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X. Hu



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    MA 07 - ALK, ROS and HER2 (ID 673)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA 07.13 - NGS Sequencing Based Liquid / Tissue Biopsy Identified Coexistence of HER2 Amplification and Mutation in Advanced NSCLC Patients (ID 9737)

      15:45 - 17:30  |  Author(s): X. Hu

      • Abstract
      • Presentation
      • Slides

      Background:
      Human epidermal growth factor 2 (HER2, ERBB2) mutations / amplifications have been identified as oncogenic drivers in 2-5% of lung cancers. It has been reported that hybridization capture-based next-generation sequencing (NGS) could reliably detect HER2 amplification in qualified breast and gastroesophageal tumor tissue samples. However, there is little data in lung cancer, especially for advance NSCLC with only ctDNA samples available.

      Method:
      We reviewed 2000 consecutive samples from advanced NSCLC patients sequenced in our institute between 2015 and 2016. Tumor biopsy and/or ctDNA samples were analyzed using hybridization capture-based NGS ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations at least 59 genes (range 59 – 1021 genes).

      Result:
      We identified 54 samples from 48 patients with HER2-mutation or amplification in the cohort (54/2000=2.7%). The 54 samples included 14 tissue biopsy samples, 37 ctDNA samples, and 3 pleural effusion samples. Thirty-six samples carried HER2 mutations, and 23 samples carried HER2 amplification with 5 samples have concurrent HER2 mutation and amplification. A 9-base pair (bp) in-frame insertion in exon 20 (Y772_A775dup) was detected in 18 samples (18/36=50%). In addition, there were 5 other insertions in exon 20; eight single bp substitutions (S310F) in exon 8; three exon 17 V659E mutations (from the sample patient with 3 ctDNA samples submitted at different time); one exon 19 D769H mutation; and one exon 21 V842I mutation. Amplification were identified in 23 samples, with copy number range from 3.8 to 19.6 in tissue samples (n=7, medium 11.6); from 4.3 to 51.8 in ctDNA samples (n=16, medium 7.3); 3.2 and 6 in the 2 pleural effusion samples. Interestingly, the allele frequency (AF) of HER2 mutation was the maximal in 4 of the 5 patients with concurrent HER2 mutation and amplification. Two patients were EGFR-TKI resistant with EGFR L858R mutation remaining and HER2 mutation and amplification might be the major reason for the resistance.

      Conclusion:
      HER2 mutations might coexist with HER2 amplification in advanced NSCLC patients, and it could be detected simultaneously with hybridization capture-based NGS sequencing both in tissue and liquid biopsy samples. Further quantative analysis of HER2 amplification / mutation and anti-HER2 therapeutic effects are underway.

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    P2.01 - Advanced NSCLC (ID 618)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P2.01-029 - Real World Report of Clinical Outcomes of Bevacizumab in First-Line or Later-Line Treatment for Patients with Advanced NSCLC (ID 8999)

      09:00 - 16:00  |  Author(s): X. Hu

      • Abstract
      • Slides

      Background:
      Bevacizumab combined therapy has been demonstrated superior efficacy and well tolerability in first-line and later-line treatment by various scales of prospective control trials. But it is still lack of direct evidence endorsing bevacizumab as first-line (1L) over later-line (LL) use.

      Method:
      We retrospectively evaluated the effectiveness of bevacizumab contained therapy as 1L or LL treatment in patients with advanced NSCLC. Primary outcome was progression-free survival (PFS), and the secondary objectives were objective response rate (ORR), disease control rate (DCR) and safety. Subsequently, an exploratory analysis was conducted in subgroups regarding to patients drive genes status including EGFR and ALK.

      Result:
      From Jul. 2009 to Dec. 2016, a total of 159 patients with NSCLC were enrolled. Baseline characteristics were well balanced between 1L and LL groups. The median follow-up time was 10.7 months. Comparing to LL, the median PFS in 1L was significant longer (9.7 months vs 4.1 months, HR=0.28, 95% CI 0.15-0.52, P<0.0001). Short term effects of ORR and DCR both had improved trends in 1L than LL. Interestingly in subgroups, WT group (median PFS 11.3 vs 3.4 months, HR 0.2, 95% CI 0.08-0.48, P<0.0001) and WT+UN group (median PFS 11.3 vs 3.4 months, HR 0.25, 95% CI 0.12- 0.51, P<0.0001) had better effectiveness as 1L than LL over the whole population. The ORR and DCR had consistently similar response in subgroups comparison (Table 1). There was no unexpected safety issue documented. Figure 1



      Conclusion:
      Although it was limited in retrospective design, this precious real world evidence indeed exhibited superior clinical effectiveness in first-line use of bevacizumab indicating a better choice rather than later line use, particularly to EGFR&ALK wild type or unknown patients.

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    P2.03 - Chemotherapy/Targeted Therapy (ID 704)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      P2.03-028 - Third Generation EGFR Inhibitor AST2818 (Alflutinib) in NSCLC Patients with EGFR T790M Mutation: A phase1/2 Multi-Center Clinical Trial (ID 8968)

      09:30 - 16:00  |  Author(s): X. Hu

      • Abstract
      • Slides

      Background:
      AST2818 (Alflutinib) was designed to inhibit EGFR active mutations as well as the T790M acquired resistant mutation. The purpose of this study was to determine the safety and antitumor activity of AST2818 in EGFR T790M positive non-small cell lung cancer (NSCLC) patients after the first-generation EGFR-TKIs treatment failure.

      Method:
      Patients with histologically diagnosed, EGFR T790M mutant stage IV NSCLC were considered eligible, and they should have documented disease progression on EGFR-TKIs. In a 3+3 dose-escalation design, AST2818 was orally administered every day on a 21-day cycle at doses ranging from 20mg to 240 mg (NCT02973763). AST2818 was then explored in a dose-expansion cohort at doses ranging from 40 to 240 mg every day. Plasma samples were collected to evaluate pharmacokinetics of AST2818. EGFR T790M mutation in tissue samples was detected by amplification refractory mutation system. The primary endpoint was to determine dose limiting toxicity and objective response rate (ORR). Adverse events (AEs) were evaluated by CTCAE 4.03, and efficacy was assessed per RECIST v1.1 every 6 weeks.

      Result:
      From December 27, 2016 to August 21, 2017, 17 patients received at least one dose of AST2818 across four cohorts (20mg, 40mg, 80mg and 160 mg QD). Maximum tolerated dose has not been reached. The most common treatment-related AEs were grade 1 proteinuria (25%, 3/12). Other AEs included fatigue and prolonged Q-T interval, etc, all less than 10% and grade 1 or 2. The first 12 patients had been evaluated with an ORR of 58.3% (7/12) and a disease control rate of 91.7% (11/12). Profound and sustained tumor regression had already been observed at 20mg cohort. AST2818 plasma exposure, measured as Cmax and AUC 0-24h showed a dose-proportional increase. Figure 1



      Conclusion:
      AST2818 was well tolerated and had promising clinical activity with durable disease control in EGFR T790M mutant NSCLC after first-generation EGFR-TKIs treatment failure.

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    P3.04 - Clinical Design, Statistics and Clinical Trials (ID 720)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Clinical Design, Statistics and Clinical Trials
    • Presentations: 1
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      P3.04-007 - A Prospective Study of Apatinib in Advanced Small Cell Lung Cancer Patients Failed from Two or More Lines of Chemotherapy (ID 10041)

      09:30 - 16:00  |  Author(s): X. Hu

      • Abstract
      • Slides

      Background:
      Small cell lung cancer (SCLC) is an aggressive and invasive variant of lung tumors,and its treatment strategy is poor. Apatinib is an oral TKI against VEGFR-2. We determined the efficacy of Apatinib as third- or later-line treatment in advanced SCLC.

      Method:
      The study was expected to enroll 30 patients diagnosed with advanced SCLC. Patients received oral Apatinib 500mg QD and make an efficacy evaluation after first cycle, then every two cycles once again. The primary endpoint was progression-free-survival (PFS).

      Result:
      From November 10, 2016 to June 18, 2017, 10 patients were enrolled. 1 patient showed PR when make efficacy evaluation the first time, 8 patients were evaluated SD and 1 patient showed PD due to liver metastasis. Although only one patient showed PR, all the patients’ target lesions were reduced, as figure 1. Figure 1 Up to June 18, 4 patients out of the group due to PD, the PFS is 28 weeks, 19.8 weeks, 13 weeks and 4.7 weeks respectively. Another 6 patients are still investigated, as figure 2, the blue bars are their PFS . Figure 2





      Conclusion:
      Apatinib in advanced SCLC is worth expecting.To further investigate the role of Apatinib in SCLC patients, large sample and additional clinical trials are needed.

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