASE, the Chinese Biomedical Database (CBM), and the China National Knowledge Infrastructure (CNKI) databases to identify relevant studies that analysed HCC tissues for P14 and MGMT gene methylation status; we then performed a meta-analysis. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated to evaluate the association between gene methylation and the risk of HCC. Results: Ten studies that assessed P14 gene methylation in 630 HCC tumour tissues and nine studies analysing MGMT methylation in 497 HCC tumour tissues met our inclusion criteria. Our meta-analysis revealed that the rate of P14 methylation was significantly higher in HCCs than in adjacent tissues (OR 3.69, 95%CI 1.63-8.35, p=0.002), but there was no significant difference in MGMT methylation between HCC and adjacent tissues (OR 1.76, 95%CI 0.55-5.64, p=0.34). A subgroup analysis according to ethnicity revealed that P14 methylation was closely related to the risk of HCC in Chinese and Western individuals (Chinese, OR 7.74, 95%CI 1.36-44.04, p=0.021; Western, OR 3.60, 95%CI 1.49-8.69, p=0.004). Furthermore, MGMT methylation was not correlated with the risk of HCC in Chinese individuals (OR 2.42, 95%CI 0.76-7.73, p=0.134). The combined rate of P14 methylation was 35% (95%CI 24-48%) in HCC tumour tissues and 11% (95%CI 4-27%) in adjacent tissues, whereas the combined rate of MGMT methylation was 15% (95%CI 6-32%) in HCC and 10% (95%CI 4-22%) in adjacent tissues. Conclusions: These results suggest that the risk of HCC is related to P14 methylation, but not MGMT methylation. Therefore, P14 gene methylation may be a potential biomarker for the diagnosis of HCC.

Background A high expression of squalene epoxidase (SQLE) is related to tumor occurrence, development, and prognosis in a variety of cancers. In this study, the expression and significance of SQLE was analyzed in patients with squamous lung cancer and pericarcinoma tissues. Methods The SQLE mRNA and protein expression were separately examined by semi-quantitative reverse transcription polymerase chain reaction, fluorescence quantitative polymerase chain reaction and Western blot in 65 cases of squamous cell lung carcinoma tissues and adjacent non-cancerous lung tissues. Results The expression of SQLE mRNA and protein in lung squamous cancerous tissues was significantly higher than in pericarcinoma tissues (63.07% vs. 44.61%, P = 0.0348; 67.69% vs. 38.46%, P = 0.0008). The positive expression rate of SQLE mRNA was not associated with gender, age, smoking, or tumor size (P > 0.05). The expression of SQLE mRNA was closely correlated with poor differentiation, clinical stages, and lymphatic metastasis (P < 0.05). The expression of SQLE mRNA was negatively associated with overall survival rate (P < 0.05). Conclusion A high expression of SQLE was found in squamous lung cancer tissues. The high expression of the SQLE gene may be closely related to the occurrence and development of squamous cell lung carcinoma. SQLE expression predicts a poor prognosis and may serve as a novel lung carcinoma molecule marker.