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    BIOMARKER:

    HER-2 G778_P780dup

    i
    Other names: ERBB2, CD340, HER-2, HER2, NEU, NGL, V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2
    Entrez ID:
    2064
    Related biomarkers:
    Expression
    Mutation
    CNA
    Fusion
    Others
    2ms
    DESTINY-PanTumor01: A Study of T-DXd for the Treatment of Solid Tumors Harboring HER2 Activating Mutations (clinicaltrials.gov)
    P2, N=102, Active, not recruiting, AstraZeneca | Trial completion date: Jan 2028 --> Jul 2026
    Trial completion date • Metastases
    |
    HER-2 mutation • HER-2 L755S • HER-2 S310F • HER-2 V777L • HER-2 S310Y • HER-2 G778_P780dup • HER-2 D769Y • HER-2 V842I • HER-2 A775 • HER-2 D769H • HER-2 G660D + HER-2 S310F • HER-2 P780-Y781insGSP • HER-2 R678Q • HER-2 T862A • HER-2 YVMA
    |
    Enhertu (fam-trastuzumab deruxtecan-nxki)
    6ms
    Clinical and genomic landscape of ERBB2 and ERBB3 mutated breast cancer (SABCS 2023)
    Here we describe the clinical and genomic characteristics of a large cohort of ERBB2/3-mut breast cancers. We identify a notable enrichment of ERBB2/3-mut in lobular histology and metastatic tumors and tendency for co-alteration with CDH1 and multiple transcription factors reflecting the unique biology of ERBB2/3-mut breast cancers. Further analyses on an expanded cohort (n >6000 pts), including outcomes on HER2-directed antibody-drug conjugates (T-DXd) and targeted therapies such as PI3K inhibitors, will be presented at the 2023 SABCS Annual Meeting.
    Clinical
    |
    HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • ARID1A (AT-rich interaction domain 1A) • NF1 (Neurofibromin 1) • RUNX1 (RUNX Family Transcription Factor 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • CDH1 (Cadherin 1) • FOXA1 (Forkhead Box A1) • MAP3K1 (Mitogen-Activated Protein Kinase Kinase Kinase 1) • GATA3 (GATA binding protein 3)
    |
    HER-2 negative • HER-2 mutation • HER-2 L755S • HER-2 S310F • HER-2 V777L • ERBB3 mutation • HER-2 G778_P780dup • ERBB3 G284R
    |
    MSK-IMPACT
    |
    Enhertu (fam-trastuzumab deruxtecan-nxki)
    7ms
    NCI-2022-04099: Testing the Safety and Tolerability of the Anti-cancer Drugs Trastuzumab Deruxtecan and Neratinib for Cancers With Changes in the HER2 Gene (clinicaltrials.gov)
    P1, N=30, Recruiting, National Cancer Institute (NCI) | N=18 --> 30
    Enrollment change • Combination therapy
    |
    CD4 (CD4 Molecule)
    |
    HER-2 positive • HER-2 overexpression • HER-2 amplification • HER-2 mutation • HER-2 L755S • HER-2 A775_G776insYVMA • HER-2 S310F • HER-2 V777L • HER-2 G778_P780dup • HER-2 D769Y • HER-2 L869R • HER-2 V842I • HER-2 H878Y • HER-2 L866M • HER-2 A775 • HER-2 G309A • HER-2 P780-Y781insGSP • HER-2 R678Q • HER-2 R896C • HER-2 T862A • HER-2 YVMA
    |
    Nerlynx (neratinib) • Enhertu (fam-trastuzumab deruxtecan-nxki)
    9ms
    Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with solid tumors harboring specific HER2-activating mutations (HER2m): Primary results from the international phase II DESTINY-PanTumor01 (DPT-01) study (ESMO 2023)
    In heavily pretreated pts with limited Tx options, T-DXd demonstrated encouraging anticancer activity and long DoR across multiple tumor types with HER2m and a range of HER2 expression levels, with a known safety profile. Translational research will help characterize pts who may derive greatest benefit from T-DXd.
    Clinical • P2 data • Pan tumor
    |
    HER-2 (Human epidermal growth factor receptor 2)
    |
    HER-2 positive • HER-2 overexpression • HER-2 mutation • HER-2 L755S • HER-2 S310F • HER-2 V777L • HER-2 S310Y • HER-2 G778_P780dup • HER-2 V842I • HER-2 A775 • HER-2 D769H • HER-2 P780-Y781insGSP • HER-2 R678Q • HER-2 T862A • HER-2 YVMA
    |
    Enhertu (fam-trastuzumab deruxtecan-nxki)
    1year
    Poziotinib in Treatment-Naïve Non-Small-Cell Lung Cancer Harboring HER2 Exon 20 Mutations: ZENITH20-4, A Multicenter, Multicohort, Open-label Phase 2 Trial (Cohort 4). (PubMed, J Thorac Oncol)
    Poziotinib demonstrated clinically meaningful efficacy with a manageable toxicity profile for treatment-naïve NSCLC patients harboring HER2 exon 20 mutations.
    P2 data • Journal • HER2 exon 20
    |
    HER-2 (Human epidermal growth factor receptor 2) • TYK2 (Tyrosine Kinase 2)
    |
    HER-2 mutation • HER-2 exon 20 insertion • HER-2 G778_P780dup • HER-2 exon 20 mutation • HER-2 exon 23 mutation
    |
    Pozenveo (poziotinib)
    1year
    Neratinib in Treating Older Patients With Stage IV HER2-Positive Breast Cancer (clinicaltrials.gov)
    P2, N=25, Completed, City of Hope Medical Center | Active, not recruiting --> Completed | Trial completion date: Dec 2022 --> Sep 2022
    Trial completion • Trial completion date • Metastases
    |
    ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3)
    |
    HER-2 positive • HER-2 negative • HER-2 L755S • HER-2 A775_G776insYVMA • HER-2 S310F • HER-2 V777L • HER-2 L755P • ERBB3 mutation • HER-2 S310Y • HER-2 G778_P780dup • HER-2 D769Y • HER-2 L869R • HER-2 V842I • ERBB3 V659E • HER-2 G778_S779insCPG • HER-2 L755_T759del • HER-2 A775 • HER-2 D769H • HER-2 R678Q • HER-2 R896C • HER-2 YVMA • ERBB3 L755S
    |
    Nerlynx (neratinib)
    over1year
    Poziotinib in non-small-cell lung cancer patients with HER2 exon 20 mutations: A pooled analysis of randomized clinical trials. (PubMed, Medicine (Baltimore))
    Poziotinib demonstrates moderate antitumor activity in previously treated HER2 exon 20 mutant NSCLC patients with a manageable safety profile. In addition, different subgroup mutations show various benefits of poziotinib treatment. Large-scale and multiarm clinical trials are warranted to confirm a suitable population and therapeutic strategies.
    Clinical • Retrospective data • Review • Journal • HER2 exon 20
    |
    HER-2 (Human epidermal growth factor receptor 2)
    |
    EGFR mutation • HER-2 mutation • HER-2 G778_P780dup • HER-2 exon 20 mutation • HER-2 A775 • HER-2 exon 23 mutation
    |
    Pozenveo (poziotinib)
    over1year
    Poziotinib inhibits HER2 mutant-driven therapeutic resistance and multi-organ metastasis in breast cancer. (PubMed, Cancer Res)
    The most highly recurrent HER2 mutant, L755S, was particularly resistant to neratinib but sensitive to the pan-HER TKI poziotinib, alone or in combination with fulvestrant. Similar therapeutic effects of poziotinib were observed in both an engineered HER2L755S MCF7 model and a patient-derived xenograft harboring a HER2G778_P780dup mutation. Overall, these findings support the need for clinical evaluation of poziotinib for the treatment of HER2 mutant metastatic breast cancer.
    Journal
    |
    ER (Estrogen receptor)
    |
    HER-2 mutation • HER-2 L755S • HER-2 G778_P780dup
    |
    Nerlynx (neratinib) • fulvestrant • Pozenveo (poziotinib)
    over1year
    High activity of poziotinib in G778_P780dup HER2 exon 20 insertion mutations in non-small cell lung cancer (NSCLC) (ESMO 2022)
    Conclusions Poziotinib is highly active in G778, a common HER2 ex20ins alteration, in both treatment-naïve and previously treated patients with NSCLC. The AE profile was typical of a TKI.
    HER2 exon 20
    |
    HER-2 (Human epidermal growth factor receptor 2)
    |
    HER-2 mutation • HER-2 exon 20 insertion • HER-2 G778_P780dup • HER-2 exon 20 mutation • HER-2 exon 23 mutation
    |
    Pozenveo (poziotinib)
    almost2years
    NCI-2022-04099: Testing the Safety and Tolerability of the Anti-cancer Drugs Trastuzumab Deruxtecan and Neratinib for Cancers With Changes in the HER2 Gene (clinicaltrials.gov)
    P1, N=18, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting
    Enrollment open • Combination therapy
    |
    CD4 (CD4 Molecule)
    |
    HER-2 positive • HER-2 overexpression • HER-2 amplification • HER-2 mutation • HER-2 L755S • HER-2 A775_G776insYVMA • HER-2 S310F • HER-2 V777L • HER-2 L755P • HER-2 G778_P780dup • HER-2 D769Y • HER-2 L869R • HER-2 V842I • HER-2 H878Y • HER-2 L866M • HER-2 A775 • HER-2 G309A • HER-2 P780-Y781insGSP • HER-2 R678Q • HER-2 R896C • HER-2 T862A
    |
    Nerlynx (neratinib) • Enhertu (fam-trastuzumab deruxtecan-nxki)
    almost2years
    NCI-2022-04099: Testing the Safety and Tolerability of the Anti-cancer Drugs Trastuzumab Deruxtecan and Neratinib for Cancers With Changes in the HER2 Gene (clinicaltrials.gov)
    P1, N=18, Not yet recruiting, National Cancer Institute (NCI) | Trial completion date: Aug 2023 --> Jun 2024 | Trial primary completion date: Aug 2023 --> Jun 2024
    Trial completion date • Trial primary completion date • Combination therapy
    |
    CD4 (CD4 Molecule)
    |
    HER-2 positive • HER-2 overexpression • HER-2 amplification • HER-2 mutation • HER-2 L755S • HER-2 A775_G776insYVMA • HER-2 S310F • HER-2 V777L • HER-2 L755P • HER-2 G778_P780dup • HER-2 D769Y • HER-2 L869R • HER-2 V842I • HER-2 H878Y • HER-2 L866M • HER-2 A775 • HER-2 G309A • HER-2 P780-Y781insGSP • HER-2 R678Q • HER-2 R896C • HER-2 T862A
    |
    Nerlynx (neratinib) • Enhertu (fam-trastuzumab deruxtecan-nxki)
    almost2years
    NCI-2022-04099: Testing the Safety and Tolerability of the Anti-cancer Drugs Trastuzumab Deruxtecan and Neratinib for Cancers With Changes in the HER2 Gene (clinicaltrials.gov)
    P1, N=18, Not yet recruiting, National Cancer Institute (NCI)
    New P1 trial • Combination therapy
    |
    CD4 (CD4 Molecule)
    |
    HER-2 positive • HER-2 overexpression • HER-2 amplification • HER-2 mutation • HER-2 L755S • HER-2 A775_G776insYVMA • HER-2 S310F • HER-2 V777L • HER-2 L755P • HER-2 G778_P780dup • HER-2 D769Y • HER-2 L869R • HER-2 V842I • HER-2 H878Y • HER-2 L866M • HER-2 A775 • HER-2 G309A • HER-2 P780-Y781insGSP • HER-2 R678Q • HER-2 R896C • HER-2 T862A
    |
    Nerlynx (neratinib) • Enhertu (fam-trastuzumab deruxtecan-nxki)
    almost2years
    Molecular characteristics of ERBB2-activating mutations in Chinese patients with NSCLC. (ASCO 2022)
    We report mutational landscape and characteristics of ERBB2 in Chinese NSCLC patients.The prevalence of activating ERBB2 mutations was 3.1% in Chinese NSCLC patients. 80.1% of ERBB2 activating mutations were in TKD and 19.9% were in the non-TKD. The non-TKD mutations might also be used as a therapeutic target in ERBB2-directed target therapy.
    Clinical • Tumor Mutational Burden
    |
    EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability)
    |
    TP53 mutation • EGFR mutation • HER-2 amplification • HER-2 mutation • TMB-L • HER-2 S310F • HER-2 G778_P780dup • HER-2 A775
    almost2years
    Real-world frequency of non-small cell lung cancer with ERBB2 exon 20 insertion (Exon20ins) mutations by site of insertion. (ASCO 2022)
    This real-world databases identified the helix as the most frequent insertion region of Exon 20 (∼72%). Exon20ins mutations were found less frequently in the loop (∼28%).
    Clinical • Real-world evidence
    |
    EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2)
    |
    HER-2 mutation • EGFR exon 20 insertion • HER-2 G778_P780dup • HER-2 exon 20 mutation • HER-2 A775 • HER-2 exon 23 mutation
    2years
    Neratinib in Treating Older Patients With Stage IV HER2-Positive Breast Cancer (clinicaltrials.gov)
    P2, N=25, Active, not recruiting, City of Hope Medical Center | N=40 --> 25 | Trial completion date: Oct 2021 --> Dec 2022
    Enrollment change • Trial completion date
    |
    ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3)
    |
    HER-2 positive • HER-2 negative • HER-2 L755S • HER-2 A775_G776insYVMA • HER-2 S310F • HER-2 V777L • HER-2 L755P • ERBB3 mutation • HER-2 S310Y • HER-2 G778_P780dup • HER-2 D769Y • HER-2 L869R • HER-2 V842I • ERBB3 V659E • HER-2 G778_S779insCPG • HER-2 L755_T759del • HER-2 A775 • HER-2 D769H • HER-2 R678Q • HER-2 R896C • ERBB3 L755S
    |
    Nerlynx (neratinib)
    2years
    Trial of Ado-Trastuzumab Emtansine for Patients With HER2 Amplified or Mutant Cancers (clinicaltrials.gov)
    P2; Trial completion date: Feb 2022 --> Feb 2024 | Trial primary completion date: Feb 2022 --> Feb 2024
    Trial completion date • Trial primary completion date
    |
    HER-2 (Human epidermal growth factor receptor 2) • MUC16 (Mucin 16, Cell Surface Associated)
    |
    HER-2 amplification • HER-2 L755S • HER-2 S310F • HER-2 V777L • HER-2 G778_P780dup • HER-2 A775
    |
    MSK-IMPACT
    |
    Kadcyla (ado-trastuzumab emtansine)
    3years
    Trial of Ado-Trastuzumab Emtansine for Patients With HER2 Amplified or Mutant Cancers (clinicaltrials.gov)
    P2; N=100 --> 135
    Enrollment change
    |
    HER-2 (Human epidermal growth factor receptor 2) • MUC16 (Mucin 16, Cell Surface Associated)
    |
    HER-2 amplification • HER-2 L755S • HER-2 S310F • HER-2 V777L • HER-2 G778_P780dup • HER-2 A775
    |
    MSK-IMPACT
    |
    Kadcyla (ado-trastuzumab emtansine)
    3years
    Trial of Ado-Trastuzumab Emtansine for Patients With HER2 Amplified or Mutant Cancers (clinicaltrials.gov)
    P2; Active, not recruiting --> Recruiting | Trial completion date: Feb 2021 --> Feb 2022 | Trial primary completion date: Feb 2021 --> Feb 2022
    Trial completion date • Trial primary completion date • Enrollment open • Clinical
    |
    HER-2 (Human epidermal growth factor receptor 2) • MUC16 (Mucin 16, Cell Surface Associated)
    |
    HER-2 amplification • HER-2 L755S • HER-2 S310F • HER-2 V777L • HER-2 G778_P780dup • HER-2 A775
    |
    MSK-IMPACT
    |
    Kadcyla (ado-trastuzumab emtansine)
    over3years
    Conformational landscapes of HER2 exon 20 insertions explain their sensitivity to kinase inhibitors in lung adenocarcinoma. (PubMed, J Thorac Oncol)
    Kinase conformational landscape dictated by the length of αC-β4 loop and residues at HER2 776 and 778 position explains TKI sensitivity in ex20ins. This finding could guide therapeutic decisions with currently available therapies and future drug development strategies.
    Journal
    |
    EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2)
    |
    HER-2 exon 20 insertion • HER-2 G778_P780dup • HER-2 exon 20 mutation • HER-2 A775
    |
    Gilotrif (afatinib) • Irene (pyrotinib) • Vizimpro (dacomitinib) • Pozenveo (poziotinib)
    over3years
    Neratinib in Treating Older Patients With Stage IV HER2-Positive Breast Cancer (clinicaltrials.gov)
    P2, N=40, Active, not recruiting, City of Hope Medical Center | Trial completion date: Oct 2020 --> Oct 2021 | Trial primary completion date: Oct 2020 --> Oct 2021
    Clinical • Trial completion date • Trial primary completion date
    |
    ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • IL6 (Interleukin 6)
    |
    HER-2 positive • HER-2 negative • HER-2 L755S • HER-2 A775_G776insYVMA • HER-2 S310F • HER-2 V777L • HER-2 L755P • ERBB3 mutation • HER-2 S310Y • HER-2 G778_P780dup • HER-2 D769Y • HER-2 L869R • HER-2 V842I • ERBB3 V659E • HER-2 G778_S779insCPG • HER-2 L755_T759del • HER-2 A775 • HER-2 D769H • HER-2 R678Q • HER-2 R896C • ERBB3 L755S
    |
    Nerlynx (neratinib)
    4years
    Trial of Ado-Trastuzumab Emtansine for Patients With HER2 Amplified or Mutant Cancers (clinicaltrials.gov)
    P2; Trial completion date: Feb 2020 --> Feb 2021 | Trial primary completion date: Feb 2020 --> Feb 2021
    Trial completion date • Trial primary completion date • Clinical
    |
    HER-2 (Human epidermal growth factor receptor 2) • MUC16 (Mucin 16, Cell Surface Associated)
    |
    HER-2 amplification • HER-2 L755S • HER-2 S310F • HER-2 V777L • HER-2 G778_P780dup • HER-2 A775
    |
    MSK-IMPACT
    |
    Kadcyla (ado-trastuzumab emtansine)
    5years
    Trial of Ado-Trastuzumab Emtansine for Patients With HER2 Amplified or Mutant Cancers (clinicaltrials.gov)
    P2; Trial completion date: Feb 2019 --> Feb 2020 | Trial primary completion date: Feb 2019 --> Feb 2020
    Trial completion date • Trial primary completion date • Clinical
    |
    HER-2 (Human epidermal growth factor receptor 2) • MUC16 (Mucin 16, Cell Surface Associated)
    |
    HER-2 amplification • HER-2 L755S • HER-2 S310F • HER-2 V777L • HER-2 G778_P780dup • HER-2 A775
    |
    MSK-IMPACT
    |
    Kadcyla (ado-trastuzumab emtansine)
    5years
    Trial of Ado-Trastuzumab Emtansine for Patients With HER2 Amplified or Mutant Cancers (clinicaltrials.gov)
    P2; Recruiting --> Active, not recruiting
    Enrollment closed • Clinical
    |
    HER-2 (Human epidermal growth factor receptor 2) • MUC16 (Mucin 16, Cell Surface Associated)
    |
    HER-2 amplification • HER-2 L755S • HER-2 S310F • HER-2 V777L • HER-2 G778_P780dup • HER-2 A775
    |
    MSK-IMPACT
    |
    Kadcyla (ado-trastuzumab emtansine)
    6years
    Trial of Ado-Trastuzumab Emtansine for Patients With HER2 Amplified or Mutant Cancers (clinicaltrials.gov)
    P2; Trial primary completion date: Feb 2018 --> Feb 2019 | Trial completion date: Feb 2018 --> Feb 2019
    Trial completion date • Trial primary completion date • Clinical
    |
    HER-2 (Human epidermal growth factor receptor 2) • MUC16 (Mucin 16, Cell Surface Associated)
    |
    HER-2 amplification • HER-2 L755S • HER-2 S310F • HER-2 V777L • HER-2 G778_P780dup • HER-2 A775
    |
    MSK-IMPACT
    |
    Kadcyla (ado-trastuzumab emtansine)
    almost7years
    Trial of Ado-Trastuzumab Emtansine for Patients With HER2 Amplified or Mutant Cancers (clinicaltrials.gov)
    P2; N=72 --> 100
    Enrollment change • Clinical
    |
    HER-2 (Human epidermal growth factor receptor 2) • MUC16 (Mucin 16, Cell Surface Associated)
    |
    HER-2 amplification • HER-2 L755S • HER-2 S310F • HER-2 V777L • HER-2 G778_P780dup • HER-2 A775
    |
    MSK-IMPACT
    |
    Kadcyla (ado-trastuzumab emtansine)