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Yi-Chen Zhang



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    MA15 - Colliding Approaches - EGFR and Immunotherapy (ID 916)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 107
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      MA15.06 - Circulating Tumor DNA Portrays the Resistance Landscape to a Novel Third Generation EGFR Inhibitor, AC0010 (ID 13641)

      14:05 - 14:10  |  Presenting Author(s): Yi-Chen Zhang

      • Abstract
      • Presentation
      • Slides

      Background

      In a Phase I/II dose-escalation and expansion study conducted at Guangdong Lung Cancer Institute, AC0010 demonstrated promising efficacy and good tolerability in advanced NSCLC patients with EGFR T790M-mediated resistance to previous EGFR TKIs, (NCT02330367). As disease progression (PD) with EGFR T790M-directed therapy also emerges over time, we investigated the resistance mechanisms to AC0010 in this study.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Serial ctDNA samples obtained from patients who developed PD with AC0010 were analyzed using ultra-deep sequencing capturing 295 cancer-related genes. Alterations that were absent before treatment and acquired at PD or that increased in abundance during treatment were identified as putative resistance mechanisms.

      4c3880bb027f159e801041b1021e88e8 Result

      Longitudinal plasma samples were obtained from 23 patients who progressed on AC0010 (data cut-off October 14, 2016; figure1). Putative resistance mechanisms to AC0010 were identified in 19/23 patients (>1 putative resistance mechanism was detected in some patients). EGFR amplification was the predominant resistance mechanism (21.1% [4/19 patients]), followed by TP53 loss of heterozygosity (15.8% [3/19]). EGFR C797S mutation, Met amplification and mutations in the PI3KCA pathway each occurred in 10.5% of patients (2/19). SCLC transformation, ERBB2 amplification, CD79A_A32G mutation, CDKN2A_R80 mutation, CRLF2 amplification, MLH1 amplification, Rb1 loss, and concurrent rise in the allelic fraction of tumor suppressor gene TP53 and Rb1 were each detected in 5.3% of patients (1/19). In a patient with PD following single-agent AC0010 and EGFR amplification as the putative resistance mechanism to AC0010, subsequent treatment with AC0010 plus nimotuzumab (EGFR monoclonal antibody) successfully overcame resistance, resulting in a response that lasted for 7.7 months.

      fig 1_study profile.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The resistance landscape to AC0010 appears to differ from that described previously with osimertinib. In this cohort of patients in China, EGFR amplification was the predominant resistance mechanism to AC0010 and could be potentially overcome by EGFR dual inhibition.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-99 - Detecting HER2 Alterations by Next Generation Sequencing (NGS) in Patients with Advanced NSCLC from the United States and China (ID 11285)

      16:45 - 18:00  |  Author(s): Yi-Chen Zhang

      • Abstract
      • Slides

      Background

      Advances in NGS have led to an increase in identifying specific actionable gene alterations across tumor types. We collected data on HER2 gene alterations detected by NGS from patients with advanced NSCLC and analyzed clinical characteristics and HER2 targeted treatments.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients diagnosed with advanced NSCLC and underwent NGS testing from Jun 2014 to Dec 2017 at Memorial Sloan-Kettering Cancer Center (MSK) and Guangdong General Hospital (GGH) were included. NGS platforms were MSK-IMPACTTM in MSK and GeneSeek or BurnStone in GGH. Descriptive statistics are used in data analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      2200 patients from MSK and 490 patients from GGH underwent NGS testing. HER2 mutation and/or amplification were detected in 91/2200(4.1%) patients and 28/490(5.7%) patients from MSK and GGH respectively. Clinical characteristics were listed in Table1. 37.4%(34/91) and 21.4%(6/28) patients from MSK and GGH received HER2 targeted therapies. More patients were enrolled to HER2 inhibitors clinical trials in MSK(24.2%) than GGH(7.1%). The characteristics of HER2 alterations are summarized in Table2.

      Table 1. Comparison of HER2 alterations in advanced NSCLC patients from U.S. and China

      MSK

      N (%)

      GGH

      N (%)

      Total Patients

      91

      28

      Age at Diagnosis (years)

      <=60

      34 (37.4%)

      13 (46.4%)

      >60

      57 (62.6%)

      15 (53.6%)

      Sex

      Male

      37 (40.7%)

      14 (50%)

      Female

      54 (59.3%)

      14 (50%)

      Smoking History

      Former/Current Smoker

      53 (58.2%)

      7 (25%)

      Non-Smoker

      38 (41.8%)

      21 (75%)

      Histology

      Adenocarcinoma

      84 (92.3%)

      25 (89.3%)

      Squamous Cell Carcinoma

      5 (5.5%)

      0

      Misc

      2 (2.2%)

      3 (10.7%)

      HER2 status

      Mutation

      48 (52.7%)

      16 (57.1%)

      Amplification

      32 (35.2%)

      11 (39.3%)

      Mutation + Amplification

      11 (12.1%)

      1 (3.6%)

      HER2 targeted treatment

      34 (37.4%)

      6 (21.4%)

      Enrolled to HER2 inhibitors clinical trials

      22 (24.2%)

      2 (7.1%)

      Table 2. HER2 alteration in advanced NSCLC patients from U.S. and China combined

      NGS Result

      Mutation Only

      N (%)

      Amplification Only

      N (%)

      Mutation + Amplification

      N (%)

      Total Patients 64 43 12

      Age at Diagnosis (years)

      <=60

      31 (48.4%)

      20 (46.5%)

      8 (66.7%)

      >60

      33 (51.6%)

      23 (35.9%)

      4 (33.3%)

      Sex

      Male

      39 (60.9%)

      19 (44.2%)

      7 (58.3%)

      Female

      25 (39.1%)

      24 (55.8%)

      5 (41.7%)

      Smoking History

      Former/Current Smoker

      31 (48.4%)

      24 (55.8%)

      5 (41.7%)

      Non-Smoker

      33 (51.6%)

      19 (44.2%)

      7 (58.3%)

      Histology

      Adenocarcinoma

      58 (90.6%)

      39 (90.7%)

      12 (100%)

      Squamous Cell Carcinoma

      1 (1.6%)

      4 (9.3%)

      0

      Misc

      5 (7.5%)

      0

      0

      HER2 targeted treatment

      Yes

      19 (29.7%)

      14 (32.6%)

      7 (58.3%)

      No

      45 (70.3%)

      29 (67.4%)

      5 (41.7%)

      8eea62084ca7e541d918e823422bd82e Conclusion

      The incidence and clinical characteristics of HER2 alterations in advanced NSCLC were similar between two large cancer centers in the U.S. and China. These data support U.S.-China collaboration in clinical trials for patients with rare molecular subsets of NSCLC to accelerate new cancer drug development.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.03 - Biology (Not CME Accredited Session) (ID 935)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.03-34 - Combined Molecular and Radiological Evaluation Unveils Three Subtypes of Disease Progression to a Third Generation EGFR TKI (ID 12055)

      16:45 - 18:00  |  Presenting Author(s): Yi-Chen Zhang

      • Abstract
      • Slides

      Background

      The definition of disease progression (PD) to EGFR TKIs has evolved from RECIST to a combination of clinical and RECIST evaluation. Patients with dramatic, local or gradual progression to third generation EGFR TKIs have been tailored to different subsequent treatment strategies. However, little is known about progression to third generation EGFR TKIs from molecular perspective.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Longitudinal plasma samples were collected from T790M-positive patients who progressed on a third generation EGFR TKI AC0010 in a phase I/II study in Guangdong Lung Cancer Institute. A pre-defined and unified molecular and radiological evaluation of PD were performed. Ultra-deep sequencing capturing 295 cancer-related genes was performed to track the changes in ctDNA to depict molecular PD, which was defined by acquired SNV/SCNV, or ≥20% increase in allelic fraction/copy number of pre-existing SNV /SCNV or both. Radiological PD was defined by RECIST.

      4c3880bb027f159e801041b1021e88e8 Result

      As of October 2016, 102 serial plasma samples from 23 patients with clinical PD were included. Three subtypes of PD to AC0010 were revealed (Fig1). Molecular PD occurred prior to radiological PD in 43.5% of patients (10/23), with an average lead time of 3.0 months. Molecular PD occurred concurrently with radiological PD in 39.1% of patients (9/23). Interestingly, 17.4% of patients (4/23) experienced radiological PD prior to molecular PD, with molecular PD occurred during AC0010 continuation beyond progression (CBPD) in 3 patients. Of patients experienced clinical stable PD in extracranial lesions, radiological PD occurring prior to molecular PD group (n=2) demonstrated longer duration of AC0010 CBPD than molecular PD occurring prior to (n=3) or concurrently with radiological PD groups (n=4) (Median, 5.6 months vs. 1.9 months vs. 1.8 months).

      fig1 three subtypes of pd.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study revealed 3 distinct subtypes of PD to AC0010, providing insights into PD by combining molecular and radiological evaluation and might guide the optimal time for treatment switch and personalized subsequent treatments.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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