^
    8d
    Epidermal Growth Factor Receptor (EGFR) atypical mutations in Non-Small-Cell Lung Cancer (NSCLC): 'where the streets have no name'. (PubMed, Crit Rev Oncol Hematol)
    To date, afatinib remains the only approved agent specifically indicated for tumors harboring selected atypical variants-namely S768I, L861Q, and G719X-based on regulatory approvals by the FDA and EMA in 2018...Specifically, we will examine the efficacy of first-, second-, and third-generation EGFR TKIs in this subgroup, discuss the mechanisms underlying resistance, and highlight the clinical implications of the recently proposed structure-function-based classification of EGFR mutations. Finally, we will review emerging evidence from ongoing clinical trials of novel therapeutic agents, including bispecific antibodies and next-generation inhibitors, which may offer new opportunities for patients with atypical EGFR-mutant NSCLC.
    Review • Journal
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR L861Q • EGFR G719X • EGFR S768I
    |
    Tagrisso (osimertinib) • Gilotrif (afatinib)
    12d
    Combining Furmonertinib With Local Therapy for Inoperable Early-stage Lung Cancer: A Phase II Trial (clinicaltrials.gov)
    P2, N=45, Not yet recruiting, Shanghai Pulmonary Hospital, Shanghai, China
    New P2 trial
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR mutation • EGFR L858R • EGFR L861Q • EGFR G719X • EGFR S768I
    |
    Ivesa (firmonertinib)
    14d
    REZILIENT4: A Study to Assess the Efficacy and Safety of Zipalertinib Versus Placebo for Adjuvant Treatment in Participants With Stage IB-IIIA NSCLC With Uncommon EGFR Mutations, Following Complete Tumor Resection (clinicaltrials.gov)
    P3, N=360, Recruiting, Taiho Oncology, Inc. | N=141 --> 360
    Enrollment change • Trial initiation date
    |
    EGFR L861Q • EGFR G719X • EGFR S768I
    |
    cisplatin • carboplatin • pemetrexed • zipalertinib (CLN-081)
    27d
    Intrathecal Pemetrexed for Leptomeningeal Metastasis in EGFR-Mutant NSCLC (clinicaltrials.gov)
    P2, N=23, Recruiting, Taipei Veterans General Hospital, Taiwan | Not yet recruiting --> Recruiting | Trial completion date: Jun 2027 --> Dec 2027 | Trial primary completion date: Jun 2026 --> Dec 2026
    Enrollment open • Trial completion date • Trial primary completion date
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR T790M • EGFR L861Q • EGFR G719X • EGFR S768I
    |
    Tagrisso (osimertinib) • pemetrexed
    1m
    REZILIENT2: A Study of Zipalertinib in Patients With Advanced Non-Small Cell Lung Cancer With Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertions or Other Uncommon Mutation. (clinicaltrials.gov)
    P2, N=220, Recruiting, Taiho Oncology, Inc. | N=324 --> 220
    Enrollment change
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR L858R • EGFR exon 19 deletion • EGFR L861Q • EGFR G719X • EGFR S768I
    |
    zipalertinib (CLN-081)
    2ms
    U31402-A-U102: U3-1402 in Metastatic or Unresectable Non-Small Cell Lung Cancer (clinicaltrials.gov)
    P1, N=312, Active, not recruiting, Daiichi Sankyo | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
    |
    KRAS mutation • KRAS G12C • EGFR L858R • EGFR exon 19 deletion • ALK fusion • EGFR L861Q • ROS1 fusion • EGFR G719X • KRAS G12
    |
    patritumab deruxtecan (U3-1402)
    2ms
    EAY131-A: Testing Afatinib as Potentially Targeted Treatment in Cancers With EGFR Genetic Changes (MATCH - Subprotocol A) (clinicaltrials.gov)
    P2, N=19, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Jan 2027
    Trial completion date
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR mutation • EGFR L858R • EGFR L861Q • EGFR S768I
    |
    Gilotrif (afatinib)
    2ms
    EAY131-E: Testing AZD9291 as Potentially Targeted Treatment in Cancers With EGFR Genetic Changes (MATCH-Subprotocol E) (clinicaltrials.gov)
    P2, N=19, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Jan 2027
    Trial completion date
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR mutation • EGFR T790M • EGFR L861Q
    |
    Tagrisso (osimertinib)
    2ms
    D516KC00001: A trial to learn how safe Dato-DXd is and how well it works in people with NSCLC that has advanced after receiving osimertinib (2024-511362-37-00)
    P2/3, N=200, Recruiting, AstraZeneca AB | Active, not recruiting --> Recruiting
    Enrollment open
    |
    EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR T790M • EGFR L861Q • EGFR G719X • EGFR S768I
    |
    cisplatin • Tagrisso (osimertinib) • carboplatin • pemetrexed • Datroway (datopotamab deruxtecan-dlnk)
    2ms
    TAS6417-302: Study Evaluating Zipalertinib with Chemotherapy for Lung Cancer Patients with Uncommon EGFR Mutations After Surgery (2025-521775-31-00)
    P2/3, N=131, Recruiting, Taiho Oncology Inc.
    New P2/3 trial
    |
    EGFR mutation • EGFR exon 20 insertion • EGFR L861Q • EGFR G719X • EGFR S768I • EGFR exon 20 mutation
    |
    cisplatin • carboplatin • pemetrexed • zipalertinib (CLN-081)
    2ms
    WSD0922-FU for the Treatment of Glioblastoma, Anaplastic Astrocytoma, or Non-small Cell Lung Cancer With Central Nervous System Metastases (clinicaltrials.gov)
    P1, N=56, Active, not recruiting, Mayo Clinic | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    EGFR mutation • EGFR L858R • EGFR T790M • EGFR amplification • EGFR L861Q • IDH wild-type
    |
    WSD0922
    2ms
    An Open-Label Phase 1/2 Study of Itacitinib in Combination With Osimertinib in Subjects With Non-Small Cell Lung Cancer (clinicaltrials.gov)
    P1/2, N=59, Completed, Incyte Corporation | Active, not recruiting --> Completed
    Trial completion
    |
    EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR T790M • EGFR L861Q • EGFR G719X
    |
    Tagrisso (osimertinib) • itacitinib (INCB039110)