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Xiaorong Dong



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    EP1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 206)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.16-14 - Efficacy of First-Line Continuous Maintenance of Pemetrexed Therapy for Lung Adenocarcinoma When Administered at Routine or Extended Intervals (Now Available) (ID 1822)

      08:00 - 18:00  |  Presenting Author(s): Xiaorong Dong

      • Abstract
      • Slides

      Background

      Background: Lung cancer is the most common cancer and the leading cause of death due to cancer worldwide , The benefit of maintenance therapy with pemetrexed with or without antiangiogenesis inhibitors has been observed in previous studies. However, continuous maintenance therapy with the pemetrexed-antiangiogenesis combination has rarely been evaluated in the real world setting. In real life, patients may not receive maintenance therapy or may receive delayed maintenance therapy (stopping interval of >21 days) owing to many factors. The purpose of this study was to obtain real-world data on the maintenance of local progressive and metastatic non-squamous non-small cell lung cancer (NSCLC) in first-line patients treated with or without pemetrexed antiangiogenesis, and to evaluate the effect of extended interention on clinical outcomes.

      Method

      Methods: 168 patients with stage IIIB or IV lung adenocarcinoma who had not been treated previously received pemetreplatin-induced chemotherapy with or without anti-angiogenesis inhibitors (bevacizumab or rh-endostatin) every 3 weeks for a course of 4-6 weeks.The efficacy and safety of 112 patients without progression after induction chemotherapy were analyzed.

      Result

      Results: 70 of the 112 patients received continuous maintenance therapy, with or without an anti-angiogenesis inhibitor, until the disease progressed.42 patients did not receive continuous maintenance therapy.The median duration of maintenance therapy was 4(range 1-26);The median interval of each maintenance treatment cycle was 40 days (ranged from 21 to 77 days).The optimal objective efficiency of maintenance group and non-maintenance group was 48.6% and 33.3%, respectively.At an average follow-up of 14.6 months, the median progression-free survival was 11.5 months (95% CI: 9.8 -13.2 months) and 6.8 months (95% CI :5.4-8.2 months,p < 0.001), and the median overall survival was 40.1 months (22.5 - 57.7 months) and 18.0 months (10.4-25.6 months,p = 0.001) in the maintenance and non-maintenance groups, respectively.The most common grade 3-4 adverse event in both groups was neutropenia (18.6% vs. 19.0%).

      Conclusion

      Conclusion: prolongation of maintenance time is feasible, and for patients without progression after first-line induction therapy for lung adenocarcinoma, continuous maintenance therapy with or without combination of pemetrexed with anti-angiogenesis is essential for survival benefits.

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    OA02 - A New Vision of Targets and Strategies (ID 120)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      OA02.03 - The Third Generation EGFR Inhibitor (EGFR-TKI) HS-10296 in Advanced NSCLC Patients with Resistance to First Generation EGFR-TKI (Now Available) (ID 766)

      10:30 - 12:00  |  Author(s): Xiaorong Dong

      • Abstract
      • Presentation
      • Slides

      Background

      HS-10296 is an oral, potent, high selective third generation EGFR tyrosine-kinase inhibitor (EGFR-TKI) for sensitizing mutations, and the EGFR Thr790Met (T790M) resistance mutation which has been demonstrated by phase I study. This phase II, open-label, multicenter single-arm study was designed to confirm the efficacy and safety of HS-10296 in a large population of non-small-cell lung cancer (NSCLC) patients with EGFR T790M mutation, who had progressed after first generation EGFR-TKI treatment.

      Method

      Patients aged at least 18 years with centrally confirmed EGFR T790M-positive mutations, locally advanced or metastatic (stage IIIB/IV) NSCLC after first generation EGFR-TKI treatment received HS-10296 110 mg orally once daily until disease progression, or intolerable toxicity, or patient withdrawal. Patients with asymptomatic, stable brain metastases not requiring steroids were allowed to enroll. The primary endpoint was the objective response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1 every 6 weeks. Response endpoints (ORR and disease control rate [DCR]) were assessed in response analysis set. Secondary end points including progression-free survival (PFS), duration of response (DoR), depth of response (DepOR), overall survival (OS) and safety were evaluated in full analysis set. The final data cutoff was on Jan 5, 2019. The study is still ongoing.

      Result

      Totally, 244 patients (median age 60.8) entered study in 36 sites in mainland China (189 patients) and Taiwan (55 patients) between May 16, 2018 to Oct 23, 2018. 2 patients were excluded from the evaluable for response analysis set (n=242) due to absence of measurable disease at baseline by independent central review. At data cutoff, 182 (74.6%) patients remained on treatment. The median duration of follow-up was 4.7 months. 160 of 242 patients achieved confirmed partial responses by independent central review. The ORR was 66.1% (95% CI: 59.8-72.1). The DCR was 93.4% (95% CI: 89.5-96.2). The most common adverse reactions (≥ 10%) were blood creatine phosphokinase increased (43 [17.6%]), aspartate aminotransferase increased (29 [11.9%]), pruritus (28 [11.5%]), rash (28 [11.5%]) and alanine aminotransferase increased (26 [10.7%]). The most common all-causality grade 3 and 4 adverse events were blood creatine phosphokinase increased (14 [5.7%]) and hyponatraemia (4 [1.6%]). Serious adverse events were reported in 30 (12.3%) patients, of which 19 (7.8%) were investigator assessed as possibly treatment-related to HS-10296. Three deaths were due to adverse events; one was related to cardiopulmonary failure, other two events occurred after disease progression. There was no interstitial lung disease during study treatment.

      Conclusion

      HS-10296 has demonstrated good clinical benefit with minimal toxicity in patients with EGFR T790M-positive NSCLC patients who have progressed after first generation EGFR-TKI treatment. The Phase III study has already launched comparing HS-10296 with gefinitib in advanced NSCLC patients with EGFR sensitizing mutations. (The study was sponsored by Jiangsu Hansoh Pharmaceutical Co., Ltd.; ClinicalTrials.gov number, NCT02981108)

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    OA04 - Immuno Combinations and the Role of TMB (ID 126)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      OA04.03 - A Randomized Phase 3 Study of Camrelizumab plus Chemotherapy as 1<sup>st</sup> Line Therapy for Advanced/Metastatic Non-Squamous Non-Small Cell Lung Cancer (Now Available) (ID 1682)

      15:15 - 16:45  |  Author(s): Xiaorong Dong

      • Abstract
      • Presentation
      • Slides

      Background

      Platinum-based chemotherapy remains 1st line therapy for advanced non-small cell lung cancer (NSCLC) without oncogenic drivers in China. Camrelizumab (SHR-1210, a potent anti‒PD-1 monoclonal antibody) has shown promising activity in multiple malignancies. Here, we report interim analysis results on efficacy and safety of camrelizumab plus carboplatin/pemetrexed as 1st line treatment in Chinese advanced/metastatic non-squamous NSCLC patients with negative oncogenic drivers.

      Method

      In this open-label, randomized, multicenter phase 3 study (SHR-1210-303), patients with advanced/metastatic, non-squamous NSCLC with negative EGFR or ALK were stratified by sex and smoking history (≥ 400/year versus ˂ 400/year) and were randomly assigned (1:1) to receive 4 to 6 cycles of carboplatin (AUC=5) plus pemetrexed (500 mg/m2) with or without camrelizumab (200 mg), followed by pemetrexed with or without camrelizumab as maintenance therapy up to disease progression or intolerable toxicity. Treatment was given every 3 weeks. Crossover to camrelizumab monotherapy was permitted for patients in the chemotherapy arm who had confirmed disease progression. The primary endpoint was PFS per blinded independent central review according to RECIST v1.1. Secondary endpoints included ORR, DCR, DoR and OS. Data of subgroup analysis will be reported. Clinical Trials.gov number: NCT03134872.

      Result

      Between May 12, 2017 and Jun 6, 2018, 419 patients were randomized, among whom 205 received camrelizumab plus chemotherapy and 207 received chemotherapy treatment. After a median follow-up of 11.9 months, median PFS was 11.3 months (95% CI 9.5‒not reached) in camrelizumab plus chemotherapy arm and 8.3 months (95% CI 6.0‒9.7) in chemotherapy arm (HR 0.61 [95% CI 0.46‒0.80], p=0.0002). ORR, DCR, DoR and OS with camrelizumab plus chemotherapy were superior to chemotherapy (Table 1). Grade 3/4 adverse events occurred in 66.8% of patients in camrelizumab plus chemotherapy arm and 51.2% of patients in chemotherapy arm. There were 5 treatment-related deaths in camrelizumab plus chemotherapy arm and 4 in chemotherapy arm.

      Table 1. Responses per blinded independent central review and overall survival in the total study population

      Camrelizumab plus chemotherapy

      (n=205)

      Chemotherapy alone

      (n=207)
      p-value
      Objective response rate 60.0% (53.0‒66.8) 39.1% (32.4‒46.1) p<0.0001
      Disease control rate 87.3% (82.0‒91.6) 74.4% (67.9‒80.2) p=0.0009
      Duration of response (months) 17.6 (11.6‒NR) 9.9 (8.5‒13.8) p=0.0356
      Overall survival (months) NR (17.1‒NR) 20.9 (14.2‒NR) p=0.0272
      Data are shown in % (95% CI) or median (95% CI). NR: not reached.

      Conclusion

      First-line camrelizumab plus chemotherapy shows substantial clinical benefit in patients with advanced/metastatic non-squamous NSCLC with negative EGFR or ALK in terms of PFS, ORR, and OS and acceptable safety profiles. The combination should become novel standard 1st line therapy for this population.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-29 - MLPH Promotes Epithelial–Mesenchymal Transition and Brain Metastasis via Cdc42/PAK1 Signaling in Non-Small Cell Lung Cancer (Now Available) (ID 2119)

      09:45 - 18:00  |  Presenting Author(s): Xiaorong Dong

      • Abstract
      • Slides

      Background

      Brain metastasis (BM) is associated with poor prognosis, recurrence, and death in patients with non-small cell lung cancer (NSCLC). Therefore, a better understanding of molecular mechanisms underlying NSCLC development and progression could provide helpful insights for NSCLC prevention and effective treatment. Melanophilin (MLPH), an actin-based transport binding partner, involves in cancer progression. However, the role of MLPH in NSCLC remains unclear. Here we elucidated the functional significance, molecular mechanisms and clinical impact of MLPH in NSCLC.

      Method

      RNA-Sequencing was performed to identify differentially expressed genes in lung tissues of NSCLC patients with (BM+) and without BM (BM-). The expression of MLPH was examined in the serum of BM+ and BM- patients by PCR. Integrative database analysis was used to examine MLPH levels in NSCLC tissues and analyze the relationship between MLPH levels and patient survival. Lentivirus containing small hairpin (sh) RNA targeting MLPH or empty vector was designed to explore its role in NSCLC. The cell counting kit-8 assay, wound healing assay, transwell assay, flow cytometry analysis, Phalloidin staining, xenografted tumor model and brain metastasis model were used to determine the effects of MLPH on the proliferation, migration, invasion, EMT, tumorigenesis and brain metastasis of NSCLC. Western blot analysis was used to explore the underlying mechanism.

      Result

      High-throughput sequencing showed that MLPH mRNA was significantly differentially expressed in lung tumors between BM+ and BM- NSCLC patients. MLPH was frequently overexpressed in NSCLC tissues and cells, and high levels of MLPH correlated with poor prognosis of NSCLC patients. Silencing MLPH by shRNA suppressed NSCLC cell proliferation, migration, invasion and TGF-β-induced EMT, and triggered cell cycle arrest and apoptosis. Being in consistent with the in vitro findings, the in vivo experiment exhibited that knockdown of MLPH inhibited xenograft tumorigenesis and brain metastasis in nude mice. Mechanically, we identified TGF-β as a key downstream effector of MLPH. MLPH silencing attenuated Cdc42/PAK1 signaling activation at least in part through the downregulation of TGF-β. Furthermore, EMT phenotypes changes caused by MLPH knockdown were partially dependent on TGF-β inhibition.

      Conclusion

      Our findings uncovered the role of MLPH in NSCLC progression and provided evidence for MLPH positively modulating the Cdc42/PAK1 signaling pathway to promote EMT and metastasis via TGF-β in NSCLC cells. MLPH may have the potential as a therapeutic target against metastatic NSCLC.

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      P1.01-44 - The Role of Microbiota on the Development of Non-Small-Cell Lung Cancer (Now Available) (ID 2055)

      09:45 - 18:00  |  Presenting Author(s): Xiaorong Dong

      • Abstract
      • Slides

      Background

      The functional role of microbiota on the development of cancer has attracted an accumulating attention recently. However, the impact of fecal and sputum microbiome in the formation and development of Non-small-cell lung cancer (NSCLC) are mostly unknown. Our study aimed to characterize and compare fecal and sputum microbiome of NSCLC patients with healthy control subjects, and analysis the fecal microbiome of NSCLC patients with or without brain metastasis (BM).

      Method

      We collected 102 fecal and 71 sputum samples from Wuhan Union Hospital. The Illumine Miseq sequencing platform was used to analyze 16S rRNA variable regions V3 and V4 in these samples. C57/BJ mice were treated with an antibiotic cocktail to postnatally deplete the microbiota. The effect of antibiotic was subsequently investigated both in xenograft model and brain metastases model.

      Result

      Clinical characteristics of the participants including age, gender and body mass index were matched between the compared groups. (1) The sputum microbial diversity of healthy control group (n=18) was higher than NSCLC group (n=53, P < 0.05). Genus Actinomyces was significantly more abundant in sputum samples of NSCLC patients than the healthy controls (P < 0.05), while Neisseria was more abundant in the controls. The area under the curve of genus Actinomyces used to predict lung cancer was 0.71 (95% CI: 0.69 - 0.91). (2) However, no difference in alpha diversity was showed between the fecal microbial of healthy control group (n=22) and NSCLC group (n=80). Genus Haemophilus was significantly more abundant in fecal sample of NSCLC patients than the healthy controls (P < 0.05). The area under the curve of genus Actinomyces used to predict lung cancer was 0.75 (95% CI: 0.65 - 0.84). (3) The alpha diversity of fecal microbial was similar between patients with brain metastasis group (BM+, n=18) and patients without BM group (BM-, n=32). But there were some differences in the microflora structure between the 2 groups. (4) An impaired microbiota of mouse, antibiotic treatment, promoted tumorigenesis in subcutaneous xenograft, but inhibited tumorigenesis in brain metastasis. Impaired microbiota at least partially influenced the progression of Lewis cell line through acute and chronic inflammation of the intestine.

      Conclusion

      The genus Actinomyces in sputum samples and Haemophilus in fecal samples were abundant in NCSLC group and exhibited moderate classification potential. The microflora structure of BM(-) and BM(+) group was significantly different. Antibiotic treatment at least partially influenced Lewis progression through acute and chronic inflammation of the intestine.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-34 - Endostar Combined with Whole Brain Radiotherapy in Patients with NSCLC Brain Metastases (Now Available) (ID 1956)

      10:15 - 18:15  |  Presenting Author(s): Xiaorong Dong

      • Abstract
      • Slides

      Background

      Brain metastasis (BM) is the leading cause of poor prognosis, recurrence, and death in non-small-cell lung cancer (NSCLC) patients. The effectiveness of whole-brain radiotherapy is unsatisfactory. Endostar was reported as an anti-angiogenic agent, which could promote vascular normalization in tumor. This study is to investigate the influence of endostar combined with cranial radiation to survival, cerebral blood flow, immune status and quality of life of the patients.

      Method

      28 NSCLC patients with multiple brain metastasis(more than four)were randomly divided into two groups. The experimental group (n = 14) received WBRT (30Gy/10F) combined with Endostar (15mg/m2, 7days), and the control group (n=14) received WBRT (30Gy/10F) alone. Tumor progression and survival of the patients were established by certified oncologists based on whole brain MRI scan. Magnetic resonance perfusion imaging was carried out pre- and one month post-radiation to detect regional cerebral blood volume (rCBV), regional cerebral blood flow (rCBF), mean transit time (MTT) and transit time to peak (TTP) of the contrast medium. The changes of blood T lymphocyte subpopulation, the cognitive function and overall healthy level were evaluated pre- and post- radiation every two months against the MMSE, MoCA and EORTC QLQ-C30 scales.

      Result

      The median progression free survival (mPFS) was 211 days vs. 84 days (P=0.2204), while the median intracranial PFS (miPFS) was 333 days vs. 192 days (P=0.1882) and the median extracranial PFS (mePFS) was 311 days vs. 84 days (P=0.0873) between the Endostar group vs. the control group, but neither with significant difference, may for the limit of sample size. Moreover, compared with the control group, rCBF of the lesion in the Endostar group decreased more evidently (-69.0286±87.4532 vs. -25.3444±233.4, P=0.6158), rCBV decreased slightly (-13.1286±389 vs. -510.8±800.1, P=0.1545), MTT increased (69.0571±1190.7 vs. -483.3±1885.1, P=0.5108) and TTP increased (156.6±1232.8 vs. 102.1±864.1, P=0.9185), indicating that endostar group had a better control of the cerebral perfusion and the tumor. The T lymphocyte subpopulation increased in the Endostar group, especially the CD3+CD8+ T lymphocyte but without significant difference compared with the control group(P=0.1447). At the same time, after cranial radiation, the cognitive function, physical, role, social and emotional functions improved in the endostar group, while a small fluctuation in the control group with significant difference(P<0.05).

      Conclusion

      Our study showed that endostar could improve survival of the patients, adjust cerebral perfusion and promote control of lesions, ameliorate the immune status, while improve cognitive function and quality of life of the patients at the same time.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-34 - Fractalkine Attenuate Irradiation-Induced Brain Injury Through Promoting the M2 Polarization of Microglia (Now Available) (ID 2136)

      10:15 - 18:15  |  Presenting Author(s): Xiaorong Dong

      • Abstract
      • Slides

      Background

      Radiation-induced brain injury (RIBI) is an unavoidable adverse side-effect induced by cranial radiation therapy. The neuro-inflammation mediated by activated microglia has been proved to be a key role in RIBI by our previous researches. Studies have demonstrated that vascular endothelial cells are damaged by irradiation and Fractalkine (FKN), a crucial mediator modulating the biological activity of microglia, is released. However, the role of FKN in RIBI was poorly understood. The aim of this study was to investigate the effect of FKN on RIBI and its underlying mechanisms.

      Method

      Human Umbilical Vein Endothelial Cells (HUVEC) was subjected to 10 Gy or sham irradiation, FKN expression was detected by Western blotting (WB), qRT-PCR and ELISA, γH2AX formation and nuclear translocation of p65 was analyzed by immunocytochemistry (ICC). BV-2 cells received 10-Gy irradiation after being cultured for 3 h with or without FKN (100ng/ml), or co-cultured with HUVEC. Moreover, the CX3CR1 (the receptor of FKN on microglia) wide-type (CX3CR1WT) and CX3CR1-knockdown (CX3CR1-/-) mice were employed and subjected to lateral ventricular injection (ICV) of 5 μl FKN lentivirus or vector 3 days before 10-Gy whole brain irradiation. The polarization of microglia in vitro or in hippocampus and its inflammatory factors release were evaluated through measuring the signature genes, protein and cytokines of M1/M2 phenotype by RT-PCR, WB and ELISA at different time-points after irradiation. Hippocampus neurogenesis was evaluated through detecting the proliferation marker BrdU/nestin and differentiation marker BrdU/NeuN by immunofluorescence (IF) respectively. Neurological function was evaluated by morris water maze (MWM) at 6 weeks after RIBI , and the relationship between microglia and vascular was explored by IF. Then the in vitro phagocytosis assays were performed to investigate if FKN could promote BV2’ phagocytic function.

      Result

      The expression of FKN in HUVEC was increased by 10 Gy irradiation, simultaneously, γH2AX formation and p65 nuclear translocation were observed. FKN regardless from exogenous or secreted by HUVEC could promote the M2 polarization of microglia and inhibit inflammatory response in vitro, it also enhanced neurogenesis in hippocampus, and improved function recovery in CX3CR1WT mice, but not in CX3CR1-/-mice after RIBI. More interestingly, activated microglia migrated to blood vessels in CX3CR1WT mice was observed in vivo by IF. What’s more, BV2 cells phagocytized more fluorescent microspheres when treated with FKN.

      Conclusion

      The FKN/CX3CR1 axis plays an important role in RIBI, and might be an underlying target for the treatment of radiation-induced cognitive impairment.

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