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Bo Yuan



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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-126 - The Co-Occurring Genomic Landscape of ERBB2 Exon 20 Insertion in Non-Small Cell Lung Cancer (NSCLC) and the Potential Indicator of Response to Afatinib (Now Available) (ID 1284)

      09:45 - 18:00  |  Presenting Author(s): Bo Yuan

      • Abstract
      • Slides

      Background

      Human epidermal growth factor receptor 2 (ERBB2, HER-2) 20 exon insertion (ERBB2ex20ins) has been identified as an oncogenic driver in lung cancer, for which no valid therapy is currently approved. Concurrent alterations may elucidate its refractory features. Previous studies on Afatinib, a pan-ERBB inhibitor, have revealed an inconsistent clinical activity of it for this group of patients.

      Method

      Plasma or tissue samples of 112 patients with ERBB2ex20ins were performed next generation sequencing (NGS) for 59 or 1021 cancer-related genes in a Clinical Laboratory Improvement Amendments-certified Laboratory from July 2016 to December 2018. The sequencing data of MSKCC Cohort was downloaded from the public Cancer Genome Atlas Database. The clinical outcomes of 18 patients receiving Afatinib treatment were collected by each contributing doctor in charge and pooled for analysis.

      Result

      Among the 112 patients, most of cases were female (54%, 60/112) and adenocarcinoma (68%, 76/112). Considering the insertions sites, three subtypes were A775ins (71%; 79/112), G776indel (17%; 19/112) and P780ins (12%; 14/112) in the order of frequency. 80.4% (90/112) of patients had at least one additional alteration. The most frequent co-occurring genes were TP53 (66.1%, 74/112), LRP1B (18.2%, 10/55), EPHA5 (9.1%, 5/55), MLL3 (9.1%, 5/55) and RB1 (8.0%; 9/112). Putative other driver aberrations were mutually exclusive from ERBB2ex20ins. Furthermore, cell cycle pathway was the most commonly involved pathway (84.0%; 94/112) of all the concurrent genes. No substantial differences of concurrence in genomic or pathway level were observed among the three ERBB2 insertion subtypes. The co-occurring genomic feature of ERBB2ex20ins in Our Cohort of Chinese people had an overall strong concordance with the MSKCC Cohort from the United States (R2=0.74, P<0.01). For the prognosis, patients had a worse OS when co-occurring mutation in TP53 [median OS:14.5m (95%CI: 12.7m-16.3m) vs 30.3m (95% CI: not reached)], while the OS was not significantly different among three subtypes. The median duration time for patients with disease control of Afatinib was 4.5 months (95%CI: 3.6m-5.4m; range: 2.5m-13.4m). Of note, ERBB2ex20ins in subclonal status was a significantly independent factor relating to shorter PFS of Afatinib [median PFS: 1.2m (95%CI: 0.8-1.6m) vs 4.3m (95%CI: 3.3m-5.3m), P<0.05]. Dynamic detection in two patients found ERBB2 amplification may be a resistance mechanism for Afatinib.

      Conclusion

      Concurrence of genetic alterations in NSCLC patients with ERBB2ex20ins was common. The complex genomic characteristic should be fully considered by stratifying patients according to potentially relevant co-mutations other than ERBB2 insertion sites in the designing regimens for them. In addition, the therapeutic effect of Afatinib on patient with ERBB2ex20ins is limited, the clonal status of ERBB2ex20ins may be an important factor with prognosis value.

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