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    BIOMARKER:

    ROS1 L2086F

    i
    Other names: ROS1, ROS Proto-Oncogene 1 Receptor Tyrosine Kinase, V-Ros Avian UR2 Sarcoma Virus Oncogene Homolog 1, C-Ros Oncogene 1 Receptor Tyrosine Kinase, Proto-Oncogene Tyrosine-Protein Kinase ROS, Proto-Oncogene C-Ros-1, MCF3, ROS, V-Ros UR2 Sarcoma Virus Oncogene Homolog 1 (Avian), ROS Proto-Oncogene 1 Receptor Tyrosine Kinase, Transmembrane Tyrosine-Specific Protein Kinase, Receptor Tyrosine Kinase C-Ros Oncogene 1, C-Ros Receptor Tyrosine Kinase, Proto-oncogene C-Ros, C-Ros-1
    Entrez ID:
    6098
    Related biomarkers:
    Expression
    Mutation
    CNA
    Fusion
    Others
    12ms
    Comprehensive review of ROS1 tyrosine kinase inhibitors (TKIs)-classified by structural designs and mutation spectrum [solvent front mutation (G2032R) and central β-sheet 6 (Cβ6) mutation (L2086F)]. (PubMed, J Thorac Oncol)
    Despite ROS1 fusion positive (ROS1+) NSCLC accounting approximately 1-2% of NSCLC, there is a dizzying list of ROS1 tyrosine kinase inhibitor (TKIs) being developed in addition to two approved ROS1 TKIs, crizotinib and entrectinib...Additionally, the less known central β-sheet 6 (Cβ6) mutation ROS1 L2086F confer resistances to next-generation ROS1 TKIs (taletrectinib, lorlatinib, potentially NVL-520) that can be overcome by cabozantinib as documented in published patient reports and may potentially by certain L-shaped Type I ROS1 TKIs including gilteritinib which is approved as a FLT3 inhibitor for AML. Future clinical trials should investigate cabozantinib and gilteritinib to repurpose them as ROS1 TKIs that can target Cβ6 mutation.
    Review • Journal
    |
    FLT3 (Fms-related tyrosine kinase 3) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
    |
    ROS1 fusion • ROS1 positive • ROS1 G2032R • ROS1 L2086F
    |
    Xalkori (crizotinib) • Rozlytrek (entrectinib) • Lorbrena (lorlatinib) • Xospata (gilteritinib) • Cabometyx (cabozantinib tablet) • Augtyro (repotrectinib) • taletrectinib (AB-106) • zidesamtinib (NVL-520)
    over1year
    Exceptional response to lorlatinib and cabozantinib in ROS1-rearranged NSCLC with acquired F2004V and L2086F resistance. (PubMed, NPJ Precis Oncol)
    This case builds the case for cabozantinib as an agent to overcome ROS1 L2086F resistance. It also highlights the efficacy and safety of using combination of ROS1 TKIs to overcome complex resistance patterns.
    Journal
    |
    ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
    |
    ROS1 rearrangement • ROS1 L2086F
    |
    Lorbrena (lorlatinib) • Cabometyx (cabozantinib tablet)
    over2years
    A Phase 2 Study of Lorlatinib in Patients With ROS1-Rearranged Lung Cancer With Brain-Only Progression on Crizotinib. (PubMed, JTO Clin Res Rep)
    No grade greater than or equal to 4 adverse events were observed. Lorlatinib induced durable intracranial responses in patients with ROS1-rearranged NSCLC and prior isolated CNS progression on crizotinib.
    P2 data • Journal
    |
    RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • CCDC6 (Coiled-Coil Domain Containing 6)
    |
    RET fusion • ROS1 fusion • CCDC6-RET fusion • ROS1 rearrangement • ROS1 G2032R • ROS1 L2086F • ROS1 G2032R + ROS1 L2086F
    |
    Xalkori (crizotinib) • Lorbrena (lorlatinib)
    almost3years
    Phase II Study of Lorlatinib in Patients with ROS1-Rearranged Lung Cancer with CNS Progression on Crizotinib (IASLC-TTLC 2022)
    No grade 5 adverse events were observed. The study was terminated early after enrollment of 16 of 22 planned patients due to the commercial availability of off-label lorlatinib.Conclusion s : The CNS-penetrant next-generation ROS1 inhibitor lorlatinib is an effective salvage therapy for patients experiencing isolated CNS progression on crizotinib.
    Clinical • P2 data
    |
    RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • CCDC6 (Coiled-Coil Domain Containing 6)
    |
    RET fusion • ROS1 fusion • CCDC6-RET fusion • ROS1 rearrangement • ROS1 G2032R • ROS1 L2086F • ROS1 G2032R + ROS1 L2086F
    |
    Xalkori (crizotinib) • Lorbrena (lorlatinib)