^
    3ms
    Comprehensive non-small cell lung cancer targets: From computational prediction to clinical breakthroughs in overcoming drug resistance. (PubMed, Biochem Pharmacol)
    Second, it examines clinical progress in targeting classical oncogenic drivers, exemplified by the fourth-generation tyrosine kinase inhibitor amivantamab against epidermal growth factor receptor (EGFR), and explores mechanisms of drug resistance, such as T790M and C797S mutations, along with emerging strategies like synthetic lethality-based interventions. Third, it discusses combination regimens-such as osimertinib co-administered with savolitinib-that mitigate resistance by synergistically inhibiting compensatory signaling pathways, thereby enhancing clinical outcomes. Future research priorities include the design of multi-target therapeutics and the refinement of AI-driven target discovery frameworks. This review addresses current limitations in targeted NSCLC therapy and offers insights to guide future therapeutic development.
    Review • Journal
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR T790M • EGFR T790M + EGFR C797S
    |
    Tagrisso (osimertinib) • Orpathys (savolitinib) • Rybrevant (amivantamab-vmjw)
    5ms
    FL30: an epidermal growth factor kinase inhibitor overcoming T790M and C797S mutations through unique conformational modulation mechanism. (PubMed, Int J Biol Macromol)
    The IC50 comparable to the Osimertinib - one of the most renowned EGFR-TKIs - emphasizes the remarkable success of the design approach...Kinetic studies, molecular modeling, and Plasmon Internal Reflection Surface-Enhanced Infrared Absorption (PIR-SEIRA) microscopy suggests that FL30 binds to the orthosteric site while inducing the transition of the mutant EGFR toward an inactive-like state. These findings highlight FL30's potential for further optimization and propose a novel approach for developing targeted therapies that combine orthosteric binding with allosteric modulation.
    Journal
    |
    EGF (Epidermal growth factor)
    |
    EGFR mutation • EGFR L858R • EGFR T790M • EGFR L858R + EGFR T790M • EGFR T790M + EGFR C797S
    |
    Tagrisso (osimertinib)
    6ms
    EGFR mutations in non-small cell lung cancer: Classification, characteristics and resistance to third-generation EGFR-tyrosine kinase inhibitors (Review). (PubMed, Oncol Lett)
    Third-generation EGFR-TKIs (such as osimertinib) markedly improve patient survival by selectively targeting the T790M mutation, but novel resistance mutations, such as C797S, limit their long-term efficacy. Combination therapies (such as MET proto-oncogene, receptor tyrosine kinase/EGFR dual-target inhibitors) and fourth-generation TKIs (such as BLU-945) offer novel directions to overcome resistance. Future research should focus on precise subtyping, dynamic monitoring of resistance mechanisms and regulation of the immune microenvironment to advance personalized treatment for NSCLC.
    Review • Journal
    |
    EGFR (Epidermal growth factor receptor) • MET (MET proto-oncogene, receptor tyrosine kinase)
    |
    EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR T790M • EGFR G719X • EGFR S768I • EGFR T790M + EGFR C797S
    |
    Tagrisso (osimertinib) • tigozertinib (BLU-945)
    8ms
    Prevalence and molecular correlates of acquired EGFR resistance mutations in non-small cell lung cancer (NSCLC). (PubMed, Expert Rev Anticancer Ther)
    While T790M and C797S mutations are well-described, we also observed a significant number of L718 mutations in osimertinib-treated patients. These data support NGS evaluation of NSCLC that has become resistant to EGFR TKIs.
    Journal • PD(L)-1 Biomarker • IO biomarker
    |
    EGFR (Epidermal growth factor receptor) • PD-L1 (Programmed death ligand 1) • TP53 (Tumor protein P53) • CTNNB1 (Catenin (cadherin-associated protein), beta 1)
    |
    TP53 mutation • EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR T790M • EGFR T790M + EGFR C797S
    |
    Tagrisso (osimertinib)
    10ms
    (SYMPHONY) Phase 1/2 Study Targeting EGFR Resistance Mechanisms in NSCLC (clinicaltrials.gov)
    P1, N=177, Terminated, Blueprint Medicines Corporation | Phase classification: P1/2 --> P1 | Trial completion date: Jan 2025 --> Oct 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Jan 2025 --> Oct 2024; Sponsor decision, not related to safety concerns
    Phase classification • Trial completion date • Trial termination • Trial primary completion date
    |
    EGFR mutation • EGFR T790M • EGFR T790M + EGFR C797S
    |
    Tagrisso (osimertinib) • tigozertinib (BLU-945)
    almost2years
    (SYMPHONY) Phase 1/2 Study Targeting EGFR Resistance Mechanisms in NSCLC (clinicaltrials.gov)
    P1/2, N=190, Active, not recruiting, Blueprint Medicines Corporation | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    EGFR mutation • EGFR T790M • EGFR C797S • EGFR T790M + EGFR C797S
    |
    Tagrisso (osimertinib) • tigozertinib (BLU-945)
    almost3years
    Acquired EGFR Resistant Mutations and Co-mutations in Tumors Of Non-small Cell Lung Cancer Patients Treated With Tyrosine Kinase Inhibitors (TKI) (LALCA 2023)
    "While T790M and C797S mutations are well described, we document L718V mutations in osimertinib-treated pts with an original L858R. We need to increase NGS in pts who develop resistance because it is very heterogeneous and will help to develop new TKIs."
    Clinical
    |
    EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • MET (MET proto-oncogene, receptor tyrosine kinase) • MSI (Microsatellite instability) • SMAD4 (SMAD family member 4) • CTNNB1 (Catenin (cadherin-associated protein), beta 1)
    |
    PD-L1 expression • TP53 mutation • EGFR mutation • TMB-H • MSI-H/dMMR • HER-2 amplification • PIK3CA mutation • EGFR L858R • MET amplification • EGFR T790M • EGFR C797S • EGFR T790M + EGFR C797S • HER-2 amplification + PD-L1 expression
    |
    PD-L1 IHC 22C3 pharmDx
    |
    Tagrisso (osimertinib)
    over3years
    Audit of Molecular Mechanisms of Primary and Secondary Resistance to Various Generations of Tyrosine Kinase Inhibitors in Known Epidermal Growth Factor Receptor-Mutant Non-small Cell Lung Cancer Patients in a Tertiary Centre. (PubMed, Clin Oncol (R Coll Radiol))
    "This study shows the wide spectrum of primary and secondary EGFR resistance mechanisms to first, second and third generation of TKIs and helps us to identify newer therapeutic targets that could carry forward the initial advantage offered by EGFR TKIs."
    Journal
    |
    EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MET (MET proto-oncogene, receptor tyrosine kinase) • FGFR3 (Fibroblast growth factor receptor 3) • EML4 (EMAP Like 4) • CTNNB1 (Catenin (cadherin-associated protein), beta 1)
    |
    KRAS mutation • EGFR mutation • PIK3CA mutation • EGFR L858R • MET amplification • EGFR T790M • EGFR amplification • EGFR exon 20 insertion • MET exon 14 mutation • EGFR C797S • MET mutation • ALK translocation • EGFR exon 20 mutation • EGFR T790M + EGFR C797S • EGFR negative • EGFR E709A
    |
    therascreen® EGFR RGQ PCR Kit • Oncomine Focus Assay • Oncomine Lung Cell-Free Total Nucleic Acid Research Assay
    |
    Tagrisso (osimertinib) • erlotinib • Gilotrif (afatinib) • gefitinib
    over3years
    Phase 1/2 Study of BLU-945 in Patients With Common Activating EGFR-Mutant Non-Small Cell Lung Cancer (IASLC-WCLC 2022)
    Preclinically it has shown activity as monotherapy in osimertinib-resistant patient-derived xenograft (PDX) models. Patients may receive treatment until disease progression or unacceptable toxicity. Recruitment is ongoing and approximately 30 sites will be open for enrollment across North America, Europe, and Asia.
    Clinical • P1/2 data
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR T790M • EGFR exon 20 insertion • EGFR C797S • EGFR exon 20 mutation • EGFR T790M + EGFR C797S
    |
    Tagrisso (osimertinib) • tigozertinib (BLU-945)
    over3years
    Plasma-Based Next Generation Sequencing for Molecular Characterization of Lung Adenocarcinoma: A Multicentric Cohort From Argentina (IASLC-WCLC 2022)
    This analysis provides the first description of NGS genotyping on liquid biopsy of a cohort of patients with advanced NSCLC in Argentina.
    Clinical • Tumor mutational burden • MSi-H Biomarker • BRCA Biomarker • Next-generation sequencing
    |
    EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • FGFR2 (Fibroblast growth factor receptor 2) • PTEN (Phosphatase and tensin homolog) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • STK11 (Serine/threonine kinase 11) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • DNMT3A (DNA methyltransferase 1) • NF1 (Neurofibromin 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • CDK12 (Cyclin dependent kinase 12) • CHEK2 (Checkpoint kinase 2) • CSF3R (Colony Stimulating Factor 3 Receptor)
    |
    TP53 mutation • EGFR mutation • MSI-H/dMMR • KRAS G12C • EGFR T790M • KRAS G12V • EGFR C797S • ALK mutation • KRAS G12 • KRAS Q61H • EGFR T790M + EGFR C797S
    |
    FoundationOne® Liquid CDx
    over3years
    Developing of EGFR resistant mutations to Tyrosine Kinase Inhibitors (TKI) in Non-Small Cell Lung Cancer (NSCLC) (IASLC-WCLC 2022)
    Acquired resistance in EGFR mutant NSCLC remains very heterogeneous; the frequency of individual mutations is low, one of the reasons might be lack of testing at resistance. While T790M and C797S mutations are well described, this report also documents a significant number of L718V mutations, primarily in osimertinib-treated pts with an original L858R. These data support the need to increase NGS evaluation of patients with EGFR mutant lung cancers who have developed clinical resistance.
    PD(L)-1 Biomarker • MSi-H Biomarker • IO biomarker
    |
    EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • SMAD4 (SMAD family member 4) • CTNNB1 (Catenin (cadherin-associated protein), beta 1)
    |
    PD-L1 expression • TP53 mutation • EGFR mutation • TMB-H • MSI-H/dMMR • PIK3CA mutation • EGFR L858R • EGFR T790M • EGFR C797S • EGFR T790M + EGFR C797S • EGFR G724S
    |
    PD-L1 IHC 22C3 pharmDx
    |
    Tagrisso (osimertinib)